- DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, EDUCATION, AND RELATED AGENCIES APPROPRIATIONS FOR 1998

[House Hearing, 105 Congress]
[From the U.S. Government Publishing Office]

DEPARTMENTS OF LABOR, HEALTH AND HUMAN
SERVICES, EDUCATION, AND RELATED AGENCIES
APPROPRIATIONS FOR 1998

========================================================================

HEARINGS

BEFORE A

SUBCOMMITTEE OF THE

COMMITTEE ON APPROPRIATIONS

HOUSE OF REPRESENTATIVES

ONE HUNDRED FIFTH CONGRESS

FIRST SESSION
________

SUBCOMMITTEE ON THE DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES,
EDUCATION, AND RELATED AGENCIES

JOHN EDWARD PORTER, Illinois, Chairman

C. W. BILL YOUNG, Florida DAVID R. OBEY, Wisconsin
HENRY BONILLA, Texas LOUIS STOKES, Ohio
ERNEST J. ISTOOK, Jr., Oklahoma STENY H. HOYER, Maryland
DAN MILLER, Florida NANCY PELOSI, California
JAY DICKEY, Arkansas NITA M. LOWEY, New York
ROGER F. WICKER, Mississippi ROSA L. DeLAURO, Connecticut
ANNE M. NORTHUP, Kentucky

NOTE: Under Committee Rules, Mr. Livingston, as Chairman of the Full
Committee, and Mr. Obey, as Ranking Minority Member of the Full
Committee, are authorized to sit as Members of all Subcommittees.

S. Anthony McCann, Robert L. Knisely, Susan E. Quantius, Michael K. Myers,
and Francine Mack, Subcommittee Staff
________

PART 4B

(Pages 1309-2552)

NATIONAL INSTITUTES OF HEALTH

________

U.S. GOVERNMENT PRINTING OFFICE

41-861 O WASHINGTON : 1997

------------------------------------------------------------------------

For sale by the U.S. Government Printing Office
Superintendent of Documents, Congressional Sales Office,
Washington, DC 20402

COMMITTEE ON APPROPRIATIONS

BOB LIVINGSTON, Louisiana, Chairman

JOSEPH M. McDADE, Pennsylvania DAVID R. OBEY, Wisconsin
C. W. BILL YOUNG, Florida SIDNEY R. YATES, Illinois
RALPH REGULA, Ohio LOUIS STOKES, Ohio
JERRY LEWIS, California JOHN P. MURTHA, Pennsylvania
JOHN EDWARD PORTER, Illinois NORMAN D. DICKS, Washington
HAROLD ROGERS, Kentucky MARTIN OLAV SABO, Minnesota
JOE SKEEN, New Mexico JULIAN C. DIXON, California
FRANK R. WOLF, Virginia VIC FAZIO, California
TOM DeLAY, Texas W. G. (BILL) HEFNER, North Carolina
JIM KOLBE, Arizona STENY H. HOYER, Maryland
RON PACKARD, California ALAN B. MOLLOHAN, West Virginia
SONNY CALLAHAN, Alabama MARCY KAPTUR, Ohio
JAMES T. WALSH, New York DAVID E. SKAGGS, Colorado
CHARLES H. TAYLOR, North Carolina NANCY PELOSI, California
DAVID L. HOBSON, Ohio PETER J. VISCLOSKY, Indiana
ERNEST J. ISTOOK, Jr., Oklahoma THOMAS M. FOGLIETTA, Pennsylvania
HENRY BONILLA, Texas ESTEBAN EDWARD TORRES, California
JOE KNOLLENBERG, Michigan NITA M. LOWEY, New York
DAN MILLER, Florida JOSE E. SERRANO, New York
JAY DICKEY, Arkansas ROSA L. DeLAURO, Connecticut
JACK KINGSTON, Georgia JAMES P. MORAN, Virginia
MIKE PARKER, Mississippi JOHN W. OLVER, Massachusetts
RODNEY P. FRELINGHUYSEN, New Jersey ED PASTOR, Arizona
ROGER F. WICKER, Mississippi CARRIE P. MEEK, Florida
MICHAEL P. FORBES, New York DAVID E. PRICE, North Carolina
GEORGE R. NETHERCUTT, Jr., Washington CHET EDWARDS, Texas
MARK W. NEUMANN, Wisconsin
RANDY ``DUKE'' CUNNINGHAM, California
TODD TIAHRT, Kansas
ZACH WAMP, Tennessee
TOM LATHAM, Iowa
ANNE M. NORTHUP, Kentucky
ROBERT B. ADERHOLT, Alabama

James W. Dyer, Clerk and Staff Director

C O N T E N T S

__________

NATIONAL INSTITUTES OF HEALTH

VOLUME 4

Page

National Institutes of Health Overview........................... 1

National Cancer Institute........................................ 199

National Eye Institute........................................... 419

National Center for Human Genome Research........................ 495

National Institute of Allergy and Infectious Diseases............ 583

National Institute of Environmental Health Sciences.............. 711

National Institute on Deafness and Other Communication Disorders. 805

National Heart, Lung, and Blood Institute........................ 865

National Institute on Drug Abuse................................. 983

National Institute on Alcohol Abuse and Alcoholism............... 1091

National Institute of Diabetes, Digestive and Kidney Diseases.... 1177

National Library of Medicine..................................... 1309

National Institute of Nursing Research........................... 1377

Fogarty International Center..................................... 1443

National Institute of Arthritis and Musculoskeletal and Skin
Diseases....................................................... 1491

National Center for Research Resources........................... 1573

National Institute of Child Health and Human Development......... 1635

National Institute of Dental Research............................ 1737

National Institute of Mental Health.............................. 1809

National Institute on Aging...................................... 1915

National Institute of Neurological Disorders and Strokes......... 2001

National Institute of General Medical Sciences................... 2095

Office of AIDS Research.......................................... 2155

Office of the Director and National Institutes of Health
Buildings and Facilities....................................... 2249

Wednesday, March 5, 1997.

NATIONAL LIBRARY OF MEDICINE

WITNESSES

DONALD A.B. LINDBERG, M.D., DIRECTOR
KENT A. SMITH, DEPUTY DIRECTOR
DAVID J. LIPMAN, M.D., DIRECTOR, NATIONAL CENTER FOR BIOTECHNOLOGY
INFORMATION
DONALD C. POPPKE, EXECUTIVE OFFICER
SUSAN U. LEVINE, BUDGET OFFICER
HAROLD VARMUS, M.D., DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS
Mr. Porter. The subcommittee will come to order.
We're very pleased this afternoon to welcome Dr. Donald
Lindberg, the Director of the National Library of Medicine, who
will be the first of three institutes to appear this afternoon.
Dr. Lindberg, why don't you introduce the people at the
table with you and then proceed with your statement.

Introduction of Witnesses

Dr. Lindberg. Yes, sir. We have on the far left Don Poppke,
our Executive Officer, next, Sue Levine, our Budget Officer,
next, Kent Smith, our noble Deputy Director of NLM, and on my
right is Dr. David Lipman, who is the Director of the National
Center for Biotechnology Information.

Opening Statement

Mr. Chairman, I thank you very much for the privilege of
appearing before you. My full statement for the record reports
the status of many aspects of the Library's work in the past
year and our plans for the new year. In this brief oral
statement, I would like to highlight four items, with your
permission--the Visible Humans, the Internet Grateful Med, our
telemedicine projects, and the Human Gene Map.

National Information Infrastructure

I should say that all four of those are the result of NLM's
commitment to develop and support the best biomedical
application of the National Information Infrastructure, NII.
The NII was the result of the High Performance Computing and
Communications program. As you will remember, the Congress
authorized this program in 1991 permitting 12 Federal agencies
to join forces and funds to develop improved computing and
communications to address problems that are common to the
agencies in the country.
Inevitably, however, this work becomes dominated by the
funds and the mission and concerns of what are called the ``Big
Four'' science agencies--Department of Defense, Department of
Energy, NASA, and NSF. Still, with the support of this
Committee and HHS, the NLM and other NIH institutes have also
participated. So there is a biomedical component, and I'm
grateful for that.
The developments I will show you today represent HPCC work
from the National Library of Medicine. There are others, but I
think these four highlight the developments.

visible humans

First, the Visible Humans. This is a blow-up of the cover
of the February issue of LIFE magazine. I should explain a
little bit about the project. Visible Human is a fully
computer-digitalization of the interior of a three-dimensional
structure of a human being, one male and one female, including
CAT scanning and MRI. This was originally designed to assist
medical students and surgeons to learn and remember anatomy.
Yet, now there are more than 750 licenses to individuals,
institutions, and companies. This is in 26 countries I might
say. So the applications far exceed what we originally
imagined. You have before you the LIFE magazine. In this issue,
they state my opinion correctly, ``Visible Humans forever
change the way we see ourselves and the way doctors heal us.''
[See figure 1.]

[Page 1311--The official Committee record contains additional material here.]

The following are examples of applications that others have
developed using this database. First, planning and rehearsing
prostate and brain surgery; the same for radiotherapy of brain
tumors; design and testing of automobile crash dummies;
battlefield trauma management; a virtual or fly-through
colonoscopy in place of the uncomfortable and less complete
procedures with a rigid tube.
In summary, this is a milestone development. It is
relatively cheap, $1.4 million over the course of three to four
years; it has stimulated good scientific ideas and commercial
products; it is all in the public domain and it is available
via the Internet; and it was made possible by the HPCC money,
the improved networks and the improved computer capability.

internet grateful med

Next, I would like to draw attention to our work in the
Internet Grateful Med. Grateful Med is a system that allows
doctors and, indeed, the public to search MEDLINE, the
Library's largest and most consulted database, and other
databases as well. Senator Bill Frist, who, as you know, is a
physician, demonstrated Grateful Med at a recent TV broadcast.
He said, ``MEDLINE can be critical for doctors in reaching the
correct diagnosis and developing a soundtreatment plan,
resulting in lives saved, limbs spared, and disease prevented,
unnecessary treatment avoided, and hospitalization reduced.'' We agree.
Internet Grateful Med is easy to use as well. The instant appeal of
Internet Grateful Med has resulted in a dramatic increase in use, as
you can imagine, and a little extra increase occurred after Ann Landers
printed a letter from Dr. Michael DeBakey, a member of our Board of
Regents, praising the new system. The display shows the letter.
[See figure 2.]

[Page 1313--The official Committee record contains additional material here.]

We are almost ready to introduce yet another MEDLINE-
related service. This is known as PUBMED, the name I attribute
to my colleague Dr. David Lipman, who has a fertile
imagination. This will allow the Nation's health professionals
and the general public to request from publishers the full text
of medical journal articles cited in the database. Congress has
asked the Library to facilitate access to its health
information at minimal cost. With this in mind, we're actually
now exploring whether it might actually be possible to offer
MEDLINE without charge in the U.S. to those who use our
inexpensive Internet connection service. So it would be limited
to the U.S. and those that come to us through Internet.

telemedicine

Next, I want to highlight telemedicine. I'll talk about
some projects that NLM has funded, but I should say first that
this is really the best strategy for getting excellent health
care applications onto the National Information Infrastructure.
Telemedicine involves three things--information in support of
decision-making, exchanging signals, which could be images or
blood pressure, and, lastly, arrangements to practice medicine
at a distance. With this in mind, it is obvious that these
projects don't arise within the Library; they arise in
competitive grant and research contract proposals from the
universities and the great hospitals.
About 70 such proposals were peer reviewed last year. We
were able to fund 19 really good projects this past year. The
map shows the country-wide distribution of the work in 13
States and the District of Columbia. You have a listing of the
detail of the projects, but I'll mention just a few things.
[See figure 3.]

[Page 1315--The official Committee record contains additional material here.]

The telemedicine projects include efforts to send vital
signs from ambulances to the emergency room, to facilitate
renal dialysis, to assist in home-care of high risk newborn
infants, to give specialty consultation in rural areas, and to
prevent drug interaction complications in the elderly. I could
give you details on any of those. I should say, too, that NLM
sponsored, along with HCFA and VA, a study by the National
Research Council attempting to set out ways to evaluate
telemedicine projects and the institutions that accepted these
grants agreed to implement those NRC evaluation criteria.

human gene map

Lastly, I want to draw attention to the Human Gene Map.
Scientists at the NLM National Center for Biotechnology
Information, which is headed by Dr. David Lipman, on my right,
have recently released the Human Gene Map. This, too, is based
on daily use of the high-speed Internet to exchange data
between research centers around the world. The project uses
high performance computers to compare each new sequence
submitted to those already known, and to compute comparisons
between all of the known information from the literature, other
relevant molecular biology databases, and the known relevant
chemical structure. Then, lastly, the use of Internet supports
the tens of thousands of inquiries per day into this database.
To see the gene map, one metaphorically dials up NLM and
NCBI Home Pages on Internet. You see before you a picture of
what that Home Page looks like. This display was, if you will,
a centerfold of Science Magazine a month ago, its molecular
biology issue. Here, we see graphical presentations of the 23
human chromosome pairs and a picture plot of the number of
genes at each point on the chromosome. This is of great use to
the scientists who can kind of point and click and get down to
the actual sequence that may characterize those genes. He or
she can then see what that all looks like and even do searches
and comparisons. Morethan one scientist has said that the
existence of such a map would have saved years of research for any
particular one of these genes.
[See figure 4.]

[Page 1317--The official Committee record contains additional material here.]

The Home Page also has information about the general nature
of the disease, references to foundations and patient advocacy
groups, and to the scientific and popular literature. Thus, the
public and the scientist may use precisely the same database
and each may pursue the topic to the extent he or she desires
and in the fashion their interest and education permits. In
many respects, the Human Gene Map tries to take a complex
subject out of the lab to make it understandable in the
classroom and the home.
I should also say that in the work with these advanced
information systems and our outreach, and the use of the new
technology such as the Visible Human and Internet Grateful Med,
we work in partnership with the National Network of Libraries
of Medicine and particularly the medical library community.
NLM's request is for $152,689,000 for fiscal year 1998. I
would, of course, be pleased to attempt to answer any questions
you might wish to raise.
[The prepared statement follows:]

[Pages 1319 - 1323--The official Committee record contains additional material here.]

outreach

Mr. Porter. Dr. Lindberg, thank you for your good
statement. You might be interested to know that I was at a
community health center in the inner-city in Chicago about
three weeks ago, they were receiving an award from HRSA for
working on an award-winning outreach program with Americorps
volunteers, and as we went through the health center, there
were television screens and NLM was on those screens.
Dr. Lindberg. Great.
Mr. Porter. They said they use your services all the time.
Dr. Lindberg. Must be a good place. [Laughter.]

human genome map

Mr. Porter. Excellent place. Dr. Lindberg, the publication
last fall of the Human Genome Map with over 16,000 genes was an
enormous technical feat. What were the major challenges in
coordinating all the data from multiple sources and in setting
up World Wide Web accessibility?
Dr. Lindberg. Well, I'm going to give a quick answer and
invite my colleague, Dr. Lipman, to answer you more fully, if
you agree. It seems to me that looking at it slightly from the
outside that his biggest challenge was to establish scientific
credibility with a number of top genome research centers around
the world. First, you have to have people trusting you and
working with you, and then technology permitted the cooperation
amongst those people that wanted to cooperate. So it was really
a very international project, as I understand it. But I would
like to invite Dr. Lipman to comment further.
Dr. Lipman. As you know, collaboration is very important
but it is not always achieved. In this particular case, our
group, which had a very large collection of EST sequences,
which are partial gene sequences, had done a lot of
computational work to select particularly promising snippets of
DNA sequence which could be used for mapping. We then contacted
the groups who do the mapping and told them that we had done
this work which would facilitate their work, and we got into
sort of a quid pro quo situation where we would provide them
with the agent, so to speak, to map and they would provide us
back the information.
Initially, in this mapping world, a lot of people have
their own maps, their own sort of coordinate systems, and it is
hard to integrate that information. In cross-checking trying to
cross-validate the information we were getting, we could point
out that there were errors at times and that it would benefit
everybody if they would work with a single coordinate system.
And so we managed to in fact get them all to do that and, in so
doing, improve the accuracy of everybody's work.
Dr. Lindberg is of course right that the collaboration
happened because in fact we were really seen as scientists
participating and not just technicians. And then I think the
basis was really the basis of all scientific collaborations,
which is that both parties could benefit.
Mr. Porter. Once the genome map is five times as big when
it includes all genes, will the map be too big to be
manipulated on the Web?
Dr. Lindberg. I think I can handle that one; that's easy.
No, certainly not. Although I think part of the gamble is, of
course, that the computing power keeps going up without our
doing much of anything about it. There is enough of a market
that the companies do that. The communications take a lot more
effort. But, again, the country is pretty much committed to
maintaining and advancing Internet. The President has announced
the next generation Internet to go 100 times faster, and 1000
times faster in some cases, with more security than the present
ones. So we think NCBI and the others will keep out ahead of
the problem.

bioinformatics

Mr. Porter. The job prospects for those in the field of
bioinformatics are extremely strong. Private industry is
scrambling to find Ph.D's trained in computer science,
information technology, and genetics to help them manage
overwhelming quantities of data being produced from genetic
sequencing. Is NLM participating in training these
bioinformatics experts?
Dr. Lindberg. Yes, sir. I think we saw the problem, Ican't
say we're out ahead of it because I think it is a serious problem. The
young men and women with knowledge of molecular biology and informatics
are hot items and are definitely sought after. I should say that 20
such individuals are training at NCBI, the National Center for
Biotechnology Information, at NLM under Dr. Lipman. NSF funds another
11. The Library of Medicine has supported training grants in medical
informatics for over 20 years, 25 years. They are now renewed
competitively every five years. There are 12 sites, 12 American
universities with medical informatics training. About 100 post-docs
total are supported by that program. We allocate slots especially
toward molecular biology, so that adds another probably two dozen to
the pool. The Department of Energy and the Sloan Foundation support
another five. So these are smallish numbers, although they are very,
very good people being produced.
I think essentially the post-doc experience of working in
Dr. Lipman's lab is really wonderful, and the systematic, I
would say more formal, educational work in the universities is
our best bet, those two combinations. But we are aware of the
problem and certainly working it.
Mr. Porter. Are you at all concerned that industry will
lure these specialists out of academia, depleting the talent
needed to educate the next generation?
Dr. Lindberg. That's always a problem. In our country, we
really don't assign people to their jobs; we let them go where
they want to go. So I imagine that there will be attractive
enough jobs in the Federal labs to attract a cadre.
Mr. Porter. Provided we give you the resources you need to
pay for them.
Dr. Lindberg. Right. Exactly.
Mr. Porter. Recently some pharmaceutical companies have
begun to support academic informatics programs. Will this ease
the problem of maintaining strong academic training programs?
Dr. Lindberg. I think that they will. A lot of the people
at least that I see in NCBI are really so thrilled to be there
that we have to go around and ask them to turn the lights out
every once in a while and go home and get some sleep. It's
really an exciting place, an exciting time for people in that
field. I think everybody realizes that, just as in former days
when we were trying to discover and produce antibiotics, it
will inevitably shift to an industrial base, as it must. Any
drugs that result are multi-billion-dollar enterprises. So I
think most people in the field welcome the participation of a
profit-making company, a pharmaceutical company, especially
those that have committed themselves to placing the results of
these studies in the public domain. Merck particularly, as you
know, has insisted that the ESTs that they paid for be placed
in the public domain available to them and their competitors.

internet users

Mr. Porter. You reported a 20 percent increase in users in
1996 fueled by the popularity of your Internet service. Can you
keep up with this level of user growth or do you risk having
some of the same capacity problems as America Online?
Dr. Lindberg. I'll tell you where they've got their
problems is in the network and usually it is at local routers.
We have actually studied this pretty carefully. We're not
having those troubles, with the exception of our support of
users overseas. There, an interesting proposition, but
basically they don't have the good infrastructure that the U.S.
has and of course there will always be difficulties in both
places. But we've looked at it quite carefully and, generally
speaking, the limit in capacity is not our computers or the raw
capability of Internet, but rather local routers. The problem
will correct itself in time.

next generation internet initiative

Mr. Porter. Last October the administration announced its
Next Generation Internet Initiative to create high-speed
networks that are 100 to 1,000 times faster than today's
Internet. NLM was originally included in the initiative but the
President's budget doesn't seem to allocate funds for this
purpose. Can you tell us what is the status of this initiative
and NLM's involvement in it?
Dr. Lindberg. I can tell you only what I know publicly,
that the President made a release to the press announcing the
next generation Internet. We were quite happy to read that it
would involve $100 million a year in new money, and it would be
managed by the four agencies I mentioned plus mine. I was sort
of surprised when, as the budget subsequently was distributed,
NIH dropped out and NIST dropped in. Obviously, I think that
NIH and NLM as part of it have a great deal to contribute to at
least the applications that will be part of this next
generation Internet. I just don't think medicine will be
included if there is nobody medical at the table. So the
original level that was discussed of $5-$10 million a year
certainly wouldn't be excessive, it might be an appropriate
level to support biomedical applications. But we'll do the best
we can with whatever budget we have and we'll give it as good a
priority as we can.
Mr. Porter. As an aside, Dr. Lindberg, let me say that we
do not find it surprising at all that the President's budget
doesn't reflect his rhetoric. In fact, two weeks before his
State of the Union address and two weeks and a couple days
before he submitted his budget, he was in my district saying
how important biomedical research was and then submitted a
budget that I think vastly underfunds the importance of
priority of biomedical research. So I'm not surprised that you
don't find the money in the President's budget. We're simply
going to have to do a better job than the President has done in
this regard and provide you the resources that you need.
Mr. Bonilla.

telemedicine

Mr. Bonilla. Thank you, Mr. Chairman. Before I ask Dr.
Lindberg a couple of questions, I want to thank you, Mr.
Chairman, for trying to delay and wait for me this morning. I
could not attend this morning's hearing because we had a
memorial service for Frank Tejeda, Congressman from my home
town, and then I was unavoidably detained by a meeting with the
Majority Leader and the Speaker on another issue. So I
appreciate your patience with me today on these matters.
Dr. Lindberg, I would like to start out by asking about
telemedicine. According to a GAO study, there is no Federal
strategy currently existing to maximize the Federal investment
in telemedicine, which is amounting now to about $646 million
spread across 9 Federal departments and agencies government-
wide. I have an interest in this not only because of this
subcommittee, but also the National Security Subcommittee of
which I'm also a member. The Department of Defense is the
largest Federal investor in telemedicine with $262 million and
is considered a leader in developing this technology. The GAO
suggests that DOD is in the best position to develop a
telemedicine strategy due to the major investment and that it
manages the largest health care systems in the world.
The major medical facility in my district is hundreds of
miles away from those that need the medical attention the most.
I represent an area that is 58,000 square miles, 600 miles of
it the Texas-Mexico border. My district is larger than all 29
States East of the Mississippi individually. The medical
schools in my district tell me that they have the technology to
implement telemedicine technology but lack a strategy at this
time. Many in my district agree that this technology has the
potential to overcome any professional isolation of rural
doctors by allowing them to participate in immediate
consultation with specialists.
My question is, what is the level of cooperation and
coordination with DOD? Do you have a shared vision on
telemedicine's potential and its application?
Dr. Lindberg. Right. Well, it's an interesting question. I
think that I'm pretty well aware of the work in the DOD that
you refer to. Certainly, I understand why it is highly
appropriate for DOD to be interested in telemedicine. NASA also
for similar reasons; you can't reach out in space to reach your
astronauts.
The GAO report you refer to I have read. We were, in fact,
asked to comment on it before it was released. It is specific
to DOD. It isn't really a careful study of the whole U.S. Some
of the numbers, for instance, are a little bit jumbled because
of the different ways of accounting. While I respect the DOD
work, in fact, Rick Satava, one of their chiefs, is a good
friend and I've seen his work up close, they have their mission
that is different from problems of domestic U.S. nonmilitary
medicine. Our problem will not be solved by battlefield
management strategy. We'll benefit from their instrumentation,
we pretty much know about that.
So far as the exchange of information, there really is a
joint working group on telecommunications within the Department
of HHS and shared with Commerce. We meet very, very regularly.
NIH and NLM have representatives on that group. So I think that
the information is exchanged quite sufficiently. We do not have
unnecessary duplication and/or waste, none of that.
There's another factor that makes me say don't try to make
a global plan for the whole country, particularly leading with
DOD. The reason I think it is such a wonderful area is that
every week I see a brand new, innovative, wise application that
I wasn't smart enough myself to think of. So if I picture some
small group going off making a plan and a strategy for the
country, it worries me a whole lot that they will think about
it as it is now rather than as it might come to be.
There is one other area in which I have met with the DOD
Acquisitions Deputy Secretary, and they are aware that they
will need to get a commercial industrial component to
telemedicine strategy. That doesn't take a highfalutin
committee to come to that conclusion. Somebody has got to
manufacture the instruments. The Pentagon has a program, which
we have met with them and NASA, to look into considering
whether we perhaps should be working with companies directly to
enhance their ability to produce instruments that DOD then
wants to use.
So I think that we're on top of that problem. I don't
advise that it should be this national strategy at the moment
until we know how far and how good the field really is. The
only part of the strategy I would say that should be national
is the commitment to evaluation, which is why we work with the
National Research Council. All this sounds newer than it is. As
an idea, telemedicine was quite apparent in the 1965 regional
medical program days and I have many, many pictures of friends
and colleagues, including Mike DeBakey doing instruction in
surgery from Texas to Geneva over the satellites. That's
telemedicine. NLM worked also with NASA for a satellite that
operated over the whole Western U.S., the WICHI and WAMI
program. These were great ideas. They were pretty expensive.
Everyone was enthusiastic.
I personally believe telemedicine is a great strategy. I
don't want to see it go away again the way of the hula hoop. I
think that it will have the best outcome if we force ourselves
to evaluate what's the medical benefit. Is there a dollar
savings or additional expenses, and to whom? That's as far as I
would recommend going on a national strategy.

nlm telemedicine projects

Mr. Bonilla. It's interesting that you seem comfortable
then with just the exchange of information. I can assure you
that we're not going to let this go the way of the hula hoop
either. I think it is very, very important. I'm not a medical
expert, but from what my researchers and doctors tell me, this
is something that is necessary not just to survive, but to
thrive in the future.
I have another question about that. How effective are the
19 telemedicine projects currently funded by NLM? I guess you
touched on that in general terms, but I would like to hear more
specifics.
Dr. Lindberg. I think the main appeal to me is that we
didn't particularly set out to scatter them around the map of
the U.S. That is the beautiful part of the United States and
NIH, that if you just evaluate the scientific merit of these
proposals, everybody kind of comes into play reasonably well.
NLM actually funds a Circuit Librarian Program out of San
Antonio, Texas, that is kind of long-lived and very useful I
think.
But if I look at those particular ones that are on the map
and the little listing that you have, let me mention just a
couple that struck me as innovative and surprising. One says
``Massachusetts. Provide care to high risk newborns and their
families.'' It seemed odd to me, first of all, because it comes
out of Boston which is very much of a city, not a rural area.
Yet, what they are actually doing is pretty inexpensive but
good telecommunications sending equipment home with the
families of high risk newborns so that they can essentially get
a consultation with the hospital before they double panic and
hop into a taxi cab or an ambulance to bring the baby back and
forth to the emergency room, which is very, very common.
They've actually made feasibility studies of this and it is a
fairly low-cost proposition. So that in a sense you have the
same communication difficulties within a big city as you do in
a more rural area.
We've done work in West Virginia. There, the application is
attempting to get specialty consultation to very rural areas.
We have quite a bit of experience with that. It works quite
well.
I know that the Congress is very receptive I think to the
telemedicine ideas, I think rightly so. I think it is
delivering a benefit back home where it is needed.
Mr. Bonilla. There is a lot of interest not just on this
subcommittee, but with members of other committees in this
Congress on advancing telemedicine. I did notice that noneof
these projects is in the State of Texas. I'm wondering if you see any
future projects, starting any new ones, and, if so, what are the
chances of having them in the State of Texas?
Dr. Lindberg. I'm not sure that we got an application from
Texas. We did not get an application from San Antonio which is
where I would have expected it to come from. I should mention
one other, if you'll permit.
Mr. Bonilla. Sure.
Dr. Lindberg. The one in Oregon is teledermatology, how to
diagnose skin and so forth. That has an additional feature
because in telemedicine typically you will expect to try to
achieve very high band-width rate or speed of transmission so
you can see high resolution, color, and sometimes even some
applications require you see the patient walk in front of the
camera. Of course, that's expensive. The cheapest of the
applications would be if you could use ordinary telephone
lines. That's what this one in Oregon does, the so-called
``store and forward'' technology. The expert is at the Oregon
Health Sciences University and then the users are in small
towns in eastern and western Oregon where there are no
dermatologists.
We have had this young man come and give a presentation to
our Board of Regents. It was quite amazing. The pictures were
taken, of course with some training, of the patients out in the
small places with a computer digital camera, then sent by
ordinary phone line so the dermatologist can see it whenever he
or she needs to as kind of an appendix to e-mail, and then he
showed some of the diagnoses that were made. These are patients
in some cases who had the same complaint for ten years who had
seen three or four doctors without any relief. Once the picture
arrived in Portland, it took three seconds to give a diagnosis
of treatment. It was nothing. So what a grateful patient. In a
couple of cases, they unfortunately were malignancies that had
been missed and not diagnosed and treated correctly.
So we were tremendously impressed that at the low end of
the thing, the low cost end, it still was working very
surprisingly nicely. That's another reason that I think we
should not prematurely spell out exactly how it should be done,
because these bright ideas are coming up all over the country.

outreach

Mr. Bonilla. That's very interesting, doctor. I appreciate
your examples. I have a question in another area, my last
question, Mr. Chairman. I understand that NLM has made great
strides in the past year with its Visible Human project and the
Internet Grateful Med program. Can you tell us if the Library
has engaged in active outreach activities designed to ensure
that the Nation's health care providers and health information
specialists are aware of these and other NLM services?
Dr. Lindberg. Yes, sir. In the case of Visible Human, this
is going rather well already on its own. We have made
presentations at library associations which I think have in
turn brought this to the attention of the hospitals and the
doctors. The major users of Visible Human really have been
surgeons and radiologists. So they are selling themselves. It
was first introduced, actually, I did it at the Radiological
Society of North America, RSNA. There were something like
85,000 radiologists present and I think I met them all in one
half hour.
[Clerk's note. Later corrected to ``55,000'']
It is, again, a case where the new applications are being
discovered by those who are out in the world using it. We have
a licensing agreement, although there is no exchange of money,
so we do know how the applications are used. We share that
information on a Home Page, and we've had one meeting with all
those licensees. So I think that is probably our outreach
there.
The more traditional outreach work that we do is pointed at
Internet Grateful Med. We have given actual grants to connect
people to Internet and then to give training for health care
professionals' use of these systems. There have been about 300
such outreach awards. There are special areas of outreach, for
instance in toxicology, in some areas of the country. I am
reminded that the reason you don't see Texas on that particular
map is that we just completed a project with the Texas
Department of Health, that ended in March 1996 and that
involved 10 public health sites, so that was an outreach area.
And 70 percent of those participants who had training said that
they would continue to use Grateful Med. So we think that's
probably working. Participating sites I guess would probably be
areas that would be familiar to you--San Angelo, Tom Green
County Health District, Texas Department of Health Field Office
in Fort Stockton, MARFA Rural Health Clinic, Guadalupe Valley
Hospital, these are all I think pretty small places, Texas
Department of Health Field Office in Beaville and Laredo, Rio
Grande, Eagle Pass. So that's pretty rural and has met with
success we think.
Mr. Bonilla. Dr. Lindberg, thank you very much.
Dr. Lindberg. Thank you, Mr. Bonilla.
Mr. Porter. Thank you, Mr. Bonilla.
Mrs. Lowey.

internet grateful med

Mrs. Lowey. Thank you, Mr. Chairman, and thank you, Dr.
Lindberg. I have been absolutely intrigued by the whole MEDLINE
issue and the issues surrounding it. The availability of
MEDLINE on the World Wide Web is just an amazing development.
What it does is make a wealth of information available to the
general public which was once the province of medical
professionals only.
Could you share with us your views about how will access to
this information change health care. Will it make Americans
better consumers? When you write your reports for the medical
journals, do you keep in mind the fact that these are going to
go on the Web and the average consumer is going to be reading
it? Could you discuss that with us.
Dr. Lindberg. Yes. I think those are very perceptive
remarks. We are concerned about the opportunities that Internet
Grateful Med offers for communicating starting out with
patients and families and having as an ultimate goal the
public. But there's a lot of the public, so we have to be a
little bit modest.
NLM has historically tried to serve the public through the
health care profession. It is hard enough to do that but I
think we're now doing a good job with it. I think you're right
though that the public now is so much better educated and more
receptive to medical knowledge than they were when even I was a
medical student, the opportunities are much greater. We used to
still have conversations about should the patient be told the
truth. Most patients didn't want to be told the truth, we
believed. I think that is all in the past. I think now you have
a well-educated population that seeks information.
As a library, we've always held to the tradition that no
information is secret or privatized. It has always been opento
anyone who wants to use it.
The patient groups, the sort of help yourself groups or the
disease-oriented groups we know to be very effective, starting
out with ileostomy clubs and that sort of thing. We haven't
been able to work effectively with them up until now because
one of the things is that the literature gets out of date, they
don't use bibliographical standards that even identify the date
and the place things were published to know whether they're
accurate and timely or not. All that is beginning to change as
the Web allows the central creation and maintenance of a
database and the access by others without having to physically
be connected to it.
A bigger problem we think is the highly variable quality of
the information on the World Wide Web. I guess it is
commonplace to say that, but you can get 1,000 hits but how
many of them are actually worth reading? We wish that we could
say that we have a plan whereby NLM would certify all the
medical knowledge. We're trying an experiment that is not yet
ready for a public test. I'm associated with a group in which
an attempt has been made to issue a kind of a medallion
agreeing that the site obeys a certain set of ethical
constraints or discloses when they are commercially biased.
This is working. There are 21,000 sites on the Web that
actually say that they comply with this medical standard. The
next issue of the Journal of the American Medical Association
will have an editorial by George Lundberg urging that attention
be directed to exactly that problem, although he doesn't spell
out a prescription that solves the problem.
So I guess I have to just agree with you that it is a
wonderful challenge and opportunity. We're sort of barrelling
in to try to find out how much work would be involved in doing
a really excellent job. There are a certain set of areas that I
would describe where we really are seeking to give information
directly to the public. The first, because it had special
appropriations, is AIDS. If you didn't give information to the
people, what good would it be? The second is in our support of
work of the National Cancer Institute in their PDQ. It has a
formal section for the patient and for the doctor and either
could go to either section. The Agency for Health Care Policy
and Research produced clinical practice guidelines which,
again, we worked with them on. It is modeled on the cancer
model so that there is a formal section well-said for the
patient and a formal section well-said for the doctor.
We did another experiment starting four years ago, I guess
almost five now, with EPA. EPA was given an authorization by
the Congress to collect certain data about the release of 400
toxic chemicals it turns out are released, amazing large
amounts, in 45,000 places in the country and then the data are
collected quarterly. We accepted EPA's request that we assist
in making this available to the public. We do that through a
computer database, CD-ROMs, and a variety of other things. The
library community helps us greatly by trying to give
instruction on how to use that as an outreach effort that I
could describe in further detail with Historically Black
Colleges and Universities.
In any case, the attempt there is to bring the information
to the public. We don't do it as well as we would like to be
able to do it. You run up against the fundamental difficulty
that the data are really about chemicals. If you will only talk
to the machine about chemicals, it will love you and give you
the information right away. But if you talk to it in ordinary
terms, it is obtuse. To some extent we get around it by letting
people enter their zip codes and it will immediately tell you
where are the sites that are releasing chemicals and so forth.
But ultimately it gets down to chemicals.
Some of this is easier said than done. So there is a
particular case, of course it's more difficult than other
things, but if we really want it to be done right and to be
understood and to be kept at a high quality, we really have a
lot of work still to do on that.

monitoring information on the world wide web

Mrs. Lowey. I just wanted to follow up because I'm not sure
if I heard correctly. You said something a couple of minutes
ago about there is a stamp of approval. In other words, one of
my concerns is, whether it is cancer or ileitis or any other
illness, there can be, in addition to the group, some 50
remedies, I don't want to call them witch doctor remedies or
whatever. Could you back up and explain that to us. You said
there is some kind of a----
Dr. Lindberg. I agree with what you said. We do not feel
that we could issue such a seal of approval.
Mrs. Lowey. Oh, there is not one, then?
Dr. Lindberg. Not from NLM. There are from some other
groups.
Mrs. Lowey. Like?
Dr. Lindberg. Well, one outfit is called HON, Health On the
Net. It is a foundation in Geneva. I am an advisor to that. But
that is not U.S., it is not government, it is not world-wide.
It is accepted by some 21,000 sites, so it is kind of a
voluntary yielding to standards. But to do what you really want
us to do, we don't know how to do it yet, how to say what is
really valid, what is the best, what is reliable, what should
the patient act on. I should say that part of this is getting
the raw information to the patients. For instance, supposing
that you get a citation to MEDLINE. Well, you have to go to the
library, get out the article, try to understand it. A lot of
times you just would like to see the full text and PUBMED is an
attempt to do exactly that. So that would be available to the
doctors, the patients, the families, anyone.
Mrs. Lowey. Do you or does anybody monitor? I'm wondering,
Mr. Chairman, if anyone really monitors what's on the Web. For
example, if you see a proliferation of some kind of information
cure that is suddenly everywhere on the Net and you know it is
patently false, dangerous, whatever, is anybody monitoring
this?
Dr. Lindberg. Well, NIH is not a regulatory agency and FDA
is. So I would guess that would fall under FDA jurisdiction and
that they would look after such a matter.
Mrs. Lowey. Then we will pursue it.
Dr. Lindberg. I don't like to pass the buck to my
colleagues in other agencies, but NIH is not a regulatory
agency. I think when we include journals in MEDLINE, that is
indication that they are of good quality, that they are peer
reviewed, that they are acceptable and have a good track
record. That is quite different from saying that everything in
all those articles is quite correct. But at least they are peer
reviewed and they are properly presented.
We index something under 4,000 journals. We subscribe to
around 27,000. The world probably has around 50,000 or 60,000.
So what we present is sort of creme de la creme.
Mrs. Lowey. Along with that, I don't know if I've used up
my time or you've used up my time, but I think----
Dr. Lindberg. I apologize. I'll give yes or no answers.
[Laughter.]

telemedicine

Mrs. Lowey. If the Chairman would indulge me, I was also
very involved with telemedicine. I wonder if you care to
briefly talk with us about that whole area. What are the limits
of telemedicine? What do you think are its most effective
applications? Or, Mr. Chairman, do you think we should leave
that discussion for another day?
Mr. Porter. I would just say to the gentlelady that Mr.
Bonilla ventilated that subject very thoroughly but he did it
before you came in.
Mrs. Lowey. Oh, did he? Okay. I apologize.
Mr. Porter. I think Dr. Lindberg would be willing to
highlight it again.
Mrs. Lowey. If there is anything that you didn't mention
with regard to telemedicine--[Laughter.]
Mrs. Lowey. For example, I was recently talking with some
people at the Strang Clinic who were discussing the whole area
of genetic counselling. They were telling me that there are so
many people in need of genetic counselling and we can't
possibly find enough doctors who can respond. He mentioned this
as an area where telemedicine and use of the Internet and
dispensing information through that is invaluable.
Dr. Lindberg. I agree. I'm very enthusiastic personally
about telemedicine projects. I think that is the very best
strategy for getting good medical health-related use of the
National Information Infrastructure. I think we all recognize
that you want to amplify the powers of an expert, you want to
deliver the care to remote areas or even hard to get to areas
of big cities. The best is yet to come. We're not certain how
to do this.
I was describing a little bit before you came about some
applications that require very high band-width and high
resolution and, therefore, are expensive, others that are store
and forward technology, like teledermatology, that are
essentially very high benefit and very inexpensive. I think the
cities are as interesting as are the rural areas. There, the
challenges are just getting around, how big an obstacle is it
to get from their apartment back to the hospital. So one of the
applications that I mentioned in that respect is in Boston.
There is an application in New York that has to do with chronic
illness in home settings. There, too, this home care is an
application that I must say I would not have thought of. I am
pleased that innovative, good new applications come up every
month or so. Chicago also has applications of telemedicine that
are focused on outpatients. I just think it is a marvelous
area.
You speak about the genetic counseling. I don't know anyone
who is doing that using telemedicine techniques, but I do know
of a tremendous amount of worry that people have about the
medical data privacy issues connected with genetic counseling
and testing. We are looking into that as well but not as a
telemedicine project.
Mrs. Lowey. I was just thinking that between the Internet
and telemedicine, I was talking recently to a parent who is
desperately worried about a young adult, not even so young
adult, with Crohn's Disease in London and worried about what is
the treatment there, is it as sophisticated as ours. I wonder
to what extent would a physician take a file and send it
through whatever means you have now to someone at the National
Institutes of Health, to a hospital where they're expert in
that, and whether you can't essentially do a teleconference.
Dr. Lindberg. Oh, sure.
Mrs. Lowey. In the old days, you used to have to fly to New
York, fly here, go to this clinic. I would imagine, or I should
ask that in the form of a question, is this technology being
used right now where you can essentially have a teleconference
with a file remaining in London, for example, and let there be
a conference with experts in several places?
Dr. Lindberg. Yes. There are several good examples of that.
In our country, Mayo Clinic operates in four places--Rochester,
Minnesota, Florida, Arizona--and they set up exactly that sort
of system for their own patients. They are already able to deal
with this problem across state lines. Are the doctors licensed
properly to do all this? Is there a secure line? There is, they
own it. So working within that corporation, exactly what you
describe is being done on a daily basis.
In other cases, like Columbia Presbyterian, they actually
have referral systems set up to the Middle East. So for special
cases that is being done. But I think you want a more general
solution. I think we want a solution that makes this available
to really every American that needs it. That's coming.
Mrs. Lowey. I thank you. Thank you for your indulgence, Mr.
Chairman.
Mr. Porter. Thank you, Mrs. Lowey.
Dr. Lindberg, we have many more questions that we're going
to have to ask you to answer for the record.
Mr. Porter. We very much appreciate your good testimony,
Dr. Lindberg, and your wonderful leadership at the National
Library of Medicine. I think you are at the epicenter of this
revolution of knowledge and technology that is happening across
the world, and I am sure that you find your work fascinating
every single day. We very much appreciate the leadership you
are providing, and your good staff.
Dr. Lindberg. It is kind of you to say that. Thank you very
much.
Mr. Porter. Thank you, sir.
The committee will stand in recess briefly.
[The following questions were submitted to be answered for
the record.]

[Pages 1336 - 1376--The official Committee record contains additional material here.]

----------

Wednesday, March 5, 1997.

NATIONAL INSTITUTE OF NURSING RESEARCH

WITNESSES

DR. PATRICIA A. GRADY, DIRECTOR
MARY CUSHING, EXECUTIVE OFFICER
ELLEN MOUL, BUDGET OFFICER
DR. RUTH KIRSCHSTEIN, M.D., DEPUTY DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

Mr. Porter. The subcommittee will come to order.
We would like to next welcome Dr. Patricia Grady, the
Director of the National Institute of Nursing Research. Dr.
Grady, if you will introduce the people you have brought with
you, and then proceed with your statement.

Introduction of Witnesses

Dr. Grady. Thank you, Mr. Chairman. On my left is Ms. Ellen
Moul, our Budget Officer; Ms. Mary Cushing, our Executive
Officer; Dr. Ruth Kirschstein of course you know well, and Mr.
Williams, who is from the Department.

Opening Statement

Mr. Chairman, it is a pleasure to be here today to describe
for you NINR-supported research that demonstrates the relevance
and the extent of our research endeavors. I look forward to
discussing our current and planned research for fiscal year
1998. These proposed programs reflect our prior research
investment, emerging scientific needs, and opportunities
available for pursuit.
Nursing research focuses on the patient and involves
clinical research directly related to the Nation's major health
issues. Several changes are occurring in our society that
underscore the importance of this. First, the mean age of our
population is shifting to the upper decades of life. With
longer lives, we can expect an increase in chronic illnesses
which require more frequent and more costly health care.
Second, the cost is requiring us to examine health care
delivery. The demand for therapeutic innovations through
nursing research discoveries has never been greater.

pain research

Let me provide three examples for you of our unique
contributions in the area of pain, irritable bowel syndrome,
and reducing risk for cardiovascular disease. First, I would
like to highlight a health concern that is common to all of us,
that of pain. Pain generates nearly 40 million yearly visits to
health care providers, can prolong hospital stays, and may
impede recovery. Research on pain is complicated, because
although we all share a basic common physiology, the responses
to pain may differ.
Recently, an NINR-supported study on pain generated a great
deal of interest across the Nation. Investigators found that
gender plays a key role in pain relief. Women in this study
obtained satisfactory relief from seldom used kappa-opioid
drugs while men received little benefit. An advantage of kappa-
opioids is that they have fewer side-effects compared to the
more typically used morphine-like opioids. Additional work is
needed to better understand the underlying reasons for this,
such as the possible role of estrogen or testosterone in
mediating pain, and whether or not women, for example, may have
additional kappa receptors on certain nerve cells more than
men, thus enabling kappa-opioids to block pain better in this
population.
This is an important area of research with many yet
unanswered questions about better management of pain. This
research also underscores the importance of including subjects
of both genders in clinical studies.

irritable bowel syndrome

Another health problem that affects 10 to 15 percent of
Americans and two to three times more women than men involves
understanding a cluster of symptoms known as irritable bowel
syndrome, or IBS. Scientists found that women diagnosed with
IBS have a heightened activity of the sympathetic nervous
system, the so-called flight or fight system, which appears to
be linked to higher levels of stress. This study's findings can
impact positively in the area of cost-effectiveness.
Currently, IBS is diagnosed indirectly through a process of
excluding other causes. If a positive diagnosis were possible
based on scientific methods, the result could be fewer doctors
visits with subsequent savings in time for patients, and
dollars to the health care system.

cardiovascular disease

My third example is that of reducing risk for
cardiovascular disease. The roots of adult cardiovascular
disease often go back to childhood, making interventions early
in life key to achieving a healthy adulthood. Researchers have
designed and tested an eight-week intervention to reduce
cardiovascular risk factors in more than 2,200 third and fourth
graders in rural and urban areas, almost 20 percent of whom
were African-American youngsters. By the study's end, students
showed reductions in total cholesterol levels, body mass index,
and body fat, as well as increased physical endurance. This
type of study has a profound potential impact on the health of
our future citizens.

cultural diversity

As you can see, nursing research encompasses both
behavioral and biological aspects of health. Threaded through
NINR's research portfolio is an interest in the relationship
between ethnic and cultural diversity and health. For example,
if questionnaires and health assessments are in English only,
non-English-speaking subjects will be excluded from health
research findings and miss participating in studies which may
benefit them. NINR-supported researchers successfully
translated and tested an English language arthritis self-
management program into Spanish for Hispanic patients with
arthritis. This program is now useful for Spanish-speaking
arthritis patients, thus addressing their health needs and
improving their quality of life.

future research emphases

The continuing vitality of nursing research stems from the
many questions that remain to be answered. To this end, future
NINR research emphases include: research on symptoms associated
with such neurological problems as stroke and traumatic brain
injury, epilepsy, motor problems such as Parkinson's disease
and spinal cord injury, chronic debilitating problems such as
diabetes and AIDS, and studies of factors related to successful
family caregiving. NINR, in collaboration with others at NIH,
supports development of promising ways to prevent progressive
deterioration caused by these problems.

transplantation

With 12,000 organ transplantations each year and the
improved technology available, many of these patients are
surviving into their 50s and 60s, and face long-term drug
regimens which can have serious side effects. These include
osteoporosis, cancer, neurologic problems, and cardiac
dysfunction. The NINR will explore ways to improve the quality
of life of long-term transplantation survivors.

end of life

End of life issues will encompass bioethical, biological,
and behavioral studies. We plan to identify research needs in,
and address the transition to: palliative care, management of
pain and other symptoms, measurement of relief from symptoms,
and documentation of financial burdens for patients and family
caregivers.
As NINR begins its second decade at the NIH, current and
emerging research and societal issues intensify the need for
nursing research. Clinically-based, patient-oriented nursing
research is well positioned to make important contributions to
improving the health and the quality of life for all our
citizens.

fy 98 budget request

Mr. Chairman, the fiscal year 1998 request for NINR is
$55,692,000. I will be pleased to answer any questions you
might have.
[The prepared statement follows:]

[Pages 1380 - 1383--The official Committee record contains additional material here.]

justification of the budget estimates

Mr. Porter. Thank you, Dr. Grady. Dr. Grady, you are a
relatively new director of a relatively new institute. How
would you feel if Congress gave you only 2.2 percent more than
last year to work with this year?
Dr. Grady. Mr. Chairman, we would be grateful for any
increase over last year's budget.
Mr. Porter. Dennis isn't listening. [Laughter.]
Dr. Grady. But we do have big plans for growing. We have
experienced growth in a constrained economy since we came on
board. We have been very fortunate with the support of the NIH
and the budget. But we also do have very large plans that we
could implement in terms of training and in terms of
initiatives. So the more that is available, we will promise to
put it to good use.

professional judgment budget

Mr. Porter. How much did you ask Ruth to provide to you
initially?
Dr. Grady. Well, our professional judgment budget was
approximately 9 percent over this year. In fact, you mentioned
being new, there's another aspect of the newness that I could
add to that. That is the fact that the field of nursing
research is still a relatively new and growing field. We are in
the very interesting situation of funding nearly as many
trainees as we fund active researchers. So you can see that
what we're really dealing with is a field that is justabout to
explode, and we have a number of people in the pipeline and a number of
really good ideas to be able to fund.

communication with health care providers

Mr. Porter. It is important that the results of your
research studies on patient care are communicated to major
health care providers like hospitals and HMOs. What mechanisms
have you established to encourage this transfer of information?
Dr. Grady. We have several ways that we are attacking that
situation. As you have mentioned, it is a very large audience.
There are 2.2 million nurses across the country that we need to
reach, as well as other team members, to inform them of the
results of the research and to be able to implement them. We
have a number of conferences that we participate in each year.
We also have a Home Page and are using the Internet very
actively in addition to the usual peer review publications. I
also regularly write columns for the major publications in
nursing and also interdisciplinary publications such as
newsletters. We have a nursing outreach newsletter that we do
have online. And we also are very responsive to the many
inquiries that we get.
Mr. Porter. Have you found that providers are reluctant to
adopt your research findings if they have an adverse impact on
their bottom line?
Dr. Grady. An interesting thing about nursing research is,
that compared to what you've been hearing about high
technology, much of nursing research really is relatively low
technology. There are interventions that are used that are
patient-specific that tend to often effect better outcomes for
patients but without being as expensive as some others. They
are, however, somewhat more time intensive. That is an issue
that we do need to deal with.
We are funding a number of studies, for example, of nurses
working with inner-city students who are at risk for HIV or, in
fact, are HIV infected, counseling them to see if techniques
with one-on-one counseling versus small group counseling would
be more effective. In fact, we have found that working with
small groups, which is much more effective in terms of time,
has just as good outcomes as the one-on-one. So we're
experimenting with ways to deal with these issues.

clinical research conference

Mr. Porter. Your Institute co-sponsored a conference
several weeks ago at the Clinical Center to explore the options
available to maintain the continued health of clinical research
given the changes in the health care marketplace. Can you share
with us the ideas that were generated at this conference?
Dr. Grady. Yes. There were a number of very interesting
ideas generated at that conference. The major issue was
attempting to deal with the changing health care landscape,
that of managed care and HMOs coming into the marketplace. As
it turns out really, a number of issues that are dealt with by
nursing research, are very germane to, and would be helpful to
the new circumstances in which we find ourselves. Much of what
nurses do is to deal with reducing risk, promoting healthy life
styles, and prevention. So that much of what we are engaged in
is, in fact, very cost-effective and is something which used
appropriately could be useful in the new circumstances.
I will give you one example. One of our long-time funded
researchers from University of Pennsylvania, who has moved to
Ohio to Cleveland Clinic, has a model which is called a
``transitional model'' of care in which patients using this
model, which is a nurse-managed model, patients are able to
leave the hospital earlier, have fewer unplanned return visits,
and in general, fare quite well compared to patients discharged
early without this type of model. The populations that have
been addressed successfully are: mothers who would have low
birth weight infants, resulting in follow-up ahead of time,
resulting in a lower number of low birth weight babies; also,
women who have come into the hospital for unplanned Cesarian
sections, hysterectomies, and other moderate types of surgical
interventions and/or illnesses. These patients have fared quite
well with this model, and, in fact, it has turned out that it
is cost-effective. So there was a great deal of interest in
hearing the results of those particular research studies.

nursing publications

Mr. Porter. Your Institute celebrated its tenth anniversary
last fall. I'm sure you've seen an increasing maturity in the
nursing research you supported during that period. In what
journals does nursing research tend to be covered? Have nurse
researchers broken into the ``big league'' journals?
Dr. Grady. Yes. The lead study of the group that I just
mentioned to you was published in the New England Journal of
Medicine. There have been subsequent publications from that
type of research published in that journal. Also, a number of
other journals, Lung, and some of the physiology journals
related to cardiovascular health, are also regularly published
in by nurses. The major leading journal that nurses publish in,
the research journal, is Nursing Research. However, the work is
finding its way into many other journals.
Much of what is going on now in the field is
multidisciplinary and interdisciplinary. So many of these
studies, in order to address the appropriate audience, need to
be published in multidisciplinary journals. So we are covering
the waterfront, as it were.

traumatic brain injury

Mr. Porter. One of your areas of research priority is
traumatic brain injury. New legislation focuses attention on
brain injury throughout the Public Health Service both in terms
of research and services. What is already known about managing
the care of traumatic brain injury victims that could be useful
for the service demonstrations being operated by HRSA?
Dr. Grady. There are several studies in this area that are
relevant. For several years, we have funded studies related to
patients following traumatic brain injury in acute care
settings relative to suctioning procedures and other intensive-
care procedures that result in an increase in intracranial
pressure. As you may know from the background materials from
that group, one of the major dangers in the early post-
traumatic period is a further increase in intracranial pressure
resulting in further brain damage. That's an area in which
several changes in care delivery as a result of these studies
have shown the ability to either prevent the increase or
actually result in a reduction of increase while care is being
given.
There are other areas of study which impact on this. One of
our major initiatives is that of cognitive impairment,
measuring changes in brain function as it relates to learning,
memory, and awareness of one's environment. That is a major
initiative of the Institute. The difference there now from
earlier days is that the tools that are available to measure
levels ofconsciousness and responsiveness of individuals
following injury are much better. So that one can actually determine if
an intervention or a way of caring for someone is actually beneficial.
Earlier on, one could imagine that it might be or one could make an
educated guess, but now one can actually measure that. In the coming
year, we plan to encourage more applications in that area. We are
collaborating with several institutes on campus in planning for that.

currency with research

Mr. Porter. This is a question for both you and Dr.
Kirschstein. All of the directors that have testified before us
appear to us to be extremely knowledgeable in their fields,
including Dr. Grady. I wonder, Dr. Kirschstein, if you could
tell us how they receive their information. Is it sitting down
with researchers who are working on particular projects and
learning directly from them? Is it all read? How do they keep
up with the expanding knowledge in each of their fields? It
seems to me very difficult to keep up with, there is so much
going on.
Dr. Kirschstein. First of all, Mr. Porter, I think all of
us find it is extremely difficult to keep up. But the best way
they do it is by working very, very hard. They do, indeed,
spend hours and days in all sorts of settings--meeting with
researchers, going to research conferences, reading the
literature, calling in groups of experts, interacting
constantly, and then finding time, as they can, to think about
it all, synthesize it, and put it into some planning effort and
some sort of priority setting that you've been very interested
in. It is a formidable task and they all do it extremely well.
One of the reasons I think they are all so successful at it
is that they have remarkable backgrounds to begin with. They
have been well-trained, either as physicians or as research-
trained nurses, or as research scientists with other doctoral
level degrees. They have probably all had quite distinguished
careers, some more than others, nevertheless, as researchers,
and have kept their interest and their enthusiasm and their
excitement about science very current.
Mr. Porter. I might add that applies to you and Doctor
Varmus, obviously, more than perhaps anyone, because you have
got to know all of the different fields and keep up with this
vast amount of knowledge.
Dr. Grady, would you like to add to that at all?
Dr. Grady. Just that I would agree that Dr. Kirschstein
never rests. In all honesty, to pick up on that, we do find
ourselves in a number of settings. I think the best way I find
to stay informed is to be able to collect the data from a
number of sources, both from the literature, from meetings, in
person, getting out to the sites. I find that it is often very
helpful. If you are available on the Internet, or when I go to
a scientific meeting I try to visit the nearby universities and
speak while I'm there, people will bring concerns to you or
they will bring the excitement of what they're doing in the
clinic, in the laboratory to you. It helps, I think, to keep
the vitality to hear it firsthand and to be able to share in
that excitement. It makes it much more real.
Mr. Porter. Thank you very much.
Mrs. Lowey.
Mrs. Lowey. Thank you very much, Mr. Chairman. I, too,
would like to join the Chairman in welcoming you, Dr. Grady,
and your colleagues. I have been a long time supporter and
advocate for the nursing profession. I do feel that with our
focus on quality yet cost-effective care the nursing profession
has an extraordinary amount to contribute. So I really do
appreciate it. And as we move forward, I think your work on the
nursing profession will become even more invaluable and will be
paid attention to. So I thank you very much.
Dr. Grady. Thank you.

research training issues

Mrs. Lowey. Along with that, the Nurse Education Act is a
major source of support for programs for baccalaureate nurses
who become the graduate students, nurses with advanced degrees,
and faculty who perform nursing research. Would the NINR
research agenda be hurt by a decrease in the number of nurses
able to pursue a graduate degree or to move into faculty at
schools of nursing? The administration's fiscal year 1998
budget reduces spending for nursing education by 88 percent--88
percent. If that budget were to become law, what would be its
effect on nursing research?
Dr. Grady. We depend for our research practitioners on
those graduates of baccalaureate schools across the country.
The average individual entering a doctoral program already has
a bachelors and a masters degree in nursing. So we do rely on
that. For us, it is a pipeline issue, that we do need to keep
the supply coming.
As you have implied by your question, the number of nurse
researchers that are in demand exceeds the supply that is
available. So we do very much need to keep that group coming.
As I mentioned earlier, we are a young field and so the
pipeline effect is really an important issue. We have many
people who are entering training but we're just barely getting
to where we need to be.

women's health issues

Mrs. Lowey. Can you please update the subcommittee with
regard to your work to improve women's health. For example,
several years ago you were involved in an initiative with the
Office of Research on Women's Health to examine whether women
should undergo hysterectomies for noncancerous conditions. What
is the status of that project, and could you please highlight
your work on other women's health issues?
Dr. Grady. Yes. Regarding the issue of hysterectomies in
women, the report has now been published and it was found that
there are fewer hysterectomies being performed on women for
noncancerous conditions now than there were previously. There
are a number of questions being asked before that is done. It
is not the obvious first choice option which reportedly it had
been in the past, although the data was more hearsay then than
now.
We are involved in a number of women's health areas. We, in
fact, are one of the recipients of a fair number of resources
from the Office of Research on Women's Health who co-funds
through us to address several areas of women's health. Let me
take the issue of screening for breast cancer for older women
who are obviously at risk. This has been a problem group both
in cities and also in rural areas. We are funding, for example,
one study which is a, let me use the word, linkage study,
meaning something different than you've heard earlier this
week. Basically, this is a study to test whether linking up
young women who are very aware of the risks and the dangers and
accept this as an important tool, linking up younger women with
older women to try to use a sort of mother-daughter approach to
getting those women in for testing. The preliminary results are
encouraging.
We also are participating in the Swan-Study of Women Across
the Nation, that is a consortium with the Aging Institute,
addressing the health of older women.We fund one of the seven
clinical sites. The area that we fund focuses primarily on the health
needs of African-American older women.
We also are funding a study looking at sleep disturbances
in women with fibromyalgia. This, as you know, is a problem
that has a much higher incidence in women than men. Sleep
disturbance and pain are associated problems. We're funding a
study in that area, one of only a few studies looking at those
issues.
We also are funding a number of studies looking at
improvement in prenatal care to try to identify women at risk
for low birth weight babies, women who are part of underserved
rural populations, getting them in. We have one such study that
is funded in Hawaii that resulted in a decrease in the number
of low birth weight babies and also in a large increase in
women in that group coming in for prenatal care. That was an
interesting study in that what it did was to use specifically
tailored approaches to the population so that it incorporated
not just the well-known principles of promoting health in
prenatal women and early child birth, but also looked at the
cultural component and investigated the use of native healers
in that population. By incorporating them on the team, there
was a much larger response to that initiative.
I could go on. Women's health is a major focus of many of
our studies.

breast self-exams

Mrs. Lowey. I was disturbed by the report yesterday that
the results of a study that took place in Shanghai, China,
challenged whether breast self-exams are effective in detecting
cancer. News reports stated that there are few studies on the
efficacy of breast self-exams. This would seem to be a
necessary area of research, perhaps between your Institute and
the National Cancer Institute. Could you please comment?
Dr. Grady. I think that is an interesting observation.
Because of the availability of many high technologies now,
there has been a period of time when less attention has been
paid to breast self-exam as a way of detecting small cancers. I
think that for populations, as an adjunct to other
technologies, that it still is thought by many to offer a
useful screening approach. We do not currently fund studies
that specifically are looking at the efficacy of that, although
we do fund studies which are encouraging women to do breast
self-exam along with the other healthy life style choices. In
fact, we do co-fund with the Cancer Institute one such study
which looks at a variety of screening methods to encourage
people to use them, but it does not specifically look at the
efficacy of one versus the other. But it is something that we
do need to attend to.

counseling for genetic screening

Mrs. Lowey. In the area of genetic screening, as we all
know, genetic tests for breast cancer are available in the
private market. Additional genetic tests for diseases such as
Alzheimer's will be available soon. I am very concerned about
the development of counseling strategies to help individuals
and families decide whether or not to undergo these genetic
tests. If they decide to, how do you deal with the possible
results. Nurses, it would seem to me, can play, and should
play, a significant role in helping to develop such counseling
programs. Perhaps you could discuss with us the role the
Nursing Institute is playing in this area. To what extent are
you coordinating your work with the Human Genome and National
Cancer Institute?
Dr. Grady. We agree with you that nurses could, and should,
play an important role in that area. We are collaborating with
the National Human Genome Research Institute and the National
Cancer Institute as well in this area. Specifically, we have
collaborated with the Genome Institute in bringing nurses
together from across the country who are involved in genetics
in any way to look at what will ultimately be a core curriculum
for nurses in genetics, and to look at the areas of need for
counseling and to identify issues involved. We also participate
with them in funding several grants under the ELSI program that
is a part of the Genome Institute.
We also fund several others along the lines of using a
decision-making approach. One such grant is looking at the
decision-making for those people who are considering BRCA-1
testing. So we are addressing this from a number of areas and
expect to continue to do that as time goes on.
As you all have heard on several occasions from Dr.
Collins, the percent of the genes that are identified as part
of the Human Genome that actually are one gene-one disease is
probably roughly as low as 10 percent. The other 90 percent of
the genome will code for a predisposition. A misspelling in a
particular gene will result in a predisposition to developing a
disorder but not necessarily a certainty. The other factors
that would play into it are factors such as diet, exercise,
environment, and many others that we have not yet identified.
As this body of information grows, the role of individuals, in
this case it would be specifically the nurse, to identify what
factors can be modified and to try to work with patients to
intervene to either diminish the risk or introduce a healthy
life style will become much more important as time goes on.
Mrs. Lowey. I thank you, Dr. Grady. I think, as the
population is getting older, the role of nurses working with
chronic illness, with the patient, with the families will
become increasingly important. I thank you again. I look
forward to working with you. Thank you, Mr. Chairman.
Dr. Grady. Thank you.
Mr. Porter. Thank you, Mrs. Lowey.
Dr. Grady, we have many more questions for you for the
record that we would ask that you answer.
Thank you for the fine job you're doing at NINR. We hope to
do better by you than the President has done in his budget.
That, of course, depends upon the overall budget and the budget
allocations. Obviously, you, along with the other directors of
the institutes, are doing wonderful work. You need resources to
advance that work. You need resources to keep good people
involved. We want to do the best that we possibly can to help
you do that.
Dr. Grady. Thank you, Mr. Chairman. We appreciate that.
Mr. Porter. Thank you.
The committee will stand in recess briefly.
[The following questions were submitted to be answered for
the record.]

[Pages 1391 - 1442--The official Committee record contains additional material here.]

----------

Wednesday, March 5, 1997.

FOGARTY INTERNATIONAL CENTER

WITNESSES

PHILIP E. SCHAMBRA, Ph.D., DIRECTOR
STEPHANIE J. BURSENOS, DEPUTY DIRECTOR
RICHARD MILLER, EXECUTIVE OFFICER
RUTH KIRSCHSTEIN, M.D., DEPUTY DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF
HEALTH AND HUMAN SERVICES

Mr. Porter. The subcommittee will come to order.
Next we are pleased to welcome Dr. Philip Schambra, the
Director of the Fogarty International Center. And Dr. Schambra,
why don't you introduce the people you brought with you, and
then proceed with your statement.

Introduction of Witnesses

Dr. Schambra. Thank you very much, Mr. Porter.
To my left is Mr. Richard Miller, the Executive Officer of
the Fogarty Center. To my right is Ms. Stephanie Bursenos, the
Deputy Director of the Fogarty Center. And of course, you know
Dr. Kirschstein and Mr. Williams, to her right.

Opening Statement

Mr. Chairman, if I may I'd like to submit my full statement
for the record and give a brief oral presentation, starting out
by commenting that once again it's my distinct privilege to
present the programs and accomplishments of the Fogarty
International Center.
As you know, our namesake, John Fogarty, served as Chairman
of this committee for 18 years, from 1949 to 1967. He was the
first of a continuing lineage of Congressmen and women who have
enabled NIH to become the world's leader in the pursuit of
health through biomedical research. The Fogarty International
Center was established by Congress specifically to improve
health through international scientific cooperation. This broad
mandate has required us to set priorities and concentrate our
resources on strategic health areas.
As an outcome of our long-range plan, we've identified
scientific training programs with developing nations as our
foremost priority to prepare the United States to meet urgent
global health challenges.
Our working principle is to coordinate our programs, not
only across NIH, but across the Federal Government. In fact,
almost 60 percent of the funds managed by the FIC, including
AIDS funding allocated by the Office of AIDS research, are
derived from other NIH or Federal components, who view FIC as a
means of advancing their international goals. Moreover, these
intra and interagency alliances reduce administrative costs and
streamline management.
The model for FIC's global health efforts is our AIDS
International Training and Research Program. Since its
inception in 1988, more than 1,000 scientists from over 80
countries have received training in the United States, and now
assist us in our international prevention efforts. This past
year, the program documented a substantial decrease in the
prevalence of HIV in the population of one foreign country as a
result of a systematic prevention strategy.
The long-range objective is to create these same
partnerships to meet the challenges of new and emerging
infectious diseases, environmental pollution and unsustainable
population growth. The aim is to demonstrate a compelling
leadership role for the United States in reaching global
solutions to global problems through biomedical research
training. Since the completion of our long-range plan, we have
launched research training programs on population and health
with the National Institute of Child Health and Human
Development of NIH, and on environmental and occupational
health with the National Institute of Environmental Health
Sciences at NIH, and the Centers for Disease Control, and in
new and emerging infectious diseases with the National
Institute of Allergy and Infectious Diseases at NIH.
These early investments are already yielding public health
benefits. For example, in 1996, a scientist from Gabon received
research training on Ebola virus at Yale University under our
training program in new and emerging infectious diseases. Upon
return to Gabon, he traced the origin of an Ebola-infected
patient to a rural lumber camp. And because of his special
training, he was able to perform the required laboratory
studies in collaboration with CDC scientists.
As a consequence, Gabon was able to confirm the Ebola
outbreak, take appropriate treatment and prevention measures,
and undertake a research program to identify the natural
history of the virus.
In addition to these research training programs, FIC
undertakes concerted efforts to bring new resources and
scientific perspectives to global health through allianceswith
other Federal agencies. In cooperation with the National Science
Foundation and the Agency for International Development, and with the
strong endorsement of this Committee, in 1993 the FIC initiated the
International Cooperative Biodiversity Groups Program. Its purpose is
to discover new drugs from the earth's biological resources, while
preserving national ecosystems and promoting economic growth through
drug development.
Since its inception, over 3,000 species of plants and
insects have been examined for their potential therapeutic
properties. Bioactive samples are now being tested as candidate
drugs against certain cancers and viral diseases, malaria and
degenerative neurological disorders.
Finally, Mr. Chairman, last year, Dr. Varmus noted to the
committee that a special panel would be established to review
the ways in which the NIH carries out its commitments to
international health. The report of the panel, co-chaired by
Dr. Joshua Lederberg of Rockefeller University and Dr. Barry
Bloom of Albert Einstein Medical College is now completed. And
I'm pleased to note their strong recommendation of a
strengthened international role for all NIH components.
I'm particularly pleased that the panel endorsed the
directions pursued in the FIC long-range plan. They cite the
plan as a thoughtful and forward-looking approach for guiding
FIC's future activities and commend the Center for
demonstrating a leadership role. The report does recommend that
FIC reassess several longstanding fellowship programs in light
of its more recent global health priorities. This
recommendation is consistent with internal discussions
currently underway with Dr. Varmus and others within the NIH
leadership.
I'd like to conclude by noting that the political basis for
public investment in biomedical research emerged from our
Nation's critical needs during World War II. Today, the pursuit
of health through research again is essential for our Nation's
security. Scientific solutions to global health threats require
a coordinated global response.
Congressman Fogarty once remarked that our international
health programs can be characterized as enlightened self-
interest, since it can be amply demonstrated that we receive as
well as give.
With the support of Congress, FIC will continue to advance
this important mission through international cooperation.
Thank you, Mr. Chairman. Our fiscal year 1998 budget
request is $16,755,000. And I'll be pleased to answer any
questions that you or members of the committee may have.
[The prepared statement follows:]

[Pages 1446 - 1449--The official Committee record contains additional material here.]

other countries leading in biomedical research

Mr. Porter. Thank you, Dr. Schambra.
I will forego my usual question about your 2.3 percent
increase, because I think Mr. Williams has coached all of you
to answer roughly the same way.
Let me ask a general question that I'm just kind of curious
about. What other countries, in the order of magnitude and
quality, have research communities that are somewhat comparable
to the United States? Japan, Germany, France?
Dr. Schambra. That is certainly an easy one to answer, and
you've started----
Mr. Porter. There are none?
Dr. Schambra. Japan has a superb biomedical research
enterprise as a whole, indeed, in all fields of science,
developed since the Second World War. Canada is certainly a
leading scientific power. In fact, second to none as the
largest foreign collaborator with the United States. A great
number of our research grants given to foreign scientists,
about half, go to Canadian scientists.
Germany, France, very predominantly. The United Kingdom and
other countries in Western Europe, Holland and the Netherlands
are all leading countries in biomedical research. The
Scandinavian countries are important powers in this field as
well.
Mr. Porter. Now, since World War II, 30 percent of the
Nobel prizes awarded to scientists for research discoveries
under NIH support were received by foreign researchers. This
seems like quite a remarkable statistic, given that less than 1
percent of NIH extramural grants in that period went to foreign
investigators.
How should we interpret this statistic? Should we assume
that competition for NIH grants is so intense that only the
very top international grantees win grants? Or should we be
concerned about the competitive standing of U.S. researchers?
Or is this a function of some other factors?
Dr. Schambra. I think first and foremost, what it means is
that NIH research administrators know how to pick winners. And
in fact, it also illustrates, I think, very vividly, the
importance of international collaboration between scientists,
in this case, leading scientists who have made major
discoveries that have led to the ultimate recognition of
winning the Nobel prize. It is important for the NIH to support
that type of international collaboration.
Dr. Kirchstein. Mr. Chairman, if I may add something. There
are policies at NIH that only a certain number of awards will
be made to scientists abroad, so that the vast majority of the
money can be provided to United States investigators.

fellowship programs

Mr. Porter. Under the NIH Visiting Program, more than 2,000
foreign scientists are supported each year in fellowships and
assignments to the NIH intramural program at a cost of more
than $70 million. Does this large international training
program swamp the impact of the smaller Fogarty training
programs, which also bring foreign scientists to the United
States?
Dr. Schambra. Well, yes, I think in fact it does, Mr.
Chairman. And the realization of that fact alone, in
conjunction with other considerations, has led us to modify
some of our fellowship programs in recent years. When I became
Director of the Fogarty Center in 1988, our major investment,
in fact, was in training foreign scientists in the United
States.
But it represented only about 130, at the most, foreign
scientists coming to the United States, and them mostly from
the developed regions of the world. About three-quarters of the
scientists came from Western Europe and Japan, and other
developed countries of the world. These were small numbers
compared to the very large numbers you cited who come from
abroad to work just in the intramural research program at NIH.
So we felt that given that fact, and the much more
demonstrable need to provide training for scientists from
developing countries and countries that had just emerged into
the democratic sphere of international life in EasternEurope
and the former Soviet Union, that we would in fact reduce our programs
and focus on those scientists to the preference of offering fellowships
very broadly in competition with the intramural research program at
NIH.
Mr. Porter. Do you have any data on the number of trainees,
or the proportion of trainees that stay in the U.S. after
completing their training rather than returning to their home
countries?
Dr. Schambra. We looked at that question in connection
with, in fact, a program I just cited a few years ago. I don't
have up to date, that is current figures, but then in excess of
90 percent of the fellows that we were training under our
programs returned to their home country. Even today, the nature
of the foreign scientists who we bring under our various
training programs to the United States for training come under
visa provisions that require them to return to their home
country after finishing their training.
In addition, we usually make it a condition of their
training here that in fact they have a place to go back to, and
they in fact intend to go back to their home country. But that
can't, of course, be 100 percent. But I'd say 90, 95 percent is
probably a pretty good batting average.
Mr. Porter. Do you have data on the percentage of
international trainees in Fogarty programs who go on to compete
successfully for NIH research grants?
Dr. Schambra. At one time, and in fact also in connection
with this particular program, we did look at that question.
Frankly, I don't remember what the data at that point showed,
Mr. Porter, but I'd be pleased to provide that for the record.
[The information follows:]

Fellowship Programs

The study I have referred to focused on the percentage of
fellows who returned to their home countries and the types of
employment pursued following their return. However, we now have
begun to monitor the number of FIC-supported fellows who are
subsequently supported by other NIH institutes. Under the AIDS
International Training and Research Program, an important share
of former trainees now participate in international research
projects supported by NIAID. These include, for example,
studies of natural history of HIV in Haiti and in Senegal,
prevention research in Thailand on vaginal microbicides and
studies in Uganda on the relationship between HIV and
tuberculosis.

Dr. Schambra. As Dr. Kirchstein pointed out, the number
would be extremely small, in view of the fact that about 1
percent of NIH research grants in total go to foreign
scientists.
Mr. Porter. Yes, I understand that the number is relatively
small. But you could still see how many go to ones that you've
trained.
Dr. Schambra. Right, absolutely.

external panel review

Mr. Porter. As you mentioned, the Lederberg panel
commissioned by Dr. Varmus to review the structure of the
Fogarty Center recommended last September that the Center's
current mission and structure be retained in large part. It
did, however, suggest that three training programs, Scholars in
Residence, Senior International Fellowships, and International
Research Fellowships, be reduced significantly. The 1998 budget
appears to straight line these three programs. Do you disagree
with the panel's judgement?
Dr. Schambra. Having developed a long-range plan, we have
been looking particularly at those programs for their validity
and relevance in today's situation.
As far as the budget projections for fiscal year 1998 are
concerned, some of the money that is in that straight line is
for the purpose of paying for commitments that have been made
in prior years. In the case of the International Research
Fellowship Program, that is the program that I referred to a
moment ago as having already been very substantially reduced to
about a third of its size from some five years ago.
We are in discussion with Dr. Varmus and the leadership at
NIH about the future of these programs and alternatives that
might be in fact more pertinent to today's needs on the
international scene.
Mr. Porter. The Lederberg panel also recommended that a
critical review of Fogarty's functional units be undertaken in
the near future to determine the most efficient use of its
resources. Do you plan to follow up on this recommendation?
Dr. Schambra. Yes. In fact, we do. I'm pleased to say that
that, too, can be seen as an encouragement to continue the
process that we've already started several years ago with our
long-range plan, and which, in fact at that time, we did
reorganize the Fogarty Center, reducing the number of operating
branches from five to three divisions. As you know also, Dr.
Varmus, with the support and encouragement of this committee,
is arranging for a complete review of the administrative
functions of the entire NIH. And we would certainly be a part
of that process as well.
Mr. Porter. Finally along this line, the Lederberg panel
recommended that the Fogarty Center should take a more active
role with the National Library of Medicine in exploiting
contemporary methods of communication to facilitate
international science. In what ways have you observed the
Internet changing international research communication?
Dr. Schambra. Well, clearly, this has been perhaps one of
the most profound technical developments, even aside from the
international aspects, in terms of communication between
scientists. But now, when scientists can communicate with
relative ease and relatively low expense over long distances,
it brings a whole new perspective to the meaning of
international collaboration.
It is one of the topics that we again, I'm pleased to say,
identified in our long-range plan as one that needs much closer
analysis to see how it would, in fact, change the way we would
go about supporting and conducting and encouraging
international scientific collaboration.
I'm very pleased that Dr. Lindberg invited me to be a
member of a planning panel, chaired by Dr. Donald Frederickson,
and on which Dr. Lederberg also sits, to look at the future
international activities of the Library, and through that and
subsequent discussions we hope to develop a joint approach to
addressing exactly this question.

human frontier science program

Mr. Porter. Dr. Schambra, the Human Frontier Science
Program is an effort to encourage global science collaborations
funded mostly by the Japanese government. Is the Fogarty Center
involved in this project?
Dr. Schambra. To the tune of a half a million dollars a
year we are, which is currently a third of the NIHcontribution
to that program.
Mr. Porter. Should your resources be used--well, I guess
you're saying yes.
Dr. Schambra. I was going to say that also, in fact our
involvement has been much more than that. That was sort of a
flip answer.
But when the program was first discussed among the various
governments, following the proposal by the Japanese Prime
Minister in 1987, the Fogarty Center, on behalf of NIH, played
a leading role in developing the concept of the program and the
mechanisms through which it would operate. And in fact,
assisted them in setting up a grants program modeled very much
along the lines of NIH's.
We're certainly pleased to see the program prosper and
grow, because we, the United States, have been the principal or
predominant beneficiaries of the program. The decision for the
Fogarty Center to contribute half a million dollars, I think it
was made by the leadership of NIH. I have no argument with it.
Because I think it's a very, excellent program and it ought to
be supported in one fashion or another. And whether it comes
from our budget or collectively from the Institutes, I think is
an administrative judgment.
Mr. Porter. Are there other similar programs funded outside
of Fogarty and NIH that provide resources for international
research collaboration?
Dr. Schambra. Outside Fogarty and outside NIH, the answer
is yes. I would say that probably every agency in the Public
Health Service, in this Department, has an international office
and is involved to a greater or lesser extent in international
scientific collaboration.
Every Department of the Government has a strong
international presence and office. I would say that there are
very few of them that have a direct appropriation to support
international scientific collaboration, but would have to
depend on funds that are appropriated to other components of
the agency, for the most part.

former soviet union--state of science

Mr. Porter. What is your assessment of the state of
scientific enterprise in the former Soviet Union? From press
reports, it sounds like a massive brain drain is occurring as
government funding for science there evaporates.
Dr. Schambra. Well, I think that's a very pertinent and
very serious question for the Russians these days. There's no
question that the state of science all told in the former
Soviet Union is in a state of near disaster. It's a question of
funds being made available to pay a payroll, it's funds being
made available to keep the electric power on and the heating on
in facilities, to buy supplies and reagents.
I think that one of the things that we have been able to do
and do very quickly through the appropriation of the Fogarty
Center some years ago, in fact, was to provide small grants
that were given to American scientists who wanted to
collaborate with known competent Russian scientists, and help
them through a period of time until other sources of funding
could come to their support. George Soros, in the private
sector, for example, the National Science Foundation, and other
sources in the European Community as well.
It is indeed a constant matter of concern that Russian
science not disintegrate. Because there is a great deal of good
science and good potential in the future. We just want to make
sure that it goes into useful purposes.
Mr. Porter. Are you training Russian scientists now as part
of your program?
Dr. Schambra. Yes, as part of our program, speaking very
broadly, for NIH, we have about, I think six, they're number
six in the order of countries with scientists in the NIH
intramural research program. I think at the last count there
are somewhere between 130 and 150 Russian scientists working in
the intramural program at NIH.
Mr. Porter. The problem is when they return, where do they
get the resources to pursue any kind of research at home?
Dr. Schambra. That is a concern. And one of the ways that
they would get resources is through the Fogarty International
Research Collaboration Award program, the FIRCA program. We
have this program now, I believe it's in its fourth year, it
started out as a program specifically focused on developing
relations with Latin American scientists, but then when the
opportunity arose in the former Soviet Union and Eastern
Europe, it was made available to them as well.
These grants, while given to American researchers who want
to collaborate with Russian researchers, are intended to
provide support principally for the foreign scientists, the
Russian scientists, in the form of the types of materials, the
types of supplies that he or she would need to conduct
research, to travel and stay in contact with their American or
foreign colleagues.
Mr. Porter. Maybe in their case, for the short term, we
ought to encourage them to stay here, the good ones.
Dr. Schambra. Better here than some other places in the
world.

biodiversity program

Mr. Porter. Your budget justification states that a
significant percentage of most prescribed drugs, such as
antibiotics, have their origin in natural products. We are
familiar with the cancer drug, taxol, which comes from the
Pacific yew. But what are some other examples?
Dr. Schambra. In fact, just to provide an overall figure,
I'm not sure that I could provide the names of the prescription
compounds, but our latest studies show that something like 57
percent of the most commonly prescribed drugs in the United
States today come originally from natural compounds. Quinine is
originally from a natural compound, aspirin is from a natural
compound. The rosy periwinkle, which was discovered in
Madagascar, provides vincristine and vinblastine, which is a
very effective treatment for certain types of cancer.
Dr. Kirchstein. You may remember that many of the
antibiotics came from fungi; penicillin was originally bread
mold, streptomycin is from a fungus that was discovered in New
Jersey many, many years ago. So large numbers of them came,
many of them have not been synthesized and had custom designing
done to them. But the source is there.
Mr. Porter. How much funding does your budget include for
the biodiversity program? How much is spent on this effort
throughout NIH by other institutes like Cancer, which has a
substantial drug testing program for natural products?
Dr. Schambra. To answer your latter question, in fact, we
did a survey when we began our biodiversity cooperative group's
program several years ago. I think at that time we found out
that there were 12 Institutes, about half of the Institutes at
NIH, were involved in developing pharmaceuticals from natural
products for their particular purposes. I think the total
dollar amount was about $60 million. And a third of that
represented the Cancer Institute.
As far as our international biodiversity program is
concerned, Mr. Porter, that is funded currently at the total
level of $2.5 million a year, of which about $1.5 million comes
in a direct appropriation to the Fogarty Center. And as you
know, the remaining amount comes from other Institutes at NIH,
Allergy and Infectious Diseases Institute, the Heart Institute,
the Cancer Institute, from the National Science Foundation and
at one time from the Agency for International Development. And
we haven't given up trying to attract them back to that program
when it's up for renewal.
[Clerk's note.--Later corrected to ``$1.3 million'']
Mr. Porter. Well, if we give them some resources, they
could participate.
Dr. Schambra. That's right.
Mr. Porter. Some of the drug companies are participating in
your biodiversity program. How much do they invest in this on
their own each year, independent of the Fogarty program?
Dr. Schambra. We've estimated that to date, they have
invested in kind or in cash probably about $1.5 million in
total that we can clearly identify.
Mr. Porter. How does the technology transfer aspect of your
biodiversity program work? Do you sell licenses to drug
companies to develop the substances identified by the Fogarty
research? And is this a source of royalty income for NIH?
Dr. Schambra. The way the program works is through five
cooperative agreements, which are neither contracts nor grants,
but something in between. They fall under the provisions of the
Bayh-Dole Act, in which any intellectual property developed
under those agreements belongs to the grantee.
Between the grantees themselves, where there is a
university component, probably an academic component, and an
industrial component, they will have developed among themselves
an agreement for revenue sharing or income sharing for any
product that arises.
I might mention incidentally that in my opening remarks, I
commented that we have about 3,000 samples that have been
investigated for their pharmacologically active properties.
Twenty-five of those have shown real promise and are in further
tests right now. And we have one that has proceeded to the
stage of applying for a patent.
Mr. Porter. You tested 3,000 natural substances in two
years. How many acres of rain forest are lost to development
each day, and at the current pace, will you lose the race
against deforestation before you can test the unique substances
these forests contain?
Dr. Schambra. That's a very good, hotly debated question. I
think that one hears a wide range of answers to the question of
how much are we losing on a daily basis.
Let me try to answer it from the point of view of
biological species, many of which, in fact, probably most of
the undiscovered species are found in these tropical rain
forests. It's estimated that there are somewhere between 10
million and 30 million species of various diversity around the
world. Of that number, perhaps 10 percent are known to science,
of that total number of 10 million to 30 million species, only
1 percent or less have actually been explored for their
pharmaceutical potential.
It's estimated that in the next 30 years, that we could
lose as much as 20 percent of the planet's biological diversity
at the rate that it is disappearing today. I think that will
give you a sense of how quickly the rain forests and other
natural environments are disappearing as well.
Mr. Porter. And even our ability to clone won't help this?
Dr. Schambra. That's right. [Laughter.]
Mr. Porter. Dr. Schambra, thank you very much, both for
your good testimony this afternoon, for your very direct
answers to our questions and for the excellent job you're doing
at the Fogarty International Center. We thank you, sir.
Dr. Schambra. Thank you very much, Mr. Porter.
Incidentally, before we close, if I might give you one of
the tangible products that has come from our international
biodiversity program, it is a publication on biodiversity and
human health that reflects the proceedings of a symposium that
we ran in conjunction with the Smithsonian Institution. I think
that you might find it very interesting reading. It makes the
case very cogently for the importance of the relationship
between biodiversity and human health and the health of all.
Mr. Porter. Thank you very much. If it's informational, I
can receive it under House rules.
Dr. Schambra. Strictly informational, sir.
Mr. Porter. Thank you, Dr. Schambra.
The subcommittee will stand in recess until 10:00 a.m.
tomorrow.
[The following questions were submitted to be answered for
the record.]

[Pages 1458 - 1489--The official Committee record contains additional material here.]

----------

Thursday, March 6, 1997.

NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES

WITNESSES

DR. STEPHEN I. KATZ, DIRECTOR
DR. STEVEN J. HAUSMAN, DEPUTY DIRECTOR
MARGARET S. KERZA-KWIATECKI, EXECUTIVE OFFICER
ROBYN J. STRACHAN, BUDGET OFFICER
DR. HAROLD VARMUS, DIRECTOR, NIH
DENNIS WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF
HEALTH AND HUMAN SERVICES

Mr. Porter. The subcommittee will come to order.
Before we begin this morning, I want to make everybody
aware of a change in our hearing schedule. The hearing
scheduled for tomorrow will be postponed until later in the
month. The House is not in session tomorrow. And I want to be
sure that all members will have the opportunity to be here and
to hear the testimony of the Office of AIDS Research, the
Office of the Director and the Buildings and Facilities. And so
we will announce when that hearing will be scheduled. It will
be later this month.
This morning we want to welcome Dr. Stephen Katz, the
Director of the National Institute of Arthritis and
Musculoskeletal and Skin Diseases for his testimony. And Dr.
Katz, if you would introduce the people at the table with you
and then proceed with your statement.

Introduction of Witnesses

Dr. Katz. Good morning, and thank you very much.
I'm pleased to introduce Ms. Kerza-Kwiatecki, who is our
Executive Officer; Ms. Robyn Strachan, who is our Budget
Officer; Dr. Steve Hausman, who's the Deputy Director; and of
course, Dr. Varmus and Mr. Williams.

Opening Statement

I'm delighted and honored to appear before this committee.
Our research areas cover many common and very chronic diseases
that affect our joints, bones, muscles and skin, and compromise
daily life for many Americans. I would like to share some of
the progress made in our plans for seizing upon scientific
opportunities in four areas: osteoarthritis, autoimmunity, skin
cancer and osteoporosis.

osteoarthritis

Osteoarthritis is the most prevalent disease of the joints.
It is characterized by progressive degeneration of the
cartilage, which results in pain and dysfunction. It can affect
any joint, but most commonly affects the hip or the knee joint.
It takes a staggering toll in human suffering and economic
costs. Osteoarthritis and related disorders account for more
than half of all of the total hip replacements and over 85
percent of all the total knee replacements that are done in
this country.
It is predicted that osteoarthritis will affect 70 percent
of our over age 65 group in our country, an astounding number
of Americans. We've developed a multi-pronged approach to
osteoarthritis in terms of the research agenda. Recent research
results have provided some important clues to help understand
and develop new strategies or innovative strategies to the
prevention and treatment of osteoarthritis, and also to the
basic understanding of osteoarthritis.
Highlights during this last year include finding that a
normal cellular component, nitric oxide, can affect cartilage
cells. Cartilage cells are the cells that line the joints. It
can affect it in many ways. It can affect how it produces
certain of its products. It can also kill these cells. By
killing these cells, and not having any replacement for these
cells, there's nothing left of the cartilage. So nitric oxide,
from many different studies that have been reported this year,
has been a central focus for many different laboratories as a
potentially important molecule to look at as far as its causing
destruction.
Laboratory studies have supported these findings in that,
if one takes antioxidants and uses antioxidants like vitamin C,
vitamin E, beta carotene, in a test tube you can reverse some
of these effects. Amplifying these findings, there are recent
reports indicating that dietary factors, particularly
antioxidants like vitamin C, may play an important role in the
treatment of osteoarthritis of the knee. And we do have some
preliminary clinical studies that have recently been reported.

total joint replacement

A major advance also in the treatment of osteoarthritis is
of course total joint replacement, in which damaged joint
surfaces are replaced with metal and/or plastic components.
These joint replacement procedures have generally been regarded
as a very effective means of reducing pain and functional
limitation associated with severe osteoarthritis. A NIAMS
supported study verified the cost-effectiveness of total hip
replacement.
So if one takes a 60-year-old woman who needs total hip
replacement, gets total hip replacement, over a 20-year period
there is a cost savings of $117,000, just for medical costs.
That has nothing to do with quality of life, and of course,
quality of life is markedly improved in that she can then care
for herself.
Total joint replacements, however, are not without their
problems, including concerns for the effect of the implant on
the body. There is concern that a patient may develop
osteolysis. Osteolysis is the disappearance of bone around the
implant. And we are particularly interested in understanding
why that happens. Because once it happens, it's very hard to do
a second implant. The revision surgery becomes very, very
expensive.
We're also exploring the utility of non-surgical approaches
to osteoarthritis. Since previous studiesindicated that certain
antibiotics, such as doxycycline, inhibit the enzymes that are produced
within the joint which destroy the cartilage, we are co-sponsoring an
ongoing clinical trial on the effects of the antibiotic doxycycline on
osteoarthritis. And I look forward to reporting progress about these
studies to you next year.

genetic studies

As you've heard in prior testimony during this past week,
genetic studies have provided important insights in many areas
of medicine. The same is true for us in the area of
autoimmunity, that is, in lupus erythematosus and rheumatoid
arthritis, as well as in skin cancer.

systemic lupus erythematosus

In lupus, very recently UCLA scientists have provided the
first evidence linking a particular chromosomal region to lupus
susceptibility. This is a particularly important finding,
because it's found across all ethnic groups, that is, in
African-Americans, in Asians, and Caucasians. This should
facilitate identifying the specific gene involved, and from
there, the even more difficult step will be pursued, and that
is, identifying the function of the gene.

rheumatoid arthritis

This knowledge may open up new ideas regarding treatment or
even prevention strategies. The same types of advances have
been made in our intramural research program in rheumatoid
arthritis. In this case, the genes have been identified in
animal models rather than human beings. These animal models
with rheumatoid arthritis show that susceptibility and severity
is associated with certain gene types.
I should say that we have made a major commitment to
identifying susceptibility genes in lupus and in rheumatoid
arthritis patients through various consortia that have been
organized by extramural scientists since these studies require
large numbers of patients and particularly important, families,
to look at.

skin cancer

Also in the area of gene study, in the skin cancer called
basal cell carcinoma, which is the most common form of human
cancer, scientists this year have discovered that there are
mutations in the human version of a gene that has its analog in
fruit flies. And it was the gene that was first identified in
fruit flies that now has translated to our knowledge of human
disease.
This gene is thought to be important for controlling cell
growth. And with the mutation of this gene, there is no longer
control of cell growth. These studies were initially identified
in a very rare disease, very, very rare disease that probably
doesn't occur in a thousand people in the country. But these
findings are now extrapolatable to the very common form of
basal cell carcinoma, and should provide us with a better
understanding of the molecular basis of these diseases, and
potential new approaches to therapy.

osteoporosis

Finally, I want to say a few words about new findings in
osteoporosis, the leading cause of bone fractures. The clinical
activity and mechanism of action of estrogens, which are
important determinants in bone integrity in women, have been a
major focus of our Institute's supported research. Since not
all women are suitable candidates for estrogen replacement, it
is important to determine the mechanism of estrogen action and
determine alternative therapies. The effects of estrogen are
complex, but there is much to be learned about the biochemical
pathways through which they act.
In recent research results, investigators have shown that
estrogen induces death in the cells that actually break down
bone. As you know, bone is a dynamic process, it's being broken
down all the time, it's being built up all the time, and it's
being broken down by cells called osteoclasts. And recent
studies have demonstrated that estrogen and also estrogen
analogs have an effect on these osteoclasts. They may produce
premature death in the osteoclasts, which breaks down bone, and
as a consequence, the buildup is much better. So that's one of
the mechanisms by which estrogen produces good bone.
These findings should provide us with new information on
not only estrogen but also other drugs that may be used to
produce the same types of effects.
In conclusion, let me say that significant strides have
been made in our understanding of diseases of bone, joints,
muscles and skin. I am confident that the initiatives I have
shared with you will do much to advance our knowledge of
fundamental life processes and how they go awry in disease.
Diseases that affect these tissues have the capacity to
profoundly alter quality of life. The goal remains as always to
improve the health of the American public, to reduce the burden
of disease, and to enrich the quality of life of all Americans.

fy 1998 budget request

The budget request for NIAMS for fiscal year 1998 is
$258,932,000. I would be pleased to answer any questions you
might have.
[The prepared statement follows:]

[Pages 1495 - 1498--The official Committee record contains additional material here.]

Mr. Porter. Dr. Katz, we're going to have to stand in
recess because of a vote on the House Floor, so I'll leave you
with a thought that you can ponder, your answer to my usual
first question, what would you really like to have, rather than
2.4 percent. And the subcommittee will stand in recess until I
return.
[Recess.]
Mr. Bonilla [assuming chair]. Dr. Katz, I ran into Mr.
Porter on the way out and he said to go ahead and begin
questioning.
Dr. Katz. Thank you.
Mr. Bonilla. I did review your testimony in advance, and
I'm sorry I wasn't here to actually hear you.
But the committee will now resume order, and I'd like to
ask you a couple of questions, if I can.
Dr. Katz. Of course.

repetitive motion injuries

Mr. Bonilla. Last year, Dr. Katz, you testified before this
committee that there were important questions that remain
unanswered about the causes of and preventive measures for
repetitive motion injuries. Since your testimony last year,
have we learned any more about the causes of these injuries?
Dr. Katz. Yes. We are constantly learning more. At the
National Institute of Arthritis and Musculoskeletal and Skin
Diseases, we are supporting a broadarray of studies in terms of
repetitive motion injuries that are looking at very molecular as well
as clinical studies.
So for example, in carpal tunnel syndrome, we've learned
from a study in Boston the effect of certain types of surgery
in terms of producing trigger fingers, which are often produced
in carpal tunnel syndrome. We've learned that this type of
surgical procedure is beneficial in patients with carpal tunnel
syndrome. We have also learned since last year that certain
types of repetitive injury, for example, thrust injury, can
produce certain types of molecular changes in cellular
components.
So we're constantly learning more about repetitive motion
disorders. We are supporting a broad portfolio of research that
goes from the very fundamental to the clinical.
Mr. Bonilla. You touched on a couple of specific causes and
effects that result in injuries. Are the causes of these
disorders clearly identified and quantitatively related to
their occurrence? You touched on that and gave a couple of
examples, but if you would elaborate a little bit more, I would
appreciate it.
Dr. Katz. In certain industries where there is repetition
and high force and awkward posture, it is thought that there is
very good evidence that there is association between repetitive
motion disorders, which affect mainly upper extremities, from
the wrists to the elbows to the tendons to the carpal tunnel
syndrome, to the tension neck syndrome, all of that related to
repetitive motion, and sometimes low back pain is thought to be
due to repetitive motion.
So in those industries, such as the meat and poultry
industry or automobile manufacturing, where there is repetitive
motion and also in data entry and computers, it is thought that
there is an association between repetitive motion disorders and
repetitive motion injury.
Mr. Bonilla. Is it fair to say, Dr. Katz, that we need
additional research before we can answer the fundamental
questions about what causes both upper and lower body extremity
complaints, and what measures we can use to manage and prevent
them? I understand we're making progress, but do we have a long
way to go?
Dr. Katz. We are making progress as a consequence of a
joint conference in 1994 that we supported along with the
American Academy of Orthopedic Surgeons, and the National
Institute of Occupational Safety and Health. As a consequence
of recommendations from that conference, we have put out, or it
will be out very shortly, a program announcement targeting many
of the areas that you've talked about: in terms of learning, of
gaining new information on the pathophysiology, that is the
mechanisms involved in what these injuries are; the
standardization of definition for disorders, identifying
tissues that are injured, the nature of the injury, etc.; the
diagnosis of the disorders; prospective studies of the value of
functional capacity assessments, and predicting the successful
return to work in patients who are affected; clinical studies
to identify the optimal therapy; and the development of further
delineation of ergonomic changes that are required in order to
prevent these types of problems.
Mr. Bonilla. There's a lot more to be done in the research
area, based on this long list of questions that remain.
Dr. Katz. There is a lot of research to be done.

ergonomics products

Mr. Bonilla. I'd like to refer now to a recent Washington
Post article on this subject. There's been a lot of conflicting
information about so-called ergonomic products. You've probably
seen some of those on the market that claim to do one thing,
but you're not really sure what they can do when you wind up
buying them and putting them in your home or office. Last
week's Washington Post had an article about how confusing this
information is for consumers. In particular, there seems to be
a debate about keyboard design.
What, in your view, Dr. Katz, is the state of the art
regarding knowledge about the optimal design for a keyboard
that would minimize an individual's risk of developing
repetitive motion complaints, such as carpal tunnel syndrome?
Are there other equally or more important factors that could
contribute to that risk? If so, what are they, and can we
distinguish among these causes as to their relative
contribution to a specific individual's complaint?
Dr. Katz. That's a difficult question for me to answer,
because I'm not an expert in that particular area. In terms of
the design of keyboards, I would have to leave that to the
ergonomics experts.
Mr. Bonilla. And there are ergonomic experts out there,
Doctor?
Dr. Katz. There are said to be ergonomics experts.

musculoskeletal disorders

Mr. Bonilla. Who are some of the leading researchers in the
field of MSDs who have received grants from NIAMS, Dr. Katz,
and how are they selected?
Dr. Katz. They're selected through a peer review process.
Some of our experts on musculoskeletal disorders, when it comes
to repetitive motion disorders, are supported through our
centers program. We have a centers program in Boston, that is,
at Harvard Medical School. Jeffrey Katz--no relationship--has a
part of that project, and he is looking at the carpal tunnel
syndrome. He's looking at all aspects of carpal tunnel
syndrome, looking at outcomes of treatment, and also looking at
studying the person's attitude towards work in terms of its
effect on return to work from carpal tunnel syndrome.
Other people around the country are also working on it.
There are actually in some of our other centers, people who are
looking at various aspects of carpal tunnel syndrome on a
molecular basis. The names specifically, actually I can give
you, if you give me one second. We do have a portfolio in that
area.
Mr. Bonilla. I only have about 10 minutes to go, Mr.
Chairman--I'm kidding. [Laughter.]
Dr. Katz. Let me give you a sense of what the people are
doing in this area. Dr. Arthur Veis is an expert in the
structure and assembly of collagen molecules and fibrils, and
the project is being supported to understand the basic events
involved in the formation of the supporting tissue in the body.
Dr. Evan Flatow is supported on a career award to study the
pathobiology of rotator cuff tendon injury. In other words, all
of the injury of the rotator cuff is in the upper extremity,
and all of these--tendonitis, rotator cuff injury--are thought
to be related to this area.
Arthur Olenick is an investigator at one of our centers. He
is looking at the long-term goals of describing the
epidemiology of musculoskeletal disorders in the State of
Michigan,characterizing the resulting disability and to assess
the role of various risk factors, that is, gender, age, source of
injury, industry, occupation, etc. Dr. Julia Fawcett is looking at the
disability of carpal tunnel syndrome. She's an investigator at one of
our centers as well.
I've already talked about the studies at Harvard, the
outcomes of therapy for carpal tunnel syndrome, which
investigators are looking at as a part of a centers project--
Drs. Vogel, Burke, Baines, and there are many others whom we
are supporting through various mechanisms in the Institute.
Now, how we make those decisions was the last part of your
question. We make those decisions through the peer review
process. Many of these grants are for research project grants
which are submitted and reviewed by our Division of Research
Grants study sections. They're given a high priority score and
are consequently funded, because we think these are important
areas of research to pursue.
Mr. Bonilla. What studies does NIAMS currently have
underway that could shed light on the issue of the cause or
prevention of RMIs or MSDs, and when will those studies be
completed? If no studies are underway, are there plans to
initiate such studies? Is this an important avenue of research
for NIAMS, or should it be, if it's not currently?
Dr. Katz. Well, it is an important area, and that's the
reason why we're putting out this program announcement. If it
were not an important area for study, we wouldn't have
supported and co-sponsored the meeting in 1994 on repetitive
motion disorders. So we view it as a very important component
of our work. We have recently hired an orthopedic surgeon who
is in charge of our orthopedics program. And he interacts with
NIOSH in terms of letting them know what we are doing in the
way of this type of research.

ergonomic standards

Mr. Bonilla. Thank you. As you know, Dr. Katz, I'm asking a
lot of questions about this, because it's a question that we
all have about ergonomics standards. I am willing to consider
turning the entire issue over to science to look at perhaps
developing some standards for workplaces down the road. My
concern is that we're not at the point yet where science
supports promulgating rules or standards by OSHA or any other
regulatory body. And I just want to make sure that it's the
scientists and the people who are experts at it that are
involved, as opposed to anyone else who just may think they
understand the issue and really don't understand it.
Dr. Katz. I should tell you that my understanding is that
NIOSH has recently done a comprehensive study, what's called a
meta-analysis, in other words, an analysis of many studies. I
have not seen the conclusion of that. But they have done that
in order to assess what is the state of science in terms of the
relationship with ergonomics.
So I look forward to that, and I'm sure that that will be
transmitted to you as well.
Mr. Bonilla. Do you know when that's going to be complete,
or is it already complete?
Dr. Katz. I think it's under review now.
Mr. Bonilla. Okay.
Dr. Katz. I am in contact with Dr. Rosenstock, and she told
me that it was under review now. So it shouldn't be too long.
Mr. Bonilla. Thank you, Dr. Katz.
Dr. Katz. Thank you.

human cloning

Mr. Porter [resuming chair]. Thank you, Mr. Bonilla.
Before I begin with questions for Dr. Katz, I want to ask a
question of Dr. Varmus. I understand, Dr. Varmus, that over on
the Senate side, Senator Frist is going to have Ian Wilmot in
next week to testify from Scotland. I think we're going to be
embroiled in this over a long period of time.
But I want to give you an opportunity to clarify your
remarks yesterday to the Science Committee about human cloning.
Last week, before this subcommittee, you stated you found the
notion of human cloning to be repugnant. You also cautioned
against rapid legislative action before the scientific and
ethical issues involved were thoroughly considered.
From press reports yesterday, you reiterated your concern
about precipitous legislation, but also opened the door to the
possibility there might be some very limited circumstances in
which human cloning would be ethically permissible. You cited
as an example untreatable infertility in couples intent on
having genetically related offspring. I think that particular
circumstance is one that many people would include in your
characterization as being repugnant.
Did the Washington Post accurately report your comments
before the Science Committee, and can you describe more fully
what circumstances you feel might justify human cloning?
Dr. Varmus. Mr. Porter, let me try to outline what I said
and what I intended to say. My personal view is that there is a
very clear case to be made against the use of human cloning for
research purposes. I have an open mind about the possibility
that in the minds of some, that's not myself, but in the minds
of some, there might be a utility for the technology in certain
very limited situations of reproductive incapacity.
I don't presume to make a judgment. I haven't taken a stand
on this. But I do feel that we have time for a debate in which
all sides can be heard to address the issue. As I pointed out
yesterday, my personal bias in situations of profound
infertility is that there are other options, the most obvious
being adoption or in vitro fertilization, in which, for
example, a sperm donor's contribution replaces the contribution
from the parent.
I also think it's very important, as I tried to point out
yesterday, to use this occasion to come to grips with what I
perceive to be an excessive devotion to the idea of the gene,
perhaps an idea that we as scientists, excited about genetics
research, have fostered in public discussions. We ought to be
more concerned with passing on our principles than passing on
our genes.
In the context of the family life, experience that
generates human beings is most importantly carried out. I'm
concerned that our current obsession with genes is diverting us
from the need to focus on the experience and the education and
the instruction that is involved in raising children. That
having been said, some people still desire very strongly to
have what they consider their own children. I sometimes find it
difficult to see my genes in my own children, perhaps because I
haven't spent enough time educating them, I don't know. But the
point is that we need to reflect on some of the historical
precedents here, in two contexts. First, we need to remember
that about 20 years ago or so, when in vitro fertilization was
introduced, there was a high degree of abhorrence of the idea
of test tube babies. And yet in vitro fertilization is now
commonly accepted by virtually everyone as a reasonable course
in situations oflow sperm count or other obstacles to having
children by the most natural process.
I think it's also important to remember these historical
precedents of in vitro fertilization, of gene therapy, and of
recombinant DNA, when considering whether it's appropriate to
proceed to legislation. I worry about legislation in the
context of scientific issues because of the possibility that we
will create laws that are difficult to reverse before we have
had the kind of discussion of other kinds of voluntary or rule-
determined regulation processes that we've achieved regarding
other controversial areas of research, such as gene therapy and
recombinant DNA.

human cloning for transplants

Mr. Porter. Luckily, the founders of our country made our
legislative system so cumbersome that it's very unlikely we
pass anything very quickly in any case.
I was going to follow up with a question, then I'll
recognize you, Mr. Miller.
Dr. Varmus, would there be a situation where you had a need
for a transplant, like bone marrow transplant, where cloning
would ensure that there would be no rejection of the tissue? Is
there any possibility, or would that be a gene that's already
damaged, and you wouldn't want to deal with anyway? I'm not
sure how it would work.
Dr. Varmus. Let me expand on that a little bit. When you
and I discussed these issues last week, I pointed out that the
excitement in the scientific community about the results
reported from Dr. Wilmot's lab are especially exciting because
those experiments tell us that there may be ways to, in a
sense, reprogram the genes. It might be possible, by making use
of what we learn from a deeper study of the observations that
Dr. Wilmot has made, to design tissues required for medical
uses.
So, for example, a patient who needs a bone marrow
transplantation could conceivably, with a deeper understanding
of those rules, receive a transplant in which the nucleus from
some unaffected cell perhaps a skin cell, has been transferred
into some neutral recipient cell under conditions that would
instruct the reconstructed cell to become the cells that would
normally be present in the blood, recreating bone marrow, but
bone marrow in which every cell has the surface antigens of the
recipient. That would be an ideal match.
Mr. Porter. You're creating bone marrow, not an individual?
Dr. Varmus. That's correct. That's point number one. I
don't think anybody would have any reservations about that,
although I could imagine legislation that created a fence
around research that would prevent the use of human DNA, for
example, to do such experiments. That worries me.
The second issue is one that I think many people have
talked about as a possible situation in which human cloning
would be acceptable. I myself have grave reservations, for
reasons I'll mention in a minute. But one could imagine, for
example, parents who had, say, a three-year-old child who had
leukemia. The child might be under treatment, doing all right,
but the parents anticipate a need for a bone marrow
transplantation at some point.
The parents might indeed be trying to have another child,
and they might say, well, why don't we have a child who is
compatible antigenically with the child we already have. In a
sense, the parents might think, we are going to give to our
three-year-old child a twin, three years later, that he
unfortunately did not already have. There are some children
with leukemia who have a twin and have the advantage of
receiving a bone marrow transplant that offers very little risk
to the recipient.
But our child doesn't have such a twin. So let's have one.
That new child will be different in the way it's brought up and
will have different experience. It will be a different child.
We must get beyond the fantasy that it will be an instant new
three-year-old that looks identical to and acts exactly like
the three-year-old the parents already have.
I can imagine that. I think there are some profound issues
raised by that kind of a decision to have children. It creates
an expectation for the marrow donation that requires the
newborn child to be a willing donor. And I think that's the
kind of ethical issue that does need to be discussed.
This is not dramatically different from an ethical issue
that has already been considered, and that is the possibility
of parents having another child who might have a one in four
chance of being a histo-compatible donor to an already living
ill child. It raises the stakes a bit, because now there isn't
the roll of the dice--the child would have a totally compatible
set of genes.
Now, I hasten to add with all this that there are still
many unknowns in cloning, even in animals. The fact that Dolly
is alive has not told us all we need to know about the
efficiency of the process, whether mutations might have
occurred in that famous udder cell used as a donor; whether
changes have occurred in chromosomal structure, particularly at
the ends of chromosomes, that would affect the aging process.
All of those are unknowns, and I think any contemplation of
human cloning, even if there were to be agreed-upon rare
circumstances in which it might be permissible, is still going
to be many, many years off.
Mr. Porter. And we don't yet know, because I understand
that this was one out of 270 some odd attempts, whether this
can be replicated. This may be just something that----
Dr. Varmus. We don't know.
Mr. Porter. We don't know yet.
Dr. Varmus. There could be considerable variation among
species, there may be technical advances that allow it to occur
more efficiently. I think we're still in an extremely early
phase.

position on human cloning

Mr. Porter. Well, we'll call this, your example, a late
twin example.
My last question is, do you know yet what Ian Wilmot will
say when he comes to testify before Senator Frist's committee?
Is his position on human cloning----
Dr. Varmus. I have not discussed it with him, but he is
going to be visiting NIH next week. It turns out that he was
invited by the National Institute of Child Health and Human
Development many months ago, based on his earlier work, to come
and speak at the NIH next Thursday.
Mr. Porter. I bet there won't be much interest in that.
[Laughter.]
Dr. Varmus. Well, we decided to move it to a smaller room.
[Laughter.]
But I look forward to meeting him then.
Mr. Porter. Thank you, Dr. Varmus.
I yield to you, Mr. Miller.

president's actions on human cloning

Mr. Miller. What was the President's Executive Order, what
did he do the other day?
Dr. Varmus. The President did two things. First, he issued
an executive order that would make it impermissible touse
Federal funds for human cloning. Now, as you and I know, the NIH is
forbidden to use Federal funds for research that leads to the creation
of human embryos including research that might lead to human cloning.
So we could not do any research in this area.
But the President and his advisors felt it was appropriate
to make the ban very clear, applying to all agencies, and
applying to any circumstance of human cloning, research or not,
to reassure the public. I think this was a fair thing to do.
I don't believe the Federal Government is or would be
likely to support human cloning through any vehicle other than
our Department, but I think it was definitely a reasonable
thing to do, to provide public confidence that the Government
is holding things in abeyance until the National Bioethics
Advisory Commission can have a full debate on the issues.
The other thing that he did was to ask for a voluntary
moratorium on human cloning and research related to or
involving human cloning in the private sector. I believe that
the important issue was, again, to reassure the public that the
biotechnology industry is not busily working in these areas.
In fact, as you have no doubt observed, the biotechnology
industry was highly supportive of the President's action,
because it provides them an opportunity to say publicly that
they are not even interested in doing such research, that their
concerns are elsewhere. I don't think they wanted to be tainted
with any public perception that they approve human cloning.
Mr. Miller. What input did you or Dr. Collins have in those
decisions?
Dr. Varmus. We were involved in the discussions about how
they should be carried out. And as you know, I was with the
President, as was Secretary Shalala and Harold Shapiro from the
National Bioethics Advisory Commission and Jack Gibbons from
the Office of Science and Technology.
Mr. Miller. Were you called in after the decision was made?
Dr. Varmus. We were consulted throughout the few days
before.
Mr. Miller. I saw in the Post this morning, a front page
article, a news analysis article, that mentions this. But it
mentions it from a political perspective, which raises the
question that, and Dick Morris even makes a comment, in the
article, that the President is trying to do little things to
distract the media attention away from his other problems, and
doing things like he did in the campaign about talking about
school uniforms.
And Dick Morris' quote in this article is, well, ``the
headline in the article is, `President forbids human cloning,'
rather than what took place at the White House in the Lincoln
Bedroom.'' It bothers him that decisions are being made for
political reasons like this rather than the well thought-out
type of policy decisions. That's what the inference of that
article was, and I just raise that question.
Dr. Varmus. I think there's good reason not to go along
with that. I think, first of all, that by making
pronouncements, the President appears before the press and
opens himself to questions, some of which were about his
pronouncement, and some which were about the other policy
matters that you mentioned. So I think if he wanted to remove
himself----
Mr. Miller. I don't mean to put you in the political
predicament, it raises the question that we want to have good
policy on these types of things.
Dr. Varmus. The President has a serious interest in these
issues. He is very concerned about the public reassurance and
the opportunity for his Commission to debate these questions in
an open forum without the threat of pending experiments that
would be repugnant to the public.

professional judgment budget

Mr. Porter. Dr. Katz, question number one----
Dr. Katz. Let's see, where were we? [Laughter.]
Mr. Porter. I figured I could just say question one and
you'd know what I was talking about.
Dr. Katz. I got it.
Mr. Porter. Professional judgment budget, or----
Dr. Katz. I got it. Well, of course we do fund the very
best that we think will yield important information in all
areas. And we're constantly reprioritizing in terms of funding
the best. We have many exciting and outstanding research
proposals that we cannot fund. And our professional judgment
budget would get us to the NIH average in terms of the success
rate, with an amount of $280 million, which reflects a 9
percent increase in our budget.
Mr. Porter. And that is what Dennis Williams knocked down?
[Laughter.]
Dr. Katz. No, I wouldn't say that. I would say that
discussions go on frequently with Dr. Varmus in terms of
discussing our budget, our needs, the areas of emphasis that he
talked about in his opening statement, that all of the
Institute directors are addressing. They are broad areas of
emphasis in which the budget is organized.
Mr. Porter. My real question is, what was submitted by NIH
to the Department for your Institute? Do you know that?
Dr. Katz. I don't.
Dr. Varmus. There was no submission by Institute, just one
overall number.
Mr. Porter. Just one number for NIH.
Dr. Varmus. Initially.

antibiotic treatment

Mr. Porter. All right. You mentioned doxycycline. It is
destructive of what tissue or cells?
Dr. Katz. Doxycycline is an antibiotic. So it destroys
bacteria. But many of these chemicals have other effects. And
it was shown some years ago that doxycycline has an effect on
inhibiting certain types of enzymes, which are called
collagenases. And that's the reason for the interest in
doxycycline in osteoarthritis. One of the pathways to
destruction of cartilage is thought to be due to enzymatic
degradation of the cartilage cells, and doxycycline is thought
to block this process. And it's been shown to be effective in a
form of osteoarthritis in dogs. As a consequence, there was a
proposal sent to us--a research project grant--which received a
very high priority score, and that's why we funded it.
Mr. Porter. And that is going on right now?
Dr. Katz. That is going on right now.
Mr. Porter. Dr. Katz, you weren't here then, but 15 years
ago, almost before this subcommittee, was a Dr. Brown of
Virginia who was doing exactly that. I don't know if
doxycycline was the antibiotic of choice, but he was providing
treatment to his patients, and we had his patients in here to
testify, telling us that he had miraculously cured them after
years of suffering.
Dr. Katz. I think that was a different form of arthritis.
Mr. Porter. Different form?
Dr. Katz. That was for rheumatoid arthritis. And the basis
of that treatment, as I understand it, was because it was
thought to be a disease in which bacteria or some type of
organism which was sensitive to an antibiotic, was part of the
causative agent. So it's a completely different form of
arthritis. And in fact, the Institute was asked a few years ago
to do a study using doxycycline in rheumatoid arthritis. And
such studies are going on right now. I will report those
results to you when they come out.
In rheumatoid arthritis, there are two main studies. One is
in North Carolina, done by Dr. St. Clair, and the other is done
within the clinical research center at NIH.
Mr. Porter. My recollection is that the issue revolving
around those studies is the question of time. Because if I
remember, Dr. Brown's patients and Dr. Brown, who testified one
year before the subcommittee, this was a long-term kind of
treatment that lasted four or five years. Is your clinical
trial lasting that long a time?
Dr. Katz. No. The study that's going on now, the IV study,
is a double-blinded study that's going on for 12 week periods.
But there was another study that was requested by the Congress
about seven years ago. This was a multicenter study using
antibiotics, again in rheumatoid arthritis, different disease
than osteoarthritis, to test an antibiotic for rheumatoid
arthritis. And this is what we call the MIRA study, that is,
minocycline in rheumatoid arthritis. That was a multicenter
study that's been completed. It showed a very marginal benefit
of minocycline, long-term, in patients with rheumatoid
arthritis.
Mr. Porter. But now you're finding that the antibiotics may
work very well in osteoarthritis?
Dr. Katz. In osteoarthritis, in the dog model, they have
been shown to be effective. And we have no clue as to whether
it will be, but we thought it was a very good scientific
opportunity to pursue, since it does affect so many people and
there is a good basis for those studies.
Mr. Porter. Antibiotics are being tested as a treatment for
both osteoporosis and osteoarthritis. Is there a common
mechanism at work? Is it thought the antibiotics somehow
inhibit the substances that degrade both bone and cartilage?
Dr. Katz. I'm not familiar with the antibiotic studies in
osteoporosis.
Mr. Porter. It's over in the Aging Institute, my staff
tells me.
Dr. Katz. There is a study that was just started in
osteoporosis, because there was a preliminary finding that was
thought to be beneficial in terms of building up bone. So they
are pursuing that. And I can't tell you which antibiotic it is.

osteoporosis

Mr. Porter. We've heard testimony about osteoporosis,
largely in the context of it being a women's disease. Your
justification indicates that men also suffer from osteoporosis,
and that one-third of all men will be affected by the age of
75.
Given the focus on estrogen as a treatment for osteoporosis
in women, will entirely different treatment regimens be needed
to be developed for male patients, or can estrogen be used
there, too, and if so, what are the side effects?
Dr. Katz. We know that history tells us that estrogens have
been used in men, in older men, for prostate cancer. This was
years ago. And there were many side effects from the estrogens.
What we've done with this, through the Federal Working
Group on Bone Diseases, which includes many of our NIH
Institutes as well as 10 other Federal agencies, is we have put
out a program announcement to study osteoporosis in men,
because they do represent 20 percent of people who are
affected. Men are about a decade or a decade and a half behind
women in terms of osteoporosis. And through studies like those
I talked about with regard to the role of estrogen in blocking
osteoclasts, or in causing osteoclast death, we're looking for
other agents that may be used that can simulate those findings,
that can be used in men without having the other side effects
that one gets, the feminization, etc.
Also, there are forms of estrogen now that are being
developed that have specificity for certain types of tissue. In
other words, as opposed to current estrogens, which have an
effect on all tissues, there are estrogens that are being
developed that will specifically bind to receptors in bone, for
example, rather than in breast tissue. And that's the goal for
the future, in terms of developing more specific therapies.
They may be called estrogens now, in the future they may be
called something else.
Mr. Porter. Does Shannon Lucid, the space shuttle
astronaut, provide any lessons for osteoporosis researchers as
her accelerated bone loss in space is analyzed and treated?
Dr. Katz. I think she represents what many of the
astronauts have taught us in terms of bone, in terms of
weightlessness and loss of gravity, and in terms of the
importance of load on bone formation. We have had cooperation
with NASA for a long time in terms of co-sponsoring studies
that look at just this question of bone loss and
weightlessness. There are many studies now that have shown that
certain types of exercise are very helpful in terms of building
the integrity of bone.
And I believe----
Mr. Porter. Even at an advanced age?
Dr. Katz. Yes. And I believe that she, as a consequence of
some of these studies, rigorously exercised while she was in
space, using some of these load concepts that have been
developed through NASA and through the NIAMS and through other
Institutes' research in this area.
Mr. Porter. Mr. Miller, I yield to you.
Mr. Miller. No questions, Mr. Chairman.
Mr. Porter. Mrs. Lowey.

osteoporosis

Mrs. Lowey. Thank you, Mr. Chairman. And I thank you, Dr.
Katz, for appearing before us.
I'd like to follow up on the osteoporosis question. We're
aware that, as has been discussed, that osteoporosis is the
leading cause of bone fractures in older women and older people
in general. And while hormone replacement therapies can help
women to gain bone mass and thereby decrease their risk for
fractures, there is evidence that for some women, estrogen
supplements can unfortunately increase their risk for breast
cancer.
What has your Institute learned that would help women to
prevent osteoporosis so they could avoid the difficult choice
about whether or not to take estrogen supplements, at least
until more evidence about the risks of estrogen are known and
perhaps you could also discuss any work that's being done
concerning estrogen replacement therapy.
I think what we find too often is that there are a great
many questions involved, and women are puzzled because of the
inadequate research concerning estrogen replacement therapy.
And if there's a history of breast cancer in their family, this
is not the direction that most choose to pursue.
Dr. Katz. You've gotten to the real issue of the concern
with regard to estrogen and osteoporosis. But there are other
means that women and men have to reverse susceptibility to
osteoporotic fractures. A recent study reported from Dr. Recker
and Dr. Haney from Creighton University in Nebraska showed that
if one adheres to an adequate dosage of calcium in patients who
have already had one fracture, once you have one vertebral
fracture, you're very likely to get another one within a very
short amount of time--a calcium dosage of 1,500 milligrams per
day would prevent a second fracture in a significant number of
them.
So that's one issue that's obviously being looked at.
Another issue was one that I addressed in my opening statement,
which is the interesting and important findings that open up
many scientific opportunities with regard to understanding how
estrogens work. Because once one understands how they work, one
can try to devise other chemicals that will do the same thing.
Estrogens recently have been demonstrated to cause death of
the cells that actually break down bone. One has a constant
breakdown and buildup of bone. If you can kill off the cells
that are breaking down the bone and continue building up the
bones, you're not going to have as much osteoporosis as long as
the integrity of the bone is still good.
And what these scientists have found is that estrogen will
kill off these osteoclasts, which are the bone degrading cells.
This provides us with an opportunity to look for other
chemicals that will interfere with the osteoclast formation and
get the beneficial effect of blocking the degradation of bone
while continuing to get the buildup.
So there are estrogens that are actually being developed
that have been reported to have a specific effect on bone as an
end organ as opposed to breast tissue. So all estrogen
receptors are not exactly the same.
There was a very good review in the New York Times this
week in the science section, showing what companies are
actually trying to do in terms of looking specifically at end
organ effects of estrogens.

stress and arthritis

Mrs. Lowey. Thank you. In this month's publication of the
Arthritis Foundation, there is an article about the role of
stress in arthritis. It points out that while many sufferers of
arthritis believe stress plays a key role in their disease,
researchers have had a difficult time substantiating a link,
because stress is a difficult thing to measure. If stress is
something that people can control, or at least try to control.
Dr. Katz, can you please comment on whether or not you
think that more research should be done on the link between
stress and arthritis, either with regard to preventing the
disease or treating the symptoms?
Dr. Katz. I would say there have been many studies that
have tried to address the issue of stress. Often it's the
control group that's the difficult group to really compare the
tested group to. It is clear, though, in rheumatoid arthritis
in particular, that there is a certain empowerment of patients
if they take control of their disease. There are studies that
we have supported through educational programs, particularly
the ones at Stanford from Kate Lorig, that have shown that
patients who take charge and become more involved in their
disease--obviously you can't do this if you're depressed with
stress, but you can in other circumstances--have a much better
outlook and a much better prognosis in terms of dealing with
their rheumatoid arthritis.
So clearly, one can, in a positive way, say there is
something that one can do about one's symptoms and dysfunction
from arthritis by taking charge of it.
Mrs. Lowey. You're talking about dealing with the symptoms?
Dr. Katz. Right.
Mrs. Lowey. You're not relating it to the actual----
Dr. Katz. To the actual cause and effect. Right.
Mrs. Lowey. I know there are people that have worked with
hypnotherapy and other forms of stress reduction, because they
feel its impact. But again, you're talking about the symptoms?
Dr. Katz. Right.

gender and autoimmunity

Mrs. Lowey. You're not talking about the actual illness.
We know that women are more likely than men to develop
lupus and other autoimmune diseases. In your budget
justification, you note that your Institute joined with several
other Institutes at NIH to issue a program announcement
inviting applications for basic research on the ways in which
gender influences the development of autoimmune disease.
What is the status of this endeavor? Did you receive many
applications? How much money will be allocated to this
research, and when will you begin to have research findings?
Dr. Katz. As a consequence of a conference that was
sponsored by several groups at the NIH, including the NIAID,
the Office of Research on Women's Health, the Office of
Research on Minority Health and the NIAMS, there was a program
announcement in May of 1996, for soliciting studies on gender
and autoimmunity. So far, we have not gotten much in the way of
response to that program announcement. But we look forward to
it. As you know, a program announcement is in existence for
quite some time, and to get the community interested in looking
at that, sometimes it takes some time.
Mrs. Lowey. Thank you, Dr. Katz.
Dr. Katz. Thank you.
Mrs. Lowey. Thank you, Mr. Chairman.

cartilage repair

Mr. Porter. Thank you, Mrs. Lowey.
Dr. Katz, last month research findings were reported from
the Mayo Clinic of a technique called biological resurfacing
that successfully restored joint cartilage damaged in injuries,
thus delaying the need for joint replacement. How wide an
applicability does this technique have?
Dr. Katz. Those studies from the Mayo Clinic are supported
by our Institute, and are really just starting. There are many
studies that we are supporting that are addressing this
question. Cartilage is a tissue that when it's destroyed, it's
not replenished like some of the other tissues, like liver
that's replenished, like skin that's replenished. Once the
cartilage is gone, it's gone.
So we are supporting many studies that are looking to
replenish the cartilage. There is a study from San Diego by Dr.
Coutts who is looking at rib perichondrium. These are rabbit
studies, as are the Mayo Clinic studies. They're taking the
very superficial parts of a rib, the chondrocites, which are
part of the cartilage, and they are transplanting them into
specific injuries that are made in rabbits in the joints.
The same is being done by Dr. Driscoll, I believe it is, at
the Mayo Clinic, who is looking at the bone periosteum, that is
the most superficial layer of bone. He thinks these cells may
be precursors to cartilage cells. But these types of studies
are really in their early stages, and I would say that the
reason we are supporting them is because they offer a high
likelihood of success in terms of resurfacing of cartilage.

breast implants and autoimmune diseases

Mr. Porter. Dr. Katz, the debate about the dangers of
breast implants has been heated. Women who feel they have been
injured by the implants often cite symptoms that fall within
the jurisdiction of your Institute, autoimmune diseases such as
lupus and scleroderma. On the other hand, the scientific
evidence on breast implants is sometimes derided as junk
science.
What does your review of the evidence lead you to believe
about the health impacts of breast implants?
Dr. Katz. Well, there are several studies that have
addressed this head-on. And our conclusion from all these
studies is that there is no causal relationship between
implants and well-defined rheumatic disease, that is,
rheumatoid arthritis, lupus erythematosus or scleroderma.
Despite that, there is a lingering doubt as to whether
there is an association between silicone breast implants and an
atypical or an undifferentiated form of rheumatic disease.
Because of our concern about this lingering doubt, we have
organized a round table discussion on April 17th, which is
going to be chaired and paneled by people who have had no
particular stance one way or the other. They are going to hear
from the community of scientists and clinicians about this
undifferentiated rheumatic disease and help us determine if
there is anything that we can do to further elucidate whether
there is an association.
So we are addressing that issue head-on--the lingering
doubt of atypical, undifferentiated or ill-defined rheumatic
disease and whether it can in fact be defined. We utilize
people from our Advisory Council, Dr. Arend, for example; from
our Advisory Council, and people from the community who are
good scientists, who are good clinicians, who can assess
information for us as a panel.

gulf war syndrome

Mr. Porter. Dr. Katz, we've discussed with the
Environmental Health Sciences Institute the general scientific
evidence related to Gulf War Syndrome. Has your Institute done
any work on the particular symptoms of joint stiffness and pain
and skin rashes to determine whether they are caused by
exposures in the Gulf War?
Dr. Katz. We have not addressed any studies on the Gulf War
syndrome specifically. But many of the symptoms that are
defined in the Gulf War syndrome, that is, cognitive
disabilities, specific types of muscle and joint pains, and
skin rashes, are a constant concern to us, because these cover
many of the symptoms that we are concerned with within the
Institute.
And there is a disease, for instance, fibromyalgia, which
is a now well-defined disease that has many of the symptoms
that relate to some of the symptoms of Gulf War syndrome. And I
think that from our activities in fibromyalgia--for example,
from our workshop, from the support of many studies in
fibromyalgia, from our recently held conference that I talked
about in my Congressional justification statement on the
neuroscience and endocrinology of fibromyalgia syndrome--
something may be learned about some of these symptoms that are
said to be related to the Gulf War syndrome.
So the symptoms, we are addressing those symptoms.

depression and osteoporosis

Mr. Porter. Representative Lowey raised the question of
stress. I've been interested in the ways that stress and
emotional states may affect physical health as well. But even I
wouldn't have expected the research finding from the Mental
Health Institute linking depression to a significantreduction
in bone mass in women. The average age of the women in the study was
41. But they had bone loss equal to that of a 70 year old.
What are the scientific explanations for why depression
might lead to bone loss?
Dr. Katz. That's a very interesting question. I think even
in that paper, there were some speculations, but there was no
cause and effect relationship. That is, there are two findings
that may be true, true and unrelated, or they may be true, true
and related. If they are related, theoretically they could be
due to some neuroendocrine problem, or they could be due to the
fact that people are not taking care of themselves in terms of
being depressed--not eating properly. But that would just be
all speculation on my part.
Mr. Porter. Are you doing any studies in this area?
Dr. Katz. We are not.

central nervous system lupus

Mr. Porter. Two-thirds of patients with lupus are now
thought to suffer some sort of brain or behavioral problems as
result of the disease, in addition to the skin and joint
ailments we more commonly associate with lupus. How does this
autoimmune disorder affect the brain, and do physicians know
how to treat this aspect of the disease?
Dr. Katz. That's a very important question. I think that
central nervous system lupus has been known for quite some
time. In fact, I should tell you that one of the first patients
whom I ever saw in the clinic had lupus erythematosus, and she
had central nervous system lupus with coma at times.
The mechanism by which the brain is affected is not known.
It's undoubtedly related to the inflammation that occurs
elsewhere, because virtually every organ system is involved in
lupus. Organs can be involved as a target of autoimmunity, in
other words, the cells of the body are attacking itself; this
could happen in the kidney, in the brain, in the lungs, etc.
So the mechanism of injury is presumably a similar
mechanism as is found in other organ systems. I know that the
American College of Rheumatology has discussed with our program
director convening a conference that will address how to
diagnose CNS lupus more specifically, number one, and number
two, about a year and a half ago, we co-sponsored a meeting of
the New York Academy of Sciences that directly addressed
central nervous system lupus to direct attention by
investigators to this important area.

fibrodysplasia ossificans progressiva

Mr. Porter. Dr. Katz, Science magazine reported last August
on the identification of a signalling protein that erroneously
signals the formation of bone, causing a rare disease which
converts soft connective tissues into bone, fusing the skeleton
and leading to complete immobilization. There is apparently
hope that a therapy may some day be developed to block the
production of this protein. Beyond the small population of
people affected with this disease, could this finding have
implications in the opposite direction for those facing
deterioration of bone through osteoporosis or other diseases?
Dr. Katz. I think that's a very good example of how
studying a very, very rare disease, fibrodysplasia ossificans
progressiva--is that okay? [Laughter.]
It's a disease that is studied by Dr. Kaplan at the
University of Pennsylvania; he has really been the champion of
the small number of patients who have this disease. And much of
his research is supported by our Institute. But all of his
research for years has had a focus on these patients, although
he has not been able to directly develop any sorts of
mechanisms related to this disease.
And it's because of his long-term interest in studying
what's called the bone morphogenetic proteins, that is,
proteins that help produce bone, that he realized that in these
patients, wherever they have inflammation, wherever these
lymphocytes go to an inflamed area, the lymphocytes start
producing bone.
So understanding the mechanism for these patients, that's
number one important, number two important is the potential of
interfering with these bone morphogenetic proteins that are
produced by T cells in areas of inflammation for these
patients. But then as you say, one would like to convert these
findings to some way of building bone.
We know that the immune system and the blood system have a
lot to do with bone, in terms of the precursors of bone
producing cells found in the bone marrow.
And in this regard, our Institute is sponsoring a workshop
this summer on bone and the hematopoietic and the immune
systems, to look at these particular points of the interaction
between T cells and other cells of the immune system and of the
bone system, and of the bone marrow with bone.
So Dr. Kaplan's discovery is a very important advance in a
very rare disease. It could have wide application.

collaborative research

Mr. Porter. Perhaps more than most, you seem to coordinate
with other Institutes on a whole host of disease areas. Allergy
for autoimmune diseases, Cancer for skin cancer, Aging for
osteoporosis, NIDDK for estrogen replacement, for example. When
grant applications are received in these disease areas, how do
you decide which Institute will fund them?
Dr. Katz. The application is sent to the Division of
Research Grants, which has well-defined criteria as to which
Institute has a primary and which Institute has a secondary or
tertiary interest in that particular area. So for example, when
it comes to bone formation, in terms of NIDDK and NIAMS, when
it involves endocrine factors like parathyroid hormone, usually
NIDDK is given a primary designation for that type of research.
When it comes to estrogen, we are often given the primary,
because that is our particular focus. There are many institutes
that have an interest in bone--The Dental Institute, Child
Health--for example, many Institutes have an interest. And
there is a Division of Research Grants guideline which the
primary reviewer looks at and then makes the designation. Our
program people will then look at that designation, if there's
some sort of a mistake or controversy, then it is discussed.
To the investigator this process is transparent; the
investigator really doesn't care who funds that application, as
long as it's funded. So it does make it transparent to the
investigator.
Mr. Porter. How often do you co-fund projects with other
Institutes and how much funding do they contribute to
activities that are part of your Institute's mission?
Dr. Katz. We do a lot of that. In the fiscal year 1996,
there was almost $2.5 million co-funded. And in the same year,
we received in reimbursements from various Institutes and
various offices within the Office of the Director about $3.8
million. And this type of activity goes on because ofthe
interactions between program staff and various offices.
So for example, the Office of Research on Minority Health,
John Ruffin's office, or the Office of Research on Women's
Health, Vivian Pinn's office, we have a lot of interaction with
them. They don't have authority to directly pay applications.
There are many applications that we receive, in terms of areas
of research on women's health and on minority health that they
are interested in and we are interested in, so they will co-
fund many of those applications.
Our total co-funding for 1996 was over $6 million. And this
is really how we can work together, number one, and also make
the dollars go much farther.
Mr. Porter. Dr. Katz, you have answered all of our
questions very well and forthrightly. We appreciate your
testimony this morning. We particularly appreciate the
excellent job you are doing at your Institute. And thank you
very much for your appearance here.
Dr. Katz. Thank you very much.
Mr. Porter. Thank you, sir.
The subcommittee will stand in recess.
[The following questions were submitted to be answered for
the record.]

[Pages 1517 - 1572--The official Committee record contains additional material here.]

----------

Thursday, March 6, 1997.

NATIONAL CENTER FOR RESEARCH RESOURCES

WITNESSES

DR. JUDITH L. VAITUKAITIS, DIRECTOR
DR. LOUISE E. RAMM, DEPUTY DIRECTOR
DR. DOV JARON, ASSOCIATE DIRECTOR FOR BIOMEDICAL TECHNOLOGY
ANNE E. SUMMERS, BUDGET OFFICER
DR. HAROLD VARMUS, M.D., DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

Mr. Porter. The subcommittee will come to order.
We are pleased to welcome Dr. Judith Vaitukaitis, Director
of the National Center for Research Resources, and we apologize
to you for all these votes, but there isn't much we can do
about them.
I am able to stay until 12:30, and we'll just do our best
to get as far as we can.
Dr. Vaitukaitis. Certainly.
For the record, I will submit my opening statement----
Mr. Porter. I think I would prefer hearing your oral
summary, at least, if you would like to do that.

Introduction of Witnesses

Dr. Vaitukaitis. Okay, fine.
Before I do that, I would like to introduce Dr. Dov Jaron,
farthest down to my left, who is the Associate Director for
Biomedical Technology; to my immediate left is Anne Summers,
our Budget Officer; on my immediate right is Dr. Louise Ramm,
who is our Deputy Director; and, of course, Dr. Varmus, and Mr.
Williams from the Department.

Opening Statement

Mr. Chairman, it is a pleasure to appear before you today
on behalf of the National Center for Research Resources in
support of the fiscal year 1998 budget. NCRR has a unique
responsibility for biomedical research infrastructure at the
National Institutes of Health. That infrastructure can be
compared to a great locomotive that transports passengers--in
this case scientists, who explore disease and its remedies--
toward ever-changing destinations. Investigators depend on NCRR
to create, develop, and provide the ``engine'' or
infrastructure of modern science.
In 1998, NCRR's programs will continue to foster
development and access to critical research resources and tools
ranging from those for clinical research, animals,
repositories, and high-end biomedical technologies. In
addition, NCRR will develop and continue an initiative that
will focus on understanding the structure and function of the
brain and its dynamic changes with time, the fourth dimension.
That effort will lead to improved knowledge about
neurodegenerative diseases, such as Parkinson's and
Alzheimer's, as well as many others.
Another initiative will focus on development of innovative
software and techniques for use with high performance computers
and telecommunications facilities to increase the number of
biomedical technology resources and their applications that can
be remotely accessed by investigators across the country over
the next generation of the Internet. Magnetic resonance imaging
resources and other imaging and modelling resources essential
for structural biology are candidates for that kind of
approach.
In conjunction with the Regional Primate Research Centers,
investigators will focus on the development of novelvaccines
for AIDS. Studies that may pave the way for developing vaccines against
HIV in humans were recently reported by scientists at the NCRR-
supported New England Regional Primate Research Center. Investigations
with rhesus monkeys showed that vaccine protection against intravenous
challenge with simian immunodeficiency virus, similar to its human
counterpart, could be attained with live attenuated vaccine from which
certain viral genes had been deleted. These and other related efforts
will be extended to help identify an effective vaccine for HIV.
There are several other priorities that are outlined in our
justification and in our longer opening statement.
Now, Mr. Chairman, the fiscal year 1998 President's budget
request for NCRR is $333,868,000. I would be happy to answer
any questions you may have.
[The opening statement follows:]

[Pages 1575 - 1578--The official Committee record contains additional material here.]

use of animals in research

Mr. Porter. Thank you, Dr. Vaitukaitis.
Contrary to the expectations of several years ago, will the
use of vertebrate animals in research stay constant, or
increase, because of genome research with its emphasis on
knockout mice?
Dr. Vaitukaitis. The use of transgenic and knockout mice
has increased markedly over the past several years with the
advent of that technology. The number of animals being used in
research, based on USDA data, has stayed relatively level or
decreased somewhat. The mice that are being used are much more
complex and much more costly to develop, and are used to
address specific questions that could not be addressed with
other forms of animal models. So with the mouse models and
other invertebrate and vertebrate models, the total use of all
animals in research will probably continue to decline somewhat.
The use of primates in research has been declining for the past
several years because of the marked cost of holding these
animals for investigators in specialized facilities.

chimpanzees in research

Mr. Porter. That's my next question. We have been
approached by groups who have developed draft legislation which
they believe will resolve the problem of the long-term care of
research chimpanzees who are no longer being used in research,
but who have a life span of as much as 50 years. We understand
that the National Research Council will soon issue a report on
the subject.
Do you have some idea of what they will recommend? And when
do you expect NIH to develop a response to the report?
Dr. Vaitukaitis. To answer the last question first, we are
expecting the report from the National Research Council later
this month. I will have to take a look at the scope of that
report before we can know the timeframe it would take to
develop a response.
Chimpanzees in research is a complex issue, because in the
wild there are only about 125,000 to 150,000 chimps, and in the
U.S. there are about 2,100 chimps; of those, 400 are in zoos,
and the remainder are used for biomedical research. In 1975,
the U.S. Government signed an international treaty prohibiting
the importation of chimpanzees, so consequently, since 1976,
there have been no imported chimps.
When the AIDS epidemic--or pandemic--raised its head in the
1980s, the National Academy of Sciences did a study looking at
the resource needs for addressing that whole area of research,
and one of the recommendations from the National Academy was to
provide chimpanzees to investigators for research, noting that
the number of chimpanzees available was restricted.
Consequently, the Division of Research Resources, a predecessor
organization of NCRR, was directed to start a chimpanzee
breeding program. Currently we have 538 chimpanzees in that
breeding program. When it was begun, the animal rights people
were concerned that the animals could not reproduce in
captivity, and that their life span would be shortened.
However, they were wrong on both counts. In captivity the
chimpanzees live longer, for over 50 years, and they reproduce
so well that we are now actually giving them contraceptives so
that they will not breed, to try to keep the population that we
have in our chimpanzee program constant.
The cost of supporting these animals averages about $20 per
day, per diem costs, and we maintain this breeding colony in
the southern part of the United States, where costs are more
favorable for that activity. There have been about 115
chimpanzees used for vaccine research over the last several
years, and about 145 or 150 animals used for HIV research.
Now, the ones that have been used for HIV research are
actually being used again for other HIV-related activities;
just because an animal has been infected with HIV does not
necessarily mean that that animal is permanently retired from
research.
So we have to look at this precious pool of animals, and
it's a conundrum in terms of what to do with it. That's why we
sought the advice of the National Research Council on this very
important issue.
Mr. Porter. Does your daily cost of caring for research
chimpanzees--does that compute to a lifetime cost of $300,000
to $400,000, as we've been led to believe?
Dr. Vaitukaitis. Per animal? No. It's roughly, in current
dollars, about $20 per day.
Mr. Porter. They live 50 years, though.
Dr. Vaitukaitis. The animals aren't retired until they are
probably--it would be variable--probably in their 20s and 30s.
So it's the last 15 to 20 years of their life span that they
would need to be supported.
There is an arrangement with the Food and Drug
Administration, the Centers for Disease Control, and the
National Institute of Allergy and Infectious Diseases to
provide what is termed ``lease fees'' or endowments for animals
that are returned to the source for housing the chimpanzee. The
current going price for that is about $55,000 per animal to
assure the retirement of that animal.

chimpanzee retirement

Mr. Porter. We understand that Jane Goodall is in town
right now, and that there's a proposal that she has made to
provide a kind of ``reserve'' for chimpanzees that are no
longer used in research. Have you talked to her and do you know
about this?
Dr. Vaitukaitis. No, I have not recently talked to her, but
I know of her interest in that. That is an issue that the
National Research Council report will address.
As I said, it's a conundrum in terms of what to do with
these animals, since we'll never be able to get these animals
again because they're limited in the wild. We can't import them
from the wild. There is a limited resource in this country, and
the chimpanzee has been an invaluable model for vaccine
development against hepatitis. There may be another virus that
is not currently evidenced, like HIV, that chimpanzees may be
the ideal model for. So we have to figure out ways of making
sure that we have access to those animals if we need them, but
also to keep the cost down and support them in a way that would
be most cost-effective.
Mr. Porter. I guess there are many issues associated with
this. For example, do you put chimpanzees that have been made
HIV-positive back into the wild? What happens to that
population? I can see a lot of very great difficulties in how
you deal with these animals.
Dr. Vaitukaitis. We don't think that the HIV-infected
animals should be placed back in the wild. In fact, it's not
clear that the animals, even those that are not HIV-infected,
could be placed back in the wild, based on studies with other
nonhuman primates.
Mr. Porter. I would imagine there's an issue as to whether
some of these chimpanzees that have been bred and never been in
the wild, what effect that would have upon their existence.
Dr. Vaitukaitis. Absolutely.
Mr. Porter. Do NIH grants for researchers using chimpanzees
include any component for care of the animalsonce the
experiment ends?
Dr. Vaitukaitis. I can't address that specifically. I know
that for the animals used by intramural scientists, funds are
provided for them through the Allergy Institute or the Cancer
Institute, and I know that some of the other animals--about
150--are endowed in this way, but some of these certainly have
been used for extramural research purposes. The funding source
does make provision for retiring the animal to New Mexico State
University or the Coulston Foundation or the Southwest
Foundation, or wherever the animal would be housed.
Mr. Porter. But if there is an NIH grant to an academic
medical center that involves the use of chimpanzees in their
research, you don't have any responsibility for those animals
at all? Or later?
Dr. Vaitukaitis. We at NCRR do not.
Mr. Porter. No? You would only have responsibility for
those used intramurally?
Dr. Vaitukaitis. Currently, in the breeding colonies that
we have, we own none of those animals. However, we feel a moral
obligation to help support those animals, unless the
institutions that are hosting those colonies wish to assume
that responsibility.
This is an area where we need help through the National
Research Council report.
Mr. Porter. So there is no national repository of research
chimpanzees where there is some clear policy affecting all of
them?
Dr. Vaitukaitis. That covers the entire group? No, because
most of the animals are actually owned by the site where they
are hosted, the universities, or by private companies.
Mr. Porter. Exactly. So there is no national policy on what
happens to the chimpanzees after they've finished their
scientific role?
Dr. Vaitukaitis. That's correct.
Mr. Porter. Should there be?
Dr. Vaitukaitis. There probably should be, to be certain
that the animals are treated humanely for the remainder of
their natural lives.

chimpanzee retirement

Mr. Porter. Do you have any knowledge what some of the
academic health centers or research centers do with animals
like these after they have finished their scientific role?
Dr. Vaitukaitis. They just maintain them as best they can.
I know that some of them look to see if there are zoos nearby
that would be willing to take them on, at least on an interim
basis, to help alleviate some of the costs of maintaining these
animals.
Mr. Porter. Because, as you say, they probably have 20 to
30 years of remaining life, and in some cases maybe even much
longer, after the research role is completed, and that's both a
huge cost and a huge responsibility, it seems to me.
Dr. Vaitukaitis. That's absolutely true. Some of these
animals can be reused for other kinds of research studies. Once
they are HIV-infected, they can be used for other HIV studies,
and the other animals could be used for linguistic studies,
other vaccine studies, and other behavioral studies.
Mr. Porter. Can I ask Dr. Varmus--Dr. Varmus, do you think
there ought to be a national policy and something done to
provide a way to take care of research chimpanzees?
Dr. Varmus. We're hoping the NRC report will address that.
Mr. Porter. Do you think they're looking to all the animals
involved--in other words, those all around the country?
Dr. Varmus. That's my assumption. The charge was fairly
broad. We asked them to look at national policy regarding
chimpanzees used for research.
Mr. Porter. Now, how many of the entire population that
you've described are considered surplus now? That is, their
role has been fulfilled?
Dr. Vaitukaitis. We technically don't consider any of them
surplus----
Mr. Porter. Well, that's probably a misuse of the word. I
meant those whose scientific role has been fulfilled----
Dr. Varmus. Retired.
Mr. Porter [continuing]. And they are retired, yes.
Dr. Vaitukaitis. All I can tell you is that there are about
150 animals that have been returned to the source from which
they were leased in the first place. But those animals can
still be reused for other research, HIV research or some other
related research. That would be out of a pool of roughly 1,700
animals in the biomedical research arena.

ncrr strategic plan

Mr. Porter. All right.
You're beginning a process to update your 1994 strategic
plan. If you are doing strategic plans every three years, does
that indicate that the pace of change in your programs which
provide research resources and technologies is so rapid that
you need to rethink your approaches almost constantly?
Dr. Vaitukaitis. Our strategic plan is really a living
document. It has to evolve constantly. The strategic plan we
published in 1994 was such that we have completed--have
implemented, or are in the process of implementing--about 90
percent of the recommendations within that plan. So it takes
about a year and a half or two years to move forward, to update
that plan, in concert with the research community. That's
basically where we are at this point.

transgenic research animals

Mr. Porter. A number of years ago, when the Jackson Lab in
Maine burned, there was great concern that there would be an
inadequate supply of specialized lab mice for NIH grantees.
Since that time there has been an explosive growth in the
development of even more specialized knockout mice, as we
mentioned. Has the supply of all these specialized lab animals
kept up with the demand?
Dr. Vaitukaitis. The demand is increasing steeply. We have
funded Jackson Labs as a shared resource to take on established
knockouts and transgenics that then can be made available to
the general biomedical research community. Through our
construction program we have also provided them substantial
levels of construction money to enhance their facilities. We
have actually had to increase the level of support to Jackson
Labs for this activity, over a very short period of time double
it, and we seem to be holding at a reasonable level right now.
But these technologies are very expensive, and investigators
would prefer that a resource like the Jackson Labs handle the
animals, validate them, and share them with other investigators
around the country. This need is a continuing one, and as the
techniques become even more sophisticated, better mouse and
other models will be developed. There is also a need for other
models that are larger animal models, other than just the mice.

euthanasia of research animals

Mr. Porter. Is euthanasia of so-called ``surplus''
laboratory animals prohibited under animal use guidelines or
Federal policy?
Dr. Vaitukaitis. Euthanasia is permitted for terminal
experiments and for animals that are in pain or in discomfort.
Euthanasia of chimpanzees is something that we do not do
because there are no guidelines for that. It's an endangered
species, and it's a concern of both investigators, as well as
animal rights individuals.

general clinical research centers

Mr. Porter. Dr. Varmus' Advisory Panel on Clinical Research
has made several recommendations about the NIH General Clinical
Research Centers, which are administered by your center. They
suggest that the NIH centers should be more broadly available
to investigators supported by non-NIH funds. What is your
reaction to this proposal?
Dr. Vaitukaitis. This is actually an ongoing activity for
investigators at the General Clinical Research Centers, or
GCRCs. In 1990, the level of support to investigators using the
centers was a little over a billion dollars. Of those funds, 72
percent came from the NIH, and the other sources were about 5
or 6 percent from other Federal agencies, and the remainder of
the funds were from the private sector. Between that time and
1995, in a little over a five-year period, the level of support
to investigators has increased from $1.0 billion to $1.5
billion, and the portion from NIH has stayed relatively the
same, about 70 percent. But the increased funding to
investigators using GCRCs from drug companies has almost
doubled, from about 8 percent to almost 16 or 17 percent. There
is also other funding from the private sector.
It is the standard practice for investigators to get other
sources of funding for pilot studies or other related
activities, in addition to competitive funding from the
National Institutes of Health. That is not a problem for the
GCRCs; that's a standard operating procedure for them.
Mr. Porter. The panel also recommended that General
Clinical Research Centers should shift their orientation more
heavily to outpatient care. I know that the centers have been
moving in this direction the last several years. What share of
their patient load is presently outpatient, and how much more
will they be able to increase that proportion?
Dr. Vaitukaitis. Outpatient-based research is the major
form of research at GCRCs. In fiscal year 1995, for which we
have complete data, there were 270,000 outpatient research
visits as opposed to 82,400 inpatient research days. The rate
of increase of the outpatient visits is almost at a 45 degree
angle, and we suspect that when we get the reports for the last
fiscal year, that those numbers will continue in that same
direction. My guess would be that we will approach about
290,000 to 300,000 outpatient research visits for 1996, and
stay steady in terms of the number of inpatient research days.
Mr. Porter. With the current pressures on clinical research
in academic health centers, are you considering increasing the
number of your General Clinical Research Centers to help
support the clinical research enterprise?
Dr. Vaitukaitis. We are receiving more applications from
institutions that do not currently have GCRCs because of the
impact of managed care and the cost of doing clinical research.
We are trying to accommodate these institutions as best we can
within the framework of what we have available.
Mr. Porter. Do the General Clinical Research Centers enter
into agreements with private industry to conduct clinical
trials or test experimental surgical procedures?
Dr. Vaitukaitis. Yes. We have a category of research in the
GCRCs called ``Category D''--it happens to be D for drug
company-related research. The drug company is responsible for
paying the cost of doing that research, and there is an offset
back to the GCRCs for hosting that research. The research must
be done in such a way that it does not restrict the
investigators reporting their findings through the scholarly
process of reporting in peer review journals.
Mr. Porter. And is this a mechanism that will be used more
broadly to supplement the resources of the centers?
Dr. Vaitukaitis. The Category D days, as well as the
Category C days, in the outpatient units, have been the major
source of third-party funding for GCRCs. In 1995 there was
about $15 million in third-party offsets to operate the GCRCs
and help them keep cost-effective. Of that $15 million, about
$9 million was for Category C, or boarder, patients; $2 million
was from Category B, or research patients who had to be
hospitalized because of their underlying disease, and were also
research patients; and about $4 million was for Category D
patients. Category C and D patients are those that are helping
offset the costs of operating the GCRCs, both on the inpatient
and the outpatient sides.

extramural facilities construction

Mr. Porter. Your budget requests $4 million for extramural
facilities grants. Given the pending backlog of facilities
requests and the small number that can likely be accommodated
with this funding, would it be more cost-effective to allocate
this funding to a program such as the Shared Instrumentation
Program, which could help more institutions?
Dr. Vaitukaitis. The research facility needs are
considerable, and to shift that to Shared Instrumentation, I
think--although $4 million is not that great a level, and it
would make it easier to handle administratively, but
programmatically, there is a huge need for construction out
there. For instance, HBCUs have 40 percent of their research
space whichis not acceptable for modern research. That's been
an unmet need for some time, and those institutions are not covered,
for the most part, by the Centers of Excellence setasides through the
construction program.
A recent report from the National Academy of Sciences has
estimated that there is about $10 billion of research facility
needs that has been pent up across biomedical research. For the
first time in their tracking of that data there has been a 40
percent decrease in research construction carried out by
medical centers, and a 9 percent decrease across all academic
institutions in the country.
We are seeing that there is a need out there, but there are
priorities that we have in putting the NIH budget together in
terms of funding investigators through the research project
grants. So it's a question of priority-setting at this point.
Mr. Porter. What does the President's 1998 budget request
for the facilities construction program operated by the
National Science Foundation?
Dr. Vaitukaitis. The comparable program of the National
Science Foundation contains no funds in their request. There
were none in 1997, and there was $50 million in 1996.

virtual laboratories

Mr. Porter. You have funded some of the first work in
virtual laboratories, that is, the sharing of sophisticated
equipment like electron microscopes and MRI systems, over the
Internet, with digital controls run through a personal
computer. How widely used is this technology in biomedical
research? Is it an eligible item for reimbursement under a
regular grant application?
Dr. Vaitukaitis. There is no charge to investigators for
access over the Internet. This approach to creating virtual
laboratories over the Internet is an evolving process. The
current Internet has difficulty handling information exchange
in real time. It really won't be until the next generation of
Internet, which is 1,000 times faster, that we can really
handle the large amount of information that would go over the
Internet.
This would create access for a wider array of investigators
to high-end technologies over the Internet and provide online
collaborations among individuals from different disciplines by
using this kind of technology. It would be a very cost-
effective way to approach some aspects of research.
Mr. Porter. So it's not today an eligible item for
reimbursement?
Dr. Vaitukaitis. That's correct.

coordination of imaging activities

Mr. Porter. As we discussed with Dr. Varmus last week, some
in the radiology community are interested in the creation of a
separate institute at NIH for diagnostic radiology and imaging,
to draw together these activities which are currently dispersed
throughout the NIH. To what extent does your center already
perform this coordinating role?
Dr. Vaitukaitis. Our role at NIH is to develop high-end
technologies, including those for imaging, which includes a
whole host of technologies for whole animal, human organ, or
molecular structure imaging. We coordinate with the other parts
of NIH to determine the needs of their investigators who are
funded predominantly through the research project grant
mechanism.
Some of the institutes have developed some very specific
imaging technologies that are within the direct mission of
their institute, but our role is to provide the research
infrastructure, and hence our interaction with the other
institutes is one of a collaborative approach in that we are
trying to develop those technologies that investigators who are
funded by the other institutes can gain access to.

regional primate research centers

Mr. Porter. We understand that you have begun a major
evaluation of the NIH-funded network of primate centers. Has
the mission of these centers changed since the original
facilities were funded in the 1960s? Are separate primate
facilities still the most efficient way to conduct this type of
animal research?
Dr. Vaitukaitis. The seven regional primate centers are
really a set of seven national laboratories that are unique.
They would not be able to be reproduced anyplace else in this
country, or anyplace else in this world, for that matter.
As primate-based research has become more precious--there
are fewer investigators doing it because they can't afford to
do it within their own institutions--primate centers host
probably a third of all biomedical research that relates to
primate-based research in this country. We are looking at a way
of more cost-effectively arranging how the primate centers
operate in order to accommodate more investigators, if
possible. The tension on these centers is that they can't
accommodate many more investigators within their current
configuration, and we're trying to see if there's a better way
of doing it.
Mr. Porter. Dr. Vaitukaitis, I think you've answered our
questions. We have a few more for the record.
We very much appreciate your answering the questions, the
good testimony, and the fine job that you're doing. Thank you
very much.
Dr. Vaitukaitis. Thank you.
Mr. Porter. The subcommittee will stand in recess until
1:30 p.m.
[The following questions were submitted to be answered for
the record.]

[Pages 1587 - 1634--The official Committee record contains additional material here.]

----------

Thursday, March 6, 1997.

NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

WITNESSES

DUANE ALEXANDER, M.D., DIRECTOR
DR. YVONNE T. MADDOX, DEPUTY DIRECTOR
DR. FLORENCE P. HASELTINE, DIRECTOR, CENTER FOR POPULATION RESEARCH
BENJAMIN E. FULTON, ASSOCIATE DIRECTOR FOR ADMINISTRATION
DONNA S. CASADY, ACTING BUDGET OFFICER
DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF
HEALTH AND HUMAN SERVICES

Mr. Porter. The subcommittee will come to order.
We have now confirmed a new hearing date for the NIH groups
that were originally scheduled to testify tomorrow morning,
including the Office of AIDS Research, the Office of the
Director and Buildings and Facilities. These will now be heard
on Thursday, March 20, at 10:00 a.m.
This afternoon we are pleased to welcome Dr. Duane
Alexander, the Director of the National Institute of Child
Health and Human Development. Dr. Alexander, it's good to see
you.
Dr. Alexander. Good to be here, Chairman Porter.

Introduction of Witnesses

Mr. Porter. If you will introduce the people that you
brought with you, and then proceed with your statement, please.
Dr. Alexander. Thank you.
Beginning on my left, I'd like to introduce Dr. Florence
Haseltine, the Director of our Center for Population Research;
Mr. Ben Fulton, our Executive Officer; Ms. Donna Casady, our
Budget Officer. To my right, Dr. Yvonne Maddox, our Deputy
Director. And you know Dr. Varmus and Mr. Williams.

Opening Statement

Mr. Chairman, the NICHD is charged by the Congress to
conduct research on maternal and child health, the population
sciences and medical rehabilitation. Last year, during our
appropriations hearings, I reported good news of research
advances and the awarding of the Nobel prize to two of our
long-time grantees. I'll be continuing many of those same
themes this year, as these positive trends continue, including
reduction in the Nation's infant mortality rate and high honors
for NICHD-supported scientists.
Following on the 4 percent decline in infant mortality in
1994 that I reported last year, the trend continued with a 6
percent decline from 1994 to 1995, and the preliminary data for
1996 looks similarly encouraging. Since the NICHD was
established in 1962, the U.S. infant mortality rate has
declined by 70 percent. Most of this decline can be traced to
NICHD research advances, particularly to improvements in
preventing or treating respiratory distress syndrome and the
Back to Sleep campaign.
This campaign is based on NICHD research, and recommends
that healthy infants be placed on their backs to sleep, to
reduce the risk of sudden infant death syndrome, or SIDS.
Stomach sleeping has changed from 80 percent of babies to 25
percent of babies, and deaths due to SIDS have declined by 30
percent in the last three years. Since the campaign, 1,600
fewer babies annually die of SIDS.
The introduction of surfactant treatment developed from
NICHD and NHLBI research continues to reduce deaths from RDS.
Still, nearly a thousand infants a year suffer from a breathing
problem called hypoxic respiratory failure. A new therapy,
using inhaled nitric oxide, has just been shown by NICHD
research to rescue many of these infants, and avert the need
for a costly surgical procedure used to oxygenate the infant's
blood.
A brief historical note dramatically illustrates the
progress from NICHD research. In 1963, President Kennedy's
infant son Patrick was born prematurely and died of respiratory
distress syndrome. Despite all his advantages, his doctors and
his parents could only watch helplessly as Patrick struggled to
breathe, because we didn't know the cause of RDS, and there was
no treatment.
Now, with treatment with surfactant, new respirators,
better isolettes and advanced intravenous fluid therapy,
premature babies have a far better chance to live. When Patrick
Kennedy was born, an infant with RDS at his weight and
gestational age had a 95 percent chance of dying. Today, an
infant at that weight and gestational age has a 95 percent
chance of living.
This has been a year of unprecedented acknowledgement of
research supported by NICHD. It began with the award of the
1995 Nobel prizes to Dr. Eric Wieschaus and Dr. Edward Lewis,
whose basic research on birth defects had been funded by NICHD
for decades. The awards continued last fall, when two NICHD
intramural scientists, Dr. John Robbins and Dr. Rachel
Schneerson, received the 1996 Albert Lasker Clinical Research
Award for their landmark development of a conjugate vaccine for
Hemophilus influenza type b, or Hib. The Lasker prizes are
often referred to as the American Nobel prizes.
For many years, the leading cause of acquired mental
retardation in the United States was brain damage from
meningitis due to Hib. The Hib conjugate vaccine reduced Hib
meningitis from 20,000 cases a year to fewer than a hundred.
This is one of the NIH's greatest contributions ever to public
health.
Completing the cycle of the world's leading scientific
awards, Dr. Ryuzo Yanagimachi, an NICHD grantee for 29 years at
the University of Hawaii, was awarded Japan's equivalent of the
Nobel Prize, the 1996 International Prize for Biology.Dr.
Yanagimachi's animal research has laid the foundation for much of
today's human infertility treatments.
Not all our research has been honored with such
distinguished prizes, but much of it has already made a
significant difference in peoples' lives. One dramatic
achievement has been the development of an effective treatment
for the inherited disease cystinosis. NICHD scientists in the
NIH Clinical Center identified the basic defect in the disease,
developed a drug to treat it, and tested it in a clinical
trial. Prior to this treatment, affected children were severely
stunted in growth, went blind from cystine crystals deposited
in their eyes, lost their kidney function and died by age 10
unless they received a kidney transplant. Today, with early
diagnosis and drug treatment, the development and lives of
these children are entirely normal.
NICHD has led an expanded research program in autism. A
research conference on autism was held in 1995, followed by a
solicitation for research grant applications focused on
neurobiology and genetics. Funding these applications this year
will markedly expand autism research and bring new scientists
into the field.
Abnormalities of brain development can result in children
having difficulties in learning. Almost half of all the
students receiving special education in this country have
learning disabilities. Screening procedures have been developed
for preschool identification of risk for learning disabilities.
Longitudinal studies using a new approach for children with
these reading disabilities have been conducted in ordinary
classrooms in several states. Approximately 97 percent of this
group of high-risk children is now learning to read using these
techniques.
At any time, any of us can suffer an injury or an illness
that changes our entire life. Christopher Reeve has turned his
own tragedy into a remarkable stimulus for research. Thanks to
NICHD research, a new generation of assistive technology is
becoming available. Novel imaging techniques facilitate rapid
fabrication of prosthetic and orthotic devices that are
customized to fit individual users. An advanced portable oxygen
system will help school children with breathing problems, and
an electronically controlled knee-lock device will improve
lower limb bracing to increase mobility.
We study issues related not only to the individual but to
families and populations as well. We lead a Government-wide
effort to improve Federal statistics and research on
fatherhood. Also, as many more women are joining the work
force, the issue of child care is increasing in importance.
Last year, the early results of the NICHD study of early child
care showed that, in and of itself, child care by non-maternal
figures does not adversely affect the mother-child
relationship. This study continues to examine other important
issues in the first seven years of life.
A major study of adolescent health is concluding, and will
soon be available to help understand the social changes and
structures influencing teenagers and their needs.
Mr. Chairman, the awards and achievements we report to you
today represent part of the return on the long-term investment
of the American people provided by the Congress which has made
these lifesaving advances possible. The fiscal year 1998
President's budget request for NICHD is $582,032,000, excluding
AIDS. I will be pleased to answer any questions.
[The prepared statement follows:]

[Pages 1639 - 1642--The official Committee record contains additional material here.]

autism

Mr. Porter. Dr. Alexander, we congratulate you and your
Institute on these awards and recognitions. I think it's fair
to say that this subcommittee believes that your reward ought
to be more than a 2.5 percent increase. And your work is far
more important and of greater priority in my mind, at least,
than that figure would represent. We'll see if we can improve
on that but, every year in appropriations, you start from
ground zero and have to build the case.
So we will have our work cut out for us in terms of
addressing the priority that I think certainly most of the
members of this subcommittee believe biomedical research to be
for our country. And we hope that we can do better than the
President has suggested. We'll have to wait and see.
Dr. Alexander, autism is thought to affect 400,000 people
in the United States, with a devastating emotional and
financial impact. Is it fair to say that there has not been
very substantial progress made in the biological understanding
of autism in the past 15 years?
Dr. Alexander. That's quite an accurate statement, Mr.
Porter. Unfortunately for many years, the biological
investigations of autism were back-burnered because of a belief
that this was a psychogenic disorder caused by abnormal
parental interactions with their children. As we have studied
the condition more, we have come to realize that this is
probably not the case, that this is probably a neurologically
or even genetically based disorder, probably related to some
abnormality of brain functioning, perhaps as a result of either
a genetic disorder or some intra-uterine insult to the brain.
Our efforts now are being directed to these particular
aspects of the autism spectrum disorders. And in fact, we have
just completed the competition under a request for grant
applications for neurobiology and genetic studies of autism.
These grants are being funded come April. We have received
additional funds from Dr. Varmus to supplement the funds that
the Institutes can put toward this area of research.
And we believe that we have assembled a top group of autism
researchers, as well as people in the neurosciences and
genetics who have not worked in autism before. We believe that
we stand poised to make major advances in our understanding of
autism, and hope that we will be able to produce the kinds of
results that we are anticipating in making real progress
against this disorder.
Mr. Porter. I think you've indicated this is possibly true,
but is it likely that advances in autism through research will
also help shed light on other illnesses like obsessive
compulsive disorder, attention deficit disorder, and learning
disabilities?
Dr. Alexander. I think there's a high likelihood of that.
Anything that we learn about brain functioning and abnormal
behaviors, such as these disorders manifest, will help whether
we're studying one or the other. There is carryover to the
other condition. And I believe that the work we're going to be
doing on autism will probably help us to understand these other
disorders as well.

autism centers

Mr. Porter. Do you think the field of autism research could
benefit from a center based approach?
Dr. Alexander. This has been something that we've
discussed. I'm not sure that the field is ready for centers
yet. The program project grants that we are going to be funding
have many characteristics of centers. As these projects develop
and function over the course of the next few years, we'll be
able to assess whether they are functioning quite capably as
program project grants, or whether there might be a need for a
centers approach.
Right now, it's the belief of myself and the other
Institute directors involved in autism research that a centers
based approach would be premature.

autism research investigators

Mr. Porter. According to autism family support
organizations, one of the biggest problems in the field is the
small number of talented scientists who are actually working in
it. Do you agree, and are you taking steps to encourage more
scientists to enter the field of autism?
Dr. Alexander. We are. This increase in funding in autism,
particularly using the program project grants, willcertainly
attract investigators to this field, both people who have not been
working in autism before, who are experienced, as well as young
investigators. There is ample room in these particular program project
grants for young investigators to be brought on to work with people who
are more established in the field and represent the new entry of people
who will continue an interest in autism research.

learning disabled children

Mr. Porter. Dr. Alexander, recent findings suggest that
learning disabled children have trouble distinguishing between
some spoken syllables, perhaps indicating that the auditory
system is the focus of the defect, rather than the language
centers of the brain. Does this mean that early training aimed
at helping learning disabled children distinguish between
sounds could prevent them from ever becoming impaired?
Dr. Alexander. That's a very promising area of research
that needs to be pursued. We're not sure yet whether this group
of children who demonstrate deficits in the auditory system
represents a sub-class of children with learning disabilities
who demonstrate this overall problem with phonological
processing, or whether it represents just a totally distinct
group. We need to study this area further.
The studies that we are doing, the studies that the
Neurology Institute is doing, and the Deafness and
Communication Disorders Institute is doing in these areas I
think will help us to sort out whether these are clearly
different categories of children who have different bases for
their learning disability, or whether they are all part of the
same kind of a continuum.
We need to do more work that's going to pursue that. We
will be aided in that work with some of the new sophisticated
techniques of neuroimaging, and other methods that will help us
to investigate this in a very clear way.
Mr. Porter. How are you disseminating the results of these
studies relating to learning disabled children?
Dr. Alexander. We're working, both independently ourselves
and producing information from the Institute for others to
disseminate. Certainly, the work our investigators are doing is
being published. Each year we are putting out a book about the
year's progress in learning disabilities. And we have worked
cooperatively with the Department of Education in producing a
set of information called Learning to Read-Reading to Learn
that is being disseminated widely by the Department of
Education.
We're also working actively with the learning disabilities
associations, and there are several of these, to disseminate
information to parent groups about the progress that's being
made. Also, Dr. Reid Lyon, from our Learning Disabilities
Research Program, has testified to the Congress, has testified
before a number of State legislatures, and parent groups in
States around the country about the results of this research on
learning disabilities. And the word is getting out about the
progress that's being made.
We are also sponsoring with the Learning Disabilities
Association a summit here in Washington in April, with the
concluding event here on Capitol Hill, also in an effort to
disseminate the word about research from this program.

sids back to sleep campaign

Mr. Porter. Your Back to Sleep campaign, urging parents to
place infants on their backs when sleeping to prevent SIDS,
which you mentioned in your testimony, has been quite
successful in reducing the number of SIDS deaths. What research
strategies are you pursuing to address the remaining SIDS
cases?
Dr. Alexander. Well, we're not satisfied that we've done
all we can do yet with just Back to Sleep. We're at the point
now where about 25 percent of babies are still sleeping on
their tummies. We are going to be intensifying the Back to
Sleep campaign with the goal of achieving 90 to 95 percent back
sleeping in infants. Because we believe that just with this
measure, we probably can reduce SIDS by over 50 percent and not
stop at 30 percent reduction where we are now.
We're also not satisfied that we yet understand the basic
underlying mechanism of SIDS. Our basic research has given us
some tantalizing leads, some suggestions and clear indications,
in fact, that there is a area of the brain stem, called the
arcuate nucleus, that has a deficiency in neurotransmitter
receptors in infants that die of SIDS, compared to infants who
die of other causes.
This could explain, in fact, why infants placed in the
tummy sleeping position could bury their face in the covers and
not detect that they are in fact suffocating, that their levels
of oxygen are dropping and carbon dioxide are rising, and turn
their head to the side to clear their airway. If they don't
have those receptors there, they don't get the message. So we
believe that this is an explanation for a substantial number of
infants with SIDS.
We are also conducting a study of home infant monitoring,
the CHIME study, Collaborative Home Infant Monitoring
Evaluation, looking at whether the latest generation of apnea
monitors can in fact pick up preceding events or clues that a
SIDS death is impending in time to arouse an infant, if parents
are there and can respond to an alarm.
Also, if in fact we are able to demonstrate that this
defect in neurotransmitters is an underlying mechanism for
SIDS, we will be looking for some markers of that defect, or
some way to detect it, so that we could determine the infants
in the population that are at the greatest risk of SIDS, and
monitor them particularly intensively.

premature labor and delivery

Mr. Porter. Premature labor and delivery are leading causes
of infant mortality. What clinical trials are you currently
pursuing in this area?
Dr. Alexander. We're very excited about our prospects here,
Mr. Porter. We have gotten some evidence from some basic
studies as well as from some small, preliminary clinical
trials, to suggest that a condition called bacterial vaginosis
is associated with premature labor in a number of instances.
And it could account for a substantial portion of the premature
deliveries in this country, as well as account for the higher
proportion of premature labor and delivery in the African-
American population.
Studies identifying bacterial vaginosis either by a vaginal
smear or using a new technique called detection of fetal
fibronectin by a vaginal cervical swab give an indication of
the presence of this condition, which increases the risk for
premature labor and delivery.
We now have major clinical trials underway looking at both
these methods of detection, followed by initiation of treatment
with antibiotics to try and eradicate the bacterial vaginosis
infection to see whether eliminating that infection can in fact
reduce the increased risk of premature labor and delivery.
There is evidence from a small preliminary trial that this
might be the case. We have now started definitive studies to
provide clear indication of whether this will work. If it does,
this should give us our first real handle on a means to detect
and intervene to prevent premature labor and delivery.
Mr. Porter. Thank you, Dr. Alexander.
Mr. Hoyer.

early child care

Mr. Hoyer. It's good to see Dr. Alexander, whom I get to
see regularly at places around Maryland. He and his wife are
neighbors, and we're glad to see him here.
Early child care. A lot has happened in my life, some not
so happy; but one happy thing, I had a new grandson on November
18th. And one of the wrenching things that my 32 year old
daughter is going through is that he's now three months old and
he's starting child care and she's going back to work. This
happens to hundreds of thousands of young people, so I'm very
concerned about child care.
I'd like to hear a little bit more about the studies that
seem to show that there is not an adverse effect from non-
maternal care for a period of time during the day. Could you
expand on that? It's obviously a very, very important issue for
our country, as we see more and more women in the work force,
welfare reform requiring work, all of that. This is a critical
area of study.
Dr. Alexander. You're right on target with the question and
the concern, Mr. Hoyer, which is the reason that we initiated
this study some years ago. At the present time, more than half
the mothers of infants, children under a year of age, are in
the work force. And those infants are being cared for either by
a father, a grandparent, some other relative, a small group day
care home, or a large day care situation. And parents are
concerned about whether placing the infant in a child care
situation is going to have a good, bad, or indifferent effect
on that child's development, that child's relation with family,
and the whole family's interaction with the child.
Because of this very clear trend, back in 1988, we
initiated this NICHD Study of Early Child Care, trying to get
an answer to the questions that were really beguiling parents.
Does early child care have a good, bad or indifferent influence
on my child and the rest of my family. We started this study
with a competition to select 10 sites around the country with
top-notch investigators where we could accumulate 1,200
families for a prospective study and evaluation of the impact
of child care.
Children have been picked up at birth and followed with
intensive evaluation at several points in their lives. They are
presently completing their four and a half year evaluations,
and they will be continuing the study until age seven. We're
currently trying to decide whether to extend that study any
longer.
The evaluations have been completed now with the data
analysis through the 15 month evaluation, and we're starting on
the 3 year data. The finding that I mentioned in my opening
statement was one that came to the public last spring, and
indicated an answer to the question most frequently asked, and
the concern that had been raised: will placing my child in a
day care situation have an adverse effect on my relationship
with that child.
And the study, based on the 15 month evaluation, gave a
reassuring answer for parents. It showed that regardless of
where that day care was being provided, whether it was the
other parent, a relative, large or small day care setting, that
there was not an adverse influence or a positive influence on
the maternal-child relationship, that the child and mother did
just fine, as long as there was not some other problem with the
mother-child relationship in the home.
So this data, I think, got wide publicity at the time and
gave a lot of reassurance to parents who were in the same
situation as your daughter. We are asking a lot of other
questions; obviously the issue of maternal-child attachment is
not the only one. What are the effects on social development,
on language development, on cognitive development, on other
forms of parent-child interaction? On the child's health?
One thing we do know is that children in day care get more
ear infections and other upper respiratory infections than
children who are not. But they seem to do okay anyway.
So the assessments of the data from this study continue.
There will be about five more papers and public presentations
released this spring. And data from this study are continuing
to become available.
As I say, we'll be following these kids through age seven,
and we will be learning an awful lot about the day care
situation. It is everybody's hope that all the data will be as
reassuring as the initial findings that were released, but we
don't know.
Mr. Hoyer. Well, that is reassuring, and I'm going to get a
copy of that study and send it down to Susan. She'll be glad to
hear it.
Dr. Alexander. We'll be glad to provide it.

learning to read

Mr. Hoyer. She is a very conscientious parent, and very
concerned about it.
Let me ask you about another question that the Chairman
talked a little bit about in the autism field; learning to
read, how children learn to read, how that occurs. You
indicated there was a relationship between you and the
Department of Education on this issue, and you've disseminated
certain materials. How particular have you gotten from your
perspective in your Institute on the specific teaching
techniques in terms of learning to read, phonics versus whole
language, and that whole debate?
Dr. Alexander. We've gotten very specific about that, Mr.
Hoyer. Once we had identified some specific problems that
characterized children having difficulties learning to read, it
was our intent to look at interventions to see if we could
overcome these difficulties. And we made a very specific point
of testing these interventions in a school situation in a
clinical trial type of methodology. So we developed ways to
test, first of all, children, pre-school, for the presence of
these particular difficulties we call phononemic awareness or
phonological processing. And we're able to identify the
children who are at highest risk of reading disability, based
on this pre-school testing.
In a number of States, in California, in Texas, in New York
and Florida and several other places, we have now conducted
interventions looking at a phonics-oriented type of approach,
but a modification of the traditional phonics that's intended
to teach the skills involved in decoding of words, using
phonetic types of skills and approaches. With these techniques,
we have demonstrated that these children are usually able to
learn to read and come close to the rest of their peers by the
end of the third grade in most instances.
There is still a very small group, maybe 3 percent of this
group, that in spite of this intervention don't make it. Their
reading problem is probably based in a different way than the
techniques that we're using are able to overcome. And we need
to study that further.
But the basic finding is that we can identify these kids
before they start school. We can intervene with this phonics-
oriented approach in the regular classroom with training of the
regular classroom teacher, and have these kids performing up to
grade level in most instances by the end of second or third
grade.
We are now trying to look at variations on these teaching
techniques, applying them in a wider variety of school
settings. And we're also asking a slightly different question,
that is, when a high proportion of the students in the school
are likely to suffer learning disabilities that affect their
reading skill, can you apply this kind of technique with
everybody in the class, and not just a subgroup that's at high
risk. Can you apply the same principles with the whole
classroom and have this approach work and improve the reading
skills of everybody and bring them, not just up to grade level,
but in many instances above grade level.
So that's the next step that we're going to be taking with
this, as well as looking at the whole relationship of the
modified phonics approach with integration of some forms of the
whole language approach. And throughout this, we are in contact
with the Department of Education. We are working with them,
providing them with the results, and working with them to try
to make sure that the appropriate information is passed on to
teachers, to teacher training schools, and to boards of
education.

web page

Mr. Hoyer. In terms of that, I've been very interested,
with the National Library of Medicine; a decade ago, I started
talking about this. And I am essentially computer illiterate,
as most of the people are in my generation who don't have to
use a computer, and who unfortunately--or fortunately--have
people working with them who are really very facile with the
use of computers.
But on this Web page, if the teacher in the classroom
wanted to get that information on your Web page, is that
available?
Dr. Alexander. That's one of the things we're doing, yes.
Mr. Hoyer. When you say one of the things we're doing,
we're getting it on or it is on?
Dr. Alexander. It is not on yet, but it will be.
Mr. Hoyer. Okay. Because this is critically important to
the classroom teacher, it seems to me, to have that information
at their fingertips, where we spent a lot of money centralizing
this information. Again, my daughters, I've got a 25 year old
daughter that when something happens, I just ask her about it.
I don't have to ask CRS about it any more, she sits down,
accesses the internet, and she's got it for me in minutes,
almost. It's incredible.
It's just an unbelievable power that she has to access that
information; that if the classroom teacher or the local
practitioner in Timbuktu who's got a computer on his or her
desk can access that information, it's going to make a
revolutionary difference to be able to get what Alexander has
at his or her desk anywhere in the world, essentially.

asthma

Last question, Mr. Chairman, I appreciate your tolerance. I
have to leave, unfortunately, I have another hearing.
I'm interested in asthma, and I was concerned about what is
an alarming rise in childhood asthma. To what do we attribute
that, and what are we doing?
Dr. Alexander. We don't know just what the cause of the
increase is. There are many different and often conflicting
claims. The most frequent one that we hear is that it's related
to increased air pollution, environmental air pollution. Others
claim that there are other antigens in the home that are
increasing, and that as we further close up our homes for
insulating purposes that there's greater exposure to these.
I don't think anyone knows for sure what the cause of
increased asthma is. But it's very clear that this is the only
condition that's increasing in children, and the only thing,
other than AIDS, that's increasing deaths in kids.
The primary responsibility for asthma research lies with
the Heart, Lung and Blood Institute and the Allergy and
Infectious Disease Institute. And they're making major efforts
in this. And in fact, Dr. Varmus, with funds from the Pediatric
Research Initiative, has targeted asthma in children as one of
the three areas for focus for the use of these funds this year.
So there will be an increased effort in that.
Dr. Varmus. It's also highlighted in the areas of emphasis
for 1998.
Mr. Hoyer. Good. I appreciate that.
Let me ask you something. You mentioned environmentally
related issues. To what extent do we continue to look at the
psychosomatic implications of asthma?
Dr. Alexander. I think there is still interest in that. But
I think that the trend of today is to look more at specific
triggers, environmentally induced triggers of asthma, rather
than so much a psychogenic component.
Mr. Hoyer. Thank you.
Mr. Chairman, thank you again for allowing me this time,
and Doctor, thank you for what you did today and what you've
been doing, and all your colleagues at NIH. The Chairman is
absolutely correct, the more investment we make the better
payoff for our people. Thank you.
Dr. Alexander. Thank you, Mr. Hoyer.

protection from asthma

Mr. Porter. Thanks, Mr. Hoyer.
Let me follow up with two questions in this area, since
we've opened it. We heard from Dr. Lenfant that, paradoxically,
exposure to respiratory infections at a young age may offer a
protective effect against asthma. And that asthma, the
antibodies or whatever may be produced from those exposures are
not as great today as they used to be in the past, and that
therefore, children are more subject, and adults more subject,
to this disease. Are you following this kind of research?
Dr. Alexander. This has been a hypothesis that's been put
forward with some supporting data from one study, the claim
being that with vaccination, immunization, for example, we are
less exposed to the antigens that the children used to be
exposed to and actually get an illness. Whether or not there's
any strong support for this hypothesis, I think, remains to be
tested. This is one interesting idea that's been put forward. I
think we'll see some more research on that. But I don't think
we know enough yet to say that there's a very strong indication
that that's the case.
Mr. Porter. The EPA has recently promulgated new
regulations on particulate matter that will affect cities all
across the country. Were you consulted in regard to their
action, because they've cited the increase in asthma as one of
the reasons for this. Were you consulted with regard to these
regulations?
Dr. Alexander. My Institute was not. My suspicion is that
the National Institute of Environmental Health Sciences
probably was, and probably NHLBI and NIAID, who are the ones
who have the major responsibility for research in children with
asthma. And I know that one of the motivating factors in these
regulations was the hope that by doing so, we would perhaps
decrease the incidence of childhood asthma and the severity of
it.
Mr. Porter. Ms. DeLauro.

PREVENTING PROBLEM BEHAVIOR

Ms. DeLauro. Thank you, Mr. Chairman.
And thank you, Dr. Alexander, thanks for all the wonderful
work that you all do here. If you don't mind, I'd like to just
say hello to my pal, Dr. Haseltine. How are you?
If you could, please, Doctor, profile for the committee
your Institute's efforts on preventing problem behavior among
middle school students. Tell me a little bit about what's
planned in that area.
Dr. Alexander. There are several separate efforts here. One
of these, the local effort that is one of the most visible
ones, is an effort from our Division of Epidemiology,
Statistics and Prevention Research. It's involved in the public
school system, the middle schools, in one of the Maryland
counties, and involves development of baseline measures of
behavior in middle school students, and then interventions
targeted to reduce the likelihood and frequency of some of
these problem behaviors.
Currently, we've completed the baseline data gathering
year, and are in the first year of implementation of some of
the interventions in this school system where we are making
interventions in some of the schools and not in some of the
control schools, and measuring the differences in these target
behaviors at the completion of the study.
We are also supporting individual investigators in studies
looking at middle school behavior in a number of areas. And
then we have a number of studies, the largest being the
adolescent health study, which is post-middle school, but some
of the middle schools are in that, as well, a series of studies
on minority youth health behaviors that are in eight different
sites around the country that are targeting particularly high
risk sexual behavior, as well as violence prone behavior.
So there's a wide variety of studies that are addressing
this issue. The most on-target of those is the one in the local
school system.
Ms. DeLauro. You talked about violence and substance abuse?
Dr. Alexander. Substance abuse, yes.
Ms. DeLauro. When you talk about interventions, tell me
what you're thinking about.
Dr. Alexander. There are a variety of these. Some are
almost traditional educational interventions. Others are peer
education types of interventions, where they will either be
talked to by their own age peers or older age adolescents who
come and talk in the schools about some of these health
behaviors and problems.
Others involve teaching approaches to conflict resolution,
for example, for the violence prone behavior. So there's a wide
variety of these. Some are targeting health behavior,
nutrition, exercise, elimination of some health problem
behaviors. Some also target smoking behavior, and a variety of
others.

MIDDLE SCHOOL CHILDREN

Ms. DeLauro. I'm interested because of what I have done as
a start to this within the community that I represent,
something called Kick Butts Connecticut campaign. It takes
about 50 or 60 middle school kids, [and the schools have been
enormously cooperative in allowing us to come in and talk to
the kids have been] and shows videos and have material on
smoking and its effect on youngsters, and what it means to
smoke as an adult and so forth. We have, what I call, a little
army of middle school kids who are going into the elementary
schools. We have worked with the elementary schools to go in
and do skits, ask their questions, role play to address this.
We've also used some eighth graders to come in to talk with
the middle school youngsters. We've just started this
initiative, so I don't have any data or analysis. But we have
at least interested a bunch of youngsters in getting engaged in
being mentors and carrying this as a health message.
I'm interested in what you're finding in terms of the local
schools and some of these health related issues. Because I
continue to believe that with kids, they can have a strong
effect on each other.
We've seen this with something we've got called an anti-
crime youth council. This council talks about crime and violent
behavior. It's been in existence for about three years, with
juniors and high school kids, who are again in the schools
talking about how kids themselves can deal with the issue of
crime and what their responsibilities are.
Dr. Alexander. We're eager to get the results of this. As
your experience was, ours here has been no difficulty getting
into the schools. We were welcomed.
The problem is, many places have done things like thisand
variations on the theme. Very few of them have done it in a research
context, or in a way that it can be evaluated. What we have attempted
to do here has been to do this in a research context, where we
collected baseline information before we went in with the intervention,
tested different types of interventions, to address the same problem,
and then followed up the students to see whether the interventions made
any difference at all, and which of the interventions were the most
effective.
So we hope by approaching this in a research context we can
gather information that will help many middle schools around
the country to design programs that will take advantage of what
we have learned here and apply them in a local way.
You are absolutely right in terms of the timing here. This
is the group where the health behaviors and social behaviors of
the future are shaped. There are many disorders that we see in
adulthood that can be avoided if we shape the health behaviors
correctly in this age range, if we can avoid smoking, if we can
avoid inappropriate sexual behavior, if we can avoid the
violent behavior, if we can improve nutrition and dietary
behavior. We can have an impact on a large number of diseases.
So we hope that what we learn from these studies, done in a
research context, can provide valuable information to many
schools around the country that would do a similar thing.
Ms. DeLauro. Your results, I think, are particularly
critical for us. I for one would love to see them, because we
can take the research and make the local application. And I
believe that those of us who serve in public life can do this.
We can work with our community. It's a way in which we can have
a direct effect.
We're trying this and trying to engage, the middle school
kids. When these kids meet and come into training, I have also
had an office filled with their parents who were there taking
an interest in what the kids were doing. So you wind up dealing
with both kids and parents.
Dr. Alexander. We're also looking forward to the results
and we'd be happy to share them with you.

DRUG DOSAGES FOR CHILDREN AND PEDIATRIC PHARMACOLOGY RESEARCH UNITS

Ms. DeLauro. Okay.
Just one other question that has to do with children, I'm
not sure that this is cause and effect, but we do have people
being moved into managed care. More prescriptions for
antibiotics that are going to replace doctors visits, etc. Then
you've got prescription drugs dosages that have been tried out
on adults but not kids. That could be harmful to kids. What is
the Institute doing in terms of dealing with the proper usage,
and dosages for drugs for children?
Dr. Alexander. Well, Ms. DeLauro, you've put your finger on
a very major problem in pediatrics. About 75 percent of all the
drugs that are available by prescription have never been
studied or tested in children. So they don't have a pediatric
indication listed. And this is a problem. Because children
react differently to drugs than adults do.
We say oftentimes, a child is not a small adult. And the
smaller a child is, the less they are like an adult. They
metabolize drugs differently, absorb them differently, excrete
them differently, and they stay around for different lengths of
time. And a liquid formulation of a drug that's often necessary
particularly for younger children may be quite different than a
pill formulation of a drug.
So drug companies are able to get drugs introduced to the
market based on adult studies, and never do any studies on
children. Those drugs are obviously of value for children, and
pediatricians often wind up prescribing them, even though there
is not a basis, a specific indication listed for them for
children.
We have tried several ways to get around this. One of our
major responses has been to establish a network of pediatric
pharmacology research units. There are seven sites around the
country, awarded competitively as cooperative agreements, with
the top researchers in pediatric pharmacology in the Nation,
where we provide not only top notch capabilities for clinical
trials and laboratory capabilities for doing a number of the
analyses that are required, but also access to a patient
population of children where there is experience in doing
studies, experience in institutional review boards in reviewing
applications to do this work, and experience in investigators,
nurses, the whole team that's capable of doing high quality
clinical trials in children.
We don't fund a clinical trial. We fund some of the basic
metabolic studies. But the clinical trials are funded by
industry. We tried to take away from industry the capability of
saying, well, it's too hard to do these studies, there's no
patient population available, there's nobody experienced in
doing these studies. It's there now. And we have publicized
this widely to industry, and encouraged them to make use of
this resource for doing drug studies in children.
That's now taking off. We have a number of drugs now that
have gotten pediatric indication labels because of studies that
have been done in this network. We have a large number of drugs
that are under study in the network now, and are in the process
of getting pediatric indications. And we have hopes that this
network is going to be able to provide an expanding resource
and capability for pharmaceutical companies to do the drug
testing in children that's necessary.
The FDA has been very cooperative with us in this effort.
They have prodded industry and encouraged them to get studies
done in children very quickly, either concurrent with adult
studies or not far behind. And we hope that this problem is on
its way to resolution.
Ms. DeLauro. Thank you very much, and thank you for your
work. I appreciate it.
Dr. Alexander. Thank you.
Mr. Porter. Thank you, Ms. DeLauro.
Mr. Wicker.

LEARNING TO READ

Mr. Wicker. Thank you, Mr. Chairman.
Dr. Alexander, I notice in your testimony you mentioned
that your Institute's researchers have been using non-invasive
neuroimaging methods to study brain systems that are involved
in the ability to read.
Dr. Alexander. Yes.
Mr. Wicker. A recent article in the Chicago Tribune cites a
quote from Reid Lyon, Research Director of your Institute,with
respect to reading skills. And Mr. Lyon is quoted as saying, we know
what to do, we have the information within our grasp. We just can't get
the message across. That's what makes the issue so frustrating.
I wonder if you could comment on that, and tell us what
science has discovered that might provide us more effective
tools.
Dr. Alexander. We know what to do in a large number of
children. We're learning what to do in many others. We have the
ability to identify a substantial proportion of the children
who are at risk for learning disabilities before they begin
school. We know what to do to help a large proportion of those
children to learn to read.
We are in the process of learning how to do that in a more
effective way, by testing variations on the theme, if you will,
of the interventions that we have found to be effective, to see
if there are ways that we might make those more effective for a
larger percentage of children.
There remains a group of children for whom these techniques
don't always work. And those children certainly require
additional study and evaluation. One of the things that we're
doing involves this neuroimaging technique. It's called
functional magnetic resonance imaging. And it's a non-invasive
method of studying what's going on in the brain of children.
Because it is non-invasive, doesn't involve x-rays, we're able
to use it in normal children. And it's teaching us a lot about
how the brain functions.
The neuroimaging studies have identified differences in
activation sites, differences in processing activities, of
areas of the brain in children with learning disabilities
compared to children without. One of the things that we're
studying right now is if we apply these remedial techniques,
does the picture of the neuroimaging change in these children?
Will they become more like their normal reading contemporaries,
and their functional neuroimaging picture?
I don't think we're going to be at the point where
neuroimaging is the diagnostic criterion for learning
disabilities. We have paper and pencil tests that work much
better and much less expensively for that than a neuroimaging
test does. But they do help us to study the basic underlying
neurological problems that may be at the core of problems with
learning to read, and help us to understand that whole process.
Mr. Wicker. Which children are candidates for these
functional MRIs?
Dr. Alexander. At the present time, these are just children
who are participating in some specific research studies. There
are sites that have a particular interest in the underlying
brain mechanisms associated with learning disability, and also
have at their institutions exceptionally good capability for
doing these studies. These are not easy to do. It requires
sophisticated equipment, techniques, and people to interpret
the images that we get.
So there are just a couple of sites around the country
where we are funding these particular studies of functional
neuromagnetic resonance imaging to try and assess the
underlying brain function or dysfunction of children with
reading disabilities.

children with reading disabilities

Mr. Wicker. Based on what you know at this point, do you
have an opinion about the advisability of using volunteers on
children to assist children with reading disabilities as
opposed to trained professional teachers?
Dr. Alexander. I think children differ in what they're
going to benefit from. All children can benefit from having a
volunteer who reads with them, works with them in their early
years of learning to read. A child with reading disability may
not benefit from a volunteer who does not have some extra
training above and beyond just reading a book to that child. A
child with a reading disability may very much enjoy having a
story read to them. But that may not have anything to do with
improving their ability to read.
If we want to try and improve the ability to read, one of
the useful things is increasing the desire to learn to read,
and the association with that volunteer reading the stories and
books to them may increase that desire. But if we want to help
overcome basic underlying problems of phonemic awareness and
phonological processing and so forth, it's going to take
probably more than just an untrained volunteer. It will take a
teacher who is trained in the intervention techniques that have
been shown effective in helping these children.
Some of these techniques are not extremely difficult to
teach a volunteer. And if there's a volunteer with an ongoing
relationship with a child with a learning disability, that
volunteer can learn from the trained teacher how to apply these
techniques with that particular student, and be a substantial
help to that child in amplifying what the teacher is able to do
in a limited time they have to interact with the child in
helping that child overcome the basic difficulty.
These are not very difficult things to do. They can be
taught to volunteers who can work with kids to help them.
Mr. Wicker. Thank you, Mr. Chairman.
Mr. Porter. Thank you, Mr. Wicker.
Mrs. Lowey.

infertility research

Mrs. Lowey. Thank you, Mr. Chairman. And welcome, I do
apologize that I missed your presentation.
With regard to infertility research, in your testimony, you
did state that your Institute has completed several clinical
studies on the causes of infertility. How close are these study
results to commercial application, that is, to assisting
couples seeking infertility treatment, and what is the process
of taking these findings and making them useful to the public?
Dr. Alexander. The two findings that I described in the
opening statement have just been made, so they are very early.
We now have to pursue what the underlying bases of these
abnormalities are, and also determine whether or not there are
hormonal interventions or some other interventions that can be
made to overcome the specific difficulties. So there is a
substantial amount of work yet before they are ready for broad
clinical application.
We would hope that we can understand very quickly the
underlying pathology and develop interventions that will be
ready for clinical trials fairly soon.

maternal mortality

Mrs. Lowey. Thank you. We think of death due to childbirth
as a thing of the past. Yet every day, two to three women die
from pregnancy-related conditions. Many of these deaths can be
prevented. I'm working on legislation to improve maternal
health through strengthening our surveillance of pregnancy-
related mortality and morbidity data, increasing the use of
folic acid to prevent birth defects, provide for better follow-
up care after the birth of a child, and improving the quality
and use of ultrasound tests.
Can you briefly comment on the research you aresupporting
in the area of maternal health, and in particular, any research looking
at maternal mortality? Following up on that, I met with some people
from the CDC yesterday and one of the questions I asked them in
response to questions that were asked of me was whether their research
has led to any connection between infant defects, child defects, and
drug use during teen years. Could you comment on that as well? We're
talking about prevention, how do you prevent birth defects. It was
brought to my attention, and this person, everything you read may not
necessarily be valid. But was telling me about information they read
that did make a connection.
Dr. Alexander. OK. First with regard to maternal mortality.
Decreasing maternal mortality has been one of the great public
health triumphs of this century. At the beginning of this
century, a woman who was pregnant faced a 1 percent chance of
dying as a result of that pregnancy. Now, it's less than 1 in
10,000. There's still over 300 women a year in this country
that die from complications associated with pregnancy. And
every one of those is too many. Pregnancy should be a condition
which any woman can approach without any fear of death,
certainly.
The rarity of maternal mortality today makes it a difficult
thing to study. One of the things that is associated with
maternal mortality is infection. One of the hoped-for benefits
of our bacterial vaginosis study, where we are looking at
treating bacterial infections of the vagina and cervix during
pregnancy with antibiotics as a means of reducing infant
mortality due to premature labor, may in fact have as a side
benefit that we will look at the potential of reducing maternal
mortality associated with infection. That would be an outcome
that we would hope we would see.
Aside from that, the causes of maternal mortality are
largely hemorrhage and some other complications that occur
later, following delivery. As I say, the rarity of it is great,
but it makes it a difficult topic for study.
As far as birth defects in association with drug use during
pregnancy are concerned----
Mrs. Lowey. Not during pregnancy.
Dr. Alexander. Before pregnancy.
Mrs. Lowey. Right.

drug use before pregnancy

Dr. Alexander. We do have a study that's going on looking
at the complications, in fact, on the infant, of drug use
during pregnancy. We don't have any studies at the present time
looking at impact of prior drug use on birth defects in the
infant. There was a flurry of interest maybe 15 years ago in
association with some reports of chromosome breaks, in
particular, being more frequent among teenagers who were using
drugs, particularly marijuana and LSD.
That research has not proven consistent in subsequent
evaluations. I'm not sure what work the CDC has been doing that
you discussed with them. I'm not familiar with that.
Mrs. Lowey. None.
Dr. Alexander. OK. That's a good reason not to be familiar
with it. But we are not doing any work in that area at the
present time.
Mrs. Lowey. Is that because there is no one out there who
thinks there's a connection, or you're focused on other things?
It would seem to me, certainly we're aware of the tremendous
difficulties that the crack babies have, so that the pregnant
women who are on drugs and then leave us with thousands and
thousands of crack babies, cause a tremendous impact on
society, not to minimize the impact on them and their families.
I just wondered, in pursuing this, is it because your
hypothesis leads you or to the work done, that there is no
connection?
I would think that if there is any possible thesis that
there may be a connection, after all, the eggs are there, are
they the same eggs that are there during that time that the
teenagers or older youngsters are experimenting, that we should
be looking in that area, unless you're discounting it. So I'm
puzzled by your response.
Dr. Alexander. I think that the reason we're not now is
that the work was done, like I say, 15 or so years ago. And the
early suggestions and indications that there were problems with
chromosome breaks and so forth did not pan out. And people who
did follow up these adolescents with a history of drug abuse
did not in fact find a higher incidence of birth defects in the
offspring.
The CDC has a very intensive birth defects monitoring
program that they probably discussed with you that follows the
incidence of about 25 or so birth defects around the country
over time, and looks for any changes in incidence, and tries to
track any fluctuations that they see to any causative event.
And they have not seen any association from that study that I'm
aware of with drug use or abuse in adolescents prior to
pregnancy.
We do have a maternal lifestyle study that's going on in
our neonatal network that's a collaborative effort between us
and the National Institute on Drug Abuse and the Administration
on Children and Families. This has picked up a cohort of women
screened from a total of 19,000 pregnant women, identified
about 1,000 of those who did have a history of drug exposure
during pregnancy, picked up their infants, who screened
positive on meconium screening in the newborn period, went back
and got very detailed drug abuse histories from the mothers,
whose infants screened positive, and is following these
infants, looking at their behavioral development in particular.
This is being done at three of the sites in the neonatal
network.
We now have followed these infants to about three years of
age, it's our intent to follow them at least through beginning
of school, trying to look at just exactly what their cognitive
and behavioral profile is, and associate that, if possible,
with the maternal drug exposure history. It's very difficult to
do this kind of research, because there is a lot of
environmental influence on this that's very difficult to
separate out from the actual influence of what happened as a
consequence of the mother's drug abuse during pregnancy.
This study gives us the best shot of anything that's ever
been done of trying to make that distinction and try to
separate out effects of drug use during pregnancy from the
environmental situation in which that child is raised
subsequently.

teenage drug use and pregnancy

Mrs. Lowey. I think my time is up. So I'm to conclude that
based upon all available evidence, whether it's crack cocaine,
marijuana, heroin, used by a woman in her teenage years who
then becomes pregnant and gives birth, there is no connection
between that drug use and breakdown in cells, chromosomes or
whatever?
Dr. Alexander. This is not a subject that has been studied
extensively. The limited studies that have been done, and they
are probably too limited, have not to my knowledge given any
clear evidence of an association with birth defects.
Mrs. Lowey. Just to follow up, you're saying they're
probably too limited.
Dr. Alexander. Yes.
Mrs. Lowey. So you would say----
Dr. Alexander. I don't think we have a definitive answer to
your question based on the work we've done.
Mrs. Lowey. Has there been any effort to put some more
money into that research? I just think that the tremendous
problems of drug use, which seem to be on the increase again,
permeating every part of our society, and again, this was
brought to my attention, and I'd be most interested in
continuing the dialogue with you.
Dr. Alexander. That's not something that we have done, Mrs.
Lowey. I think it's something that we ought to take a look at
and try to get an assessment on how adequate the studies are
that have been done, and make a determination in conjunction
with our colleagues in the National Institute on Drug Abuse, in
particular, and probably the CDC as well, as to whether this is
an issue that ought to be reopened and reexamined.
Mrs. Lowey. And I'd appreciate if you'd get back to me on
that.
Dr. Alexander. We'll do that. Thank you.
Mrs. Lowey. Thank you.
Mr. Porter. Thank you, Mrs. Lowey.
Mrs. Northup.

phonics based reading system

Mrs. Northup. Yes, thank you. I'd like to return to the
question of learning disabilities and what sort of
recommendations you make to the Department of Education. I
noticed in your statement that you talked about a phonics based
reading system being sort of the preferred, I suppose, in a
remedial form for a child that has learning disabilities to
learn to read. For example, a dyslexic child.
Dr. Alexander. Based on our studies, it is the preferred
initial one, but not the exclusive one. These kids who have
this particular problem with phonological awareness and
processing seem to learn better with a phonics based approach,
not a strict, rigid phonics only approach, but a modification
of the old phonics approach, where they are taught word
recognition and basic reading with a phonics based approach
initially.
This seems then best followed along maybe by the second or
third grade with introduction of the more whole language
approach that's been used more recently in schools. But
starting these kids with this particular disability with a
whole language approach doesn't work. They do benefit from the
whole language approach once they have mastered the basic
skills of word recognition, decoding and reading.
Mrs. Northup. And that's what your scientific
investigations show?
Dr. Alexander. That's where we are right now. We're not
done.

children with learning disabilities

Mrs. Northup. Well, there's considerable anecdotal evidence
in schools that are strictly for children, for example with
dyslexia, that their phonetic system does truly remedy that
child's problems for years. If they go to these schools, local
ones, for three to four years, and then transfer back into a
mainstream situation, they'll do fine.
I guess I have to ask you what sort of recommendations you
make when 20 percent of the school population has that problem
and there is literally, in our schools, no phonetic based
system for children until they are accomplished readers. I have
supported new efforts at better ways of engaging children in
learning. But I do think we leave our children with learning
disabilities behind when we do that.
I just wondered if you'd comment on that first.
Dr. Alexander. I think you're absolutely correct. And our
data also show that if these kids are not identified early, if
we wait until third grade or so to pick them up until they meet
the technical criteria of a year or two years behind in reading
before we can begin any remediation, it's too late. Seventy-
five percent of these kids who are not intervened with until
third grade wind up never being able to read adequately by the
time they're in high school. So early identification is
important.
We've also, I think, gotten very clear evidence that we
have passed on to reading experts, to our colleagues in the
Department of Education, to colleagues in States, that this
population of children we can identify early on as at high risk
for learning disability benefits most from a phonics based
approach, and that they are not going to benefit from a whole
language approach. If they are going to learn to read, they
have to have this kind of an intervention and this kind of a
teaching approach.
Mrs. Northup. With that said, I have great experience with
this issue myself, with children and the profound effect it has
made on them to take them out of the public system and put them
in three years of remediation. How can we continue spending
money like we do to put children in a classroom that's totally
based on whole language, which may be great, and I'm convinced
in many cases it is, for children who are not learning
disabled, and provide them totally mainstreamed in there with a
little bit of a support system?
When you're talking and saying that when you get to it if
you try to remediate them at third grade or fourth grade it's
too late, they're high risk and they almost never make up for
the lack in that basic education skill.
Dr. Alexander. Right.

intervention programs

Mrs. Northup. Would you agree then that it's not enough to
send a tutor in for an hour or two, but to put that child in an
intensive remediation program that allows them to be re-
mainstreamed?
Dr. Alexander. I think that our evidence indicates that you
are absolutely correct, that this child does, in order to learn
to read, has to have that kind of intensive intervention. I'm
not sure that we know yet that that can't be done in a regular
classroom. That's what we're still trying to learn. And in
fact, the studies that we have done, in California and Texas
and New York, have kept these kids in a regular classroom,
provided the teacher with training skills in this intensive
modified phonics approach for these kids, and have demonstrated
this kind of an improvement with the kids in the regular
classroom.
Now, what we're trying to learn is, whether we can apply
these kinds of techniques in the whole classroom, so that
everybody is learning with the same kind of procedure, not just
the kids who are identified as high risk for learning
disabilities.
Mrs. Northup. Well, let me just say, you raise some
profound questions. And there are millions and billions being
spent that do not reflect the science that you're talking
about.
Number one, I would like to see the studies that show a
child that is mainstreamed in a whole language process that a
little bit of support, either an aide in that classroom, that
that remediates the child. I've seen no evidence of that.
And number two, what you've just suggested is that maybe
the whole class would learn better phonetically. There are
whole States, including Kentucky, that have just gone in the
direction of mandating, and I have to tell you I was part of
that, mandating whole language for the school system, because
we were convinced that it engaged all children.
But if that leaves 20 percent of the population behind,
that's a pretty startling fact, especially if what you tell me
is that the older, the more traditional phonics based system
would benefit all children. Here's a system that 20 percent
lose out. I've seen no evidence, and I hope you'll provide me
the studies that you say give evidence, that it's just as
effective to try to have whole language classroom and one aide
in there, for example, that provides a little bit of tutoring
for kids that are learning disabled. That's entirely different
than intensive remediation.
And now we know from your studies that if this isn't
accomplished by third or fourth grade, they're left behind
forever. That's pretty powerful information and the education
community really ought to know about that.
Dr. Alexander. What we don't know, is if it is just as
effective. One of the issues we are trying to address now is
whether it is even more effective if the whole class is on a
phonics oriented approach and the whole class benefits from
that, rather than some kids one system, some another.

phonics based system

Mrs. Northup. Key question. That's a key question. But in
the meantime, we know that children that are learning disabled
need a phonics based system. Are we experimenting on whether we
can leave them in a whole language system and give them a
little bit of tutoring?
Dr. Alexander. Yes, we are trying to learn that, along with
these others. And really as a product of what we have learned,
other States have gone the opposite direction, States like
California and Texas that have been on a whole language system
are now mandating a phonics oriented approach. So the pendulum
swings.
Ms. DeLauro. Would the gentlelady yield?
Mrs. Northup. Sure.
Ms. DeLauro. Just to follow up, you're talking about third
or fourth graders, but with the information you're now
beginning to uncover, can we find out information about a child
that's learning disabled from zero to three? How do we find
this in the zero to three period? What then are the
implications?
What can be done to impact that at an earlier time, thereby
avoiding the process that winds up compounding year after year
after year and whether it's mediation, etc. How early we can
uncover the problem and what are the implications?
Dr. Alexander. That's a question that we don't have an
answer for yet. We thought we were doing pretty good to pick up
these kids at four or five. If we could pick them up sooner, it
would be terrific. We don't have the capability of doing that.
Mrs. Northup. Let me reclaim my time.
Ms. DeLauro. Sure.
Mrs. Northup. The fact is that these children learning in
the newer phonetic ways is a very proscribed system of
learning. It literally takes them from where their visual and
hearing impairment begins to the point of where they are very
accomplished readers. And there are whole schools that do this
now. They have a 95 percent success rate. And they've been in
existence long enough to prove that these kids graduate from
colleges, and they are not impaired in the future. A few of
them happen to be my children.
In the meantime, we have parent after parent whose children
go to the public school system who diagnose them as dyslexic,
who then the school says, we're going to give them, we're going
to mainstream them all day, every day, except for one hour on
Monday, Wednesday and Friday, or we're going to put a tutor or
whatever, and the child never gets out of the learning disabled
class. Meanwhile, we are paying Federal funds for this child
that's so diagnosed and never is remediated, when we know of a
system that works.
I think, I didn't realize until I listened to you and read
your statement how clear your evidence is in this area and how
abusive it is to those children who are in the public school
system that refuses to accept your scientific information.
Dr. Alexander. We're going to do the best we can, Mrs.
Northup, to get that information out. I described earlier to
Mr. Porter some of the efforts, and to Mr. Hoyer, some of the
efforts we're making to do that. We will have a learning
disability summit co-sponsored with the Learning Disabilities
Association here in Washington in April, with the concluding
day here on Capitol Hill. Efforts will be made at that time for
some very broad dissemination to Congressional staff members.
And also, this again will be a joint effort with the
Department of Education. So we are trying to get information
out that we have so far. We are trying to broaden the research
base that we have to examine some additional questions about
how best to serve these children, and hope that we can turn
around a situation that we know now is intolerable.
Mrs. Northup. Well, in the meantime, since we have a system
that works that's not available in most school systems,
intensive remediation based on phonics in first grade, maybe
what we need is for children that are diagnosed to have a
voucher so that they can go to these special programs for three
years, and go to a school that has a 95 percent success rate,
so that they get out of not having to be remediated the whole
rest of their educational years.
Mr. Porter. The gentlelady's time has expired. We do have
Dr. Slavkin and the Dental Research Institute yet on our
afternoon agenda. The gentleman from Mississippi has asked you
to yield. Why don't you yield to the gentleman then we'll
finish our discussion.
Mrs. Northup. I would be happy to yield.
Mr. Wicker. I really didn't take all my time. [Laughter.]

phonics

Just a quick follow-up on that. Is phonics the answer for
everybody? An administrator told me that there's a substantial
population where phonics doesn't work at all.
Dr. Alexander. That's why we need to be a bit careful about
saying that this is the approach for everybody. There are some
kids, the majority of kids, who learn fine with the whole
language method. We don't know whether they wouldlearn equally
as well if we had an all phonics method.
Probably with this, as with most things, the truth is
somewhere in between, that most kids probably learn best with
an initial phonics approach, and then move better into a whole
language approach, as they are ready and able to do so.
We do need to do some additional studies to find out, just
what is the best way to teach not just the LD kids, but the
kids who are not LD as well, and how to accommodate the needs
of a variety of kids in a regular classroom to the best extent
that we can.

research on fatherhood

Mr. Wicker. Thank you. And my last quick question concerns
your Institute leading a Government-wide initiative to improve
research on fatherhood and develop policies to assist and
encourage men in their role as fathers. Other than the obvious,
what are you accomplishing there?
Dr. Alexander. This is a broad based kind of an approach.
Part of it is trying to just improve the Federal statistics
base. We have a lot of statistics and measures about mothers,
about children, but not nearly as many about fathers. We need
to get better information about fathers, their participation in
raising children, how their work and family responsibilities
are shared, just what they do in terms of their engagement with
children these days. Their roles are changing, as is a mother's
role.
We're also trying to look at various influences on how a
father is able to fulfill his role in the home. Jobs,
joblessness, time, and a variety of other factors. So it's a
very broad kind of an approach. This has been underway now for
about a year and a half. There have been several conferences on
this.
There will be sort of a wrap-up conference held at the
National Institutes of Health in two weeks. And this will bring
together a number of the different efforts that have been going
on in various agencies to both improve the statistics effort
that the Federal Government is engaged in to gather information
about fathers, and their participation in the family and work
types of activities, as well as efforts to stimulate an
increased amount of research on fathers and their role with
children.
Mr. Wicker. Thank you.
Mr. Porter. Thank you, Mr. Wicker.
Dr. Alexander, thank you for your very good testimony, and
for the wonderful work that you do at your Institute, the
honors that have been received by researchers, both within the
Institute and funded by the Institute. It's very, very
impressive to us. Obviously the recognition is well deserved,
and we appreciate the fine work that you're doing there.
Thank you very much.
Dr. Alexander. Thank you, Mr. Porter. We appreciate your
support.
[The following questions were submitted to be answered for
the record.]

[Pages 1665 - 1736--The official Committee record contains additional material here.]

----------

Thursday, March 6, 1997.

NATIONAL INSTITUTE OF DENTAL RESEARCH

WITNESSES

HAROLD C. SLAVKIN, DIRECTOR
DUSHANKA V. KLEINMAN, DEPUTY DIRECTOR
YVONNE H. DU BUY, EXECUTIVE OFFICER
EARLENE S. TAYLOR, BUDGET OFFICER
DR. HAROLD VARMUS, DIRECTOR, NIH
DENNIS WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF
HEALTH AND HUMAN SERVICES

Mr. Porter. The subcommittee will come to order.
Next on our agenda is the National Institute of Dental
Research. Dr. Slavkin, welcome. We're delighted to see you.
We're sorry, we're a little late in getting started here. We
had a very--obviously you heard the very spirited discussion we
had at the end, there.
Please introduce the people who are with you at the table
and then proceed with your statement.

Introduction of Witnesses

Dr. Slavkin. Thank you.
To my left is Yvonne du Buy, the Executive Officer for the
Institute; and then to her right is Earlene Taylor, our Budget
Officer; our wonderful Deputy, Dushanka Kleinman; and of
course, Dr. Varmus and Mr. Williams.

Opening Statement

I'm celebrating my 20th month as part of Dr. Varmus'
leadership team, and at the same time, I'm getting ready to
celebrate a birthday that I would like to share with you, and
that is the 50th birthday of the National Institute of Dental
Research. On June 24th, 1948, the Dental Institute was created,
at a time when life expectancy was about 62 years of age, when
dental caries, tooth decay, was rampant in the United States,
and when the typical adult could look forward to being
edentulous by the 45th year of life.
Some 50 years later, the United States is enjoying the
finest oral health in the world, in no small measure because of
the investment in the science of oral health. Children born
today can pretty much take for granted fluoridated drinking
water, fluoride in toothpaste, mouthwashes, dental sealants,
panorex x-rays, all kinds of preventive measures that improve
oral hygiene.
The measurable outcome is that 90 percent of the adult
population in this country still have their teeth at the time
of death. That is a remarkable tribute to a relativelymodest
investment in the National Institute of Dental Research. It's
calculated that this investment is saving roughly $4 billion per year
in the oral health bill of the United States.
That is a wonderful yesterday. But as we take inventory of
where we are today and look to the future, there are some
terrific things going on. Last year when I had an opportunity
to give my first show and tell, I was very excited about
sharing with you an exciting paper that was published in Nature
Genetics in which an overview was done showing that there were
40 craniofacial syndromes in which the genes had been
identified and had been mapped to particular chromosomes, and
that a molecular understanding was evolving for diagnosis.
That was in February of 1996. We now have identified and
mapped over 100 such craniofacial syndromes. What I'd like to
show you with these prompts is an example of two of them that
are extremely interesting. This particular disorder, called
anhydrotic ectodermal dysplasia, was first diagnosed by the
famous Charles Darwin and written up in 1875. He had made a
trip to India and identified four generations of males who were
losing their hair, had no teeth, had no sweat glands, and
presented with this unusual phenotype, ectodermal dysplasia--
EDA.
Scientists supported by the NIDR as well as other
colleagues around the world this year, in August of 1996,
reported the EDA gene on the X chromosome, mapped it and found
it to be a transmembrane receptor associated with epidermal
tissues. This is leading to a standard diagnostic approach to
this disease.
Also, as you can see, these children are born without
teeth. The NIDR took the leadership in developing implant
technology to be able to create sort of miniature dentures that
are fabricated through the life of these children until they
reach maturity. These are individual children who have high
self-esteem, can get through the socialization in the school
setting and go on to become college graduates and do very, very
nicely.
The next example I want to highlight is a counter-intuitive
discovery, primarily done by our colleagues at Johns Hopkins,
at one of our centers for craniofacial anomalies led by a very
outstanding geneticist, Mimi Jabs. This is an example in which
one human gene, when there are multiple point mutations, a
misspelling in one letter of the genetic code, gives rise to
five different syndromes, all due to these mutations in a very
particular region, a busy region in the molecule of fibroblast
growth factor receptor type 2.
This discovery is leading very quickly to new diagnostics,
opening up a better understanding of normal development. These
same observations are also relevant to other Institutes at the
NIH and other colleagues.
The last example is looking at this child with ectodermal
dysplasia with no teeth, and the inability to have a dentition.
An area has evolved over the last few years referred to as
biomimetics, to mimic biology. That is, if one knows enough
about the biology, then in theory, one could design and
fabricate a biological solution to certain kinds of clinical
problems.
Here on your left is a typical example of growing cells in
tissue culture in two dimensions where over time, they
aggregate and make cartilage, which is stained in a bright blue
color.
Scientists have recently developed a strategy where you can
take these same cells but grow them in a matrix and produce a
three-dimensional form. In the lower right of the figure, you
can see efforts to fabricate structures that have three-
dimensional forms--a biomimetic approach toward developing new
joints, new synovial joints, new temporomandibular joints, new
hip replacements, new cardiovascular valves.
In this area, through the generous support of Dr. Varmus,
and through collaboration with the Heart Institute, we're
starting an initiative on new therapeutics, taking the basic
biology and moving it towards the ultimate realization of
having biological solutions to knee joints or hip replacements
or tooth replacement or valves or any of those tissues which
need to be repaired, regenerated or augmented.
So that is a reflection of where we are at this point. And
I just wanted to mention in closing that as a smaller
Institute, our future, if you will, is through leveraging our
resources with other partners to be able to pursue these kinds
of problems. For example, I'm pleased to report that by
collaborating and co-funding with the National Cancer
Institute, we've now set up four centers of oral cancer in the
country. By collaborating with the Burroughs-Wellcome
Foundation, we've been able to set up a genome study of a yeast
called candida albicans which is expressed in immunosuppressed
individuals. We hope this effort will lead to new diagnostics
and new therapeutics.
In closing, Mr. Chairman, the fiscal year 1998 request for
the National Institute of Dental Research is $191,081,000. I
would be very happy to answer any of your questions.
[The prepared statement follows:]

[Pages 1740 - 1747--The official Committee record contains additional material here.]

Mr. Porter. Dr. Slavkin, thank you for your excellent
statement, I might say without notes, except you had to read
the final number. [Laughter.]
Dr. Slavkin. That's the hard part.
Mr. Porter. Well, that was a very impressive presentation,
and we appreciate it very much.
Dr. Slavkin. Thank you.

dental amalgams

Mr. Porter. You're funding two clinical studies examining
the health effects of mercury-containing dental amalgams in
children. This has been a concern for some time. Do you expect
these two studies to provide definitive information about the
safety of amalgams?
Dr. Slavkin. The short answer is, I hope so. A number of
people over the last five or six years have looked at the
clinical efficacy and the costs and benefits of dental
amalgams. To date, we have no scientific evidence that says
that dental amalgams are harmful.
But we do have a very strong environmental concern to try
not to contribute to putting mercury into the environment.
We're supporting research to quickly come up with a non-mercury
containing solution in the short term. We're doing two
prospective randomized clinical trials, one taking place in
Lisbon, and the other taking place in New York, in northern New
York, near the University of Rochester.
The effort is designed to look at, with modern assays, if
there are immunological consequences, effects on antibiotic
resistance, or is there anything that we can define as a
negative consequence of dental amalgam alloys. Those studies
are just beginning. They are supported for five years. We hope
they will put closure on this issue.
Meanwhile, and independently, we want to get away from
mercury-containing dental restorative material being used on
people in this country. And that is the tack that we're taking.
Mr. Porter. Well, I think you answered this, but let me ask
it anyway. Given that children today have so few cavities, have
you had trouble finding a study population for your clinical
trial?
Dr. Slavkin. In this country, we seem to have at least two
kinds of children. We have children and grandchildren, like my
own, who have no evidence of dental caries. This is probably
shared by many of us in the room today. But we have a number of
children in this country, especially in the inner cities of
this country, who, with limited access and with a number of
issues associated with poverty and inappropriate nutrition,
etc., do present rampant dental caries, and do need solutions
to those problems.
So, in almost every urban setting in this country, one can
find appropriate populations to look at.
Mr. Porter. Does the low incidence of caries mean that
there is little commercial interest in developing alternative
substances for fillings, should problems be found with the
currently-used amalgams? In other words, if you found something
new, would you get a commercial interest in it?
Dr. Slavkin. Despite the remarkable progress that's been
made from fluoridating drinking water and developing dental
sealants and improving dental hygiene, even in that context, in
the United States last year, 200 million fillings were placed.
In part because of our cultural diversity, a number of people
live in this country who were not necessarily brought up with
fluoridated drinking water and fluoridated toothpaste.
So as a consequence, the background noise, if you will, of
this advance in technology, is still 200 million fillings were
placed last year, of which about 70 million were dental
amalgams.

biomimetics

Mr. Porter. You are increasing your effort in biomimetics,
the creation of replacement parts for body tissues and bones,
which you discussed here. You indicate that it is a rapidly
growing area in biotechnology with considerable private
investment interest. If that is the case, what is the
appropriate role for your Institute in developing these
materials? What can you contribute that private industry
cannot?
Dr. Slavkin. In the hearings this year and last year, I
think you've seen example after example where the NIH is
perhaps at its best in doing fundamental basic scientific
inquiry. We then move into translational research, where there
are prototypes, before it goes to industry, before it goes to
practicality, where expertise by NIH-supported scientists
fulfills that requirement in this process of going from basic
to translational to patient oriented to eventually the
community.
In this case, the opportunity is really focusing at that
translational level; for example, to move the discoveries of
extracellular matrix molecules and their different genes toward
prototypes for the replacement of a cornea, replacement of the
pancreas or salivary glands, or certain kinds of manipulations
for cartilage, bone and ligaments. And there is a very exciting
interest in the investigator-initiated research community to
really pursue these and bring these ideas to fruition.

fluoridated water

Mr. Porter. Thank you. We've heard for years of the
benefits of fluoride in preventing dental caries. But
apparently India is in the midst of a battle about whether
toothpaste with fluoride should carry warning labels, because
very high levels of fluoride occur naturally in the drinking
water, to the point that millions of Indians have been crippled
by fluorosis.
Is this phenomenon of heavy fluoridation of water an
aberration of nature that doesn't occur elsewhere in the world?
Dr. Slavkin. It's a very good question, and the answer is
no. The creative insight that really led to fluoridation was
observed by an American dentist in Colorado, Frank McKay, who
made the observation that children who lived in Colorado had
something called ``Colorado Brown-Stained Teeth.'' These
children were consuming water from the Colorado River, and in
that community, there was no evidence of tooth decay.
Scientists were able to make that leap and that association.
That is the downside of fluoridation, that like everything
there is a benefit and a risk. In levels of one part per
million fluoride, the benefit is to profoundly reduce dental
caries. If you have excess fluoride in the water supply, or in
the food supply, then mottled enamel or fluorosis becomes
evident. In those parts of the world that have that
situation,they have either put it into the food supply in
excess, or it's in the natural water in excess, so they have to
be concerned, and act accordingly.
Mr. Porter. So why would they want to put it in their
toothpaste at all, if they have an excess already? Why do they
need to?
Dr. Slavkin. I have not been privileged to the discussions
they're going through. I don't know.

tmd conference

Mr. Porter. At last year's hearing, you were frank with us
in saying that we don't know much about how to treat or even
diagnose temporomandibular disorder, TMD. You held a technology
assessment conference last May on TMD management. Did that
conference produce any agreement about treatments, or at least
promising research areas?
Dr. Slavkin. It did an excellent job in identifying
excellent research opportunities, specifically to focus on the
etiology and pathogenesis of temporomandibular joint diseases
and disorders. But it very strongly concluded that at this time
in history, there is not a treatment that is being recommended.

oral complications of diabetes

Mr. Porter. What studies are you supporting in the area of
diagnosis, treatment and prevention of the oral complications
of diabetes?
Dr. Slavkin. Diabetes, as I'm sure you're aware, is an
extreme challenge because of the oral manifestations, such as
diabetic neuropathies, ulcerations that don't heal, teeth that
become mobile, rampant yeast and bacterial infections, and
activation of viruses. There's a whole field of problems. In
particular, the Pima Indians in this country have been looked
at, because they have the highest frequency of diabetes. They
have been remarkably helpful in illuminating some of these
kinds of problems.
We have investigators both in our intramural research
program and in our extramural research program who are looking
at the genetics of diabetes, looking at ways of focusing on
this balance between anabolic and catabolic degrading tissues
processes. So it's an effort to understand the physiology and
the cell biology between insulin and glucagon. We are pursuing
that in terms of basic research and ways of making earlier
diagnoses; we are interested in using saliva as a non-invasive
tissue to be able to diagnose glucose levels and correlate them
with serum levels to determine pre-diabetic conditions.
We're also in the early talking stages of developing a
relationship with the Juvenile Diabetes Foundation, based in
New York, to see about co-funding opportunities. So we're very
interested, and are supporting that work.

future expectations

Mr. Porter. Dr. Slavkin, you mentioned that your Institute
will be celebrating its 50th anniversary next year. With the
pace of science and technology, perhaps it's unfair to ask, but
could you hazard a guess as to the areas of accomplishment that
are likely in dental research in the next 50 years?
Dr. Slavkin. I hope there are. I guess it's easy to say
because many of us won't be there to keep score. But the human
genome project, of course, will be completed before 2005. A
gene-based diagnosis for the viral infections and the bacterial
infections and yeast infections, I believe, will be a given.
Drugs will be designed based on the legacy of the genome study,
so that there will be enormous specificity for analgesics for
the management of chronic pain, for example. I think we'll
understand bone formation and bone resorption, so that issues
of osteoporosis affecting the craniofacial areas will be
significantly advanced.
But having sat through the previous interview with my
colleague, Dr. Alexander, one of the areas that needs attention
is birth defects and the issue of trying to make inroads in
reducing the burden of birth defects. Currently, the numbers
are 1 in 28 or 1 in 33 live births. That is just too high for a
highly civilized country.
So in that area, it really leaves the bench sciences, and
it becomes public education and better communication and
modifying human behavior, and a better understanding of
prenatal care. Those areas, I suspect, will go much slower,
because they're dealing with the philosophy of the human
condition. And in those areas, we tend to progress very slowly.
Mr. Porter. Thank you, Dr. Slavkin.
Mrs. Lowey has asked to be taken out of order, because she
has to catch a plane. So, Mrs. Lowey.

osteoporosis and oral bone loss

Mrs. Lowey. I'll just ask two brief questions, and I thank
you.
I'm very interested in the connection between osteoporosis
and oral bone loss, if there is. Are you continuing to pursue
the relationship between osteoporosis and oral bone loss, and
what do you feel are the potential benefits of this research to
people who may be at risk for osteoporosis?
Dr. Slavkin. As you probably heard earlier in the day from
my colleague, Dr. Steve Katz from NIAMS, we and NIAMS and Aging
and NIDDK co-support a number of activities and initiatives
focusing on women's health as specifically related to
osteoporosis. A data base has evolved that is very compelling
that osteoporosis is a player in the resorption of bone in the
oral cavity.
But to define precisely under what conditions, with
estrogen therapy and without estrogen therapy, we have studies
that are currently in progress, one at the University of
Alabama in Birmingham, with very high-resolution radiography,
to precisely define changes in bone density, bone density mass,
and to identify individuals who are truly at risk as opposed to
sort of a background of osteoporosis that might be tolerable in
some situations.
The answers are not yet in. Those are still research areas
in progress. We're all looking at understanding the basic
principles of coupling between bone formation and bone
resorption, identifying the cytokines, identifying what turns
on osteoclasts, and also how to retain the bone matrix
optimally throughout an extended life span. It's still very
much basic research inquiry at this point.
Mrs. Lowey. I thank you. Just among my colleagues, this
recently has been the subject of conversation. There seems to
be a good deal more work in osteoporosis generally, rather than
any connection to bone loss. Is that because this is more
recent research, and there really hasn't been much work on bone
loss in the mouth?
Dr. Slavkin. You touch upon a very profound issue.
Mrs. Lowey. Frankly, I was surprised, as we were pursing
this.
Dr. Slavkin. Yes. All of us in the room who were
undergraduates of some fine university, we recognized there
were two cultures, the science versus the humanities. And in
the research area, until recently, there was not as much
crossover, cross-disciplinary, multi-disciplinary activity as
there should be or could have been. I think you're
experiencing, and we all are, much more collaboration. People
are realizing that the problems of medical or dental
orthopedics, and the orthopedic-related issues, have an
enormous amount in common.
So there's co-supporting, people are doing grants together,
working in centers together, going through training programs
together. And I think that's changing the scientific culture.

gender and pain

Mrs. Lowey. Thank you. And lastly, I understand there have
been some recent findings relating to gender and pain. Could
you share some of these findings with us?
Dr. Slavkin. It was an exciting observation that was
published in November of last year in the periodical, Nature
Medicine, by a group at U.C. San Francisco, John Levine and his
colleagues. They were basically using a model of men versus
women having wisdom teeth extracted, and looking at different
kinds of analgesic drugs; specifically, they're called mu kappa
opioid or kappa opioid analgesics.
The surprise was that a particular regime of analgesic
worked specifically well for females and not for men and vice
versa. That opens up a very fresh opportunity to rethink the
differences between men and women in terms of the reporting of
pain, the tolerance of pain, the response to opiates, and the
response to non-opiate analgesics. There are many scientists
who have become very interested, both at the fundamental
science point of view in terms of receptors and signalling
processes, all the way to what could this mean clinically.
Dr. Varmus last year gave a terrific lecture at the
American Pain Society meetings which were held in Washington.
He indicated that he was asking Zach Hall, Director of the
Neurology and Stroke Institute, and myself to co-chair a trans-
NIH effort to bring everyone together who has a common interest
in the management of chronic pain and the science of pain, to
really see if we could coordinate internally what we're doing
much more effectively, and then from that position of strength,
do the same with other Federal agencies when appropriate.
To get this started, we created a trans-NIH interest group
which is now in place. We're planning a ``New Directions in
Pain'' research conference which will be held at the NIH in
November, I believe it's November 21st and 22nd, at the Natcher
Building, which will focus on trying to get people who are not
necessarily in the pain research field to move their expertise
and their intellectual prowess to begin to think about these
areas.
We have gotten a buy-in from 21 of the Institutes and
centers and offices at the NIH. I think there's a very terrific
interest in trying to see if we can get this much better. This
is a $100 billion a year industry, pain pills. This is
impacting on basically four out of every five adults over 65,
who suffer from some type of chronic pain. So it is, with
changing demographics, a very significant problem. I think the
NIH is trying to position itself to be even more effective.
Mrs. Lowey. Thank you. And thank you, Mr. Chairman.
Mr. Porter. Thank you, Mrs. Lowey.
Before I call on Mr. Wicker, Dr. Slavkin, I have to leave
at 3:30 and I'm going to ask Mrs. Northup to take the chair and
finish the hearing. But let me say that you're doing a
marvelous job as one of our newer directors. You're obviously
very excited by the work that you find yourself in and the
great progress that is being made, and we very much appreciate
the fine job that you're doing.
Dr. Slavkin. Thank you.
Mr. Porter. Mr. Wicker.

tmj disorders

Mr. Wicker. Thank you, Mr. Chairman.
Let me just ask you to answer basically one question. If
you would, elaborate on your answer to the Chairman about TMJ
disorder. What do we know about the nature of this disease, and
why did the panel come to the conclusion that it did?
Dr. Slavkin. The temporomandibular joint is a synovial
joint like the joints in our elbows or knees. But it's one of
the busiest joints in the body, because it's essentially always
moving.
Mr. Wicker. Some more than others. [Laughter.]
Dr. Slavkin. Yes. As we breathe and speak, etc. And as you
might imagine, when you look at it clinically, there are 7
million people who report temporomandibular joint dysfunction.
Most of these people are women. Most of the women are of child
bearing age. It is not clear how much of TMD is a problem of
premature osteoarthritis, how much of it is a neuromuscular
disorder, or how much of it might be transient or hormonal.
Clinicians have taken on the problem basically from their
specialty points of view. Some assumed that the surfaces of
teeth were the variable and would try to adjust the surfaces of
teeth. Others performed surgical removal of the joint and put
in silastic implants, thinking that might be the solution to
this problem. And others have used behavioral modifications,
biofeedback therapies, and nutritional changes.
The panel came together, looked at the information that was
available, and concluded that without prospective, randomized
clinical trials, the evidence that is available does not
support any one of these approaches with clinical efficacy. The
recommendation was, we need to get a handle on the etiology and
pathogenesis of TMD. And TMD may turn out to be four or five
disorders rather than a single disease or disorder. We put out
an RFA, we got a good response, we have funded a number of
grants, we've got people around the country beginning to work
on this problem.
We're hopeful that in the near future, we will know about
the etiology and pathogenesis, and then there could be a
rationale that's evidence-based for diagnosis and treatment.
Mr. Wicker. Your grants that you funded, how are they
progressing and are you expecting results from them?
Dr. Slavkin. From the conference that was held, which was
last April, to the funding of the grants which probably
happened in September of 1996, we haven't gone far enough to
get a progress report. There's a large scientific meeting
that's coming up later this month in Orlando, where there will
be 4,000 or 5,000 scientists who are interested in oral health.
And within that mix, some of the preliminary studies on TMD
will be reported. But it's still quite early.
Mr. Wicker. Is TMJ the subject of discussion by your trans-
NIH pain research consortium?
Dr. Slavkin. Yes.
Mr. Wicker. Thank you.
Mrs. Northup [assuming chair]. Mr. Hoyer.

fluoridation

Mr. Hoyer. Dr. Slavkin, welcome.
Dr. Slavkin. Thank you.
Mr. Hoyer. I've had a great interest in the Dental
Institute over the years. Dr. Loe, of course, an outstanding
Scandinavian leader, and we Danes cared about that.
And he pointed out, which you have also pointed out, I
believe you used the $4 billion figure in your statement, in
terms of the savings that have been effected by theinvestment
of a relatively small amount of money, a relatively large payoff.
I asked Dr. Lenfant a little earlier in the week about a
similar analysis. It's more difficult, obviously, there,
because it's not as discrete an analysis. Nevertheless, we
obviously have gotten a real payoff for the investment that we
made.
In the course of your testimony you mentioned, and the
Chairman was talking about the fluoridation, the Communist
threat that was going to undermine the country, as you recall,
it occurred to me--well, I have all these personal experiences
and have no place to put them. [Laughter.]
Up until 1989, I always lived in a city or a suburb, for my
entire life. And as a result, I drank city water, through a
pipe. Now I live in the country and I drink water from the
ground, the aquifer. It occurred to me, and my wife had us get
some bottled water as well, some spring water.
Do either one of those have any fluoride in them of
significant value to oral health? Or are we undermining the
oral health of rural people? It just never occurred to me. But
are rural people, other than getting Crest or whatever they
get, they don't have fluoride in their water.
Dr. Slavkin. Well, Mr. Hoyer, we typically don't provide
the service of coming to peoples' homes and measuring the
fluoride level, but in your case----
[Laughter.]
Mr. Hoyer. I can see it tomorrow in the Washington Post,
Hoyer pressures NIH to test his fluoride. [Laughter.]
Is there a difference in the oral health of rural children
on non-city fluoridated water?
Dr. Slavkin. It really depends, case by case. We have in
the country perhaps 10,200 water supplies that are fluoridated
at the level of one part per million. And there are a number of
sources of water which already are fluoridated, where there is
no need to add fluoride.
And in the food supply, fluoride has been added to
mouthwashes and some brands of commercially available bottled
water that people use in their homes.
Mr. Hoyer. That's my question. Commercially bottled water
does add fluoride?
Dr. Slavkin. I can't speak universally.
Mr. Hoyer. Read the label, I understand.
Dr. Slavkin. Right. But it is an element in the larger food
supply, and because many people purchase food that comes in
cans with fluoridated water, there is always the potential risk
of having too much fluoride, vis-a-vis mottled enamel.
Mr. Hoyer. I heard you say that. That was interesting. That
was not the question I had, but I was interested, because it
occurred to me that an awful lot of kids live in rural areas
that don't have the city water.

diagnosis of cleft palate

In any event, cleft palate, you've talked about a lot of
this and I understand that was your first, I was a little late,
I missed your first slide. In terms of cleft palate, can that
be diagnosed in utero, and can it be affected, can we operate,
can we do something to alleviate the condition in utero?
Dr. Slavkin. Clefting occurs in approximately 1 in 500 live
births; in utero, it can be diagnosed with ultrasound,
noninvasively. But the formation of the face begins to happen
at the 19th day of pregnancy, post-fertilization. So the face
is forming usually before the woman knows that she's pregnant.
The ultrasound diagnosis is made after these developmental
processes have taken place.
So the state of the art is really to have teams of people,
pediatricians, plastic surgeons, various dental specialties,
work together to address the special needs of a newborn child
with surgical closure. We don't have a way in utero to correct
this facial deformity at this time. The treatment that is
currently available runs about $100,000 to $110,000 per child.
And so looking at 1 in 500 live births per year, it's a
little bit under $1 billion a year in costs, and the treatment
extends from closure of the lip soon after birth to a series of
reconstructions that often go well into the adolescent years.
And clefting has speech and hearing consequences. So it really
requires a costly team approach to habilitate these kids so
they become productive and do very well.

medicare coverage for dental care

Mr. Hoyer. Doctor, last question, I know Mrs. Northup has
to leave--are we critical? Because I can stop if you need to
get out. They don't want to leave just a Democrat in the room
alone. [Laughter.]
They're very nervous about that. Everybody can understand
that concern, of course.
Congressman Cardin and I, and perhaps others, I don't know
how many co-sponsors we have, are about to put in a bill that
will deal with Medicare covering certain instances of
outpatient dental care. The premise being that the ounce of
prevention of that dental care will save effectively
substantial multiple dollars, because of the dental care that
is issued.
I'm not asking you a question about that, I don't know
whether you were aware of that or whether my staff--you're
shaking your head, you were aware of it. Okay, good.
But I think that in an era where we're talking about
prevention being cost-effective, Congressman Cardin and I,
Congressman Cardin is of course on the Ways and Means Committee
dealing with HCFA and dealing with the Medicare issue, believe
that this could be a real savings for seniors to get outpatient
dental care, if in fact it is related to certain specific areas
where the lack of care will then lead to much greater costs.
Again, that wasn't a question but I wanted you to be aware
of it. I'm glad to hear you're aware of it, and we'll be
following up with you.

dentist scientist program

I said that was the last thing, but I know my good friend
Nick Cavarocchi is in the back of the room here, who does a
terrific job for health care generally. And I have been very
interested, as you know, in the dental scholarship program and
fellowship program. I frankly have not focused on what the
status of that is. What is the status of that?
Dr. Slavkin. At the moment, in that pipeline of the dental
scientist fellows, they are being recruited for job positions
two or three years before they're completing their training.
The supply and demand issue is very skewed towards recruiting
the DSA fellows into dental and medical schools.
For many young people who are seeking that particular
career path, and measuring the outcome in terms of getting a
job and a very good job, they are very pleased. From our point
of view, the DSA program is part of an agenda for training and
then, in mid-career, retraining to keep people as current as
possible with all of these scientific opportunities that you've
been hearing about last week and this week.
We're very proud of the DSA program, which was an idea that
Harold Loe put forth a little over a decade ago. It's really
been staffing a lot of dental schools around the country with a
much higher caliber of faculty member. We're very proud of it.
Mr. Hoyer. Congresswoman Northup, I will tell you, you
heard that was Dr. Loe's idea. It was, but he made me think it
was my idea. And we worked on it pretty hard together.
[Laughter.]
So it worked pretty well. And you will have that
experience, sitting on this committee. A lot of people will be
able to give you Northup ideas.
Thank you very much.
Mrs. Northup. Thank you, Congressman.
I have one question in one area I'd like to ask you--
several questions. Before I start, I might point out to
Congressman Hoyer just a little bit of anecdotal advice. If you
start having dental problems after you've moved to the country,
before you think about fluoride, I've noticed that age has
something to do with that. [Laughter.]
Mr. Hoyer. Boy, oh, boy. This is a rougher hearing than I
thought it was going to be. I wouldn't know, but it's certainly
something I'll watch out for. [Laughter.]

spit tobacco and oral cancer

Mrs. Northup. Dr. Slavkin, I was surprised in your
presentation there was nothing about snuff tobacco and the
relationship between the use of snuff tobacco and cancer of the
throat and mouth. Does that fall under your investigation?
Dr. Slavkin. Yes. Briefly, one of the things we were very
pleased to do in this current year was to fund four centers for
oral cancer: one at the University of Alabama, a cooperative
program between the University of Chicago and Northwestern, a
center at U.C. San Francisco on the west coast, and M.D.
Anderson with the University of Texas at Houston.
Oral cancer is the life and death issue in oral health,
with about 42,000 cases a year, about 9,000 deaths, unusually
skewed towards African-American men who are 44 years of age or
older, who have the highest prevalence. I think it's the fifth
most common source of death of cancer in that particular
community.
And to address it, we absolutely are committed to a number
of programs designed to convince young people that chewing
tobacco is not the way to get better statistics in baseball.
You can do it without that. We're finding young kids trying to
emulate behavior, and thinking that spit tobacco is the linkage
to catching and throwing and so forth.
So we're working with organized baseball, we're working
with NCI, we're working with the Oral Health Alliance. The spot
announcements on television during the baseball series where
the athlete looks into the camera and talks about a successful
career without spit tobacco is part of this campaign.
Kentucky and Tennessee are two specific areas with very
high prevalence of oral cancer in relatively young people
because of the preponderance of this habit. And we want to do
something about that.
Mrs. Northup. Well, I am aware of the problems in Kentucky
and the rising use among the youth. And I hope that you will
focus a lot of research on it, and point that in the direction
of the education community, so that children become aware of
it.
Do you do studies about the amounts of fiberglass that
exists in snuff?
Dr. Slavkin. I can check. I am not familiar with fiberglass
as a component of snuff.
Mrs. Northup. I'm pretty sure I'm right, what my children
tell me is that the difference between snuff and chewing
tobacco is that there are the fine particles of fiberglass in
the snuff that ever so slightly, almost undetectable, develop
cuts in the gum so that the juice and the tobacco are
immediately absorbed into the bloodstream, as opposed to
chewing tobacco, which has an entirely different concept.
Dr. Slavkin. We will definitely look into it. I wasn't
aware of that.
Mrs. Northup. Would you let my office know if you all have
any evidence about that.
Dr. Slavkin. Sure.
Mrs. Northup. Actually, for several years, I have been
under the impression that that was a very well recognized
difference between those two products. So in fact, the research
and the cause and effect and the immediacy of the problem would
be different between the two products if that understanding is
correct.
Dr. Slavkin. Right.
Mrs. Northup. Are you beginning the research on oral cancer
in teens that comes as a result of the use, I'm talking about
teens and early 20s, of snuff and its effects?
Dr. Slavkin. Yes, I think there was, because of the
profound changes in our culture, a bias, not based necessarily
on science, that all cancer was a problem of more mature
individuals. But it's been rediscovered that we must pay close
attention to young children. And we're finding nine year olds
and ten year olds using spit tobacco in baseball leagues around
the country, in so-called well off socioeconomic communities as
well as in have-not communities. We will pay attention to this.
Mrs. Northup. Okay, Congresswoman Pelosi.
Ms. Pelosi. Madam Chair, I'm sorry, but other
responsibilities kept me from being here. I don't want to hold
up, I just want to get the testimony and read through it.
Mrs. Northup. Okay. That concludes our afternoon session.
Thank you very much.
Mr. Hoyer. Time to take a nap.
Mrs. Northup. That age thing. [Laughter.]
In closing, I'd also like to thank you, Dr. Varmus, for
being here the last week and a half, and I thank your
colleague. This has been very enlightening, very illuminating,
very interesting. I think the entire subcommittee has very much
appreciated your testimony and we look forward to continuing it
March 18th.
With that, I'll recess the committee until Tuesday at 10.
Thank you very much.
[The following questions were submitted to be answered for
the record.]

[Pages 1759 - 1807--The official Committee record contains additional material here.]

----------

Tuesday, March 18, 1997.

NATIONAL INSTITUTE OF MENTAL HEALTH

WITNESSES

STEVEN E. HYMAN, M.D., DIRECTOR, NATIONAL INSTITUTE OF MENTAL HEALTH
RICHARD K. NAKAMURA, PH.D., ASSOCIATE DIRECTOR FOR SCIENCE POLICY,
NATIONAL INSTITUTE OF MENTAL HEALTH
WILLIAM T. FITZSIMMONS, EXECUTIVE OFFICER, NATIONAL INSTITUTE OF MENTAL
HEALTH
GEMMA M. WEIBLINGER, SPECIAL ASSISTANT TO THE DIRECTOR, NATIONAL
INSTITUTE OF MENTAL HEALTH
J. RICHARD PINE, BUDGET OFFICER, NATIONAL INSTITUTE OF MENTAL HEALTH
HAROLD VARMUS, M.D., DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

Mr. Porter. The subcommittee will come to order.
We continue today with the hearings of the National
Institutes of Health. This morning we are pleased to welcome
Dr. Steven Hyman, the Director of the National Institute of
Mental Health.
Dr. Hyman, why don't you introduce the people at the table
with you and then proceed with your statement.
Dr. Hyman. Of course.

Introduction of Witnesses

I have to my right Dr. Varmus, the NIH Director, and Mr.
Dennis Williams from the Department.
And from the National Institute of Mental Health, beginning
on my left, Mr. William Fitzsimmons, Executive Officer; Mr.
Richard Pine, the head of our Budget Office; Dr. Richard
Nakamura, the head of our Policy Office. And this is Mrs. Gemma
Weiblinger, who is our Legislative Liaison and my Special
Assistant.

Opening Statement

It's my pleasure to appear before you to discuss the
research programs of the National Institute of Mental Health,
programs dedicated to understanding the brain, its role in
behavior, and what goes wrong in the brain to produce mental
illness. More than 5 million Americans have schizophrenia,
major depression, manic depressive illness, severe anxiety
disorders, obsessive compulsive disorders, anorexia nervosa and
other severely disabling mental disorders. Additional millions
of Americans suffer other mental disorders that occur across
the life span from autism in childhood to dementias frequently
complicated by mood disorders and psychotic symptoms in the
aged. All told, mental disorders cost the Nation more than $148
billion each year.
Throughout the world, moreover, the relative burden of
mental disorders will increase as a cause of disability and
death as medical science conquers infectious disease. Indeed,
the World Health Organization has noted that without marked
improvements in recognition and treatment in the next 30 years,
and I call your attention to this table up on the easel, and
you have a copy of this, major depression alone will rival
chronic ischemic heart disease as the single leading cause of
Disability Adjusted Life-Years lost worldwide. Thus it's clear
from a public health point of view that mental health demands
the best science that we can apply.
[See table 1.]

[Page 1811--The official Committee record contains additional material here.]

Fortunately, the opportunities for scientific progress have
never been greater. We now recognize that mental illnesses are
disorders of a specific organ, the brain, just as coronary
artery disease is a disorder of a specific organ, the heart.
Given the complexity of the brain, the task of understanding
its function and dysfunction is formidable. But ultimately to
make progress, we must understand mental disorders in terms of
molecular and cellular processes in the brain, the assembly of
neurons, that is the nerve cells into circuits, and the brain's
interaction with the environment, including the broader context
in which we all live.
Examples of progress from the past year include
identification of a protein marker on the surface of nerve
cells that, early in brain development, may guide
specificemerging cells to become part of the brain's limbic system, a
set of structures that are involved in the control of motivation and
emotion.
In addition, observation through functional magnetic
resonance imaging has permitted us to see alterations in brain
circuitry during different processes of learning, that is, the
experience of life literally changes brain function in a long-
lived way. In addition, for the first time, we've seen
convincing evidence through neuroimaging of the circuits
involving a structure called the amygdala, which are the cause
of fear and almost certainly anxiety disorders in the human.
With the tools of molecular genetics, a team has identified
a gene which is likely to prove to be the ``master controller''
of our daily biological rhythms, including the sleep-wake
cycle, which is markedly disregulated in mood disorders, and is
also crucial to understanding a variety of human problems,
ranging from insomnia to jet lag.
Two teams together have markedly deepened our ability to
add, alter or inactivate genes in the mouse, leading to what I
think are remarkable discoveries on the molecular and cellular
bases of memory of place in the rodent. But more importantly,
providing novel methods of dissecting gene-brain behavior
relationships.
It is noteworthy that much of the science that will get us
to the level of understanding that we need to deal with mental
disorders is interdisciplinary, spanning the level from
molecules to behavior and even more broadly, to social context.
As we look to the coming year, we will continue to strengthen
our efforts in fundamental molecular biology, in neuroscience,
in basic behavioral science. We must also look to success in
the realms of clinical and health services research. Thus we
are engaged in a very thorough review of our approach to the
complex human genetics of vulnerability to mental disorders. We
are planning a renewal of our efforts in clinical trials and in
the understanding of the effectiveness of new treatments in the
complex settings provided us by the real world.
I want to emphasize our commitment to children, in
particular, our commitment to developmental brain research and
clinical and services research focused on childhood and
adolescent mental disorders. As many as 20 percent of young
Americans between the ages of 7 and 14, approximately 10
million children, have a mental disorder that is enough to
compromise their ability to learn and to develop, for example,
normal family and peer relationships. Our knowledge base in
this area clearly is an area where we must focus.
One example is a severe disorder of communication and
behavior which is autism. Family and twin studies point to a
genetic cause for autism, and NIMH researchers at three
different locations are now studying families using a
combination of strategies. And I think the likelihood of
finding susceptibility genes in the coming years is high.
I highlight the area of autism, though, also because it
reminds me to point out that this is a new arena of cooperation
among four NIH Institutes, each of which brings to bear
valuable and different perspectives on the problem of autism.
And the collaborative spirit at NIH, I think, makes all our
work better.
Let me conclude by looking forward in the clinical and
services realms, since I highlighted in the beginning progress
more in the basic science realms. In the coming year, as I
noted, we'll see new initiatives in the genetics of
vulnerability to mental disorders. We will push to develop
novel programs to translate what we learn from basic brain and
behavioral research to clinical applications, ranging from
neuroimaging to therapeutics, and we will begin reforming our
approach to clinical trials and adapting what we learn to the
needs of people in the real world.
An additional important task for mental health services
research will be the study of the impact of managed-care on the
mentally ill, a particularly vulnerable population.
For the scientific activities that I have briefly
highlighted here and for related programs, NIMH requests
$629,739,000 for the fiscal year 1998.
Thank you, Mr. Chairman, and I will be pleased to answer
any questions.
[The prepared statement follows:]

[Pages 1814 - 1817--The official Committee record contains additional material here.]

global burden of disease

Mr. Porter. Thank you, Dr. Hyman.
As you mentioned, the 1996 WHO study of the global burden
of disease found that neuropsychiatric disorders are important
to health status and economic productivity in developing as
well as developed countries. To reiterate, the study predicted
that major depression will be the second leading cause of
disability worldwide in the year 2020. If these figures are at
all accurate, are we likely to have the therapeutic tools to
address disorders of this magnitude, and will developing
countries be able to afford them?
Dr. Hyman. That's a very important question. And of course,
not much farther down the list would come other mental
disorders, such as manic depressive illness and schizophrenia.
And just to reiterate, the demographic trend you point out
reflects partly the hope that we will be able to conquer the
first three on this list, which are infectious diseases in the
developing world. And I would also point out that the
demographic trends which create the picture that is projected
for 2020 already in many cases are in place in the developed
world.
In order to make an impact, we clearly need new therapeutic
tools, in several regards. First, taking major depression as an
example, we are fortunate to have medications, a combination of
which can now treat depression in 80 to 90 percent of people.
But given a disorder that is so common and so disabling, the
fact that there are 10 to 20 percent of people who remain as
yet fairly treatment resistant is a problem. In addition, we
have not yet been able to fully address the issue of
recurrences throughout life, and indeed, in many cases, the
depression may become more treatment refractory over time. We
need more research, therefore, in understanding the fundamental
brain mechanisms that lead to depression in order to develop
really novel medications that will supplement the armamentarium
that we have.
In addition, staying close at home here in the developed
world, we have a major issue in terms of the recognition of
major depression. It is unfortunately a fact, demonstrated by a
great deal of research, that major depression is recognized
only about 40 percent of the time in many clinical settings,
and under-treated when it is recognized. So that in addition to
providing new treatments, we also need an educational effort to
overcome stigma, to overcome the unfortunate tendency not to
see mental disorders as real brain diseases which are worth
intervening in.
Mr. Porter. And about the cost, if you have the therapies
and you have the diagnosis made in developing countries, is the
cost for these drugs high or low, and would they be affordable?
Dr. Hyman. The cost of these drugs is certainly not cheap.
But to give you an example, the most modern antidepressants
that are widely used in the United States cost between $70 and
$90 a month. And while this is a staggering cost for developing
countries, there are first of all tradeoffs, in that, the use
of these drugs will markedly enhance economic productivity.
More than that, we hope that as new compounds become available,
competition among various treatment modalities may indeed
decrease the overall costs.
Mr. Porter. I recall about 10 years ago discussing what the
developing world could do about AIDS. And WHO told me that they
had virtually, in most countries, for example, in sub-Sahara
and Africa, they had no money to spend whatsoever on treatment,
no money to spend to even help people as they were dying from
the disease. And the only thing they could hope to do was spend
a little bit of money on public education to try to prevent the
disease from occurring in the first place. Seventy dollars a
month would be--a dollar a year would be a lot.
Dr. Hyman. I agree. One thing that is rather striking,
however, if you look at this list, is that four of the five
diseases are actually preventable, based on obvious behavioral
maneuvers. And interestingly, that does not include unipolar
major depression. But ischemic heart disease, cerebrovascular
disease and chronic obstructive pulmonary disease, are
projected to be such problems based on the growing epidemic of
tobacco use in the developing world. And of course, road
traffic accidents also have the potential for behavioral
prevention.
It is interesting, therefore, that one of the things
implied by your questions is that hopefully we can, through
research on risk for the etiology of major depression,
schizophrenia and other mental disorders, eventually prevent
their occurrence. But at the present time, there clearly are no
known readily modifiable environmental risks.
Mr. Porter. I hope that by the year 2020 we're sending them
our pharmaceuticals to help them, rather than our cigarettes to
kill them.
Dr. Hyman. I agree.

use, needs, outcomes and costs for child and adolescent populations

Mr. Porter. You have temporarily halted a large research
project on children's mental health services known as UNOCCAP
because of concerns about the study design. I understand the
project has a $45 million price tag. And it certainly seems
prudent to review its design before going into the field. What
are the major concerns about the UNOCCAP study? Could the study
be modified to address these concerns without major delays, or
would you have to initiate an entirely new project?
Dr. Hyman. This is a very important question for our
Institute. It is clear, first of all, that we have great needs
in the area of child mental health, including understanding the
epidemiology of mental disorders in children and also their
service needs. Just a moment's reflection tells us that
children are not just like little adults. And so the diagnosis
of depression in a seven year old needs special modifications.
We undertook as an Institute a number of years ago a very
ambitious project to understand the epidemiology but also the
service needs of children. In retrospect, a number of things
happened. The proposed idea of this very big project was likely
quite ambitious. In addition, and I want to be very clear to
say ahead of time that I absolutely value health services
research, but this was being planned during the time when NIMH
was in transition because of the health services research
setaside, and had to move from 9 to 15 percent of its budget
over a small number of years toward health services research,
which meant that there were not felt to be, by my predecessors,
funds to do the epidemiology first and then the health services
needs second. But rather, everything was combined into a rather
large study.
And then the world changed radically. Which is to say that
with the failure of comprehensive health reform legislation,
there were all kinds of changes in the service delivery system,
as you know, with the growth of managed care. Taking these
things into account, the UNOCCAP investigators made what was an
attempt at an altered study design to meet these, to turn the
shifting sands of health service delivery systems from a
liability into an advantage. Unfortunately, with all of these
changes, the structure that had been created by UNOCCAP and the
ambition of the study made the overall structure unwieldy.
Therefore, because of this change in design, I asked for a
thorough scientific review. And I engaged our council in
overseeing the results of that review.
Both the review group and the council found that there were
many valuable things that have come from UNOCCAP, including
study instruments to be able to understand both childhood
diagnoses across various ages, and also service needs. But they
also found that the project was more ambitious than could be
accomplished with the time allotted. Therefore, a
recommendation has been made to focus on finishing the
development of these very valuable instruments that will be
used in a wide variety of children's studies, and to thoroughly
validate them. I'm also concerned that these instruments be
translated into Spanish and be culturally appropriate for use
in a diversity of populations.
We will appoint an oversight committee to see whether there
is appropriate time and appropriate organization to move beyond
this instrument development phase. I think if the study were to
end with the instrument development phase, something extremely
valuable will be learned. I do not want to use taxpayer money
in a way that would not be well focused or serve the needs of
children well. And if the oversight panel does not agree that
the study should proceed beyond this stage, it won't.
Mr. Porter. Is the oversight panel the subcommittee of your
advisory council that you've asked to do a review?
Dr. Hyman. No, I'm sorry. I should have clarified that. The
National Advisory Mental Health Council working group asked
actually for an expert scientific oversight panel to be
appointed, literally to follow this collaborative agreement
within the Institute. And we have already identified, not
everyone has said yes yet, but five people to serve on that
oversight panel. They will report to council and to me. And
council and I have entered, I think, into a very constructive
partnership on this.
Mr. Porter. So the subcommittee has completed its work and
recommended this oversight committee?
Dr. Hyman. That is correct. They recommended that the study
be limited in its scope at this point, that there be an
oversight committee, and that anything beyond the initial
validation of instruments be approved by the oversight
committee.

setaside for mental health services research

Mr. Porter. The 15 percent requirement for mental health
services research----
Dr. Hyman. That is correct.
Mr. Porter [continuing]. Staff tells me that that was part
of the old ADAMHA statute.
Dr. Hyman. That is correct.
Mr. Porter. And was retained on its transfer to NIH. NIH is
about to be reauthorized. Have you asked the authorizing
committee to make any changes in that part of the law?
Dr. Hyman. I have not had those conversations. Let me say
that health services research, especially as we enter an era of
managed care, is a very important area of research. And it's
also a part of research that helps us translate clinical
studies into understanding in the real world. My philosophy,
however, is that specific setasides limit flexibility to pursue
scientific opportunity. However, one of the accomplishments of
the setaside, I think, was to develop a mature and vibrant
health services research field, which should no longer need any
special protection, but should be able to compete with the rest
of the scientists applying in our portfolio.
Mr. Porter. I have to say, and I want Dr. Varmus to know
this as well, I've had some conversations with the Chairman of
the authorizing committee in the House, Mr. Bilirakis of
Florida, about directing NIH. It seems to me that if the
appropriating committee attempts to do their very best not to
politically direct research but the authorizing committee goes
ahead and does it, you're bound to what they put into the law.
So I think it's just as important that in the authorizing
mode, that all of us send messages that the least amount of
direction is the best, and the greatest amount of flexibility
and decisions being made by science rather than politics are
best for everyone. I've really been talking to Mr. Bilirakis
about this and the importance of it. We'll see what happens.
Dr. Varmus. We delivered some of those messages yesterday
when Mr. Bilirakis and several of the other committee members
visited NIH for several hours.
Mr. Porter. Good.
Ms. Pelosi.

needle exchange programs

Ms. Pelosi. Thank you, Mr. Chairman.
Dr. Hyman, thank you very much for your testimony and for
your leadership at the National Institute of Mental Health.
I was fascinated by ``clock'', as one who commutes on a
regular basis to California I'll be very interested in
following that jet lag and sleep, day-night aspects of your
research.
Again, I want to thank you for your leadership at NIMH.
Your work is so important to so many families in America. Many
people come to our offices to talk about health care reform,
and say that they are locked into what they are doing because
of a mental illness that their child or another family member
may have. That's one aspect of it.
Of course, the other aspect is what it means to that
individual and what it means to the family. So for many
reasons, personal, fiscal and otherwise, we all look to you and
thank you for giving us hope. Your investment in brain research
does just that. And, as you know, the disruption and lost
productivity in our economy, is staggering.
I also want to commend you and NIMH on your behavioral
research and your leadership in convening the recent consensus
conference on interventions to prevent HIV risk behaviors. This
is a very important report and useful to us in Congress. I hope
that we will pay attention to the science. And I want to ask
you a question about that.
Your outside experts cite an impressive body of evidence
that needle exchange programs work. Studies show a reduction in
risk behavior as high as 80 percent, with estimates of 30
percent or greater for reduction in HIV infections. The
secondary impact on reduction in women and children may be even
greater than the 30 percent.
I cite from your report that there are over 100 needle
exchange programs in the United States, compared with more than
2,000 in Australia, a country with less than 10 percent of the
U.S. population. And the studies show a reduction in risk
behavior as high as 80 percent, with an estimate of 30 percent
or greater reduction of HIV in intravenous drug users.
This is your report. You're familiar with it. I just want
to call it to the committee's attention.
It's my understanding that researchers now estimate that if
Congress were to change our current policy and support needle
exchange programs that an additional 5,150 to 11,000 plus cases
of HIV infection could be avoided by the year 2000. Based on
science, do you agree with the outside experts, Dr. Varmus and
Dr. Leshner that Congress should lift the ban on Federal
funding for needle exchange programs?
Dr. Hyman. Yes, just one clarification. Of course, it's not
my report because the consensus panel was picked independently
of NIH. But we ensured through NIH that they had access to all
the data, positive, negative and so on. I think that from a
public health point of view, the data on needle exchange is
particularly compelling, in no small part, because the sharing
of needles is such an efficient way of transmitting the AIDS
virus that we could rely not simply for these studies on self-
report of altered behavior, but one can actually see changes in
sero-conversion to HIV.
And I won't belabor what you've already read, but I think
from a public health point of view----
Ms. Pelosi. Please do.
Dr. Hyman. Well, from a public health point of view, the
data in favor of needle exchange is very strong, indeed.
Ms. Pelosi. Thank you, Doctor. Dr. Varmus.
Dr. Varmus. We continue to make a distinction, Ms. Pelosi,
between the data on seroconversion, which is quite easy to
obtain and to interpret, and the more ambiguous data on the
incidence of drug use in needle exchange programs.

sexual abstinence in aids prevention

Ms. Pelosi. Of course. Thank you for making that
distinction, Dr. Varmus.
As you know, in the welfare legislation, Congress provided
$50 million, as some of us are just finding out, for programs
for teaching adolescents abstinence from sexual behavior. This
is far more money than we've been able to provide to CDC for
programs that have been proven to work. While I support any
programs to teach adolescents abstinence, I think we are
delinquent if we don't teach abstinence ``plus.'' It is my
understanding that this ``abstinence'' only approach is in
direct conflict with science, since it ignores evidence that
other programs would be more effective.
What do we know about abstinence only education programs?
Do you think this expenditure of $50 million could in fact
increase the number of new HIV infections?
Dr. Hyman. This is, of course, a very sensitive issue,
because it treads not only on public health areas, but also on
profoundly personal health values. Indeed, we have studied in
as yet unpublished studies of abstinence-only education versus
education which suggested abstinence but also emphasized safe
sexual practices, should adolescents choose to engage in them
despite admonitions to abstinence.
What has been found is that abstinence-only programs do
indeed delay the onset of sexual activity in adolescents, and
tend to decrease the amount of sexual activity in those who
have already begun. In several studies, however, the weakness
in the abstinence-only approach--from a public health point of
view--is that when adolescents then do become sexually active,
they are not aware of practices of safe sexual behavior, and
thereby may expose themselves to the risk of HIV.
Ms. Pelosi. Well, as the mother of five, I know many
parents in America, all, I could probably say, would be very
concerned about this, and certainly would support the idea of
abstinence. But I want to make a distinction, Mr. Chairman,
between abstinence only and abstinence plus. It could be very
effective as opposed to the disadvantage we're placing these
young people when we know what the possibilities are.
Dr. Hyman. I'm also the father of three young children and
I have very similar kinds of concerns. And I think the really
important issue is to recognize that there have been a lot of
concerns that education about safe sexual practices would
somehow increase the likelihood that children or adolescents
would engage in sex, or engage in it earlier. And the kinds of
programs that we are most interested in, recognize that there
is a dual benefit in delaying the onset of sexual activity, and
when sexual activity occurs for people to engage in practices
that are not going to put at risk for HIV transmission.

prevention of childhood mental disorders

Ms. Pelosi. Thank you, Doctor.
Our Chairman asked the question I was going to ask on
children's mental health. I didn't know if you wanted to add
anything about ways that we could prevent the onset of mental
disorders in children.
Dr. Hyman. This is a very vexed area. Indeed, I'm having a
council-based review of our entire prevention portfolio. And
let me say that given our current state of knowledge, the
actual prevention of most cases of depression or manic
depressive illness does not seem scientifically feasible.
But there is an incredible public health need that is going
unmet, which has to do with the identification of children at
risk who are already showing symptoms of mental disorder early
in life. The data suggest that these children are being
recognized as having mental health problems very late. Often,
kids get put in the wrong--I hate to use the term--but they're
put in the wrong bin, they're called bad kids instead of kids
who are in need of help.
And one of my goals, indeed, one of the critical goals of
the Institute, post UNOCCAP would be to provide the kind of
epidemiologic and diagnostic information and also public
education so that we recognize these children.
But a second very important area is therapeutics. You might
not be aware, and it's rather staggering, that there is only a
single, well designed, federally-funded study at this point of
the use of modern anti-depressants in adolescents. And we
really need to do not only greater work in recognition but also
in therapeutics for these children, so they can come to school
ready to learn, and so they can form their normal relationships
with peers and family. And I think it's really absolutely
critical.

world-wide burden of depression

Ms. Pelosi. Can I just ask one quick question, Mr.
Chairman?
On this chart, Dr. Hyman, why did you not include, when you
put unipolar major depression, you didn't include bipolar.
Dr. Hyman. To make this readable, I just gave you the top
five causes. This is a chart that I did not prepare, but
actually came from the World Bank. The World Bank and the World
Health Organization were interested in basically what is the
burden of disease. That is, not just mortality, but healthy
days lost, that people are unable to function in normal life
roles, including work.
And it turns out that for the entire world, the left hand
column represents the five main causes of Disability Adjusted
Life-Years (DALY) loss currently, and the right column is their
projection. Not far behind are manic depressive illness and
schizophrenia. And the reason that these rank so high is
because the onset of mental disorders tends to be early in
life, and the course tends to be chronic or recurrent.
So a disease like schizophrenia, tragically, will often
strike just as someone is emerging into young adulthood and
ready to become a contributing member of society. Then
obviously, is unable to work.
Ms. Pelosi. And AIDS is not on there because we're hopeful
that----
Dr. Hyman. AIDS is, I believe, expected to be the tenth
leading cause by the year 2020.
Ms. Pelosi. Of course, having more devastating effects in
certain areas.
Dr. Hyman. That's correct. This is divided over the entire
globe.
Ms. Pelosi. I appreciate it. Thank you very much, Dr.
Hyman.
Thank you, Mr. Chairman.
Mr. Porter. Mr. Stokes.
Mr. Stokes. Thank you, Mr. Chairman.
Good morning, Dr. Hyman.
Dr. Hyman. Good morning.

minority investigators and research subjects

Mr. Stokes. Dr. Hyman, one of my major concerns is that
Federal agencies utilizing taxpayer funds reflect diversity in
terms of the hiring practices at those agencies. Can you give
me some idea of how diversified the upper echelons of your
agency are?
Dr. Hyman. Of our total staff, 20 percent are under-
represented minorities. At GS-14 and above, it is 12 percent
[clerk's note: later corrected to ``8'']. But I have to tell
you that diversity is very important, not only within our
staff, but also among potential grantees.
These difficult problems need every good mind we can
possibly bring to bear on them. And we can't afford to lose
anyone through failed educational opportunities. And I'm
extremely proud of some of the programs NIMH has for getting
college students, for example, who are minorities, involved in
science and seeing them through.
Mr. Stokes. Would you include in the record a staffing
grade distribution table, both below and above GS-14?
Dr. Hyman. I'd be delighted to.
[The information follows:]

[Page 1826--The official Committee record contains additional material here.]

Mr. Stokes. You mentioned grantees. And last year, when
your Institute testified here, you indicated that you had taken
part in an NIH-wide major initiative to track the enrollment of
women and minorities over the course of funded grants. I
understand that this initiative would allow the Institute to
evaluate the success of its inclusion policy in achieving the
Institute's goals. What are the findings of that effort?
Dr. Hyman. I believe I'm going to have to provide those
findings for the record.
Mr. Stokes. All right.
[The information follows:]

initiative to track enrollment of women and minorities

The NIH-wide initiative to track the enrollment of women
and minorities over the course of funded grants is an ongoing
activity for which data is still being gathered. For this
reason the findings of this effort are not yet available. NIMH
can report the following: 1) More than 88% of applications
involving human subjects were found to meet the inclusion
requirements as submitted (see table below). 2) Review
procedures are in place to identify applications that do not
meet the inclusion requirements. 3) Applications found to be
unacceptable with regard to inclusion receive an administrative
code of ``U'' that results in a bar-to-funding. 4) Applicants,
whose grants would otherwise be approved for payment, may
submit additional information to meet the inclusion
requirement. After receipt of this additional information,
these grants are submitted to the NIMH Associate Director for
Special Populations for final determination that the inclusion
requirement has been met. Approval at this level results in
removal of the bar and subsequently to funding of the award.

LEVEL OF COMPLIANCE WITH INCLUSION POLICY IN NEW EXTRAMURAL GRANT
APPLICATIONS AS ASSESSED DURING SCIENTIFIC PEER REVIEW
------------------------------------------------------------------------
Council assignment \1\
-------------------------------
1/95 5/95
------------------------------------------------------------------------
Total number of applications reviewed... 1,973 1,989
Number of applications with human
subjects............................... 1,261 1,182
Number (percent) of applications that
met the inclusion requirements as
submitted.............................. 1,161(92.1%) 1,050(88.8%)
Number (percent) of applications with
unacceptable gender inclusion (Code G--
H)..................................... 53(4.20%) 41(3.47%)
Number (percent) of applications with
unacceptable minority inclusion (Code
M--U).................................. 79(6.26%) 59(4.99%)
Total number (percent) unacceptable \2\. 34(2.70%) 30(2.54%)
------------------------------------------------------------------------
\1\ These council dates were for the first councils that received
applications after the implementation date for the 1994 Guidelines.
\2\ Some applications had deficiencies in both gender and minority
inclusion.

Mr. Stokes. I understand that NIMH supports minority
research centers.
Dr. Hyman. That's correct.
Mr. Stokes. The centers are confirming cultural differences
in the expression of disease symptoms. As one would expect,
such differences if not adequately taken into consideration can
result in misdiagnosis and inappropriate treatment. What are
some of the most significant findings of this research? Tell us
how the results of the research are being incorporated into
your basic and clinical research initiatives.
Dr. Hyman. That's true. I think it is very important to
recognize that the incidence of major mental disorders is often
quite uniform across different populations worldwide, but that
the expression of symptoms may differ. For example, to take the
simplest example, there may be cultural taboos about admitting
to depression which may be stronger or weaker in different
populations. People may focus more on psychological symptoms in
one population, and on somatic symptoms in another population.
In order to take this into account, let me return to the
instruments that are being developed for the UNOCCAP study. We
are involved in and going to have, for example, Spanish
language versions of these instruments, but not one Spanish
language version, but rather a version that would be culturally
sensitive. You can imagine that if an interviewer goes into a
family and starts asking a list of diagnostic questions, those
questions really have to be attuned to things that the family
will find understandable and important to respond to.
This is a major investment for the Institute.
Mr. Stokes. Doctor, I understand the Institute is
sponsoring studies of ethnically defined populations as they
respond to psychoactive drugs, is that correct?
Dr. Hyman. This is correct. Once, again, there may be
differences in different populations in the metabolism of drugs
and in the way the body handles them.
Mr. Stokes. Tell us why this type of research is important,
and what your findings have been.
Dr. Hyman. One interesting finding recently was to actually
look at African-Americans and their metabolic ``handling'' of
lithium. And it turns out that lithium, which is still the
standard treatment for manic depressive illness, is
compartmentalized differently between red blood cells and the
serum, that is the free component of lithium, in a way that
might make African-Americans more sensitive to the side effects
of lithium. This kind of information is really critical if we
are going to have broadly useful therapeutics for a wide
variety of medications. And I believe that not enough attention
has been paid to this kind of diversity.

brain as the touchstone of nimh research

Mr. Stokes. Dr. Hyman, one of the areas of your budget
submission, the biology of the brain, is one of your
majoremphasis areas. Tell us what is your Institute's role in the
initiative and how is the initiative expected to further expedite
advances in mental health treatment, prevention and early diagnosis?
Dr. Hyman. That's a tall order. Because in many ways, that
relates to the entire mission of our Institute.
In essence, it's clear that serious mental disorders are
disorders of the brain that evolve through the workings of
genes together with the environment. We are obviously
collaborating with the nine other NIH Institutes that have a
large amount of brain research in their budgets, sometimes on
specific programs, and sharing information.
But for us, we recognize that new treatments, the eventual
identification of preventable environmental second hits that
interact with genes and a whole variety of other interventions
are going to require that we understand the genes which confer
vulnerability to mental disorders, how they work in the brain,
how they're modified by environmental factors, and what
molecules and cells in the brain might be targets for novel
therapies.
Let me give you just one example to make this concrete. We
have discovered, as a community, that there are certain
circuits in the brain, especially involving something called
the amygdala, which are involved in fear. Normally, fear is a
very important adaptive response. Without fear, people might do
all kinds of things to get themselves into trouble.
However, this very same circuitry, when it malfunctions,
can give rise to a variety of severe anxiety disorders,
including panic disorder and post-traumatic stress disorder.
We're beginning to understand in detail, in animal models,
exactly how--not to be too dramatic--but exactly how these
circuits can be usurped, or hijacked, in mental illness. And
we're beginning to take those animal models to the human level,
using functional neuroimaging.
Now, the opportunity in understanding these circuits, we
can now say, okay, this is a part of the brain that gets sick
in these anxiety disorders, and what are the critical molecular
targets in these brains that can be used as targets for
therapeutics? What kind of behavioral or psychotherapeutic
interactions might reverse some of these changes, and how might
we follow them in humans with neuroimaging?
In essence, the basic biology of brain disease forms the
fundamental groundwork for our understanding of mental illness
and for the production of new treatments.

RESEARCH NEEDED ON CHILDHOOD DISORDERS

Mr. Stokes. Let me mention another area. Earlier on, you
mentioned mental illness in children.
Dr. Hyman. Yes.
Mr. Stokes. I would imagine that this would be an area of
great interest to many parents throughout the country. I think
it would be helpful if you were to tell us firstly to what
extent mental illness in children constitutes a major problem;
and secondly, whether you have developed some type of a profile
of these children. How can parents, at an early stage,
ascertain whether or not a child fits a certain profile?
Dr. Hyman. Mr. Stokes, I have to say with some concern that
we do not have the information that parents and schools need in
order to know what problems children are facing. And part of
this is the difficulty of recognizing symptoms as they are
reflected through the changing developmental profile of
children. That is, someone who gets depressed at seven might
look different from eight and from nine. One of the things that
we have to do is to take the basic behavioral science, for
example, that we support, and bring it out of the laboratory
more effectively, and into the arena of the real world, where
we can develop the kinds of usable symptom checklists and
interviews which would allow us to identify children who are
having problems with mental disorders.
And in addition, one of the goals for use of the UNOCCAP
instrument that I described to Mr. Porter, is the ability then
to take that kind of information and gain the appropriate
epidemiologic information. I have to tell you that we are
starting, again, from a really deficient knowledge base, and
this is going to be one of the major goals for me at NIMH, to
make sure that we have this information for children.
I should tell you, although it's slightly off the point of
your question, but I find it heartening that there's been a lot
of interest in this from other agencies. Secretary Shalala
asked us to brief her on Attention-deficit/Hyperactivity
Disorder several weeks ago. And we've had several very
productive meetings, including some planned collaborations with
ACYF, especially with respect to using Head Start sites
potentially as an arena in which to start to look at some of
these problems.
Mr. Stokes. Then, from what you are saying to us, this is
an area in which we obviously have yet a long way to go.
Dr. Hyman. Yes, we do. I agree.
Mr. Stokes. Do I still have additional time, Mr. Chairman?
Mr. Porter. You have 30 seconds.
Mr. Stokes. I doubt if I can pose another question in that
time. Thank you.
Mr. Porter. Thank you, Mr. Stokes.
Mr. Miller.
Mr. Miller. You seem a little more comfortable in that
position than you did a year ago.
Dr. Hyman. Yes, that was with two weeks experience.

SOCIAL WORK RESEARCH

Mr. Miller. Glad to have you.
Two different lines of questioning. One is, I see in your
budget a social work area, would you explain to me what you're
doing in the social work area and what these centers are, and
are they locked into funding for a long time, and why they're
in your area?
Dr. Hyman. These centers were really requested in
Congressional language. And the logic of these centers is that
social workers are often on the front lines of making actually
very important decisions about the future of children and
families and the disposition of children, and also on the front
lines in treating a lot of mental illness. And the concern of
the Congress in writing this language was that there were not
adequate research traditions in social work and that evidence-
based science within social work would help social workers make
better and more informed decisions and be better able to use
the science of mental health in their daily activities.
Mr. Miller. How much money are we talking about?
Dr. Hyman. We have, I think, five centers, it's just under
$3 million.
Mr. Miller. And you fund these centers through an annual
grant?
Dr. Hyman. They get a grant. The center grants are
generally for five years.
Now, the total number of centers in the Institute is
capped, that's NIH policy and it's my policy, at 50 centers
total. So this then would be a percentage of our total research
centers.
Mr. Miller. My daughter is getting a Masters in Social
Work. I'm just surprised to see it's in your area.
Dr. Hyman. We do end up spanning from molecules to society.
Why this research is actually in NIMH rather than another
agency is an issue that Congress helped us decide. [Laughter.]
But wherever it is, I think it's very important that social
workers have evidence based information. I think that's really
critical.

TRAINING OF MINORITY RESEARCHERS

Mr. Miller. I agree with the idea of the need for them,
where it really fits in.
Let me just get clarification on this whole issue of
diversity, and discuss it within your Institute. Both
intramural and extramural research, aside from knowing a
specific minority type of study, but does that come into play?
Because this is peer review. And so is there any weighing, if
it's a minority, does that have any----
Dr. Hyman. What we basically, I think this is true across
NIH, that what we're interested in is scientific excellence.
We're also interested, however, in bringing every talented
American who is interested in science sort of up to a level
where they can compete in peer review. So we have a number of
programs, the Career Opportunities in Research--COR--program
for college students, for example, and minority supplements to
grants, which are not costly but, I think, represent important
manpower development programs.
When it comes to standard research grants, all decisions
are made on scientific and technical merit and on the mission-
specific priorities of the Institute.
Mr. Miller. So the main area of minority support is really
at the beginning research level?
Dr. Hyman. That's targeted, yes, it is really to bring
under-represented minorities in a full-blooded way into this
research enterprise.
Mr. Miller. Thank you, Mr. Chairman.
Mr. Porter. Thank you, Mr. Miller.
Mrs. Lowey.

NEW DRUGS FOR SCHIZOPHRENIA

Mrs. Lowey. Thank you, Mr. Chairman. And welcome, Dr.
Hyman.
I believe that one of the most important contributions that
biomedical research has made towards elevating human suffering
is the development of drugs for the treatment of mental
illness. And I understand that a second generation of anti-
psychotic drugs are being developed for schizophrenia. I also
understand that new anticonvulsant drugs are available for
manic depressive illness.
Can you describe to us how these new medications are more
beneficial in treating these illnesses?
Dr. Hyman. Yes. There's a very good, and I'll keep it
brief, but a very good story about anti-psychotic drugs, which
is, it began with a serendipity, which was the discovery of a
drug called Clozaril. Clozapine is the chemical name. This drug
has been known for a long time. It was not widely used, because
1 percent of people who take it develop a life--threatening
blood disorder.
And yet there was something about it. It didn't cause some
of the same terrible side effects in the motor system and
emotional withdrawal of the standard anti-psychotic drugs. And
so, despite the risk of the blood disorder, clinical trials, in
which NIMH played a key role, showed that Clozaril had unique
ability to treat people with schizophrenia and no liability of
causing these terrible extra-pyramidal, or motor side effects.
This discovery absolutely reinvigorated drug discovery in
anti-psychotics, both in federally-funded laboratories and also
in the pharmaceutical industry. And what we're seeing with
drugs like risperidone, olanzapine, sertindole--are basically
the children of clozaril, that is, attempts to make medications
which will have the beneficial therapeutic effects of clozaril,
but without the risk of this blood disorder, without other
problems with Clozaril, such as a risk of causing seizures.
And frankly, all of these drugs will have their place in
treating people with schizophrenia and other psychotic
disorders. We, as an Institute, now need to do the kinds of
studies that I think the Federal Government is best at, which
are studies which will help clinicians and families know which
of these drugs will be most useful first, and in what setting.
At the same time, however, we can't be satisfied, because
all of these drugs, as good as they are, simply palliate, but
do not cure, schizophrenia. And it's only by really struggling
more with the genetics and the fundamental neurobiology that we
will have more fully adequate treatments in the future.

TRANSLATION OF RESEARCH INTO TREATMENT

Mrs. Lowey. I thank you. At your last advisory council
meeting, you proposed the creation of a working group to
oversee the translation of treatment discoveries to the actual
care of patients. I happen to believe this is extremely
important, particularly given the pace of change in research on
major mental illness.
Can you share with us how your research might more quickly
or more effectively be made available to medical providers?
Dr. Hyman. There are two major areas that have come to
myattention. The first is actually in our centers program that Mr.
Miller had asked about. I would like to encourage some proportion of
our centers to be centers where basic scientists and clinical
researchers might come together. So that I don't tell you too many
different stories, let's just stick with this idea of fear and the
amygdala. We already have one center, in fact, actually two centers,
where attempts are being made to translate this knowledge about
circuitry involved in fear and anxiety disorders into treatment by
bringing together basic scientists who work on animals with clinical
researchers who use neuroimaging and also, in one case, with treatment
researchers.
This is the kind of model where we can, in essence, ask
basic scientists and clinical researchers who speak
fundamentally different languages to work together over the
long term so that they really understand each others' problems.
The second area where I think some subset of our scientists
can engage in translational research is in our intramural
program. The scope of the intramural program and its size,
along with the question which I have been asking myself, which
is, what is the justification for an intramural program, what
unique advantages does it have, well, one of them is that this
critical mass can allow some subset of our scientists to
engage, again, in sustained dialogue, sharing information that
will bring clinical knowledge to basic scientists and speed the
progress from basic science to clinical applications.
I have to say, I'm always concerned, however, that we don't
ask a lot of people to become either fish or fowl. It's got to
be really only a subset of outstanding scientists who are
involved in making these translations. Because so much progress
really is made within disciplines, by pushing molecular
biology, by pushing neurobiology, for example.
Mrs. Lowey. Lastly, and it's really related, I have become
very concerned recently because of some experiences I've
witnessed, concerning the treatment of mental illness by HMOs.
I'd like to ask you generally the positive and negative impacts
thus far.
But my concerns are the following. Because time in treating
patients is such a factor, have you seen a rush towards
treating the patient with medication, which indeed may be
appropriate, however, not giving the appropriate psychotherapy
and the time that the patient needs? In fact, I have become
aware in discussions more recently that there has been a
movement in psychotherapy towards psychotherapies that may not
be the same for everybody.
Dr. Hyman. That is correct.
Mrs. Lowey. Whereas there used to be the usual, the
procedure, and they are trying to direct it, especially with
seniors, where seniors are being moved into HMOs, for some
seniors, the medication may have such extraordinary side
effects. And if there isn't the appropriate therapy with it, I
am concerned about the treatment. This is a long question.
Dr. Hyman. You're absolutely correct about psychotherapy.
In the old days, it is true that often the approach was, here's
the treatment, now what's the problem. But indeed, as we've
become extremely sophisticated about particular diagnoses,
about different age groups, we recognize that for many
disorders, a combination of medications and targeted focused
psychotherapies are often the most successful treatment.
A good example might come from panic disorder, where
someone will have spontaneous, overwhelming panic attacks which
will lead them, over time, to constrict their lives because
they are afraid to have a panic attack in some place where they
might not be able to escape. They associate these terrible
symptoms with places that they've been. Medications, for
example, may abolish panic attacks. But someone might remain
housebound without cognitive behavioral psychotherapy, which
may very well be quite short lived, but is absolutely
important.
And so guidelines for treatment that are appropriate,
whether in a fee-for-service or managed-care setting, really
ought to look at the whole package of treatments that are
necessary for a good health outcome.
Now, the managed-care situation is complex. On the one
hand, by keeping costs down, managed care could make mental
health treatment available for all Americans. And as you know,
we've been engaged in the last year in this parity debate and
the Domenici-Wellstone amendment made the first early steps
toward parity. The major concern being, just as I've told you
how common mental disorders are, that treatment would break the
bank.
Well, by controlling costs, managed care makes parity not
only feasible but, in our analysis, quite affordable. And above
all, the doctrine of medical necessity that exists within
managed care means that we are encouraged to tell the
difference between someone who is sick, someone who has panic
disorder, schizophrenia, manic depressive illness, versus
someone who is less sick, and make those kinds of triages, so
that the fear that there were millions of people on waiting
lists for psychoanalysis would not literally break the bank.
Now, the downside, however, is that in our zeal to cut
costs, we may also cut recognition and treatment. I think one
of the goals as a Nation, as we face managed care in general,
is to ensure that managed care involves the management of
quality, to make sure there are appropriate guidelines and
implementation of guidelines, and not simply the management of
cost.
Because I agree with you, if somebody comes into their
primary care practitioner and the primary care practitioner is
doing a very good job, but has only a very short time to
interact with the patient, and has to ask a whole list of
questions, it will be difficult to elicit information about
mental illness. These are often very personal matters, the
patient might be unfortunately ashamed. And you can't just have
a list, you know, headaches, blurry vision, are you depressed,
are you an alcoholic, any stomach aches, that's not going to be
effective.
And I think we have to keep our eye on that.
Mrs. Lowey. I believe my time is up, Mr. Chairman, and I
thank you.
I do hope we can continue this dialogue. Because I'm very
concerned that it is easier to give a person Prozac, for
example, or another drug, and say, well, it's going to take six
weeks to kick in, and in the meantime, this young person is
really finding their lives grossly interrupted at that time.
Dr. Hyman. What we need are health outcomes, what we need
to do is have a report card based on actual health outcomes and
not on simple process variables that don't necessarily tell us
whether the patients are doing well.
Mrs. Lowey. Thank you. This is a longer conversation, but I
appreciate your indulgence, Mr. Chairman. And thank you, Dr.
Hyman.
Mr. Porter. Thank you, Mrs. Lowey.
Ms. DeLauro.
Ms. DeLauro. Good to see you, Dr. Hyman.
Dr. Hyman. Good to see you again.

treatment of mental illness in children

Ms. DeLauro. Let me just follow up a bit with what my
colleague Mrs. Lowey was talking about. First, let me just
applaud you in terms of your commitment to clinical research. I
guess it's page 4 of the testimony that says ``To be sure that
we capitalize fully on these priorities, the NIMH attaches high
priority to research to translate basic findings into the realm
of clinical investigation and application.'' We really do
applaud that effort.
I too have this real concern and particularly I want to
talk about children. You and I have talked about this. Children
are being treated for mental health disorders with medication
rather than with therapy. Yet clinical trials for medication
such as Prozac have not been done on children. Drugs that are
highly effective for adults may be harmful, even deadly, if
they're given to children. But we just don't know, because
children have not been included in clinical trials.
What is it that we can do to make sure that the dosages of
drugs for children to treat mental health are of help to them
and don't wind up harming them?
Dr. Hyman. We need to know many things. First of all, we
should always recall that having an untreated or under-treated
mental disorder is not where we want to be. We want to find the
most effective treatments so that children can learn and
children can develop normally. And one of the really chilling
facts of epidemiology is that we're recognizing that the age of
onset of depression, for example, is getting younger and
younger in all western countries. We really need, for example,
to be able to grapple with this.
So what we need to do is expand trials of drug efficacy.
First of all, ask the question, does the drug actually work in
children. And what are the tradeoffs in terms of toxicity.
We have a small number of studies of adults, and none in
children, of the long-term effects of drugs such as anti-
depressants. Now, again, I want to balance this by saying,
there is no, there is little doubt that untreated depression
and all of its psychosocial sequelae are a bad thing for a
developing brain. But at the same time, we have got to know
what the long term treatment with anti-depressants does to the
developing brain.
We've gotten a bit of good news in the past year, which is
that women who, because they had such severe depression, had to
remain on anti-depressants during pregnancy, and who have taken
the modern serotonin reuptake inhibitor anti-depressants have
given birth to children who seem, as we begin to follow them,
healthy and without any developmental abnormality. But we
mustn't lose our vigilance.
So we need trials of efficacy, we need longer term trials.
And we need, in order to do this, to work closely with FDA and
other agencies to ensure that a whole therapeutic armamentarium
is available for children.
Ms. DeLauro. We agree that it needs to be done. How are we
implementing what we know needs to get done here?
Dr. Hyman. We have actually, in collaboration with the
National Institute of Child Health and Development, attached
pediatric psychopharmacology research centers onto a number of
their existing pediatric pharmacologic research centers. In
addition, we are going to try to, through program announcements
and conferences, interest the field, many of whom have worked
on adults, to get involved in these issues of children, and
certainly, in developing part of our 1998 budget with Dr.
Varmus, this was one of our major areas of emphasis.
Ms. DeLauro. To include children?
Dr. Hyman. To include children, yes.
Ms. DeLauro. Here we are talking about mental illness. But
this is true of children across the board. And I would be very,
very interested in what you are doing in terms of putting
children----
Dr. Varmus. We recently had a workshop on inclusion of
children in trials throughout the NIH. It was hosted by the
National Institute of Child Health and Human Development. But
we'd be happy to provide you with some information from that
workshop.
Ms. DeLauro. I would like to see that. Because I think it's
important what you do, and I also think it's important to deal
with this issue on the local levels as well--what the doctors
are doing or not doing, and that they are the beneficiaries of
this information, or to try to call some attention to this area
in an effort to help you, but also to help youngsters in this
process.
[The information follows:]

[Pages 1837 - 1839--The official Committee record contains additional material here.]

Mr. Porter. Will the gentlelady yield for just a moment? I
want to catch Mrs. Lowey before she leaves, and say to members
of the subcommittee, who have expressed some frustration with
our schedule, that I feel the same frustration. I have just
signed off on a revision of the schedule for next year that
will spread the hearings out a little bit more and allow us to
spend more time with the institutes and with other agencies and
departments under our jurisdiction.
I might say that we are attempting toward the end of our
hearing schedule this year, to bring back certain of the
Institutes that we felt didn't get enough time. And I also just
looked at the schedule for next year, which suggested we have
Mental Health and Aging in the same morning time frame and
said, ``no, no, let's spread them out.'' Because we feel we're
shortchanging members and Institutes both in having them so
compacted.
I thank the gentlelady.
Mrs. Lowey. And I thank you. And I do apologize, but as the
Chairman knows, I wish I could spend some more time. Thank you
very much.

brain development and mental illness

Ms. DeLauro. Thanks, Mr. Chairman. It really is unfortunate
that we don't have the time, but it's truly difficult to be in
three places at one time. I don't have to tell you that. But we
don't need to give short shrift to anyof the Institutes here.
Because we're very much interested in the work.
Again, let me just follow up on this children's piece. If
you covered this before I came in, I apologize. It is about the
issue of mental illness in youngsters. And much of what we know
about mental illness comes from the study of adults and these
circumstances. How are we working at looking at mental health
in children and how children are diagnosed with mental health
illness? And if you can make a connection for me, if you will,
I mean, we are doing all of this work on the study of the
brain, or the development, and so forth, and how is that all
being tied in to where we're, so we can see these things
earlier than they normally manifest themselves?
Dr. Hyman. What you're asking is actually very
sophisticated, and it points to the fact that so much of this
science has to be interdisciplinary. One of the most exciting
conferences that I have attended is a conference that was put
on by our basic neuroscience division on brain plasticity in
early development. And it brought together a wide variety of
scientists, developmental neurobiologists, molecular
geneticists, ranging to people who studied the Romanian
orphans, to people who study the effects of stress on the
brain, and people interested in compensatory education.
And we recognized with great humility the difficulty of
bringing all of this information together, but also the
necessity of starting in a serious way to do this if we are
going to derive the information that's very important.
So for example, in the mental health arena, we have to
discover the genes that create vulnerability to mental
disorders, not only because these are potential targets of
treatment, not only to make a diagnosis, but also because these
genes, which create vulnerability and not the certainty of
illness, will permit us to be able to identify what else in
development might occur that would be a potentially modifiable
environmental second hit, turning vulnerability into disorder.
All of these things will require concerted effort on many
fronts in the Institute.
And then I think bringing people together periodically to
recognize where we are and how we have to set priorities in
order to make progress.
Ms. DeLauro. How far along do you think we are in terms of
how much we know about mental illness in children, and how
children are diagnosed with mental illness, in your
professional judgment?
Dr. Hyman. In my professional judgment, it is very early,
it is to my mind a national emergency that compared with what
we know about adults, what we know about children does not
serve children, their development, our educational system, or
our work force very well at all.
Ms. DeLauro. Until we're able to grasp that, I mean, we
have pieces surrounding the process, a Yale child study is
trying to deal with the effect of violence in kids. And that's
in the realm. But until we get some move along, I noted your
words here, it's a national emergency, we need to move on a
national emergency that's dealing with youngsters, because
there's a whole lot of things that get triggered.
Dr. Hyman. It is, but nature has given us a very hard
problem. The building of the brain, which is the most complex
structure in the known universe, with all due respect to the
other institutes----
[Laughter.]
Dr. Hyman [continuing]. Is something that is going to
require an immense and thoughtful effort. And there's a lot of
smoke, frankly. We go between, ``it's all genes'', and ``it's
all environment'', and really digging in and making those
connections is going to require a long-term investment in the
fundamental science of development and plasticity.
But the point you're raising, which is so important, is
that it cannot be narrow. We have to understand everything from
genes to the broad social context if we're to understand how
the brain is built and how people become who they are.
Ms. DeLauro. Thank you.
And thank you, Mr. Chairman.
Mr. Porter. Thank you, Ms. DeLauro.
Before I call on Mr. Wicker, I want to explain one other
thing. The Chair has been proceeding under these principles,
and will continue to do so. Those members who are here at the
time the subcommittee is called to order will be part of the
initial group and in the question period, we will then start
with my questions followed by a minority member, then a
majority member, then a minority member and the like, for those
who are here at the time we are called to order.
For those who come later, we will simply put them into the
order of their arrival and call on them in the order of their
arrival. And I've also said, and have been following a third
rule, that we will give special treatment for ranking members
who request it, so that they can come and go and get back to
their other subcommittees if their duties require them to do
so.
I also would say to members that we have been allowing ten
minutes for questioning. Today we expected there would only be
a few members here, because we don't have votes until 5:00
o'clock, but suddenly there were six or seven. And that's what
sometimes causes us to go over.
So perhaps the Chair will adjust the time for questioning
downward as the necessity may appear, so that we can give a
fair amount of time to each of the Institutes or agencies
before us for that day.
Mr. Wicker.
Mr. Wicker. Well, where does that leave me, Mr. Chairman?
[Laughter.]
Mr. Porter. You're known as one of our most patient
members. [Laughter.]
Mr. Wicker. I think the Chair may have been suggesting that
I was the last member of the subcommittee to arrive.
Mr. Porter. I would suggest your arriving right at the
beginning, then you know where you are. [Laughter.]

relationship of mental illness to other physical illnesses

Mr. Wicker. By now Dr. Varmus and the members of the
subcommittee have heard me mention several times that my home
State of Mississippi has one of the highest rates of death due
to heart disease in the Nation. I mention it again today in the
context of the National Institute of Mental Health, because I
understand that there is some new research concerning a
connection between depression and heart disease. The
information I have says that depression perhaps carries as
grave a risk of heart disease as elevated levels of
cholesterol.
I wonder if you could elaborate on this research, how
significant a connection do you think there is, and where is
this research leading as a practical matter?
Dr. Hyman. That's a good question, Mr. Wicker. And indeed,
Mississippi being a rural State, our research suggests that
citizens are less likely to seek treatment fordepression, both
because of the lack of services, but also because of often rural
traditions of self-sufficiency, and stigma, and shame. So sometimes
it's a compounded problem in some of our States.
There has been very suggestive data for years about the
association between coronary artery disease and depression. The
problem with most previous studies is it could not sort out the
cause and the effect. It was certainly known that people who
had had myocardial infarctions were depressed at very, very
high rates. And indeed, they were often untreated using the
very poor logic of, well, if you had had a heart attack,
wouldn't you be depressed. And the answer may truly be yes, but
in fact, all the data suggests that people do much better, and
indeed mortality is lower, if you aggressively treat the
depression.
Now, the new piece of data which is important actually
comes from an epidemiologic study initiated by NIMH a few years
ago, just simply to look at the incidence of different mental
disorders. But because we had this population, it was possible
to follow them prospectively. And therefore, everyone with
depression could be followed, and one could look at the
incidence of heart disease in these people who entered knowing
they were depressed but not having heart disease.
And it was found that in people who had a history of major
depression, there was a four-fold increased risk of heart
disease.
Now, there were some technical flaws in the study. So it
needs replication. But there are some very interesting facts
here that can be sorted out. One possibility is that people who
are depressed are less likely to adhere to medical regimens
such as taking their anti-hypertensives or exercise or weight
loss. One factor that was ruled out, however, was smoking. That
is, the investigators corrected for smoking. So that's not the
villain in this piece.
But the other possibility is that the brain disease of
depression activates a whole variety of hormonal responses in
the body, including the elaboration of stress hormones like
cortisol, which affect metabolism and might actually produce
atherosclerosis. Many people with depression are often agitated
and have higher levels of norepinephrine and epinephrine
circulating, which might contribute to hypertension.
Therefore, the disease of depression may be an independent
risk factor. What we need to know is, first of all, can this be
replicated prospectively? Second of all, and most importantly,
and the Heart Institute is already involved in something like
this, can we intervene? That is, can aggressive treatment of
depression actually prevent heart disease, or for people who
have had heart attacks, can it decrease mortality? And I'm very
optimistic about the possibility of doing those studies and
getting valuable results.
I would only add that with that information, then, we will
have to redouble our efforts to get primary care physicians and
physicians in all States and settings to recognize and
intervene in depression.
Mr. Wicker. Who's carrying on this study?
Dr. Hyman. The National Heart, Lung, and Blood Institute is
proposing a study of intervention right now. We are still
following this sample. The investigator who published the most
recent prospective data is William Eaton, who's at Johns
Hopkins.

circadian rhythms and mental illness

Mr. Wicker. Okay. Well, that's very encouraging.
Tell me what we're doing in the area of research into the
relationship between altering sleep patterns and manic
depression.
Dr. Hyman. That's a very interesting and important area.
But lacking a good animal model of manic depressive illness, we
have had to do all of this research on human subjects, and
therefore, in a non-invasive way. But it is clear that altered
sleep, one clear public health factor is that altered sleep
patterns, like shift work, should be avoided by people with
manic depressive illness, that changes in their daily schedule
may actually initiate episodes of mania.
In addition, there are some very tantalizing findings that
sleep deprivation actually elevates mood. There are other
findings that have to do with people who don't have manic
depressive illness, but there are clear mood changes depending
on the time of day. And I know sort of at 3:00 or 4:00 in the
afternoon, except for my self-prescribed mega-dose caffeine
therapy, I would often start drooping and have some mood
changes.
We're really beginning to get a handle on this. For this
reason, I think it's so exciting that we have almost in hand
the first, the key switches in the hypothalamus, which may be
controlling our internal clocks, and which may give us better
tools to see what's happening, both in people with manic
depressive illness, but also in the rest of them.
Mr. Wicker. What do you have almost in hand?
Dr. Hyman. A gene--I'm sorry, I mentioned it in my opening
statement. An NIMH-funded researcher, Joseph Takahashi, at
Northwestern University, has over many years narrowed in on a
gene that seemed to be the master controller of our normal,
free-running daily periods. That is, what gives us our own
internal 24 hour cycles.
And this is going to lead, I think, to very important
information about understanding our circadian rhythms and what
goes wrong. I mean, it's important, such genes were actually
known, but they were known in the invertebrates. There were two
genes, ``per'' and ``timeless'', that were known in flies, for
example. But this is the first mammalian gene. And it looks to
be the key controller of our 24 hour cycles.

eating disorders

Mr. Wicker. Okay. One more question. On the first page of
your testimony you mention a number of disorders, including
anorexia nervosa. I'd be curious to know what we've been able
to accomplish there, but also, if you could, give me a little
of the history of this disorder.
Dr. Hyman. One fact is that from everything we can tell,
all eating disorders are increasing in incidence. But this is
especially true, not of anorexia nervosa, but of bulimia. And
basically, what one has, and this is a particular scourge among
high school and college age women. What one has is basically
youngsters learning from each other about weight loss
techniques and binging and purging.
Then what happens in vulnerable people is they find they
can't stop, that this takes on a life of its own. And part of
this increased incidence really is real, that is, probably
there was not this kind of incidence of eating disorders 40
years ago. The question is, would these women have been
perfectly well 40 years ago?
Here the evidence is rather complex. We find eating
disorders often in the same families that have depression and
substance abuse. So one possibility is that this is a
manifestation of some underlying problem that might have
alsomanifested itself as depression and then indeed, many women with
bulimia also have depression.
Now, there's good news about bulimia, and then I'll get
back to anorexia nervosa, which is that we've made a lot of
progress in treatment. The combination of modern serotonin
reuptake inhibitor anti-depressants, the Prozac-like drugs,
that hide those, plus behavioral psychotherapies, really have a
marked effect on improving the symptoms and course of bulimia.
Anorexia nervosa, I'm sorry to report, remains a difficult
to treat and refractory disorder. Fortunately, it is relatively
uncommon, but common enough, depending on the severity,
affecting between half of 1 percent to perhaps 2 percent of
women at some level of severity. But at its highest level----
Mr. Wicker. Almost entirely women?
Dr. Hyman. Almost entirely women. More than ten to one
women.
And there's still perhaps a 10 percent mortality. This is a
very severe disorder.
Medications that we have provide modest benefits. But
there's no medication that is really profoundly successful in a
large number of women. The mainstay of treatment is still
cognitive and behavioral therapies, including such common
sensical things as, you have to achieve a certain weight in
order to partake in desired activities. But we have a long way
to go in anorexia nervosa.
Mr. Wicker. Thank you very much.
Mr. Porter. Thank you, Mr. Wicker.
Dr. Hyman, we have many, many more questions. This is very
frustrating not to have sufficient time, and we will simply
have to put them in the record in order to give at least some
time to Dr. Hodes.
I might say that what I have planned to do is to add on at
the end of our hearing schedule the three Institutes that
previously we felt we didn't have enough time with. And I'm
going to ask each member of the subcommittee if they will
submit to me an indication of any other Institutes that they
would like to invite back as well.
Then on another day, we will also have before us for the
information of the subcommittee members and Dr. Varmus, NCI,
NIDDK, NHLBI, OAR and if we can, Dr. Varmus, yourself, for a
panel on the priorities of funding by disease, an issue that
has been raised so often by so many members that I think we
ought to spend some time and really address that.
The three Institutes that we have now that were not given
sufficient time are NCI, NHGRI and NIAID. And there may be
more.
So thank you very much, Dr. Hyman, for the fine job you're
doing. We'll have to put our questions in the record.
You may be invited back, and thanks for your good statement
and answers to the questions that were posed.
Dr. Hyman. Thank you very much.
Mr. Porter. Thank you, sir.
We'll stand in brief recess.
[The following questions were submitted to be answered for
the record.]

[Pages 1846 - 1913--The official Committee record contains additional material here.]

----------

Tuesday, March 18, 1997.

NATIONAL INSTITUTE ON AGING

WITNESSES

RICHARD J. HODES, M.D., DIRECTOR, NIA
TERRIE WETLE, PH.D., DEPUTY DIRECTOR, NIA
COLLEEN F. BARROS, EXECUTIVE OFFICER, NIA
KARYN S. ROSS, FINANCIAL MANAGER, NIA
HAROLD VARMUS, M.D., DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF
HEALTH AND HUMAN SERVICES
RUTH KIRSCHSTEIN, M.D., DEPUTY DIRECTOR, NIH

Introduction of Witnesses

Mr. Porter. The subcommittee will come to order.
I apologize for the time constraints that we've found
ourselves under. You may well be invited back.
Dr. Hodes, I have to leave at 12:00 o'clock, because I have
a speech to make out at American University over the noon hour.
And I have asked Mr. Miller if he could take the Chair at that
time and finish up the hearing.
So I hope that you have time to stay a little bit longer if
necessary.
Dr. Hodes. Certainly.
Mr. Porter. Thank you, sir. Would you introduce the people
you have brought with you and then proceed with your statement.

Opening Statement

Dr. Hodes. I think Mr. Williams from the Department and Dr.
Varmus have already been introduced.
To my left, Karyn Ross, who's the Financial Manager for the
Institute; Dr. Terrie Wetle, the Deputy Director; and Colleen
Barros, the Executive Officer of the Institute.
The National Institute on Aging supports research on the
basic aging process as well as research on a variety of age-
related diseases and conditions, including Alzheimer's disease,
cancer, cardiovascular disease and osteoporosis. The overriding
goal of all this research is to improve the quality of life for
older Americans and their families.

alzheimer's disease

The NIA leads a national effort in research on Alzheimer's
disease, a devastating disease which as you know affects
approximately 4 million Americans at present, taking an
enormous toll on the patients, their families, caregivers, and
the public. Some of the recent discoveries in Alzheimer's
disease and the pace of the discovery are typified in the first
poster, illustrating some of the findings of underlying genetic
relationships to Alzheimer's in the period from 1990 through
the present.
[See figure 1.]

[Page 1917--The official Committee record contains additional material here.]

There have been descriptions now of three genes on
chromosomes 21, 14 and 1, which are responsible for the
familial form of Alzheimer's disease, often of early onset,
affecting individuals as early as their 30s, 40s and 50s. The
fourth factor, ApoE, a gene on chromosome 19, is associated as
a risk factor for the more common form of later onset
Alzheimer's disease.
This genetic information has already been translated into a
number of steps toward application. It has been shown over the
past year, for example, that combinations of modern techniques
of brain imaging, together with genetic analysis, have
suggested the ability to diagnose abnormalities in brain
function as many as 20 years before the appearance of symptoms,
providing an opportunity to identify disease early, and an
opportunity to intervene before irreparable damage has been
done to the brain.
In addition to these diagnostic issues, we've moved a step
toward understanding risk factors for Alzheimer's disease.
Among the risk factors identified are age and genetics. We've
also uncovered over the past year or two more dramatic
information about possible protective factors.
[See figure 2.]

[Page 1919--The official Committee record contains additional material here.]

There's been a good deal of scientific as well as press
interest in the role of estrogens resulting from recent
demonstrations that women who have a history of estrogen use
have dramatically lower incidence of Alzheimer's than those who
have never used estrogens.
In the area of anti-inflammatory agents, a great deal of
basic research has suggested that there might be a role
forinflammation and immune response in the pathology of Alzheimer's
disease. And in fact, there has been a good deal of attention paid to
the finding that individuals who have a history of using anti-
inflammatory agents for diseases such as arthritis have dramatically
lower incidence, once again, of Alzheimer's disease.
In both of these cases, the epidemiologic and basic science
imperatives now converge on the need for direct clinical
testing. And in the areas both of estrogen use and anti-
inflammatory agents, there are in fact clinical trials
underway.
In the area of anti-oxidants, there's been a good deal of
basic science showing that oxidative damage appears to be a
candidate for a part of the mechanism involved in death of
neuronal cells. And here once again, trials testing the effect
of antioxidants on the progression of Alzheimer's disease are
in progress. And in fact, as early as next month, we expect
publication of one study which will again emphasize yet another
area for hope in the treatment of this disease.

biology of aging

The basic research supported by the Aging Institute and
across NIH tends to find underlying biological processes which
are critical to many of the problems and processes of aging.
Over this past year, there's been discovery of a number of
genes in lower organisms which, when expressed in altered
forms, are capable of extending both the health and life span
of organisms several fold, providing interesting opportunities
for translation into areas of understanding and intervention
relevant to humans.
Interventions such as caloric restriction provide another
interesting phase of scientific advance. Studies showing that
restricting animals calorically by 30 percent while maintaining
nutrition has dramatic outcomes in reducing incidence of
diseases such as cancer, and in fact of prolonging life span by
35 percent and more. Once again, these studies will be the
basis for determining whether there are interventions
appropriate for human use.
The issue of translation of discoveries such as this into
practice and application is, as for all Institutes at NIH, a
high priority. Cardiovascular disease, for example, remains the
major cause of death among older Americans, accounting for
nearly 50 percent of deaths of Americans 65 and older.
In the past year, there's been identification of stiffening
of large and medium size arteries as a potential risk factor
for serious cardiovascular events. Taking advantage of
information such as this, intervention studies have been
carried out with efforts using, in one case recently reported,
a diuretic based anti-hypertensive therapy to reduce
hypertension association risk with the finding that five years
of such treatment has lowered the risk of serious
cardiovascular consequences by 34 percent. In fact, that risk
reduction in absolute terms was nearly double for diabetics
than for non-diabetics.

demography of aging

Overall, all of these issues take on an imperative with the
change in demography of the American, in fact, the world,
population. The demographic predictions for the population of
the world in the next 50 years are summarized or illustrated in
this format. What you can see in 1950 and in 1995, the near-
present, is a very familiar sort of pyramid, in which, in lower
ages at the bottom, there are the greatest numbers of people
living, with a very rapid decrease toward small numbers living
to advanced age.
[See figure 3.]

[Page 1922--The official Committee record contains additional material here.]

A dramatic change in that is expected, as you can see
illustrated here, for the year 2050, with what is called a
squaring of that curve, a great increase in the number of
people at advanced ages, and a great increase in the ratio of
older to younger individuals, making more imperative our
efforts to find solutions to the problems of disability and
poor health in older people.
The next poster illustrates some of the good news that has
again been published of late, with a good deal of attention
even in today's press, from a study that will be appearing in
the proceedings of the National Academy of Science. This study
has followed participants in the National Long Term Care Survey
from 1982 through the present.
[See figure 4.]

[Page 1924--The official Committee record contains additional material here.]

What you can see graphed here in the upper line in red is
the number of individuals over 65 in the United States who were
expected to be disabled if the rates of disability reported in
1982 had not changed. The lower line in blue illustrates the
actual observed numbers of Americans with disability observed
in 1982 through 1994.
The difference between that predicted by unchanged rates
from 1982 and those which reflected decreased rates of
disability observed over these years amounts to 1.2 million
fewer Americans disabled in 1994 than would have been predicted
if those rates had not changed.
Our challenge and the opportunity for the years to come is
to sustain and in fact to accelerate these changes based on
increased understanding of the mechanisms which underlie the
cause of disability, and the discovery of ways to intervene to
alter those risk factors.
Mr. Chairman, thank you for the opportunity to discuss
these issues with you. The fiscal year 1998 budget request for
the National Institute on Aging is $495,202,000, and I welcome
an opportunity to answer any questions you might have.
[The prepared statement follows:]

[Pages 1926 - 1932--The official Committee record contains additional material here.]

disability research

Mr. Porter. Thank you, Dr. Hodes.
We note that you gave your entire testimony without a
single note, not even a heading or anything like it, which is
very, very impressive.
Let me ask regarding this chart, since you've got a rising
population above 65 but declining rates of disability, are the
absolute numbers more or less remaining constant?
Dr. Hodes. You can see, or almost see on the scale in that
lower curve that the absolute numbers of disabled Americans
increased from 6.4 million in 1982 to 7.1 million in 1994. From
1989 to 1994, it's a very small slope, an increase from 7.0 to
7.1 million.
It has been projected, and of course, projections become
more speculative than recorded fact, that what amounts here to
a 1.2 or 1.3 percent decrease in the rate of disability per
year over this time period would need to be increased to
approximately 1.5 percent to produce a straight line projected
into years to come.
Mr. Porter. Reading today's Washington Post and the article
that resulted from the release, have researchers put forward
any predictions about the longer term savings in Medicare, if
the trend continues? In other words, they've mentioned
substantial savings in one year. What would it amount to into
the future? Can we balance the budget on this?
Dr. Hodes. These areas remain certainly far too speculative
for me to engage and involve a good number of factors, other
than projections of disability. It needs to be emphasized how
complex such a projection is. That is, there are enormous
savings presumably associated with decreases in disability,
since disabled persons cost the health care system far more
than non-disabled persons.
There also are costs to the research and the interventions
which are responsible for those changes. Certainly those
involved in policy and those involved in balancing the budget
and Medicare finances are highly concerned with these issues.
Our efforts in terms of generating research such as this are to
provide such policy makers with the information which is vital
to their projections.
Mr. Porter. Can I ask you about the release itself? Was the
release done by NIA or was it done by Duke University?
Dr. Hodes. There were separate releases from NIA and from
Duke, which is fairly typical of the way a lot of such
discoveries are handled. The institution that funds the
research is always welcome and most often will issue its own
press release. In selected instances, NIA and NIH will
supplement, complement or cooperate in those releases. In this
case there were two.
Mr. Porter. And was the timing----
Dr. Hodes. Dr. Varmus reminds me that journals, such as
PNAS, will often also highlight specific articles and issue
their own releases. So it's not uncommon for there to be
multiple releases.
Mr. Porter. I'm very happy that the release was made and
these questions are not at all critical. But was the timing of
the release, did it have anything to do with the timing of your
testimony today?
Dr. Hodes. If so, it was orchestrated by powers far beyond
our own. It's of interest that the release for the publication
in PNAS was initially scheduled for the day before the original
date of scheduling for our Institute's testimony.
Coincidentally, when you altered our schedule, the article's
publication was delayed, and so it appeared one day before our
current hearings. None of this had anything to do with our
intervention, to our knowledge.
Mr. Porter. I think that's, whatever caused this timing, I
believe that the good news has to come out and be highlighted
more than the bad news. This is obviously very, very good news
and something that has captured the press's attention and I
think will also capture the public's attention. And it's
something that I want to very much encourage.
Dr. Varmus. I'd like to emphasize, though, we don't really
know the explanation for the decreased disability rates. While
we think that medical research plays some role, there are many
other factors alluded to in Dr. Manton's paper that really
contribute, and the relative contributions made by the various
components have yet to be sorted out.
Mr. Porter. It's funny, you anticipated my next question
perfectly.
Dr. Hodes. I would add only that the sorting out of those
causes is in fact a very high priority in the research that
will be forthcoming based upon this finding.

alzheimer's disease

Mr. Porter. Well, it certainly got Senator Kennedy
interested in more money for research. And I think that's all
to the good.
The news about decreasing disability rates in the aging
population is welcome. But is there any similar news with
regard to Alzheimer's disease? Will the increasing numbers of
older Americans afflicted with Alzheimer's swamp whatever
beneficial impact lower disability rates may have on health
care expenditures and the quality of life? You partially
answered this in your opening remarks.
Dr. Hodes. But it's a very important question. The
incidence of Alzheimer's disease as noted is very highly age
related. In the age range from 65 to 74, the prevalence of
Alzheimer's is about 3 percent. By the time it reaches the age
group 85 and over, it's been estimated to be as high as 47
percent, that is, nearly half the people 85 and over. The
extrapolation of these demographic projections for an increase
in the age 85 and over population in the United States over the
decades to come, would indeed have staggering consequences if
there is not an increased ability to delay, prevent, or treat
Alzheimer's disease.
And that is a part of the underlying urgency behind that
effort. I think there is reason for optimism. There are
candidates for effective treatments. There are candidates based
on our increased understanding of the basic biology of the
disease. But the urgency is clear.

demographic research

Mr. Porter. Dr. Hodes, some researchers believe that there
is a practical limit to age span of about 85 years, while
others think typical life spans could extend into the upper
90s. Average life span obviously has major implications for the
depletion of the Social Security and Medicare trust funds,
independent of the health status of the population. Is there
anything in demographic research to provide counsel to the
Social Security actuaries or are findings on life span too
uncertain at present?
Dr. Hodes. Clearly, the research area of demography has a
great deal to offer to the policy makers in particular.
However, in precise answer to your question, the recent
publication summarizing efforts at projecting average life
expectancy in the American population over decades to come is
most notable for the very wide confidence limits. So wide, that
the implications for, for example, the expenditures in Medicare
and Medicaid leave enormous ranges of uncertainty. And I think
one has to concede at times that some of these projections are
simply beyond the level of current science to be carried out
with fine limits of discrimination.
So just as you alluded to in your suspicions, the
projections by various equally skilled and expert investigators
and agencies are extremely diverse, reflecting uncertainty in
those estimates.

alzheimer's disease

Mr. Porter. Another study reported last week suggested that
small, silent strokes may cause much of the memory loss and
dementia associated with Alzheimer's disease, and that symptoms
of Alzheimer's can be prevented by preventing strokes. How
should we interpret this finding, that the dementia that is
thought to be linked with Alzheimer's is really a consequence
of small strokes instead? And this particular study was done
with female subjects. Do you expect the results also to be
confirmed in male subjects?
Dr. Hodes. This was an extremely interesting study that was
carried out on a population of nuns, the School Sisters of
Notre Dame, a population that has been highly committed to the
study who have been followed over years with very detailed
analyses of cognitive function and with a commitment to autopsy
or post-mortem examination of brains. And the finding, as you
note, reported last week, was that there was a dramatic effect
of clinically undetectable but pathologically detected strokes
which influenced the amount of clinical dementia, of memory
loss, that occurred in individuals with Alzheimer's.
In fact, the findings of the study showed that these
strokes had an effect on cognitive function only in individuals
who also had Alzheimer's disease; that is, the population of
nuns who did not have pathologic findings of Alzheimer's did
not have any changes in cognitive function as a result of the
stroke. So that in this population, for the kind of microscopic
strokes being detected, it appeared that it was not a confusion
of diagnoses, but an effect on the symptoms of Alzheimer's
disease of concomitant cerebrovascular disease and stroke.
The implication is, of course, that even with the diagnosis
of Alzheimer's, and even apart from efforts to directly
intervene to treat the causes of Alzheimer's itself, there may
be room for preventing some of the clinical manifestations of
Alzheimer's by preventing strokes, by treating hypertension,
for example, in those populations at risk.
Mr. Porter. Thank you, Dr. Hodes.
Ms. DeLauro.

quality of life

Ms. DeLauro. I want to follow up on the question that the
Chairman was asking with regard to the article in the
Washington Post. That research often, may succeed in reducing
Medicare and Medicaid costs, I think it's fair to say that
experience to date has been that while research improves the
quality of life and life spans, oftentimes new tests and
treatments have generally increased rather than decreased
medical spending.
I just wanted to ask what's different about this research
that's going to lead us to expect cost reductions.
Dr. Hodes. I think it's an important and very complex
question, to which there is not a simple answer. Indeed, there
are some interventions which have enormously positive outcomes
on the quality of life, on health and on life expectancy which
may be costly.
There are also, I must hasten to add, others which are not.
Last year, for example, I had the opportunity to present to the
Committee an example that resulted from several studies carried
out by investigators at Yale who were studying interventions
for falls, in those individuals at highest risk for falls. And
in that study investigators discovered multifaceted
interventions which were capable of reducing by 44 percent the
incidence of falls in a group at high risk.
There was a subsequent follow-up to that study which
analyzed the costs, including the costs of carrying out the
study and of the intervention itself. That case concluded that
there was a net savings, even with those factors accounted for,
in the range of $3,000 per patient per year, and a net decrease
in all medical costs as a result of that intervention.
Clearly, our highest priority is to find interventions that
will improve the quality of life and avoid disability and
disease. But not to be disregarded is our commitment and
responsibility to attempt to identify those which will also be
cost effective and cost saving.
Ms. DeLauro. Well, I applaud the interventions and where
they can lead. But I think in some instances we've looked at
where we have increased health care costs for a variety of
reasons. I'm hopeful that that doesn't have to be the case, and
that we can in fact, with what you and others are doing, to
bring those costs down. That's where people can take advantage
of what the discoveries are.
Dr. Hodes. I apologize for borrowing perhaps an over-used
example, but one highlighted frequently was the case of polio,
and the high cost of technology for iron lungs, a technology
that was not definitive, the comparison of course being the
discovery of the cause of that disease and the ability to
immunize in a highly cost-effective way. And that is certainly
a model to which we aspire for most of those problems which we
confront at present.

embryo research

Ms. DeLauro. This subcommittee has debated the ethical and
scientific pros and cons of embryo research in each of the last
two years. And I anticipate that we will have that debate and
discussion again. I understand that this research may hold
particular promise in the treatment of Alzheimer's and in
Parkinson's disease.
What has been the impact on your research of a complete ban
on federally-sponsored research in the use of human embryos?
Dr. Hodes. I think that ban has had very little effect on
the research areas supported by our Institute. In the areas you
mentioned, such as Parkinson's, I think there, and again this
has been largely conducted through collaboration, most of the
funding is conducted through the Neurology Institute, and
sources of tissues and cells other than those restricted by the
ban have allowed research to progress. I think it has not been
a great cost to the research conducted by the Aging Institute.

osteoporosis

Ms. DeLauro. Osteoporosis, as you know is a serious problem
on the elderly, particularly women. My understanding is that
it's likely to become a more serious problem, as today's young
people are not eating enough calcium, or taking in enough
calcium. Bones stop being able to absorb calcium by age 22.
What research on improved osteoporosis treatments is
currently underway and how promising are the findings?
Dr. Hodes. Well, there are a number of promising
interventions that have pointed out the efficacy, as you are
probably aware, of increased dietary calcium, of adequate
vitamin intake to support both absorption and use of that
calcium, and the role of estrogen and estrogen replacement
therapy.
One recent study just initiated by the Aging Institute is
attempting to capitalize on preliminary findings in an animal
model which is showing that a unique approach to treating
osteoporosis with a drug called minocycline that's related to
tetracycline, may provide an additional effect to the drugs
currently in use, most of which prevent resorption. Minocycline
has shown promise in animal experiments of allowing the actual
addition of bone and increased bone strength, in addition to
reducing the amount of bone loss that often occurs with aging
and after estrogen withdrawal, for example.
Therefore I think in summary it's fair to say that we are
looking at the level of clinical trials of many of the more
established treatments, and in small scale clinical
interventions, we are trying to take advantage of basic science
research which identifies innovative metabolic approaches to
altering the balance of calcium deposition in bone.
Ms. DeLauro. Thank you.
Thank you, Mr. Chairman.

health care savings

Mr. Miller [assuming chair]. Let me follow up with a couple
of questions that had been asked earlier, and that is, this
Duke study about understanding why we're going to save money. I
remember we were saying if you encourage people to smoke more,
they'll die earlier, we'll save money on health care. That's
obviously a ridiculous statement. With people living longer,
we're going to spend more money on their total health care.
So how do we save money, just do the arithmetic?
Dr. Hodes. Again, excuse me for emphasizing that our
primary goal, of course, is the maintenance of quality of life
and life without disability. And the concern you mentioned
comes next. But it is nevertheless an important one. There are
a number of facts that I think surprise individuals at times.
There is no doubt that the longer one lives, the longer one is
going to need care, including medical care.
However, the costs of medical care later in life actually
decrease substantially as age proceeds. So the medical care in
the final year of life, for example, is much less costly for
individuals 90 years old than for 80 or 70 or 60,
whichindicates that the prolongation of life does not necessarily mean
the extension of high costs to the degree that one might deduce unaware
of those figures.
Mr. Miller. We're all affected by our own personal stories,
and I lost my father-in-law three years ago at age 91, my
mother-in-law two years ago at age 87, and my mother's 87 and
in a nursing home. When you see the quality of life being so
poor, and you start wondering, will I see my mother again on
Monday. And she's got a tube in the stomach, she's just going
on, it's not a great quality of life.
I think she knows me when I visit her, at least I have a
feeling she does. She's been like this for a year. Her whole
body's wearing out. There's no real diagnosis as such. It's
just old age.
And as Mr. Porter asked, that's the question, how long
before, does old age overcome the diagnosis of a specific
disease, not necessarily Alzheimer's, she's not swallowing,
that's the reason she had the tube put in. At what stage does,
how long can you prolong?
Dr. Hodes. The answer to how long we can prolong life is of
course not precisely known. I fully sympathize, I think all of
us have the same very emotional experiences with loved ones,
with family, and the difficulties people incur with aging. Our
goal is clearly not, as a result of research, to extend life at
any cost and at any quality. It really is to try to extend life
of high quality.
What is reassuring about studies such as this, showing
decreased disability, is as noted in the article, for example,
is that the gain is high even for those people of the greatest
disability. That is, we're not only decreasing disability for
people at the margin, while people at an extreme of disability
go unimproved; rather the statistics show that there has been a
real improvement in the quality of life measured by decreased
disability even in the most disabled population, and even in
the oldest of the most disabled population.
And I think that's clearly what we all aspire to, not just
allowing people to live some months or years longer, but
finding a way to do that, such that the most disabling and
distressing and anguishing of diseases are reduced and improve
the quality of life.
Mr. Miller. The percentage of people in institutions,
nursing homes or other institutions, has that been declining or
does it depend on the statistical measure you use?
Dr. Hodes. Yes. There has in fact been a decrease in the
numbers of people institutionalized below those expected from
previous rates. Some of it may be accounted for by the decrease
in disability shown here. Other components of it appear to be
accounted for by changes in decisions about
institutionalization.
This also, of course, clearly relates to quality of life.
For many individuals, if there's a way to provide the
infrastructure, the research, the mechanism, to allow people to
cope in a home setting, or non-institutionalized setting, that
is likely to result in a higher quality of life for families
and individuals. That as well as the decrease in disability
itself are likely contributors to the decrease in
institutionalization over the expected levels in recent years.
Mr. Miller. My Congressional district in Florida has more
senior citizens than any Congressional district in the United
States. So I've got my area, Sarasota, Bradenton, has lots of
retirees. So it's an area of great interest.
But it's also different because people that move to Florida
have broken their ties to the north. And there's a higher rate
of institutionalization in Minnesota, for example, than in
Florida, because people move into mobile home parks and take
care of each other.
Dr. Hodes. I think you're right, that social and family
settings have a great deal to do with these outcomes.

falls in the elderly

Mr. Miller. Last year, I remember when we were talking with
the CDC during their appropriations hearing, they were talking
about doing research on falls in the elderly. And I was
intrigued by why they were doing it. Do you do that type of
study?
Dr. Hodes. Yes. I mentioned briefly some of the research
conducted on falls, which is still ongoing, is attempting to
first identify the causes of falls in older people. That
research was highly successful as reflected by the fact that
the next stage, designing interventions based on the
identification of risk factors, has shown in clinical settings
the ability to decrease falls nearly half in individuals at
high risk. And to do so with interventions that are highly
cost-effective.
I think the CDC becomes involved in monitoring the
incidence of this disability, or the causes of disability in
the population, and being potentially a source for monitoring
any changes in clinical outcomes, which might occur as a result
of widespread application of the kinds of clinical
interventions that have been identified by ongoing research.
Mr. Miller. By monitoring, you mean more of a statistical
measuring?
Dr. Hodes. Yes.
Mr. Miller. Because I got the impression it was actually
the research on how to prevent falls, and they were talking
about using inflatable devices around elderly people for
falling. I was just curious why they were doing that research
and, not that you oppose that research, it seems more logical
to be in your realm.
Dr. Hodes. Yes. Research such as the specific one that you
mentioned, the use of padded devices to try to prevent
fractures at the time of falls, is supported by NIH and by NIA
specifically. Once again, as to the degree that those
interventions are used in more widespread fashion across the
population, a monitoring of their effectiveness might be a part
of surveillance by CDC.
Ms. Kirschstein. Mr. Miller, the CDC has a Congressional
mandate to study injury prevention.
Mr. Miller. Right, it's in the injury area.
Ms. Kirschstein. Yes.
Mr. Miller. And we're hearing this in another area, why is
CDC doing it, before they were talking about social work in
mental health, and I don't object to what they're doing, it's
just, wait a minute, we're having another area doing the same
thing, and is there an overlap and duplication. It seems like
it's more logical under your area of research than CDC.
But that's how they're justifying their program. I don't
mean to put you on the spot in that.
Thank you very much.
Mr. Wicker.

prostate cancer

Mr. Wicker. Thank you, Mr. Chairman.
First of all, tell me about this new blood test on prostate
cancer that could let us know earlier about a possible
diagnosis.
Dr. Hodes. That's an extremely interesting story. It was
reported some years ago, on the basis of research carried out
within the intramural program actually at the National
Institute on Aging, that sequential measurements of prostate-
specific antigen over time could allow diagnosis of prostate
cancer several years before it was otherwise identifiable.
More recently, a new finding, published and publicized in
January, indicated the use of a new test, devised
collaboratively again, through the intramural program of the
Institute on Aging, together with investigators at Johns
Hopkins, that looked at compartments of the PSA or prostate-
specific antigen. In fact, it looked at ratios of free to total
and reported that using this measurement, it was possible to
identify prostate cancer up to 10 years before diagnosis.
Now, all of this is in the context of a fair controversy
about the role for diagnosing prostate cancer early. Prostate
cancer can be aggressive and it can be less aggressive. And in
some individuals, its progress is sufficiently slow that it's
actually an issue of current medical debate whether it is
justified to intervene surgically since at an extreme, the
clinical course might be so slow as to never cause a clinical
problem.
What is going to be published this month in fact, and has
just passed its embargo, so I'm comfortable being able to speak
about it, is a further elaboration on the study that I think
you were referring to in which it is reported most promisingly
that use of the ratio of free to total PSA not only allows
prediction of prostate cancer, but as reported by these
investigators, allows a distinction between what are likely to
be aggressive and non-aggressive cases of prostate cancer.
It's one finding published in a journal which will await
repetition and replication. But if true, it would, I think, be
enormously important in decision making on how one uses the
diagnostic criteria to make therapeutic decisions. If the more
aggressive cases could be identified as those which would most
benefit from intervention such as surgery, while cases less
likely to be aggressive could be spared the morbidity of that
treatment, this would indeed be an important advance.
Mr. Wicker. You alluded to a recent controversy. And that
surrounds even whether the test should be given at certain
ages, is that correct?
Dr. Hodes. I think that's correct. And it derives from the
controversy of what one should do with the finding. The
argument would follow that if indeed a positive finding on this
test, meaning a likely diagnosis of prostate cancer, had no
clear therapeutic implications, because one simply didn't know
whether to treat or not, some would argue it's questionable
whether the test should even be done. That's clearly a complex
question, and there is not a unanimous opinion. But I think
that's the essence of the current controversy.

alzheimer's disease and ibuprofen

Mr. Wicker. But it is interesting that a scientist would
suggest that we could know too much too early. It strikes me,
as a layman, as being quite interesting.
Well, let's see. You mentioned on Alzheimer's disease a
cooperative study about prevention and treatment, and you
mentioned a bunch of combinations, selegilene, vitamin E,
prednisone, estrogen therapy perhaps. What are we learning
about the relationship between Alzheimer's and ibuprofen? Where
does that come in?
Dr. Hodes. On the basis of suggestions that anti-
inflammatory agents might have a protective role on development
of Alzheimer's, a study was carried out in the Baltimore
Longitudinal Study on Aging, part of the intramural program of
the NIA.
In this study, there were individuals who were followed
with examinations every two years for extended periods of time,
up to decades. It was possible to do a retrospective analysis
looking at the history of people over 15 years and ask whether
they did or did not have a history of use of anti-
inflammatories, ibuprofen being one of them. And asking in turn
whether there was a relationship between this history and the
likelihood or risk of developing Alzheimer's disease.
And it was found that individuals who had taken ibuprofen
had approximately 50 percent the likelihood of developing
Alzheimer's as those who did not. Even more striking for those
who had been taking ibuprofen for two years or more, there was
a 60 percent reduction in the likelihood of developing
Alzheimer's. I have to emphasize that this is an observational
study.
It is strongly suggestive, but will not take the place of a
direct treatment study in which individuals are for example,
randomized in such a way that they are taking a pill and are
unaware whether that pill is ibuprofen or a drug or a placebo
which is being compared.
That is the form of study which is most able to, with
certainty, predict the utility of the therapeutic intervention.
And it is likely now, based on the study that I mentioned and
that you asked about, that such intervention studies will be
proposed and supported in the very near future.
Mr. Wicker. How far away is your agency from issuing a
report saying, it's a good idea to take some of these drugs?
Dr. Hodes. The time frame for a study, a demonstrated
efficacy, is of course dependent upon the disease. In the case
of Alzheimer's disease, which is a slowly but unfortunately
progressively debilitating disease, there is a period of
follow-up likely to be in the range of a minimum of two years
that one will have to observe to see if a population is altered
in the course of its disease.
If one is looking to prevent disease, and if one begins
with a population that doesn't have Alzheimer's and waits for a
number of those, even if one selects a high-risk population, to
develop disease, to see whether treatment A or treatment B
makes a difference, one is likely to be talking about follow-
ups of at least five years and perhaps more. That is, for a
study initiated today, even if all the patients immediately
began taking the drugs of comparison today, there is likely to
be a lag of this many years before, with certainty, a
recommendation could be made.
Now, some of the studies that I've mentioned to you, one
involving prednisone and one involving estrogen, are underway,
and the results of those studies are likely to be reported
within the next one to two years. The more extensive, larger
studies based on some of these new candidates will have a lag
time that is therefore proportionately longer.
Mr. Wicker. Are these studies with prednisone and estrogen
among so-called high-risk populations?
Dr. Hodes. The ongoing studies at present for estrogen and
with prednisone are in individuals who already have a diagnosis
of Alzheimer's disease. These studies are looking to see
whether the progression of disease is altered or slowed by
treatment.
The second generation of studies, that of actual prevention
by finding people at a high risk for disease although they have
no disease, is the generation of studies that we are just
embarking on now. The candidates for such interventions will
frequently come from the first set of studies.
So when one has a drug which seems to slow the progression
of disease, a natural next generation of study will be to say
if that intervention is moved to an earlier point in time, when
detectable clinical damage has not occurred, to ask whether
that same intervention will actually prevent the development of
disease which is of course the most hoped-for objective of such
intervention.
Mr. Wicker. Who are high-risk people?
Dr. Hodes. The most clear-cut answer for high risk, as I've
indicated, is, for example, if one chooses a population that's
at age 85. I've also mentioned some of the genetic risk
factors. One could pick individuals with a given Apo-E type,
which I must add is not a guarantee or an absolute predictor of
disease, to identify an even higher risk population.
I'd mentioned that modern techniques of brain imaging can
identify abnormalities in individuals years before the
detection of symptoms. The screening of individuals by such a
technique in principle, though an expensive approach, could
identify individuals at high risk to develop clinical disease,
though not having the disease at present.
Currently, investigators are looking individually and in
combination at such identifiers as age, genetic risk factors,
brain imaging techniques, which collectively may be able to
identify populations at a high risk which would be appropriate
candidates for intervention.

genetic research

Mr. Wicker. And finally, let me just ask you what the
Institute is doing with regard to attacking age-related
diseases by manipulating or mutating genes? And I wonder if you
could comment on some of the ethical questions which might
arise in that connection.
Dr. Hodes. Well, the approach to manipulating genes is
being carried out extensively in animal models. In a number of
them, mutations are identifiable which will have substantial
effects on life span prolongation and on health span
prolongation.
Our principal goal in these studies is to identify biologic
processes altered by the genetic manipulations which will give
clues to interventions in humans that will not necessarily
necessitate genetic interventions. The genetic interventions,
as has been often discussed, carry scientific, medical and
ethical complications that in the near future are probably
going to be prohibitive.
But that doesn't diminish the value of using genetic
studies in animal models to pinpoint the biologic processes,
the biochemistry that may be modifiable by other than genetic
manipulation in humans, and therefore, the genetic studies may
be quite valid and important in suggesting interventions
appropriate to humans.
Mr. Wicker. I don't understand what you mean. What would be
an example of that?
Dr. Hodes. Well, an example would be taking a gene from one
of the familial forms of Alzheimer's disease, a mutation
associated with Alzheimer's, and introducing that into a mouse,
as has been done over the last year or two, making a transgenic
mouse that expresses an abnormal human gene associated in
certain families with early onset Alzheimer's.
It's been observed that such animals develop lesions in the
brain that look like Alzheimer's, and as they grow older, in
the case of mice, this means by nine months of age or older,
they develop abnormalities in learning that appear to be at
least broadly defined analogous to what one sees in
Alzheimer's.
Now that one has gone this far, finding out the error in a
gene, one can in an animal model look for ways to reverse it.
For example, introducing an enzyme that will do the job that
the mutated gene product in the affected patients can't do,
thus eliminating the toxic material that might play a role in
Alzheimer's disease.
Mr. Wicker. Thank you.

long-term care

Mrs. Northup [assuming chair]. Thank you.
Doctor, I have just a couple of questions. Have you all
done any research that looks at nursing facilities and the
possibility that they have individualized, or whether or not
they do have individualized or intensive therapies? Considering
as you look at the aging process there are a number of
different reasons and ways people wind up in nursing homes, how
intensive or individualized are the therapies and how much
difference does that make?
Dr. Hodes. It's a very important question that is being
pursued by an active research program supported by the Aging
Institute. There is a serious look at so-called special care
units, for example, which may be tailored to the special needs
of individuals with dementia, or individuals with HIVinfection
in another domain. The interest and importance here is both to find out
how these special care units address the special needs of the
individuals in those units and how in turn that impacts on the function
of the remaining patients in a nursing facility.
So, for example, the questions being asked at present, are
how special care units are defined across the country, how many
of them there are, and then to look, most importantly, at
practices and how those practices affect the quality of life of
patients, of family and of staff, which ultimately will be of
importance as well. And there appear to be suggestions in at
least some of these studies that there are advantages to
individuals, again to cite the example of dementia, for care in
a special care unit.
And there are also secondary gains to the patients in the
rest of the institution who are better cared for when their
standard can be separated and distinguished from the standards
that need to be applied to those in special care units.
Mrs. Northup. But that's not widespread today, I suppose,
that there are those opportunities for families who have a
parent, for example.
Dr. Hodes. The numbers, in fact, are increasing
significantly and quite rapidly over time. And a part of the
intent of the studies is to monitor these changes as they
occur.
So I think you're correct that this is still at an early
stage. But it is a practice which is expanding quite rapidly.

predictive testing

Mrs. Northup. One other question, and actually, you may
have touched on this, I had to step out for just a minute. What
are the dangers and what do you do about it, and I know that
Alzheimer's is not the only area where we're beginning to be
able to do predictive testing. You do a test on me and you tell
me, hey, you are high risk for Alzheimer's. We obviously know
there are the financial questions. What does that do to my
insurance?
But what are we doing in terms of the emotional and
psychological effect of that sort of predictive testing,
especially because that clearly has to forerun any sort of
therapy to try to offset that?
Dr. Hodes. You've asked an enormously important question,
and you've touched on some of the important considerations,
those related to health insurance, the finances, and in
addition perhaps the most central one, the emotional impact. In
the case of Alzheimer's disease, the circumstances are
particularly complex.
For a small proportion of the cases, the so-called familial
Alzheimer's disease, for which at least three genes have been
identified, the diagnosis in that genotype, of identifying an
altered gene, has a very high, nearly 100 percent, predictive
value that that individual will develop Alzheimer's. In that
sense, it's equivalent to cystic fibrosis or some of the other
defined genetic diseases.
That needs to be separated, and I think it is not so well
separated in the minds of, unfortunately, all of the public
from the cases--where probably 95 percent of Alzheimer's at
present, where, although we may be aware of a risk factor such
as Apo-E 4, this by no means predicts disease with certainty.
So we have an added level of complexity in having to interpret
for individuals what the outcomes of these tests might be.
This is all superimposed on a situation in which at present
there are no definitive or preventive interventions. All of the
circumstances will hopefully of course be altered in the future
if or as we develop interventions.
In the meantime, recommendations of panels which we ask to
revisit this repeatedly, panels consisting of scientists, and
of ethicists as well, have been to suggest that genetic testing
for Alzheimer's be carried out only in either experimental
settings where communications or results may be anonymous, that
is, individuals may not know the results of their tests, or
carried out as an adjunct, in individuals that already have the
diagnosis of dementia.
And here, I have to say there's a difference of opinion
among experts, both ethicists and scientists, who would allow
in that situation the possibility that if you have a diagnosis
of dementia, the question of whether it is Alzheimer's or not
might be assisted by the use of this genetic test, in
association with other tests, there is discussion of whether
that is an appropriate means.
But there is widespread agreement that genetic testing at a
population level to find out whether you've got a higher or
lesser predisposition based on genetic statistical assessment
at this point is simply unwarranted and rather unanimous
recommendations are against such testing at present.
Mrs. Northup. Thank you, Doctor, and members of the panel.
We are recessed until 2:00 o'clock today.
[The following questions were submitted to be answered for
the record.]

[Pages 1946 - 2000--The official Committee record contains additional material here.]

----------

Tuesday, March 18, 1997.

NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

WITNESSES

DR. ZACH W. HALL, PH.D., DIRECTOR
DR. AUDREY S. PENN, M.D., DEPUTY DIRECTOR
RICHARD L. SHERBERT, JR., EXECUTIVE OFFICER
ANDREW C. BALDUS, BUDGET OFFICER
DR. HAROLD VARMUS, M.D., DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

Mr. Porter. The subcommittee will come to order.
Let me apologize to you for the delay. I was out at
American University making a speech on human rights in Hong
Kong. I apologize. There just aren't enough hours in the day
some days.
This afternoon we're pleased to welcome Doctor Zach Hall,
the Director of the National Institute of Neurological
Disorders and Stroke. Before you give your testimony, would you
introduce the people whom you've brought with you, and then
please proceed with your statement.

Introduction of Witnesses

Dr. Hall. Yes. This is Dr. Audrey Penn, on my right, who is
the Deputy Director of our Institute, on my far left is Mr.
Richard Sherbert, who is the Executive Officer of our
Institute, Mr. Andy Baldus, who is the Budget Officer for the
Institute, and we have at the end of the table Mr. Williams
from the Department, and Dr. Varmus, whom I assume is a fixture
at this table.

Opening Statement

Mr. Chairman, thank you for the opportunity to appear
before this committee. These appearances are a real pleasure
for me because we are in an era of unprecedented progress in
research on the brain and its diseases, and I appreciate the
opportunity to share with you some of the important advances of
the last year. As you may know, this is Brain Awareness Week. I
was, this morning, at a symposium at the NIH that is being held
in connection with Brain Awareness Week and heard several
exciting talks on recent progress in Alzheimer's disease and in
epilepsy. This afternoon there will be talks on addiction, on
development of the brain, on mental illness, and on learning
and memory.
The symposium, which is reporting the latest findings from
some of our most distinguished and promising scientists, is
sponsored by 12 Institutes at the NIH working together to
promote and support research on the brain. We work together in
a number of areas of mutual interest that include Alzheimer's
disease, sleep, pain research, autism, and neurological aspects
of AIDS.
Our own Institute, the National Institute of Neurological
Disorders and Stroke has responsibility for more than 600
neurological disorders. These include a number of well-known
disorders that affect millions of Americans--stroke,
Alzheimer's disease, epilepsy--as well as a number of less
well-known diseases and disorders that affect maybe a few
hundred people. These include such things as ataxia-
telangiectasia, Friedreich's ataxia, and Batten disease--
diseases which, although they affect only a few people, are
nevertheless devastating to those who have them and to their
families.
Our research brings new hope to those suffering from
neurological disorders. As you know, in the past we've had
little to offer those suffering from brain disease. When I was
in medical school and first became interested in neurological
disease, I was told by my advisors that if I was interested in
the intellectual challenge of diagnosis, I should go into
neurology, but that if I wanted to make people well, I should
find something else. Fortunately, that chilling judgment is
changing as we understand more and as we begin to find new
treatments.
Today, I want to tell you about our progress in three
important disease areas: stroke, Parkinson's disease and
developmental disorders.
Stroke is a major health problem in the United States;
500,000 Americans have a stroke each year, of whom
approximately one-third die. The total number of those who have
suffered a stroke in our society is currently estimated to be 4
million people. Many of these have significant disabilities and
must receive care. The estimated cost to the Nation is $40
billion per year for stroke.
Last year at this time I reported to you that the NINDS,
working with investigators and hospitals and medical
institutions across the country and with the private sector,
had organized a clinical trial showing the first effective
treatment for stroke. The trial found that prompt
administration of a so-called clot-buster--tPA--to those with
the most common form of stroke gave a 30 percent increase in
the chance for full recovery.
One might think that such a dramatic result would lead
immediately to widespread use of this treatment across the
country. But, in fact, there is a fundamental problem.
Treatment with tPA is most effective when it is given within
three hours after the symptoms first appear. Beyond that time,
there is an increased risk to the patient which, at least with
present information, makes its use unacceptable.
In order to get people to the hospital and give them tPA
within three hours stroke must be treated as an emergency.
Since there has been previously no effective treatment for
stroke, this requires a massive change in attitude on the part
of patients and their families, on the part of physicians, on
the part of emergency room personnel, and on the part of
hospitals.
Last December, our Institute convened a major symposium
that brought together all of those concerned with acute care
for stroke--doctors, nurses, paramedics, as well as hospital
and patient representatives. The purpose of the symposium was
to provide guidelines for health care providers implementing
acute stroke therapy in a variety of medical settings across
the country, from small rural hospitals, to suburban hospitals,
to large urban hospitals, to those in academic medical centers,
each with different problems. Our Institute continues to take a
leading role in coordinatingpatient and professional
organizations in the vast educational effort that will be required to
realize the benefit of this important research.
Let me make another point about these findings. We hear
much these days about the high cost of modern technology in
medicine. tPA, in fact, is one of the products of modern
technology, since it is made by recombinant DNA technology, and
its use adds to the immediate cost of stroke treatment. And
yet, this investment pays off. A recent follow-up study on the
patients in the NINDS clinical trial showed that tPA use
results in dramatic long-term savings. Those treated with tPA
stay in the hospital for a shorter period of time, and more are
discharged to their own homes rather than going to nursing
homes or to rehabilitation centers. When this is extrapolated
to make an estimate, the best figures are that tPA use will
save $4 to $5 million for every 1,000 patients treated. So not
only does its use then bring significant health benefit to the
patient, but also results in a substantial cost-saving.
Let me now turn to Parkinson's disease, where we have
dramatic recent progress of another kind to report. In 1995 our
Institute and three others sponsored a workshop whose purpose
was to identify new directions of research for this terrible
disease. A major conclusion of that workshop was that
Parkinson's disease was likely to have a larger genetic
component than had been appreciated. In response to that
suggestion and insight, NINDS initiated a collaborative project
with the National Human Genome Research Institute and with a
group of extramural researchers. Within a year after that
project was initiated, we had important and dramatic results to
report.
In an issue of the journal, Science, published last
November, we reported that in a single large family Parkinson's
disease was found to result from an alteration in a small
region of chromosome 4. Research continues with the effort to
identify the gene involved and to determine if it is important
in other families. But the significance of this is that one of
the major tools of modern biomedical research, molecular
genetics, can now be brought to bear on the problems of
Parkinson's disease. We hope that identification of the gene
involved, even if it doesn't affect a large number of patients,
may offer us key insights into understanding why nerve cells
die in Parkinson's disease, a question about which we presently
have really no idea.
Let me finally turn to developmental disorders of the
brain. As you know, over the last several years, scientists
have made tremendous progress in identifying genes for a number
of developmental disorders, including spinal cerebellar
ataxias, ataxia-telangiectasia, Batten disease, and others.
You're familiar with many of these findings, as I and my
colleagues have reported them to you year after year. These
disorders make it very clear that genetic factors play a
critical role in brain development.
But I'd like to make the opposite point today, and to
emphasize the critical role of experience in brain development.
Much recent research emphasizes what we already intuitively
know; that is, we are not simply the product of our genes, but
that our early experience shapes in important ways how our
brains become wired up and how we use them. We have become
increasingly aware that even our adult brains have a surprising
capacity for reorganization. This was illustrated in a very
dramatic way by a recent research finding in our Institute that
showed that when blind people read braille, they use a part of
the cerebral cortex, in the back, that normally responds only
to visual stimuli and not at all to touch. So this part of the
cortex then has been at least functionally rewired to be used
in the service of braille reading.
The capacity for functional reorganization, as we know, is
particularly well developed in children. A dramatic
illustration of this is the astonishing recovery of children
who have had large parts of their brain removed for intractable
epilepsy. One would predict in many cases devastating
consequences, but they show, again, a remarkable ability to
reorganize and use the parts of the brain that they have
remaining for their normal learning and development and to
carry out functional tasks.
Research at our Institute and others is revealing more
about how early experience shapes the normal brain. We are also
learning that in some cases the developing brain establishes
maladaptive patterns of learning that lead, or can lead, to
learning disabilities in children. Our Institute recently
sponsored, in collaboration with the Office of Rare Disease
Research, a workshop on neuroplasticity in rare developmental
disorders. One of the things we heard at that workshop was that
many of the children that have ``learning disabilities'' are
perfectly capable of learning, and that by altering their
experience in controlled ways we can help them achieve
significantly improved performance. The conceptual basis for
this discovery, which is now being explored clinically, grew
out of fundamental research on the ability of the cortex to
reorganize following a section of the nerves in animals.
This combination of basic and clinical research is what
makes brain research in this era such an exciting one and gives
it such promise for future progress.
Mr. Chairman, the funding year 1998 budget request for
NINDS is $722,712,000. I am pleased to answer any questions
that you might have.
[The prepared statement follows:]

[Pages 2005 - 2009--The official Committee record contains additional material here.]

diseases of aging

Mr. Porter. Thank you, Doctor Hall.
I have a question for Doctor Varmus, and I think I know the
answer but I want to make sure. We just had the National
Institute on Aging here and Doctor Hodes and we talked about
stroke, Alzheimer's and Parkinson's. Does NIA have the lead on
any disease, or are those always in other Institutes and NIA
simply relates them to aging?
Dr. Varmus. There is coordination of Alzheimer's research,
but the National Institute on Aging has the lead for
Alzheimer's.
Mr. Porter. Say again.
Dr. Varmus. The National Institute on Aging has the lead
for Alzheimer's.
Mr. Porter. Okay.
Dr. Hall. I should say also several other Institutes do
carry out research in Alzheimer's disease. Our own particular
portfolio is very biologically based. One of the important
things that Richard Hodes did, actually, was to establish a
working group on Alzheimer's among those Institutes that are
concerned with it. The directors have gotten involved in this
as well, and we have met several times. It has been extremely
useful in exchanging expertise and being sure that our
portfolios are well-coordinated. We often have overlapping
interest and the current mood, I would say, among those
Institutes is that that's perfectly all right and that we will
cooperate in those areas where we do have overlapping interest.
We also have, each of us, areas in which we are distinctively
interested.

administering tpa for stroke

Mr. Porter. Absolutely. I understood that. I just wondered
whether NIA had the lead or whether you had the lead.
Is it possible to administer tPA on site or in the
ambulance, or do you have to administer it in the hospital?
Dr. Hall. Let me address that, because that's a very
important question. tPA, as you know, is a clot-buster, so
while it breaks up clots, it also makes coagulation more
difficult. There are two kinds of stroke--ischemic strokes and
hemorrhagic strokes. Let me simply remind you that stroke
results from an interruption in the blood supply to the brain.
That can come about in two ways. If you block the arteries or
some part of the circulation in the brain, you get what's
called ischemic stroke; if small blood vessels break, then you
get a hemorrhage and that also effectively stops the
circulation in that area and the cells are without oxygen and
without nutrient.
tPA has the capacity to benefit and to help those with
ischemic stroke, but it is dangerous for those with hemorrhagic
stroke and you certainly do not want to give it to those
patients. About 80 percent of stroke patients have ischemic
stroke, and that is the most important thing to be found out.
You do that with a CT scanner. So any hospital that has a CT
scanner can give acute stroke treatment.But it would be very
dangerous to give tPA in the absence of knowing whether it is ischemic
or hemorrhagic.
And so part of marshalling the efforts to bring about acute
stroke treatment involves the mechanics of getting somebody to
the hospital, first of all making sure that they do have the
symptoms for stroke, because many patients report or think
they're having a stroke and it turns out after a few questions
you find out quickly that they do not, so that first screen is
done, and then arrangements are made to get a CT scan very
quickly. In large crowded hospitals, that means they go to the
head of the line, and there's a protocol for that. There also
has to be an arrangement that once the scan is obtained it
needs to be read immediately, and that often is a time block by
the time you can find somebody who has the time and can drop
what they're doing to read it, and so you have to have an
emergency protocol for that. And then also the pharmacist needs
to be alerted in advance so that the tPA is there ready to be
given when it's decided that it is appropriate. So all of these
things have to be coordinated to get the tPA to the patient
within that three hour time window. Of course, the worst thing
of all would be to give a patient with hemorrhagic stroke a
tPA. And so for that reason, everything waits on the CT scan.

future of brain research

Mr. Porter. At a FASEB conference last week, Doctor Arthur
Kornberg of Stanford predicted that ``following the decade of
the 1990s in which science has been dominated by gene hunters,
the next decade will be ruled by head hunters who study the
functions of the brain.'' Do you share the view that brain
research will be the next science frontier conquered?
Dr. Hall. Without doubt. I'm actually pleased to hear
Doctor Kornberg say that. I did my post-doctoral fellowship
years ago in his department at Stanford. I had at that time
already committed to the nervous system, and maybe, I'd like to
think, perhaps some of my enthusiasm rubbed off on him. But, at
any rate, I very much agree with that. There are several
reasons for saying that.
I think one of them is that the brain is the most complex
organ that we have. It's the highest product of human
evolution, if you will. It is incredibly complicated. When I
began my career there were many who thought it was too
complicated to get serious answers; you could not do
experiments that gave you hard answers if you worked on the
brain. And as the methodology has developed and as techniques
have improved, I think what has now happened is that our tools
and our technology are now up to working on these very
complicated problems. And that is reflected I think, by the
flood of people who are now coming into brain research.
One of those tools certainly is genetics. It is estimated
that a third of all genetic diseases have neurological
consequences. Of the large number of diseases that I mentioned
for which our Institute is responsible, a significant number of
those are genetic diseases. And by identifying the gene, one
gets a powerful clue to what may be going on with the disease.
We've seen this in ALS with the identification of a superoxide
dismutase, the enzyme responsible for at least a portion of
those with familial ALS. It gives us an important clue that
oxidative reactions are probably important in the
neuropathology of the neurons that die in ALS.
Imaging is another important tool that has really
revolutionized what we do. It gives us literally a new view of
the brain. The fact that one can look at the human brain in a
non-invasive way is truly remarkable. As you know from some of
the testimony by my colleagues, one can see the effects of
drugs on the brain in this way; one can even ask people to
think of particular things and see what areas of the brain
light up. So many of the most subtle and complex things that
the brain does, things that involve intention, or things that
involve, even in a recent study, one's gut feelings about
something, now can be addressed in a biological sense. One can
actually ask what parts of the brain are involved in making
these decisions, are there cells that we can find that are
actually responsible for carrying out these tasks.
So in that sense, we are able to address more and more
complex problems. I think the future is bright and important
for brain research.

ninds budget increase

Mr. Porter. My next question begins with the words ``in the
aftermath of Christopher Reeves' spinal cord injury.'' But
before I ask that, there was a great deal made at the time of
the injury to Christopher Reeves, a public figure, an actor and
entertainer, and he even appeared at the Democratic National
Convention to talk about the importance of spinal cord injury
research. Your budget has a 3 percent increase in it. Do you
think that reflects the priority that we ought to have for
spinal cord injuries and other neurological disorders?
Dr. Hall. Maybe we should check afterwards on the budget
figures. Those are not the figures I have, but I may be wrong
about that.
Mr. Porter. No, I'm talking about overall increase for your
Institute.
Dr. Hall. Oh, sorry, for our Institute. I thought you meant
for spinal cord.
Mr. Porter. No, I only have it by Institute. But we can ask
that, too. [Laughter.]
Dr. Hall. That's fine. I think we have a number of
opportunities in research on diseases of the brain. I would be
happy to talk to you about the particular opportunities in
spinal cord research which are important. But in many, many
areas we have opportunities to make important advances. The
rate at which those advances are made depends on our budget.
I'm here to defend the President's budget, the 2.5 percent
increase, or approximately that, and we are pleased with that
increase. We would, of course, do more----
Mr. Porter. Why are you pleased with that increase?
Dr. Hall. Well, I'm pleased that it's not a decrease in
these Washington days.

spinal cord injury research

Mr. Porter. Let's talk about spinal cord injury research.
Dr. Hall. Let's do. [Laughter.]
Mr. Porter. What's the baseline level of effort in spinal
cord injury research, and how much of an increase did you make
in that in 1996 and what do you project for 1997?
Dr. Hall. Yes. Our figures for 1996 were approximately $47
million, and our estimated figure for 1997 is approximately $50
million. And it was those that I was looking at when I spoke
before.
[Clerk's note.--Later provided, ``the 1995 baseline was $39
million.'']
Spinal cord injury presents a tremendous problem for us in
that it seems like almost an impossible task. There are
literally millions of nerve fibers that go out from the brain
to connect with the circuits in the spinal cordthat control the
muscles that allow us to move and that convey our sensations from our
body back to the brain where they can be used. In spinal cord injury,
these connections are damaged or in some cases broken. And the idea of
trying to attempt that rewiring seems almost a Herculean task.
But we are helped by the fact that even a small amount of
regrowth and regeneration can often restore significant
function. And for those who have spinal cord injury, even a
small restoration of function can mean an important improvement
in the quality of life. The ability, for example, simply to
grasp a glass or grasp a pen or to use one's hands and fingers,
even if not doing fine movements, can add immeasurably to what
one is able to do and to one's independence.
We are finding that there are ways in which we can improve
that regeneration. We just heard on Monday at the NIH a
visiting scientist from Switzerland who has found that the
white matter, the myelin that coats our nerves, actually
contains a substance that inhibits nerve growth. And the
purpose of this normally is to, we think, confine the growth in
the nervous system to those areas in which it is important for
adaptation. If you remove that inhibition in his case, he's
done it experimentally with antibodies, but there are other
ways to do this--then one can obtain much more regeneration,
and often in an appropriate way so that one can get partial
restoration of function, more than one would have believed. And
in experiments done in collaboration with scientists in the
United States, there has really been some remarkable progress
made in showing functional restoration.
The other half of it is we are finding more and more about
those molecules that can stimulate regrowth. These are growth
factors. They occur in minute amounts. We know some of them, we
don't know all of them. There's been a great deal of active
research recently in trying to identify them. I think last year
at this time I spoke about the identification of one, a factor
called netrin that had been hypothesized for years but has
finally been identified. And so, in a sense, with this
combination of an attractant and removing the inhibitor, taking
off the brake and putting on the gas, if you will, it is
possible to get some regrowth.
There are a number of other problems that we're interested
in and making progress on. One of the things that happens when
you damage a piece of nerve cord is that the glia that are
responsible for making the wrapping of the long fibers, that
essentially insulate the fibers that run up and down the cord,
die. Recent research shows that some of those die in a delayed
fashion as a result of a process called apoptosis; that is,
they in essence commit suicide. We are very interested in
understanding the factors that regulate this suicide program in
those cells with the idea that if they can be saved, then they
can help remyelinate the regenerating cord after that.
So in spite of the fact that this is a tremendous problem,
we are making some limited progress. I don't think anybody
thinks it will be easy. And we are unlikely to be able to
completely regenerate a cord within any time span that we see.
But the important point is that we don't necessarily have to do
that. And so we are continuing this research.
The other area that we have been investigating are acute
treatments that limit the damage after injury. Our trial
several years ago on the use of methylprednisolone, for
example, has been responsible for limiting the injury to a
large number of patients in this area.
So we see a number of opportunities. As you may know, our
Institute allocates its funds through the competitive peer
review process and, by long-standing agreement with our
Advisory Council, the first 80 percent of our funds is spent
strictly according to priority reflecting scientific excellence
and opportunity. So we are pleased to see that this area is
developing and that grants in this area are developing as well.
Mr. Porter. Can you say that again, the first 80 percent of
your funds are?
Dr. Hall. Yes. The first 80 percent of our funds are given,
by agreement with our Council, strictly according to the
percentile score as judged by----
Mr. Porter. What about the other 20 percent?
Dr. Hall. The other 20 percent we can award out of order,
and we do that on the basis of several criteria which include
so-called creativity/originality, applications that perhaps
didn't score as high as they might but that have unusually
creative aspects to them that would bring something genuinely
new to a field; areas of particular interest that we think
might have been overlooked or are particularly promising; we
look to support young investigators, and we also in some cases
have an ongoing established group that has been active, we
expect them to continue to be productive, but for one reason or
another they've fallen below the line, and we feel there may be
an investment to be lost, sometimes it's animals or sometimes
it's personnel, if they were to have a lapse in funding.
Mr. Porter. Looking at spinal cord injury, whether it's
before or after Christopher Reeve was injured, research in this
area is just as important in any case.
Dr. Hall. Yes.
Mr. Porter. But the President of the United States seemed
to respond to that particular injury and the public interest in
spinal cord injury after Christopher Reeve was injured. How do
you respond to the commitments the President has made in these
areas and still adhere to your principles of not earmarking
funds for particular diseases?
Dr. Hall. Do you want to answer that? Doctor Varmus----
Dr. Varmus. The two of us worked together in an attempt to
stimulate the field. Doctor Hall arranged a workshop that made
it clear that we have special interest in this area, and that
did bring a lot of people together and stimulated grant
applications that met the review criteria. Do you want to speak
specifically about the grants that have been supported?
Dr. Hall. Sure. Yes, we've supported a number of grants
that look at the factors that influence cell death in these
spinal cord----
Mr. Porter. Let me interrupt you, Dr. Hall. I understand,
but did that have anything to do with Christopher Reeve being
injured or the President's commitments?
Dr. Hall. Yes.
Mr. Porter. It did?
Dr. Hall. Yes, it did.
Mr. Porter. Would you have done this anyway, or did you
only do this because the President indicated this was something
he wanted to talk about?
Dr. Varmus. It was a combination. I think it was a
fortunate collision of an interest in doing something in
response to public interest in this condition, but there have
been a series of developments in the study of nerve regrowth--
particularly the study in the rat model that Dr. Hall
mentioned--has provoked a great deal of interest in the
opportunities for regeneration of nerves in the spinal cord, in
particular.
Some of the money that was used for meeting the President's
commitment was from my Director's Discretionary Fund, and some
was generated by the use of my 1 percent transfer authority. So
a number of things were cobbled together to meet the
President's commitment.
Mr. Porter. Again, I don't at all question the importance
of spinal cord injury research, but I think that political
earmarking for diseases is reprehensible whether it's done by
the Congress or by the Administration. It seems to me that
we've got to be very careful that we aren't responding to the
particular topical events of the news, but rather are seeking
the best science.
You're telling me you're seeking the best science, and
that's certainly good enough for me, but, on the other hand, I
worry that we could get to a position where we will be
directing most of what you do because Members of Congress are
interested or the President is interested. That's not what we
ought to be about, it seems to me. We talked about this a great
deal. I just wanted to see what your answer would be in respect
to this particular circumstance.
The Department of Defense and the VA are both major players
in spinal cord injury research as well, are they not?
Dr. Hall. Yes.
Mr. Porter. Who is doing the largest amount of research in
this area?
Dr. Hall. I don't have the figures for spending in those
areas. We could certainly get them for you. I do know that when
we gave our workshop we certainly let representatives of those
organizations know and they were in attendance. But I don't
have the figures.
Mr. Porter. Can you provide those for the record, Doctor
Hall?
Dr. Hall. We can provide them.
[The information follows:]

SPINAL CORD RESEARCH
----------------------------------------------------------------------------------------------------------------
Fiscal Year
Agency -----------------------------------------------
1995 actual 1996 actual 1997 estimate
----------------------------------------------------------------------------------------------------------------
Department of Defense........................................... $12,000,000 $4,200,000 $5,850,000
Veterans Affairs................................................ 6,000,000 6,500,000 7,200,000
----------------------------------------------------------------------------------------------------------------

Mr. Porter. As you indicated, another approach to spinal
cord injury was tested last year when researchers formed
bridges across severed spinal cords in rats with multiple fine
nerves. In conjunction with growth factor, the procedure
allowed certain limited recovery of function. In the short
term, do these reconstructive therapies hold greater promise
than studying cellular processes?
Dr. Hall. Well, those procedures arise, in part, from the
study of cellular processes. It is actually precisely that
study that I was referring to before, because one of the key
features in that study was to provide bridges across the cord,
the brain is on my left, you have the spinal cord here, you
have an injury, and what you want to do is then make bridges
from this side to the other. The point was to lead those
bridges into the gray matter and to avoid the white matter.
That was done for the specific reason that cellular work had
led to the realization that there was an inhibitor substance in
white matter that would prevent regeneration. And so the
combination of having bridges that would be hospitable for
growth, providing an extrinsic growth factor, and avoiding the
white matter in the construction of these were all key
features. So it's not an either/or situation. Those arise out
of, those represent the application of insights that have come
from cellular and molecular work to this complex clinical
situation, if you will, involving an animal.
I think the conditions under which those were done, very
carefully controlled for the purposes of the experiment, of
course there was a nice clean break made and so forth, are
rarely the conditions that you see in spinal cord injury in the
clinic. So they cannot be simply transported wholesale from the
experimental situation to the real life situation. But by
telling us what factors are important and by validating, if you
will, these insights from cellular and molecular studies at the
tissue level, these then provide the basis for future study and
I think are an important foundation for research that is now
going on.
An important aspect of those experiments, I might add, was
showing not only did you get fibers growing across, but you
also got functional recovery. And this ties into the point I
was making before that sometimes only small amounts of regrowth
are sufficient to give you a surprising amount of functional
recovery. And extensions of those experiments, some of which I
heard about earlier this week, as I mentioned to you, indicated
that the regenerating axons don't simply regenerate randomly,
but appear to regenerate in an appropriate way to reestablish
control of the brain over these spinal cord circuits that are
local circuits that remain intact.

genetics of parkinson's disease

Mr. Porter. As you mentioned, last fall researchers
identified a specific genetic region in a large Parkinson's
prone family in Southern Italy that seems to be linked to the
disease. This upset the conventional wisdom that Parkinson's
was not genetically linked. Do you think this finding will
prove to be an important clue to Parkinson's, or is the disease
likely to have multiple causal factors including those which
are environmental?
Dr. Hall. Our suspicion is that the disease arises through
some combination of genetic and environmental factors. And for
many years, much of the interest in the field focused on
environmental possibilities in part because of a discovery
which you may have heard of made on the West Coast some years
ago in which a number of young people were found to have
essentially a very severe form of Parkinson's disease that was
traced to their use of a drug that was contaminated by a
substance that actually destroyed the same cells that die in
Parkinson's disease. This was carried out by researchers in
California and at the NIH. One of the consequences of that was
to increase interest in the possibility that there might be
some environmental toxin that was acting in the same way as
this drug contaminant did.
So there have been a number of studies that have looked for
such an environmental influence. So far nothing has been
identified that acts in such an effective way. It is known that
in certain cases after a viral infection, on occasion there has
been the development of Parkinson's symptoms. So it can be
influenced by external events.
But people had really sort of overlooked the genetic angle,
or many people had. What we found at the meeting was that there
were large families who had many patients in them with
Parkinson's disease and in which it appeared to be inherited in
a very clear-cut fashion. And so we, as I said in my opening
statement, put together this collaboration and we have worked
with the Human Genome Institute which has really provided the
very latest in gene hunting technology to pursue this. So in
this large family it is very clear that a defect or an
alteration in a single gene causes Parkinson's disease. And I
might add, this is perfectly typical Parkinson's disease as far
as we know. There might be a slightly earlier age of onset, but
it appears indistinguishable from any classical Parkinson's
disease.
The question is, first of all, will this particular gene
prove to be important in other families even though it may not
exert as strong an influence, perhaps because the mutation is
different or something of that sort. We now have the tools to
begin to ask that question. And then the other point is that
even if this gene turns out to be important in the most extreme
case only for this family, our hope is that it will provide
this important clue to what's going on. We simply do not know
why cells die in Parkinson's disease. Wehave a number of
clinical trials, these are all aimed at trying to replace the cells
that have died, but the cells continue to die. It is a progressive
disease, as you know, and we simply don't know why.
Huntington's disease, Alzheimer's disease, ALS, Parkinson's
disease, all are neurodegenerative diseases in which cells die
for unknown reasons. In each case, a specific population of
cells is involved, and in each of those cases these are adult
onset diseases, these are cases in which people function
perfectly well for many years and then something happens and
these cells die. We think there may be links between those. We
are very interested in perhaps looking at using what's been
found with one disease to try to understand another. The
powerful tool that has been missing so far in Parkinson's has
been molecular genetics and we now think that tool is at hand.

targeted research

Mr. Porter. I want to go back to what I said earlier about
the President's commitments on spinal cord injury research. I
don't mean to suggest that there's anything wrong with the
President being very interested in this and promoting and
encouraging NIH to work harder in this area. I also will
suggest that many Members of Congress do exactly the same
thing. The fact that Silvio Conte and George O'Brien both had
prostate cancer certainly led to a greater concern about that
disease I think in NIH. We have members all the time that
express concern about diseases. We wrote into the report last
year an urging that you pursue research on therapeutic
approaches to Parkinson's disease, and I think you might have
just answered that question of what you've done.
But, again, there's nothing wrong to have that concern. My
worry is that we begin to have all of science politically
directed, that's what worries me. I'm sure it worries you also.
What share of your research portfolio would you categorize
as basic research that cannot appropriately be designated as
targeting one disease or another?
Dr. Hall. Those judgments are somewhat arbitrary, as you
know, but our guess is somewhere between 60 and 65 percent of
our research is directed at fundamental mechanisms that may be
applicable to a variety of diseases but are not targeted to a
specific disease.
Mr. Porter. And Doctor Varmus, would Neurology's percentage
of research that is basic mirror that for NIH as whole? Is that
about where everyone is?
Dr. Varmus. It's difficult to say, Mr. Porter. I think one
of the things that makes this a hard question to answer is that
a lot of research can be construed as being focused on one
disorder but is clearly applicable to others. That's a little
different from the question you asked, but it's something, I'd
have to consider in answering your question.

neurodengenerative disease initiative

Mr. Porter. Your Institute has been involved in the
neurodegenerative diseases initiative funded for the past two
years through the Office of the Director. Can you give us your
impressions of how well this mechanism of centralized funding
has worked?
Dr. Hall. Let me ask, I'm not sure. There are two things.
One is, we have the Biology of Brain Disorder Initiative which
is part of each year's budget. We also have through the Office
of the Director a group of us have funded research on
neurodegenerative diseases, and perhaps it is that you're
asking about.
Let me tell you what we did, and we will do something like
that again this year I think, and that is that a group of
directors of the Institutes who are concerned with
neurodegenerative diseases met, we then asked for applications
for those Institutes that had projects that were in this area
that were deserving of funding, we actually extended that
beyond the small group to any Institute who had a project in
this area that they wished to be considered. We then actually
invited Dr. Varmus to sit with us if he would and look over
these various applications, and then we discussed their
excellence, importance, interest, and on that basis recommended
funding for the various Institutes. So it was, in essence, a
mini competition, if you will, in that area.
Mr. Porter. The 1998 budget for the Office of the Director
does not include funding for the neurodegenerative diseases
initiative and, instead, indicates that the research projects
funded will be supported by the individual participating
Institutes. What projects from the initiative will be supported
from your 1998 budget and at what funding level?
Dr. Hall. From the 1998 budget, we don't know. Our sense
would be to take those deserving applications in 1998 that were
not going to be funded by our own funds and then apply them to
the neurodegenerative initiative in the same competitive way.
So in that sense, I can't tell you that we are pre-planning
what those particular funds might be. That is, we will look at
the applications that come in. We have not gone to the
community, if you will, and said we want applications in this
area because they're going to be used in the neurodegenerative
disease area.
Dr. Varmus. We could provide on estimate of the continuing
cost from the 1996-97 awards.
Dr. Hall. Yes, that's true. We have made awards in the past
that will continue, and so we will fund those.
Mr. Porter. Maybe you can provide those figures.
Dr. Hall. We'll be happy to provide those figures.
[The information follows:]

funding for the neurodegenerative diseases initiative

In FY 1996 an additional $3.5 million of NINDS
neurodegeneratie research was supported with funds from the NIH
Director's Discretionary Fund and the NIH Director's use of the
one percent transfer authority. The commitments from these
awards will be supported by the NINDS and total $3.6 million
for FY 1998.
In a similar manner, FY 1998 commitments for research
projects funded by the NIH Office of the Director in FY 1997
will be supported by the institute that has responsibility for
administering the project. Funding to meet these commitments in
FY 1998 is estimated to be around $8 million, based on the FY
1997 appropriation.

Dr. Hall. We have not actually made the 1997 awards yet, so
in that sense we will do that this year. A little bit later in
the year when we've had a significant number of applications
come in, we will sit down and we'll say what promising things
we were unable to fund this year in this area. We will do the
same again next year.
Mr. Porter. And then those will be funded out of your
Institute's funds? Because the Office of the Director doesn't
have any budget for that, correct?
Dr. Hall. We have in some cases matched those funds.
Dr. Varmus. Remember, Mr. Porter, that in general when
we've initiated new projects either through a specific earmark
for the Office of the Director or through the use of the 1
percent transfer authority, we pay the initial year's support
with that money from the Office of the Director, then the
Institutes have picked up the outyear costs.

estrogen and stroke

Mr. Porter. Throughout our hearings we have talked a great
deal about the benefits and hazards of estrogen use. Your
budget justification mentions yet another possible use of
estrogen to prevent strokes in post-menopausal women. What
properties of estrogen might be expected to have a protective
effect against stroke?
Dr. Hall. You're quite correct. We have a large clinical
trial that will look at the effects of estrogen in post-
menopausal women. We're very interested in that trial. We
expect it to report in 1998 if all goes well and we will see
what happens. The gender difference in stroke is interesting.
Women, on an age-adjusted basis, have a slightly lower risk for
stroke than men, but because women in general live longer and
because the risk for stroke is age-related, more women than men
end up being affected by a stroke particularly in later years.
So this leads to the suggestion that there is maybe some
beneficial effect in terms of a hormonal effect that might be
responsible for the gender difference. So we hope that this
trial will provide some support for that.

possible therapeutic effects of nicotine

Mr. Porter. For many years there has been evidence that
smokers seem to have a reduced risk of developing Parkinson's
disease. Nicotine has also been suggested as a potential
treatment for Alzheimer's disease. Now that nicotine has become
available in numerous non-tobacco forms without the risks of
smoking, do you think the evidence is suggestive enough to
support research into the possible therapeutic effects of
nicotine?
Dr. Hall. Yes. We, in fact, do support an interesting
project on the therapeutic effects of nicotine. There was an
article in the New York Times in which I stated incorrectly
that we were not supporting such a project, but I found out
later that we were. It's an interesting one, and that is for
patients with Tourette's Syndrome in which there are so-called
tics in which people make sudden unexpected movements or
sometimes say things that they cannot control, then
haloperidol, which is an antipsychotic agent, given in low
doses has proven to be useful for these patients. The side-
effects of that are ameliorated by nicotine.
But it has been very difficult to get the patients. These
trials have been carried out on adolescents, and nicotine, if
given orally, is very bitter and they tend not to take it. So
what's been developed now is a skin patch whereby the nicotine
actually is absorbed through the skin. That is in trial. We're
very interested in the possibility that will be beneficial.
Certainly anything that would help these young people, we would
be very interested in.
Mr. Porter. But that's not having a therapeutic effect,
that's offsetting side-effects from the drug itself, right?
Dr. Hall. Yes, it is. Yes. That's correct.
Mr. Porter. Are there any possible therapeutic effects of
nicotine itself?
Dr. Hall. There is an old observation that smokers, as you
mentioned, do not get Parkinson's disease. And within the last
year, there has been some experimental support at the cellular
basis for that. I think whether one would use nicotine and how
it might be used in that context is at present only
speculative. My guess is it will not be a key agent. And we
don't have any plans at present to pursue that. So with the
exception of the Tourette's case, we are not actively pursuing
any case with nicotine.

prion hypothesis and mad cow disease

Mr. Porter. In January, Science magazine published a study
questioning the leading hypothesis about the cause of Mad Cow
disease. Abnormal forms of proteins called prions have been
thought to cause Mad Cow disease although no infectious disease
has ever been shown to be caused by proteins. Do you think the
new Science study is persuasive enough to send researchers and
funding agencies in new directions looking for the cause of Mad
Cow disease?
Dr. Hall. This is a long-standing question. At its core is
a scientifically very important idea, and that is, infectious
agents replicate so that if we are infected with a virus, the
virus divides to produce more viruses, and that's how the
infection is spread within the body and spread from person-to-
person. We know that viruses and bacteria replicate through
their DNA by dividing and splitting.
The question of the prion diseases, which were originally
called ``slow viruses,'' was a very perplexing one. Research at
our Institute originally showed that some of the neurological
diseases, specifically kuru and later Creutzfeld-Jakob disease
and others, were actually caused by an infectious agent. That
is, you could take brain material from someone who had kuru and
give it to an animal and the animal would develop symptoms.
This is the same thing that happens in Mad Cow disease, that it
is transmitted.
Now the question is, what is the transmissible agent? There
have been literally decades of research that have gone into
that question. I think it's fair to say that most people
believe now that it is a protein, although the issue is not
settled beyond doubt. The current hypothesis that is being most
actively investigated is that the protein goes in and it is in
an altered conformation that makes it infectious, and that when
it goes into the body, it then induces in some catalytic manner
the normal protein of the body to take on this altered
conformation. And in that sense, the altered protein replicates
itself even though there is no nucleic acid involved. And then
that altered protein is transmitted to the next animal, and so
on.
The study that appeared in Science reported that in some
animals, and not all, by the way, but in some animals that had
the symptoms of these diseases, they were unable to detect
these altered proteins. Whether that is a fundamental
observation or a detection problem, we are not yet sure. I
think that is the real question, as to whether or not they are
there and simply not detected, or whether in fact, as some
people believe, there is another infectious agent and that this
change in the protein simply allows the infectious agent to
come in and do its work.
So research in this area will continue. We actually support
people on both sides of that dispute, some who believe that it
is the protein and others who are less sure. It is from a
biological point of view a fascinating point, it is even a
revolutionary idea. And as you know also, it has had tremendous
economic-social consequences through the spread of Mad Cow
disease in Britain.
Mr. Porter. Thank you, Dr. Hall.
Ms. Pelosi.
Ms. Pelosi. Thank you, Mr. Chairman. Dr. Hall, Dr. Varmus,
everyone, welcome. Thank you, Dr. Hall, for your testimony and
for your good work at your Institute. Once again, Mr. Chairman,
may I express my pride in a leader from the University of
California-San Francisco making such a wonderful contribution
to science under Dr. Varmus' leadership.
This committee, I just love it, it's such a wonderful place
to serve because of all the good testimony we receive, and
under the leadership of our Chairman, the good work that the
committee is able to accomplish. I don't know what is sadder,
the days when people come in and they're talking about diseases
that effect large numbers of people in the population, like
cancer or AIDS, or the days when people come in and it's a
small population, a small universe that is affected because you
know it is going to be very difficult to build the public
support. Dr. Varmus would not want that to happen in any event,
that we would be sticking with our basic biomedical research--
but, in any event, that enough attention is paid in one way or
another to some of the rare diseases that we see families have.
I want to just ask about a couple of those.
Dr. Hall. Please do.

amyotrophic lateral sclerosis

Ms. Pelosi. In our report language last year, we talked
about Lou Gehrig's disease and the need to sustain the momentum
of current research. The committee encourages you to enhance
your support of brain research relevant to ALS.
Forgive me, Mr. Chairman, if that's already been addressed.
Dr. Hall. ALS is a very active area of research right now,
one that we're particularly interested in. I actually had used
it earlier this afternoon as an example of a disease in which
we have been able to make progress through insights in
molecular genetics. About 10 percent of patients with ALS have
a familial form of the disease, which means they inherit an
alteration in their DNA which causes them to get it. In some of
those cases, a portion of those cases have been shown to be due
to alterations in a specific gene that encoded, in fact, an
enzyme that was very familiar to us, an enzyme called
superoxide dismutase. Basic science had studied that enzyme for
years and it was one of those cases where clinical
investigation suddenly is able to plug into a vast body of
knowledge that was there waiting for it.
The discovery that this enzyme was the problem led to the
idea that there must be something wrong with the disposal or
the generation of very dangerous compounds or class of
compounds in ourselves called ``free radicals'' which are very
reactive and which can do damage. These are generated as a by-
product of energy metabolism and the cells have a special
machinery to dispose of these.
Further research has indicated that it is not the absence
of the enzyme that causes problems, but it appears that the
altered enzyme actually itself is a pernicious agent and that
it does bad things to the cell. We don't yet know what that is,
but we think the enzyme, because of the alteration, doesn't get
rid of these free radicals in the way it should but actually
generates a particularly dangerous class of those free radicals
and that they attack the cell.
What's happened then is one has been able to take this
altered gene that was responsible for ALS in these families,
put it into mice, and now we are studying in mice what happens,
what the pathological process is, how it is that these mice
develop motor symptoms, which they do. It is a relatively good
model for the disease. We hope that this will also be a place
where one can investigate potential therapies. I think you'll
hear later this afternoon from Dr. Cassman about some basic
research that has gone on involving some of the pathological
processes in these cells that occur during ALS.
So this is an active area. In fact, I hope to be able to
attend a workshop later this spring in Boston on motor neurons
and ALS. We're very interested.

human embryo research

Ms. Pelosi. Thank you, Dr. Hall. I'm going to skip a couple
of diseases and go to another question in the interest of time.
We've had quite a lively debate in our subcommittee and in the
full committee about human embryo research. I was interested in
what you had to say here about Parkinson's disease in your
testimony. And I wondered if the actions taken by our
committee, and therefore the Congress, on the restrictions on
human embryo research have had an impact on your work?
Dr. Hall. No. The work that you refer to that we support
concerns experiments in which aborted fetuses have extracted
from them the cells that make the chemical that's missing in
Parkinson's disease, dopamine. These cells then are put into
adult brains of people with Parkinson's disease. We are now
carrying out two clinical trials to see if this treatment is
effective. Because these are not human embryos that were
created, these are aborted fetuses and they don't come under
the human embryo research bans. So this work is not prohibited.
Let me just say that no one believes that in ten years from
now this will be the way we will treat Parkinson's patients.
The reason that we're doing this is that there is a strong
feeling that it may be more effective to give dopamine, the
missing compound, by cellular secretion than by giving L-dopa,
a precursor which people take and which has to enter the brain
and get converted and so forth. L-dopa, as you may know, is not
in the end a definitive therapy for Parkinson's disease. People
develop side-effects, it becomes ineffective. And so the idea
is that maybe if it were given in a more natural way it might
be effective. The only cells that we know that one can put in
the brain and have function in this way right now are cells
from these young nervous systems. If those experiments are
successful, then we will proceed to devise engineered cells
that will do this in a different way. This will not in any
long-term or large sense be the source of cells that will be
used for therapy.
Ms. Pelosi. That's interesting. I was also interested in
terms of the in vitro fertilization, the debate that we had
about the remains or the----
Dr. Hall. Our Institute is not involved in that at all.

spinal cord injury research

Ms. Pelosi. Okay. I thank you. Spinal cord injury, if I may
just quickly, Mr. Chairman. Is there reason to be hopeful that
with all the advances in science and technology that--well,
could you address that, please?
Dr. Hall. Yes, indeed. There is. We have made much progress
in understanding the factors that make nerve cells regenerate
and grow axons, the long extensions that they have. And we now
know factors that positively stimulate them to grow and we also
know that the nervous system has factors in it that prevent
their growth. It actually has been a long-standing mystery or
one of those well known puzzles that if you cut nerves in the
peripheral nervous system, that is the nerves that run down
your arm, they will regenerate. But if you cut nerves in the
central nervous system, they don't. One of the reasons they
don't is because there are substances that prevent this in the
central nervous system. Presumably these are there to prevent
aberrant connections being made in adults.
We are finding ways of blocking that inhibition, if you
will. And so there are some initial, very promising studies
suggesting that you can increase the growth of nerves in spinal
cord-injured animals and that this increase results in
functional recovery. So we are very heartened by that and very
eager to explore that further.
Ms. Pelosi. When you say cut cells one place and another
and compare the impact, when you bruise the spinal cord, is
that the equivalent of cutting cells or is that something else?
Dr. Hall. Yes. Well, several things happen in spinal cord
injury. In fact, most spinal cord injuries are not clean cuts
but are cases in which the vertebra are broken and actually
compress the axons. So there's damage on several levels. The
axons that run down the cord are sometimes damaged as if they
had been cut. There is also edema, that is swelling of the
cord, and the cells that are responsible for making the
insulation around the axons die, we are now finding out,
sometimes with a delay. We are trying to explore ways in which
that cell death can be prevented.
So it is not simply the physical separation of the cells,
but a lot of the trauma has to do with increased pressure,
edema, there is often an inflammatory reaction, and all of
these factors contribute to spinal cord injury. So it is really
a very complex sort of injury. It is not something as simple as
a clean cut would imply.
Ms. Pelosi. I appreciate your elaboration. I was encouraged
by what your statement said on the subject and by your
testimony.
Dr. Hall. Absolutely.
Ms. Pelosi. Thank you very much, Dr. Hall.
Thank you, Mr. Chairman.
Mr. Porter. Thank you, Ms. Pelosi.
Thank you, Dr. Hall. You did an excellent job of
testifying, except for the answer to my question as to why you
don't want more money. [Laughter.]
Mr. Porter. We very much appreciate the fine job you're
doing at your Institute. Thank you for your appearance here
today.
Dr. Hall. Thank you very much, Mr. Chairman.
Mr. Porter. We will stand in recess briefly.
[The following questions were submitted to be answered for
the record.]

[Pages 2026 - 2093--The official Committee record contains additional material here.]

----------

Tuesday, March 18, 1997.

NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

WITNESSES

DR. MARVIN CASSMAN, PH.D., DIRECTOR
MARTHA PINE, EXECUTIVE OFFICER
DR. W. SUE SHAFER, PH.D., ASSOCIATE DIRECTOR FOR EXTRAMURAL ACTIVITIES
G. EARL HODGKINS, FINANCIAL MANAGEMENT OFFICER
DR. HAROLD VARMUS, M.D., DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

Mr. Porter. The subcommittee will come to order.
We are now pleased to welcome Dr. Marvin Cassman, the
official Director of the National Institute of General Medical
Sciences. Congratulations, Dr. Cassman, on your becoming a full
director rather than just an acting director. Congratulations
also on your Institute having, together with the OAR transfer,
passed the $1 billion mark in budgeting.
Why don't you introduce the people at the table with you
and then proceed with your statement.

Introduction of Witnesses

Dr. Cassman. Thank you, Mr. Porter. I'm pleased to be here
officially. On my far left is Mr. Earl Hodgkins, who is our
Financial Management Officer, on my immediate left is Ms.
Martha Pine, the Executive Officer of the Institute, and Dr.
Sue Shafer, on my right, the Associate Director for Extramural
Activities.
I'm very pleased to be here and to present to you the
programs of the National Institute of General Medical Sciences.

Opening Statement

Today, I would like to highlight several recent discoveries
that have emerged from NIGMS-supported basic research. This is
something we do every year, of course, but this year I
particularly want to use these highlights to illustrate that
important discoveries do not occur in a vacuum, but build on a
large body of previous work. This is another aspect of what Dr.
Varmus in his opening remarks called ``culminations and
inspirations.'' These breakthroughs are the culmination of
decades of research representing the inspirations of many
investigators. Isaac Newton said that the reason he could see
so far was because he stood on the shoulders of giants. The
reason that these exciting new discoveries are emerging is
because they have been built on the efforts of a community of
scientists. It is one of the goals of the NIGMS to ensure the
continuing productivity of this basic research community.
One of the benefits of the NIGMS' long-term support of
basic research is that major discoveries can emerge in
unexpected places. The breakdown of materials in the cell was
for many years considered to be an essential process but, until
recently, it was not viewed as very interesting or even very
complicated. After all, waste removal has never had much
appeal. But it turns out that both in our external environment
and in our internal environment, in the cell, the process of
removing unwanted or obstructive material is complex, highly
regulated, and of central importance in our lives. There are
indications that the failure of cells and tissues to properly
dispose of molecular waste may be a factor in some diseases,
including one which was just mentioned, ALS, Lou Gehrig's
disease.
On the poster to my left, you see a pathway that begins
when a cell is stressed. One consequence of stress on cells,
not necessarily human stress, is that proteins unfold from
their highly ordered structure and lose their ability to
function. In some circumstances this is irreversible and the
molecule has to be disposed of. This is done by tagging it with
another molecule called ubiquitin, that's the left-hand branch
of that pathway, which signals to the cell that the protein's
time is up.
[See figure 1.]

[Page 2097--The official Committee record contains additional material here.]

Ubiquitin was discovered more than 20 years ago and it was
found to be ubiquitous in almost all cells and organisms;
hence, its name. It was given the name of ubiquitin because
nobody really knew what it did. It took quite a long time of
patient investigation, much of it by NIGMS-supported
investigators, to understand that its primary function was in
this removal of proteins that have become damaged in some way.
Recently, the ubiquitin story has taken an interesting
turn. We now know that in addition to waste disposal, the
selective and irreversible destruction of proteins by their
coupling to ubiquitin also provides a means of regulating
cellular processes. For example, perhaps the most significant
new advance in understanding how cell division is controlled
comes from the discovery this year by an NIGMS-supported
investigator of a large cellular particle which contributes to
the regulation of the cell cycle of growth and division through
targeting specific cell cycle proteins for destruction by
coupling them to ubiquitin.
Understanding how this activity fits into the complex
process of cell division is likely to provide further insights
into the behavior of the cell cycle in normal and aberrant
cells. It also demonstrates that the protein degradation system
is being used by the cell not only to eliminate proteins that
are damaged or no longer needed, but in the regulation of
cellular processes as well. As one NIGMS investigator stated in
a recent publication, ``Protein degradation represents a
chapter of cellular regulation that is just beginning to be
written.'' And all this from two decades of investigation of an
initially unknown compound.
On the right side of the poster you see a second possible
response to stress in the unfolding of proteins, the refolding
into an active form assisted by a compound called a chaperonin.
Now, how proteins fold into their three dimensional active
forms is one of the central questions of biology and it is one
that's been studied for many years. But all along a key tenet
that everyone has basically agreed on is that proteins don't
need any help to fold, all the information is contained in the
chemical structure of the protein itself. So it was a totally
surprising and completely unexpected discovery that in the cell
there exists this class of compounds which have been named
chaperoninsthat help proteins fold. Obviously, once again, the
name chaperonins are by analogy to the chaperones who once accompanied
and protected young ladies.
Apparently at least some proteins need a helping hand, or
maybe a helping molecule, to achieve their mature folded form.
The utility of chaperonins in the cell's economy and the way
they function have been vigorously addressed by several NIGMS-
supported researchers, one of whom has determined the structure
of a chaperonin in great detail. I wanted to show you this
because it is beautiful, apart from anything else. You're
looking at a chaperonin from the top down. It is a ring made up
of seven separate and different subunits. There are actually
two of these rings stacked one on the other. You can't see the
second one, of course, because it is hidden below. The ring
forms this doughnut-shaped cavity and in the cavity the
unfolded protein sits and is shielded as it folds.
[See figure 2.]

[Page 2099--The official Committee record contains additional material here.]

This structure will help in understanding the mechanism of
proper folding in the cell and may give clues to dealing with a
number of diseases. Failures in correct folding of proteins
have been implicated in retinitis pigmentosa, Tay-Sachs
disease, and cystic fibrosis. This fundamental discovery will
affect all of them and probably many more. Understanding the
rules that predict correct folding, as well as the process by
which it occurs, may help clarify the basis of these and other
diseases.
I should point out that the problem of how proteins fold is
a very difficult one to solve. A variety of approaches to
understanding this process have been supported by NIGMS for
many years, even when progress appeared painfully slow. In
recent years, the pace has picked up dramatically and major
advances have been made, in part, due to a continuing
investment in this field over a long period of time.
The step-by-step progress of science also yields tools that
can be of enormous importance both to industry and in the basic
research laboratory. I've given several examples of these in my
written statement, but I'll focus only on one, and that's on
the next poster which shows the developments in the production
of transgenic, or knock-out, mice--mice which have had genes
introduced or removed. Two NIGMS investigators have been
largely responsible for the development of this approach, and
it's been based on the underlying basic research which is
listed on the left-hand side of this poster. The highlights in
gold are those areas in which NIGMS investigators have had
major involvement.
[See figure 3.]

[Page 2101--The official Committee record contains additional material here.]

As you can see, many of the fundamental advances that
resulted in the generation of transgenic mice have emerged from
NIGMS-supported research. Now if you look on the right-hand
side, you will see the mouse models that have been developed so
far. Two of them are highlighted because two of them have been
developed by NIGMS researchers, the mice that have the cystic
fibrosis gene and one in which high blood pressure is being
examined. But as you will see, most of the other mouse models
are being supported by other NIH Institutes, as is quite
reasonable because they are being used for the specific
purposes of understanding the diseases that those Institutes
are targeted toward.
All of these discoveries build upon and were supported by
many outstanding investigators whose individual contributions
make up the body of science. It sometimes appears that progress
moves seamlessly, without a hitch, because discoveries appear
with such frequency. However, investigators sometimes stall in
their efforts, and in order to ensure that temporary
difficulties do not permanently cripple an otherwise productive
laboratory, and to maintain momentum in the field, we have
instituted a bridge funding mechanism for investigators whose
applications fall just beyond our payline. This is intended to
benefit the investigators by allowing them time to maintain
their progress; to benefit the Government by ensuring that an
investment in individuals and research is not lost; and to
benefit science generally by maintaining the scope and breadth
of effort that ultimately yield the discoveries that transform
our world.
Two other major areas of NIGMS support are training
andprograms designed to increase the number of under-represented
minorities in the biomedical sciences. I've discussed these programs
previously before this committee. I'll leave the detailed remarks for
my written testimony. Rather, I would like to conclude by looking at
these programs through the lens of history.
The seminal document in the development of the modern
research effort in the United States is generally agreed to be
Vannevar Bush's 1945 report called ``Science: The Endless
Frontier.'' This is a document more often cited than read,
which is a pity because it still has a great deal to tell us.
At one point, Bush quotes from an advisory committee, which
said the following: ``We think we probably would not, even if
we were all-wise and all-knowing, write you a plan whereby you
would be assured of scientific leadership at one stroke * * *.
We think it is much the best plan, in this constitutional
Republic, that opportunity be held out to all kinds and
conditions of men whereby they can better themselves. This is
the American way, this is the way the United States has become
what it is. We think it is very important that circumstances be
such that there be no ceilings, other than ability itself, to
intellectual ambition.''
This sentiment is applicable to all of our programs, but in
particular it reflects the purposes of the Minority
Opportunities in Research program, which is to ensure that
under-represented minorities have an opportunity to achieve the
scientific leadership of which Vannevar Bush wrote.
Mr. Chairman, the fiscal year 1998 budget for the National
Institute of General Medical Sciences is $992,032,000. I would
be pleased to answer any questions that you may have.
[The prepared statement follows:]

[Pages 2104 - 2107--The official Committee record contains additional material here.]

goals of the director

Mr. Porter. Thank you. It is $1,020,000,000 with the OAR
transfer.
Dr. Cassman. With the OAR transfer, absolutely. Yes.
Mr. Porter. Dr. Cassman, now that the ``acting'' has been
removed from in front of your title, you get the vision
question. Now that you've ascended to the top position, what
goals have you set for the Institute during your tenure, and
what steps are you taking to achieve them?
Dr. Cassman. I think that not a unique, but a major
responsibility of the NIGMS is to ensure the continuing
productivity of basic research in the biomedical sciences. That
means balancing a lot of different demands on the system. It
means ensuring that established investigators with ongoing
active programs are not disrupted in their research efforts and
maintain the ability to continue to be productive. That has to
be balanced against the needs of new investigators, and the
needs of the scientific community and of the country to have
new investigators come into the research system. It means
making sure that areas that are dynamic and evolving continue
to get the resources that they need but without starving the
new opportunities that continually emerge. We look for new
opportunities, for new ideas. We try to facilitate the
development of the basic research effort, and we try to balance
all of the needs that our community and that the broader
research enterprise in the United States faces.
One of the major things of course that we do is interact
with the extramural community, with our scientists, and with
our advisors, to get continued input into where science is
moving and to make sure that our portfolio is balanced in such
a way that all of the needs are addressed, not always met in
full, of course.

research in chemistry and physical sciences

Mr. Porter. Dr. Varmus has often noted that biomedical
research depends upon other disciplines--physics, chemistry,
mathematics, and computer science, for example--to thrive. Does
NIGMS support the lion's share of research in these other
disciplines at NIH?
Dr. Cassman. Certainly in chemistry, I don't think there's
any doubt of that. Physics, probably. Physics has an input in a
variety of different ways, including instrument development
which occurs in many parts of NIH. Mathematics is an area where
I think we need to have more involvement. In fact, we have been
having discussions recently with individuals who have an
interest in applying mathematical approaches to biological
systems. I don't really believe that we are encouraging
mathematicians to be as involved as they can and should be.

interim funding

Mr. Porter. As you mentioned, you've instituted a program
to provide interim funding to some unfunded competing
continuation grants. Applications that fall within 10percentile
points of the payline are eligible and will receive a third of the
grant's total cost. When will these researchers apply again for full
award? What success rate do you expect them to have?
Dr. Cassman. Those are interesting questions. The award is
made for only one year. So we expect them to apply within that
one year period so that there will be no hiatus in funding. In
the past, the success rate of this group of investigators has
been somewhere between 55 and 65 percent.
I would hope that the resources that we are providing
through the interim funding will make them more successful, not
necessarily in the immediate future, because this is really to
tide them over, but to ensure that there is no break in the
progress of their research, so that when they come in in the
future they will be more successful than perhaps they have been
in the past. That's one of the things we're going to follow to
see whether this program in fact has been useful.
Mr. Porter. How much funding do you allocate to these
interim grants?
Dr. Cassman. It will be about $3.5 million.
Mr. Porter. Do any other Institutes operate similar
programs?
Dr. Cassman. Other Institutes are approaching the issue in
other ways. I don't believe that there are any others that are
doing bridge funding in this form.
Mr. Porter. Your program has been criticized by some in the
university community because it caps indirect costs at 25
percent. How have you responded to these concerns?
Dr. Cassman. This was never intended to be a program
through which we could provide full support, we just don't have
the resources, for either the investigator or the institution.
It is an interim funding mechanism; it is not a full-funding
mechanism, it's a partial funding mechanism. I feel that it's
appropriate that we share the burden of supporting these
investigators for this one year period where we are providing
the one-third support in direct cost.
Mr. Porter. I'm not sure that fully answers what I've
asked. Obviously, there are institutions that have indirect
costs that are far higher, correct?
Dr. Cassman. The indirect cost rate is lower than the full
negotiated level. That's, first of all, consistent with other
programs at NIH, such as the Shannon Awards, which are interim
funding programs, and it is simply a reflection of the fact
that this program only provides partial funding either through
direct costs or indirect costs. I have no theoretical objection
to giving full cost to both in terms of direct and indirect,
but we don't have the resources for it.

high risk research

Mr. Porter. Your budget justification mentions plans to
support innovative high risk research through two year pilot
grants. You had previously tried another approach to supporting
higher risk research. What are you hoping to achieve, and why
did your first program not meet this objective?
Dr. Cassman. In the first program, we were looking at
applications that came in just through the normal route, and
looking at applications that did not fall within our normal
payline, in fact, in some cases fell far beyond it, and where
the reviewers would say things such as, ``This is a terrific
idea but--but there's not enough preliminary information'',
``but we're not convinced the investigator can do it''--or
because there was a lot of controversy. There really weren't a
lot to select from. People do not send in applications that
they don't think will be funded.
So what we're doing in this new program is more proactive.
We're soliciting applications that we hope will be somewhat
controversial, that have substantial experimental risks but
promise substantial benefits.

new investigators

Mr. Porter. You also mention efforts to support adequate
numbers of new investigators. Are you creating a new research
mechanism to address this need?
Dr. Cassman. No. No, we're not. Since 1992, we've given
specific advantage to investigators who have no other source of
support, and in particular new investigators. We're continuing
to do this. I urge the staff to look carefully at new
investigators coming in within 10 percentile points of our
payline, and even a bit further. I'm also co-chair of a
committee looking at the means that NIH uses to bring new
people into the system and the mechanisms that we use, and to
determine whether those mechanisms have been successful,
whether they're doing what we hope they will do.

stimulation of research fields

Mr. Porter. You intend to assess your grant portfolio to
identify gaps in research coverage. If you find areas that are
not being adequately addressed, what steps will you take to
increase research in those areas?
Dr. Cassman. What we normally do is we get advice, as I
said earlier, from members of the extramural community, and
from our advisory council. We usually hold at least a workshop
to determine what kind of approach is appropriate, and then we
put out a specific request for applications in that area.

employment prospects for research trainees

Mr. Porter. We continue to hear reports of considerable
anxiety and stress in the biomedical community about job
prospects, of positions having hundreds of applicants, and of
young scientists moving from one post-doc to another rather
than being able to secure a permanent job. At Dr. Varmus'
December advisory council meeting, at least two members
indicated concerns about this and felt the council should take
a more active role in assessing the problem. They also
questioned whether the periodic workforce studies by the
National Academy of Sciences provided useful information.
First, Dr. Cassman, can you give us your personal
assessment of the situation? And then, Dr. Varmus, can you tell
us how you plan to follow up on the suggestions of the members
at your advisory council?
Dr. Cassman. There's certainly some pressure on the
workforce. I don't think there's any doubt of it. How much is
not yet clear. Unemployment, as measured by the various indices
that the American Chemical Society, for example, or the
Federation of Societies for Experimental Biology use when
they're looking at this, have not, until very recently, shown a
significant increase in unemployment. Nevertheless, I do feel
that the opportunities are fewer now than they certainly were
during a period of high growth. But it's difficult to be able
to project that very easily.
The main point to remember is that all of our training
programs train for eight to ten years in the future, and that
we as a Nation, maybe anybody actually, are pretty bad at
predicting things that far out. Attempts to estimate supply and
demand in the past have been dreadful and have usually failed
miserably. I don't think we can make our adjustments now on the
basis of the fluctuations in the current situation. I think it
has to be left to the individuals who have an interest in
pursuing an area of excitement and great promise, and where
those individuals, I really do believe, will find jobsthat are
quite appropriate to their interest.
Dr. Varmus, you have to give your half of this.
Dr. Varmus. I'll be brief, Mr. Porter. Basically, the next
meeting of my advisory committee will be devoted, at least in
part, to this issue. Many of the members were unacquainted with
the National Academy of Sciences study that is done every three
or four years. We will have them read that report, and we'll
provide them with data that Dr. Cassman and Dr. Ellie
Ehrenfeld, Director of the Division of Research Grants, have
been putting together with respect to the state of young
investigators.
We want to distinguish very clearly between the problems in
obtaining grants on early applications and the problems of
finding jobs. We also distinguish between the difficulty in
obtaining jobs in a very restricted academic market and the
other opportunities for using an advanced degree in science to
work in industry, Government, or other sectors of our economy.

scientists employed as temporary workers

Mr. Porter. The Washington Post carried a story recently
describing the increased use of highly trained temporary
employees in scientific labs. Is this principally an issue for
private industry, or is it becoming more common in university
labs as well?
Dr. Cassman. As far as I know, it is really an industrial
issue. I'm not aware of temporary employees of the kind that
was described in the article, which I did read, being involved
in academic institutions at all.

research training collaborations with industry

Mr. Porter. Bruce Alberts, the head of the National Academy
of Sciences, proposed last week at an AEI-Brookings conference
that new hybrid models should be developed for students to
blend the university research setting and the biotech company
so that young scientists would have models other than the
traditional tenure track as a career route. Are the NIH
research training programs flexible enough to support training
in settings like these should they be developed?
Dr. Cassman. Absolutely. In fact, they already do. We have
specifically at NIGMS a biotechnology training program that
requires some involvement or some interaction with industry,
frequently an internship and in other instances collaborative
research, a variety of different ways. But in addition, our
other training programs frequently have interactions both on
the research level and on the teaching level with neighboring
biotechnology companies. So I think this is not an uncommon
phenomena even now.

rationale for stipend increases

Mr. Porter. NIH has increased 1997 training stipends for
pre-doctoral students and those in their first and second years
of post-doctoral training. The President's budget proposes
another stipend increase for the first two post-doctoral years
for fiscal year 1998. What guiding principle is NIH using in
these stipend decisions? Are you trying to achieve parity with
other Federal training programs?
Dr. Cassman. Would you like to respond?
Dr. Varmus. It's difficult for us to achieve parity with
all the programs. But we recognize that we have not been
providing cost-of-living increases to our trainees, so they've
fallen farther behind. Therefore, we have made a decision as a
group, at a meeting of the Institute directors, to increase the
level of support.
Mr. Porter. Stipends for post-doctoral fellows beyond their
first two years of training have remained unchanged since 1991.
Dr. Varmus. They were relatively high, however, compared to
the first two years. We tried to get the first two years up to
what amounted to a fairer relationship to the more advanced
years.

evaluations of national research service award training

Mr. Porter. Your advisory council last September heard the
preliminary results of an ongoing evaluation of the National
Research Service Award training programs. What are the major
findings of the study to date?
Dr. Cassman. That's an analysis that is being conducted of
all of the NRSA programs at central NIH. I don't believe it is
completed yet, although I understand that early this summer at
least a preliminary version of the report should be available.
Mr. Porter. Can you share that with us when you get it?
Dr. Cassman. Oh, yes. Of course.

compliance with nrsa payback requirement

Mr. Porter. Your Institute is responsible for monitoring
compliance with the payback requirements for research training
grants. In general, what kind of track record do trainees have
in fulfilling their research payback requirement?
Dr. Cassman. Very high. It's difficult, I can't give you a
good number, but I'm pretty sure it's under 1 percent where
we've had problems with compliance.

medical scientist training program

Mr. Porter. Do you intend to increase your emphasis on the
Medical Scientists Training Program which supports joint Ph.D.-
M.D. trainees in order to ease the difficulties clinical
researchers are facing in the new health care environment?
Dr. Cassman. Our training programs have stayed essentially
constant in numbers. The increases have been primarily through
stipend increases and occasionally to compensate for
inflationary increases in tuition payments. We don't really
have any plans at this point to differentially increase the
MSTP program. It would mean taking away resources from the
other graduate training programs and those are the programs
which support MSTP because the MSTP trainees do their research
in the graduate programs.
Dr. Varmus. I would add, Mr. Porter, that it isn't
necessarily the case that M.D.-Ph.D. awards lead to greater
protection for clinical investigators, because an awful lot of
our M.D.-Ph.D. graduates end up doing basic research that's not
clinical in nature.
Mr. Porter. Well, that's my next question. What information
do you have on the career outcomes of researchers who have
completed the Medical Scientists Training Program?
Dr. Cassman. We're doing a study now. I hope within the
next year it will be complete, and we can report on exactly
that, on the career outcomes. There have been previous analyses
of these but none very recently. The last one I believe was in
1984.
We do know something about the career progression but it is
more anecdotal than it is concrete. They tend to be among the
best students at any institution. They do extremely well when
they get out. They have a very good record of getting research
grant support. Many of them are in clinical departments even
though, as Dr. Varmus pointed out, they may be doing basic
research, which I think is very appropriate because one of the
intents of the program was to bridge basic and clinical and
their presence helps in that bridging. I can give you more
details I hope next year at the hearing.

research areas pursued by young investigators

Mr. Porter. What can NIH do to avoid imbalance in the
research areas chosen by young investigators; that is, toomany
students targeting one trendy field and ignoring other important areas.
Can the research training program be managed to address this problem?
Dr. Cassman. Well, we ask our training program directors to
give us their best--their best students, their best faculty,
their best programs. Beyond that, we try not to direct them.
The programs that we have are all multi-disciplinary to begin
with; they are not very highly targeted in some very narrow
specific research area. And, in fact, we're hoping to broaden
them even further. So I don't think that there is a lot that we
can do, and perhaps not a lot that we should do, about that. It
is still really up to the student to make that decision and
they'll go where the exciting work is being done, no question
about that.
Mr. Porter. Dr. Varmus, do you want to add to that?
Dr. Varmus. I do think this is an important question, Mr.
Porter. We haven't talked all that much about this as an
institution. But I think an argument can be made for trying to
generate programs that would allow post-doctoral fellows,
especially those of great excellence, to work independently
within an existing laboratory for one or two years. The
difficulty, as I'm sure you know, is that people who are good
tend to train in labs that are very productive, often working
in the most exciting areas. They develop research programs in
those areas and then, when it's time for them to seek a job and
apply for a grant, they naturally have to undertake their
activities in that area. They are never given an opportunity to
develop something novel in an atmosphere in which they have
some protection.
So I would like at some point to develop with a program
that would allow us to diversify the scientific community a
little more dramatically than we have been able to.

training programs of the howard hughes medical institute

Mr. Porter. The Howard Hughes Medical Institute supports
almost $90 million in science education activities annually,
from elementary to post-graduate. Do any of the Howard Hughes
post-graduate programs target the same research trainee
population as NIH programs, particularly in the minority area?
Dr. Cassman. Actually, the Howard Hughes programs, the
post-doctoral programs are quite limited. The only one that I
am aware of is to M.D.s who have had at least two years of
clinical experience. So it is essentially a reentry program
almost. Beyond that, I don't believe they really target
anything else, certainly nothing that's in the area that we
deal with.

percentage of ph.d.s awarded to minorities

Mr. Porter. Have there been any encouraging recent trends
in the percentage of Ph.D.s in the life sciences awarded to
minority students?
Dr. Cassman. The numbers are still very low. The last
number that I'm aware of, which is based on 1994 data, shows
that it is maybe just about 5 percent of the total.
[Clerk's note.--Later corrected to ``6 percent''.]
There is some indication that the bachelor's degree
production in the life sciences may be picking up, and of
course that's a necessary prerequisite. But right at the
moment, it's still very poor.
Mr. Porter. I might say we're also concerned about this in
the education area, because the percentage of minority students
getting advanced degrees is going down and that's of great
concern.
Dr. Cassman. Yes, the numbers are difficult to interpret.
Mr. Porter. What share of these minority Ph.D. students
graduate from minority institutions compared to so-called
majority schools?
Dr. Cassman. That data is usually reported by the
Department of Education and the National Science Foundation in
different publications they have. The only minority schools
that they identify are the HBCUs, the Historically Black
Colleges and Universities. There are other definitions--
Hispanic, for example. The University of Texas at El Paso has
something like a 65 percent Hispanic population and could be
considered a minority school, but it is not measured that way
in their evaluation. So if you look at the HBCUs, on the order
of 12 percent of the African-American Ph.D. degrees in the life
sciences come from HBCUs. That's really the only number that I
have available for minority institutions.
[Clerk's note.--Later corrected to ``10 percent''.]

gender differences in response to trauma

Mr. Porter. One of the researchers you support has found
that more males than females die after a traumatic injury, and
that those males who survive are often more sick. Sex hormone
levels are thought to be an explanation for this result. How
might hormone levels modify response to trauma? And what
implication could this have for the treatment of injury?
Dr. Cassman. It's another example of the intrinsic
superiority of the female. [Laughter.]
Dr. Cassman. What happens is that after trauma there is
frequently hemorrhagic shock; there's a loss of blood. One of
the things that happens as a result of that is a reduction in
the immune response. So people with hemorrhagic shock tend to
be more prone to infections and, particularly in that kind of
debilitated condition, therefore are more prone to die from
infections.
But this doesn't appear to be as true for females as for
males. The answer appears to be not that females have something
that the males don't have, but rather vice versa. The
testosterone levels in the blood apparently in some way
predispose men to this ultimate reduction in immune
responsiveness. There have been some studies recently showing
that anti-testosterone inhibitors provided for a short period
of time help in reversing this effect in males. That's still
underway in the preliminary studies.
Mr. Porter. Dr. Cassman, you have answered all of my
questions. I don't even have any for the record. We thank you
for your good statement and your very direct answers. We're
delighted that you are now complete and no longer acting. And
we're delighted that a Chicago boy and a University of Chicago
boy made good. [Laughter.]
Dr. Cassman. Well, thank you, Mr. Porter. I appreciate
that.
Mr. Porter. The subcommittee will stand in recess until
10:00 a.m. tomorrow.
[The following questions were submitted to be answered for
the record.]

[Pages 2116 - 2153--The official Committee record contains additional material here.]

----------

Thursday, March 20, 1997.

OFFICE OF AIDS RESEARCH

WITNESSES

WILLIAM E. PAUL, M.D., DIRECTOR
WENDY WERTHEIMER, SENIOR ADVISOR
DONNA ADDERLY, SENIOR BUDGET ANALYST, OFFICE OF FINANCIAL MANAGEMENT
HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

Introduction of Witnesses

Mr. Porter. The subcommittee will come to order.
We continue today with hearings on the National Institutes
of Health, and we are pleased to welcome Dr. William Paul,
Director of the Office of AIDS Research. Dr. Paul, if you would
introduce the people with you, and then please proceed with
your statement.
Dr. Paul. Thank you, Mr. Porter. I am delighted to have the
opportunity to appear before you.
I would like to introduce my colleagues. They are Ms. Wendy
Wertheimer, who is a Senior Advisor at the Office of AIDS
Research; Ms. Donna Adderly, a Senior Budget Analyst in the
Office of Financial Management; and, of course, I don't need to
introduce Dr. Varmus and Mr. Williams, but I will formally do
that.

Opening Statement

Mr. Chairman, this has been a year of progress and promise
in AIDS research, a year clearly demonstrating the dividends
made possible by our national investment in biomedical science.
So striking was this progress that Science Magazine named the
``New Weapons Against HIV'' as the breakthrough of the year,
and Time Magazine named Dr. David Ho, an NIH-supported
investigator and a member of our Advisory Council, as its Man
of the Year.
We can take collective pride in the dramatic changes that
have occurred just since our hearings last year. Protease
inhibitors, a new class of drugs, used in combination with
other antiretroviral therapies, have been shown to dramatically
diminish the amount of HIV in the blood of an infected
individual. Receptors for molecules called chemokines have been
identified as critical co-factors for HIV infection, providing
us with an entirely new set of targets for anti-HIV therapies
and new approaches for vaccine development.
These critical advances have brought a sense of hope and
renewed vigor to the AIDS research community and to our
patients. But it is essential to point out that the news, while
good, cannot lead to complacency. The covers of many magazines
may fantasize about the ``end of AIDS,'' but, Mr. Chairman, the
end of this pandemic is not yet in sight.
The new drugs, while promising, are not a panacea. We do
not know how long the benefits will last. It is far from clear
whether immune function of treated individuals can be restored
without additional intervention. There are many for whom the
new drug regimens have not been effective or for whom the side-
effects are not tolerable. Because of their expense, these
drugs are not affordable or accessible to many who need them.
Furthermore, the sobering fact is that we have made little
progress against the devastating spread of the epidemic around
the globe. AIDS is the number one cause of death among young
adults in the United States. Rates of increases in AIDS cases
in the U.S. are greatest for women, for adolescents, for
persons infected through heterosexual contact, for minorities,
and for injecting drug users. Worldwide, more than 29 million
people have been infected with HIV, with more than 3 million
new infections in just the past year. The great majority of
these infections occur in the poorest parts of the world, in
countries without the resources or the health care systems to
benefit from the new anti-HIV drugs.
AIDS has brought about a significant decline in overall
life expectancy in many African countries, threatening the
economies of these already-poor nations, and robbing them of
their workforce. A safe and an effective AIDS vaccine is an
urgent global public health imperative. Without a vaccine, AIDS
will soon overtake tuberculosis as the leading infectious cause
of death in the world.
Three years ago, the prospects in AIDS research appeared
dim. The pipeline of new potential drugs or vaccines seemed
empty. The OAR convened a small group of eminent scientists at
the Stone House on the NIH campus, a meeting which has proven
to be pivotal for AIDS research. We asked the group to help us
identify the critical gaps in our knowledge about AIDS and to
suggest what steps could be taken to open up new scientific
opportunities and move the scientific frontier forward.
The late Dr. Bernard Fields stated his firm conviction that
further advances against the virus would require that NIH shift
its priorities and its resources to bring about a rededication
to building the knowledge base about HIV and how it causes
disease. Without this knowledge, he argued, the pipeline would
remain empty.
In every budget year since then we have increased the
proportion of funding for research on basic aspects of HIV, on
the immune system, and on the mechanisms of disease, and we
have placed a greater emphasis on investigator-initiated
science. Between fiscal year 1994 and this budgetary request
for fiscal year 1998, we will have increased the number of
research grants by approximately 50 percent. This has
encouraged innovation from a wider group of investigators.
Another important initiative emerged from the Stone House
meeting. Dr. Phillip Sharp, a Nobel Laureate, stated that to
plot a course for the future, we needed to understand all of
the facets of the existing AIDS research program. He suggested
that OAR undertake a critical evaluation of the entire program
to ensure that the most promising areas of science were being
supported, the most critical scientific questions were being
asked, and the most effective use being made of Federal AIDS
research resources.
As you know, that discussion led to a review of
unprecedented scope across all the NIH Institutes and Centers,
led by Dr. Arnold Levine of Princeton University. The report,
commonly called the Levine Report, provides guidance to the NIH
for strengthening our AIDS research programs. This report is
not sitting on a shelf, gathering dust; its recommendations
helped frame the OAR's finaldistribution of the fiscal year
1997 appropriation, and are reflected throughout our fiscal year 1998
research plan and budget request.
I would like to update you about the implementation of some
of these recommendations.
The report recognized that only a truly effective
preventive vaccine can limit and eventually eliminate the
threat of AIDS. The reviewers placed a high priority on the
need to restructure and reinvigorate the AIDS vaccine program,
with leadership and guidance from eminent non-Government
scientists.
The NIH has taken important steps to carry out this
critical recommendation. Nobel Laureate Dr. David Baltimore has
been recruited to lead this effort, and he has gathered a group
of outstanding scientists to serve with him. Their charge is to
energize the development of new strategies that will lead to
the discovery and development of a safe and effective AIDS
vaccine.
To facilitate this effort, the OAR has made a major
financial investment in AIDS vaccine research. The fiscal year
1998 budget request represents a 33.6 percent increase for
vaccine research in the two-year period since fiscal year 1996,
a sign of our commitment to this effort.
The President also highlighted the importance of vaccine
research in his State of the Union address.
Some have argued that a protective anti-HIV vaccine is
simply not possible. As an immunologist, I believe there is
persuasive evidence that a protective immune response can be
induced, and that an effective vaccine is possible. I also
believe that the Government has a unique role and obligation to
support the basic research needed for the development of a
successful vaccine.
The Levine Report also urged NIH to develop a Prevention
Science Agenda, combining research on behavioral interventions
with biomedical interventions such as topical microbicides,
female-controlled barriers, methods to prevent mother-to-child
transmission, and prevention and treatment of sexually-
transmitted diseases. The OAR has convened a group of experts
to assist us in identifying the most promising areas for
additional investment.
With these actions, we believe that the necessary balance
has been struck between research to develop treatments for
those who are infected, and to develop vaccines and other
prevention methods for those who are at risk. This is a
delicate balance and one that will almost certainly shift as
science progresses.
Thus the fiscal year 1998 budget for AIDS research has been
crafted to reflect the recommendations of the Levine Report and
the broad consensus on the current scientific opportunities,
including a rededication to understanding the basic biology of
the virus and how it causes disease; a stronger vaccine
research and development effort; increased research on human
immunology; an emphasis on prevention science research; and a
vigorous therapeutic program with an efficient clinical trials
system in which there is increased participation of women and
minorities.
Mr. Chairman, we are reaping the rewards of years of work
by dedicated scientists. Those who met at the Stone House
helped us set a new course for AIDS research. We have gained
new knowledge of the basic biology of HIV and developed new
targets for therapies and vaccine development.
The science of AIDS is moving forward and opening whole new
areas of research that can advance the treatment and prevention
not only of AIDS, but of other diseases as well.
The Office of AIDS Research requests a consolidated
appropriation of $1,540,765,000 for NIH AIDS research. The
budget authorities provided to the OAR, allowing us to make
resources available where the greatest opportunities lie, are
even more critical today, as these opportunities constantly
change.
We are grateful to the committee for your continued support
for AIDS research and providing us the flexibility critical to
meeting the enormous scientific challenges posed by HIV.
I will be pleased to answer any of your questions.
[The prepared statement follows:]

[Pages 2159 - 2162--The official Committee record contains additional material here.]

Mr. Porter. Dr. Paul, thank you for that wonderful
statement. Let me say that the progress that has been made in
AIDS research makes one's heart leap for joy, and yet you warn
us, very properly, that we're only making substantial progress
and the end is not yet in sight, and we certainly need to
assure that you have the resources that you and your
investigators need to continue the fine work that you have
done. So we very much appreciate your leadership and all the
progress that is being made, and we obviously want to provide
you with the resources that you need to continue doing the fine
job that's being done.
I might add that I don't think the President is giving you
enough, but you knew that already. [Laughter.]

aids statistics

Let me ask some questions.
Perhaps because of the relative newness of the AIDS
epidemic, the number of cases is usually described in
cumulative rather than in annual terms. Can you give us an idea
of the number of new AIDS cases and AIDS deaths in the United
States on an annual basis over the past few years?
Dr. Paul. Yes. For the last year for which we have complete
numbers, the number of new diagnoses is slightly in excess of
70,000--I believe approximately 71,000. The number of deaths--
again, in the last year for which we have complete data--was
approximately 50,000. There does appear, however,in the last
six months to have been a trend towards a diminution in the death rate.
CDC's numbers suggest that death rates are now falling, possibly by as
much as 10 to 13 percent, although we will have to see that on an
annualized basis.
Mr. Porter. Were they rising in previous years, previous to
this?
Dr. Paul. Yes. The death rates--deaths have been rising
from in the mid-40,000 range to 50,000 in the last year. I
believe that would be the 1995 to 1996 year. And as I say, in
the first six months of the most recent year that we have data
for, the CDC indicates that the death rates are now beginning
to diminish.

demographic groups with increasing aids cases

Mr. Porter. In which demographic groups is the annual
number of new cases continuing to increase?
Dr. Paul. Yes. Well, we are certainly seeing increases, of
course, quite substantially, among women. Tragically, the
numbers continue to increase and the proportional burden of
this disease on members of minority populations are continuing
to rise. As I indicated earlier, the number of new cases also
amongst injecting drug users is increasing, and we are seeing a
greater degree of transmission through heterosexual means.

prospects for international availability of an aids vaccine

Mr. Porter. The international picture of HIV infection is
terribly bleak, as you said in your statement. Even if the
unimaginable occurred and a promising vaccine candidate was
identified tomorrow, how many years would it take for the
vaccine to pass through testing and approval before reaching
the international organizations that would sponsor its
distribution?
Dr. Paul. The general process through which trials are
conducted, in which we do initial safety trials, is the so-
called Phase I, and then, following the model that is used in
drugs, we do trials that establish that the vaccine actually
induces an immune response, which is the equivalent of Phase II
trials. And then, finally, conducting efficacy trials. This is
a period which probably cannot be accomplished in much less
than four to five years. That would probably be, I would have
to say, the lower limit of the time required, and that's
probably if everything is working perfectly. Unfortunately in
this business there are almost invariably needs for adjustments
that have to be made.
So were we to have in our hands tomorrow something which
eventually proved to be an efficacious vaccine, I would guess--
if I said five years, that would probably be a very optimistic
statement. But we would obviously want to push the pace of this
as rapidly as we could.

projected aids deaths without a vaccine

Mr. Porter. Assuming current demographic trends in looking
worldwide, how many people would die before the vaccine became
available to them?
Dr. Paul. Well, as I said earlier, the rates of new
infections for the last year or two have been in the range of 3
million per year. The actual number of AIDS cases worldwide now
is probably in the order of over 8 million. We have 29 million
infections, and the reason for that discrepancy, of course, is
that the epidemic is gathering force, so that many of those
infected have not yet progressed to the point that they can be
diagnosed as AIDS.
Almost invariably, we will see the great burden occur
several years out. But for every year that we don't have an
effective vaccine, we can anticipate three to four million--and
in the outyears, more--new infections.
So to answer your question appropriately, I would say that
failing good treatments, with the concept that every infected
person in poor parts of the world will eventually succumb to
this disease, each passing year is a minimum of 3 million in
new deaths.
Dr. Varmus. Just adding something, Mr. Porter, although
vaccines are traditionally thought of as being preventive,
there is the possibility of having vaccines that act in a
therapeutic manner, and that would obviously affect the
outcome.

benefits of aids research to other diseases

Mr. Porter. As you know, the committee is often drawn into
the debate about whether an inappropriate share of NIH funding
is devoted to AIDS research. Your budget justification
described quite powerfully how advances in AIDS research have
had an important impact in other disease areas. I wonder if you
would highlight these examples today.
Dr. Paul. Well, I would like to make several comments on
that point. I think it is not fully appreciated what a
remarkable accomplishment the antiretroviral therapy has been,
not only because it has such a powerful impact on patients
living with AIDS, but it really represents the first time there
has been a concerted and rational effort to develop drugs to
treat viral diseases. Until now we have had some drugs that can
treat viruses, in various limited circumstances. Almost
invariably, their ability to do so has been discovered in a--I
would say, in a serendipitous manner.
By contrast here, scientists have shown that if you take
the virus apart piece by piece and examine how it works--with
the aid, of course, and participation of the pharmaceutical
industry--drugs can be made to treat virus diseases. That's an
entirely paradigm-shifting concept. We have relied in the past
on preventing virus diseases and treating bacterial diseases. I
believe that this approach will herald an era when we will have
the ability to undertake true treatments of viral diseases.
So I believe this is, in a sense, a path-breaking concept
which is largely due to the investment the Nation has made in
HIV research.
In addition, there has been an enormous increase in our
attention to human immunology, to fundamental immunology. The
advances in this area have enormous impact for a wide range of
disorders, for virtually all of our autoimmune diseases, which
include, of course, multiple sclerosis, rheumatoid arthritis,
systemic lupus erythematosus, juvenile--so-called Type 1--
diabetes. The range of disorders which are actually caused by
disrupted immune responses is quite staggering.
So I believe that the scientific advances that have been
made by my colleagues working in this area--and by my
colleagues, of course, I mean the whole of the enterprise,
which is a very considerable one--have very great implications
for the health of the Nation and the world.

flexibility for oar to change icd distributions

Mr. Porter. Dr. Paul, I don't want to belabor a dispute of
sorts that I believe has been resolved, but in last year's
debate about the consolidated appropriation for AIDS funding
one of the arguments raised was that because of changing
circumstances, like the publication of the Levine Report, it
was important to have flexibility to change the distribution of
AIDS funding among Institutes. Yet from 1996 to 1997, the
actual changes you made in the percentage of NIH AIDS funds
allocated to each Institute were very, very small. In
retrospect, was this argument just not relevant?
Dr. Paul. Well, let me say, Mr. Porter, I believe that the
consolidated appropriation has been a very effective tool for
responding to these changes. I must also say that the
authorities that the committee has given to the NIH for this
purpose have worked rather well within the last year or two,
and I might say that I believe in large measure that has been
because we have been fortunate to have a set of personalities
in the NIH Director and the directors of the key Institutes
that work very effectively with our office, so that problems
that might have occurred are just not issues.
With regard, however, to your general point about the
distribution of resources, I don't think it is entirely fair to
say that we haven't really made changes amongst the Institutes.
Indeed, if you will look in our proposal for fiscal year 1998
you will discern that the distribution isn't even. There are
one or two Institutes that get quite substantial increases;
there are a few Institutes that are actually receiving less in
the way of proposed appropriations than in past years.
We believe that these changes reflect the imperatives of
the Levine Report, the need to increase investment in vaccine
research, in human immunology, in prevention sciences. That
logically drives the budget in certain directions.

total aids research funding

Mr. Porter. Well, again, we want to give you all the
flexibility you need to do your work, obviously, and we would
intend to do that this year as we have previously.
Do you expect to change your estimate of the total amount
of NIH funding targeted to AIDS research during 1997?
Dr. Paul. Well, of course, that's an issue that would be
decided, in association with my colleague on the right--that's
a decision that impacts not only AIDS research, but non-AIDS
research.
But my personal view is that the current practice in which
the AIDS research dollars are increasing, in concert with the
total NIH appropriation, is a wise one. It must be recalled
that we are now in a position in which the advances made in
AIDS research have an impact on science in general; but of
course, and it must be said very clearly, the great advances
that we are seeing in all aspects of science supported by the
NIH budget have enormous significance for AIDS research. And I
don't believe that we can imagine the two out of step with one
another.
So I feel very comfortable about the proposal that we are
putting forward for increases of a comparable magnitude.
Dr. Varmus. I should also say that this is in accordance
with the recommendations of the Levine Report, which argued
that the amount of the budget that is allocated to AIDS
research is appropriate and the issue is reallocation within
that amount.
Mr. Porter. It's going to be necessary to stand in recess
because there is a vote on the floor, so the subcommittee will
stand in recess until I return.
[Recess.]
Mr. Porter. The subcommittee will come to order.
Dr. Paul, I apologize. I not only had to vote, but I had to
answer press inquiries about your testimony. [Laughter.]

three percent transfer authority

Mr. Porter. Dr. Paul, do you and Dr. Varmus intend to use
the 3 percent transfer authority we have provided in the 1997
bill to move AIDS funding between Institutes?
Dr. Paul. Mr. Porter, we regard the transfer authority as a
very valuable tool, but we also recognize that the Institutes
need to plan ahead, and that moving resources in the middle of
the year can be very disruptive to them. So we have taken the
position that that transfer authority should be reserved for
really special situations, particularly situations which our
own discretionary fund cannot meet.
So we regard it as an important authority, but one that we
don't want to use simply for the sake of utilizing it. It ought
to be reserved for very special events.
So the answer is, I do not see today the need to utilize it
in fiscal year 1997, but of course, some event could occur that
might change that judgment.
Dr. Varmus. Well, Mr. Porter, we did use my 1 percent
transfer authority last year to shift some money to the AIDS
domain, before the 3 percent authority was established.

aids research proportion of total nih request

Mr. Porter. Dr. Varmus, did the proportion of the fiscal
year 1998 NIH budget request allocated for AIDS research change
at all as it went through the Department and through OMB?
Dr. Varmus. Not as a proportion of the total.
Mr. Porter. How did it change?
Dr. Varmus. It only changed because the total value for NIH
changed.
Mr. Porter. I see, like everything else changed?
Dr. Varmus. That's correct.
Mr. Porter. All right.
Mr. Miller.
Mr. Miller. No questions.
Mr. Porter. Mr. Stokes.

status of minority and women's health

Mr. Stokes. Thank you, Mr. Chairman.
Good morning, Dr. Varmus and Dr. Paul.
Dr. Varmus, as the hearings have progressed, I have on
several occasions, as you know, inquired of various Institute
heads regarding the status of minority health in our country
today. Let me now ask you, as Director of the National
Institutes of Health, what is the status of minority health in
America?
Dr. Varmus. As you know, it is----
Mr. Stokes. And let me include women also. So my question
becomes what is the status of minority and women's health.
Dr. Varmus. Well, that makes it a larger question, because
the health problems are different.
Mr. Stokes. Yes, they are.
Dr. Varmus. It is difficult to encapsulate all the possible
answers here in a short time.
In general, the health of minorities is less robust than
that of the majority population. That is particularly true in
the roughly seven areas that we and you have identified--
cancer, violence, drug abuse, hepatitis and other liver
diseases, and AIDS. Dr. Paul just recently reviewed the data
that shows that minorities bear a disproportionate effect of
HIV; 60 percent of the burden is on the minority community,
which is about 22 percent of the population.
Part of that discrepancy can be attributed to differences
in socioeconomic status and health care, but other components
are attributable to genetic differences and cultural
differences, and other issues that we're trying to understand.

role of the office of the director

Mr. Stokes. In terms of minority health, the Office of the
Director has a special role, would you agree?
Dr. Varmus. We have a leadership role, and we have a role
that is intended to promote efforts by the Institutes to
support research that leads to the betterment of minority
health, and to develop the capacity of minority scientists to
contribute to the improvement of minority health.
Mr. Stokes. In your opinion are you making any progress in
terms of that responsibility?
Dr. Varmus. We are in some ways. But in some ways it has
been disappointing to me because, as you know, I would like to
see parity of health for all people in this country.
Mr. Stokes. I know.
Dr. Varmus. We have, of course, continued to provide
support for a variety of training programs. In general, the
number of minority Ph.D.s has not changed very much over the
years. But we have achieved an increase in the number of
minority students at medical schools and, as a result,
increased the number of minority M.D.s.
I have noticed that we have seen an increased number of
research project grants going to minority applicants, nearly a
doubling since I became NIH Director. I am pleased by that. The
number is still low in proportion to the minority population,
but it is increasing with respect to the number of minority
scientists.
We have a very large investment in research that affects
minority health. It is always very difficult to decide where
the boundaries are, since many of our very large investments in
cancer and hypertension and heart disease and diabetes and many
other areas affect all populations. But when we try to look at
those grant proposals that specifically target minority
populations one way or another, we have well over $1 billion
invested in those areas.

minorities on research training grants

Mr. Stokes. I understand that the National Institutes of
Health has a requirement that underrepresented minorities be
recruited onto regular research training grants. Is that
correct?
Dr. Varmus. Yes.
Mr. Stokes. Okay. How does NIH enforce this requirement?
Are you seeing any positive results in the numbers of
minorities participating in these programs?
Dr. Varmus. I have to get those numbers for you for the
record.
[The information follows:]

Number of Minorities Recruited Into Regular Research Grants

To comply with federal mandates, all questions related to
race and gender are identified as optional on all NIH research
grant applications. Although statistics vary from year to year,
and across Institutes and Centers, a significant number of
grant applicants, 25 percent in FY 1994, choose not to identify
their race and/or gender. Since there is no way to predict
accurately the race and/or gender composition of these
applicants NIH is unable to identify accurately the number of
applications submitted by minorities and women or the number of
awards made to minorities and women. This information available
is summarized in the tables below:

GROWTH IN NUMBER OF RESEARCH PROJECT GRANTS
[Fiscal year]
----------------------------------------------------------------------------------------------------------------
1992 1993 1994 1995 1996
----------------------------------------------------------------------------------------------------------------
Total RPGs..................................... 24,033 23,952 24,964 24,899 25,519
Percent increase............................... -0.3 4.2 -0.3 2.5
RPGs to African-Americans and Hispanics........ 769 847 1,153 1,256 1,698
Percent increase............................... 10.1 36.1 8.9 35.2
----------------------------------------------------------------------------------------------------------------

GROWTH IN RESEARCH PROJECT GRANT AWARDS
[Fiscal year]
[Dollars in thousands]
----------------------------------------------------------------------------------------------------------------
1992 1993 1994 1995 1996
----------------------------------------------------------------------------------------------------------------
Total RPGs..................................... $5,459,375 $5,657,630 $5,981,328 $6,194,524 $6,612,358
Percent increase............................... 3.6 5.7 3.6 6.7
RPGs to African-Americans and Hispanics........ 158,161 192,523 261,467 284,375 421,721
Percent increase............................... 21.7 35.8 8.8 48.3
----------------------------------------------------------------------------------------------------------------

We do ask, whenever the training programs are recompeted,
that the directors of those programs provide us with
information about recruitment of minorities into those
programs.
Mr. Stokes. Okay.
Dr. Varmus. And I know that some programs have been
penalized as a result of their failure to mount an active
minority recruitment process.
We also have to take into consideration not just the
success of the minority recruitment effort, but also the
efforts that are made. And when good faith efforts are made, we
do allow some leniency, but we do require a good faith effort
and evidence that the training program is seeking, particularly
from minority schools and other places where minority
candidates are likely to be, an effort to recruit those
students into the programs.
Mr. Stokes. Please feel free to expand upon your response
in the record.
Dr. Varmus. Absolutely.
[The information follows:]

Efforts To Recruit Minorities Into NIH Training Programs

As part of the Minority Health Initiative (MHI), the NIH
through the Office of Research on Minority Health (ORMH)
focuses on the recruitment and retention of minorities in a
wide array of biomedical research and health professions. In
recognition of the underrepresentation of minorities in
biomedical research, a systematic approach has been taken
ranging from support of students at the precollege and
undergraduate levels, through graduate/post doctoral and
faculty training. ORMH collaborates with the National Science
Foundation to support science and mathematics educational
programs at the kindergarten level through grade 12, including
classroom and laboratory research experiences for student
participants, teacher training and standards-based curricula.
Community-based outreach activities to encourage minority
students to pursue biomedical careers are also conducted in
collaboration with the HHS Office of Minority Health. At the
same time, NIH continues to support the Minority Access to
Research Careers (MARC) and the Minority Biomedical Research
Support (MBRS) programs--two primary undergraduate research
training programs. The Minority High School Research
Apprenticeship Program is continuing. ORMH funds a relatively
new program called ``Bridges to the Future'' which encourages
students at key transitional points in their education to
continue for their bachelor's degree--if they started a two
year college--at partner colleges and to continue to work
toward the Ph.D. degree--if they attend terminal master's
degree institutions--at a partner university. Also, the ORMH
supports pre-existing NIH minority training and educational
programs, international research training programs through the
Fogarty International Center, as well as research supplements,
for undergraduate students. A new program co-sponsored by the
ORMH and the National Institute of Neurological Diseases and
Stroke (NINDS) has established a graduate/post doctoral
neuroscience program at Morehouse Medical School. Further, the
NIH continues to fund clinical associates programs and career
development opportunities for minority faculty development. In
the intramural program of NIH, a loan repayment program for
young clinical researchers is aimed primarily at disadvantaged
students. As with the health research agenda, the assessment/
evaluation underway by the ORMH will review these training
initiatives to ensure that they are operating as they are
intended.

aids in minority populations

Mr. Stokes. Dr. Paul, you may have already covered this
because Dr. Varmus sort of indicated that prior to my coming in
you had some comments relative to AIDS in minorities.
I happen to sit on the International Advisory Committee on
AIDS up at Harvard University. As you may know, this past
October they had a council meeting where leaders from
throughout the country were called there to Harvard to talk
about the whole problem related to AIDS. I have just recently
come from another meeting up there.
Obviously, the minority community now has had an expansive
growth in terms of AIDS. Is that correct?
Dr. Paul. Tragically, it is correct.
Mr. Stokes. Can you tell us what that situation is?
Dr. Paul. Well, in terms of numbers, in the last year for
which we have complete numbers, the new diagnoses, roughly 60
percent of those were amongst our minority community; and over
the life of the epidemic, that number is in excess of 50
percent. So minority populations make up a disproportionate
share of those infected and, unfortunately, a growing share.
There are so many bad things about this epidemic, but this is
one that I have always personally regarded as one of those
especially tragic aspects of the character of the epidemic.

aids research addressing minorities

Mr. Stokes. Dr. Paul, how does your budget address this
particular situation?
Dr. Paul. Well, in several ways. Firstly, of course, we
have taken very seriously the notion that we need to be certain
that members of minority groups and women are adequately
represented amongst our clinical trials and our natural history
studies, because it is only through that process that we can be
certain that the therapies that are developed and the
understanding of the disease will reflect the particular
characteristics of the disease in these populations.
In our large clinical trials programs, minorities are
represented in roughly the proportion in which they are
represented amongst those who are affected by the disease.
We have certain natural history studies, particularly those
targeted at understanding the disease in women and the issue of
perinatal transmission, in which minority participation is
actually in excess of 80 percent, so that we will be gathering
information which we believe has great impact on the disease in
minorities.
Further, I should say--and this is on a more worldwide
scale--that the growing emphasis is on the need to find
preventive measures, and particularly a vaccine. While of
course it would benefit all who are at risk of the disease,
since so much of that risk throughout this world occurs in the
poorest parts of this world, I believe that were we to be
successful in developing a vaccine--as I very much hope we will
and have a degree of confidence that we will--that we will have
great impact on individuals within the U.S. minority
population.

reluctance of minorities to participate in clinical trials

Mr. Stokes. Let me ask you this. I recently had a
conversation with a New York Times reporter who was writing an
article about the fact that the Tuskegee syphilis study has had
a negative impact upon the African American community, in that
the community is very reluctant to subject itself to clinical
trials.
Are you aware of this, and can you comment on that for us?
Dr. Paul. Well, it is certainly known that there is, in
many of our minority populations, a substantial suspicion. We
feel it is fundamentally unfounded, but we also understand the
basis of that suspicion regarding the motives of those who are
conducting trials.
Now, we have, as part of our research enterprise,
particularly in the behavioral aspects of that, efforts
underway to determine mechanisms that are most effective in
dealing with access to care, access to trials, and the
institution of appropriate preventive measures amongst various
populations that are culturally sensitive, because we recognize
that different groups have different needs. Indeed, I would
have to say, particularly in the prevention arena, there has
been a growing recognition that one size does not fit all, that
we need programs that are tailored to particular cultural
groups, particular racial groups, if we're going to really have
impact, and that is, I would say, a growing aspect of the way
those studies are being conducted.
Mr. Stokes. Thank you, Dr. Paul.
Thank you, Dr. Varmus.
Thank you, Mr. Chairman.
Mr. Porter. Thank you, Mr. Stokes.
Mr. Wicker.
Mr. Wicker. I will pass, Mr. Chairman. Thank you.

aids research proportion of nih funding

Mr. Porter. Dr. Varmus, to confirm what you said earlier,
if the committee is able to provide an increase larger than the
2.6 percent for NIH for 1998, will you continue to allocate the
overall NIH percent of increase to AIDS research funding? In
other words, if we are able to go to 3 percent, would then the
funding for OAR be 3 percent also?
Dr. Varmus. That is correct.

proportional increases for nih institutes

Mr. Porter. And is that the same for all Institutes? We
would simply move up in percentage terms?
Dr. Varmus. Well, we would do some negotiation, but in
general, yes.
The reason I hesitated slightly is that my objective in
proposing increases is to be sure that we can capitalize on a
number of proposals within the areas of NIH emphasis that I
have outlined for you before. Many of the proposals that the
Institute Directors made to me were not proposed for funding
within the 2.6 percent budget. If a larger budget is available,
I would like to be able to work with committee staff to try to
develop a budget that allows us to take advantage of the many
specific opportunities that Institute Directors have
identified.
Mr. Porter. Speaking for myself, you simply have to tell us
what allocations you want to make, and we will attempt--we
will, as far as I'm concerned--we will simply reflect your
priorities.
Dr. Varmus. Needless to say, I appreciate that.

prevention science working group

Mr. Porter. Dr. Paul, as you mentioned, one of the areas
emphasized by the Levine panel was the need for enhanced
research into AIDS prevention strategies. Has the prevention
science panel headed by Dr. James Curran made its
recommendations?
Dr. Paul. Dr. Curran, as you know, is leading this panel
that consists of some 10 members, derived from institutions
outside NIH. They have made an initial set of recommendations.
We had set aside a pool of resources that the Institutes could
have access to this year in an effort to sort of ``jump start''
this prevention science process. They have made recommendations
for the use of these resources; indeed, the Institutes are
aware of them, and have responded to them with a large series
of proposals. Indeed, we are going to make the distribution
very shortly.
Amongst the areas they have indicated would be studied, are
behavioral studies in particular, revolving around the new
therapies for HIV, how we can improve adherence to these
difficult therapeutic regimens, dealing with the issues of HIV
transmission by individuals under therapy. So that's one area
they have focused on that is particularly important. They also
stressed issues regarding maternal-to-fetal transmission, and
particularly the behavioral and the non-vaccine biomedical
prevention areas.
A further area that they particularly focused on was
research on injecting drug users, with particular emphasis on
mechanisms to foster getting them into drug treatment so that
techniques could be used to diminish the burden of injecting
drug use as an approach, of course, to diminishing the risk
that would adhere to those who are such users.
But beyond that, we look to this group over the next
several years to be providing a changing agenda that the
Institutes can use in crafting their plans for the future. So
they have an immediate task, which they've done, and a longer-
term task, which they are in the process of carrying out.

the new generation of aids researchers

Mr. Porter. Last June, an article in Science Magazine
suggested that a new generation of AIDS researchers appeared to
be overtaking the pioneer AIDS researchers, although theynoted
exceptions like Dr. Fauci, who ranks as a powerhouse in both groups.
[Laughter.]
Do you think this characterization of a changing guard is
correct? And do you feel the new group of researchers is more
collegial and less competitive, as the Science article asserts?
[Laughter.]
Dr. Paul Well, I like to look at it somewhat differently. I
think there was a core of truth in the article, in the sense
that there has been developed in AIDS research a young group of
outstanding scientists, largely as a result of the Nation's
investment in this field. First-rate scientists have grown up
in this field and are doing terrific work.
On the other hand, the ``old guard,'' as we put it, is not
so very old----
[Laughter.]
Dr. Paul [continuing]. And they are holding their own very
well.
So I like to think of it as having an expanded population
of first-rate scientists, doing outstanding work. Inevitably,
fields change and mature and develop; we see now a very good
spirit of cooperation and collegiality among scientists. There
always are controversies, but I think it reflects not so much
the personalities as the maturation of the scientific field.
Mr. Porter. The media loves to look at the controversies.
I have other questions, and I assume other members do, for
the record, which we would ask you to answer for the record for
us. Again I want to say what a wonderful job you are doing, and
the progress is simply the most heartwarming thing that we
hear. We want to do everything we can to help you continue that
progress.
Dr. Paul. Thank you, Mr. Porter.
Mr. Porter. Thank you, Dr. Paul.
(The following questions were submitted to be answered for
the record.]

[Pages 2174 - 2248--The official Committee record contains additional material here.]

----------

Thursday, March 20, 1997.

OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH BUILDINGS AND
FACILITIES

WITNESSES

RUTH L. KIRSCHSTEIN, M.D., DEPUTY DIRECTOR
ANTHONY ITTEILAG, DEPUTY DIRECTOR FOR MANAGEMENT
HAROLD VARMUS, M.D., DIRECTOR
STEVEN C. BENOWITZ, EXECUTIVE OFFICER
STEPHEN A. FICCA, DIRECTOR, OFFICE OF RESEARCH SERVICES
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

Mr. Porter. The subcommittee will come to order.
Next we are pleased to welcome Dr. Ruth Kirschstein, the
Deputy Director of NIH, to testify on the Office of the
Director; and Dr. Harold Varmus, to testify on buildings and
facilities.
Dr. Varmus. I am going to begin, Mr. Porter.
First of all, let me just say that in view of the limited
time available, Dr. Kirschstein and I are going to make very
brief remarks to cover these two topics and leave as much time
as possible for the questioning.

Introduction of Witnesses

I am accompanied here today, in addition to Dr.
Kirschstein, whom you know well as our Deputy Director, by Mr.
Steve Benowitz, who is the Executive Officer of the Office of
the Director, Mr. Tony Itteilag, who is the Deputy Director for
Management, and by Mr. Steve Ficca, who is the Director of the
Office of Research Services.

Opening Statement

The function of the Office of the Director is to provide
leadership for the entire NIH and coordination among its
components. The budget request for the OD this year, provided
in your summary, is $234,247,000, excluding AIDS.
There are four general domains of our activity in the
Office of the Director: first, to provide management services
for the intramural research program, the extramural research
program, and the general administrative functions of the NIH.
In those domains we have continued emphasis on our streamlining
proposals, reinvention proposals that the Administration has
fostered, including electronic grant submissions and electronic
reporting of inventions and many other such streamlining
activities.
We also are moving ahead, as I described in my opening
statement a couple of weeks ago, in improving our information
technology and in the recruitment of a central information
officer, and we are also trying, through our administrative
functions, to help control research management and support
spending, as directed by this committee, and we are carrying
out a study which you have requested and that we talked about
very, very briefly at the time of my initial statement here.
In the policy domain, we have a variety of activities that
range from technology transfer to science education to ethical
and economic issues that affect the NIH, and we coordinate
reports on a wide variety of topics we've discussed here
before, ranging from AIDS to clinical research, gene therapy,
recent reviews of the Institute directors, and many other
topics.
Program coordination in certain areas, particularly those
that have been Congressionally mandated as requiring special
offices for coordination, is carried out by a series of offices
that Dr. Kirschstein will review in just a moment, and we have
the function in our office of overseeing buildings and
facilities--I'll come back to that after Dr. Kirschstein has
spoken.
Before I turn the microphone over to her let me make two
points about overriding issues that affect our function in the
Office of the Director.
First, we are trying to make the Office of the Director
into a unit that serves the Institutes, Centers, and Divisions
in the most effective possible way. We are trying to foster
cooperation and unity of purpose among the Institutes. If there
is any legacy that I would like to leave the NIH, it is the
legacy that the NIH is one large agency in which there are many
autonomous parts, and that those parts work collegially
together, though maintaining an appropriate level of autonomy
for the Institutes and Centers while encouraging a sense of
unit, of purpose. That is an important component of what we're
trying to do.
This direction is symbolized by our annual retreat that we
talked about before. We discuss matters as trivial as the use
of the NIH logo in all communications of research findings by
different Institutes, and a variety of coordinated activities
that range from research topics we've discussed here to
competitive service centers that provide administrative
activities.
The second general point I would like to make concerns
budget formulation within the President's budget. The Office of
the Director shows a decline in our budget request, and that's
true for a number of reasons. We show little or no growth in
most of our offices because we are trying to protect our budget
priority, which is research carried out by research project
grants. We are not requesting any new research earmarks,
including those that were provided in our 1997 appropriation
bill. We are trying to restrict our research management and
service monies, as we have agreed to with this committee in the
past. And we rationalize the restrained growth of program
offices by recognizing that research is done by the Institutes
and Centers; the program offices are there to stimulate
research in those targeted areas, to coordinate that research
and to inform the public. These functions have largely been
established, and these offices have a very small commitment
base because of very small continuation costs. They are not,
for the most part, funding the bulk of the research.
I would like to extend this discussion of the program
offices by turning the microphone over to Dr. Kirschstein.

Opening Statement--Dr. Kirschstein

Dr. Kirschstein. Thank you, Dr. Varmus.
Mr. Chairman, members of the committee, as Dr. Varmus said,
cooperation over trans-NIH activities occurs through the
special programs and the special program offices which were
developed and have been established to improve the health of
women, minorities, and the medically underserved, to support
research in the social and behavioral sciences, and to
encourage research in prevention and in rare diseases, dietary
supplements, and alternative and complementary medicine.
The Office of Research on Women's Health serves as the
focal point for research related to health and disease in
women, for policies regarding the inclusion of women and
minorities in research studies, and for activities to assure
that all NIH research studies include women and minorities as
subjects, and to continue programs to increase the number of
women in biomedical research careers.
The Office of Research on Minority Health and the Minority
Health Initiative provide continued funding to improve the
health of and address the highest priority health needs of
minority populations, as well as to improve the preparation of
minority scientists for careers in biomedical sciences.
Behavioral patterns and social status are risk factors in
an array of diseases, and it is the role of the Office of
Behavioral and Social Sciences Research to encourage such
studies. This includes a trans-NIH initiative for research in
the four leading health risk factors in the United States:
physical inactivity, smoking, diet, and alcohol abuse.
The maintenance of health and the prevention of disease are
critical to the length and quality of life, and that is the job
of the Office of Disease Prevention, through a number of
subunits within it. One of the major ones, in which this
committee has had great interest, is the Women's Health
Initiative, which is a $628 million, 15-year project involving
more than 164,000 women, aged 50 to 79. It is to study
strategies for preventing heart disease, breast and colorectal
cancer, and osteoporosis in older women. The 1998 budget
request for that office is $54.7 million, and that's a decrease
from last year's level, but it's a decrease which was based on
plans because the recruitment phase of the study will be
completed in May, 1998, and then the study will go on at a
decreasing rate as data are accumulated and are analyzed. The
initiative, therefore, is on target as far as budget and
schedule.
One of the important things that is of great interest, I
think, is that we expect to reach the goal of 20 percent of the
participants of the study to be minority women, and this is
probably the largest number of minority women ever studied in a
research setting in the United States.
As interest in alternative medicine increases, the NIH has
research in that area with the Office of Alternative Medicine,
which was established to investigate and validate therapies
which are outside the general stream of therapy, and to
recommend research programs to test fully the most promising of
these practices. These are in areas of cancer, drug addiction,
asthma, and the study of pain; and in addition, in fiscal year
1998, we plan to make an award, after peer review of
applications, to a yet-to-be-selected, Congressionally-mandated
chiropractic center to foster chiropractic-related research.
We have an Office of Rare Diseases which provides
information on rare diseases and conditions. These are diseases
which have a prevalence of less than 200,000 cases a year, and
the office is very important in linking researchers interested
in those diseases with families across the country that have
such diseases within their families.
The Office of Dietary Supplements was the most recently
established office, in 1996, to support research related to the
role of dietary supplements in maintaining health and disease.
It is conducting a study to determine what types of information
are needed to respond to the public's questions regarding
dietary supplements.
The one other program I would like to mention is through
the Office of Intramural Research, which coordinates the loan
repayment program at NIH and will initiate a new clinical
research loan repayment program to repay the educational loans
of people who go into clinical investigation. We are
particularly interested, again, in attempting to increase the
number of minority physicians and scientists who go into
clinical investigation.
With that, I think we will stop so that you will have as
much time as you need for questions.
[The prepared statement follows:]

[Pages 2253 - 2256--The official Committee record contains additional material here.]

buildings and facilities

Dr. Varmus. Let me just finish briefly, Mr. Porter, with a
brief presentation on buildings and facilities.
We are requesting $190 million this year for buildings and
facilities. The major request is for continuation of the
financing of the Mark O. Hatfield Clinical Research Center, for
which you appropriated $90 million last year.
Let me give you a very brief status report on that project.
At last year's appropriations hearings we told you that we had
hired a distinguished West Coast architect, Zimmer Gunse &
Frasca Partnership, to carry out the design. We have since
hired a construction manager, McCarthy Brothers from St. Louis.
The negotiations with those entities are carried out through
our contract manager, Boston Properties, and administered
through the GSA.
We expect design development to reach the 50 percent
completion point in March of 1998. We will have a
groundbreaking ceremony, we believe, this fall, with official
excavation of the building site to occur next summer. We expect
occupancy at the end of 2001.
Other items in the B&F request are mainly renovations and
to upgrade our utilities infrastructure and modernize our
buildings, many of these projects reflecting a legacy of
infrastructural neglect over the years. About half of our
buildings are over 35 years old. Those items are catalogued in
the submission and I don't think I'll go through them in
detail.
I will note that Building 50, for which we have received
complete appropriations in 1997, will soon start construction
and we expect to occupy that new, consolidated laboratory
facility in the year 2000.
Now we would like to open the floor for questions on all
the topics that we have addressed. Thank you.
[The prepared statement follows:]

[Pages 2258 - 2261--The official Committee record contains additional material here.]

radiology and imaging

Mr. Porter. Thank you, Dr. Varmus and Dr. Kirschstein.
I have a couple of unrelated questions I would like to ask.
I believe you answered this in our earlier hearings, Dr.
Varmus, but what view do you have on creating a separate NIH
Institute for Radiology?
Dr. Varmus. Mr. Porter, radiology and other imaging
modalities are incredibly important and have attracted a great
deal of attention, both in our intramural and extramural
research programs. We have, through the Office of Intramural
Research, carried out a study of our intramural radiographic
and imaging facilities and personnel, and are trying to
coordinate that very carefully.
My personal belief--and very strong belief--is that
radiology and imaging are fundamental to the activities of
many--perhaps most--of our Institutes, that to put those
activities into a single Institute would not serve science and
would create additional administrative costs that I would not
endorse.
Mr. Porter. I knew that was your answer. [Laughter.]

cholestin

But I've been asked about it recently. I imagine that when
we have an Office of Chiropractic Research, or an Office of
Dietary Supplements, that radiologists feel short-changed that
they don't have something specific for themselves. It's simply
human nature. Thank you for that answer.
This question is probably an FDA question, but I'm very
curious about this. Have you ever heard of a product called
Cholestin?
Dr. Varmus. I heard about it roughly 15 minutes ago.
[Laughter.]
A series of calls back to the campus have failed to produce
the information that you request.
Mr. Porter. Well, I wonder, because this was advertised in
a national news magazine, and it makes health claims. It says,
``In fact, Cholestin's exclusive all-natural ingredients have
been clinically proven to lower cholesterol levels an average
of 25 to 40 points in just eight weeks.''
That would be, it would seem to me, a violation of the law
unless they actually can substantiate the health claim. It is
obviously sold over the counter.
Dr. Varmus. By tomorrow we will have----
Mr. Porter. Yes. I am very curious as to how they can do
this----
Dr. Varmus. We will see.

crc advanced appropriations

Mr. Porter [continuing]. Because it is making remarkable
health claims that, it seems to me, must be unsubstantiated.
Your budget requests $90 million for the next fiscal year
for the second installment of the clinical center construction,
but it also requests advance funding for 1999 and 2000----
Dr. Varmus. That's correct.

crc cost estimates

Mr. Porter [continuing]. For the remaining costs of the
project. Why should the committee provide the entire cost of
the construction now without access to the more accurate cost
estimates being developed?
Dr. Varmus. Well, this is a recommendation from OMB, with
the intention of ensuring that the monies necessary for
completing the project will be available. Now, as you point out
quite correctly, we will not have an absolutely accurate cost
assessment until sometime further along in the process of
design development.
I have provided for the committee members some current
pictures of what we believe the general design of the building
will look like, but obviously these are preliminary sketches.
They need to be revised in accord with budget estimates. As you
know, our initial projection for the cost of the clinical
research center we thought to be programmatically appropriate
was around $380 million. That estimate was revised down, in
consultation with OMB, to $330 million for the entire project,
and we're working within that number to try to develop an
architectural plan.
[Clerk's note.--Later corrected to ``333''.]
We believe that we can work within that plan, and we will
be reporting back to the committee about the correspondence
between design requirements and cost estimates.
Mr. Porter. Well, somehow I doubt that this subcommittee or
our counterparts in the Senate are going to allow a half-
completed building out on your campus, so I think----
Dr. Varmus. That is our hope. [Laughter.]
Mr. Porter. As we discussed last year, precise cost
estimates for construction of the clinical center will not be
available until the detailed design and space programming are
completed. What instructions have you given the planners in
developing cost estimates? Have you directed them to fit the
project within the OMB estimate of the $310 million remaining,
or have you asked them to develop an accurate cost estimate
regardless of whether it turns out to be above or below the
$310 million figure?
Dr. Varmus. Well, in a sense, both. My intention is to
develop a plan that will be within the $333 million--the $310
million remaining--for the project. We have to take into
consideration what the bed needs and laboratory needsare going
to be. The guidance at the moment is to give us the best plan they can
within the recommended budgetary amount, and if we encounter a
discrepancy between programmatic needs and what can be constructed, we
will face that at that point.

renovation of clinical center

Mr. Porter. We are frequently asked what NIH will do with
the existing clinical center building, once some of the
functions are moved to the new facility. Understanding that it
may be difficult to have a firm strategy for a period five to
ten years from now, what longer-term plans do you have for the
original building? Is it most likely that the space would be
used for labs?
Dr. Varmus. Yes. The proposal--of course, it is not a
detailed one as yet--is to use as much of the space as possible
for offices and laboratories. There will be requirements for
continual renovation because that building, as you know, has
inadequate facilities infrastructure, and we will need to
improve the utilities there. We estimate it may cost us $20
million to $30 million a year over a time period of 10 to 15
years to bring that building completely into conformance with
modern design stipulations. But we expect that most of the
building will be used, even as the new building is completed.
But there will be parts of it that will be undergoing
renovation in a multi-phase process.
Mr. Porter. And did you say you had cost estimates for
renovation?
Dr. Varmus. Not precise ones, no. But we think--Mr. Ficca
may want to correct me on this--the estimates that we've looked
at suggest that if we plan to phase the renovation over 10 to
15 years, we may have costs of around $20 million to $30
million a year.

administrative cost study

Mr. Porter. Now, you mentioned the administrative cost
study that you are conducting, at my suggestion. I am
encouraged by your serious efforts so far to make the study
comprehensive and wide-ranging, and we are pleased that you
were able to persuade Jack Mahoney to head up this effort.
Can you tell us more about how you are structuring the
study? Have you yet selected a contractor?
Dr. Varmus. We are in the process of doing the contractor
selection. We had six candidates; we have looked at their
credentials very carefully and they have been interviewed, and
we hope to be able to announce a decision very, very shortly.
Mr. Porter. There are many administrative cost centers you
could target in your study. What areas have you selected as
first tier issues to be examined, and why?
Dr. Varmus. Well, we attempted to identify areas in which
we felt we could have a major impact. The first tier of areas
to be targeted are buildings and facilities functions, equal
opportunity functions, finance, logistics, mail and printing
services, personnel and human resources, procurement, safety
and security, and space and facility management.
Mr. Porter. That sounds like everything.
Dr. Varmus. It's not everything. [Laughter.]
If you want to hear the second tier, I can give you that.
There's a lot left. [Laughter.]
But we chose areas where we thought there might be
administrative overlap, there might be opportunity for
reduction in costs, where we thought we might be able to
develop centralized services, based on past experience in
trying to generate some competitive service centers.
But I think these are the areas where we can get our
greatest gains, and we will of course keep you informed as we
move along with them.

unified information technology system

Mr. Porter. We understand that you are attempting to
integrate all the computer systems on the NIH campus into a
unified information technology system, and that you are
recruiting a chief information officer. What does this project
entail in terms of staffing and expenditures?
Dr. Varmus. I may have to have someone else help me with
the cost for staffing and expenditures, but let me explain that
over the last several years, as computers have become much more
important in the daily lives of everybody at NIH, whether
researchers or administrators, we have had a ``tower of Babel''
on campus with respect to efforts to develop optimal
information systems. At one recent count there were 37
committees working on information technology development in a
manner that was not completely cohesive.
At our recent Institute Directors' retreat, there was a
community-wide resolve to put an end to this Babel and to
coordinate our information technology development in a way that
would produce euphony. The result was putting together a
committee that didn't cost us anything--just NIH employees who
worked diligently and brought a report to me within about six
weeks, that outlined a strategy for normalizing an information
system that would allow free communication between Institutes,
that would protect the privacy of information, and that would
allow what we call ``interoperability,'' even though the
hardware might be different in different Institutes.
We have also resolved to hire a chief information officer,
as you noted. That will cost us some money, obviously. There
will be a need to have a highly-trained and well-experienced
person come to the NIH to coordinate our information services.
He or she will need an office and a few people. We believe,
however, that given the importance of information services to
everyone at NIH, that this will produce savings. I don't know
if anyone on my staff is willing to estimate what the savings
would be, but I believe that there is little doubt that an
investment in our information technology is going to have major
dividends. We already know from the activities that Wendy
Baldwin has carried out in the Office of Extramural Research
that we can make tremendous improvements in, for example, grant
submission, invention reporting, and many other activities
through an improvement in our computer technology.
Mr. Porter. Mr. Itteilag is shaking his head no, he doesn't
want to make a cost savings estimate. [Laughter.]
Mr. Porter. We will bring this up next year and see where
we are.
Mr. Miller.
Mr. Miller. I think----
Mr. Porter. You're going to yield to Mr. Wicker?
Mr. Miller. I'll come back.
Mr. Porter. And go to the end of the line?
Mr. Miller. Trade places.
Mr. Porter. Yes, you may. You yield to Mr. Wicker.

office of alternative medicine

Mr. Wicker. Well, I appreciate, Mr. Chairman, your allowing
me to go out of line.
I just want to ask a few questions about this Office
ofAlternative Medicine. How long has the office been established?
Dr. Kirschstein. The office was established in 1992, I
believe. It was not completely functioning in 1993 when Dr.
Varmus and I came, and it really began in earnest, if you will,
somewhat later.
Mr. Wicker. In 1994?
Dr. Kirschstein. In 1994.

herbal medications

Mr. Wicker. Well, I noticed that you are planning to look
into herbal medications. What is the difference between herbal
medications and the practice of pharmacognosy which, as you
know, is using natural products to develop prescription drugs?
And will this Office of Alternative Medicine be considering
pharmacognosy as it considers herbal medications?
Dr. Kirschstein. I believe it will. I would like to ask the
director of the office to give you a more specific answer,
unless Dr. Varmus would do that.
Dr. Varmus. This office, of course, is coordinating
research that is carried out by the Institutes. It doesn't have
grant authority of its own. We would welcome at the NIH
applications to study any herbal medications that are thought
to have efficacy. One of the ways in which such medicines might
be studied would be to use traditional chemical methods to try
to identify the pharmacologically-active compounds in an herbal
preparation. Classically, this has been the way many
medications--digitalis, taxol, quinine, and many others--have
been identified, and then further improved through
pharmaceutical chemistry to make better medications.
Mr. Wicker. So the office itself will not contract for the
research? The office will coordinate with various----
Dr. Varmus. It would encourage Institutes to take an
interest in areas that are brought to the attention of the
office.
Mr. Wicker. And will the various Institutes, do you think,
be contracting with universities?
Dr. Varmus. Well, not necessarily contracting with, but
inviting applications from.

office of dietary supplements

Mr. Wicker. Inviting applications from universities to
participate in this research.
All right. I notice that you mentioned the Office of
Dietary Supplements. I guess that means vitamins, is that
right?
Dr. Varmus. Vitamins and other things.
Dr. Kirschstein. Vitamins and other additions to the diet.
That office was established in 1996 by Congressional mandate,
and has been actively developing a data base regarding the
various dietary supplements. Vitamins are a very important part
of that, and probably one of the major parts.

medical nutrition therapy

Mr. Wicker. Well, I don't know if this question deals with
the Office of Dietary Supplements or the Office of Alternative
Medicine, but is the NIH coordinating any research concerning
the area of medical nutrition therapy, which I think is a term
of art? And I might add that Representative Nancy Johnson, I
understand, has a bill to allow Medicare to cover medical
nutrition therapy.
And I would ask further, before I allow you to comment on
all of this, the Lewin Group apparently has commissioned a
study which was released only recently, and it estimates that
medical nutrition therapy would save $11 million in the year
2001, and increase up to a savings of $65 million in the year
2004.
So I just ask you what you are doing, if anything, with
regard to medical nutrition therapy, and if you are aware of
any study by the Lewin Group about this treatment.
Dr. Varmus. I am not aware of the Lewin study. We do have
an Office of Nutrition that exists within the NIDDK that works
closely with the Office of Dietary Supplements. I don't know
what medical nutrition therapy is explicitly, but I'd be happy
to provide that information for the record and find out whether
either of the two offices are doing anything explicitly on that
topic.
[The information follows:]

Medical Nutrition Therapy

Medical nutrition therapy refers to specific services
provided by dietitians and health care providers. In the
Medical Nutrition Therapy Act of 1995 (H.R. 2247) this therapy
is covered under part B of the medicare program and defined as
services provided by registered dietitians and nutrition
professionals only when referred by a physician. This bill
defines medical nutrition therapy services as: ``nutrition
diagnostic, therapy and counseling service which are furnished
by or under the supervision of a registered dietitian or
nutrition professional who is legally authorized to furnish
such services under the state law of the state in which
services are furnished, as would otherwise be covered if
furnished by a physician or as an incident to a physicians'
professional services.''
The Lewin report to which this reference is made has not
yet been released (the report will be titled ``The Cost of
Covering Medical Nutrition Therapy under Medicare: 1998 through
2004''). This report was commissioned by the American Dietetic
Association with The Lewin Group. The report presents the
results of an econometric study of covering medical nutrition
therapy as a Part B benefit of the Medicare program. The study
included 16,000 Medicare patients with diabetes, and 38,000
with cardiovascular disease who participate in the Group Health
Cooperative of Puget Sound. This ground health plan has
provided coverage for medical nutrition therapy through visits
with registered dietitians for over six years. Most health care
programs do not include this benefit.
The preliminary results without a narrative interpretation
have been orally presented to the American Dietetic Association
(ADA) by the contractor (The Lewin Group). The ADA has in turn
shared their interpretation of these results with members of
Congress because the data appear in part to support their
contention that extension of Medicare coverage to include
medical nutrition therapy would reduce health care costs. The
inclusion of this benefit would provide coverage for dietetics
services.

NIDDK Medical Nutrition Research

The NIH Revitalization Act of 1993 identified the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
as the lead institute for coordinating trans-NIH nutrition
research. The Division of Nutrition Research Coordination
(DNRC), which was transferred from the Office of the Director,
NIH, to the NIDDK synthesizes and leads the trans-NIH focus for
nutrition.
NIDDK supports major clinical trials and basic research
studies to investigate both the role of diet and specific
nutrients in prevention and treatment of disease, and the
specific role of nutrients and other dietary components in the
development of disease. An example of a major recent research
effort is the trans-NIH Bionutrition Initiative. The Initiative
is supporting research on the defective mechanisms as well as
the normal processes involved in the direct roles of specific
nutrients on cellular, genetic, and metabolic processes, and
potential clinical applications.
Recently completed major clinical trials, such as the
Diabetes Control Complications Trial (DCCT) and the
Modification of Diet in Renal Disease (MDRD) Study, both
contained important dietary components. The DCCT examined
whether intensive treatment with the goal of maintaining normal
blood glucose levels could decrease the risk of diabetes
complications. A diet and exercise plan was a component of the
DCCT. The results indicate that intensive control of blood
sugar levels effectively delays the onset and slows the
advancement of diabetic eye disease, foot disease, and nerve
damage in patients with insulin dependent diabetes mellitus.
The MDRD tested whether low protein diets and rigorous blood
pressure control could slow or prevent the development of
various kidney diseases. Study results indicate that below-
normal blood pressure levels have a favorable impact on
deteriorating kidney function, particularly in patients with
proteinuria. The associated effect of protein restriction is
less potent than blood pressure reduction.
In June 1996, the NIDDK launched the Diabetes Prevention
Program (DPP) clinical trial. This major trial will explore the
feasibility of preventing or delaying the onset of noninsulin-
dependent or adult onset diabetes. The DPP will identify
volunteers with impaired glucose tolerance (IGT) levels between
100 and 139. An ``intensive lifestyle'' intervention, which
consists of a diet and exercise program designed to help
volunteers achieve and maintain a seven percent weight loss, is
one of four treatment regimens that are being studied. This
six-year study is recruiting individuals who are at high risk
of developing diabetes, including African Americans, Hispanic
Americans, American Indians, Asian Americans, and Pacific
Islanders. NIDDK will receive additional support from the
National Institute of Child Health and Human Development
(NICHD), the National Institute on Aging (NIA) and the NIH
Office of Minority Health.
In addition to these clinical investigations, basic
research on nutrient metabolism, the relative proportion of
proteins, fats, and carbohydrates in the diet, and on energy
metabolism serves as the foundation for the design of medical
nutrition therapy and dietary guidance provided to both
patients and the public. Across the NIH, similar research
serves as a foundation for nutritional recommendations in areas
of relevant illnesses, such as cancer and cardiovascular
disease.

Mr. Wicker. All right. Well, I would be very interested in
your following up with my office on it.
Dr. Varmus. As a matter of interest, was the savings
millions or billions?
Mr. Wicker. I have ``millions'' here. But as the late
Everett Dirksen said, it all eventually adds up to real money.
[Laughter.]
So I thank you, Mr. Chairman, for allowing me to go out of
order on this.
Mr. Porter. Thank you, Mr. Wicker.
Mr. Stokes.

ORWH's budget level

Mr. Stokes. Thank you, Mr. Chairman.
Dr. Varmus, Dr. Kirschstein, what is your current budget
for the Office of Research on Women's Health?
Dr. Varmus. The amount in 1997 is $17,241,000.
Mr. Stokes. Can you give us some idea of what your plans
are for future appropriation requests for this office?
Dr. Varmus. That's the 1997 estimate. The President's
budget for that office is $17,423,000.
Mr. Stokes. Okay. Is there an increase there?
Dr. Varmus. Yes. As I mentioned in my opening remarks, this
office, like all the offices, is receiving a very small
increase in the President's budget request to preserve as much
money as possible for the highest priorities, the grants that
would serve all these areas.
Mr. Stokes. This office has an important role on research
on women's health and has responsibility for collaborating with
the Institutes and Centers of the NIH in promoting research on
women's health. How high a priority does the Office of the
Director give to this particular function?
Dr. Varmus. We give it a high priority. I emphasize again,
Mr. Stokes, as I've said before, that it seems to me that the
important functions here are coordinating and instruction and
the provision of supplementary money to encourage the
Institutes to make the major investments in these areas, and I
believe that the important thing for us to do in tight
budgetary times is to continue to provide the Institutes with
the funds required to support research projects, which will be
encouraged even by slightly smaller amounts. I think the number
of supplements and co-funding enterprises carried out by the
office is actually more important than the actual dollar value
that is in each of the supplements.

national agenda on research on women's health

Mr. Stokes. I note, Dr. Varmus, that the Office of Research
on Women's Health is in the process of updating the National
Agenda on Research in Women's Health. How is that office
reaching out to ensure that issues of minority populations are
incorporated into the development of the newAgenda on Research
on Women's Health?
Dr. Varmus. I think Dr. Kirschstein would like to answer
that.
Mr. Stokes. Dr. Kirschstein?
Dr. Kirschstein. That office has been very active in that
regard. As you know, Mr. Stokes, Dr. Vivian Pinn is the
director of that office. She has been long active not only in
women's health areas, but in minority health areas as well.
Mr. Stokes. She is a very distinguished lady.
Dr. Kirschstein. Yes.
In order to update the original agenda, which was set some
years ago at a conference in Hunt Valley which I had the honor
to chair, Dr. Pinn and her staff are doing several conferences
around the country which will reach out to people interested in
women's health and the health of women in all groups, majority
women, African American women, Hispanic women, American Indian
women, in order to see what the gaps still are, and then we
will update their agenda.

women in biomedical careers

Mr. Stokes. Dr. Kirschstein, part of the mandate of the
Office of Research on Women's Health is to enhance women in
biomedical careers. What efforts are underway to increase
minority scientists as investigators in women's health
research?
Dr. Kirschstein. One of the things we have found, and I
know Dr. Pinn has found as well, is that very often, when one
provides small incentives in terms of small amounts of money
for studies in women's health or in the health of minorities,
the individuals who are particularly interested in carrying out
those projects are women or minority scientists themselves. Dr.
Pinn's efforts, through the Office of Research on Women's
Health, are to encourage women scientists who have been out of
the workforce for some time because of family responsibilities,
to reenter careers and to develop fellowships to provide them
with the updating necessary. Also, encouraging young women--
minority women in particular--to enter science, is going to and
will continue to, in one way or another, pay off in that
regard.

marc and mbrs programs

Mr. Stokes. OK.
Earlier in your testimony today you mentioned the MARC and
MBRS programs.
Dr. Kirschstein. Not particularly here, but I love to talk
about those programs all the time, Mr. Stokes.
Mr. Stokes. I know you do, and you've had that
responsibility for a number of years. I know that's a program
that you have your heart in, and I appreciate that.
Over the years the Committee has advocated increased
funding on behalf of many of the NIH minority programs, but
specifically the MARC and the MBRS programs. Can you clarify
for me whether this Committee directed any increase through the
Office of the Director for any expansion in these efforts?
Dr. Kirschstein. I don't think the Office of the Director
provided specific increases to those programs. Dr. Marvin
Cassman was testifying just two days ago and did mention those
programs. He has worked diligently, along with the Director of
Minority Opportunities for Research Programs--the More
Program--who has the responsibility for MARC and MBRS, to
increase those programs, and particularly to increase the
effectiveness of those programs. They have worked very hard to
have the students in those programs enter biomedical sciences.
One of the things that has clearly happened is something
Dr. Varmus mentioned previously, which is that there has been a
real increase through the efforts of MARC and MBRS, for
minority students to enter medical careers. It has been, as you
know, more difficult to persuade them--with, perhaps, good
reason--to enter into fields that are not so medically driven.
On the other hand there is an increase, therefore, in
medically-trained minority investigators whom, we hope, will be
moving into clinical research.
Dr. Varmus. I might just add that Dr. Ruffin, who as you
know is the head of our Office of Research on Minority Health,
has been aggressive and imaginative in establishing a number of
other minority training programs, including the Bridges to the
Future Program and other undergraduate training programs that
are funded through other minority research initiatives.

minority funding increases

Mr. Stokes. I was about to move into that area, Dr. Varmus,
because, as you know, I have a keen interest in the viability
of the NIH Minority Health Initiative and the Office of
Minority Health.
How does the recommended increases for these programs
compare to the overall increase in the NIH budget?
Dr. Varmus. It is lower, and it is lower for the reasons
that I outlined before. These are programs which provide
supplements and encouragement to programs and grants that are
run by the Institutes. My primary concern, in this fiscal
situation that we're in of a fairly modest increase for NIH as
a whole, is to preserve the ability of the Institutes and
Centers to be able to make new grants.
I believe, in consultation with Dr. Ruffin, that the office
can continue to provide that stimulation of interest in these
programs without an appreciable increase in the financing of
the initiative.
Mr. Stokes. Well, let me ask you this. When these two
important programs were established and funded by this
Subcommittee, it was contemplated that these resources and
program activities would be utilized as an opportunity to sort
of ``prime the pump'' at the other NIH institutes. The goal was
to improve their overall effort to solving problems associated
with the health status disparity that exists in the Nation
among minorities when compared to non-minorities.
I am concerned that, instead, these funds have become the
primary source of NIH funds dedicated to research on minority
health. Is that correct?
Dr. Varmus. That isn't so, Mr. Stokes.
Mr. Stokes. It's not so?
Dr. Varmus. No, it's not so.
Mr. Stokes. Then, what is the situation?
Dr. Varmus. I believe the office is still serving the
``pump-priming'' function. There have been very appreciable
increases, well ahead of the overall increases for NIH, in
previous years. The amount of money that NIH spends on minority
health, as I explained, is a number that is open to
definitional issues, but a conservative estimate is well over a
billion dollars, roughly $1.2 billion. And, of course, the
Minority Health Initiative is, in total, I think, about $61
million.
So the office is serving the priming function that you
described, and I think it is doing so very well.

funding for minority researchers

Mr. Stokes. An article appeared in the Chronicle of Higher
Education pointing out that a relatively minor amount of NIH's
budget is awarded to minority researchers. Has that situation
improved any?
Dr. Varmus. Yes, it has, Mr. Stokes. That article appeared,
I believe, in 1992 or 1993----
Mr. Stokes. It appeared in 1993, actually.
Dr. Varmus [continuing]. And reflected numbers from 1991.
Mr. Stokes. That is right.
Dr. Varmus. And all is not as well as you and I would like
it to be, but I recently found some figures that I think will
provide encouragement to you as they do to me, suggesting that
since I came to NIH in 1993, the number of research project
grants awarded to African Americans and Hispanics has doubled
from roughly 850 to roughly 1,700. Now, that is probably an
underestimate, because not all applicants for our grants self-
declare their racial identity; but nevertheless, while the
number is proportionately lower than the number of
underrepresented minorities in the research population by about
two-to three-fold, it still augurs well for the future and I
believe it does reflect a number of things, including the
effect of our training programs, our interest in trying to
promote minority health, and the technical workshops we have
provided for a number of institutions to try to improve the
ability of minority applicants to compete successfully for our
grants.
Mr. Stokes. Mr. Chairman, how much time do I have
remaining?
Mr. Porter. Your time has expired, I am sorry to say.
Mr. Stokes. All right. Thank you, Mr. Chairman.
Mr. Porter. Thank you, Mr. Stokes.
Mr. Miller.

minority research grants

Mr. Miller. Mr. Chairman, I have a couple questions to
follow up on what Mr. Stokes asked about minorities.
For grants, if you are a minority, does that give you an
advantage in receiving a grant?
Dr. Varmus. No.
Mr. Miller. How are you able to double the number of grants
to minorities?
Dr. Varmus. I think by improving the quality of
applications that come from minority investigators, and
training more effective minority investigators, and by
providing them with better facilities.

minority funding

Mr. Miller. You say that of your budget, $1.2 billion can
be identified as minority----
Dr. Varmus. No, no. We have identified roughly $1.2 billion
as research that pertains to minority health; that is, it
addresses issues that are special concerns.
As I explained to Mr. Stokes a little earlier, this is a
difficult problem definitionally because one could argue that
since diabetes affects minority populations more profoundly
than it does majority populations by some modest measure, that
any research on diabetes is working to the benefit of minority
health. So what we try to do is identify within that portfolio
those projects which are specifically targeting problems that
especially affect minority populations or use minority
populations in greater numbers in clinical trials, or look, for
example, at the pattern of diabetes pathogenesis among the Pima
Indians, and therefore it can be categorized as a minority
effort.
Mr. Miller. Do you have a report that summarizes how that
$1.2 billion--I missed the session; you did have one
presentation that included minority issues earlier, last month.
But where did you get the $1.2 billion? Do you have a report
that reflects that and shows how that was derived?
Dr. Varmus. Yes, I believe we do. The number comes, of
course, from the various ways in which we catalog all of our
research. But we certainly can provide for you the information
that you require about how those numbers are developed and what
they represent.
[The information follows:]

[Page 2273--The official Committee record contains additional material here.]

quotas

Mr. Miller. You do not use quotas in biomedical research?
Dr. Varmus. We do not.

undergraduate and secondary education

Mr. Miller. What do you do in the area of undergraduate and
even secondary education? Do you get involved in that?
Dr. Varmus. Yes, we do. In fact, Dr. Kirschstein is
involved in some of these----
Mr. Miller. Not just minorities, but in all areas?
Dr. Varmus. In all areas. We do that through a variety of
mechanisms, some being the kinds of minority training programs
that have already been mentioned briefly, and Dr. Kirschstein
might elaborate on them, but also through our Office of Science
Education, which is providing outreach to many schools in this
area--and of course, many of those schools do have very large
minority populations. Secretary Shalala and I were just this
week, for example, at Eastern High School, where they have an
academy that is sponsored by the Department of Health and Human
Services, and we were there promoting the interest of those
young people in science in a school that is almost entirely
African American. So there are many ways in which we do
outreach. We could very easily provide you with a list of those
activities.
Mr. Miller. There is another vote coming, so let me just
proceed. Maybe you can get me that information.
[The information follows:]

[Pages 2275 - 2288--The official Committee record contains additional material here.]

nih organizational structure

Mr. Miller. In sitting through the presentations, not only
today but all the time, I see--I haven't heard from the
Pentagon recently, but they're very big with acronyms, and I
see you are, too----[Laughter.]
Mr. Miller [continuing]. But I think I counted 12 new ones
here.
Mr. Porter talked about the administrative study. The
question I have is, the Office of Science Policy or the Office
Intramural Research or the Office of Dietary Supplements--you
never close those down, I'm sure. Mr. Porter asked the question
in the area of imaging; you're not going to create one. In the
area of AIDS, you did not create a new Institute, because five
years from today or ten years from today it may be a very
different situation.
Basically, you can never shut one down. I mean, I'm a
business school professor; the number of people that have to
report to you probably violates all organizational management
charts. I would hate to see your organizational chart right
now.
Dr. Varmus. Oh, I don't think it's all that bad.
[Laughter.]
Mr. Miller. Well, how many Institutes are there? There are
17 or 18 Institutes?
Dr. Varmus. Well, 22.
Mr. Miller. And then all of the offices.
Dr. Varmus. Institutes and Centers. It depends on what you
call them.
Mr. Miller. Okay.
Dr. Varmus. And then there are some Divisions that are
independent, as well.
Mr. Miller. Is this administrative study going to be
looking at any consolidation? At some stage--what was the one
that was mentioned a few minutes ago that the Congress asked
you to create, the Office of Alternative Medicine?
Dr. Kirschstein. And Dietary Supplements.
Mr. Miller. Dietary Supplements. That was a mandate?
Dr. Kirschstein. Yes.
Mr. Miller. I'm not saying that that shouldn't be
investigated or studied or such, but I get concerned that
you're getting an organizational structure that----
Dr. Varmus. Some of this, you recognize, is at the
directive of Congress.
Mr. Miller. But there are some things where you need to
take an overview and say, ``Wait a minute; are we getting
ourselves just added and added and added, organizations and
offices and Institutes?'' Is this administrative study going to
look at that at all? Or is it too sensitive politically?
Dr. Varmus. Well, you should recognize that not all these
offices are, in fact, reporting directly to me. Some of them
have been located within Institutes; some of them have been
located within larger offices, such as the Office of Disease
Prevention. So we have tried to impose some order on the system
so that those of us who are at the upper echelons are not
overloaded by people reporting to us.
Mr. Miller. Have there been any studies about the overall
organization of NIH to consider that factor? How many more
offices were just created? Two in the last Legislature?
Dr. Varmus. Well, I don't think it's appropriate for us to
ask our consultants to tell us whether or not Congressionally
mandated or authorized institutions should be continued. We are
asking them to look at lines of reporting and to look at the
overall administrative structure. But the emphasis has been on
functions which we believe might be consolidated and
streamlined, fundamentally in response to the concern of the
committee, as expressed by Mr. Porter, that we have as few
full-time employees and as few dollars as possible allocated to
these functions that could be considered ancillary to research,
and not research itself.

plans for new institutes

Mr. Miller. Do you have any plans for any new Institutes?
Are any being discussed?
Dr. Varmus. I do not. [Laughter.]
Mr. Miller. I guess the one on the Human Genome Project was
the last one that became an Institute.
Dr. Varmus. That's correct. That, of course, was an
existing Center which changed in name but not appreciably in
function. There were some minor administrative changes, but it
was already operating more or less as an Institute, with an
intramural program and many authorities.

listing of nih facilities

Mr. Miller. What facilities do you have outside of
Bethesda, the main campus of NIH?
Dr. Varmus. Well, we have facilities in Poolesville,
Maryland; Baltimore, Maryland; and North Carolina--we could
provide you with a list of them. We have quite a few.
[The information follows:]

NIH FACILITIES IN THE BALTIMORE/WASHINGTON AREA
[Excluding Bethesda Campus]
------------------------------------------------------------------------
Facility Location
------------------------------------------------------------------------
NIH Animal Center................ Pooleville, Maryland.
Frederick Cancer Research & Ft. Detrick, Maryland.
Development Center (FCRDC).
NIA/Gerontology Research Center.. Baltimore, Maryland.
NIDA/Addiction Research Center Baltimore, Maryland.
(lease).
NIMH/St. Elizabeth's Hospital.... Washington, D.C.
------------------------------------------------------------------------

Mr. Miller. How about outside the greater Washington area?
Do you have any?
Dr. Varmus. Yes, we do. We have some in Montana, in North
Carolina, in Arizona, and in quite a few other States, and some
of those are requiring funds this year for upgrade of
facilities. We could certainly provide you with a complete list
of that.
[The information follows:]

NIH/FACILITIES OUTSIDE THE BALTIMORE/WASHINGTON AREA
------------------------------------------------------------------------
Facility Location
------------------------------------------------------------------------
NIEHS............................ Research Triangle Park, North
Carolina.
NIAID/Rocky Mountain Laboratory.. Hamilton, Montana.
Primate Center................... Perrine, Florida(\1\).
Primate Center................... Sabana Seca, Puerto Rico(\2\).
Primate Center................... New Iberia, Louisiana.
NCI/Seattle Field Station (lease) Seattle, Washington.
NIDDK/Phoenix Epidemiology & Phoenix, Arizona.
Clinical Research Branch
(agreement with Indian Health
Service facility).
------------------------------------------------------------------------
\1\ Ownership being transferred to the University of Miami, Florida.
\2\ Property being execssed through GSA, ownership expected to transfer
to the University of Puerto Rico.

Mr. Miller. Are you planning more expansions around the
country?
Dr. Varmus. No, we're not.
Mr. Miller. Is that a problem, having facilities around the
country?
Dr. Varmus. Well, we have, of course, reviewed all these
institutions with regularity. There are a couple of small
facilities that we have, one in your home State, Mr. Miller--
the Animal Center in Florida--and another small building in
Puerto Rico, both of which we intend to transfer to the State
or territorial authorities.
Mr. Miller. Thank you very much, Mr. Chairman.

minority funding

Mr. Stokes. Mr. Chairman, would you yield to me for just a
moment?
Mr. Porter. I would be happy to yield to you, Mr. Stokes.
Mr. Stokes. Thank you, Mr. Chairman.
Let me see if I can just clear up something that comes to
my mind with reference to a question posed to you by Mr.
Miller. He had asked you about the $1.2 billion of your budget
which may in some manner impact upon minority health as a
result of research in that particular area. You have indicated
an allocation of about $1.2 billion, is that correct?
Dr. Varmus. I would say that's probably a conservative
number, because that number is determined by looking at
projects that very clearly are intended to benefit minority
health specifically, as opposed to, say, any cancer project,
which, as you and I know, would be of benefit to minority
populations, which do have a disproportionate burden of cancer.
Mr. Stokes. I think it is important for the record to show
the amount that remains in your budget after the application of
the $1.2 billion. The $1.2 billion comes out of what budget
total?
Dr. Varmus. The total budget is $12.7 billion. Mr. Stokes,
if I may, I understand where your line of questioning is going,
but I would say that it's important to recognize that virtually
everything we do is going to benefit the health of virtually
everyone.
Mr. Stokes. Hopefully.
Dr. Varmus. Hopefully.
Mr. Stokes. The disparity that we've been talking about as
it relates to minorities, the disproportionate disparity,
obviously is not affecting everyone.
Dr. Varmus. Yes, but I would be hard-pressed to identify
research which is disproportionately directed toward majority
populations. Some, I'm sure, is, but----
Mr. Stokes. The fact is that you are identifying
approximately $1.2 billion that you feel has some impact upon
the health of minorities, or--am I misstating you?
Dr. Varmus. Yes, I think you are, with due apologies. I
think that perhaps I'm not making myself totally clear.
Mr. Stokes. Okay.
Dr. Varmus. That research is identified by criteria that we
will have to look at more closely, but it is research that is
not just in any way likely to improve minority health, but is
specifically addressed to a problem that has--in a way that
investigates, for example, what might be the differences
between stroke in African American and white populations or
that uses a population of study patients who are largely
minority, as opposed to a study of breast cancer, which is
studying breast cancer generically and would have important
benefits for the minority population because, as you know, the
mortality rates for African Americans from breast cancer are
higher. The study is of breast cancer per se, but I would argue
strongly that it is very likely to have benefit for all people.

Concluding Remarks

Mr. Porter. Could I suggest to the gentleman from Ohio that
there is very little time left in the vote, but also that we
are going to have NIH back again, and Dr. Varmus will be here,
and this question can be raised at length, if you would like to
do that.
Mr. Stokes. I appreciate that, Mr. Chairman. Thank you.
Mr. Porter. Dr. Varmus, this concludes our first round of
NIH hearings, 13 in all, with 26 hours of testimony. You and
your colleagues have been very patient to spend all these hours
with us, and we are considering taking a little bit of money
and making a laboratory in the basement of Rayburn for you----
[Laughter.]
Mr. Porter [continuing]. So that you can be here
practically full-time.
Dr. Varmus. I would appreciate that, Mr. Chairman.
Mr. Porter. I think you realize how valuable these
opportunities are for members of the subcommittee and how much
we enjoy the sessions, and that's why we hope that you and your
colleagues can return in May at the conclusion of our regular
hearing cycle to discuss in more detail some of the issues we
feel we haven't had sufficient time to discuss in this process,
and we'll look forward to seeing you then.
Thank you so much.
Thank you, Dr. Kirschstein.
The subcommittee will stand in recess until 2:00 p.m.
[The following questions were submitted to be answered for
the record.]

[Pages 2293 - 2429--The official Committee record contains additional material here.]

----------

Tuesday, June 10, 1997.

NATIONAL INSTITUTES OF HEALTH

WITNESSES

HAROLD VARMUS, M.D., DIRECTOR
RICHARD KLAUSNER, M.D., DIRECTOR, NATIONAL CANCER INSTITUTE
CLAUDE LENFANT, M.D., DIRECTOR, NATIONAL HEART, LUNG AND BLOOD
INSTITUTE
PHILLIP GORDEN, M.D., DIRECTOR, NATIONAL INSTITUTE OF DIABETES AND
DIGESTIVE AND KIDNEY DISEASES
WILLIAM PAUL, M.D., DIRECTOR, OFFICE OF AIDS RESEARCH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF
HEALTH AND HUMAN SERVICES
HON. GEORGE GEKAS, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF
PENNSYLVANIA
HON. CONSTANCE A. MORELLA, A REPRESENTATIVE IN CONGRESS FROM THE STATE
OF MARYLAND
HON. GEORGE R. NETHERCUTT, JR., A REPRESENTATIVE IN CONGRESS FROM THE
STATE OF WASHINGTON
HON. PATSY T. MINK, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF
HAWAII

Mr. Porter. The subcommittee will come to order. I am
delighted to welcome back our panel of NIH witnesses for this
hearing on the process NIH uses to set research priorities. It
is a special pleasure for the subcommittee to have a second
opportunity in the course of one hearing cycle to talk to
representatives from NIH.
We have invited this morning members who are not members of
the committee, who have expressed an interest in this subject,
and we expect that some of them will arrive in the course of
the hearing this morning.
Today's hearing is the outcome of discussions during our
first round of hearings in which some members expressed
concerns about whether NIH was appropriately taking into
account various factors, such as health care expenditures, in
allocating research dollars among various diseases. My own
views on these matters are well established. I have stated
scientific opportunity as judged by scientists, not
politicians, should be the guiding principle in NIH resource
allocation decisions.
I do not believe that science fundamentally operates on a
disease-specific basis. So much of the research that NIH
supports is basic, unplanned, untargeted and unpredictable and
serendipitous in its outcomes. As we have heard on many
occasions, research aimed in one direction frequently provides
benefits in an unexpected direction. Forcing a categorization
of research in one disease area versus another can often be an
exercise in futility and a hazardous diversion in funding
debates.
But I want to give an opportunity for a full airing of
views on the subject. I am not without sympathy to the
arguments that some of the disease groups raise. I understand
how passionately they care about research and the victims of
the diseases they represent. I intend to raise several
questions myself that voice their concerns.
I hope that today members will take advantage of this
hearing to raise these issues that often simmer beneath the
surface so the NIH leadership and the Institutes directly
involved can respond. I hope this discussion will resolve some
concerns before we approach markup. My first concern is to
maintain the health of the NIH enterprise, and I fear that the
fighting between diseases, this ``siblicide'', as one
journalist dubbed it, represents a threat both because it
undermines public support for NIH and because it could provoke
ugly battles that result in NIH funding being cut overall.
We will hear an opening statement from Dr. Harold Varmus,
the Director of NIH, and other NIH representatives will be
available to answer questions.
I yield to Mr. Obey, our Ranking Member.
Mr. Obey. Well, thank you, Mr. Chairman. I hadn't intended
to make a statement, but let me simply make an observation.
I have served on this subcommittee some 23 years, and
during that time, two things have been self-evident. Number one
is that this subcommittee has traditionally put as its highest
priority support for biomedical research, which is largely
funded through NIH. The second thing that has become abundantly
clear to me is that there are tremendous political pressures
which are brought upon both NIH and representatives in Congress
on questions of funding levels for various Institutes to attack
various diseases.
I do not want to suggest at all that the process by which
NIH arrives at its allocation decisions is absent political
considerations. It is not. I think NIH is just as pummeled by
political pressures as are Members of Congress. You have
various groups who want dollars that you provide and they are
going to find justifications to improve their bargaining
position.
But having said that, I would say that the dangers of
political pressure on Congress resulting in bad allocations of
resources in the biomedical field are infinitely larger than
the dangers of political pressures on NIH itself, because what
I find is that all too often, when Members of Congress get into
this disease-of-the-month club business, they more closely
resemble Daffy Duck than they do Jonas Salk.
So it seems to me it is crucial that while this committee
recognizes it has a legitimate right and indeed a
responsibility to review the decisions made by NIH, it is also
incumbent upon us to insist that the decisions that are made
are free, are made as free as possible from political
pressures. In fact, I think the intervention of this committee
in any decisions made by NIH ought to be simply interventions
that increase your ability to withstand political pressure,
rather than decrease it.
That is a distinction that I would draw, and I hope that
this hearing will contribute in at least some small measure to
ours and your ability to do so this morning.
Mr. Porter. Thank you, Mr. Obey.
Dr. Varmus, why don't you introduce your colleagues and
then proceed with your statement.

Opening Statement

Dr. Varmus. Thank you. Mr. Chairman, at your hearings over
the last several weeks, and indeed the last several years, we
have frequently had occasion to touch on decision-making and
resource allocation at the NIH, and I am grateful to you today
for providing this dedicated forum to discuss these important,
contentious and unfortunately complex issues at greater length
than usual.
My job will be to present the process in general, to
describe some of the underlying principles. Then, I will be
joined by my colleagues, Dr. Claude Lenfant, Director of the
National Heart, Lung and Blood Institute, Dr. Phil Gorden,
Director, National Institute of Diabetes and Digestive and
Kidney Diseases, Dr. Richard Klausner, Director of the National
Cancer Institute, and Dr. William Paul, Director of the Office
of AIDS Research, to answer questions about the specific
processes, the specific mechanisms used in the different units
of NIH in relation to specific programs.
I think, before we get into some of the more contentious
issues, it is useful to remember that over the past half
century the NIH has enjoyed a good relationship with the
Congress, the public, and the Administration; that very
productive relationship has been responsible for many of the
discoveries that have improved health around the world,
deepened our knowledge of living organisms and placed the
United States in the forefront of medical research and
development.

observations and principles for resource allocation

Today we are meeting to discuss how we spend the money we
receive from you each year, namely, what kinds of decisions
must be made, who makes those decisions, and what factors need
to be considered when making them.
Underlying these simple questions are some fundamental
issues. How much of our budget should be spent on plans to
conquer specific diseases? How much should be invested in basic
research? How should the NIH, as part of the Federal
Government, generally respond to threats to health posed by
specific diseases or injuries? And thirdly, where should the
final authority reside in making important decisions about the
distribution of our resources?
In the interest of trying to consolidate the underpinnings
of our decision-making process, I am going to confront these
issues through 10 observations based on historical facts, on
some operating principles and on my personal experience as
Director of NIH that I believe help explain how we manage our
budget.
The first of these observations is that resource allocation
is not a single issue. In fact, it embodies many decisions that
are made during a complex process of deciding how to spend our
money. So, first, the administration and the Congress must
determine how much money is appropriate to give to each
Institute and Center. Then each Institute and Center must
decide how to allocate its funds to different kinds of
mechanisms; that is, to investigator initiated grants, to
contracts, to centers, to the intramural program, or to
training programs.
Then each Institute must also judge two additional things:
which specific applications for grant support to fund and
whether to emphasize certain research topics within its
authorized domain.
The net effect of these several decisions will be to
determine how much across the NIH is devoted to certain
categories, certain scientific disciplines or certain diseases.

commitment base

The second perspective is a pragmatic one, well-known to
this committee but worth emphasizing here: only a relatively
small portion of our budget can be realigned each year. As you
all know very well, many historical decisions provide a firm
framework for our budget, decisions that led to the creation of
Institutes, research centers that are supported by the
Institutes, and the intramural research program.
Furthermore, a very substantial portion of our funds are
already committed to grant recipients as a consequence of
giving multiyear awards and receiving annual budgets. As a
result, a fairly small fraction of each year's budget, perhaps
10 percent, can be affected by changes in funding policies.

limitations to planning science

The third observation is a philosophical one, but important
to remember, and that is, to echo a remark you made, our
ability to plan science is limited and, indeed, excessive
efforts to plan science can inhibit progress. Science attempts
to discover what is unknown, and, in that sense, is inherently
unpredictable. History has repeatedly shown the benefits of
allowing some component of our research activity to be governed
solely by the imagination of individual scientists. As a result
of that policy, some of the research done by each Institute or
Center may be difficult or, indeed, impossible to explain as
part of a research program against a specific disease.
Now, sometimes we can say about a research strategy that it
can be planned, but it lies outside the boundaries of a
specific disease. The genome project is a good example. But
historically, we have many examples that fall into other
paradigms. For example, the development of recombinant DNA
research and the methods that now underlie the entire
biotechnology industry and its production of important
therapeutic reagents dramatically illustrates the need for
unplanned, untargeted, high quality, fundamental science. There
are many contemporary illustrations that will yield the same
fruit: our efforts to understand cell death, our attempts to
paint the three-dimensional structures of proteins, and many
other areas that now can't be assigned to a specific disease,
but, I believe, will be the foundations on which beneficial
applications of our research will ultimately develop.
So, overall, the Institutes cannot, and should not provide,
entirely precise plans for their complete research portfolio.

criteria for decision making

The fourth point is also an important one to remember, and
that is that there are many criteria which have to guide the
development and expenditure of our budget. There is no single
criterion that applies. So when we try to answer the questions
I raised earlier--how much to give to a singleInstitute, how
much to devote to a certain discipline, how much to spend on a certain
disease or certain grant mechanism or which applicant among many to
fund--we have to consider many kinds of demands that we are responsible
for answering.
We need to respond to public health needs, but those needs
themselves can't be correlated with research in any single way
using any single metric. We need to be responsible to support
work of the highest caliber. Excellence is our creed and we try
to judge that by peer review.
We are responsible for seizing scientific opportunities and
we know all scientific opportunities are not equally
approachable, regardless of their importance for public health.
We have to depend on advisors of many kinds, including program
managers in the Institutes, to help capitalize on recent
advances.
We also must be responsible for maintaining a diverse
research portfolio so we feel we are advancing on all fronts,
if at different speeds on different fronts, at all times.
Finally, we need to help ensure a strong scientific work
force and research facilities, so maintenance of the scientific
infrastructure is also part of our domain.

advice in decision-making

The fifth point is that we attempt to evaluate these many
criteria for making decisions by seeking advice from a large
number of sources. This is our outreach program. We have
scientific review groups composed of accomplished investigators
to review grant applications. We have national advisory
councils with members of the public, and the medical and
scientific community to review Institute policies. We organize
large numbers of conferences, workshops and other studies to
gather opinions on a variety of health and scientific and
ethical and administrative issues. The Institutes and my office
have coordinating committees and program offices that review
scientific progress, develop long-range objectives, and
formulate budgets and initiatives. We have extramural advisory
groups that are asked to look at trans-NIH activities--that is,
activities that extend across Institute boundaries: the
clinical center, gene therapy, clinical research, my use of my
one percent transfer authority.
We consult frequently with members of other agencies and
other components of the administration, Congressional Members
and staff and, importantly, with professional and health
advocacy organizations. But I have to emphasize, despite this
large outreach of consultancy, despite these many means of
gathering opinions and evaluating them, assembling each
Institute's research portfolio is a difficult and highly
imperfect process, and it is one for which the Institute
directors and I must assume the ultimate responsibility.

imprecision of disease coding

The sixth issue is one that causes us great difficulty. We
know that numbers alone provide a hazardous way for assessing
and designing a research portfolio. Now, the public and the
Congress have a right to know how our money is spent, and we
make great efforts to find out and determine those numbers for
the public that provides the dollars by trying to account for
the amount of money that we provide to specific diseases, to
various research activities, and to separate grant mechanisms.
But we know that the coding of funds by disease category,
although useful as a general guide, is also inherently
imprecise.

parkinson's disease

I have provided for you, in the back of my written
testimony, one example, in the context of Parkinson's disease.
I point out to you the large difference between the number of
grants that can be assigned specifically to research on
Parkinson's disease--that is, specifically and unambiguously to
Parkinson's disease--and the much bigger number of grants
assigned to topics such as nerve cell biology, dopamine
metabolism, nerve degeneration, topics that have obvious
implications for understanding and treating this disease.
The charts also show that many Institutes are involved in
these activities; not just Neurology and Mental Health, but
indeed virtually all the Institutes have some role in research
that has an effect upon the development of our understanding of
this disorder. And this is a reflection of the fact that beyond
these widening circles, there is yet the other possibility that
the most important discovery will come from a totally
unexpected direction. For reasons of this kind, there is no
right amount of money or right number of projects for any
disease.

science cannot be purchased

The seventh point is one which I find particularly
important to emphasize in this context and that is that
scientific work is not simply a commodity sitting on a shelf
that we can purchase. To shift priorities in a way that makes
effective use of our monies in these fiscally restrained times
requires talent and ideas, not just budgetary realignments.
Campaigns to expand research on specific diseases often
focus on efforts to increase spending on those diseases. But in
order to spend such money effectively, it is first necessary to
identify scientific opportunities and use them to attract
established investigators. We try to make use of several means
to do this. We invite scientists to workshops that highlight
new opportunity and needs in a field; we try to advertise an
Institute's interest in increasing funding in that area; and we
try to train new scientists to work in a designed area.

budgetary constraints

The eighth point is a modern reality, and that is that the
decision to increase support in one area of medical research
now usually constrains the support of something else. Those who
follow the history of the development of NIH know that there
have been decisions over the years to create new Institutes and
to markedly expand programs in certain areas, accompanied by
dramatic increases in the NIH budget. No programs needed to be
attenuated as a result of those large increases.
This is no longer the case. Recent budgetary increases,
while welcomed and appreciable, have been modest by historical
standards and, therefore, when directed to spend more for
certain diseases in certain areas, do run the risk of
constraining spending in other areas, and even, perhaps most
importantly, in our highly productive, nontargeted areas.

resource allocation by nih

The ninth point is one of potential contention, and that is
that methods for resource allocation at the NIH are, in my
view, preferable to excessive congressional directives. We know
that many fields of biomedical research deserve increased
support and could move faster with more funds. But as I pointed
out, resources are currently limited, so pushing funds
vigorously in one direction is liable to impede funds in
another. This situation compels caution.
Our requests for increased funding are carefully considered
by the Institutes, by my office, by me. Both of these we now
feature in the NIH areas of emphasis which represent the
results of prolonged deliberations between the Institute
directors and me. These areas of emphasis aim to exploit recent
discovery, such as theisolation of new genes for human
diseases. They aim to encourage studies of diseases that have been
relatively neglected, poorly controlled, or recently made more
accessible to scientific study, and they aim to strengthen research
technologies--computer science, imaging devices, neuroscience, gene
mapping--that are applicable to a broad range of disciplines or
diseases.
The final point is that many novel and powerful means are
available and should be used to heighten the interest of
scientists and the public benefits of their research, that is,
their application to disease. I understand, we at the NIH all
understand, that the public and the Congress are often
frustrated with the pace of progress, and that is so for a
number of reasons.

pace of research

Medical science is inherently hard and slow. Advances don't
occur at equal rates against all diseases. Sometimes the long-
term relevance of the basic science that we do is relatively
obscure, and scientists themselves may be deficient in
comprehending or indeed communicating the connections between
their work and its potential value to the public.
I have argued here that the best solutions to such
frustrations are not excessive directives to reroute dollars to
specific diseases. Instead we encourage advocates for those
specific diseases to advance their causes in a variety of
innovative ways. For example, many of us have seen how
advocates for the study of specific diseases can be effective
either at the local or national level by visiting individual
scientists or by visiting professional societies, and thereby
stimulating the interest of working investigators in the
unappreciated implications of those investigators' work. I have
seen this strategy effectively used by proponents of research
on a variety of diseases, most obviously cystic fibrosis,
ataxia telangiectasia, scleroderma, and several others.
The NIH often responds to concerns that research on a
specific disorder is underserved by convening a workshop to
evaluate opportunities, to bring potentially collaborative
disciplines together, and to stimulate the interest of new
investigators. We have had major workshops developed in this
way on a variety of subjects. Perhaps the better publicized
were on autism, spinal cord injury, and Parkinson's disease;
another will be held soon on diabetes mellitus.
One workshop brought together clinicians and geneticists
who then collaborated to identify a new chromosomal locus that
predisposes to a familial form of Parkinson's disease. The
research opportunity created by this finding will attract new
investigators and could be the basis for major advances against
the more common, nonfamilial form of the disease.
Mr. Chairman, thank you for the opportunity to talk at
length on these issues. I and my colleagues will be happy to
answer questions that you and your colleagues might have.
[The statement of Dr. Varmus follows:]

[Pages 2439 - 2470--The official Committee record contains additional material here.]

Mr. Porter. Dr. Varmus, thank you for that statement of
principles.
The subcommittee will operate under the 5-minute rule today
because of the large number of Members who are present, and we
will go back and forth between the Majority and the Minority.
Although we would be delighted to have her, we are going to
count Patsy Mink of Hawaii among the Majority instead of
Minority because she is sitting on our side; and questions can
be answered not only by Dr. Varmus but by anyone who would like
to comment on them.

aids and scientific opportunity

Dr. Varmus, you talked about scientific opportunity in
allocating research dollars. This is a kind of chicken-and-egg
situation, though, isn't it? In other words, don't you really
create scientific opportunity in a sense when you allocate
money to a particular research field, and that encourages
talented scientists to move into that area?
Advocates use the AIDS field as an example, asserting that
the best scientists followed the AIDS dollars and shifted their
work to that field. Isn't what is hot and new and interesting
to scientists also part of this?
And I wonder if you could explain whether you believe that
scientific opportunity leads or follows the infusion of
resources. In other words, can't resources create opportunity
and encourage people to work in that field?
Dr. Varmus. Well, it is a very complicated relationship,
Mr. Porter. Needless to say, when the money is available, it is
likely to lead to some findings that will then generate new
opportunities. But that is a slow process.
In the case of AIDS that you mentioned, I would argue that,
in fact, the opportunities were fairly limited in the beginning
until we knew that a retrovirus was the causative agent. At
that point, it became clear that there were in fact already
very deeply built-in opportunities, because a large number of
investigators, myself included, have been working on
retroviruses for other reasons for about 20 years. The result
was that we knew a tremendous amount about that class of
viruses.
As soon as it was apparent that it was likely that AIDS was
caused by such a virus, the accumulated knowledge was, in
itself, the platform from which new opportunities for pursuing
AIDS developed. We knew about the proteins made, we knew about
enzymes that were made by these viruses. The methods for
understanding pathogenesis and understanding the targets for
drug intervention were already inherent in the problem.
Mr. Porter. But don't you believe that once you put
resources there, that you then tend to get a lot of proposals
that follow the resources?
Dr. Varmus. You get the proposals, Mr. Porter. The
difficulty, of course, is deciding in a constrained
environmentwhat is the most efficient use of resources.
I do agree with you that if we applied a large amount of
funds to a specific area, that eventually we would make
progress and create some new opportunities, but the money
itself is not sufficient. One has to ask in a period of
constrained resources whether we should be--it is very
difficult for us to stimulate all areas at once. We have to
have a rationale for saying we are going to take money away
from an area where money could be more productively used and
add it to an area where opportunities, at the moment, may seem
limited.
Now, this is not to say areas of limited opportunity are
not areas we would fund. We are funding them. But the question
is, how do we assign the dollars that are flexible in each
year's budget? I think we have to do that by taking into
consideration a variety of factors. I think this is the place
where our job is most difficult; namely, we hear, as you do,
the stories that describe the impact of disease upon
individuals, and we know that additional funds will be a
benefit. But we have to make some decisions about where the
benefits are likely to occur most quickly and most effectively
at that time.

factors in resource allocation

Mr. Porter. We often hear from disease or patient advocacy
groups that you are not taking into account such things as the
number of deaths attributed to a particular disease, the number
of cases of a particular disease nationwide or worldwide, the
indirect cost of the disease, the cost of the disease for
government program such as Medicare, Medicaid, or Ryan White,
the measurement of years of potential life lost, quality-
adjusted life-years or disability-adjusted life-years and the
like.
Can you tell us what role those kinds of things play in
your decisions for allocating resources?
Dr. Varmus. Well, Mr. Porter, your list of indices reflects
part of the problem; that is, there are many ways to try to
gauge the impact of disease upon society. Each of those gives a
somewhat different outcome.
We are of course extremely sensitive to our basic mission,
which is to do science that benefits health; and we of course
would be remiss if we were not spending large amounts of money
on the diseases that have the greatest impact, by a variety of
measures. But what becomes very difficult and, to my mind, not
credible, is to try to take any single indicator and to use
that as a metric by which to design a funding strategy.
So if we were not supporting research on a disease that
clearly had a major role in public health, we would be
extremely remiss. But beyond that fairly proximate outline that
tries to correlate our research spending with disease impact,
the refinement of the process, I believe, needs to depend more
heavily on the scientific opportunities.

committee report language

Mr. Porter. What is appropriate for Congress to do in
expressing our concerns? Obviously, I assume that you think
that congressional appropriations that are specific to a
particular disease would be inappropriate, but what about
language in a report, directive language in a report or
encouraging language? Why don't you tell us what you do with
that.
Dr. Varmus. We welcome that. We are a creation of the
public will. We are one of the great manifestations of our
democracy, and we believe that we should be responsive to the
public, and you are the representatives of the public who
indicate to us what public concerns are.
There are a variety of ways for us to respond to such
language. One is what I find the most pedestrian: to give you a
report. What I find the most useful is for us to take your
suggestions of an area of concern to try to bring together
people who work on that problem and related problems, have a
conference that addresses the public's concern about the
issues, and seek the possibility that there are opportunities
we have not seized adequately.
We are imperfect and the process is imperfect. We have
repeatedly heard this year that we are not providing adequate
support for research on diabetes. My response and the response
of my colleagues is not the defensive one of saying, no, what
we do is perfect. Instead, we have organized a very important
workshop that will be held the first week in September and will
bring to Bethesda not only people in the diabetes field, but
people working on research in fields related to diabetes, in
hopes that we will identify new areas of research that will be
beneficial to patients with the disorder.
Mr. Porter. Well, you are imperfect, but Congress is more
scientifically imperfect. But we obviously all have great
concerns in certain areas and we feel free to express those in
the report accompanying the bill, and you are saying you want
to respond to that and state what the truth is, and I think it
is a very good process.
Mr. Obey.

expenditures for aids and other diseases

Mr. Obey. Dr. Varmus, let me follow up on the Chairman's
questions that relate to your expenditures on AIDS versus other
diseases.
The argument is made that because many more people die of
heart disease and cancer than die of AIDS that somehow we ought
to look at those numbers and calibrate our expenditures to
attack those problems accordingly. But I think there are other
factors that ought to be taken into consideration.
Since NIH was created, or over any other time frame that
you care to cite, can you tell me how much has been spent, in
total, on cancer?
Dr. Varmus. Well, we have been spending--it will take me a
little time to give you the precise numbers; I can give you
those for the record, but since 1971 when the Cancer Act was
passed, we have been spending, do you know, a billion dollars?
[Clerk's note.--Later changed to ``$20 billion.'']
Dr. Klausner. About $28 billion.
Mr. Obey. Let me simply, if you don't have the numbers, my
staff happened to have compiled them for me.
Dr. Klausner. This is how we negotiate our budget.
Mr. Obey. My understanding is, from 1967 to 1997 we have
appropriated for the Cancer Institute some $35 billion; the
Heart, Lung and Blood Institute, we have appropriated some $21
billion; Diabetes, Digestive and Kidney Diseases, $12.5
billion. AIDS, in comparison to the $34 billion for the cancer
institute and the $21 billion for heart, lung and blood
institute, over that period, AIDS, we have spent about $13
billion. And I would point out that we spent hundreds and
hundreds of millions of dollars prior to 1967 to attack cancer,
to attack heart and other cardiovascular problems, to attack
other diseases, simply because we didn't have AIDS until just a
few years ago.
And so it seems to me that there may be a very good reason
why the expenditure per death is higher on AIDS than it is on
other diseases, simply because we are starting from a zero
knowledge base with AIDS, and we are still starting from a
fairly low knowledge base, and we have had a lot of years to
learn things about heart disease and cancer, and we haven't had
as many years of research with respect to AIDS. So it just
seems to me we ought to be very careful before we take the
simpleminded approach of looking at only one index by which to
measure what we are spending.

nobel laureates

The second question, how many NIH officials over the past
10 years have been the recipient of Nobel prizes in science?
Dr. Varmus. Grant recipients?
Mr. Obey. No, how many Nobel prize winners have been in
positions of responsibility at NIH over the past decade or so?
Dr. Varmus. It depends on what you mean by responsibility,
administrative responsibility? Probably very few. At least one.
Mr. Gekas. One is sitting here.
Dr. Varmus. Equal to or greater than one.
Mr. Obey. How many Nobel prize winners have sat on your
peer review panels.
Dr. Varmus. I would have to check. It depends on whether
you ask before or after the receipt of the Nobel prize.
Probably quite a number before. Fewer afterwards.
Mr. Obey. My point is, it would be a significant number of
people.
Dr. Varmus. That is correct.
Mr. Obey. How many Members of Congress have received Nobel
prizes?
Dr. Varmus. Peace or medicine?
Mr. Obey. No, medicine. I think the answer is obvious.
How many persons who serve in decision-making spots at NIH
have received academic training in science and medicine?
Dr. Varmus. Virtually all.
Mr. Obey. How many members of this subcommittee have
received academic training in science or medicine?
Dr. Varmus. No one at the table today. There are some in
the Congress.
Mr. Obey. As I total it up, we have a lawyer, an insurance
executive, a TV executive, a lawyer, another lawyer, another
lawyer, a businessman, a teacher on the Republican side of the
aisle; and on the Democratic side of the aisle we have a
lawyer, a lawyer, a public official, a public relations
consultant, a political activist and a fugitive from Russian
studies. That is me.
The point I am simply trying to make is, I think it is
perfectly appropriate for us to exercise our responsibilities
to taxpayers and to the average American citizen to see that
you are making decisions absent political pressures. But I do
think that there ought to be a certain modest sense of humility
which accompanies those evaluations, given the fact that we are
likely to be responding at least as much to political pressures
as we are to our own scientific knowledge on this side of the
table. And I would simply note that in case anybody on the
subcommittee is even mildly interested.
The only other thing I would say is with respect to AIDS, I
think there are pressures on you, both up and down for funding.
I mean, no matter how much you appropriate for AIDS it will
never be enough for the AIDS activists, and no matter how much
you appropriate to AIDS it will always be too much for gay
bashers in this society. And I think it is our obligation to
resist pressures in either direction, so you do have maximum
opportunity to put the money where you have the greatest
scientific opportunity rather than political opportunity.

managing public information

The only other observation--this isn't a question; it is
just another observation. I guess my main concern with the way
NIH and the scientific community has operated the last
generation has been, I think, their view that we must
constantly feed the public with as much good news as possible
in order to keep support out there for biomedical research, and
I find that to be false.
I happened to note Daniel Greenburg's article in the Post a
couple of days ago with which I substantially agree. I think it
is important for people to understand how little progress we
have made in a number of these areas, not dismissing for a
moment the importance of whatever breakthroughs we have had.
But I think we have to resist this constant analogy that we get
between the moon shot and, say, a cure for cancer or any other
disease. We are able to go to the moon because we have reached
a certain point in our understanding of engineering, in our
understanding of ballistics, and in our understanding of
trajectory and mathematics, in our understanding of propulsion;
and when we reach that critical level of understanding in all
those related fields, we are able to accomplish a relatively
simple engineering feat.
It is not a simple engineering feat to discover various
forms of cancer or anything else, and it seems to me the best
way that we can respond to the public's concern is to provide
enough funding to basic research so that we eventually do reach
that critical mass so that then what we spend in disease-
specific ways can have a greater chance of success, and I think
that we have responsibility on this side of the table to
remember that.
Thank you, Mr. Chairman.
Dr. Varmus. Thank you, Mr. Obey.

congressional biomedical research caucus

Mr. Porter. Thank you, Mr. Obey.
We are pleased to be joined by a number of our colleagues
who have been invited to sit in with us this morning, and
George Gekas is the chairman of the Congressional Biomedical
Research Caucus.
And, George, we are delighted you are here.

Statement of the Hon. George Gekas, a Representative in Congress From
the State of Pennsylvania

Mr. Gekas. Yes, I thank the Chairman. I also note the
presence of our Cochair, the lady from California, Ms. Pelosi;
and thank Dr. Varmus for giving us the opportunity several
years ago to light the fire under the advocacy for biomedical
research, which resulted in our forming the caucus. But I want
Dr. Varmus to understand that the reason that he is Executive
Director today of the NIH is because of Biomedical Research
Caucus. That is going to be in my memoirs.
But, in any event, it is a wonderful relationship we have
struck up and has resulted in, we believe, education of the
Members on many aspects of the subject to which Mr. Obey has
alluded here today, and we want to continue cooperation between
our caucus and the NIH, of course.

commitment base

One thing that struck me from the testimony that you
offered, Dr. Varmus--I don't find it in trying to look through
the written part, but you alluded to the fact, or stated that
only 10 percent of the total funding for a particular year
really is allocatable; that is, with the ongoing grant
contracts and work in progress, as it were, which has a
multiyear feel to it, that when we start arguing about
Alzheimer's and Parkinson's and cancer and diabetes, we are
only talking about allocating, or reallocating, 10 percent.
Dr. Varmus. That is it roughly. It will vary from year to
year, indeed from institute to institute depending upon their
commitment base for that year.
Mr. Gekas. So we are really arguing here, when we try to
apply congressional pressure to emphasize one disease or
another on very little of the total package, and I think that
is a message that we are responsible for transmitting to the
public that work in progress, as it were--I can't think of a
better term to use--receives most of the continued funding.
Dr. Varmus. We do consider that a large number with respect
to dollars and a major responsibility. Moreover, when we make
decisions, those decisions tend to be perpetuated over multiple
years because when a decision is made to develop a program it
becomes part of the commitment base for succeeding years.
Mr. Gekas. Where do we stand then in the proposition that
we have referred to, to try to double the funding for NIH, the
appropriations, to double the current level of funding over the
next 5 years in which effort the Chairman of this committee has
lent his name--in fact is a key part of. Would that go to that
10 percent, shall we say in the next 5 years, but making it 20
percent?
Dr. Varmus. That would make a big difference with respect
to the number of dollars that we had to mold to specific new
opportunities and concerns.
Mr. Gekas. But part of that would go to the ongoing work?
Dr. Varmus. No, no, that would be new money for new
initiatives and for expansion of existing ones.

coding for parkinson's reserach

Mr. Gekas. Well, we want to continue that effort, and we
will keep you apprised of the progress that we make in that.
There is only one other question that I would like to ask.
When you settled on Parkinson's disease as a way to give us
an example of how related research awards, which may never have
started with the idea of curing Parkinson's or--when you say
they are related, that is what I want to know.
Dr. Varmus. Yes, the reason I displayed the findings in
that way was to show that there really are three cohorts of
grants. One in which it is unambiguously clear that the grant
is directed towards Parkinson's. It might be a clinical trial
of a new drug against Parkinson's or the use of fetal tissue in
transplantation research to treat Parkinson's. And then there
is a collection, a cohort of grants in which the work is
directed to, for example, dopamine metabolism. We know that
dopamine is important in Parkinson's research, but also
important in schizophrenia and other neurological and mental
disorders.
And then there is a third cohort of research that I could
not display for example, on cell death. As you know,
Parkinson's disease is dependent on certain cells in the basal
ganglia. Cell death is the fundamental mechanism by which that
disease arises. And yet it is possible for someone studying
that cell death in a fibroblast, in tissue culture, to make the
seminal discovery that turns our thinking about that disease.
That research would not be funded as Parkinson's-related
research because there would be no way to show the relationship
at the time that the grant was awarded.
Mr. Gekas. My point is that you could prepare such a chart
for each disease, could you not?
Dr. Varmus. Easily, yes.
Mr. Gekas. And some would be related.
Dr. Varmus. This is part of our coding problem, Mr. Gekas.
I am glad you brought it up.
Mr. Gekas. So that we return to the thesis that was first
uttered by the Chairman in his opening remarks that basic
research and the emphasis that we put on our scientific
community on that level, seeps up, as it were, to reach all the
diseases with which the public is so much concerned.
Dr. Varmus. A very good example of that is the Genome
Project, which is obviously built on the idea that we will
identify all of the genes that contribute to the development of
human diseases, and yet the Genome Project, per se, is not
money attributable by this kind of accounting to one disease or
another. Ninety-eight percent of the money that the Genome
Institute spends on extramural research is not categorized by
disease. Nevertheless, we know that as disease genes are found,
the impact on the study of those diseases is dramatic and new
opportunities are obviously created when you identify the
precise gene that is involved in the causation of that disease.
Mr. Gekas. With that, I want to thank the Chair for
recognizing the value of the Biomedical Research Caucus, for
his co-working with it on many different subject matters, and
to allowing me to put myself on record as endorsing the
Chairman's concept that the reliance on the new discoveries yet
to be made should be placed on the scientific community with a
nudge from the Congress as necessary. Thank you very much.
Mr. Porter. Thank you, Mr. Gekas. The staff has reminded me
that if I proceeded in the way that I first announced, I would
be violating my own principle. So what we will do is recognize
back and forth those who were present at the start of the
hearing, and then we will recognize those Members in order of
arrival so that from this point on, next will be Mr. Stokes,
then Mr. Miller, then Mr. Nethercutt, Mr. Hoyer, Mrs. Mink, Ms.
Northup, Mr. Istook, Ms. Pelosi, Ms. Morella, Mr. Oberstar and
Mr. Moran.
Mr. Stokes.

strategic plan

Mr. Stokes. Thank you, Mr. Chairman. Dr. Varmus, the
previous Director of NIH instituted a strategic plan to help
guide the Agency's direction in setting priorities. Can you
describe the framework of that plan to the Subcommittee and
tell us to what extent it has been updated under your
directorship?
Dr. Varmus. Well, I can tell you a little bit about the
process of developing the plan. The plan itself has never been
put into action. It involved reorganizing a number of aspects
of the way in which we categorize our research. When I came to
NIH, neither the Department of HHS nor I were willing to
espouse the plan in detail.
What I thought was extremely useful, about the notion that
Dr. Healey put into practice, was the idea of engaging the
extramural community more actively in the process of thinking
through where the NIH was headed. Indeed, I and many of my
colleagues here participated in very useful discussions at
various locations around the country, trying to predict future
directions as best we could, and thinking about what we would
do with additional resources. The process was more important
than the product.
I have tried to emulate that in a somewhat different way. I
am a little suspicious of efforts to develop one single plan
for the entire NIH. Instead, I think it is more appropriate to
consider reviews of special programs, reviews of Institutes,
reviews, for example, of our extramural program, gene therapy
research, and clinical investigation. I have tried to do that
with as much involvement of extramural scientists, disease
advocates, and professional societies as I have been able to
do.

trans-nih disease categories

Mr. Stokes. I understand that NIH tracks its investment in
targeted diseases under the designated label--trans-NIH areas;
is that correct?
Dr. Varmus. Well, yes, we do have numbers for the
expenditure on certain diseases or other activities across all
the Institutes.
Mr. Stokes. How do these diseases qualify for this label?
Dr. Varmus. Frequently because in the past Congress has
asked us to follow those numbers.
Mr. Stokes. To what extent is there overlap in the
reporting of funding amounts in these ``trans'' areas?
Dr. Varmus. Very often there is considerable overlap for
some of the reasons we just discussed with Mr. Gekas.

nih spending on minority initiatives

Mr. Stokes. I would like to refer back for a moment, to our
original hearings during this session of the Congress. At that
time, pursuant to a question I posed, you indicated that NIH
spends over a billion dollars on minority initiatives at NIH.
You are familiar with that?
Dr. Varmus. Yes, I am.
Mr. Stokes. I am interested in knowing exactly how and
where those dollars are being spent. When I use the term,
``minority initiatives,'' I mean those funds that are being
spent directly on minority programs, particularly on what the
DHHS Secretary and others referred to as the 6 plus 1.
As you know, in the DHHS report on minority health focused
on cancer, cardiovascular disease, stroke, diabetes, unintended
injuries, homicide, infant mortality, chemical dependency and
AIDS. What I would like to have you do, and you can do it now
or provide it for the record, is for each of these health areas
tell us how much money has been allocated, and for what
specific initiative.
Dr. Varmus. I think we probably would need to do that for
the record to be accurate. Obviously, in each of those areas,
there are projects that are focused very heavily on the
minority component. There is research that emphasizes the
minority component and there is research that would work both
ways as, of course, the research that is minority emphasized.
The minority number I gave you at the previous hearing
encompasses not just those seven categories, but several others
as well. We can provide you with a breakdown by Institute and
by disorder and we would be happy to do that.
Mr. Stokes. That is what I would like to have you do for
the record. For tracking purposes, how does NIH define minority
health, women's health, children's health, senior's health, and
aging research? How are these definitions used? What amount of
funding is spent in each of these population categories?
Dr. Varmus. I don't have the precise definitions with me,
so I would have to provide those for the record, if I could.
[The information follows:]

NIH Definitions of Selected Population Groups

The following are definitions that NIH uses to report
funding for research on minorities, women, children,and
elderly/aging. In using these definitions and in comparing
funding reported for different population groups, it is
important to keep in mind that there is considerable overlap
among those populations groups and as a result, there is also
some overlap in the research reported for each. For example,
research on a disease that affects minority women
disproportionately would be reported under both research on
minorities and women's health research. Also, most definitions
are developed in response to concerns of particular groups and
have evolved as concerns and issues have changed. For this
reason, definitions and data reported below are not consistent
over time. Changes in definitions are noted below.

minority

Research efforts related to individuals of non-Caucasian
descent, and individuals of Hispanic descent.

women's health

For research on diseases, disorders, or conditions that
occur primarily in women (such as breast cancer, mammography,
osteoporosis, etc.). This will include both clinical or applied
research and basic research. Prior to reporting FY 91 data,
women's health research reporting focused on single-gender
diseases; studies to evaluate gender differences; and studies
of diseases, disorders and conditions that are unique to women.
Such an approach did not fully reflect the true scope of
women's diseases, and NIH, in collaboration with other Public
Health Service agencies; developed a more inclusive and
consistent definition of women's health research.

children

Research on children can be defined as studies in all
categories of biomedical research (e.g., basic, clinical,
epidemiological, behavioral, prevention, treatment, diagnosis,
as well outcomes and health services) that relate to diseases
conditions, or the health and/or development of neonates,
infants, children, and adolescents up to age 21. This age
grouping is consistent with recommendation by the NIH
Director's Panel on Clinical Research, the NIH Inclusion of
Children in Research Committee, and the American Academy of
Pediatrics.

elderly (aging)

According to the Research on Aging Act of 1974, which
established the National Institute on Aging, research on aging
encompasses ``biomedical, social, and behavioral research and
training related to the aging process and the diseases and
other special problems and needs of the aged.'' ``Elderly'' is
often regarded as interchangeable with ``aged,'' and neither
term is defined by any single, discrete chronological boundary,
reflecting the fact that both normal and abnormal biomedical,
behavioral, and social processes act on a continuum over the
lifespan. Research on aging therefore focuses on issues of
importance to health and quality of life of people in later
stages of the lifespan through studies of a diversity of
relevant events.

funding for population research

Mr. Stokes. Also, if you would, provide for the record the
current total funding investment in each of these population
categories across the NIH. What is the percent change in the
investment in each of these categories for fiscal years 1995,
1996, and 1997, and fiscal year 1998 estimate? Provide for the
record a chart that displays the amount and percent change in
funding for each of the population categories, for each year--
for the period fiscal year 1984 to 1997, also include the
fiscal year 1998 estimate. Would you do that for us?
Dr. Varmus. I would be happy to do that. It will involve
some hard leg work.
I would also caution, Mr. Stokes, that there is going to be
a subjective component to those assignations because, as you
know, in all of our research activities there is going to be a
component that we would like to believe benefits all. And there
is research that is not categorized as minority that benefits
minorities. There is research that is categorized as minority-
oriented research that, of course, benefits the majority. So
there are not any clear-cut boundaries, but within the limits
of our definitions, which we will provide for you, we will do
those computations.
[The information follows:]

[Page 2481--The official Committee record contains additional material here.]

Mr. Stokes. I can appreciate that. I understand perfectly
what you are saying. Let me go back to the previous question
where you made reference to the use of the various definitions,
I am assuming you can clearly identify the amounts.
Dr. Varmus. Yes, we can identify them and you will see that
the definition will be helpful, but nevertheless, there will be
a subjective component in deciding how much of any single grant
should be assigned to that category.
Mr. Stokes. Thank you.
Mr. Porter. Thank you, Mr. Stokes.
Mr. Miller.

public relations for nih

Mr. Miller. Dr. Varmus, welcome again.
As one who is a very strong supporter of NIH, I am really
excited to be on this particular subcommittee and to be able to
express my support. I was interested in your tenth point, which
was basically stating that you needed to do some better PR, and
I see that all the time when we have Mohammad Ali who will come
and testify on behalf of Parkinson's or Arnold Palmer on
cancer. I think it is something that we need to push for as to
the success and what a crown jewel that the NIH is and
definitely be proud of how our tax dollars are used.
As a strong fiscal conservative, I can argue very often
against programs, but this is one that I argue for, and I think
we need to develop a better program because so many people
think that NIH funding is 10 percent that is intramural rather
than the extramural. That, in effect, is what you point out in
your tenth point. You don't want to use the word PR, but we
need to market what good is being done there.
And I agree with our Chairman and Mr. Obey that we need to
be careful not to politicize it. For example, in the past
couple of weeks I have had letters to the editor in my local
paper criticizing me for not supporting the Mo Udall bill. It
was targeting money for Parkinson's disease research. Last
week, we had testimony about autism and it is very emotional.

aids research coordination

AIDS is an issue that comes up, and maybe Dr. Paul, however
you want to answer it, discuss the uniqueness of that. Why it
developed the way it has, why its research is different overall
affecting other diseases than, say, just cancer research or
diabetes research and why the approach has been in that area.
Dr. Varmus. I am not sure that it is inherently different
from a disorder like diabetes, which also affects many organ
systems. But, as you point out, Mr. Miller, one of the
characteristics of the problem posed by HIV and AIDS is the
multiplicity of organ systems affected by it. One of the
consequences has been that we have a different mechanism for
allocating our dollars for AIDS.
That is, rather than absorb the administrative burden of
creating a new institute to work on AIDS, we developed a
coordinating office, which Dr. Paul leads. I will ask him to
comment on this in just a moment. That office coordinates the
funding through every NIH Institute and Center, each of which
has some responsibility for the various components: the
different organ systems that are involved in the manifestations
of AIDS, and the different kinds of approaches that range from
structural biology to behavioral research to drug abuse
research to control of the opportunistic infections and cancers
that occur during the disease.
AIDS is one of the most complex problems we have had to
confront. It is also an infectious disease, it affects young
people and some of our most disadvantaged citizens and has
posed a wide variety of problems, and it is a disease that we
have had to respond to in fairly recent times, as Mr. Obey
pointed out. The response has been acute because of public
concern about the magnitude of the problem, the lethality of
the disease, the unusual situation of having to cope with a
viral infection for which vaccine efforts have been
frustrating. We have had to develop for the first time
effective pharmaceutical approaches to the control of the
disease. We are very proud of the fact that, in conjunction
with the drug industry, we have had remarkable successes doing
that.
We have also had the advantage of advance preparation due
to a deep prior investment in virology, immunology, cancer, and
many other basic research endeavors. This prepared the way for
us to proceed with alacrity against this disease. Bill, you may
want to comment.
Dr. Paul. Yes, thank you. I think Dr. Varmus has laid out
one of many of the important issues. I would like to emphasize
one or two. HIV infection and AIDS is unusual in one very
important respect. It is a disease which has come on the scene
both suddenly and with frightening impact. Before 1980, we were
virtually unaware of its existence at all. It is now the
leading cause of death of young adults in the United States and
it will shortly be the leading cause of infectious death in the
world.
It poses a remarkable challenge to us and a challenge which
the government took up very quickly and did so within its
normal mechanisms. The research on the various aspects of HIV
infection was dispersed to the individual Institutes in a
manner rather different than an established disease.
Rather than form an Institute--and I think wisely the
Congress did not move in that direction--the use of our
established mechanisms, together with an office such as the OAR
to coordinate that work, has allowed the Institutes to use all
of their normal mechanisms without disruption of them. And yet
for us to have a mechanism through the OAR which allows
resources to be moved to the areas where opportunities are the
greatest in a relatively rapid manner has been critical. We
have been able to illustrate that.
For example, in the last year or two, we have been able to
change direction and markedly increase our resources devoted to
vaccine research without having a marked disruption that might
have been achieved had we not had a coordinating mechanism.
So I would echo Dr. Varmus' statement. We face a new
disease, a disease of still uncertain significance for the
United States and the world, but a disease that has already
established itself as a leading cause of death of young members
of our society.
Mr. Miller. Thank you, Mr. Chairman.
Mr. Porter. George Nethercutt of Washington.

Statement of the Hon. George R. Nethercutt, Jr., a Representative in
Congress From the State of Washington

diabetes research

Mr. Nethercutt. Thank you, Mr. Chairman. And thank you for
allowing me to join this panel today. As a member of the
Appropriations Subcommittees, I have a special interest in the
subject of diabetes. And I certainly welcome all of you
gentlemen here and thank you for all of your good work, because
it is truly good work.
Dr. Varmus, I heard you testify that the NIH would be
remiss not to spend money on diseases that have the greatest
impact, and I think you are correct. And so my question goes to
the issue of diabetes and the relative spending that is done
and has been done over the years on diabetes research and the
Institute, NIDDK versus other Institutes. And I am not here to
diminish the importance of other diseases, but I am here to
emphasize the importance of diabetes because it has a
tremendous impact on society. Something like $137 billion a
year in costs that spans a wide range of complications from
heart disease to kidney disease to blindness to amputations,
all the horrors that all diabetics know about.
So, my question is this: Do you acknowledge, Dr. Varmus,
that there has been lesser emphasis on NIDDK spending and
diabetes as opposed to the wide range of other diseases over
the years? In other words, when NIH spending has gone up in
other areas, my information is that NIDDK spending has gone
down, and I am wondering if there is an explanation for that,
and if so, what it is.
Dr. Varmus. I don't think it is quite fair to say that
diabetes research has suffered in comparison to all other major
diseases. Over the last few years, there have been a number of
new initiatives at the NIH that account for much of the
increase in our spending: For example, increases in spending on
AIDS, the creation of new institutes, and a number of other
initiatives. Diabetes research has been well-supported for many
years, and I think one would have to make the comparison with a
large variety of other disorders to substantiate the claim that
you just made.
I would point out that my view of the proper metric here is
not to try to correlate some number with the dollars that we
assign to diabetes research. This is a number that is
constrained by our ability to make the categorical assignments
and the same problems that I described for Parkinson's Disease.
But you have to consider the impact of a wide range of other
research activities upon the creation of opportunities in
diabetes research. For example, we have many kinds of studies
of blood vessels. It isn't all categorized as diabetes
research. Some of it is in cancer and some is in heart disease,
and, of course, that all has an impact on the well-being of
diabetics.

adequacy of spending on diabetes

As you know, we have had many challenges from the diabetes
advocacy groups about the adequacy of spending on diabetes
research. I don't mean to defend absolutely what we do, because
it is an imperfect process. That is why we have decided to have
this very broad workshop, which is not intended to discuss
recent research discoveries, but instead to bring together
experts to evaluate our spending and our research initiatives
in the area of diabetes, to ask whether the various components
of diabetes research are all being pursued with the appropriate
degree of enthusiasm and attracting the right kinds of
personnel, because I do believe there are many opportunities.
We also have opportunities to improve the lives of
diabetics that the country has yet to take full advantage of.
As you know very well from your own experience with the
disease, we have learned a great deal through the work of the
Diabetes Institute over the last several years about means to
control the complications of diabetes. Yet we know that a very
substantial number of patients with diabetes are not yet
properly controlling their blood sugar. They are not seeking
help for diabetic retinopathy at a significantly early stage.
Those components of health care also need to be improved. We
recognize that there are many ways that we can do better, and
we are trying to look at ways in which we can pursue them.
Mr. Nethercutt. I appreciate that and I think it is a wise
move to have this diabetes research symposium coming up this
fall. I have legislation I have introduced that would
essentially do that gentle nudging to NIH that says, let's have
a plan and decide in what areas and what specific subject areas
would provide the greatest opportunity for curing this disease.
And so I think the conference that is coming up this fall leads
certainly in that direction.

nih resource allocation procedures

Let me ask one other question as you talk about categorical
assignments. I am wondering--and incidentally, I had a great
visit to NIDDK earlier. I guess it was last year, and I am very
well aware of the great basic research that is being done there
and other places. What input is there, and what input do you
use from the directors of the various Institutes of NIH in
determining the allocation of funding for those respective
Institutes? Is there a vote of some kind? Is there consultation
regularly? I am just wondering from the committee's standpoint,
what can we understand about the internal procedures for
deciding who gets what?
Dr. Varmus. Well, we are not sufficiently democratic to
have a vote. I am not sure how well that would work. It might
be one vote for each proposal. But there is an intense
consultation process which begins within the Institutes, each
having its own process for doing this, using the scientists who
are grantees and intramural scientists of the Institute,
advocacy groups, and other advisors, who are consulted during
the course of the year to think about a number of issues--
including how grants are reviewed, what the criteria should be
for funding, how much should be spent on various mechanisms,
and whether there should be more centers or fewer centers, or
increases in training in certain areas. The wide panoply of
questions that I addressed in my testimony would be looked at
either annually or every other year to try to determine whether
the Institute is on the right course.

areas of emphasis

Then, at a point during the development of the President's
budget for NIH, I consult with each Institute director in a
process that has been, frankly, evolving since I came to NIH.
This year, for example, I asked each Institute director to
bring to me candidate proposals for inclusion in what I called
the NIH Areas of Emphasis.
These are six broad areas in which I try to summarize, in a
trans-Institute way, the major themes in modern medical
research that I believe should be the vehicles for advancing
medical science, particularly in the current restricted
financial environment.
What we try to do in building the budget is to provide the
money for the commitment base and money to continue the support
of investigator-initiated projects that simply depend upon the
imagination and direction of investigators. In addition, we
provide, through the Areas of Emphasis, new programs that are
intended to either expand or initiate programs that we think
are particularly valuable for fostering either broad research
that may affect a variety of disciplines, or areas of research
that we believe are currently undersupported, because NIH has
not paid sufficient attention to them in the past, or because
the discovery of a new gene has created opportunities that need
to be pursued, or because a methodology has come about that now
allows us to study the disease in a new way.
For example, the Genome Project has made it possible for
the Cancer Institute to begin to look at the anatomy, if you
will, of a cancer in a different way by looking at the totality
of expression of genes in each individual cancer, an advance
that I believe will completely change our attitude toward the
prevention, diagnosis and treatment of cancers over many years.
Those investments are the ones that are highlighted in the
areas of emphasis, and that is a document that is prepared by a
series of consultations.

one percent transfer authority

In addition, as part of our yearly assessment of what is
going on during that fiscal year, we consider as a group
initiatives proposed by the Institutes that can be funded by
transferring money from one Institute to another. And only 20
or 30 or 40 million dollars is usually transferred in that
process. It is a combination of discussions among the Institute
directors and advice that I receive from external advisors who
are brought in to discuss these issues with me that result in
the final determination that is then sent to your committee.
Mr. Nethercutt. Well, I thank you very much for your good
work. I have just commended to my colleagues on the panel, the
recent editorial that was written in the Journal of NIH
Research entitled, ``Mix Science and Politics? Of Course.'' I
think it goes to a lot of the comments that you have made here
today that there are a lot of influences that decides who all--
--
Dr. Varmus. And I would point out that the Journal of NIH
Research is not a journal written by the NIH.

final authority for decision-making

Mr. Porter. Mr. Hoyer.
Mr. Hoyer. Thank you, Mr. Chairman. Essentially, this
committee has been a committee of advocacy for NIH. Doctor, in
page 2 of your statement, you talk about where the final
authority resides for making these important decisions, i.e.,
the allocation of resources. Notwithstanding the fact that we
have lawyers, Indian chiefs, and refugees from Russian studies,
the Founding Fathers put the authority here. What we try to do
and what Mr. Obey and Mr. Porter have argued for is that we
need to put a great deal of reliance on your judgment. But,
ultimately the decision resides here, and, therefore, we have
these hearings as opposed to simply saying, whatever Dr. Varmus
says is what we do.
It is interesting and important to note that the scientific
community doesn't always agree.
Dr. Klausner might want to answer one of the questions that
I want to ask you. The New England Journal of Medicine
published an article which is an update of the previous
proposition that in the allocation of resources within the
Cancer Institute or within NIH, we are spending too much money
on trying to cure cancer as opposed to preventing and
dissuading people from activities which lead to diseases.
I think that is an interesting big picture item which we,
nonscientists, will ultimately have to decide on. I have no
doubt that we will continue the way we have gone, so I don't
think it is going to change policy, but I think it is an
appropriate question. I would like to hear your comments on
this and Dr. Klausner's, comments, and perhaps other members of
the panel, because ultimately, big dollars are put here because
the people give those of us in Washington monies and hope we
will spend it wisely. We have to try to decide how to do that.
Dr. Varmus. Let me comment briefly before turning the
microphone over to Dr. Klausner, about the initial comment you
made about where the responsibility resides. I absolutely agree
that the responsibility for giving out money to the Institutes
resides with you, and of course, the administration. But there
is that additional responsibility of deciding exactly how the
money is spent within the Institute.
Obviously, we are answerable to you because if you don't
believe we spend it well, you give us less next year. But those
decisions made within the budget that is given to any
individual Institute, at the moment, at least, are our
responsibility.
Mr. Hoyer. And I do not want to be misunderstood. We agree,
of course. The proposition that our Chairman and our Ranking
Member were stating was that we have made a judgment that the
best interest of the taxpaying public is that it is not a
political decision. I think that is the position of the two
most influential members of our committee, and I think we all
agree on that. But in that context, the public does expect us
to make judgments as to whether we are spending their money
wisely.
And then I go to this study where, having gone through a
recent experience, I was very frustrated by the fact that we
could not impact the situation that confronted our family. And
every family in America has been confronted with this. After we
spent a lot of money, how come we cannot impact the situation?
As I understand, the proposition of the article is that we
really have not made a whole lot of difference. Mortality rates
are essentially the same. Not in every category, but
essentially overall, adjusted for life expectancy, mortality
rates are essentially the same and, therefore, what we ought to
do is shift our priorities to a greater focus on prevention.

cancer mortality rates

Dr. Varmus. We do have some differences with regard to Dr.
Bailar's article. I think Rick might want to comment on them.
Dr. Klausner. Yes, I would be delighted to. The main take-
home message of Dr. Bailar's analysis, which is a reanalysis of
what the American Cancer Society and the NIH have done using
public numbers, is that we agree that something remarkable has
happened. Cancer mortality rates were going up all century.
They were going up. And around 1990, the overall rate stopped
going up and since then we all agree they are beginning to
drop.
Now is cancer defeated? Absolutely not. A disease that is
going to kill about 550,000 people this year is not defeated.
But the sound bite from the New England Journal has been that
efforts devoted to cancer have been a failure. I must say I
don't feel I am being defensive, but the numbers don't support
the sound bite. They are dropping. The mortality rates are
dropping.
Where I disagree with Dr. Bailar is why and what are the
implications for policy. We agree about the numbers.
Dr. Bailar says treatment will fail, that we have been
promised it for years. The problem is cancer is not one
disease. It is many diseases. And if you are now going to go
from the aggregate lumping of total mortality, whether we look
at total mortality of all diseases, you are not going to learn
anything until you look disease-by-disease. The reality is when
we look disease-by-disease, the mortality rates are really
falling.
The answer for some is prevention. With lung cancer, we
have not made much progress for treatment. We think we know how
to prevent it. Gastric cancer is plummeting and we actually
have no idea why. Breast cancer mortality rates are really
beginning to fall. That is ascribed to a combination of early
detection and treatment, and I will propose that the vast
majority is the use of adjuvant therapy, which has been
recently shown for colorectal cancer to reduce mortality by 20,
or 30 percent. Forty years ago, people argued childhood cancer
couldn't be cured. Don't try it, they said. Now, 80 percent of
our children with cancer are cured.
Now, Dr. Bailar says that is not enough, the numbers are
not enough. What do we say on prevention? Again, the question
is what are the numbers? The NCI spends 38 percent of its
dollars on what the prevention community broadly defines as
prevention, and we keep looking for new leads and investments.
A blue ribbon panel was constituted last year by me of
experts from throughout the country on prevention. This report
will be given to me next week, in fact, about how we should be
studying prevention better. But we currently spend 38 percent
of our dollars on prevention. Prevention requires knowing
causes. It is not simple. There is no more likely going to be a
magic bullet for a single cure for cancer than a magic bullet
in prevention.
An article that I am sending to the New England Journal is
subtitled from a quote from Yogi Berra, and that is ``When You
Come to a Fork in the Road, Take It.'' What do we mean by that?
When we look at the reason we are making incremental progress,
progress that we all agree is too slow, it is being made for
many reasons. It is a combination of prevention, early
detection and treatment.
We need to take our victories where we can. When we come to
the fork in the road where we are seeing progress in both
treatment, and as he says, early detection--but early detection
doesn't cure anything without an effective therapy--and
prevention, we need to do all of it. We spend about 31 to 35
percent of our dollars directly on treatment versus 38 percent
on what we talk about as prevention; that is, prevention,
intervention, understanding the cause--you can't do prevention
if you don't understand cause--epidemiology, predisposition,
environment, et cetera.
Mr. Hoyer. Doctor, I have one last question, but the
article, I think, would be interesting for the Members to have.
Dr. Klausner. I will have to submit it through the New
England Journal. They have asked me to write it and we will
have to see if they accept it.
Mr. Hoyer. It would be interesting, even if they don't
accept it.
[The information follows:]

Cancer Research Article

Upon completion of the article, I would be pleased to
submit it for the record.

funding for autism

Mr. Hoyer. We had some very compelling testimony from a Dr.
Rothman, whose brother is a Member of Congress from New Jersey.
His testimony really crystallized what we are talking about. He
has a child with autism. There are apparently 380,000 cases of
autism in the United States. He made the analogy between
autism, cystic fibrosis, and M.D., and referred to how Jerry
Lewis raises a lot of money. He made the comparison between
about a $33.88 expenditure on autism per afflicted individual,
$1,000 on muscular dystrophy, and $1,200 on cystic fibrosis.
His point was that you have $20 billion in consequential
expenses relating to the 380,000 autistic children and adults,
but we were doing very little to combat it. Chairman Porter
made a very compelling statement you know, we have got to
listen to the scientific community. We will put report language
in, but, ultimately, we do not want to make a political
decision.
I thought the Chairman's comments were on target and I
agree with him. But on the other hand, from this parent who
happens to be a medical scientist and a doctor's standpoint, he
compares a telethon and a lot of dollars at the NIH, on M.D.
and cystic fibrosis which have far fewer individuals afflicted.
This doctor says to himself, how are you making these
decisions? How do we answer that individual?
Dr. Varmus. Let me answer with respect to autism. I don't
find it extremely useful to try to do the comparison disease-
by-disease. But I do find it useful to focus on autism as a
disorder. We recognized a few years ago that autism was a much
more complex brain-based disorder than had commonly been
thought.
A workshop was carried out in part in response to a
congressional suggestion in 1995 and organized by the Child
Health and Human Development Institute. A great deal was
learned in that workshop about, first of all, the idea that
autism was probably not a single disorder, but instead as many
as five or six different disorders. There were also clues
available as to anatomical abnormalities in the brain.
It was agreed among the members that were involved in this
workshop that we needed to place additional emphasis on the
families that had been studied, attempting to identify genetic
components, and to do more neurophysiological and
neuroanatomical studies of this disease.
The result has been a new initiative involving several
Institutes at the NIH. There is a small coordinating group.
This year I have used my one percent transfer money to help
underwrite the genetic studies of autism. I believe that we are
going to see, as a result of the process, there will be a quite
similar result to what I tried to describe in my opening
testimony for Parkinson's Disease. I think that this is one
place where advocacy and a few new scientific developments have
synergized to allow us to identify some ways to promote the
study of this disease.
Mr. Hoyer. Thank you. And thank you, Mr. Chairman, for the
extra time you gave me.
Mr. Porter. We will take it off your next series of
questions.
The Chair has eight Members on the list. This would take us
somewhere between 12:15 and 12:30. Dr. Varmus, do you and your
colleagues have time to stay with us?
Dr. Varmus. I certainly do, and my colleagues would be
agreeable.
Mr. Porter. Patsy Mink of Hawaii.

Statement of the Hon. Patsy Mink, a Representative in Congress From the
State of Hawaii

detection of ovarian cancer

Mrs. Mink. Thank you very much, Mr. Chairman. I certainly
want to thank you, Mr. Porter, for inviting me to participate
in these hearings this morning. I do not serve on the
Appropriations Committee, so this is a rare opportunity that is
being extended to some of us who care deeply about what is
happening in the whole area of health, particularly the impacts
of research and other activities at NIH, and the implications
that it has on the general fears and concerns of our
constituents.
While I certainly support the comments of the Chair and the
Ranking Member that it would be inappropriate to politicize the
whole question of the areas of research that are being
conducted in NIH, I would be remiss if I did not take this
opportunity to express my very deep concerns about the minimal
efforts that have been done in the last 6 or 7 years in the
whole area of ovarian cancer.
I came upon this issue in 1990 when I returned to Congress
and found at that time less than $7 million that we could
identify with the assistance of NIH to ascertain exactly what
was being spent in direct research and studies and explorations
in this area.
Today, after nearly 7 years, we have somewhat less than $40
million being expended. I hope that because of the efforts of
some of us, that increase has been able to be attained. But the
point is that we are not here to make choices for the NIH. I
believe that the staff and the experts there have to make that
determination. But I do feel that the Congress has the
responsibility to express the frustrations and anxieties of the
population as large. And we are talking about 28,000 women who
are diagnosed with ovarian cancer each year. We also know that
14,000-plus die of ovarian cancer each year, and these are
fairly steady figures that have not diminished in any way over
the last 6 or 7 years.
The frustration is not an anxiety with respect to
prevention or cure. The anxiety comes from the fact that there
is really no early detection process for the assurance that
women can get because of periodic checks to ascertain that they
do not have this dreaded disease. Most frequently, the disease
is discovered too late, and as a result only 25 percent of
those that have been diagnosed with ovarian cancer can expect
to survive more than 5 years.
It seems to me with this picture of the historic reality of
this disease, that somewhere in NIH, there must be a
combination of interest, talents, and motivation to get more
research into this area for the one aspect of it, and that is
the early detection. And I would like to know from yourpoint of
view, Dr. Varmus, are we advancing our best research in this one area,
and how close are we to giving assurances to the women in this country
that in a short period of time there will be tests available in the
hands of practicing physicians that have the chance of detecting this
type of cancer?
Dr. Varmus. Thank you for the question, Mrs. Mink. I
believe that we are making progress in this area. I am going to
turn the microphone over to Dr. Klausner of the Cancer
Institute to answer in detail. I would draw your attention to
one unexpected benefit that came from the studies of genetics
in breast cancer. We now know that two recently discovered
genes that were pursued initially because they were believed to
be involved in hereditary breast cancer also predispose
strongly to ovarian cancer. Knowledge of mutant forms of those
genes is an important clue to women who may be highly disposed
and particularly appropriate targets for early detection
methods. But I think to discuss some of those methods and what
is being developed, I will turn to Dr. Klausner.
Dr. Klausner. You described the difficult situation with
ovarian cancer perfectly. You are absolutely right. We need
early detection for that reason. Dr. Varmus, before, described
a new initiative of NCI called Cancer Genome Anatomy Project.
Instead of waiting however long it might take, decades, to
discover a possible flag, a marker like PSA, but hopefully even
better than PSA for cancer, what we now have the opportunity to
do through the Cancer Genome Project is to quickly try to
identify all expressed molecules, all expressed genes in any
cancer.
We have begun that. It is up and running, and there are
five cancers chosen in the first year to initiate the project,
one of which is ovarian, and it is moving very quickly. Now, I
don't know what to promise from that. I don't know whether we
will discover a PSA or a better than PSA--which I think we can
do better--with this project, but I think this is the quickest
way to once and for all give us the tools to ask whether there
are markers to provide a blood test or some other sort of test.
I can go on to other things that we are doing, but I think that
is actually the most significant ones, and we chose ovarian as
one of the five for exactly the reason you talked about,
because we so desperately need new markers.
Mrs. Mink. Thank you, Mr. Chairman.
Mr. Porter. Mr. Istook.
Mr. Istook. Thank you, Mr. Chairman.

factors in resource allocation

Dr. Varmus, I appreciate the chance for the hearing today.
I must say, I remain disturbed and, frankly, suspicious about
some things I am hearing. I recognize, and I think we all
recognize the need to pursue scientific opportunity. The
opportunity should be pursued, but when we talk about the need,
also, to pay attention to the incidence of diseases and of
deaths in society and make that a significant factor in the
allocation of resources also, I think that NIH protests too
much; the vigor with which I hear actual denouncements of
efforts to do that.
If we talk about that, it is characterized not as us trying
to take our proper congressional role in public policy and
spending public money, instead it is characterized as an
excessive congressional directive. We are treated as though we
don't pay attention to scientific opportunity and the other
things that you properly consider, but there is such an effort
to avoid having NIH priorities expressly take into account the
number of people afflicted with different diseases, the number
of people who die from them, the cost to society and the cost
to the families and the financial cost as well, whether it be
to the Federal Government through Medicare and Medicaid
spending, things that go through HCFA, whether it be the cost
to private insurance companies or the cost to the individuals
or the lost man-hours at work, whatever it may be. I, frankly,
am tired of the NIH pooh-poohing and belittling those factors,
and I believe you are doing so, even though you don't do it in
quite those words.
The jealousy with which you try to say the pursestrings
should be under the control of persons who know better than the
rest of us is an attitude that is not healthy in our society,
and we are here trying to talk about public health.
I see ratios that are so out of proportion. We have seen it
analyzed in different ways. If you look at what NIH is doing
per patient in this country that either has AIDS or HIV, there
is $2,100 a year being spent on research on that. But per
patient with breast cancer, it is only a tenth of that, $200.
For overall cancer it is $338. Alzheimer's, $81; heart disease,
$74; Parkinson's disease, $34; diabetes $20. But diabetes has
16 million Americans that are afflicted with it. People who
face amputations and all sorts of other complications because
of it. It is a horrible disease in what it does to people.
Sixteen million people, $20 each; AIDS or HIV, the larger
category, 700,000 Americans at best, $2,100 each.
I realize you should not be driven by a strict sense of
having to have percentages and proportions. We both agree that
would be wrong. That is not the approach anybody advocates, but
when you look at the overall results and the disparity, the
system that you have now is one where all roads lead to you,
Dr. Varmus, in the decision-making. I realize that you did
research in this area before you came to NIH. You are a very
capable and accredited scientist who has the public good at
heart. But there are many others who also have the public good
at heart and there is such a disproportion here.
And I think there is a lack of recognition that 34 million
Americans with Parkinson's disease are paying for this
research. And 8 million Americans with cancer and 2 million
women with breast cancer and 16 million with diabetes, and 13.5
million with heart disease, these are the people who are paying
for the research. To be told that those numbers are at best a
negligible factor or that Members of Congress that bring it up
are being excessive is an attitude that I find extremely
disturbing.
What do you say to the administration when they overlook
your budget? When the White House exercises a role in your
spending priorities, do you subject them to the same criticism?
I am very disturbed.

priority setting

And I would like to know, Dr. Varmus, in the descriptions
that you have given us of the priority setting, are your
priority setting meetings open to the public? Are they open to
the representatives of the administration and to the White
House? Are they?
Dr. Varmus. I do not know for sure what priority setting
meetings you are talking about. As I mentioned, there are many
sessions.
Mr. Istook. Do you accept White House and administration
efforts to be involved in the prioritization process?
Dr. Varmus. I am not sure which step in the process you are
referring to, Mr. Istook.
Mr. Istook. All right. Do you have communications on behalf
of the White House that come to you saying we want these
priorities to be established in research funding?
Dr. Varmus. That happens occasionally. We, of course,
develop our budget with the OMB and with the White House. And
frankly, Mr. Istook, I don't think you are hearing what I am
trying to say.
Mr. Istook. I don't think you are hearing what I have been
trying to say, but please go ahead.
Dr. Varmus. We are discussing priorities here. We do meet
with many members of the committee; we meet with your staffs.
There is a tremendous amount of to and fro between Congress and
the NIH. And we welcome that. You are representatives of the
public.
I think you are painting me in the position of greater
authority and arrogance than is true. For example, I must take
particular care to point out that although you say all roads
lead to me and that I worked in an area of research that is
HIV/AIDS-related in the past, that the imputation that the size
of the AIDS budget is the result of my single-handed
determination to make the budget that large is really
incorrect.
Mr. Istook. I agree. It is not an effort to do that
because, frankly, I don't think there is any other disease that
has had the political involvement, you know, people in
Hollywood wearing ribbons, the media attention to it, the
millions of dollars that are given to political campaigns by
people who have a specific interest in this disease. I would
agree it is not, in that case, that all roads lead to Dr.
Varmus. But I think it is a mistake to pretend that politics
are not involved in the process and in the result we have seen
with the disparate funding for that research. It is not that
AIDS is not a terrible disease, because it is, but it is not
the only terrible disease.

nih expenditure on aids research

Dr. Varmus. My point is, that although I strongly defend
the money that we spend on HIV/AIDS, the current funding level
was actually established before I came to the NIH. It was
established by a large number of factors, including
congressional appropriations, administration wishes, public
health concerns manifested by many components of the public,
and as well as by scientific opportunities. So, you know, if
you look back at the history of the development of funding for
AIDS research, you will see that the funding was at an
extremely low level initially in the course of the epidemic,
when it was difficult to know how this disease appeared.
Many have argued, perhaps appropriately, that the
government was slow to respond. There was also a shortage of
experimental opportunities. We didn't know how the disease
arose. The CDC was heavily involved in trying to find the cause
of the disease. Once we knew that the disease was caused by a
retrovirus, there was tremendous opportunity because the virus
is one that we had tremendous information about. With the virus
spreading through the population, affecting young people, and
being universally lethal, with little prospect of a vaccine,
there was tremendous public support for pursuing this in a
vigorous way.
Mr. Istook. And there should be significant resources for
it.
Dr. Varmus. And increases occurred up to fiscal year 1994
at which point the level of funding has stabilized. We believe
that within the context of that budget we have been very
successful in trying to pursue the vast myriad manifestations
of the disorder. Because of many concerns about the AIDS
research portfolio, 2 years ago we asked over 100
investigators, many of whom do not work on HIV/AIDS, to conduct
a study of our research portfolio. First of all, they thought
that the level of funding was approximately appropriate and
that there was no need for increased funding. But they made a
number of suggestions about moving allocations from one area of
AIDS research to others, more emphasis on vaccines, and many
other suggestions.

stabilizing aids infections

Mr. Istook. Would you say, Dr. Varmus, with CDC reporting
decline in the incidence of AIDS, that a decline in the AIDS
research proportion I am going to say, not absolute numbers,
but proportion should be anticipated?
Dr. Varmus. There has been a stabilization in the number of
new infections. Dr. Paul may want to speak to this, as well. Of
course, the problem is not solely confined to this country, and
as Dr. Paul pointed out a moment ago, AIDS will soon be the
number one cause of infectious disease worldwide--a disorder of
mass destruction in many parts of the world, especially in
Africa and Asia, and still the major cause of death among our
young adults in this country. So it is not a problem that is
going away by any means. The fact that we have achieved some
level of control is not, in my view, a reason to say that the
battle is over, far from it.
Mr. Istook. I don't think anybody would say the battle is
over. The question is not whether there should be significant
resources there, because I believe everybody agrees there
should be. It is a horrible and deadly disease. The question is
one of prioritizing with other deadly diseases that affect a
far, far larger number of Americans.
Dr. Paul. Mr. Istook, I might comment if that would be
appropriate.
Mr. Istook. Sure, I think I am about to lose my time from
the Chairman.
Dr. Paul. I think Dr. Varmus has made some of the most
important points. In HIV, we face an unusual situation. Like
you, I recognize there are many other terrible diseases and
that as a Nation we have an obligation to attack them
vigorously. Here we are facing a disease which has appeared on
the scene relatively recently and of still uncertain potential.
While you rightly point out the number of infections has
stabilized within the United States in recent years, we know
this disease is running rampant throughout the rest of the
world.
It continues to evolve because it is a relatively recent
pathogen for humans. It is not like influenza or measles which
has been evolving for a millennia. We cannot predict with
confidence how this virus will interact with different
populations as it continues to move through the rest of the
world until we have a reliable means to prevent transmission--a
vaccine or other preventive means--or effective treatment for
populations who are at risk and will remain at risk.
It is my own view that this is an opportunity we have been
given to try to deal with the disease now and not leave it to
our children or grandchildren to face what may be a more severe
epidemic. So my own view is that we are facing an unusual
challenge and we have adopted an unusual mechanism. I would
argue that this is an appropriate action that the Nation as a
whole has undertaken.
Mr. Istook. Just in final statement, Mr. Chairman, I think
it is important that we understand that the research dollars
that go through NIH in AIDS are only about 20 percent,
approximately, of the overall Federal spending that is related
to this particular disease. Maybe there is some management of
the overall numbers that are in order, because I certainly
agree and I want to commend your efforts on researching this.
The Human Genome Project, I absolutely agree with you with
the extreme significance of that and other things; but I just
finally reiterate my concern that there are so many other
diseases that I feel are not getting proper priority in NIH
allocations.
Thank you, Mr. Chairman.
Mr. Porter. Thank you, Mr. Istook.
Ms. Pelosi.

aids research funding

Ms. Pelosi. Thank you very much, Mr. Chairman.
I want to join you in thanking our distinguished guests for
their fine testimony today--more importantly, for their
leadership and the important work they do at the NIH.
You are very fortunate, I think, because you have the power
to cure. Hopefully, we can match the opportunity to scientific
opportunity you have with resources so we don't miss any
opportunities. Because we certainly don't want to engage in
pitting one disease against another at the expense of missing
an opportunity someplace along the way.
Since I came so late in the game in terms of questions and
answers and had the opportunity to hear the questions of my
colleagues, it enables me to move on to another issue.
First, though, I want to thank you, Dr. Varmus and Dr.
Paul, particularly, for the justification you presented today
on the AIDS research funding. I think it holds up on the
criteria established in your presentation, Dr. Varmus.
I want to thank all the members of the panel for making
themselves available today, but also Dr. Klausner has visited
San Francisco where there is a very high incident of breast
cancer. Yes, we have a great deal of activism on the outside. I
don't call that politics; I call it America. It is good when
people speak out about a subject of which they are aware to
make sure we have the full benefit of their views in making a
judgment.
I am certain, Dr. Varmus, that you could make a chart like
this about AIDS as well in terms of the benefit it can give to
other diseases as well as aspects of--areas of NIH which
receive funding on AIDS research, is that right?
Dr. Varmus. As you know, the budget is coordinated by the
Office of AIDS Research but goes to every Institute at NIH.

unanticipated research results

Ms. Pelosi. I thank you. That is a level of politics I
couldn't possibly understand, and I appreciate how you manage
to pull that off. But I commend you for doing so, because I
know it is a challenge.
I wanted to talk about the future a little bit, because in
your remarks you talk about there are limits to ability to plan
science, the developments of recombinant DNA methods. It
illustrated the need for unplanned, untargeted, high-quality
fundamental science, as you said. The Human Genome Project,
which follows on that, of course opens so many avenues. I know
that the discovery of DNA was a culmination.
Are there any inspirations in the Genome Project which you
foresee which would inquire a huge infusion of funds? My
question comes to the point of, A, what do you anticipate your
needs down the road to be; and, B, if there were a will in the
country to double the NIH budget in the next 5 years, could you
absorb that?

genetics research opportunities

Dr. Varmus. Well, there is very little doubt that whenever
the pursuit of human genetics identifies a disease involved in
the cause of disease, we create new possibilities for
investigation. Many examples have accrued over the last few
years in the area of cancer. We believe we are on the threshold
of such discoveries in Parkinson's disease, hopefully in
autism, and in many other neurological disorders.
When a gene is discovered, you read about it in the
newspaper. To the naive reader this seems like, a--if you will
excuse the expression--a culmination. But in our view it is
just the beginning. We now have the tool. It is directed in a
multiplicity of directions.
Can we use this tool to develop tests to indicate
predisposition to disease or early diagnosis? Can we use this
gene to understand the basic mechanism by which the disease
arises? Can we use the gene and the protein that the gene
directs the cell to make to develop new therapeutic approaches?
It is that set of new experimental possibilities that are now
created by having a gene in hand that demands additional
resources be devoted to that disorder.
So the Genome Project, as we mentioned earlier, is not
classified by disease. Indeed, the entire extramural genome
budget is not classified by disease. But the outcome of the
research is to generate opportunities that clearly fall into
categorical disease areas.
Ms. Pelosi. And these are all not predictable.
Dr. Varmus. Well, in some cases, we can say yes.
If we look backward, we can say we knew there was going to
be a gene for cystic fibrosis, which is a disease of inherited
nature. The gene was discovered several years ago, creating new
opportunities for thinking about therapy and diagnosis and
understanding of the disease.
In other cases, it is a little more difficult to know. For
example, in the case of autism, which we talked about a moment
ago, or hypertension or diabetes, it is difficult to know
exactly how many genes are involved, and what the discovery of
those genes will provide.
In the area of diabetes, just last year two new genes were
identified as being important in a disorder called maturity
onset diabetes of the young. Those genes had, in fact,
previously been identified and not suspected as being diabetes
genes. But we already knew something about them. That,
obviously, creates all kinds of new inspirations, if you will,
for trying to understand diabetes more generally.

doubling nih's budget

Ms. Pelosi. You didn't say whether you could absorb the
doubling of the NIH budget.
Dr. Varmus. Well, as you know, Ms. Pelosi, NIH funds
currently about 25 percent of its grant proposals. A doubling
of our budget, we would assume, would occur in increments. Yes,
we certainly could absorb that.
We also recognize that we are not the only agency that
seeks more funds in government. The Administration has many
other objectives that the intention of the Congress and the
public is to reach----
Ms. Pelosi. Is there scientific opportunity for that?
Dr. Varmus. Absolutely.
Ms. Pelosi. So that takes me to my final point, which is we
have a problem. Because certainly if there is scientific
opportunity and we have the ability to put the resources there,
we have, I think, a moral responsibility to do so. However
important that we all clearly view the work of the NIH, it is
the same old thing. It is not the price. It is the money. And
the money just doesn't seem to be here, unless, as I say, there
is a will in the country to change that readily.
I know our Chairman would--if there was any way to have the
money, he has certainly been your champion. But instead of
having this pitting of one disease against the rest, I would
hope that we could all channel our energies toward a bigger
602(b) allocation for our committee; and so much bigger that
any increase in the NIH would not come at the expense of other
lambs in our lamb-eat-lamb allocation--job training, Head
Start--you know the list very, very well.
So what is important for me to hear from you today is that
there is scientific opportunity for not incrementally but a
drastic increase in the funding. We have to take it to the
American people to see if they want to live within the budget
constraints, which are difficult at best, and now, with the new
budget numbers in light of the budget agreement, almost
unlivable for us.
But the challenge of scientific opportunity to be matched
by the resources is one that I find irresistible. But, on the
other hand, we need the scientific community to help us with
our entire budget so you are not benefiting at the expense of
other functions within our subcommittee.
I did want to just make one other point, Mr. Chairman; and
that is to say that all of what we do here really saves money
in the end. If we are helping people be well, if we are finding
cures, if we are adding to productive years of life for people,
I wish we could have a dynamic scoring on the investments at
the NIH. But I leave that to our Chairman. Thank you all very
much again.
Thank you, Mr. Chairman.
Mr. Porter. Thank you, Ms. Pelosi.
Now, the congresswoman who has the privilege of
representing many of the NIH scientists and has the NIH campus
in Bethesda within her district, Connie Morella of Maryland.

Statement of the Constance A. Morella, a Representative in Congress
From the State of Maryland

Mrs. Morella. Thank you, Mr. Chairman. Thank you for
inviting me to this briefing. I was sitting in the corner for
most of it, so I did hear the responses and the questioning
that took place.
I must say I am very, very proud, obviously, of the
National Institutes of Health and the progress that has been
made through the years; and it only happens because of
leadership, leadership from the top and the leadership that you
all have provided as Members at the top.
You also--I think we are pretty fortunate in having such a
good subcommittee of the Appropriations Committee. It is a
pleasure to--not as a member, as someone who is not a member of
the committee--to work with that committee in terms of getting
the kind of funding that they need; and you can tell by the
questioning, by and large, how they feel.
I am going to a meeting on lupus and then osteoporosis, I
was in the Race for the Cure, and my sister died of cancer
years ago. I am very much involved in HIV/AIDS, particularly in
women where the fatality rate has increased 3 percent over the
years; and, of course, worldwide will be a problem. I think we
need to push more the breakthroughs as spin-offs, the ripple
effect. When you move into the field of HIV/AIDS and a
discovery occurs, it is one that might well be applicable in so
many other areas, so that research in these areas pays off.

information transfer

I wonder if you might indicate what is the rule? How do you
handle that? How do your other institute centers people know
about breakthroughs in one area so they can apply it?
Dr. Varmus. Fortunately, the world on the outside is not
categorized by Institutes and Centers. That is only true at the
NIH.
But when one is an outside scientist, as I was for many
years, one thinks of oneself as publicly supported by the NIH.
You are a member of a scientific community that may identify
itself as cell biology or virology or genetics. One goes to
meetings and reads journals and hears about research
developments through a wide variety of mechanisms--gossip,
telephone, the New York Times and, of course, through the usual
scientific processes.
There is an issue with respect to moving information among
the institutes, among the program managers. We have made a real
effort over the last several years to try to develop the
appropriate mechanisms for coordinating efforts among our
institutes when multiple institutes are involved in the pursuit
of any single problem.
As you have seen from the charts and much of the
discussion, it is almost inevitably the case that any single
discipline or disease-oriented area of research will command
the attention of multiple institutes. So we do that at one
extreme by having an office like the Office of AIDS Research,
with its major fiscal and scientific oversight
responsibilities. At the other end, there may be an informal
relationship in which program managers or Institute directors
from two or three Institutes will meet informally at regular
intervals to see how research is progressing and what kind of
applications they have received each year to study that
discipline.
We believe that through those two extremes, or through
coordinating committees or offices in the Office of Director or
other mechanisms, we are able to do a pretty good job of
coordinating research.
Mrs. Morella. So you think that works. It is an internal
process.
Dr. Varmus. I don't think it is always perfect. One of the
ways we try to be responsive to Congress is to develop such
bodies for coordination when the Congress perceives, or the
public perceives, we are not doing as good a job as we should
at that.

effect of public and congressional input

Mrs. Morella. Because I think it is a good way of heralding
how the hipbone is connected to the thighbone and other things.
One area of your testimony, you talked about how there is a
balancing act in determining areas of research. One segment of
that balancing act includes public input. I know this is a
difficult thing because the public may be clamoring for more
research, you know, for cancer. You and I talked about Sam
Donaldson's Million Man Woman March for Cancer Research, but I
wondered about the effect of public input.
Also, I know Mr. Istook is not here, so I can mention this.
Also the fact that the President came up with that mission
statement with regard to we will have a vaccine, you know,
against AIDS within the decade.
I am also reminded of the Office of Research on Women's
Health, and I know Dr. Kirschstein is here who is in the period
of the genesis of it. But had we not had Congress looking in on
where our priorities are or are not, if we had not had the
public then entering the picture, we might still only have a
little bit of an Office of Research on Women's Health. We might
not include them in clinical trials and protocols as we now do.
So I think that that says that there is a strong role for
congressional involvement and public input not overwhelming
what you as scientists know. But would you like to comment on
that?
Dr. Varmus. Well, I think you touched on an important
point. We are responsive to Congressional and public interests;
and I agree that we have made important advances in our
approach to women's health issues through the interest of women
advocates, the creation of a women's health office and the
writing of guidelines for inclusion of women and minorities in
research. Those have been extremely important.

aids vaccine initiative

With respect to your remark on the President's interest in
the AIDS vaccine, I would make a minor correction in what you
said and say that the President didn't say we will have it. He
gave us a challenge, not a promise. He gave us what I call
inspiration. That is, he has responded to our belief that the
prospects for an AIDS vaccine have improved.
There are no guarantees. I come back to Mr. Obey's point
earlier about moon shots. We acknowledge that this is not an
engineering feat we are undertaking. We are trying to do
something the guidelines for which are not clearly spelled out.
We are attempting to find new means to approach AIDS vaccine
development. I believe having the President speak out on that
public occasion about the possibility of doing this provides
leadership and excitement and could have a very significant
and, at this point, dollar-free contribution to the way in
which we approach the AIDS epidemic.

cost savings from research

Mrs. Morella. Finally, just a statement. I very often, in
comments to groups, will point out how much money we have saved
in terms of health, the health of the Nation by virtue of
something that has come from the NIH in the way of research. It
is a good way of bringing the point home to people in terms of
the value, tangibly, that they can see.
So thank you all very much and thank you, Mr. Porter, for
the opportunity.
Mr. Porter. Thank you, Mrs. Morella.
Ms. DeLauro.

ovarian cancer

Ms. DeLauro. Thank you, very much; and I want to thank all
of you for being here today and discussing with us the
priorities within the NIH and how the research funds are
prioritized. Obviously, the topic here is to--strong feelings
amongst members of what are the areas of research that ought to
be looked into, what are the areas that are considered
underfunded.
My commitment, as you know, has been to women's health. I
want to say thank you, though she has left, to my colleague
Patsy Mink for talking about the issue of ovarian cancer, being
one of the few survivors of ovarian cancer, and that we are
providing this amount of money in terms of diagnosis,
treatment. So I am very excited about the Genome Project, and
ovarian cancer is included in it.

politics and research

I think--while Members try to influence decisions or
really, for the most part, try to provide informed views on the
direction, I think we do need to concede that politicians--and
I am proud to be one--are not the final arbiters in this
effort.
I think one area that has been mentioned, the Parkinson's
disease--and I don't want to get into a debate about this--we
are in the business of cutting off avenues of research to look
at, you know, Parkinson's fields of research or other means. I
think if we inject the politics into this process, then we wind
up truly not serving the best interests and best health of the
public.
So we put a lot of faith and responsibility in the
judgments of NIH and the research funding priorities--not an
easy admission for those of us who are here.

clinical research

One of the things I wanted to inquire about--and I have
asked this question in different ways over the last several
months. That is, while basic research is critically important
in generating fascinating, powerful insights into disease,
without the kind of transfer, the clinical research, the
discoveries cannot really help to improve the care that
Americans receive in their doctors' offices and hospitals.
So the balance between basic research and clinical research
has been the topic of some conversation. Along with several of
my colleagues, we have introduced legislation to raise that
profile of clinical research. I want to get a sense from the
NIH of how do we ensure that the discovery--the remarkable
discovery that you are making in basic research----
And let me say with regard to the AIDS research, when you
are looking at research into blood and into suppressed
immunities, this carries over into cancer and a whole variety
of areas. This is not one specific area.
But what are the steps that we are taking at the NIH to
ensure that the discoveries that we make in basic research,
with being tested in the clinical trials, are hitting doctors'
offices across the country where that is--where the people
receive the benefit?

technology transfer

Dr. Varmus. Let me point out that there are at least three
vehicles for doing what you outline. First, something I won't
talk about in detail is technology transfer. As you know,
Congress became concerned in the late 1970s about getting the
products of our research into development, and the Bayh-Dole
Act was one way to do that. We of course, are not the only game
in town, and we want to believe the basic discoveries we make
are picked up by pharmaceutical and biotechnology firms and
carried forward into the production of benefits that can be
delivered to patients. We believe there has been a very
successful change in the way business is done.

clinical research

The second concern has to do with clinical research. I
don't mean to distinguish clinical research from basic
research; indeed some clinical research is basic. When I
arrived at NIH there was a concern that clinical research was
in a state of crisis for a variety of reasons having to do with
a decrease in the number of trained individuals going into
clinical research and the potential for underfunding of
academic research centers where clinical research is carried
out because of changes in health care reimbursement. And there
were concerns that NIH might not be adequately supporting
clinical research.
As I think you know, Ms. DeLauro, we put together a panel
of clinical research investigators and medical school leaders
to look at the clinical research portfolio whether we support
it adequately and whether we are adequately attracting new
investigators into clinical research activities, particularly
patient-oriented research. A number of things have come about
as a result of the panel's activities over the last 2 years.
One has been the simple recognition that NIH's investments in
patient-oriented or clinical research are already very
appreciable. In dollars, about 37 percent [Clerk's note.--Later
corrected to ``38''] of our grant money is going to clinical
research activities, and nearly 30 percent [Clerk's note.--
Later connected to about 27''] of our grants are in the
clinical research arena.
Secondly, we agree that there is concern about recruitment
of new clinical investigators. We are in the process of trying
to identify ways to support new clinical investigators on
faculties. We have recently established a new training program
that allows medical students to come to NIH and spend 1 or 2
years with us to develop their interests in clinical research.
We are hoping over the course of the next couple of years to
develop loan repayment programs to create incentives for
clinical investigation in the extramural sector.
We are also looking closely at the operation of our
clinical center at the NIH, the largest center for clinical
studies anywhere in the world. Your committee has been helping
us maintain at a high level of productivity through the
generation of a new building andmany new programs within the
clinical center.

information dissemination

The third area of concern is how we get information about
our discoveries into doctors' offices. We have a considerable
degree of activity in communications to advertise our results.
This is an imperfect process; it is one other agencies of
government and professional societies must help us with,
because it is a huge and expansive problem. It is one where I
think, in general, the biomedical establishment has not been
totally successful.
We talked earlier about obtaining as much benefit as would
be possible from discoveries in the area of diabetes over the
last several years. We know the science has run ahead of
clinical practice there. It is extremely important that we find
better ways to support the instruction of physicians in new
methods and new findings, and we do that. But we can't do that
alone because it is simply too expensive. It is much more
effective for us to work in conjunction with advocacy groups,
physicians and scientific societies.

ovarian cancer

Ms. DeLauro. It is an area we really ought to talk about,
because with regard to ovarian cancer, many of the women who
have been diagnosed are not getting the kind of care and
treatment they need. That is statistical data, and I understand
the difficulties in ovarian cancer, and I don't know if the
science is outpacing what is being passed on, as you mentioned
with diabetes.
But with a disease which is as insidious as it is and with
the high death rate, if we have it and we are not then properly
treating it, then, my God, to what end are we engaged, so
whatever ways in which we can assist in that third opportunity,
I think we need to explore those ways. And it is not just your
responsibility; it becomes all of our responsibility as well.
Thank you very much, Mr. Chairman.
Mr. Porter. Thank you, Ms. DeLauro.
Mrs. Lowey.

congressional support

Mrs. Lowey. Thank you, Mr. Chairman, and I do apologize.
Because of a commitment in New York, I missed part of the
testimony, but I want to join my colleagues and thank all of
you for the outstanding leadership you have shown. And I am
very pleased that the Chairman, who is probably your strongest
advocate--and I know most of us would join with him and wish we
could double our 602(b).
It is absolutely criminal to know that only 25 percent of
the grants are funded, when you think of all those
opportunities to deal with the challenges in medical research
that we are not pursuing--in my judgment, it is a real tragedy.
I, too, don't like to see one illness pitted against
another, but I think it is so important that we say, loud and
clear, and understand that we all advocate on behalf of so much
of the research that is done, whether it is in AIDS or diabetes
or breast cancer, that does affect other illnesses.
And in the area of AIDS, we know, and you have certainly
expressed to us, that so much of that research has helped us to
advance in other areas, and to not take advantage of
opportunities that exist in AIDS research is criminal as well.
So I want to applaud you in that area.
I remember when I got to Congress in 1988, looking back, if
we had not had the input of activists and congressional
members, certainly in the area of women's health, we would not
have had that partnership and moved as fast as we have moved. I
want to personally express my appreciation and thank you for
the Women's Health Initiative, for all the work you have done.
I remember talking--Dr. Kirschstein remembers as well--I
remember talking to the American Women's Medical Association,
and I remember them talking to us about their medical school
classes where they would spend 5 minutes on estrogen and a
couple of hours or a couple of days on testosterone.
And I also remember the days when there were just three
gynecologists on the staff at the NIH, so I want to personally
thank you for that cooperative effort that has moved us so far
ahead in those areas. And as a passionate supporter of
research--and I want to assure you, I care about prostate
cancer and heart disease and diabetes, and we can go on and on,
but my particular concern is with regard to the Office of
Women's Health; and I want to thank you for your concern in
just making sure we have a healthier society.

orwh's priority setting process

We know that a primary function of the Office of Research
in Women's Health is its role in identifying research vital to
women; that should be conducted and supported by the NIH. Could
you update us in how the office is functioning, how its agenda
is determined? Following up on the original Hunt Valley
conference, how is it continuing to analyze and reevaluate
priorities? I think it would be helpful for us to hear.
Dr. Varmus. I can do that very briefly, Mrs. Lowey.
About a year and a half ago Dr. Pinn, who is the director
of the office, put together a standing advisory committee
composed of outstanding physicians and investigators around the
country who were particularly concerned with women's health.
They are helping her adjust the research portfolio and set new
priorities.
The office continues to provide supplements to grants,
working closely with the many Institutes and centers, all of
which, of course, have an investment in women's health. The
purpose of most of those investments is to augment the level of
activity on grant projects that have already been approved by
the Institutes in order to provide them with extra resources,
to expand their efforts in the gender-specific aspects of the
work.
In addition, the office has responsibility for trying to
encourage the careers of women in science and provides a number
of programs that allow women to reenter the work force and stay
in the work force despite domestic responsibilities.
Another issue I should perhaps raise with you is one I know
you are concerned about: the inclusion of women and minorities
in research projects, and the guidelines that have supported
our activities in those areas that were written jointly among
offices in the Office of Director, including the Office of
Women's Health. Dr. Pinn has been involved in evaluating the
success of those efforts, and as far as we can tell, the
success has been very great; that is, we see very little
difficulty in helping our investigators to achieve compliance
with the recommendations of those guidelines.

priority setting interaction of orwh and nih

Mrs. Lowey. In looking at the Office of Women's Health over
the past few years, is there any difference in setting
priorities there compared to the way you set priorities with
the entire Institute, and what is the interaction?
Dr. Varmus. Well, I think the reasons I would say the
differences are not so great is because Dr. Pinn and her
colleagues are in fact working with the other Institutes.
Therefore, the input that goes to the other Institutes is
amalgamated into the decision-making process that goes on inthe
Office of Research on Women's Health.
Mrs. Lowey. I think that is so important because I think
the research is done across the board in almost every area. As
you revitalize the NIH clinical center, perhaps you could share
with us what considerations have been made with regard to
women's health issues.
Dr. Varmus. Women's health is part of virtually every
research endeavor. It would be difficult for me to say what
special concerns have been addressed in the plans we have
carried out so far. Most of the energy that has surrounded
revitalization of clinical center activities has had to do with
recruitment of new clinical investigators to the NIH, training
programs, the construction of the new facility, and changes in
governance of the clinical center. We believe that in every one
of these, equity is provided for gender-specific research.
I think there has been a very significant change in
attitude over the last several years. I don't believe that
there is an ingrained discrimination of a gender-specific
source at this point. If you feel there are ways in which
women's health issues are being slighted in those activities, I
would be more than pleased to entertain your views.
Mrs. Lowey. No, in fact, again in closing, I want to
emphasize I think in the last decade there has been
extraordinary progress in the attention given women's health
needs; and as we stated before, the research is done across the
Institutes and all the institutions involved.

clinical research report

Just in closing, I wanted to thank you for the report that
you have provided regarding your efforts on behalf of clinical
research. I must say I haven't read it as yet--we just received
it--but I want to thank you for the report, and I look forward
to discussing it with you. And once again I hope that we can be
of help to our Chairman and that the 602(b) will be increased
as my colleague Ms. Pelosi mentioned so we can fund a greater
share of those grants.
Thank you again.
Mr. Porter. Thank you, Mrs. Lowey.
Mrs. Northup.

information transfer in prevention

Mrs. Northup. Yes, Dr. Varmus, I would also like to talk to
you about transfer of information and results that come from
research.
In many of the medical areas, there are the dollars and the
economic reasons to transfer technology very quickly. For
example, AIDS research, then pharmaceutical companies become
involved in developing a drug that addresses the problems. That
is not so true in some quality-of-life issues, I guess you call
them prevention issues. And prevention is becoming much more
the issue in health, and I just wondered what you all are doing
to promote that.
I will give you a couple of examples. For example, drug
rehabilitation and questions of addiction. What sort of effort
does the Institute make when you come to certain conclusions
about rehabilitation, or prevention altogether, to transfer
that information to HHS so that the grants and the funding of
prevention actually follow what the research shows is most
effective.
I will give you one other example, and that is learning and
learning disabilities. We had quite a bit of testimony about
what the best way of teaching kids to read who are at risk, and
remediation for kids who have fallen behind. But in fact there
is very little evidence that the Department of Education funds
those kinds of programs, and in fact the President has proposed
a reading initiative that is as far away from that as you can
get.
So could you share your comment with me? There is no
pharmaceutical incentive or money incentive or medical
incentive or insurance incentive to have the transfer go in
those cases?

drug rehabilitation

Dr. Varmus. Yes, you are making a very good point, and it
is one we are concerned about. I am sure that more detailed
explanations of what is being done could be provided on those
two topics. I would point out in the case of drug
rehabilitation, that Dr. Leshner, Director of NIDA, works
closely with at least a couple of other agencies that are
involved, like SAMHSA and other departments within the HHS. He
also has been working closely with General McCaffrey and his
colleagues on drug control. So there are other ways to try to
translate the scientific findings into public policy.

early childhood development

As you know, the White House has had a high degree of
interest in early childhood development. We hope that from the
initiatives that have been put into place by the President in
the last year to try to emphasize the role of early childhood
development on learning, that there will be increased
interagency activities.
Mrs. Northup. I think my question specifically to you is,
what does your agency do to make the people making public
policy and appropriating money aware of your most recent
findings?

information transfer to other agencies

Dr. Varmus. I think almost all agencies involved in public
policy in those areas are aware that we do research in those
areas, and see that we are consulted. There is also an
opportunity through the National Science and Technology Council
for spreading our information among the various agencies that
are involved in those public policy decisions.
So in the area of health, for example, there is a whole
committee of the National Science Technology Council that is
devoted to health and safety, and multiple representatives of
the NIH are at those meetings.

research on learning disabilities

Mrs. Northup. I worry because I sometimes have the feeling
that if they don't call--and, quite honestly, I think that was
really true of learning disabilities and problems--that you all
do the research; and then, in a sense, the Department of
Education until recently was not aware of what the most recent
research was. Considering the dollars we are spending and how
concerned we are about that issue, I think it is important that
you initiate an effort to disperse the results of what your
considerations are.
Dr. Varmus. Well, I remember your interesting conversation
with Duane Alexander, Director of NICHD, on this topic before,
and I hope to get back to you about what is being done.
[The information follows:]

Information Dissemination of Research Findings on Learning Disabilities

The NICHD has in place a successful program aimed at
research information dissemination and in the last year has
intensified its efforts in this regard in the area of reading
development and disorders, and other learning disabilities. The
extensive work of the Institute's investigators in the area of
learning disabilities research is being published widely in
research, education, and general interest publications. The
NICHD is producing information such as fact sheets and
brochures that are being distributed by the Institute and other
agencies in both the government and private sectors. The
Institute responds daily to many requests for information from
the public and special interest groups on this subject. In
addition, the Institute annually publishes a book that
describes the year's progress in learning disabilities
research. The NICHD worked cooperatively with the Department of
Education to produce a set of information materials called
``Learning to Read--Reading to Learn'' that is being
disseminated widely by the Department of Education and other
agencies. The NICHD is working actively with the learning
disabilities organizations to disseminate information to parent
and education groups about the progress that is being made. In
addition, the scientist directing the Institute's learning
disabilities research program has testified before the Congress
and, upon request, provided information to a number of state
legislatures and parent groups in states around the country
about the results of this research. In April of this year, the
NICHD together with the Learning Disabilities Association
sponsored a Learning Disabilities Summit in Washington, D.C.,
with the concluding event on Capital Hill, to further
disseminate the research results in this area. The Institute is
working with the Department of Education to develop a national
assessment of research in reading development, reading
disorders, and other learning disabilities and, where
appropriate, a national strategy for the dissemination of that
information to the Nation's teachers and schools.

Mrs. Northup. What I am worrying about again, if we don't
ask the right questions and somebody doesn't call up, nobody
ever knows, and that is important.

Earmarks in DOD for research

I would like to ask you one other question. I absolutely
agree with us not making scientific determinations here, but of
course it is sometimes hard when you are in Congress not to
think that you can't make all the rules. We try to repeal the
laws of economics sometimes and all sorts of things.
I have noticed that the defense appropriators have decided
that they are going to earmark appropriations for such things
as prostate cancer, ovarian cancer, Parkinson's disease and
bone marrow. I was wondering if you would comment on, at least
for us, why those appropriations being earmarked by defense
aren't a good way or why they run counter to the best interest
of research.
Dr. Varmus. Well, I think that we at the NIH are
interested, have been interested in working closely with our
colleagues in the Department of Defense to make optimal use of
those appropriations. As you know, there is very strong
biomedical science in the Department of Defense through Walter
Reed and the Office of Naval Research and other components of
the Defense Department.
You are right. The monies appropriated for research are in
some cases conspicuously earmarked. We have a variety of
interactions on virtually every topic on which they received
earmarking that allows NIH scientists to interact with our
counterparts in the Defense Department, and we welcome those
interactions. In addition, the Defense Department has been
working with us in clinical trials that include Department of
Defense personnel.
So there are many ways in which we interact with them, and
to the extent to which most are appropriate for specific
diseases, we try to do the best we can to provide advice that
will allow those monies to be most wisely used.
Mrs. Northup. Okay, thank you.
Mr. Porter. Thank you, Mrs. Northup.

NIH Budget for FY 1998

I think this has been an excellent hearing, and we want to
thank you, Dr. Varmus, and your colleagues and all the members
of the audience this morning. I might say that I found
everything that you had to say highly credible, except
defending the President, who is now--and I might add, this also
includes the members of the Budget Committee and our leadership
negotiators, who have now got the NIH budget down to a 1.2
percent increase for the next fiscal year.
I am sure you find that just as unacceptable as we do, and
I hope that the expressions about our 602(b) allocation that
have been made by members of the panel this morning are ones
that come true, because it will make it very, very difficult
for us; and I am afraid the leadership of both the White House
and the Congress have made it very, very difficult to make that
a high priority and made our job much, much more difficult in
the process.
I think this is a subject that all of us have to address in
the coming calendar year and make certain that the substance,
the resources follow the advocacy. The advocacy is always
welcome, but not if it is not supported by resources.
Dr. Varmus, thank you very much.
The subcommittee will stand in recess until 10:00 a.m.
tomorrow, which is our last hearing of the year.

[Pages 2509 - 2552--The official Committee record contains additional material here.]

W I T N E S S E S

----------
Page
Adderly, Donna................................................... 2155
Alexander, Duane................................................. 1635
Baldus, A.C...................................................... 2001
Baldwin, Wendy................................................... 1
Barros, C.F...................................................... 1915
Beldon, Bill...................................................711, 805
Benowitz, S.C.................................................... 2249
Berkowitz, S.J................................................... 583
Burgess, E.S..................................................... 495
Bursenos, S.J.................................................... 1443
Casady, D.S...................................................... 1635
Cassman, Dr. Marvin.............................................. 2095
Collins, F.S..................................................... 495
Counts, G.W...................................................... 583
Cushing, Mary.................................................... 1377
Du Buy, Y.H...................................................... 1737
Dufour, Dr. Mary................................................. 1091
Fauci, A.S....................................................... 583
Ficca, S.A....................................................... 2249
Fitzsimmons, W.T................................................. 1809
Fivozinsky, C.L.................................................. 419
Fulton, B.E...................................................... 1635
Gekas, Hon. George............................................... 2431
Gorden, Phillip..............................................1177, 2431
Gordis, Dr. Enoch................................................ 1091
Gottesman, Michael............................................... 1
Grady, Dr. P.A................................................... 1377
Hall, Dr. Z.W.................................................... 2001
Haseltine, Dr. F.P............................................... 1635
Hausman, Dr. S.J................................................. 1491
Hodes, R.J....................................................... 1915
Hodgkins, G.E.................................................... 2095
Hudson, Kathy.................................................... 495
Hyman, S.E....................................................... 1809
Itteilag, Anthony...............................................1, 2249
Jaron, Dr. Dov................................................... 1573
Johnson, Laurie.................................................. 711
Jones, D.M....................................................... 983
Jordan, Elke..................................................... 495
Katz, Dr. S.1.................................................... 1491
Kerr, W.D........................................................ 805
Kerza-Kwiatecki, M.S............................................. 1491
Kirschstein Dr. R.L...........................1, 1377, 1443, 1915, 2249
Klausner, R.D.................................................199, 2431
Kleinman, D.V.................................................... 1737
Kupfer, Carl..................................................... 419
Laurence, L.E.................................................... 1177
Leasure, C.E., Jr................................................ 711
Lenfant, Dr. Claude...........................................865, 2431
Leshner, A.I..................................................... 983
Levine, S.U...................................................... 1309
Lindoerg, D.A.B.................................................. 1309
Lipman, D.J...................................................... 1309
Little, Francine................................................. 1
Long, Stephen.................................................... 1091
Luecke, D.H...................................................... 805
Maddox, Dr. Y.T.................................................. 1635
McGowan, J.J..................................................... 583
McLaughlin, Jack................................................. 419
McManus, Edward.................................................. 419
Merritt, Sheila.................................................. 865
Miller, Richard.................................................. 1443
Millstein, R.A................................................... 983
Mink, Hon. P.T................................................... 2431
Moore, Marshall.................................................. 805
Morella, Hon. C.A................................................ 2431
Moul, Ellen...................................................... 1377
Nakamura, R.K.................................................... 1809
Nethercutt, Hon. G.R., Jr........................................ 2431
Olden, Kenneth................................................... 711
Paul, W.E....................................................2155, 2431
Penn, Dr. A S.................................................... 2001
Pine, J.R........................................................ 1809
Pine, Martha..................................................... 2095
Poppke, D.C...................................................... 1309
Rabson, Alan..................................................... 199
Ramm, Dr. L.E.................................................... 1573
Richardson, C.M.................................................. 1091
Rosenthal, Laura................................................. 983
Ross, KS......................................................... 1915
Roth, Dr. Carl................................................... 865
Schambra, P.E.................................................... 1443
Shafer, Dr. W.S.................................................. 2095
Sherbert, R.L., Jr............................................... 2001
Slavkin, H.C..................................................... 1737
Smith, K A....................................................... 1309
Snow, J.B., Jr................................................... 805
Sparks, P.T...................................................... 805
Strachan, R.J.................................................... 1491
Summers, A E..................................................... 1573
Taylor, E.S...................................................... 1737
Trusty, M.K...................................................... 1091
Vaitukaitis, Dr. J.L............................................. 1573
Varmus, Dr. Harold.....1, 199, 419, 495, 583, 711, 805, 865, 983, 1091,
1177, 1309, 1491, 1573, 1635, 1737, 1809, 1915, 2001, 2095, 2155,
2249, 2431
Vennetti, J.C.................................................... 495
Wehling, James................................................... 865
Weiblinger, G.M.................................................. 1809
Wertheimer, Wendy................................................ 2155
Wetle, TelTie.................................................... 1915
Williams, D.P........1, 199, 419, 495, 583, 865, 983, 1091, 1177, 1309,
1377, 1443, 1491, 1573, 1635, 1737, 1809, 1915, 2001, 2095, 2155,
2249, 2431
Williams, T.D.................................................... 583
Wilson, S.H...................................................... 711
Zellers, C.R..................................................... 1177

I N D E X

----------

National Institutes of Health Overview

Page
Administrative Costs............................................. 53
AIDS/HIV:
AIDS and Minorities.......................................... 111
AIDS Research................................................ 83
Culminations in HIV Research................................. 3
HIV Vaccine.................................................. 29
Inspiration in HIV Research.................................. 4
Areas of Research Emphasis....................................... 79
Awareness Relating to Biomedical Research........................ 67
Biomedical Engineering Research.................................. 116
Budget Estimates:
Budget Estimates............................................. 11
Budget Estimates, Justification of........................... 148
Five Year Budget............................................. 91
FY 1998 Budget Request....................................... 43
Funding for NIH.............................................. 96
Impact of 7.5 Percent Increase............................... 22
1st President's Budget Proposal.............................. 5
Professional Judgment Budget................................. 11
Cancer:
Ovarian Cancer............................................... 33
Advances in Ovarian Cancer Research.......................... 34
Child Abuse and Neglect.......................................... 134
Child Development and the Brain.................................. 34
Clinical Research:
Clinical Research at Academic Medical Centers................ 143
Clinical Research Panel....................................129, 144
Clinical Research Program.................................... 80
Funding for Clinical Research................................ 80
Initiatives for Clinical Research............................ 145
IOM Recommendations................................19, 81, 142, 145
Peer Review of Clinical Research............................. 145
Progress in Support for Clinical Research.................... 22
Subscribers Participation in NIH Protocols................... 21
Third Party Payments, Impact of.............................. 35
Cloning:
Cloning...................................................... 13
Cloning of Humans............................................ 26
Earlier Cloning Experiment................................... 14
Ethical Implications......................................... 17
How Genes Turn On and Off.................................... 16
Legislating Cloning.......................................... 18
Medical Uses of Cloning...................................... 15
Scientific Significance of Cloning........................... 15
Use in Bone Marrow Transplants............................... 16
Comparison of Medicare Costs and Disease Research Costs.......... 36
Congressional Earmarks........................................... 85
Consensus Development Panels..................................... 23
Contraceptive and Reproductive Health Training Programs.......... 136
Contraceptive Research........................................... 70
Coordination with Other Agencies................................. 82
Culminations of Research......................................... 2
Department of Defense, Collaboration with........................ 89
Department of Education, Cooperation with........................ 130
Diabetes:
Commitment to Diabetes Research.............................. 30
Diagnosis and Detection of Diabetes.......................... 31
Increase in Diabetes Research................................ 131
Initiatives for Diabetes Research............................ 131
New Approaches to Pathogenesis............................... 65
NIH-Wide Diabetes Research Efforts........................... 64
Direct and Indirect Costs........................................ 72
Director's Discretionary Fund, FY 96 and 97...................... 45
Employment Rates for African-American Males...................... 120
Ethical, Legal and Social Implications Working Group............. 94
Ethics Training.................................................. 29
Extramural Construction.......................................... 107
Extramural Programs.............................................. 86
Full Time Equivalents (FTES):
FTE Detail by Grade Level.................................... 59
FTE Ceiling.................................................. 61
FTE Total by Institute....................................... 48
FTE Total by Mechanism....................................... 49
Human Embryo Research............................................ 92
Grants:
Administrative Burdens on Grantees........................... 88
New and Competing Research Project Grants.................... 142
Number of Applications....................................... 51
Research Project Grants...................................... 104
RPGs as Priority............................................. 113
Success Rates...............................................12, 110
Imaging Research................................................. 32
Indirect Cost Cap................................................ 66
Inspirations of Research......................................... 3
Instrumentation.................................................. 61
Intramural Programs.............................................. 87
Mammography:
Mammography.................................................. 108
Mammography Policy........................................... 25
Medicare Spending by Disease, 1995............................... 37
Minorities:
Inclusion of Minorities in Clinical Research................. 122
Investment in Minority Research Programs..................... 116
IOM Study.................................................... 103
Minority Health Standing Advisory Committee.................. 102
Minority International Research Training Program............. 100
Minority Investigators....................................... 113
Number of Minority and Women Investigators................... 105
Pipeline..................................................... 127
Research Centers in Minority Institutions.................... 128
Research Related to Minorities............................... 95
National Bioethics Advisory Commission........................... 28
National Center on Sleep Disorders Research...................... 52
Needle Exchange.................................................. 24
Neuroscience..................................................... 126
Obstetrics and Gynecology, Research in.........................135, 138
Offce of Research in Minority Health (ORMH):
Funding for Offce............................................96, 97
ORMH Co-funding.............................................. 99
Role of the ORMH............................................. 103
Opening Statement................................................ 6
Oversight and Administrative Activities.......................... 4
Panel on Potential Research on Marijuana......................... 24
Pediatric Research:
Number of Intramural Pediatricians........................... 138
Pediatric Research........................................... 137
Permanent Separations Profile.................................... 121
Pipeline for Young Investigators................................. 93
Population Research.............................................. 70
Prenatal Research................................................ 71
Public Education................................................. 50
Pulmonary Hemorrhage Among Cleveland Infants..................... 104
Priority Setting:
Allocation of Research Dollars............................... 40
Criteria for Funding Allocations............................. 40
Establishing Priorities...................................... 12
NIH Priority Setting Process.................................42, 73
Priority Setting at NCI...................................... 76
Reducing Health Care Costs....................................... 41
Research Infrastructure.......................................... 114
Research on Learning............................................. 130
Research Management and Support (RMS):
Cap on Management and Support Costs.......................... 94
One-Percent Evaluation Funding In............................ 49
RMS Funding 1990-1998........................................ 50
Research Spending Per Death for Selected Disease................. 67
Research Training................................................ 86
Shannon Awards................................................... 61
Small Business Innovation Research Grants........................ 115
Spending by Disease.............................................. 56
Taps and Assessments:
One-Percent Evaluation Set-Aside............................. 61
Taps and Assessments......................................... 63
Toll-Free Numbers................................................ 54
Women in Clinical Trials......................................... 141

National Cancer Institute

Abortion and Breast Cancer....................................... 255
Access to Care................................................... 236
Advances Against Cancer.......................................... 273
Angiogenesis..................................................... 231
Areas Impacting on Cancer........................................ 232
ASSIST........................................................... 252
Behavioral Research.............................................. 321
Breast Cancer-ABMT............................................... 236
Cancer Genetics.................................................. 259
Cancer Genetics Network...................................... 260
Cancer Genetics and Molecular Biology........................ 305
Genetics Testing............................................. 261
Cancer Survivors...............................................230, 272
Breast Cancer Survival....................................... 235
Five-Year Survival Rates..................................... 230
Office of Cancer Survivorship................................ 242
Cancer Vaccines.................................................. 263
Cancer Centers Program Review Group.............................. 269
Cancer Genome Anatomy Project.................................... 269
Cancer Mortality by Race......................................... 317
Decline in Cancer Mortality.................................. 271
Cancer Prevention................................................ 203
Clinical Trials................................................204, 278
African American Women and Clinical Trials................... 299
Breast Cancer-Molecular Markers.............................. 207
Clinical Trials in FY 1998................................... 286
Clinical Trial Educational Efforts........................... 267
Clinical Trial Agreement with The Department of Defense...... 265
Clinical Trial Agreement with The Veteran's Administration... 266
Dissemination of Clinical Trial Results...................... 284
Women in Clinical Trials..................................... 328
Clinical Treatment............................................... 236
Cloning.......................................................... 318
Collaborative Efforts............................................ 307
Combination Therapies............................................ 308
Comprehensive Cancer Centers..................................... 251
Construction..................................................... 246
Coordination Efforts with DOD..................................237, 238
Coordination of the National Cancer Program...................... 251
Detection Technologies For Breast Cancer......................... 225
Other Detection Technologies For Breast Cancer............... 224
Diet and Cancer................................................258, 311
Dissemination of Cancer Information.............................. 319
Environmental Links to Breast Cancer............................. 233
San Francisco Bay Area....................................... 234
Environmental Justice Research Activities........................ 313
Environmental Justice Collaborative Activities............... 315
Estrogen and Breast Cancer....................................... 325
``Five A Day'' Program........................................... 249
FTE Decrease..................................................... 245
Funding Allocation Decisions..................................... 226
Funding for NIH.................................................. 228
Gynecologic Cancer Research...................................... 328
Human Papillamovirus............................................. 241
Imaging.......................................................... 263
Imaging Technologies......................................... 297
Infectious Causes of Cancer...................................... 294
Institute of Medicine Cancer Study............................... 317
Intramural Program at Frederick.................................. 244
Justification of The Budget Estimates............................ 331
Mammography....................................................221, 295
Mammography Imaging.......................................... 265
Screening.................................................... 223
Measure of Successes............................................. 268
Minorities and Cancer............................................ 229
Advances in Minority Health.................................. 227
Cancer in Minority Population................................ 312
Excess Cancer Death Rate..................................... 271
Office of Special Populations................................ 229
Molecular Characteristics of Cancer.............................. 310
NCAB Subcommittee................................................ 224
NCI Panels and Advisory Boards................................... 329
New Cancer Drugs................................................. 268
NIH Reauthorization.............................................. 231
Opening Statement................................................ 199
Ovarian Cancer.................................................240, 327
Professional Judgment Budget..................................... 238
Opportunities................................................ 239
Prostate Cancer................................................236, 278
Prostate Cancer Initiatives.................................. 300
Prostate Cancer Treatment and Early Detection................ 302
African Americans and Prostate Cancer........................ 304
Radiation Therapy................................................ 246
Role of Stress in Cancer......................................... 277
San Antonio Cancer Institute..................................... 251
Science Information System....................................... 323
Implementation of The Science Information System............. 324
Statement of The Director........................................ 212
Tobacco Use and Children......................................... 247
Biology of the Brain............................................. 431
Cataract Surgery................................................. 437
Contact Lenses................................................... 437
FDA Approval..................................................... 429
Fetal Tissue..................................................... 434
Glaucoma Gene..................................................427, 429
Introduction of Witnesses........................................ 419
Long-Range Research Plan......................................... 436
Macular Degeneration...........................................429, 434
Marijuana use for Glaucoma....................................... 434
Neuron Survival.................................................. 428
Nutritional Supplements for Retinitis Pigmentosa................. 436
Opening Statement................................................ 419
Private Foundations.............................................. 435
Professional Judgement Budget.................................... 426
Radial Keratotomy Versus Laser Technique......................... 428
Retinopathy of Prematurity....................................... 430
Statement of Director............................................ 422
Transplanted Retinal Cells....................................... 433
Vision Conditions Needing More Research.......................... 437
Budget Increase.................................................. 506
Bureaucratic..................................................... 531
Center for Inherited Disease Research.....................497, 529, 543
Cloning:
Cloning and Ethics........................................... 547
Cloning Humans............................................... 515
International Cooperation.................................... 511
Potential for Hoax........................................... 514
Scientific Opportunities...................................507, 536
Why a Sheep.................................................. 515
Designer Drug Strategies......................................... 513
Diversity........................................................ 544
Ethical, Legal, and Social Implications........................499, 535
Finding the Gene...............................................497, 505
Finishing Faster:
Additional Funds Needed...................................... 525
Finding A Cure............................................... 507
Future Health Care Delivery...................................... 512
Genetic Discrimination and Privacy.............................519, 529
Genetic Testing:
Breast Cancer................................................ 508
Counseling and Control....................................... 510
Guidance..................................................... 526
Health Insurance Portability and Accountability Act of 1996...... 537
Howard University Center......................................... 543
Human Embryo Research............................................ 516
Human Genome Project:
Creation of.................................................. 541
Mapping Progress............................................. 534
Intramural Program............................................... 540
Minorities and Women............................................. 533
Newest Research Institute.................................495, 523, 532
Opening Statement................................................ 501
Oral Remarks..................................................... 495
Ovarian, Breast, and Cervical Cancer............................. 546
Prostate Cancer.................................................. 496
Protection of Patient Medical Information........................ 538
Sequencing:
Complete DNA Sequence........................................ 498
Beyond the First Sequence.................................... 498
Large Scale Sequencing....................................... 528

National Institute of Allergy and Infectious Diseases

Introduction of Witnesses........................................ 583
Opening Statement................................................ 583
AIDS:
AZT...................................................586, 588, 618
Behavioral Research.......................................... 614
Clinical Trials............................................602, 606
Global Threat................................................ 612
Minorities................................................... 632
Office of AIDS Research...................................... 611
Pediatric.................................................... 657
Protease Inhibitors..............................601, 605, 614, 623
Therapy....................................................605, 608
Treatment Strategies..................................586, 605, 612
Vaccines.........................................593, 601, 609, 633
Women........................................................ 654
Asthma........................................................... 636
Basic Research............................................594, 599, 601
Benefits of AIDS Research........................................ 654
Budget Estimates, Justification of............................... 661
Cholera.......................................................... 619
Chronic Fatigue Syndrome.............................603, 623, 631, 641
Clinical Trials.................................................. 649
Cloning.......................................................... 640
Diarrheal Diseases.............................................602, 630
Drug Issues...................................................... 617
Emerging Infectious Diseases..................................... 647
Grant Success Rate............................................... 648
Hansen's Disease................................................. 620
Hemophilia....................................................... 617
Hepatitis A...................................................... 626
Lyme Disease..................................................... 603
Malaria........................................................618, 633
Media Involvement................................................ 616
Multiple Sclerosis............................................... 603
Patient Registries............................................... 639
Primary Immune Deficiency........................................ 622
Priority Setting................................................. 628
Research Accomplishments......................................... 643
Rotavirus........................................................ 602
Sexually Transmitted Diseases........................602, 628, 652, 658
Topical Microbicides............................................. 655
Tuberculosis.........................................619, 626, 630, 640
Vaccines.............................................596, 597, 603, 642

National Institute of Environmental Health Siences

Air Quality...................................................... 763
Air Quality Standards.................................730, 736, 745
Artificial Sweeteners............................................ 725
Asthma.........................................................728, 763
Autism........................................................... 731
Beryllium........................................................ 770
Breast Cancer.................................................... 766
Budget........................................................... 747
Budget Formulation............................................... 762
Cancer........................................................... 764
Clinical Program...............................................748, 750
Clinical Research................................................ 754
Clinical Trials.................................................. 762
Cloning.......................................................... 756
Collaboration with Industry...................................... 723
Collaborations................................................... 757
Congressional Visit.............................................. 719
Contract Mechanism............................................... 727
Endocrine Disruptors...........................................719, 723
Environmental Genome Project..................................... 720
Environmental Health Hazards..................................... 756
Environmental Justice..........................................752, 767
EPA.............................................................. 749
Funding Increase................................................. 717
Grant Funding Mechanisms, Major.................................. 758
Gulf War Syndrome................................................ 724
Justification of the Budget Estimates............................ 772
Knowledge ``Bottleneck''......................................... 754
Link Between Science and Public Health........................... 721
Minorities, Improving Health of.................................. 752
Mixtures......................................................... 718
Nanofabrication.................................................. 726
National Toxicology Program....................................734, 768
New Testing Methodologies......................................720, 734
Opening Statement................................................ 711
Particulate Matter............................................... 736
Pulmonary Hemorrhage Among Cleveland Infants, Epidemic of........ 764
Retesting of Chemicals........................................... 728
Secondhand Smoke................................................. 746
Smoking.......................................................... 730
Statement of the Director........................................ 713
Success Rate..................................................... 759
Superfund......................................................734, 750
Toxicity Test Systems............................................ 747
Vitamin D and Prostate Cancer.................................... 718

National Institute on Deafness and Other Communication Disorders

Autism Research.................................................. 811
Balance Disorders in Elderly..................................... 816
Clinical Trials................................................818, 831
Cloning Technology............................................... 828
Collaborative Effort in Hearing Aid Technology................... 822
Eating Behavior and Nutrition.................................... 815
Government Performance and Results Act........................... 818
Hair Cell Regeneration........................................... 811
Hearing Aid Research............................................. 827
Hearing Impairment:
Consensus Conference Findings................................ 813
Incidence.................................................... 824
Introduction of Witnesses........................................ 805
Investigator-Initiated Research Applications..................... 832
Justification of the Budget Estimates............................ 834
Loss of Voice.................................................... 816
Multi Cultural Language Assessment............................... 830
Opening Statement................................................ 805
Otitis Media..................................................... 823
Partnership Program.............................................. 832
Public Information Activities.................................... 821
Presbycusis...................................................... 826
Research Funding................................................. 821
Sense of Smell................................................... 816
Sensory Regeneration............................................. 815
Specific Language Impairment..................................... 820
Statement of Director............................................ 807
Stochastic Resonance............................................. 812
Vaccine for Otitis Media.......................................819, 826

National Heart, Lung, and Blood Institute

Allocating Funds................................................. 888
Asthma.........................................................876, 928
Benefits from Research........................................... 890
Cardiovascular Disease in Mississippi..........................887, 926
Cell Death....................................................... 875
Child and Adolescent Trial for Cardiovascular Health (CATCH)..... 916
Chronic Obstructive Pulmonary Disease..........................921, 922
Clinical Trials and Research..............................925, 939, 942
Comprehensive Heart, Lung, and Blood Center...................... 911
Cooley's Anemia.................................................. 882
Cost Recovery.................................................... 902
Diet and Blood Pressure.......................................... 936
Education Programs........................................893, 900, 932
Folic Acid....................................................... 918
Gender Differences............................................... 930
Gene Therapy..............................................875, 878, 914
Government Performance and Results Act........................... 895
Heart Disease Death Rate......................................... 915
Heart Diseases...................884, 892, 902, 912, 926, 927, 932, 938
Human Clonine Research.........................................892, 941
Hypertension and Children........................................ 935
Hypertrophic Cardiomyopathy...................................... 905
Imaging Technology.............................................866, 873
Infants and Congenital Heart Disease............................. 934
In Utero Bone Marrow Transplantation............................. 874
Knowledge ``Bottleneck''......................................... 940
Lung and Blood Diseases..............................868, 880, 887, 896
Lung Volume Reduction Surgery..................................895, 924
Major Opportunities.............................................. 927
Minority Health............................879, 881, 925, 931, 933, 938
Organ Damage..................................................... 935
Primary Pulmonary Hypertension.................................906, 909
Salt Intake...................................................... 901
Selected Areas of Research....................................... 898
Select Pay....................................................... 903
Service Centers.................................................. 894
Sleep Disorders Research.........876, 893, 901, 907, 908, 922, 923, 936
Smoking........................................................884, 927
Specialized Centers of Research.................................. 899
Statement of the Director........................................ 870
Stroke Research................................................877, 919
Women's Health............................................913, 920, 944

National Institute on Drug Abuse

AIDS and Drug Abuse.............................................. 1002
AIDS/HIV and Drug Abuse.......................................... 1017
Alaska Needle Exchange........................................... 995
Alcohol and Substance Abuse...................................... 993
Biology of the Brain............................................. 1028
Brain Development in Adolescent Drug Users....................... 1050
Brain Imaging.................................................... 1032
Bupropion........................................................ 1006
Clinical Research................................................ 1038
Clinical Trials.................................................. 1041
Cloning.......................................................... 1040
Cocaine Craving.................................................. 1009
Cocaine Medication............................................... 999
Cocaine Medication Development...............................1005, 1006
Collaborative Effort............................................. 1027
Comparing United States Drug Abuse............................... 1003
Cost to the Nation............................................... 1029
Craving............................................................1012
Demographics of Addicts.......................................... 1003
Disease Specific Budgets......................................... 996
Drug Abuse Budget Increase....................................... 994
Drug Abuse Costs................................................. 1009
Drug Intoxication................................................ 1030
Effect of Welfare Reform on Addicts.............................. 1052
Effective Drug Treatments........................................ 1009
Effectiveness of Prevention Programs............................. 1007
Essense of Addiction............................................. 1001
Extent of the Problem............................................ 1020
Genetic and Environmental Influences............................. 1034
Impact of Drug Abuse............................................. 1030
Improving the Health of Minorities............................... 1037
Information Dissemination....................................1007, 1048
Introduction of Witnesses........................................ 983
Justification of the Budget Estimates............................ 1054
Knowledge ``Bottleneck''......................................... 1039
Marijuana for Medical Purposes................................... 1026
Medical Marijuana Concerns....................................... 1008
Medical Use of Marijuana......................................... 997
Methadone Treatment.............................................. 998
Minority and Women's Health...................................... 1044
Minority Related Research........................................ 1004
National Institutes of Health Disease-Specific Budgets........... 996
Needle Exchange...............................................997, 1023
Needle Exchange and AIDS......................................... 1008
Needle Exchange Programs......................................... 1004
Nicotine Addiction............................................994, 1000
NIDA-SAMHSA Coordination......................................... 1053
Opening Statement................................................ 983
Our Nation's Youth............................................... 1047
Outreach......................................................... 1037
Prenatal Drug Use Study.......................................... 1007
Prevention Increase.............................................. 1008
Prevention Principles Book....................................... 1006
Prevention Program............................................... 1005
Prevention Programs for Elementary and Secondary School Students. 1016
Prevention Research.............................................. 1012
Progress......................................................... 1031
Relationship Between Marijuana and Abrupt Termination of
Pregnancy...................................................... 1011
Relationship with ONDCP.......................................... 992
Research......................................................... 1012
School Based Drug Prevention..................................... 1014
Search for a Cure................................................ 1046
Statement of the Director........................................ 988
Successor Drugs of Abuse......................................... 999
Tobacco.......................................................... 1014
Vaccine Development.............................................. 992

National Institute on Alcohol Abuse and Alcoholism

Adolescent Consumption, Trends of................................ 1101
Alcoholics Anonymous, Evaluations of............................. 1103
Animal Models.................................................... 1092
Brain Function in Adolescents.................................... 1140
Chromosomes Associated with Alcoholism........................... 1123
Clinical Research................................................ 1136
Clinical Trials.................................................. 1139
Cloning.......................................................... 1138
Comparing Drug and Alcohol Use and Abuse......................... 1108
Consumption...................................................... 1109
Coordination..................................................... 1122
Coordination of Research Findings................................ 1142
Cure for Alcoholism.............................................. 1105
Dissemination of Research Findings............................... 1131
Effects of Alcohol on Development................................ 1110
Estrogen, Effect of Alcohol on................................... 1112
Extent of the Problem............................................ 1124
Fetal Alcohol Syndrome, Correlation of Heavy Drinking to......... 1111
Fetal Alcohol Syndrome........................................... 1125
Fetal Alcohol Syndrome and Early Childhood Development........... 1143
Genetic Testing.................................................. 1107
Genetics Research, Practical Applications of..................... 1107
Incidence by Gender.............................................. 1121
Institute of Medicine Assessment................................. 1132
Justification................................................1145, 1176
Knowledge of ``Bottlenecks''..................................... 1137
Liver Transplantation for Alcoholic Liver Disease................ 1113
Major Research Opportunities..................................... 1125
Medications for Alcohol Treatment................................ 1104
Medications, Promising........................................... 1118
Minorities, Improving the Heslth of.............................. 1135
Moderate Drinking................................................ 1117
Naltrexone Research.............................................. 1133
New Opportunities for Developing New Drugs....................... 1119
Opening Statement................................................ 1091
Pregnancy........................................................ 1128
Prevention....................................................... 1094
Prevention Research versus Behavioral Research................... 1121
Project Match, Rigorous Design and Findings of................... 1101
Project Northland: Positive Outcome and Lower Drug Use........... 1121
Research Advances, Application of................................ 1093
Research Dissemination........................................... 1095
Safe and Drug Free Schools....................................... 1115
Serotonin........................................................ 1112
Significant Research Opportunities............................... 1125
Statement of the Director........................................ 1096
Tobacco and Alcohol Use.......................................... 1134
Treatment Research............................................... 1094
Vulnerability to Alcoholism...................................... 1091
Welfare Reform................................................... 1141
Witnesses, Introduction of....................................... 1091

National Institute of Diabetes and Digestive and Kidney Diseases

Administrative Issues............................................ 1218
Artificial Pancreas.............................................. 1194
Budget Estimates, Justification of............................... 1184
Chromium Diabetes Study.......................................... 1236
Clinical Research................................................ 1251
Clinical Trials.................................................. 1254
Clinical Trials--Participation................................... 1249
Cloning.......................................................... 1253
Collaborative Efforts........................................1225, 1246
Cooley's Anemia.................................................. 1209
Costs of Treating Diabetes....................................... 1194
Crohn's Disease.................................................. 1257
Diabetes Education Program....................................... 1191
Diabetes Education and Research.................................. 1224
Diabetes Emphasis................................................ 1184
Diabetes Gene.................................................... 1243
Diabetes in African Americans.................................... 1256
Diabetes in Minorities........................................... 1244
Diabetes Initiative.............................................. 1240
Diabetes Prevention.............................................. 1237
Diabetes Prevention Trials....................................... 1225
Diabetes Regimen.............................................1209, 1219
Diabetes Research............................................1228, 1231
Digestive Diseases............................................... 1205
Disease Funding.................................................. 1214
Drugs That Work Selectively...................................... 1204
Effects of Alcohol............................................... 1201
End-Stage Renal Disease.......................................... 1241
Funding for Diabetes Research..........................1189, 1217, 1223
Genetics of Diabetes............................................. 1191
Helicobacter Pylori.............................................. 1249
H. Pylori Applications........................................... 1202
Health Status of Women and Minorities............................ 1245
Hepatitis........................................................ 1207
Hepatitis C...................................................... 1214
Identifying Areas of Research Emphasis........................... 1184
Immune Modulation in Diabetes.................................... 1185
Impact of Diabetes Trial......................................... 1210
Improving the Health of Minorities............................... 1251
Intramural Decision-Making....................................... 1196
Intramural Research.............................................. 1195
Introduction of Witnesses........................................ 1177
Justification of the Budget Estimates............................ 1258
Knowledge ``Bottleneck''......................................... 1252
Liver Disease in Children........................................ 1221
Liver Disease Information........................................ 1219
Locating Diabetes Information.................................... 1193
New Methods for Treating Diabetes................................ 1237
Newly Diagnosed Diabetics/Early Intervention..................... 1227
Nutrition........................................................ 1200
Nutrition and Diabetes........................................... 1255
Obesity..........................................1211, 1222, 1241, 1244
Opening Statement................................................ 1177
Organ Donations.................................................. 1250
Outside Input for Diabetes Research.............................. 1226
Peer Review...................................................... 1230
Polycystic Kidney Disease..............................1208, 1217, 1255
Prevalence of Diabetes........................................... 1188
Professional Judgment Budget..................................... 1189
Prostate Cancer.................................................. 1247
Prostatitis...................................................... 1206
Public Education Activities...................................... 1216
Public/Private Research Partnerships............................. 1255
Research Centers................................................. 1215
Restoring Insulin Production..................................... 1187
Review Process for Clinical Studies.............................. 1226
Risk for Diabetes................................................ 1239
Small Business Research.......................................... 1197
Special Research Areas in Diabetes............................... 1192
Statement of the Director........................................ 1180
Stress in Diabetes............................................... 1185
Treating and Preventing Diabetes................................. 1223
Ulcer Diagnosis and Treatment.................................... 1203
Ulcers.......................................................1199, 1228
Upcoming Diabetes Conference..................................... 1192
Urology......................................................1206, 1218
Women's Health................................................... 1193

National Library of Medicine

Bioinformatics................................................... 1325
Electronic Patient Records....................................... 1338
Genetic Databases............................................1336, 1346
Gpra Standards................................................... 1341
High Performance Computing...................................1337, 1347
Human Genome Map.............................................1316, 1324
Iaims Program.................................................... 1337
Internet.........................................1312, 1326, 1331, 1339
Justification of The Budget Estimates............................ 1355
National Information Infrastructure.............................. 1309
Next Generation Internet Initiative..........................1326, 1352
Opening Statement................................................ 1309
Outreach.....................................................1324, 1330
Personal Services Contracts...................................... 1337
Project Phoenix.................................................. 1342
Pubmed.......................................................1339, 1348
Statement of the Director........................................ 1319
Telemedicine.........................1314, 1327, 1328, 1334, 1343, 1351
Toxicology Center................................................ 1337
Underserved Populations.......................................... 1345
User Fees........................................................ 1349
Video Tapes...................................................... 1349
Visible Humans................................................... 1310
World Wide Web...............................................1333, 1343

National Inatitute of Nursing Research

Aging............................................................ 1402
Alzheimer's Disease.............................................. 1400
Breast Cancer.................................................... 1399
Breast Self-Exams................................................ 1389
Cardiovascular Disease........................................... 1378
Cardiovascular Disease in Children............................... 1396
Chronic Illness.................................................. 1395
Clinical Research Conference..................................... 1385
Collaborative Efforts............................................ 1401
Communication with Health Care Providers......................... 1384
Counseling for Genetic Screening................................. 1389
Cultural Diversity............................................... 1378
Currency with Research........................................... 1386
End of Life...................................................... 1379
End of Life Care................................................. 1397
Future Research Emphases......................................... 1379
FY98 Budget Request..........................................1379, 1413
Infant Colic..................................................... 1396
Irritable Bowel Syndrome......................................... 1378
Justification of the Budget Estimates............................ 1384
Minority and Women's Health...................................... 1406
Minority Researchers............................................. 1403
Nurse Education Act--FY 1988 Budget.............................. 1393
Nursing and Oncology............................................. 1410
Nursing Publications............................................. 1385
Opening Statement................................................ 1377
Opportunities for Ethnic Nurses.................................. 1392
Outreach and Information Dissemination........................... 1405
Pain Research................................................1377, 1399
Professional Judgment Budget..................................... 1384
Provider Care.................................................... 1398
Quality of Care.................................................. 1393
Quality of Life.................................................. 1394
Research Training Issues......................................... 1387
Rural and Ethnic Populations..................................... 1391
Sister to Sister Study........................................... 1405
Stroke........................................................... 1406
Targeted Research................................................ 1404
Transplantation.................................................. 1379
Traumatic Brain InJury........................................1386, 397
Women's Health................................................... 1411
Women's Health Issues............................................ 1388

Fogarty International Center

Biodiversity Program............................................. 1455
Budget Increase..............................................1460, 1461
Emerging Infectious Diseases.................................1463, 1464
External Panel Review............................................ 1452
Fellowship Programs..........................................1450, 1451
Former Soviet Union--State of Science............................ 1454
Human Frontier Science Program................................... 1453
International Agreements......................................... 1460
International Activities Expenditures........................1458, 1459
Justification of Budget Estimates.............................1466-1489
Minority International Research Training Program.............1462, 1463
Opening Statement................................................ 1443
Other Countries Leading in Biomedical Research................... 1450
Vitamin A Supplementation....................................1464, 1465

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Antibiotic Treatment............................................. 1507
AIDS Research.................................................... 1529
Arthritis Treatment.............................................. 1522
Breast Cancer and Osteoporosis................................... 1535
Breast Implants and Autoimmune Diseases.......................... 1512
Budget Estimates, Justification of............................... 1537
Budget Request, FY 1998.......................................... 1494
Cartilage Repair................................................. 1512
Central Nervous System Lupus..................................... 1514
Clinical Research................................................ 1530
Clinical Trials.................................................. 1533
Collaborative Research........................................... 1515
Depression and Osteoporosis...................................... 1513
Epidemiological Data Concerning Repetitive Motions Injuries...... 1520
Ergonomics...................................................1500, 1502
Fibrodysplasia Ossificians Progressiva........................... 1514
Funding for Disease Areas........................................ 1517
Gender and Autommunity........................................... 1511
Gulf War Syndrome................................................ 1513
Human Cloning....................................1502, 1503, 1505, 1532
Health Status.................................................... 1528
Low Back Pain.................................................... 1518
Minority Health Research......................................... 1530
Musculoskeletal Disorder.....................................1500, 1518
Osteoarthritis................................................... 1526
Osteoporosis...........................................1493, 1509, 1510
Psoriasis........................................................ 1535
Professional Judgment Budget..................................... 1507
Repetitive Motion Injury.....................................1499, 1525
Research Centers................................................. 1517
Research Opportuoities........................................... 1522
Research Challenges.............................................. 1532
Rheumatoid Arthritis............................................. 1493
Sexualy Transmitted Diseases..................................... 1536
Skin Cancer..................................................1493, 1524
Statement of the Director....................................1491, 1495
Stress and Arthritis............................................. 1511
Success Rate..................................................... 1536
Systemic Lupus Erythematosus.................................1493, 1528
Total Joint Replacement.......................................... 1492
Trauma Injuries.................................................. 1521

National Center for Research Resources

National Center for Research Resources.......................1573, 1604
Broader Participation............................................ 1602
Clinical Research................................................ 1591
Chimpanzees in Research.......................................... 1579
Chimpanzee Retirement........................................1580, 1581
Coordination of Imaging Activities............................... 1586
Education........................................................ 1597
Euthanasia of Research Animals................................... 1583
Extramural Construction.......................................... 1600
Extramural Facilities Construction...............1585, 1587, 1588, 1592
Extramural Programs.............................................. 1596
Faculty Investigators............................................ 1598
Funding for Selected Programs.................................... 1588
General Clinical Research Centers................................ 1583
Interest in Biomedical Research.................................. 1590
Introduction of Witnesses........................................ 1573
Minority and Women's Health...................................... 1600
Minority Research Investigators.................................. 1597
NCRR Appropriations.............................................. 1595
NCRR Strategic Plan.............................................. 1582
Near Infrared (University of Kentucky)........................... 1590
Office of Research on Minority Health............................ 1597
Opening Statement............................................1573, 1575
Pipeline......................................................... 1596
RCMI Clinical Initiative......................................... 1601
RCMI Cofunding................................................... 1600
Regional Primate Research Centers............................1586, 1587
Research Centers in Minority Institutions........................ 1592
Research Infrastructure in Minority Institutions................. 1595
Review Committees................................................ 1598
Shared Instrumentation Grants.................................... 1588
Use of Animals in Research....................................... 1579
Virtual Laboratories............................................. 1585

National Institute of Child Health and Human Development

AIDS............................................................. 1681
Alcohol and Drug Addiction....................................... 1673
Asthma........................................................... 1649
Autism........................................................... 1643
Autism Centers................................................... 1644
Autism Research Investigators.................................... 1644
Child Day Care................................................... 1674
Childhood Nutrition.............................................. 1667
Children with Learning Disabilities.............................. 1660
Children with Reading Disabilities............................... 1655
Clinical and Basic Research...................................... 1689
Clinical Research................................................ 1665
Clinical trials.................................................. 1691
Cloning.......................................................... 1691
Diabetes Research................................................ 1679
Drug Dosages for Children & Pediatric Pharmacology Res. Units.... 1653
Drug Use before Pregnancy........................................ 1657
Early Child Care................................................. 1646
Funding--Disease Areas........................................... 1671
Grant Funding.................................................... 1666
Health Status of Minority Children............................... 1684
Infant Mortality................................................. 1676
Infertility Research............................................. 1656
Infertility...................................................... 1673
Intervention Programs............................................ 1660
Intramural Clinical Research..................................... 1669
Justification.................................................... 1693
Learning Disabilities............................................ 1688
Learning Disabled Children....................................... 1644
Learning to Read.............................................1648, 1654
Maternal Mortality............................................... 1656
Middle School Children........................................... 1662
Minority Representation in Basic Research and Training........... 1689
National Center for Medical Rehabilitation Research.............. 1672
Obesity Research................................................. 1680
Opening Statement................................................ 1635
Perinatology Research--District of Columbia...................... 1665
Phonics Based Reading System..................................... 1659
Phonics Based System............................................. 1661
Phonics.......................................................... 1663
Premature Labor and Delivery..................................... 1646
Prevention Problem Behavior...................................... 1651
Protection from Asthma........................................... 1650
Pulmonary Hemorrhage in Infants.................................. 1687
Research Bottlenecks............................................. 1690
Research Centers................................................. 1670
Research on Fatherhood........................................... 1663
Research Opportunities........................................... 1685
SIDS Back to Sleep Campaign...................................... 1645
SIDS.........................................................1670, 1688
Spinal Cord Injury............................................... 1668
Strengthening Families........................................... 1670
Teenage Drug Use and Pregnancy................................... 1658
Vaccine Development.............................................. 1666
Web Page......................................................... 1649

National Institute of Dental Research

50th Anniversary................................................. 1772
AIDS/HIV......................................................... 1775
Biomimetics...................................................... 1749
Bone Research................................................1762, 1780
Cleft Palate..................................................... 1755
Clinical Trials.................................................. 1768
Clinical Research................................................ 1777
Cloning.......................................................... 1778
Congressional Justification...................................... 1782
Dental Amalgams.................................................. 1748
Dentist Scientist Program........................................ 1756
Diabetes, Oral Complications of.................................. 1750
Flouridation.................................................1749, 1754
Future Expectations.............................................. 1750
Health Status.................................................... 1767
Immune Systems................................................... 1770
Introduction of Witneses......................................... 1737
Knowledge ``Bottleneck''......................................... 1771
Medicare Coverage for Dental Care................................ 1755
Minorities, Improving the Health of.............................. 1776
Minority Groups, Reaching Ethnic and............................. 1762
NIDR Strategic Plan.............................................. 1759
Opening Statement................................................ 1737
Oral Cancer............................................1757, 1764, 1769
Osteoporosis and Oral Bone Loss.................................. 1751
Pain Research................................................1752, 1780
Priority Setting................................................. 1760
Public Education.............................................1774, 1780
Research Centers.............................................1759, 1765
TMD..........................................................1750, 1753

National Institute of Mental Health

Basic Neuroscience............................................... 1852
Brain as the Touchstone of NIMH Research......................1828-1829
Brain Development and Mental Illness..........................1840-1842
Children............................................1854-1856 1866-1867
Prevention of Childhood Mental Illness....................1823-1824
Proceedings of Workshop (Inclusion of Children in Clinical
Research)...............................................1837-1839
Research Needed on Childhood Disorders....................1829-1830
Treatment of Mental Illness in Children...................1834-1840
Circadian Rhythms and Mental Illness..........................1843-1844
Clinical and Services Research................................... 1852
Eating Disorders.............................1844-1845, 1849-1850, 1856
Funding Amounts FY 1996--FY 1998................................. 1846
Gene Therapy..................................................1868-1869
Global Burden of Disease......................................1818-1819
Table 1.......................................................... 1811
Inclusion of Women and Minorities.............................1865-1866
Initiative to Track Enrollment of Women and Minorities........... 1827
Justification of Budget Estimation............................1870-1913
Managed Care..................................................1857-1858
Mental Illness in the U.S.....................................1859-1862
Mental-Physical Relationship..................................1867-1868
Minority Employment.............................................. 1826
Minority Investigators and Research Subjects..................1825-1827
Needle Exchange Programs......................................1821-1822
New Drugs for Schizophrenia...................................1831-1832
Nutritional Factors...........................................1850-1851
Opening Statement of Director.................................1809-1817
Prevention of Childhood Mental Illness........................1823-1824
Proceedings of Workshop (Inclusion of Children in Clinical
Research)...................................................1837-1839
Regulation of Emotion............................................ 1853
Relationship of Mental Illness to Other Physical Illnesses....1842-1843
Research Needed on Childhood Disorders........................1829-1830
Schizophrenia.................................................... 1859
Setaside for Mental Health Services Research..................... 1821
Sexual Abstinence in AIDS Prevention............................. 1823
Social Work Research............................................. 1830
Suicide and Suicide Prevention................................1862-1865
Training......................................................... 1858
Training of Minority Researchers................................. 1831
Translation of Research into Treatment........................1832-1834
Treatment of Mental Illness in Children.......................1834-1840
UNOCCAP (Use, Needs, Outcomes, and Costs for Child and Adolescent
Populations)................................................1819-1820
Victims of Torture............................................1846-1849
Vulnerability.................................................... 1854
World-wide Burden of Disease (Table 1)........................... 1811
World-wide Burden of Depression...............................1824-1825

National Institute on Aging

Aging--The Exercise and Nutrition Linkage........................ 1955
AIDS............................................................. 1963
Alzheimer's Disease and Ibeprofen................................ 1941
Alzheimer's Disease..................1915, 1934, 1935, 1948, 1954, 1960
Alzheimer's Disease Genetic Discoveries.......................... 1917
Biological Processes............................................. 1958
Biology of Aging................................................. 1920
Caloric Restriction.............................................. 1949
Collaborative Activities......................................... 1959
Demographic Reaearch............................................. 1934
Demography of Aging.............................................. 1921
Disability Research..........................................1933, 1956
Embryo Research.................................................. 1936
Falls in the Elderly............................................. 1939
Genetic Research................................................. 1943
Health Care Savings.............................................. 1937
Health Status and Clinical Trial Participation................... 1861
Hypertension..................................................... 1952
Immune System.................................................... 1963
Long Term Care...............................................1943, 1965
Managed Care..................................................... 1955
Menopause........................................................ 1964
Number of Chronically Disabled Americans Age 65 and Over......... 1924
Nursing Homes--Individualized Care............................... 1950
Opening Statement............................................1915, 1926
Osteoporosis..................................................... 1937
Predictive Testing............................................... 1944
Projected Population Age 100 Years and Over...................... 1931
Prolonging Independence-Delaying Disability...................... 1956
Prostrate Cancer................................................. 1940
Protective and Risk Factors for Alzheimer's Disease.............. 1919
Quality of Life.................................................. 1936
Research Centers................................................. 1946
U.S. Life Expectancy at Age 85, 1900-1995........................ 1932
Unraveling Longevity............................................. 1963
World Population by Age.......................................... 1922

National Institute of Neurological Disorders and Stroke

Accident Prevention.............................................. 2048
Alzheimer's Disease.............................................. 2039
Amyotrophic Lateral Sclerosis.................................... 2022
Brain Diseases in Children....................................... 2039
Childhood Diseases............................................... 2035
Clinical Research................................................ 2041
Clinical Trials.................................................. 2044
Cloning.......................................................... 2043
Congressional Justification...................................... 2051
Diseases of Aging................................................ 2010
Epilepsy Research............................................2033, 2040
Estrogen and Stroke.............................................. 2020
Future of Brain Research......................................... 2011
Human Embryo Research............................................ 2023
Introduction of Witnesses........................................ 2001
Knowledge Bottleneck............................................. 2042
Mad Cow Disease and Prion Hypothesis............................. 2021
Minority Research Investigators.................................. 2037
Multiple Sclerosis............................................... 2034
Neurodegenerative Disease Initiative.........................2018, 2019
New Treatments and Discoveries................................... 2038
Nicotine, Possible Therapeutic Effects of........................ 2020
NINDS Budget Increases........................................... 2012
Opening Statement................................................ 2001
Parkinson's Disease..........................................2016, 2028
Prion Hypothesis and Mad Cow Disease............................. 2021
Research Centers Grants, NINDS................................... 2026
Specific Disease Funding......................................... 2026
Spinal Cord Injury Research......................2012, 2016, 2024, 2049
Statement of Director............................................ 2005
Stroke Research......................2010, 2020, 2031, 2036, 2047, 2049
Targeted Research................................................ 2018

National Institute of General Medical Sciences

Biology of the Brain Initiative.................................. 2121
Budget Policy.................................................... 2142
Budget Tables.................................................... 2144
Cell Biology and Biophysics...................................... 2130
Compliance with NRSA Payback Requirement......................... 2112
Employment Prospects for Research Trainees....................... 2110
Evaluation of National Research Service Award Training........... 2112
Gender Differences in Response to Trauma......................... 2115
Genetics and Developmental Biology............................... 2133
Goals of the Director............................................ 2108
Goals to be Accomplished and Priority-Setting Process............ 2140
High Risk Research............................................... 2109
Inclusion of Underrepresented Minorities......................... 2118
Innovations in Management and Administration..................... 2141
Interim Funding.................................................. 2108
Introduction..................................................... 2123
Justification of Budget Estimates................................ 2124
MARC Program.................................................2122, 2138
MBRS and HBCU Participation...................................... 2120
MBRS Program.................................................2119, 2137
Medical Scientist Training Program............................... 2112
Minority Opportunities in Research...........................2117, 2137
New Approaches to Pathogenesis...................2132, 2133, 2134, 2135
New Investigators................................................ 2110
NIGMS Organizational Chart....................................... 2125
Opening Statement................................................ 2095
Other Areas of Interest.......................................... 2141
Percentage of Ph.D's Awarded to Minorities....................... 2114
Pharmacology Research Associate Program.......................... 2140
Pharmacology, Physiology, and Biological Chemistry............... 2135
Protease Inhibitors.............................................. 2118
Rationale for Stipend Increases.................................. 2112
Research Advances................................................ 2130
Research Areas Pursued by Young Investigators.................... 2113
Research in Chemistry and Physical Sciences...................... 2108
Research Training Collaborations with Industry................... 2111
Scientists Employed as Temporary Workers......................... 2111
Special Initiatives.............................................. 2138
Special Programs................................................. 2137
Stimulation of Research Fields................................... 2110
Stipend Levels................................................... 2116
Story of Discovery: From Chemistry to Gene Therapy............... 2129
Training Programs of the Howard Hughes Medical Institute......... 2114

Office of AIDS Research

AIDS Statistics.................................................. 2163
AIDS in Minority Populations..................................... 2170
AIDS in Minority Populations..................................... 2203
AIDS Research Proportion of NIH Funding.......................... 2171
AIDS Research Addressing Minorities.............................. 2170
AIDS Research Proportion of Total NIH Request.................... 2167
Benefits of AIDS Research to Other Diseases...................... 2164
Changing Faces and Scientific Priorities......................... 2190
Clinical Trials of New Therapeutic Agents........................ 2188
Cooperation with Industry........................................ 2183
Demographic Groups With Increasing AIDS Cases.................... 2163
Direct Support for OAR........................................... 2174
Federal Biomedical Research Plan................................. 2175
Flexibility for OAR to Change ICD Distributions.................. 2165
Inclusion of Minorities in AIDS Research......................... 2193
Justification................................................2205, 2248
Latest Advances in AIDS/HIV Therapies............................ 2202
Minorities on Research Training Grants........................... 2168
Minority Participation in Clinical Trials........................ 2197
Needle Exchange.................................................. 2187
NIH Panel on Principles of Therapy for HIV Infection............. 2181
OAR Discretionary Fund........................................... 2176
OAR Collaboration with ORMH and ORWH............................. 2192
Opening Statement................................................ 2155
Pediatric AIDS................................................... 2178
Prevention Science Working Group................................. 2172
Projected AIDS Deaths Without a Vaccine.......................... 2164
Proportional Increases for NIH Institutes........................ 2171
Prospects for International Availability of an AIDS Vaccine...... 2163
Recipients of AIDS Research Funds................................ 2177
Reluctance of Monitories to Participate in Clinical Trials....... 2171
Research Plan.................................................... 2186
Role of the Office of the Director............................... 2167
Small Business Innovation Research Grants (SBIR)................. 2196
Social and Behavioral Factors of AIDS............................ 2192
Status of Minority and Women's Health............................ 2167
Status of the Development of an AIDS Vaccine..................... 2186
The Investment in Minority Research Programs..................... 2196
The New Generation of AIDS Researchers........................... 2172
Three Percent Transfer Authority................................. 2166
Total AIDS Research Funding...................................... 2166
Training for HIV Researchers..................................... 2184
Witnesses, Introduction of....................................... 2155

Offfce of the Director and Buildings and Facilities

Administrative Cost Study........................................ 2264
Area Program..................................................... 2301
Behavioral Research.............................................. 2335
Budget Request for ORMH.......................................... 2338
Building and Facilities.......................................... 2257
Child Abuse and Neglect.......................................... 2324
Cholestin........................................................ 2262
Clinical Research Issues......................................... 2304
Concluding Remarks............................................... 2292
CRC Advanced Appropriations...................................... 2262
CRC Cost Estimates............................................... 2263
Credit Card Purchases............................................ 2303
Decrease in OD Funding Level..................................... 2323
Electronic Grant Submissions..................................... 2311
Employment Separation Rates...................................... 2345
Enrollment for Women's Health Initiative......................... 2308
Extramural Associates Research Development Awards Program........ 2328
Extramural Biomedical Facility Construction Research
Infrastructure................................................. 2344
Grant Scoring.................................................... 2310
Herbal Medications............................................... 2266
Inclusion of Women and Minorities in Clinical Trials...2309, 2332, 2347
Institute of Medicine............................................ 2343
Introduction of Witness.......................................... 2249
Justification of Budget Estimates................................ 2358
Listing of NIH Facilities........................................ 2290
MARC and MBRS Programs.......................................2270, 2334
Medical Nutrition Therapy........................................ 2266
Minority Health Initiative....................................... 2300
Minority Programs................................................ 2336
Funding for Minority Programs............................2338, 2345
Funding for Minority Researchers............................. 2271
Inclusion of Minorities in Research.......................... 2330
Increasing Minority Participation............................ 2327
Minorities in Clinical Trials................................ 2351
Minority Funding.........................................2270, 2291
Minority Research Grants..................................... 2272
Minority Researchers......................................... 2337
Recruitment and Retention of Minorities...................... 2350
Representation of Minorities in Research Protocols........... 2349
Underrepresented Minorities..............................2326, 2352
National Agenda on Research on Women's Health.................... 2269
National Biomedical Research Service Positions................... 2298
National Foundation for Biomedical Center........................ 2315
New Component for Women's Health Initiative...................... 2308
NIH Organizational Structure..................................... 2289
Office of Alternative Medicine.........................2265, 2318, 2323
Alternative Medicine Research................................ 2316
Office of Alternative Medicine Budget........................ 2301
Office of Alternative Medicine Clearinghouse................. 2302
Office of Behavioral and Social Sciences Research................ 2315
Office of Dietary Supplements.................................... 2266
Office of Research on Minority Health and NIEHS Collaborations... 2293
Opening Statement................................................ 2249
Opening Statement--Dr. Kirschstein............................... 2251
ORMH-Standing Advisory Committee................................. 2341
ORWH's Budget Level.............................................. 2268
Pediatric and Neurodegenerative Initiatives...................... 2306
Plans for New Institutes......................................... 2290
Progress of Minority and Women's Health.......................... 2326
Quotas........................................................... 2274
Radioisotope Contamination....................................... 2295
Radiology and Imaging............................................ 2262
Recombinant DNA Advisory Committee............................... 2314
Renovation of Clinical Center.................................... 2263
Research Needs of Children....................................... 2323
Research of Human Subjects....................................... 2313
Re-Submission of Unfunded Grant Applications..................... 2313
SBIR Grants...................................................... 2295
Science Education Activities at the NIH.......................... 2275
Senior Biomedical Research Service Positions..................... 2295
Status of Minority and Women's Health............................ 2326
The Ryan Commmsion............................................... 2316
Unified Information Technology System............................ 2264
Women and Minorities in Biomedical Careers....................... 2333
Women in Biomedical Careers...................................... 2269
Women's Health Initiative........................................ 2298
Adequacy of Spending on Diabetes................................. 2484
Advice In Decision-Making........................................ 2435
AIDS:
Expenditures for AIDS and Other Diseases..................... 2473
NIH Expenditures on AIDS Research............................ 2494
Research Coordination........................................ 2482
Research Funding............................................. 2495
Scientific Opportunity....................................... 2471
Stabilizing Infections....................................... 2494
Vaccine Initiative........................................... 2500
AIDS and Scientific Opportunities................................ 2471
AIDS Research Coordination....................................... 2482
AIDS Research Funding............................................ 2495
AIDS Vaccine Initiative.......................................... 2500
Areas of Emphasis................................................ 2485
Biography, William E. Paul, M.D.................................. 2468
Biography, Harold E. Varmus, M.D................................. 2459
Biography, Dennis Williams, Ph.D................................. 2470
Budget:
Constraints.................................................. 2436
Doubling NIH's............................................... 2497
NIH Budget for 1998.......................................... 2508
Budgetary Constraints............................................ 2436
Cancer:
Mortality Rates.............................................. 2488
Ovarian...................................................... 2501
Ovarian...................................................... 2503
Ovarian, Detection of........................................ 2490
Research Article............................................. 2489
Cancer Mortality Rates........................................... 2488
Cancer Research Article.......................................... 2489
Clinical Research............................................2501, 2502
Clinical Research Report......................................... 2505
Coding for Parkinson's Research.................................. 2477
Commitment Base..............................................2434, 2476
Committee Report Language........................................ 2472
Congressional Biomedical Research Caucus......................... 2475
Congressional Support............................................ 2503
Cost Savings from Research....................................... 2500
Criteria For Decision-Making..................................... 2434
Curriculum Vitae, Phillip Gorden, M.D............................ 2467
Curriculum Vitae, Richard Klausner, M.D.......................... 2460
Curriculum Vitae, Claude Lenfant, M.D............................ 2465
Detection of Ovarian Cancer...................................... 2490
Disease:
Imprecision of Coding........................................ 2435
Trans-NIH Categories......................................... 2478
Doubling NIH's Budget............................................ 2497
Drug Rehabilitation.............................................. 2506
Early Childhood Development...................................... 2506
Earmarks in DOD for Research..................................... 2507
Effect of Public and Congressional Input......................... 2499
Expenditures for AIDS and Other Diseases......................... 2473
Factors in Resource Allocation................................... 2492
Factors In Resource Allocation................................... 2472
Final Authority for Decision-Making.............................. 2486
Funding for Autism............................................... 2489
Funding for Population Research.................................. 2480
Genetics Research Opportunities.................................. 2496
Imprecision of Disease Coding.................................... 2435
Information Dissemination........................................ 2503
Information Dissemination of Reaearch Findings on Learning
Disabilities................................................... 2507
Information Transfer............................................. 2499
Information Transfer in Prevention............................... 2506
Information Transfer to Other Agencies........................... 2506
Learning Disabilities:
Research on.................................................. 2507
Information Dissemination of Reaearch Findings on............ 2507
Limitations To Planning Science.................................. 2434
NIH Budget for 1998.............................................. 2508
NIH Definitions of Selected Population Groups.................... 2479
NIH Health Funding By Group...................................... 2481
NIH Expenditures on AIDS Reaearch................................ 2494
NIH Resource Allocation Procedures............................... 2485
NIH Spending On Minority Initiatives............................. 2479
Nobel Laureates.................................................. 2474
Observations And Principles For Resource Allocation.............. 2433
One Percent Transfer Authority................................... 2486
Opening Statement of the Director NIH............................ 2433
ORWH's Priority Setting Process.................................. 2504
Ovarian Cancer................................................250, 2503
Pace Of Research................................................. 2437
Parkinson's Disease.............................................. 2436
Parkinson's Disease And Related Research Awards, FY 96........... 2457
Politics and Research............................................ 2501
Prepared Statement Of Director, NIH.............................. 2439
Priority Setting................................................. 2493
Priority Setting Interaction of ORWH and NIH..................... 2505
Public Relations for NIH......................................... 2482
Research on Learning Disabilities................................ 2507
Resource Allocation By NIH....................................... 2437
Science Cannot Be Purchased...................................... 2436
Stabilizing AIDS Infections...................................... 2494
Statement of the Hon. George R. Nethercutt, Jr................... 2484
Statement of the Hon. George Gekas............................... 2476
Statement of the Hon. Patsy Mink................................. 2490
Statement of the Hon. Constance A. Morella....................... 2498
Strategic Plan................................................... 2478
Technology Transfer.............................................. 2502
Trans-NIH Disease Categories..................................... 2478
Unanticipated Research Results .................................. 2496