[Senate Hearing 107-277]
[From the U.S. Government Publishing Office]
. S. Hrg. 107-277
PROMISE OF THE GENOMIC REVOLUTION
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HEARING
before a
SUBCOMMITTEE OF THE
COMMITTEE ON APPROPRIATIONS UNITED STATES SENATE
ONE HUNDRED SEVENTH CONGRESS
FIRST SESSION
__________
SPECIAL HEARING
JULY 11, 2001--WASHINGTON, DC
__________
Printed for the use of the Committee on Appropriations
Available via the World Wide Web: http://www.access.gpo.gov/congress/
senate
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COMMITTEE ON APPROPRIATIONS
ROBERT C. BYRD, West Virginia, Chairman
DANIEL K. INOUYE, Hawaii TED STEVENS, Alaska
ERNEST F. HOLLINGS, South Carolina THAD COCHRAN, Mississippi
PATRICK J. LEAHY, Vermont ARLEN SPECTER, Pennsylvania
TOM HARKIN, Iowa PETE V. DOMENICI, New Mexico
BARBARA A. MIKULSKI, Maryland CHRISTOPHER S. BOND, Missouri
HARRY REID, Nevada MITCH McCONNELL, Kentucky
HERB KOHL, Wisconsin CONRAD BURNS, Montana
PATTY MURRAY, Washington RICHARD C. SHELBY, Alabama
BYRON L. DORGAN, North Dakota JUDD GREGG, New Hampshire
DIANNE FEINSTEIN, California ROBERT F. BENNETT, Utah
RICHARD J. DURBIN, Illinois BEN NIGHTHORSE CAMPBELL, Colorado
TIM JOHNSON, South Dakota LARRY CRAIG, Idaho
MARY L. LANDRIEU, Louisiana KAY BAILEY HUTCHISON, Texas
JACK REED, Rhode Island MIKE DeWINE, Ohio
Terry Sauvain, Staff Director
Charles Kieffer, Deputy Staff Director
Steven J. Cortese, Minority Staff Director
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Subcommittee on Departments of Labor, Health and Human Services, and
Education, and Related Agencies
TOM HARKIN, Iowa, Chairman
ERNEST F. HOLLINGS, South Carolina ARLEN SPECTER, Pennsylvania
DANIEL K. INOUYE, Hawaii THAD COCHRAN, Mississippi
HARRY REID, Nevada JUDD GREGG, New Hampshire
HERB KOHL, Wisconsin LARRY CRAIG, Idaho
PATTY MURRAY, Washington KAY BAILEY HUTCHISON, Texas
MARY L. LANDRIEU, Louisiana TED STEVENS, Alaska
ROBERT C. BYRD, West Virginia MIKE DeWINE, Ohio
Professional Staff
Ellen Murray
Jim Sourwine
Mark Laisch
Adrienne Hallett
Erik Fatemi
Adam Gluck
Bettilou Taylor (Minority)
Mary Dietrich (Minority)
Administrative Support
Carole Geagley
Correy Diviney (Minority)
C O N T E N T S
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Page
Opening statement of Senator Tom Harkin.......................... 1
Opening Statement of Senator Arlen Specter....................... 2
Opening statement of Senator Larry Craig......................... 3
Prepared statement........................................... 4
Statement of Francis Collins, M.D., Ph.D., Director, National
Humane Genome Research Institute, National Institutes of
Health, Department of Health and Human Services................ 4
Prepared statement........................................... 7
Human genome sequence............................................ 7
Finishing the human genome sequence.............................. 8
Human genetic variation.......................................... 8
Gene expression.................................................. 8
Protein structure, function, and interaction..................... 9
Promise for new treatments and prevention........................ 9
Ethical, legal, and social implications.......................... 10
Predictions for the future....................................... 10
Statement of Philip Needleman, Ph.D., senior executive vice
president, Pharmacia Corporation............................... 14
Prepared statement........................................... 17
The human genome and innovative approaches to therapy............ 17
Alzheimers disease............................................... 18
Schizophrenia.................................................... 18
Kinase genes as targets for cancer treatment..................... 19
Therapeutic approach to colon cancer............................. 19
Statement of Stephen S. Rich, Ph.D., professor, Wake Forest
University School of Medicine.................................. 20
Prepared statement........................................... 22
Etiology of type 1 diabetes...................................... 22
Genetic basis of type 1 diabetes................................. 23
Search for type 1 diabetes genes................................. 23
Paths to gene discovery.......................................... 24
Promise of genomics.............................................. 24
Statement of Jeffrey C. Murray, M.D., professor of Pediatrics,
Biology, and Preventive Medicine, University of Iowa........... 25
Prepared statement........................................... 27
Statement of Ben Affleck, Actor.................................. 30
Accompanied by:
Brad Margus, president and co-founder, A-T Children's Project 30
Joe Kindregan, A-T patient................................... 30
Prepared statement of Ben Affleck................................ 33
Prepared statement Brad Margus................................... 35
My story......................................................... 35
Steps you could take to accelerate research...................... 38
PROMISE OF THE GENOMIC REVOLUTION
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WEDNESDAY, JULY 11, 2001
U.S. Senate,
Subcommittee on Labor, Health and Human
Services, and Education, and Related Agencies,
Committee on Appropriations,
Washington, DC.
The subcommittee met at 9:42 a.m., in room SD-192, Dirksen
Senate Office Building, Hon. Tom Harkin (chairman) presiding.
Present: Senators Harkin, Landrieu, Specter, Stevens, and
Craig.
opening statement of senator tom harkin
Senator Harkin. Good morning, and welcome to today's
hearing of the Labor, Health and Human Services, and Education
Appropriations Subcommittee on the promise of the genomic
revolution.
Back in the 1980's when people first started talking about
sequencing the human gene, no one expected that we would be
finished by now. Scientists thought it would take decades to
work through all 3 billion letters of our DNA code. But thanks
to people like Dr. Francis Collins, who will be our lead-off
witness here today, and thousands of researchers all over the
world, that goal was completed, as we know, last year.
Today, in fact, we can access our entire genetic
instruction manual from a single CD-ROM. So, here is my entire
lifetime right here on a CD-ROM. We can put the whole DNA
sequence right now on one CD-ROM. That accomplishment ranks as
one of the greatest intellectual achievements in our history.
And I am proud to say that this subcommittee, working in a
bipartisan effort, provided the funds to help make it possible.
But sequencing the genome is only the beginning of the
medical advances that lie ahead. Researchers are now turning to
the even more important task of reading the human genome to see
what clues it can offer for cures and treating of diseases. For
the first time, scientists have learned how to turn off the
mechanisms in a cell that cause cancer. They are producing
drugs like Gleevec, which is showing promising results in
fighting leukemia.
They are also figuring out why a drug might work wonders on
one person but have no effect on someone else with the same
disease. Just imagine: One day soon, with the help of a simple
genetic test, doctors will be able to prescribe exactly the
right drugs for a person's particular genetic profile.
Genomics will also revolutionize the way we prevent
diseases. We will be able to find out in advance which
conditions we are susceptible to so we can take steps to reduce
the risks.
But there is a darker side to this. What happens when
someone gets fired or loses their health insurance because of a
genetic predisposition to a certain disease? What is the value
of knowing that you have a predisposition to a certain genetic
disease if you are denied health insurance because of that very
information?
That is why we need to get legislation through that would
make it illegal for employers or health insurance companies to
discriminate against people because of their genetic makeup.
All of us should enjoy the benefits of 21st century
technologies without suffering from the hardship of 21st
century discrimination.
We have an outstanding panel of witnesses to discuss these
issues this morning. We have a very special guest here this
morning, who I am sure needs no introduction. Ben Affleck is a
tremendous actor who, as many of you know, won an Academy Award
for his first script, ``Good Will Hunting''. He has also
starred in other terrific films like ``Armageddon'' and
``Balance'', and ``Forces of Nature''. Of course, as I told him
earlier, he is now my envy as a fighter pilot. I always wanted
to fly the kind of fighters he flew in ``Pearl Harbor''.
But Ben is here this morning for a different kind of war,
the war against disease. He will testify this morning on the
promise of the genomic revolution. He will talk about a
terrible genetic disease called A-T that has stricken a young
friend of his, Joe Kindregan. As a celebrity, Ben could use his
fame for all kinds of purposes, but there are few causes more
noble than fighting on behalf of those who need medical help. I
want to thank him personally for being here with us this
morning and taking up this cause.
Before we turn to Dr. Collins, let me yield to my good
friend and person that I have worked together with on a
bipartisan basis to make sure we got the funding for the Human
Genome Institute from the very beginning, Senator Specter.
opening statement of senator arlen specter
Senator Specter. Well, thank you very much, Mr. Chairman. I
commend you for the outstanding work you have done on the
genome project and for your leadership in this very important
area.
It is truly amazing that the 3 billion units are now within
range of understanding the DNA makeup of the human body, and
the potential is limitless. So, it is really an extraordinary
accomplishment, and we have to utilize these opportunities to
the maximum extent possible.
This subcommittee has taken the lead over the past 6 years
in advancing the funding for research at the National
Institutes of Health. Senator Harkin and I introduced the first
amendment to the budget to add $1 billion for NIH, which was
defeated 63 to 37. We sharpened our pencils and found a way to
prioritize funding and provide $1 billion to increase the NIH
budget in the appropriations bill.
Having failed in our efforts to get an additional billion
dollars in the budget resolution, the next year we sought an
additional $2 billion for the NIH. And again, we were
unsuccessful, this time by a vote of 58 to 42. But again, with
sharpened pencils, we found the dollars in the appropriation
bill. That has progressed so that the funding for NIH has been
increased from $12 billion to now in excess of $20 billion.
Whereas the President has put in a hefty sum this year of an
additional $2.8 billion, it will require $3.4 billion to stay
on track to double the NIH funding over 5 years, which is our
goal and which we are determined to undertake.
But we are concerned as to limitations which exist in law
prohibiting the use of Federal funding to extract stem cells
from embryos. Senator Harkin and I introduced legislation on
that 2\1/2\ years ago when it became apparent that stem cells
have tremendous opportunities. In November of 1998, this
subcommittee held seven hearings, and now I believe we have
more than 70 votes, perhaps 75, maybe even more, to reverse
that prohibition.
In this morning's New York Times, there is a disquieting
story about scientists creating scores of embryos to harvest
cells, and where there is no legislation by the Federal
Government in the field to regulate what is being done to
liberate Federal funding for research at the NIH to be
conducted with ethical standards, then the marketplace free
enterprise proceeds and you have had these human embryos
created expressly for medical experiments, which raises very,
very profound ethical questions of propriety.
So, it is my hope that these issues can be addressed, if
not by the White House to liberate the prohibition against
Federal funding, then perhaps by the Congress if that is
necessary, because I do think we have the votes in the Senate,
and some 40 Republicans signed on to stem cell research in the
House. This is a matter which must be addressed very, very
promptly in my judgment.
Today's hearing is a very important one, along the lines of
what science can do, and those of us in the Congress, the House
and the Senate, ought to be doing our utmost to provide the
support and the funding to see that this will become a reality.
Permit me to extend my regrets that I cannot stay for the
entire hearing. I am due on the Senate floor at 10 o'clock for
a special order, and we have a very important hearing in the
Foreign Operations Subcommittee of Appropriations. So, I will
be here for a time and will be following the proceeds through
staff and through the transcript.
Thank you very much, Mr. Chairman.
Senator Harkin. Thank you very much, Senator Specter.
opening statement of senator larry craig
Senator Craig. Mr. Chairman, thank you for putting together
today's hearing on the Promise of the Genomic Revolution.
Last year, a rough draft of the human genome was announced
and ignited a worldwide fervor of the possibilities of this
achievement. This advance can help people live longer and
healthier lives. Diseases once thought incurable may soon be
detectable and curable early in life. The Human Genome Project,
by producing detailed maps of the 23 pairs of human
chromosomes, has already identified the genes responsible for
such diseases as glaucoma and cystic fibrosis.
However, this enormous accomplishment has raised ethical
and social questions related to genetic information. The
potential for misuse of genetic information has extremely
serious implications, especially in relation to privacy
concerns. Access to employment and health insurance are just
two of the areas that could be affected.
As advances in medical technologies are developed using the
mapping of the human genome, it will become increasingly
important to protect patient privacy rights. The challenge will
be to balance privacy concerns with the medical benefits of
this new technology.
Again, Mr. Chairman, thank you for looking at this
important and exciting issue. I look forward to hearing from
today's witnesses.
[The statement follows:]
Prepared Statement of Senator Larry Craig
Mr. Chairman, thank you for putting together today's hearing on the
Promise of the Genomic Revolution.
Last year a rough draft of the human genome was announced and
ignited a worldwide fervor of the possibilities of this achievement.
This advance can help people live longer and healthier lives. Diseases
once thought incurable may soon be detectable and curable early in
life. The Human Genome Project, by producing detailed maps of the 23
pairs of human chromosomes has already identified the genes responsible
for such diseases as glaucoma and cystic fibrosis.
However, this enormous accomplishment has raised ethical and social
questions related to genetic information. The potential for misuse of
genetic information has extremely serious implications, especially in
relation to privacy concerns. Access to employment and health insurance
are just two of the areas that could be affected.
As advances in medical technologies are developed using the mapping
of the human genome, it will become increasingly important to protect
patient privacy rights. The challenge will be to balance privacy
concerns with the medical benefits of this new technology.
Again, Mr. Chairman, thank you for looking at this important and
exciting issue. I look forward to hearing from today's witnesses.
STATEMENT OF FRANCIS COLLINS, M.D., Ph.D., DIRECTOR,
NATIONAL HUMANE GENOME RESEARCH INSTITUTE,
NATIONAL INSTITUTES OF HEALTH, DEPARTMENT
OF HEALTH AND HUMAN SERVICES
Senator Harkin. Our first witness, Dr. Francis Collins, is
the Director of the National Human Genome Research Institute
and the leader of the International Consortium of Scientists
for Sequencing the Human Genome. He has a Ph.D. in physical
chemistry from Yale University, an M.D. from the University of
North Carolina. Among many other accomplishments, he helped
identify the genes for cystic fibrosis and Huntington's
disease. He remains actively involved in research, and he has
directed the National Human Genome Research Institute since
1993.
Dr. Collins, welcome back to the subcommittee.
Dr. Collins. Well, thank you, Mr. Chairman and Senator
Specter. Thank you also for the kind remarks about genomics. I
want to say to both of you how much we at NIH appreciate your
very strong leadership in the support of medical research that
has brought us to this point and which, as we will be talking
about this morning, holds the promise of carrying us to truly
dramatic developments in the field of medicine. But none of
this would be possible without the strong support of the
Congress, and the two of you have taken a particularly bold
stand in that regard. And it is deeply appreciated, and it
makes a difference. In fact, I would say the investment that
you boldly made about 10 years ago in the human genome project,
even before many in the scientific community were completely
convinced, is paying off in a spectacular way that we will talk
about this morning.
I am honored to be here at this hearing with a number of
other distinguished witnesses who will outline some of the
consequences. Let me say that I am particularly pleased to be
here with Joe and his family. Joe who has ataxia-
telangiectasia, is a representative of the hundreds of
thousands, millions of individuals who have health consequences
of glitches in the DNA that we hope to learn more about an
ultimately to be able to cure.
Senator Harkin, you showed this CD-ROM containing the 3
billion letters of the human DNA code. It is remarkable that it
all fits. It took a special compression program that our
colleagues in Santa Cruz designed to be able to make that
information fit on a single CD-ROM.
It is amazing that this was possible in the time table that
it was. When I was a post-doctoral fellow 20 years ago, you
could get a Ph.D. for sequencing 1,000 letters of the code. In
order to do this, we had to sequence 1,000 letters a second, 7
days a week, 24 hours a day for a sustained period of about a
year and a half. What an amazing quantum leap forward in the
speed.
And that we did and it is all in the public domain. It is
free on the Internet. Most people do not use that CD-ROM. They
go to their computer and tens of thousands of them each day are
logged on to the databases using this information to advance
their understanding of disease. I keep an informal tally of
disease genes that are identified using this information. Just
in the last 2 years, it is over 50, and those are all diseases
that otherwise would still be trapped in a bottleneck of
ignorance but now are on the pathway towards understanding and
ultimate prevention and cure.
As another example of the speed with which things are
advancing, I spent most of my scientific effort in the 1980's
trying to identify the gene for cystic fibrosis. That effort
took a number of groups, including my own, about 9 years to
come up with the right gene.
About 4 years ago, we talked with considerable excitement
about finding a gene for Parkinson's disease. That took about 9
days' worth of effort with the tools that were there.
Just a few weeks ago, there was a publication in the
journal called Nature about finding a gene for a very important
problem involving the gastrointestinal tract, called Crohn's
disease. In that instance, the investigator simply had to go to
the Internet and look up the answer. So, less than 9 seconds
involved in finding the responsible gene.
So, 9 years to 9 days to 9 seconds. This is the kind of
advance in speed that we hope to see happen as a consequence of
the genome project.
As you will hear from Dr. Needleman, that has also resulted
in the fact that we now have not 480 drug targets, we have
30,000 drug targets. And the advances in that field are truly
dramatic.
But I think it is fair to say if you drew the time line of
genomics and you tried to say where are we, we are still at the
beginning. We have a fantastic foundation here with that
sequence of the human genome. We have the code but we need to
understand it. I like to say we are now in the decryption
business. We need to understand the cryptography of the genome
to be able to understand its role in health and disease and
then bring that to the clinic as quickly as possible. As a
physician, that of course is my major personal goal.
We are, in fact, at the National Human Genome Research
Institute, in the midst of a vigorous and intense effort to
engage hundreds of the brightest minds in the scientific
community, both public and private sectors, in planning a
visionary next phase of the genome project, building on this
current foundation. That will include a number of exciting, new
projects, such as building a comprehensive picture of how human
variation is organized in the genome, which is the way that we
are going to uncover the hereditary contributions to diabetes
and heart disease and the common cancers and mental illness and
multiple sclerosis and virtually every disease that has a
hereditary contribution.
We will also--and we had a very interesting workshop the
last 2 days about this--need to sequence the genomes of a
number of other organisms because they will inform the ability
to decrypt the human genome by the comparisons. We need to be
sure we are using our sequencing capabilities in the most
scientifically robust way.
We will be investigating the way in which proteins do the
work of the genes. The genes are the instruction book. The
proteins carry out the instructions. The field of proteomics is
now the effort to understand that in a global fashion.
Go with me, if you will, though, on the basis of these
research developments to what might happen in interaction
between a physician and a patient in the year 2015. Linda, age
34, mother of two, comes in to see her physician because maybe
for the first time she is beginning to think about the need for
good prevention in her own medical care. Her physician mentions
that now in 2015 there are a number of tests that are available
to predict her future risk of illness or to make an early
detection of a current illness. Fortunately, through the good
efforts of people like yourselves, in 2015 she need not fear
genetic discrimination because that was taken care of by the
Congress of the United States way back early in the current
century. So, she decides, yes, she would like to go through
this battery of tests.
The results indicate that she has an increased risk for
heart disease, which surprises her, because her cholesterol is
normal, but cholesterol is not everything. The good news is we
have in 2015 dietary measures to reduce that risk and
noninvasive methods to detect the first sign of actual disease
at which point drug therapy is available that is precisely
suited for her genetic situation.
Another thing on her report card. It turns out that she is
at increased risk for Alzheimer's disease. She is not as
surprised there. Her grandmother had recently died of the
disorder. In 2015--and Professor Needleman may very well say
more about this--we will have interventions available,
preventive strategies for Alzheimer's disease that I believe
will be amazingly successful, both drug therapies and even a
vaccine. So Linda, now at age 34 with no symptoms probably for
a couple of decades to come, now has an intervention to keep
that terrible outcome from occurring.
Finally and perhaps initially most alarmingly to her, one
of the tests done looked at actually the peripheral white cells
in her blood stream which are, in 2015, effectively the
canaries in the coal mine to tell you that something may be
awry, using those white cells as a signal of what is going on
within. They indicate that there is a high likelihood that she
has the earliest stages of ovarian cancer. A subsequent
laparoscopy does, in fact, reveal a very small nucleus of
cancer cells, only a few hundred in number, which are easily
removed. While she would not have developed symptoms for
another 2 years, had this test not been obtained, it is likely
at that point it would have been too late.
This kind of molecular surveillance, using genetic tools,
is not science fiction in the next decade or two. So, this
scenario, which I would argue is not at all outside the realm
of reality based on the trajectory we are now on, is a very
exciting one, focusing our medical efforts on preventions,
keeping people healthy.
I would like to conclude this with a quote from Sir William
Osler. He said this exactly 100 years ago: ``Osler is the
father of medicine in most people's view because he brought the
power of rational thinking to the field.'' When asked to
describe what is medical research, Osler said, ``To wrest from
nature the secrets which have perplexed philosophers in all
ages, to track to their sources the causes of disease, to
correlate the vast stores of knowledge that they may be quickly
available for the prevention and cure of disease, these are our
ambitions.'' Bold words a century ago. But we now have the
tools to make this happen. With your strong support and the
brightest minds of the scientific community, we can make
Osler's vision come true.
Thank you, Mr. Chairman. I would be happy to answer
questions.
[The statement follows:]
Prepared Statement of Francis S. Collins
Mr. Chairman, and Members of the Subcommittee, it is a pleasure to
be here today to discuss the recent scientific advances in genetics
that will lead to improved health, and the development of therapies to
treat various illnesses. First I would like to thank the Subcommittee,
and especially you Mr. Chairman and Ranking Member Specter, for your
commitment and determination to invest in the Human Genome Project and
other areas of basic biomedical research at the National Institutes of
Health. Today I would like to focus my remarks on the recent
developments in genetics in order to give you a sense of the great
promise this field of research holds for all of us. Today you will also
hear from patients and advocates who are fighting to find a cure for
genetic diseases. All of us have gained a powerful new set of tools
from the recent advances in human genetic research. As a physician who
has taken care of patients, and as a medical geneticist who has devoted
the last decade to the Human Genome Project, I know it is critical that
we move the great promise of basic research into the clinic as quickly
as possible, in order to make significant progress towards treating or
preventing these devastating illnesses.
human genome sequence
Last year, Human Genome Project scientists capped their
achievements of the last decade with a historic milestone--the complete
initial reading of the text of our genetic instruction book. This book
is written in an elegant digital language, using a simple four-letter
alphabet where each letter is a chemical base, abbreviated A, C, G, or
T. At present, more than 95 percent of the 3.1 billion bases of the
human genome are freely available in public databases. This is an
awesome step toward a comprehensive view of the essential elements of
human life, a perspective that inaugurates a new era in medicine where
we will have a more profound understanding of the biological basis of
disease and develop more effective ways to diagnose, treat, and prevent
illness.
Between March 1999 and June 2000 the international collaborators in
the Human Genome Project sequenced DNA at a rate of 1000 bases per
second, 7 days a week, 24 hours a day. After completing the working
draft of the human genome sequence in June of 2000, Human Genome
Project scientists and computational experts scoured the sequence for
insights. They reported the first key discoveries in the February 15,
2001 issue of the journal Nature. Among the findings were the
following:
--Humans are likely to have only 30,000 to 40,000 genes, just twice
as many as a fruit fly, and far fewer than the 80,000 to
150,000 that had been widely predicted.
--Genes are unevenly distributed across the genomic landscape; they
are crowded in some regions and spread out widely in others.
--Individual human genes are commonly able to produce several
different proteins.
--The repetitive DNA sequences that make up much of our genome, and
commonly regarded as ``junk,'' have been important for
evolutionary flexibility, allowing genes to be shuffled and new
ones to be created. The repetitive DNA may also perform other
important functions, and provides fascinating insights into
history.
finishing the human genome sequence
Because of the enormous value of DNA sequence information to
researchers around the world, in academia and industry, the public
Human Genome Project (HGP) has always been committed to the principle
of free, rapid access to genomic information through well-organized,
annotated databases. Databases housing the human genome sequence are
being visited by tens of thousands of users a day. Over the coming two
years, the HGP will increase the usefulness of the human genome
sequence to the world's researchers by finishing the sequencing to
match the project's long-standing goals for completeness and stringent
accuracy. More than 40 percent of the draft sequence, including two of
our 24 chromosomes, have already been finished into a highly accurate
form--containing no more than 1 error per 10,000 bases. Finished
sequence for the entire genome is expected by 2003.
human genetic variation
While the DNA sequence between any two individuals is 99.9 percent
identical, that still leaves millions of differences. For understanding
the basis of common diseases with complex origins, like heart disease,
Alzheimer disease, and diabetes, it is important to catalog genetic
variations and how they correlate with disease risk. Most of these are
single letter differences referred to as Single Nucleotide
Polymorphisms (SNPs). With a draft of the human genome sequence in
hand, the pace of SNP discovery has increased dramatically. In fiscal
year 1999, NHGRI organized the DNA Polymorphism Discovery Resource
consisting of 450 DNA samples collected from anonymous American donors
with diverse ethnic backgrounds. NHGRI has funded studies looking for
SNPs in these samples. The non-profit SNP Consortium came into being in
April 1999, with the goal of developing a high-quality SNP map of the
human genome and of releasing the information freely. Consortium
members now include the Wellcome Trust, a dozen companies (mostly
pharmaceutical companies), three academic centers, and NIH. This has
been remarkably successful, with 5 times more SNPs being contributed to
the public domain than the consortium originally planned. As of June
22, the public database that serves as a central repository for SNPs
has received 2,972,764 SNP submissions.
With the increased knowledge about human variation, the genetic
underpinnings of various diseases, including diabetes, are being
discovered. The recent discovery of a gene, calpain-10, whose
disruption contributes to diabetes, resulted from studies linking
diabetes with genetic variations across the whole genome and then in a
specific part of chromosome 2. The newly-discovered gene variant
suggests that a previously unknown biochemical process is involved in
the regulation of blood sugar levels.
gene expression
The new-found abundance of genomic information and technology is
propelling scientists out of the pattern of studying individual genes
and into studying thousands at a time. Large-scale analyses of when
genes are on or off (gene expression) can be used, for example, to
study the molecular changes in tumor cells. This exciting new approach
combines recombinant DNA and computer chip technologies to produce
microarrays or DNA chips. Classifying cancer on a molecular level
offers the possibility of more accurate and precise diagnosis and
treatment. Intramural researchers at NHGRI have used large-scale
expression studies to discover genetic signatures that can distinguish
the dangers from different skin cancers, and that can distinguish
between hereditary and sporadic forms of breast cancer.
protein structure, function, and interaction
We must remember that we are at the beginning of genomics era, not
the end. With a global view of human genes now possible, scientists are
eager to obtain a similarly comprehensive view of human proteins, a
field called ``proteomics.'' Researchers want to know the functions of
proteins and how the proteins work together in cells. Only a subset of
all possible proteins are present in any given cells at any given time.
To study protein function on a wide scale, various groups of
researchers plan to identify the locations of proteins, their levels in
different cells, their structures, the interactions among different
proteins, and how they are modified. NHGRI is contributing to this
field by developing technologies for efficient, large-scale analyses,
particularly for determining protein interactions and measuring protein
abundance in different cells.
promise for new treatments and prevention
With the availability of a comprehensive view of our genes, genetic
testing will become increasingly important for assessing individual
risk of disease and prompting programs of prevention. An example of how
this may work involves the disease hereditary hemochromatosis (HH), a
disorder of iron metabolism affecting about one in 200 to 400
Americans. Those with the condition accumulate too much iron in their
bodies, leading to problems like heart and liver disease and diabetes.
The gene causing the condition has been identified, allowing early
identification of those in whom HH may develop. Once people at risk are
identified by genetic testing they can easily be treated by
periodically removing some blood. The NHGRI and NHLBI are engaged in a
large-scale project to determine the feasibility of screening the adult
population for this very preventable disorder.
Genetic testing is also being used to tailor medicines to fit
individual genetic profiles, since drugs that are effective in some
people are less effective in others and, in some, cause severe side
effects. These differences in drug response are genetically determined.
Customizing medicine to a patient's likely response is a promising new
field known as pharmacogenomics. For example, a recent publication in
the journal Hypertension showed how pharmacogenomics applies to high
blood pressure. Researchers found a variation in a particular gene that
affects how patients respond to a commonly used high blood pressure
drug, hydrochlorothiazide. Other recent studies reveal that doctors
should avoid using high doses of a common chemotherapy treatment (6-
mercaptopurine) in a small proportion of children with leukemia.
Children with a particular form of a gene (TPMT) suffer serious,
sometimes fatal, side effects from the drug.
Genomics is also fueling the development of new medicines. Several
drugs now showing promising results in clinical trials are ``gene-
based'' therapies, where an exact appreciation of the molecular
foundations of disease guides treatment design. One of the first
examples is Gleevec (previously called STI571), produced by Novartis
for treating chronic myelogenous leukemia (CML), a form of leukemia
that mostly affects adults. CML is caused by a specific genetic flaw--
an unusual joining of chromosomes 9 and 22 producing an abnormal fusion
gene that codes for an abnormal protein. The abnormal fusion protein
spurs uncontrolled growth of white blood cells. Novartis designed a
small molecule that specifically inactivates that protein. In phase I
clinical trials, this drug caused dramatically favorable responses in
patients, while side effects were minimal. By targeting the fundamental
biochemical abnormality associated with this form of cancer, rather
than killing dividing cells indiscriminately as most chemotherapy does,
the drug offers better treatment results and fewer toxic effects on
normal cells. In May 2001, FDA approved Gleevec (imatinibmesylate, also
known as STI-571) for the treatment of Chronic Myeloid Leukemia after a
review time of less than three months. Meanwhile, Bayer and Millennium
announced the development of another cancer drug born of genomics in
January 2001. GlaxoSmithKline is testing a new genomics-derived heart
disease drug that targets a protein involved in fat metabolism.
Johnson&Johnson is testing a drug targeting a brain receptor identified
through genomics, and involved with memory and attention. Human Genome
Sciences has four clinical trials in progress to test gene-based drug
candidates.
ethical, legal, and social implications
From its inception, NHGRI recognized its responsibility to address
the broader implications of having access to genetic information and
technology. Since the inception of the Human Genome Project Congress
has provided funds for research to study the ethical, legal, and social
implications (ELSI) of genome research. To that end one of the greatest
areas of concern has been in the area of genetic discrimination.
Recently President Bush addressed this issue in his Saturday radio
address of June 23. In that address the President said, ``Just a few
months ago, scientists completed the mapping of the human genome. With
this information comes enormous possibilities for doing good. As with
any other power, however, this knowledge of the code of life has the
potential to be abused. Genetic discrimination is unfair to workers and
their families. It is unjustified--among other reasons, because it
involves little more than medical speculation . . . . To deny
employment or insurance to a healthy person based only on a
predisposition violates our country's belief in equal treatment and
individual merit . . . . Just as we have addressed discrimination based
on race, gender and age, we must now prevent discrimination based on
genetic information. My administration is working now to shape the
legislation that will make genetic discrimination illegal. I look
forward to working with members of Congress to pass a law that is fair,
reasonable, and consistent with existing discrimination statutes.''
predictions for the future
We must not ignore the ethical, legal, social, and the commercial
issues that genetic research raises, but the promise of this research
is great for alleviating human suffering. If research continues to
proceed vigorously, we can expect medicine to be transformed
dramatically in the coming decades.
We can predict that by the year 2010, predictive genetic tests will
exist for many common conditions where interventions can alleviate
inherited risk; successful gene therapy will be available for a small
set of conditions; and primary care providers will be practicing
genetic medicine on a daily basis. By the year 2020, gene-based
designer drugs are likely to be available for conditions like diabetes,
Alzheimer's disease, hypertension, and many other disorders; cancer
treatment will precisely target the molecular fingerprints of
particular tumors; genetic information will be used routinely to give
patients appropriate drug therapy; and the diagnosis and treatment of
mental illness will be transformed. By the year 2030, we predict that
comprehensive, genomics-based health care will become the norm, with
individualized preventive medicine and early detection of illnesses by
molecular surveillance; gene therapy and gene-based therapy will be
available for many diseases; and a full computer model of human cells
will replace many laboratory experiments.
Thank you Mr. Chairman. I would be happy to answer any questions.
Senator Harkin. Dr. Collins, thank you very much for an
outstanding statement and again for all of the wonderful work
you have done in leading this project from its very beginning.
We owe you a great debt.
I would now like to recognize our former chairman of the
full committee and our ranking member of the full committee now
who has graced us with is presence for any opening statement
that he might have. Senator Stevens.
Senator Stevens. Well, thank you very much, Mr. Chairman. I
am just surveying some of the hearings this morning. So, I
stopped for a little while. I appreciate listening to Dr.
Collins. Thank you very much, doctor.
Dr. Collins. Thank you, Senator, and we appreciate your
strong support for NIH.
Senator Harkin. Senator Stevens has been a very strong
supporter of NIH for a long, long time.
I just have a couple of questions and I would like to ask
you if you might just stay while I bring the other panel up.
Dr. Collins. I would be delighted.
Senator Harkin. I may have some follow-ups after the panel
comes up.
You sort of hinted at this but some people are under the
impression that the human genome project is over now that we
have completed a draft sequence. First, is that the case, and
if not, what is left to be done?
In your written testimony, you predicted that comprehensive
genomics-based health care will become the norm by 2030. Is
there any way that we can speed this up?
So, that is sort of two parts. What is left to be done and
can we speed it up?
Dr. Collins. Well, the sequencing of the genome, getting
those 3 billion letters all determined, was the most obvious
and visible goal of the genome project. But from the outset,
this has been a multi-component effort. While it is true that
most of the original goals defined in 1990 have now been
achieved or will be in the next couple of years, all the way
along, the ability to decode, to decrypt the information has
emerged as a new and important phase of the effort.
So, you might say we are experiencing an analogy to the
field of chemistry. We are now at the point of having defined
the periodic table of the elements. The periodic table for
human biology has elements that are the normal human genes. It
has isotopes which are the variants in those genes. But just as
one would have said the field of chemistry began with the
periodic table, I think it is fair to say the field of genomics
now begins with our own human periodic table of the genes.
Now, the important issues of how do they work and how do
they interact together and how are they affecting health and
disease can get underway in earnest. I view all of that as the
natural continuation of the genome project. In fact, genomics
now spills out into virtually every area of research. Some now
argue genomics has become the central science of medical
research that every institute at NIH is investing in in a big
way and, as you will hear later, in the private sector as well.
Senator Stevens. Mr. Chairman, may I ask just two
questions?
Senator Harkin. Sure.
Senator Stevens. Dr. Collins, when will your project be
completed?
Second, how soon will it be before the information that you
have developed in the project will trickle down and be
available to the family physician?
Dr. Collins. Actually deciding when the human genome
project is completed is a bit of a semantic question. You could
say that the original goals set in 1990 are close to being
completed, but at the same time the project has evolved.
Certainly genomics as a research enterprise has probably more
promise and more applicability now than it did 5 years ago and
certainly more than 10 years ago. So, it is a little hard for
me to know exactly what to call the human genome project
anymore. Maybe you will argue that we should be more precise
about that, and that is something that we are discussing a bit
with our advisors in terms of the definitions here.
Senator Stevens. Well, should we evolve it? Should we say
that it is more than the original project now?
Dr. Collins. Well, it has become so, as we have in the
process of deciding what our goals are, and we do that very
regularly, every 3 to 5 years, with input from hundreds of
scientists. If you look at the 5-year plan for 1990 and 1993
and 1998 and the one we are building now, we have added new and
exciting components along the way because of their scientific
opportunity. The genome project is not what it was at the
beginning. I think the way to do that is to ask the scientific
community, what are the opportunities here, and then let us go
after them. That is pretty much the strategy we followed.
As far as the availability to the primary care physicians,
this is a major area of concern because most physicians have
not had much exposure to the field of genetics. The
implications of this are very quickly going to come to pass.
Every physician in primary care is going to need to practice
genetic medicine in the relatively near future. Working with
the American Medical Association and the American Nurses
Association, we have a rather ambitious agenda for trying to
provide that kind of educational information so that doctors
and nurses will be in a position of being able to implement
these exciting new opportunities and not just confuse
themselves and patients by an unfamiliarity with the new area
called genetics. We have a lot of work to do in that regard,
but I think the medical community is enormously interested in
this. The American Medical Association identifies this as the
biggest advance since antibiotics, and they are clearly
motivated to get their members up to speed and ready to
practice this kind of medicine in the most effective way.
Senator Stevens. Well, I am afraid it is so esoteric that
rural America may be left behind in this first decade of this
new century.
Dr. Collins. Well, I worry about that, Senator. Yet, at the
same time, the esoteric aspects of genetics are partly the
scientists' fault, that we tend to enshroud these developments
in complex language and using large terms with too many
syllables. In my view, genetics is actually the simplest of the
biological sciences. It makes enormous sense. If you understand
a few principles, the rest of it kind of makes sense by
immediate deduction. But we have not done, necessarily, a very
good job of explaining that.
We have recently put out--and every high school biology
teacher in this country has now access to--and we have sent out
60,000 of these--an educational kit about genetics and the
genome project to get the next generation of consumers who are
currently juniors or seniors in high school ready to
incorporate this kind of information into their thinking about
their own health.
Senator Stevens. Sorry to belabor this, Mr. Chairman.
Will we be able to link the family physician, the primary
care provider, by telemedicine to centers where he or she could
get instant consultation.
Dr. Collins. Senator, I think that is a great idea and I
think that is in fact quite potentially viable because many of
the questions that need to be answered probably could be done
electronically. I envision a circumstance where primary care
providers are provided with the kind of information that
enables them to handle the basic level of interactions about
genetic questions, but when something more complicated arises,
they are going to have to have some connection, some way to get
advice, and I think the electronic telemedicine approach is
going to be the way to go. We have a limited number, but a very
well-trained group, of medical geneticists and genetic
counselors who I believe could provide that next level of
expertise, and we have to figure out how to organize the system
and make sure the services are reimbursed for so that it
actually happens.
Senator Stevens. Thank you very much.
Thank you, Mr. Chairman.
Senator Harkin. Thank you, Senator Stevens.
Dr. Collins, one last thing before I bring the panel up. We
read yesterday that the National Cancer Institute is going to
allow its researchers to pay for access to Celera Genomics
database. I would like to have your thoughts on that since NIH
already has access to its own database for free. So, I am
wondering why would NIH be willing to pay Celera for that
information. I do not understand that.
Dr. Collins. Well, I am glad for the question because I
think it has been a little confusing what really happened here.
Basically the NCI worked out with Celera what the terms would
be if one of their intramural investigators working on cancer
decided they wanted to subscribe to the Celera database. The
cost of that runs in the neighborhood of $16,000 per year. The
researcher would have to decide whether it was worth $16,000 to
them to gain access to this private database. The Celera
database, of course, has a lot of human sequence, but 95
percent of the human sequence is available in the public
domain. And I think relatively few investigators would find it
worth the cost to go to this alternative database because the
information is in fact very similar. The Celera database also
contains information about the laboratory mouse, but in the
public sequence databases, there is about 95 percent of the
mouse sequence.
I think therefore it is unlikely that any but a handful of
investigators will probably choose to sign up for this. But I
think the NCI was anxious not to put up some artificial barrier
for the small number of investigators who for some reason could
not find what they were looking for in the freely available
databases and felt it was worth their while to make this
investment. Time will tell how many of them actually decide to
take that step.
Senator Harkin. I see. So, it is not something that is
going to take place. It is just sort of if somebody wanted to
access it, what would the arrangement be.
Dr. Collins. Exactly.
Senator Harkin. Well, I guess I would have to follow up on
this. If researchers wanted to, I would want to know why, and
if they are using Government money to do that, if the data is
already available, I would like to know more about why that
would be the case.
Dr. Collins. I can understand your wanting to know those
answers, and perhaps with a little time going by, we will see
whether people actually do sign up and if so why, and if so,
did they get what they were looking for.
Senator Harkin. Right, exactly.
Dr. Collins, thank you very much. Now I am going to bring
the panel up. I wonder if you could just wait, maybe we might
have some additional questions later on.
Dr. Collins. I would be delighted.
Senator Harkin. Our panel includes Dr. Needleman, Senior
executive vice president and chief scientific officer for
research and development for Pharmacia Corporation. He will
discuss how pharmaceutical companies are translating basic
research into actual drugs.
Dr. Steven Rich, a professor of public health sciences and
a genetic epidemiologist at the Wake Forest University School
of Medicine. He specializes in type 1 juvenile diabetes.
Dr. Jeffrey Murray, Professor of Pediatrics, Biology, and
Preventive Medicine at the University of Iowa. He was the
principal investigator of the first human genome center at the
University of Iowa. He has served as a member of the NIH review
panel on ethical, legal, and social implications of the human
genome project.
And Mr. Ben Affleck, a movie star and a screen writer,
currently appearing in the film ``Pearl Harbor''.
Mr. Affleck. It sounds so pathetic after the rest of those.
Senator Harkin. Did I really have to introduce him as being
the star of----
Mr. Affleck. Ph.D., genetics expert, CEO, schmuck actor.
Senator Harkin. Now that I will take issue with.
As I said earlier, a few years ago, Mr. Affleck befriended
a boy with a fatal genetic disease called A-T, ataxia-
telangiectasia.
Mr. Affleck. I cannot even pronounce it. I call it A-T.
Senator Harkin. And he has taken up the cause of raising
awareness about it. This young man, Joe Kindregan, is here. Mr.
Affleck will be joined by Brad Margus, the President and Co-
founder of the A-T Children's Project. He is available to
answer questions also.
But what the heck. Can we bring Joe up too? Come on, Joe.
Why do you not join us? Maybe you sit between Mr. Margus and
Mr. Affleck. Bring Joe up here. We are proud to have you here,
Joe.
I would like to ask if you could keep your comments down
to, let us say, in the realm of about 5 to 7 minutes. Then we
can get through this. We can open it up for a general
discussion. Dr. Needleman, we will start off with you and
welcome to the committee.
STATEMENT OF PHILIP NEEDLEMAN, Ph.D., SENIOR EXECUTIVE
VICE PRESIDENT, PHARMACIA CORPORATION
Dr. Needleman. Thank you, Mr. Chairman. I think my role
here is to bring the industrial perspective of the implications
and the use of human genome data.
For a perspective, I have actually lived in both worlds. I
spent 25 years in academia at the Washington University Medical
School. I was the chairman of the Department of Pharmacology. I
had wonderful support from the NIH and have actively
participated in NIH study sections. I was on the Varmus
Advisory Committee and have a great affection and appreciation
for what has been done about the NIH. I am a member of the
National Academy of Sciences and the Institute of Medicine, and
I have spent the last 12 years in Pharmacia as the head of R&D
really in the translational research to bring these discoveries
into important drugs.
We prepared a document which I hope we could enter in the
record which describes at least four uses of the human genome
in the practical development of drugs, and I will just
highlight two of those issues.
To give you perspective, I have been doing biomedical
research in the drug hunt for 40 years. The first 20 years
could really be characterized in fact by the imprinting of the
NIH. So, in the 1960's and 1970's, the supported research into
the biochemical basis of diseases really led to the selection
of some protein targets, either enzymes or receptors, that
drugs were designed around. The fruit of the labors of those
decades were drugs in hypertension, in atherosclerosis, in
ulcers, in arthritis, and some drugs in the central nervous
system.
The next 20 years have been spectacular. There have been
profound advances in chemistry, in analytical chemistry, in
computational sciences, in cell and molecular biology, and most
recently and perhaps with the most attention, the availability
of genomic data in bacteria, in fruit fly, in roundworm, in
mouse, and in man now creates a tool kit to attack problems and
disease and drugs which were inconceivable to me and my
colleagues through much of our career.
Now, I would turn to a consideration of maybe two examples
to show you how the use of the human genome's implication is
not something far off in the future, but it happens now. I am
going to pick two, work in Alzheimer's and work in cancer.
In this devastating disease Alzheimer's, if you have an
unfortunate patient who died and analyzed the brain, what you
will see is that the nerves are surrounded by tangles of
proteins known as amyloid plaque which virtually crush and
destroy the nerves. Based on genetic mapping of mutations, two
mutations were found, the so-called Swedish mutation and the
London mutation, where that protein which was wrapped around
was characterized to be over-produced. It is a small 42 amino
acid protein and it is massively over-produced in these small
families that have genetic predisposition to early Alzheimer's,
and it is insoluble, that protein derived from a large protein,
which was floating around and innocuous. So, clearly the
disease process was hypothesized to be due to something that
was a scissor that cut the big protein into a small piece that
then gloms onto the nerve and then destroys it.
The nature of the protein told us at Pharmacia what kind of
enzyme could be the scissor. We then turned to the genome
database. Understand what Francis Collins says, having other
species gives you insight. So, we were able to turn to the
worm, C. elegans, and we found a family of enzymes that had
that property. Then when we hit those genes, we went to the
human genome and fished out a human gene for a similar enzyme.
We then took that gene and put it into mice and removed
that gene from mice. It was a 90 percent reduction in the
mice's ability to make this protein that would crush the
nerves. We then published that in Nature and put it immediately
into the public database.
I can tell you this is one of the hottest targets in the
entire pharmaceutical industry. We have dozens and hundreds of
scientists, molecular biologists, chemists, and others, and we
will be advancing a drug that will start and test the
hypothesis in Alzheimer's in a reasonable period of time. This
is a high urgency.
Second problem. Let us talk about colon cancer. The history
of that actually began in my NIH days when we were studying
what was the body chemistry of arthritis, and we discovered an
enzyme called cox-2, or cyclooxygenase, which is not present in
normal cells but is turned on by disease. It is a silent gene
and it has to be turned on. We went on and discovered the drug
Celebrex, now used in millions of people, which treats the
signs and symptoms of arthritis, but it is free of many of the
side effects.
Put that aside. We then had the genetic tools and the
proteins and antibodies which we used and we supplied to
academia. We quickly learned that every stage of colon cancer
has over-expression of the cox-2 gene and protein, and that is
not normally present in the colon.
Some very elegant work in other places, especially Johns
Hopkins, showed that many colon cancer patients have a mutation
of a gene called APC. In fact, there are only a couple of
thousand of patients in the world where they have inherited
mutation, and those poor children by 10 years old have
thousands of polyps in their colon. By 30, they have cancer,
and the median death age is in the 40's. Those polyps are
loaded with cox-2.
You could take that mutation now and genetically modify a
mouse and reconstitute that disease called familial adenomatous
polyposis, FAP. When you get the polyposis, you get the cox-2,
and Celebrex suppresses those tumors in mice.
Based on that, we did a large clinical trial for 6 months,
and the FDA has now awarded us approval for the first drug
Celebrex which is a nonsurgical treatment which reduces the
volume and the number of tumors in the FAP patient. But that is
just a couple of thousand.
The much bigger disease is colon cancer called SAP. In the
United States, there may be 90,000 to 100,000 new patients a
year; 50,000 deaths. It works out that almost half of those
patients acquire the APC mutation. They express cox-2, and now
we are doing trials in thousands of patients with Celebrex
based on the genomic information, based on the mouse data and
the FAP, and we will see if we can really do something with the
third most prevalent of the cancers.
So, the other examples in the text show how genetic
information has pulled out a schizophrenia marker, and then you
have talked about Gleevec. We used genetic information. There
are 500 kinases of the nature that Gleevec hits, of which we
now could reduce to a half a dozen which are possibly involved
in cancer.
So, in summary, I would say the availability of the human
genome, the wealth of information in science from the NIH and
now other foundations has really created a fairly awesome
circumstance. It is not hard to predict that:
No. 1, you will have new disease targets. Francis Collins
realizes we move by 10- to 100-fold the number of disease
targets.
No. 2, we can have genetically modified animals that really
recapitulate human disease.
No. 3, as you said in your opening statement,
pharmacogenomics, understanding the genetic information that
tells us why patients are variable in their response and what
are the subtypes of patients will now be possible, and we can
target individual therapy for those patients.
So, I would just close by saying that it is not hard for us
in Pharmacia to see real hope in Alzheimer's, for significant
advances in cancer and arthritis. With these spectacular
advances, we will change the nature of the disease and the
quality of life with these remarkable tools that we have.
Thank you, Mr. Chairman, for letting me share this with
you, and I would be glad to answer any questions.
[The statement follows:]
Prepared Statement of Philip Needleman
My role in today's proceedings is to provide an industry
perspective on the promise and utility of human genomic data. For your
information I am Chief Scientist of Pharmacia and Chairman of Research
& Development. Prior to joining the pharmaceutical industry (in 1989) I
spent 25 years in academia serving as Chairman of the Department of
Pharmacology at Washington University Medical School. My laboratory was
actively supported by funds from the National Institutes of Health. I
am a member of the National Academy of Science and the Institute of
Medicine.
I have been engaged in the drug hunt for novel approaches to treat
unmet medical needs for more than 40 years. When I started in the 60's,
the identification and development of a new drug was a hit and miss
affair. Often the target for the drug was unknown or its mechanism
enigmatic. Many drugs entered development wholly because they showed
activity in animal models. In this way advances in drug therapy were
incremental. Furthermore, the clinical assessment of new drug
candidates in man relied on ``traditional'' physician assessment, which
in many case had no relationship to the mechanism of action of the drug
or the pathology of the disease (if either were known). With time
studies of the biochemical and cellular basis of disease led to the
discovery of putative target proteins (enzymes and receptors) that
served as the basis for drug development. During that period (roughly
70's and 80's) important progress had been made in the treatment of the
signs and symptoms of a number of critical diseases including:
hypertension, atherosclerosis, ulcers, AIDS, arthritis and some nervous
systems disorders.
Modern therapeutic strategies emerged from NIH supported research
discoveries in academia and new drugs arose from the translational
research in industry that is required to advance a promising hypothesis
or lead to a safe, effective drug. The exciting scientific progress of
the last couple of decades has been remarkable and is highlighted by:
profound advances in chemistry; information technology and
computational power; the evolution and application of cell and
molecular biology, and most recently the solution of the genome
structures of bacteria, fruit fly, worm, human and mouse. This means we
can now focus our efforts on specific genes that might be suitable drug
targets. When we understand the disease mechanism we want to impact we
have much greater control of the whole drug development process.
Furthermore, because we can now easily compare the genomes of different
species we can be much more astute decisions about the relevance of
animal models in drug development. Genomics science has given us a
toolset of sufficient sensitivity to analyze tiny samples of human
tissue, looking for biological changes associated with drug response.
Without a doubt we are in the greatest period in the history of
biomedical research and these advances will enable us to attack the
most serious debilitating diseases, including: the central nervous
system diseases (Alzheimers; schizophrenia, and depression); the many
types of cancer; the deforming effects of severe arthritis; and
diabetes. These approaches were inconceivable during much of my
scientific career.
the human genome and innovative approaches to therapy
Diseases are caused by multiple genes and have both a genetic and
an environmental contribution. Hence it is important to know the genes
that constitute humans and also to know the exact DNA sequence (or code
of each gene) so that we can identify the changes that are responsible
for causation or modification of human disease. Clearly once we know
the genes that cause human disease, we can then devise therapies for
such diseases. Already, however, we at Pharmacia (and others) are
making significant in-roads in this regard. Pharmacia was one of the
early access partners that subscribed both to Celera and the public
database of the human genome. Some specific examples of how we are
using genomic information to discover and validate new targets (ie; the
smoking guns of the disease process) and how we are carrying out the
hunt for targeted mechanism based drugs will be briefly discussed.
alzheimers disease
The study of Alzheimers Disease is one area where we at Pharmacia
have been applying Genomics. This devastating disease is characterized
by the deposition of insoluble protein known as amyloid plaques that
coil into tangles around nerves ultimately destroying the brain cells.
These plaques are small fragments that are cut by functional scissors
from a larger inactive protein called Amyloid Precursor Protein (APP)
that in itself is biologically inactive. The cuts of APP are made by
enzymes called beta-secretase (1st cut) and gamma-secretase (2nd cut)
led to the neurotoxic fragment A-beta 42.
We have focused our study on this gene pathway. Families that have
mutation of genes in this pathway develop early onset Alzheimers
Disease. Examples of such mutations are the so-called APP Swedish gene
mutation and the APP London mutation which are found on human
chromosome 21, the chromosome that is extra in Down Syndrome who
develop Alzheimers-like plaques in their brains. These mutations
increase the production of the APP fragment (A-beta 42).
We wanted to identify the gene that served as the scissors, the so
called beta-secretase with a view that decreasing its activity would
reduce the production of the A-beta that forms plaques in Alzheimers
Disease. We searched the genomic database of worms (C.elegans) and
found a number of possible candidate genes that may function as the
beta-secretase (we had an idea that such a gene belonged to a specific
gene family). We then searched the human genome database and found the
corresponding human genes and these were tested for their function as
beta-secretase. (The gene was found and we published this information
in the prestigious journal ``Nature'' Vol 402: 533, 1999).
To prove that beta-secretase was important in the genesis of the
Abeta fragment we generated mice that have all of their genes intact
with the exception of the beta-secretase gene. The engineered mice that
lack secretase make less than 10 percent of the A-beta fragment that
accumulates in Alzheimers plaques. Hence providing powerful evidence
that turning down beta-secretase will reduce the production of the
noxious material that deposits in Alzheimers plaques. Importantly also,
we were able to show that the mice appeared normal thus suggesting that
we would not expect major toxicities from drugs that reduce beta-
secretase activity. We, like many companies, plan major clinical trials
in Alzheimer's patients with selective secretase inhibitors.
schizophrenia
Similarly we have found a number of new genes that may be important
in Schizophrenia. We have identified the location of novel genes from
the human genome sequence database that belong to a specific family of
genes. These genes are found in regions on human chromosomes that are
thought to harbor schizophrenia genes (these regions are identified by
studying families that individuals with the disease and others that are
disease free and identifying regions that track with the disease). Thus
these genes are candidates for targeting schizophrenia therapy.
We have further studied one of these genes (on material purchased
from the National Institute of Mental Health) and found a change (SNP =
Single Nucleotide Polymorphism) that occurs more frequently in
schizophrenic patients as compared with non-affected family members,
adding further evidence that this gene may be a target for
schizophrenia therapy.
In addition, it is clear to many of us in the industry that
patients vary in their response to drugs. A significant component of
this variation is likely to lie in the subtle changes we see between
different genomes. Through the discovery and utilization of single
nucleotide polymorphisms (as described by Francis Collins) we hope to
be able to identify patients best suited for certain therapies as well
as those who might be a risk when exposed to certain drugs.
We are on the first step of the way to personalized medicine, where
patients can be given the best therapy based on their condition and
gene background. Pharmacia was a member of the consortium that invested
in a Public effort which detailed approx. 800,000 SNP throughout the
genome and that this facility assists in enabling this type of research
both in academic and industrial settings.
If Genomics is the study of how genetic differences contribute to
disease, Pharmacogenomics is the science of how genetic variation
influences the efficacy and safety of medicines. Doctors have always
known that many medicines work differently in different patients.
Pharmacogenomics will tell us how and why.
At Pharmacia we have begun a pioneering program to find out how
genetic type influences outcome among people who take part in our
clinical trials. This is a long term and costly exercise but we believe
it will result in better, safer clinical trials and, in turn, better
targeted drug treatments for people with different genetic types. Our
aim is to improve human health and to produce new medicines that are
safer, have more predictable side effects and are more efficacious.
kinase genes as targets for cancer treatment
Kinase genes are a class of genes that have important function in
signaling cellular responses such as cell growth and multiplication.
Changes or mutations in these genes that make them more active and
which signal an enhanced rate of cell multiplication have been found in
several human cancers and in several cancer-causing viruses.
We at Pharmacia have searched the human gene database for novel
members of the kinase class with a view of investigating which of these
may be drugable targets for cancer treatment. Upon the completion of
the sequencing of the entire human genome and its assembly (sticking
together of the different pieces of the genome) we have now determined
that there are about 500 of kinase genes.
We have initiated the important task of evaluating which of these
kinase genes play a role in cancer formation as well as working out
what they normally do for a living. We have focused our search on
kinase genes that are too active in cancers with the idea that we may
develop drugs that could reduce their activity. An example of such a
kinase is the Vascular Endothelial Growth Factor Receptor (VEGFR). This
gene is involved in the formation of blood vessels (angiogenesis) which
the tumors need for a blood supply to keep them nourished. A drug that
inhibits blood vessel formation may therefore have therapeutic utility
in the treatment of cancers. One such drug that is in clinical trials
at Pharmacia targets the VEGFR. We also have several other drugs that
target different kinase genes in various tumor types at various stages
of our drug discovery program.
In addition, we have studied a family of kinases that appear to be
actively involved in the symptoms and progression of rheumatoid
arthritis and we have started initial clinical trials to establish the
safety and efficacious of these novel drugs.
therapeutic approach to colon cancer
Our studies into the underlying processes that cause the swelling,
pain and stiffness of osteo- and rheumatoid- arthritis led to the
discovery of a protein/gene called cox-2 (cyclooxygenase) that is not
present in normal stomach or colon tissue but is turned on by tissue
injury, inflammation, and various body chemicals released by disease
processes. We ultimately developed a mechanism-based drug, Celebrex,
that specifically inhibits the abnormal cox2, and which relieves the
signs and symptoms of arthritis with a much lower level of side effects
than pre-existing therapy.
These discoveries led to the availability of new analytical tools
which allowed us and several academic laboratories to identify the
presence of cox2 in precancerous, cancerous and malignant colon cancer.
Additional experiments demonstrated that colon cancer produced in rats
with chemical treatment was associated with the appearance of cox2 and
we found that Celebrex treatment suppressed the animal tumors.
Many human colon cancers are known to involve a change (mutation)
in the human tumor suppressor gene adenomatous polyposis coli or the
APC gene. This gene is known to be ``switched off'' in these patients
and hence these colon polyps grow unchecked. A mouse model where this
gene has been ``knocked out'' or switched off also develop colon polyps
analogous to that in humans providing compelling evidence that the loss
of this gene is causative for colon cancers. These transgenic mice with
mutated APC recaptiulate the genetic and the intestinal polyps of a
human precancerous colon cancer known as Familial Adenomatose Polyposis
(FAP). The polyps from the APC mutated mice indeed exhibited cox2
expression and, again, inhibition of cox2, either with Celebrex or by
the genetic elimination of cox2, reduced the number and volume of the
precancerous polyps. Based on the demonstrated presence of cox2 in
human colon cancer; and in chemically and genetically induced colon
cancer, we conducted a 6 month clinical trial in FAP patients and
Celebrex treatment reduced the tumor volume and size of the
precancerous polyps which resulted in FDA approval of the first non-
surgical treatment of this condition. These trials provide the
essential proof of concept for a major contributory role of this
protein in the initiation and progress of tumors. However, FAP is a
rare inherited disease which occurs in just a few thousand patients.
The much larger colon cancer population, the so called Sporadic
Adenomatosis Polyposis (SAP) results in about 50,000 deaths per year in
the United States alone. Many of these patients acquire an APC mutation
and exhibit elevated cox2 levels. Based on the successful FAP data and
the compelling data strongly suggest the involvement of cox2. We are
now in the midst of large, international, clinical trials in SAP
patients being treated with Celebrex.
conclusion
In summary, the availability of the human genome database, in the
context of the years of productive discovery that have arisen from the
funding of basic research by the NIH and other foundations provides
industry with a unique toolbox for novel drug development. The
implications are awesome. You can anticipate the identification and
validation of the targets that are the engines of disease. The
candidate genes will be useable both to make reliable animal models of
human disease and will provide the reagents to start the hunt for drugs
that will alter the targets and suppress or ameliorate the disease
process. Furthermore, genomic information provides the potential
markers that will allow the identification of disease subtypes and that
hopefully would allow rapid, small trials and which might predict
responders from non-responders. We therefore can look forward to
targetted, optimal, individualized therapy. Finally, I expect that our
efforts will be providing important new treatments that will change
patient anguish, suffering and especially their quality of life. I
foresee in our own Pharmacia efforts the prospects for: disease
modification in rheumatoid and osteoarthrits; in the progression of
Alzheimers; and leading to significant advances in the treatment of
cancer.
Senator Harkin. Thank you very much, Dr. Needleman, for a
very provocative statement. I mean provocative in terms of
making people think. I really appreciate it. A very good
statement.
Dr. Rich, we will turn to you now.
STATEMENT OF STEPHEN S. RICH, Ph.D., PROFESSOR, WAKE
FOREST UNIVERSITY SCHOOL OF MEDICINE
Dr. Rich. Thank you, Chairman Harkin. Again, I am Stephen
Rich and I am a professor of public health sciences at Wake
Forest University School of Medicine. I would like to mention
that I will come back to the issue of public health at the end
of my short presentation here. But I would also like to mention
I serve as the chairman of the International Type 1 Diabetes
Genetics Consortium, which I will also come back to, which was
mentioned by Dr. Spiegel some time ago.
What has actually been accomplished in the genetic basis of
type 1 diabetes? I will just give some perspective on that.
When I first took my faculty position at the University of
Minnesota, just north of Iowa I think, some time ago, in 1980,
very little was known about the genetic basis of type 1
diabetes. We and others spent about the next 7 years
understanding that there was probably a major gene that
contributes to the genetic basis of type 1 juvenile onset
diabetes in the region that contains the major
histocompatibility complex, or the HLA region, which is
involved in transplantation and autoimmunity. So, it made
sense.
Unfortunately, at that time in the mid to late 1980's there
really was not very much known about the genetics of that
region, and we did not have the genomics resources to really go
after the genes in those very complex regions. So, we turned
our attention to did this region really contribute to
everything that contributed to genetic risk of type 1 diabetes,
and it turned out it did not. We found out that there are
multiple genes that probably contribute in addition to how it
interacts with environmental triggers. So, we know that there
are things in the environment which trigger this autoimmune
cascade that causes type 1 diabetes. So, it is the interaction
of genes and environment that really is the fundamental basis
of how this disease gets started in kids and why this is the
third most common chronic disease in children.
So, we then decided to try to find those additional genes.
In the early 1990's, it was very difficult because there still
was not the genomics material available to allow us to do that.
They were being developed, but it was only with the advent of
the human genome project that we were able to scan the entire
genome to try to find out where in the genome were potential
genes that could cause increased risk for type 1 diabetes.
This was actually a major breakthrough from the standpoint
of science of genetic basis of chronic disease or other
diseases. In the early 1990's, we began making progress. At the
same time, we were not able to find those specific genes. The
reasons were really twofold. First, we became convinced that
individual scientists working as individuals could not have
sufficient resources to track down these genes. Second, it
became apparent that the genomics material were at not the
stage to allow us to identify specific genes.
So, it has only been in the last few years that we have
been able to, No. 1, decide that united we stand and can
succeed, divided we fail. So, we formed the Type 1 Diabetes
Genetics Consortium of investigators across the world who are
interested in finding genes that cause risk for type 1
diabetes. This will allow us to collect approximately 2,500
families with two children with type 1 diabetes, two parents,
an additional child unaffected with diabetes to reform the
genome screen, to look through the entire genome to find these
genes, at least the regions, and then use the material that the
human genome project has provided us in the sequencing of the
DNA to start looking more closely at what is actually there.
This will allow us to continue to search and to characterize
these genes to help decide who is at increased risk.
Now, remember that I mentioned earlier that type 1 diabetes
is probably an interaction. It is not just genetic risk. There
are environmental triggers that cause this cascade of problems
in the pancreas that in susceptible people lead on to diabetes.
So, with the genes in hand, we can then decide what are those
environmental risk factors and then decide on a public health
basis individual screening.
Now, this gets at two issues. As Dr. Collins mentioned, you
need to take the findings from the bench to the clinic. From a
public health standpoint, we want to take the findings from the
bench to the clinic and to the community. That is where we can
actually then process our knowledge of genomics and our
knowledge of the environment and determine who really is at
risk genetically and define the interventions, as well as
defining the drug targets and the new therapies.
So, I know that the support of this committee has been
crucial in development of the genomics initiatives and the
initiatives for the Diabetes Institute to continue with the
research and the genetic basis and finding cures for diabetes
and complications. I would just like to end by saying that
timing is everything. I think we are at the stage now where the
timing for continued support in the genomics initiatives and
timing for support in the diabetes initiatives will certainly
lead us in the next, I would say, 10 years to understanding
better this terrible disease in children and hopefully come up
with a means for identifying those at risk and hopefully curing
this disease.
Thank you, and I would be happy to answer any questions.
[The statement follows:]
Prepared Statement of Stephen S. Rich
Mr. Chairman, and Members of the Subcommittee, it is an honor to be
asked to discuss with you the prospects of using the tools of the Human
Genome Project to gain an understanding of the genetic basis of type 1
diabetes and its complications. My name is Stephen Rich and I am a
Professor of Public Health Sciences and a genetic epidemiologist at the
Wake Forest University School of Medicine. I am also the Chair of the
Type 1 Diabetes Genetics Consortium and a member of the Juvenile
Diabetes Research Foundation Medical Science Review Committee.
Today I would like to focus my comments on genetic complexity of
type 1 diabetes and the accelerating progress made in understanding
genetic predictors of disease risk. I also want to describe to you the
role that the Human Genome Project has played in serving as a catalyst
for genome research in type 1 diabetes, and how we are now at a
critical phase in this research. Finally, I will present to you the
problems that need to be resolved to identify genes for type 1 diabetes
and how continued support of the National Institutes of Health,
particularly the National Human Genome Research Institute (NHGRI) and
the National Institute of Diabetes & Digestive & Kidney Diseases
(NIDDK), can address these problems.
introduction to the problem
Type 1 diabetes is the third most common chronic disease in
children, estimated to affect over 120,000 in childhood and about
300,000 to 500,000 Americans of all ages. There are about 30,000 new
cases of type 1 diabetes each year. In addition, there is growing
evidence that the number of new cases of type 1 diabetes is increasing,
perhaps by as much as 5 percent per year. All children are at risk of
type 1 diabetes (although the highest incidence is among Caucasians,
followed by Mexican-Americans and African-Americans) and the
complications of type 1 diabetes. Although the economic impact of type
1 diabetes is large (over $40,000 per case), the medical and social
impact on the person with type 1 diabetes and their families is
enormous.
In contrast, type 2 diabetes is a highly prevalent disease of
adults, with over 8 million individuals diagnosed with disease, a
prevalence rate of 3 percent of the population of the United States.
The incidence of type 2 diabetes appears to be increasing, with the
concomitant increase in obesity and physical inactivity in adults and
children. As is the case of type 1 diabetes, the risk of type 2
diabetes is present for all ethnic groups, although the non-Caucasian
populations appear to be at higher risk of disease. Mortality in people
with type 1 and type 2 diabetes is usually from the complications of
disease. Diabetes, and particularly diabetic retinopathy, is the
leading cause of new cases of blindness in the United States. It is
estimated that 12 percent of new cases of blindness are attributable to
diabetes. Neuropathy, the inflammation and degeneration of peripheral
nerves, occurs in nearly one-third of type 1 diabetic subjects.
Diabetes now accounts for almost 40 percent of all new cases of end-
stage renal disease in the United States, and persons with diabetes
make up the fastest growing group of renal dialysis and transplant
recipients. Diabetes is also a leading risk factor for atherosclerosis,
myocardial infarction and stroke. Elimination of type 1 and type 2
diabetes will necessarily eliminate diabetic complications.
etiology of type 1 diabetes
Type 1 diabetes was described more than 2,000 years ago by Aretaeus
of Cappadocia (150 A.D.) who described the disorder as ``. . . a moist
and cold wasting of the flesh and limbs into urine . . .; the secretion
passes in the usual way, by the kidneys and the bladder.'' The role of
the pancreas in diabetes was defined in 1889 by von Mering and
Minkowski, which led to the discovery of therapeutically active insulin
for the treatment of human diabetes. Epidemiological studies, beginning
with those by Elliott Joslin in the 1920's, but clarified by others in
the 1980's, demonstrated that type 1 diabetes clustered in families. At
the same time, immunological studies found that the autoimmune
destruction of pancreatic islets in type 1 diabetes was a chronic
process that could be slowly active for years prior to development of
clinical disease. Evidence of the importance of genetic factors in the
etiology of type 1 diabetes came from twin and family studies, in which
it was estimated that nearly one-half of the risk for type 1 diabetes
was due to genetic factors. Finally, an association was established
between risk of type 1 diabetes and variants of genes in the human
major histocompatibility complex (MHC), confirming the importance of
genetic factors on risk.
The etiology of type 1 diabetes remains unresolved. The
environmental factors that are required to ``trigger'' the autoimmune
destruction of pancreatic islets have yet to be identified. The genetic
factors that determine an individual's level of susceptibility to
environmental triggers are known to exist, yet most have not been
isolated. It is also likely that the interaction between an
individual's genotype with environmental exposure is important in
determining ultimate risk. Thus, type 1 diabetes is an example of a
complex genetic disease. However, given the progress made to date in
genetics of type 1 diabetes and the tools now available from the Human
Genome Project, there are data suggesting that these genes can be
identified. Type 1 diabetes may serve as a model for use of genomic
tools to understanding disease etiology, prevention, treatment and
cure.
genetic basis of type 1 diabetes
Type 1 diabetes clusters in families. The risk of diabetes in a
sibling of a person with type 1 diabetes is about 8 percent, compared
to a risk of 0.5 percent in the general population. This 16-fold
increase in risk is attributable to multiple genes, including those in
the human major histocompatibility complex (MHC) that account for
nearly one-half of the genetic susceptibility. The complexity of the
genes in the human MHC (on chromosome 6) is only now being understood,
due to the available DNA sequence data obtained through the Human
Genome Project.
Genes that confer risk for (or protection against) type 1 diabetes
also exist outside the human MHC. The availability of highly
polymorphic genetic markers (that is, a gene with alternate forms) have
made genome-wide searches possible for a number of complex human
diseases. Type 1 diabetes was one of the first diseases to be explored
in this fashion. To date, three groups have used large numbers of
polymorphic genetic markers to scan the genome at regular intervals
(roughly every 10 million base pairs of DNA sequence) in families with
type 1 diabetes. These ``genome-wide searches'' for type 1 diabetes
susceptibility genes have been performed with varying number of
families and with different level of success. The results confirm the
presence of at least one type 1 diabetes genes in the human MHC on
chromosome 6. Another gene may likely be near the insulin gene on
chromosome 11. Based upon the individual data, the number and location
of additional risk genes has been difficult to determine. In order to
maximize the available genetic data, the individual researchers have
agreed to collaborate on an international scale to help find the genes
responsible for genetic risk of type 1 diabetes. This collaborative
effort is being supported by the NIDDK and the JDRF, and has resulted
in the establishment of the Type 1 Diabetes Genetics Consortium. The
Consortium currently is combining all available genome screen data for
type 1 diabetes in order to identify potential regions of importance,
but recognizes that a much larger set of human and genomic resources
are needed to identify genes. A similar consortium, supported by the
NIDDK, is underway for type 2 diabetes.
search for type 1 diabetes genes
While specific regions of potential interest have been identified,
it has become apparent that the number of families to be collected to
provide adequate statistical power to detect type 1 diabetes genes is
much larger than originally anticipated. Recent evaluation of research
needs have estimated that 2,400 families will be needed to successfully
scan the human genome for type 1 diabetes genes. To collect the
required 2,400 families (with two parents, two children with type 1
diabetes, and one child without diabetes), to obtain important clinical
and immunological data and to perform the genome-wide search, a major
collaborative research effort will be required. This first phase of the
genome search will be followed by a collection of 5,000 families (with
two parents, one child with type 1 diabetes and one child without
diabetes), in which the resources of the Human Genome Project will be
used to narrow our region of search. Finally, the DNA and clinical
resources collected through the Consortium will be made available to
scientists to identify the genes responsible for type 1 diabetes
genetic risk. The Consortium represents an outstanding example of
public-private partnership in scientific discovery for the improvement
of public health.
paths to gene discovery
The purpose of the Type 1 Diabetes Genetics Consortium is multi-
fold. The first purpose is to collect human materials in a consistent,
ethical, and standardized manner that will expedite the identification
of disease susceptibility genes. Collection by individuals using
different protocols fail in the size of the sample collected and in the
ability to provide a common framework for sample distribution and data
collection. Having a large resource of materials that provide adequate
statistical power to discover genes has yet to be accomplished for type
1 diabetes, or other common diseases. The collection of human resources
is expensive but represents a necessary first step.
The application of existing genomic technologies is the second step
in discovery. The Human Genome Project has made available the reagents
available for the genome-wide search. Through the remarkable public-
private partnership called The SNP Consortium, there are now genetic
maps of densely spaced SNP markers that make the search for genes more
efficient. Importantly, these resources are freely available and in the
public domain. The technology for using the SNP maps is still evolving,
however, and continued support for automation and development of high
through-put technologies is needed to enable a rapid evaluation of
specific intervals in the human genome.
Development of future genomic technologies is a critical third
step. The search for genes currently requires scanning hundreds, if not
thousands, of SNP variants within a given genetic region to determine
which of many small genetic segments require further exploration. The
continued efforts of the Human Genome Project to formulate a genetic
map of conserved chromosomal segments (a ``haplotype'' map) would
facilitate an efficient screening of these candidate regions that
contain type 1 diabetes susceptibility genes. Ultimately, the
``currency'' of the Human Genome Project, the DNA sequence, will be
critical to identify those genes that affect risk of type 1 diabetes.
In that regard, it is critical that NIH efforts to sequence the genomes
of other organisms such as the mouse and the rat go forward with all
due haste. The comparison of human sequence to mouse and rat sequence
will help us pinpoint the critical regions of our own genome. In
addition, support of the animal research will accelerate the
development and exploration of better animal models of diabetes for
testing of interventions and new therapeutics.
promise of genomics
The outcome of the Type 1 Diabetes Genetics Consortium, using
resources and reagents from the Human Genome Project, will lead to the
discovery of potential type 1 diabetes susceptibility genes. This
outcome will represent the ``end of the beginning'' in genetics of type
1 diabetes. The next phase of research will focus on the function of
the candidate genes, the way they act (both in isolation and in concert
with other susceptibility genes) to increase genetic risk of type 1
diabetes, and how they are affected by environmental exposure to cause
the autoimmune cascade. The manner in which the genes interact and the
way in which the proteins are modified to increase or decrease disease
risk will require new and emerging technologies that are the future of
genomics and proteomics. These investigations will likely continue the
productive partnerships already established between the public (NIH)
and non-profit foundations.
The understanding of the genes and the gene products and their
interactions will lead to improved risk prediction based upon genotype,
not just family history and presence of immune markers. This knowledge
will permit more efficient clinical trials of compounds developed using
genomic information that holds the promise of prevention of type 1
diabetes. An example of the infrastructure for development of these
clinical trials is TrialNet, supported by the NIDDK. TrialNet
establishes a consortium of clinical centers and core support
facilities that would perform intervention studies to preserve
pancreatic beta cell function for the purpose of preventing type 1
diabetes. In early stages of molecular medicine, knowledge of genetic
risk and the identification of the environmental triggers could
establish vaccination against (for example) a virus that acts as the
autoimmune ``trigger''. Thus, the knowledge of genetic risk would first
establish a pathway to prevention against exposure. As scientific
knowledge expands, a ``genetic vaccine'' could be made available which,
in combination with the protection from environmental exposure, could
eliminate an individual's risk of type 1 diabetes.
There are enormous potential benefits of genomic research to
individuals who may carry a ``genetic load'' for type 1 diabetes, and
it is important for this research to go forward quickly. However, a
major impediment to participation in genomic investigations is the
participant's concern about potential discrimination based upon genetic
information and violations of genetic privacy. Assurance of legal and
social protection of an individual's rights from genetic discrimination
will increase participation in genetic studies, facilitate gene
discovery and enhance evaluation of novel therapeutics in clinical
trials. The use of molecular medicine and genomic public health
approaches will facilitate individual genetic risk assessment and pre-
symptomatic treatment of complex human disease. The potential to bring
an end to type 1 diabetes and its complications is real and possible,
with your continued support.
Thank you Mr. Chairman. I would be happy to discuss any questions
that you or others may have.
Senator Harkin. Dr. Rich, thank you very much for all your
work on type 1 diabetes.
Now we turn to Dr. Murray, Professor of Pediatrics at the
University of Iowa. Dr. Murray.
STATEMENT OF JEFFREY C. MURRAY, M.D., PROFESSOR OF
PEDIATRICS, BIOLOGY, AND PREVENTIVE
MEDICINE, UNIVERSITY OF IOWA
Dr. Murray. Well, Senator Harkin, I would also have to lead
out by thanking you and the committee for the wonderful support
that you have given to NIH and the other health related Federal
agencies over the years. With the self-effacing Mr. Affleck on
my left, I would also have to say that I guess I am the simple
country doctor representative that is here.
I have had the opportunity to work as a pediatrician in
both our nurseries and our genetics clinics at the university
for about 15 years now. I would like to tell you two quick
stories about patients that I saw just last week whose lives
have been very much impacted by the genome project.
The first is Rebecca and she is a 2-year-old now, who I
first saw when she was 1 day of age, who was admitted to my
nursery for a combination of birth defects that included heart
problems and inability to move her legs. Rebecca's dad is a
minister and her mom is a teacher, and she has four older
brothers and sisters. Over the last couple of years, through
the combined efforts of a number of different physicians and
nurses, we have been able to improve her life.
When I saw her a week ago, her older brother asked me, as
he had once before, if I knew what the cause of Rebecca's
problems were, and I can genuinely and honestly say that 5
years ago I would not have been able to give him an answer. But
just in the last several months, in fact particularly through
the efforts of Dr. Collins' colleague, Eric Green, at the
Genome Institute in Bethesda, we have been able to show that a
very small region on the end of chromosome 7 is missing in
Rebecca and is responsible for this collection of birth defects
that she has.
Now, while this finding by itself is not going to directly
lead to improvements or a cure for what she has, it does
provide answers for her family that they are very genuinely
seeking, and in fact, it will enable her brothers and sisters
to understand what their own reproductive risks might be when
they become older. This kind of advance is entirely due to the
very powerful resources that are available through the computer
databases and the CD that you hold up there that enable us to
look at this genetic material in a very, very fine way.
To Senator Stevens, who asked earlier about the impact on
family physicians, we have also been able to share this
information with Rebecca's family doctor in Cedar Rapids, and
he has been very appreciative of the larger body of knowledge
that he now has as well.
A second patient that I have spent a lot of time with is
Sam. Sam was born with a kind of a neural tube defect. The most
common description is something called spina bifida or an open
spine. Sam is also from Iowa, from Solon, and has had very,
very terrible mental retardation and movement problems as a
result of this.
Now, as we have just heard from Dr. Rich, the genome
project not only teaches us about genetics, but it also helps
us to understand how genes and environment interact with one
another. In the last 2 years, there has been an amazing success
story that is built off of the genetic findings of the genome
project and coupled with the work that epidemiologists and
private volunteer organizations such as the March of Dimes have
done.
We have known for several years now that folic acid, a
common B vitamin, can be used to prevent spina bifida and
related birth defects if the mother takes it beginning before
pregnancy occurs. Starting 2 years ago, the FDA mandated that
all enriched cereals and breads in the United States be
supplemented with folic acid, much in the way that vitamin D is
put in milk.
In these last 2 years, there have now been, as shown in a
report that came out a month ago from the CDC, 1,000 fewer
babies born with spina bifida in the United States. This is an
amazing achievement and the fact that there are now 1,000
healthier, happier, wonderful children running around who do
not have to suffer the pain and expense of this terrible
disability is an amazing preventive success story.
Just as Dr. Collins and Dr. Rich have told us, we now have
the opportunity to use these genomic advances to understand not
only things that we will be converting into treatments and
preventions 15 years from now, but ones that we can do today
and tomorrow and the next day. This is really a marvelous
benefit for someone like myself and I think for all of us who
have family members who might be affected with these kinds of
disorders.
I do want to also sound a couple of cautionary notes. You
brought several of these up in your introductory statements.
First of all, we need to, as you have said, temper our
enthusiasm for the excitement of these findings with concerns
about how the information might be used. When I was a member of
the Ethical, Legal, and Social Panel, we frequently had
families ask us about whether this information was going to be
used in a way that could discriminate against them in either
employment or for insurance purposes. You and others have
already made efforts in trying to minimize and limit the kind
of discrimination that can take place. But I think that this is
still a concern, and again, as Dr. Collins told us, we need to
be very vigilant that this kind of information is not used
against the very families that it is designed and meant to try
and help.
A related area to this is in the area of research that many
of us here on this panel are directly involved in and patients
who will benefit from that research. Scientists and physicians,
such as myself and others up here today, need to have access to
the families, to have families voluntarily participate in these
kinds of studies in a way that that information can be used to
be converted into the kinds of treatments and preventions and
cures that they would like to have.
At the same time, the families need to be reassured that
that information is not going to be used against them in some
way. So, scientists and physicians need to have access to
databases, the information and the DNA samples that are
contained in those, in an easy way that allow them to pursue
their scientific investigations. Families need to go through an
important process of informed consent where they give their
full and open permission to participate in these studies. And
then those same families need to be protected so that the
information contained in these research databases is not
misused in any way.
Then finally, also as we hear alluded to today as well, for
some of the findings that are taking place today, it may not be
a year or two, but it may be 5 or 10 or 15 years before the
findings are converted directly into those treatments and
preventions. We as scientists and physicians need to be careful
that we do not over-promise to families, that the fruits of the
genome project will all immediately be converted into cures and
treatments.
All of us recognize here in this room that the genome
project is also an international effort, and that involves not
only the people in the United States but many other countries
as well. It also involves many other kinds of organisms, and we
have heard that from Dr. Needleman.
The health problems of the world today include not only
things that the genome project will directly solve, but are
still built around things such as unsafe drinking water, poor
nutrition and treatable or preventable infections like HIV or
measles. So, at the same time that we are taking advantage of
these very powerful immediate advances, we need to also ensure
that the genome project is applied in a beneficial way across
all strata of society and everywhere.
Again, I want to thank you and the committee for the
wonderful support and job that you have done over the years for
NIH and the CDC and the other Federal organizations. As a
genuine practicing physician and one who really on a daily
basis gets to see these applications put into direct practice
for families, as Dr. Collins has told us, we are really at the
beginning of the genome project, not the end of the genome
project. Now we have the opportunity to convert these very,
very wonderful findings into things that are going to benefit
all of us and even more importantly I think our children.
Thank you.
[The statement follows:]
Prepared Statement of Jeffrey C. Murray
First, I would like to thank you, Senator Harkin, and the other
members of the panel for the opportunity to speak with you today. I am
a pediatrician and a molecular biologist who has spent the last 20
years of my career caring for children with prematurity and birth
defects and working in the laboratory to better understand the genetic
and environmental causes of these terrible disorders. For the last two
days, I have been attending a meeting in Bethesda, sponsored by the
Child Health Institute. This meeting brought together investigators to
see how advances in the genome project can be put to use to decrease
the terrible impact of birth defects. Birth defects afflict one in
thirty newborns and can lead to a lifetime of disability. Just last
week, before leaving for this meeting, I was seeing patients in our
genetics clinic. One is Rebecca, a now two-year-old girl I first took
care of in the intensive care nursery at our university and who is the
youngest of four siblings born to a minister father and teacher mother
in Marion, Iowa. At birth, Rebecca had several different birth defects
that prevented her from moving her lower legs and also affected her
bowels and her heart. Through the combined efforts of many physicians
and nurses caring for her, she now has a life that is far better than
could have been anticipated even a decade ago. Her parents and oldest
brother asked me what caused Rebecca to be born like this. Five years
ago, I would not have had an answer, but now I can say that through the
advances in the Human Genome Project, we have been able to identify a
very specific region on chromosome number seven that seems to be
missing in Rebecca. While this information by itself will not change
the care that we provide for her, it does provide answers for her
family and relatives and holds out the promise for us being able to
better prevent or treat children with disorders similar to Rebecca's in
the future. Up until a few years ago, it might have taken our
laboratory ten or even twenty years of work to identify this cause
while now it was completed through the work of a single graduate
student in a few months, making use of the very powerful computer
databases that contain the DNA sequence information and using genetic
maps constructed in part in the Iowa Genome Center.
Another patient I have cared for now for three years is Sam, who
comes from Solon, Iowa, and who I also first took care of in our
intensive care nursery. Sam has a very severe brain malformation of a
type called neural tube defects, which are most commonly represented by
spina bifida, or an open spine. We have known for some time that folic
acid taken as a prenatal vitamin can prevent spina bifida. Just one
month ago, in work that was sponsored by the CDC, the NIH, and the
March of Dimes, the first report appeared demonstrating that since the
FDA requirement for the fortification of folic acid in cereal grains
was instituted in 1998, the prevalence of spina bifida and related
neural tube defects has dropped by 20 percent in the United States. It
was possible to document this change by using the information provided
by birth defects registries which have received critical support from
the CDC and March of Dimes at a time when our concerns about the
genetic and environmental causes of birth defects has never been
greater or more available to change. This is an amazing success story
and a strong testament to how federally sponsored research and law can
work together to improve the lives of children and adults. This 20
percent reduction means that there are 300 fewer babies born per year
with spina bifida in the United States, sparing their families and
themselves years of pain, suffering, and expense. In this case, a
simple and safe environmental change--food fortification--has had a
dramatic impact and will now stop many other Sam's from a future of
surgery and mental retardation. This illustrates the close connection
between genes and environment and how knowledge of one can interact
with outcomes of the other. The partnerships that have led to these
remarkable findings and advances are a wonderful testament to the
support that the Senate, the House, and the President have provided
with their generous increase in funding to the NIH and in particular to
the Human Genome Project over the last several years. By continuing to
provide this kind of support, we will be able to build upon the
developments that have already taken place to provide an even more
promising future for our children filled with possibilities rather than
disabilities.
At the same time that these remarkable advances are taking place,
we need to temper our enthusiasm with a few concerns. First, the power
of DNA and gene sequencing has also raised concerns about the use of
this information in both the public and private sector. Our families
frequently ask us whether this diagnosis will have an impact on their
children's ability to obtain health insurance. The treatments for these
disorders are incredibly expensive and far beyond the means of all but
a few very wealthy families, so families need resources and assurances.
Similarly, these children, when they grow up, and their siblings are
concerned about opportunities in employment and education and whether
their genetic background will in some way influence decisions that may
affect their life choices. The Congress and the President have already
begun to address these concerns through legislation protecting
individuals from discrimination in employment or insurability, but
these regulations as well as a system of comprehensive health coverage
needs further strengthening.
In parallel with this have been similar concerns raised by
participants in research projects who provide the necessary information
to use the genome project to investigate inherited disorders. The
genome project has provided powerful tools for genetic study, but still
only tools that must now be used with real people and real diseases
like you see here today to realize the promise of the technology. The
successes that we have and will hear about in diabetes, ataxia
telangiectasia, spina bifida, and others have all been built on the
cooperation of patients and families who have these conditions and who
willingly provide information as well as blood and tissue samples for
scientific research. This information and samples reside in databases--
an essential tool for the physician-scientist in determining causes.
Yet, these individuals must be protected in their participation in
research and not have this information used in any way to discriminate
against them. While serving as a member of the Genome Project, ELSI
(Ethical, Legal, and Social Issues) Review panel, we were confronted
time and again with this seeming disparity. The potential conflict
arises in the desire for families to participate in research that will
benefit them and others balanced against their need for privacy. We
must be able to strike a balance of proper informed consent from
individuals enrolled in studies, safeguards to ensure that no outsider
can intrude on the data stored and smooth access by scientists and
physicians to the critical data and samples needed to convert genome
information into genome based treatment and prevention.
A second reality test of our enthusiasm must be that even the
identification of DNA sequence information does not itself immediately
lead to preventions and cures. One oft-sited example is that we have
known since 1949 and the work of Linus Pauling what the cause of Sickle
Cell Anemia is, a common genetic disorder frequently found in African
Americans. Although the care for individuals with Sickle Cell Anemia
has improved dramatically over the last 50 years through the efforts of
many kinds of caretakers, the promise of the genome has not yet allowed
us to cure or prevent this disorder in a primary way. We hope that many
of the findings being discovered today will lead more quickly to these
cures and prevention, but we also need to be careful not to over-
promise to the public that the fruits of our research will be immediate
in their application to their own specific disorders.
A final tempering comes from the realization that the genome is
international. In my own work in the Philippines and Brazil I have come
to know that the major problems of world health are not those of
genetics, but are simple problems best addressed through basic
sanitation and clean drinking water, with immunization against tetanus
or measles, by providing basic nutrition or population control methods
and through programs to prevent HIV, malaria, or TB. At the same time
that we are excited and enthusiastic about the work of the Genome
Project, we need to continue to be aware of the need for these
approaches to preventive medicine so often taken for granted in the
developed world.
It has been a great honor and privilege for me to have participated
in some small way in the mapping of the human genome and to have lived
at a time when I can see the successful realization of so many
scientific projects now becoming a reality in their direct application
to patient care and treatment. I can only hope that you and others like
you will continue to provide the necessary support for these projects
in creating a truly brighter future for our children and their children
to follow.
Senator Harkin. Thank you very much, Dr. Murray.
Dr. Murray gave a couple of examples. Now we turn to really
what this is all about, about a human being, about a person,
about someone for whom this promise of genomic research and the
applications that your scientists, all of you have been talking
about, is meaningful and is real.
I have the highest respect, as you know, for each one of
you, and for all of the wonderful work that you have done in
the scientific realm to bring us to this point and which you
will be continuing to do in the future. I also have the highest
respect for those who have attained a position of celebrity
status in our society because of their abilities in other areas
and who take the time and the effort to get involved in
bringing to the public conscience what we are doing here.
It is in that vein that I welcome Ben Affleck to this
table, Joe Kindregan's friend. Maybe I should introduce you
that way. Right? Joe Kindregan's friend.
Mr. Affleck. Most appropriate probably, yes.
Senator Harkin. And also Joe and Mr. Margus.
We thank you very much, Mr. Affleck, for being here and
again, as I said, for being willing to step out in front and to
publicize in a very meaningful way what it is we are all about
here.
STATEMENT OF BEN AFFLECK, ACTOR
ACCOMPANIED BY:
BRAD MARGUS, PRESIDENT AND CO-FOUNDER, A-T CHILDREN'S PROJECT
JOE KINDREGAN, A-T PATIENT
Mr. Affleck. Thank you, Senator, and I thank you and
Senator Specter for your brave leadership in this regard, your
pursuit of funding for stem cell research, the genome project,
and the model of bipartisanship and leadership that you and
this committee represent. Frankly, I am impressed and I feel
very honored to be asked to be here and I thank you very much.
Second, I am really inspired by all you gentlemen. It is
really a pleasure to sit next to you. It is truly impressive,
and what is really marvelous, beyond even all of your day-to-
day work in the business of helping of people, is your
capacity, I think equally important in many ways, to make that
process, which, as Senator Stevens mentioned, can sometimes
seem a little obtuse and complex and nebulous, tangible and
accessible to folks and to our leadership. I think that is
equally important. You have done a fine job and I am honored
and a little humbled to sit in your company.
I will try to stick to the 5-minute rule, although, you
know, in Hollywood we get 15 minutes.
To the horror of the folks I came with, I am going to speak
extemporaneously for a few moments before I go into the
prepared text and just say that ultimately why I am here is I
am obviously neither a politician nor a doctor nor even
whatever this woman does who appears to be sucking on ether
over there.
Is that not what that looks like?
That is why you look like you are falling asleep, ma'am.
It is impressive really. Able to maintain consciousness
throughout the proceedings.
I am here because of my friendship with a guy who has
really moved me and am here to talk about the human toll in
this. Sometimes we get into debates and we talk about policy
and appropriations and funding and pharmaceuticals and genome,
and it is all really tremendous and important work. But what is
also important is to remember the human costs in these things,
to remember that there is a time pressure, to remember that
they are real people doing real suffering who otherwise could
be living wonderful, normal lives.
This is why I would urge you and the committee to go to a
vote on the stem cell question, which I think has support not
only of Congress, of the Senate, but of the vast majority of
the American people who understand that this research,
particularly recently we have come to understand, can be
enormously helpful in neurological disorders and spinal cord
disorders. I am sure you would do a lot better job of
explaining why exactly, but it is.
You were asking what is A-T. It is actually pronounced
ataxia-telangiectasia.
I met Joe a few years ago. I was working at Dulles Airport.
We were filming a movie and he wanted to get a better view of
what we were doing. We just kind of hit it off. At the time I
met Joe, he was in a wheelchair but he was using a power
wheelchair, but I also learned that he loved karate and he had
a yellow belt. Since then Joe has stopped his lessons because
it has become too difficult for him to stand and balance at
attention as a result of the neurological deterioration from A-
T.
A-T affects the body's coordination. It predisposes
children to lethal cancers. It severely compromises their
immune systems. Most children with A-T are sentenced to a life
in a wheelchair. If you can imagine a disease that combines the
worst aspects of muscular dystrophy, cancer, and AIDS, you
would have a pretty good idea of what a kid with A-T and their
families endure on a daily basis. A-T is a progressive disease.
It gradually robs children of their muscle control. They lose
ability to walk, to talk, to read, and to play games. A-T is
exceptionally cruel because children with A-T lose their
physical capabilities inch by inch, but they never lose their
intellect or mental faculties. And I can assure you that Joe is
every bit as sharp and mentally alert as I am. Although there
are people who will tell you that is not saying much, he is
young.
I promise you he is a very bright, spirited young guy.
Since we first met, I have had the pleasure of seeing Joe
on a number of occasions. In fact, this past spring Joe and his
family joined me in Hawaii for the premier of ``Pearl Harbor''.
I have seen firsthand the progression of Joe's A-T. Where Joe
and I used to carry on a conversation, his mom now often has to
translate more and more of what Joe says because his speech has
been affected by A-T, although sometimes his mom jumps in a
little too much and henpecks him, and I have to tell her just
give him a minute or he tells her.
Joe and I used to be e-mail pals, and he has written me
some very funny and interesting and wonderful e-mails. It used
to be something that I really looked forward to on a daily
basis. But Joe can no longer type his part of the conversation,
so his mom does that for him now.
As Joe is entering his adolescence, he is becoming more and
more dependent upon those around him to assist him with daily
tasks. As I recall, adolescence was a time for increasing
independence. Some of us too much independence, but for Joe, A-
T has made this normal right of passage for a teenager go
backwards.
The great thing about him, however, is that he is full of
hope and optimism, just like every other kid in America. But in
his case, his hopes are somewhat different than most 12- or 13-
year-olds. He hopes the benefit of medical research on diseases
like A-T will help him to walk again, speak easily, play with
friends, and I look forward one day to playing sports with him.
These dreams will only be possible if the vision of the A-T
Children's Project is realized, which is a cure for A-T.
The A-T Children's Project is a nonprofit organization
established by Brad and Vicki Margus. Since its inception 8
years ago, the Children's Project has raised over $10 million.
They have done what many small disease organizations do,
raising money through numerous grassroots events, such as walk-
a-thons, dinners, and auctions. They have successfully garnered
the guidance from a respected board of objective scientists to
award these funds to researchers around the world studying A-T.
The A-T Children's Project has established tissue and cell
banks so that researchers interested in studying A-T can easily
obtain patient tissue or DNA. They have successfully encouraged
international collaborations among scientists from the United
States, the United Kingdom, Australia, Israel, Turkey, Italy,
France, and Germany. In addition, these collaborative efforts
have generated numerous research strategies as a result of
their two scientific conferences that they host annually.
Research funded by the A-T Children's Project has led to
the identification of a defective gene that causes A-T in
children. In addition, the A-T Children's Project has funded
the work of several labs to use genetic engineering to develop
mice with A-T. These mice have many of the same symptoms seen
in A-T kids. Now that an animal model exists, it is possible to
explore potential therapies to treat the effects of A-T and
hopefully one day find a cure.
Mr. Chairman, members of the committee, this is a
remarkable track record of progress for a small foundation in a
short time. Now it is vitally important that your leadership
ensure that kids like Joe get to the finish line.
When you have a disease that affects such a small number of
Americans like A-T, it is imperative that the resources of the
NIH be devoted to it. One of the things I am asking you here to
do is to support not only A-T but other what they call orphan
diseases, just because there are very few people who have the
disease relative to, say, Dr. Needleman's favorite disease,
which was colon cancer. There are many similar small clusters
of diseases that fall under a larger umbrella. There are
various variations of neurological disorders, and I am here to
urge you to increase funding for these diseases which
oftentimes get lost even in places like NIH because, obviously,
you are focused on diseases that afflict more people.
My message is simply this. A-T needs a bigger piece of the
NIH pie. I was just speaking extemporaneously again. The
support of the Congress and the investment of the NIH in A-T
research is vitally important if kids like Joe are to have
their hopes and dreams fulfilled.
Another important aspect of research for children with A-T
that needs to be considered is the training of clinical
researchers. As a result of the competitive health care
marketplace, it is extraordinarily difficult for clinical
researches to devote time and academic resources to
translational and clinical research initiatives. While strides
have recently been made through the passage of the clinical
research legislation in the last Congress, it is imperative
this aspect of our biomedical research infrastructure be
monitored carefully.
Increased funding for NIH will give children and adults
with neurological disorders, such as A-T, an increased chance
of reaching their full potential. With an increase in funding
at this time, along with monumental advances in genomics,
researchers will learn not only how to prevent diseases like A-
T, but how to reverse the neurological damage that has already
been done. The research is not only critical for A-T but also
for many other neurodegenerative diseases, including
Parkinson's and Alzheimer's. This Congress has the ability to
make a tremendous impact on the future of modern medicine and
the suffering of individuals and their families.
My friend Joe often refers to the time when he gets well.
He knows that the reality of his recovery is just around the
corner. Right now funding means hope for all of these families,
hope that medical research will produce a miracle in Joe's
lifetime. For Joe, it will mean a second chance at being a kid.
For me, I intend to work with him on his next karate belt as
soon as research advances get him out of his wheelchair. With
your help, these dreams will become a reality.
This concludes my formal statement. Brad and I will be
happy to answer any questions that you may have for us. Thank
you.
[The statements follow:]
Prepared Statement of Ben Affleck
Mr. Chairman, Members of the Committee, thank you for the
opportunity to appear before you today on behalf of the A-T Children's
Project. Brad Margus, President and Co-Founder of the A-T Children's
Project joins me at the witness table. Eight years ago two of Brad's
four sons, Jarrett and Quinn were diagnosed with a disease called
ataxia-telangiectasia or A-T for short. I am also honored to be
accompanied to today's hearing with a friend of mine, Joe Kindregan.
Joe is 13 years old and has A-T.
You may be asking, as I did a few years ago, ``what is A-T?'' A-T
is a genetic disease that attacks its victims in early childhood. It is
very rare, only about 600 children in the United States have the
disease, and this fact makes it all the more difficult to get doctors,
researchers, the government and pharmaceutical companies interested in
investing the millions of dollars necessary to develop innovative ways
to diagnose and treat A-T.
A-T affects the body's coordination; it predisposes children to
lethal cancers, and severely compromises their immune systems. Most
children with A-T are sentenced to a life in a wheelchair and rarely
live beyond their teens. If you could imagine a disease that combines
the worst aspects of muscular dystrophy, cancer and AIDS you would have
a pretty good picture of what a child with A-T and their families
endure daily. A-T is a progressive disease that gradually robs children
of their muscle control; they lose their ability to walk, to talk, to
read and to play games. A-T is exceptionally cruel because while
children with A-T lose their physical capabilities inch-by-inch,
children with A-T never lose their intellect or mental faculties.
Regrettably, they are trapped in a body that progressively fails them.
In addition to the neurological deterioration, their chance of getting
leukemia and lymphoma and succumbing to cancer is 1,000 times higher
than normal. In short, the outlook for these kids is horribly grim.
So, it is for Joe, Jarrett and Quinn and the hundreds of other
children with A-T across America, that I bring their plight to Congress
today. I would like to help the Committee, and your colleagues in the
Senate, understand the human aspects of this horrendous disease and
suggest some ways that Congress can assist these children and their
families.
I first met my friend Joe 3 years ago at Dulles Airport while
filming ``Forces of Nature.'' He had come to Dulles with his mom and
sister to see what it was like on a movie set. He was in a wheelchair
and couldn't see through the crowds of people so he was allowed down on
the set to get a better view.
Joe was 10 years old at the time and had just started using his
power wheelchair. During the course of the afternoon I learned that Joe
loved karate and even had attained a yellow belt. Unfortunately, Joe
had to stop his lessons when it became too difficult for him to stand
and balance at attention as a result of his neurological deterioration
from A-T.
Since we first met, I have had the pleasure of seeing Joe on a
number of occasions. In fact, this past spring Joe and his family
joined me in Hawaii for the premiere of Pearl Harbor. I have seen
firsthand the progression of Joe's A-T. Where Joe and I used to carry
on a conversation, his mom now has to translate more and more of what
Joe says because his speech has been affected by A-T. Joe and I used to
be e-mail pals, but Joe can no longer type his part of the conversation
so his Mom does that for him now. As Joe enters adolescence he is
becoming more and more dependent upon those around him to assist him
with daily tasks. As I recall, adolescence is a time for increasing
independence, but for Joe, A-T has made this normal right of passage
for a teenager go backwards.
One thing that I have learned about Joe is that he is full of hope
and optimism, just like every other kid in America. But in Joe's case,
his hopes are somewhat different than most 12 or 13 year olds. Joe
hopes that the benefit of medical research on diseases like A-T will
help him to walk again, speak easily, play with his friends, and maybe
even someday play sports again. These dreams will only be possible if
the vision of the A-T Children's Project is realized: a cure for A-T.
The A-T Children's Project is a non-profit organization established
by Brad and Vicki Margus. Since its inception eight years ago, the
Children's Project has raised over $10 million. They have done what
many small disease organizations do, raising money through numerous
grass-roots events such as walkathons, dinners and auctions. They have
successfully garnered the guidance from a respected board of objective
scientists to award these funds to researchers around the world
studying A-T. The A-T Children's Project has established tissue and
cell banks so that researchers interested in studying A-T can easily
obtain patient tissue or DNA. They have successfully encouraged
international collaborations among scientists from the United States,
the U.K., Australia, Israel, Turkey, Italy, France and Germany. In
addition, these collaborative efforts have generated numerous research
strategies as a result of their two scientific conferences that they
host annually.
Research funded by the A-T Children's Project has led to the
identification of the defective gene that causes A-T in children. In
addition, the A-T Children's Project has funded the work of several
labs to use genetic engineering to develop mice with A-T. These mice
have many of the same symptoms seen in A-T kids. Now that an animal
model exists it is possible to explore potential therapies to treat the
effects of A-T and hopefully, one day, find a cure. Mr. Chairman,
Members of the Committee, this is a remarkable track record of progress
for a small foundation in a short period of time. Now, it is vitally
important that your leadership ensure that kids like Joe get to the
finish line.
On behalf of the A-T Children's Project, we urge your continued
support of the doubling of the budget of the National Institutes of
Health (NIH). The Congress has been an incredible ally in pushing the
frontiers of research through the investment you have made in medical
research. It is vitally important that the fourth installment in
meeting this important objective be made this year.
When you have a disease that afflicts such a small number of
Americans, like A-T, it is imperative that the resources of the NIH be
devoted to it. I am confident that you have hundreds of requests
annually for funding specific initiatives at the NIH. With that said,
my message is simply this--A-T needs a bigger piece of the NIH pie if
we are to fully exploit the scientific possibilities that exist. The
support of the Congress and the investment of the NIH in A-T research
is vitally important if kids like Joe, Jarrett, and Quinn are to have
their hopes and dreams fulfilled.
The A-T Children's Project has directed resources to support basic
research looking at the biological defect and the role of the A-T gene/
protein in cells in academic laboratories. They have demonstrated the
capacity to bring together scientists on a global basis, not allowing
geographic boundaries to inhibit fully exploiting the best and
brightest scientific minds to tackle this disease. What the A-T
Children's Project does NOT have the capacity to support is the
translational research that seeks to apply the findings from basic
research to the kids with A-T. We need the government to intercede here
and encourage the NIH intramural program to work in partnership with
industry on translating the basic science advances. The new Clinical
Center at the NIH has the capacity to enhance translational research in
this crucial area.
Another important aspect of research for children with A-T that
needs to be considered is the training of clinical researchers. As a
result of the competitive healthcare marketplace, it is extraordinarily
difficult for clinical researchers to devote time and academic
resources to translational and clinical research initiatives. While
strides have recently been made through the passage of the Clinical
Research legislation in the last Congress, it is imperative that this
aspect of our biomedical research infrastructure be monitored
carefully.
In spite of the boom in biotechnology venture funding, progress in
developing new tools to accelerate research is not fast enough for kids
with A-T. While the gene was identified six years ago, faster methods
and tools for figuring out exactly what the gene and its proteins do in
healthy people and how we can compensate for its absence in A-T kids
have not been forthcoming. These types of assays and tools are vitally
important and NIH should be encouraged to pursue them.
Increased funding for NIH will give children and adults with
neurological disorders such as A-T an increased chance of reaching
their full potential. With an increase in funding at this time along
with the monumental advances in genomics, researchers will learn not
only how to prevent diseases like A-T, but also how to reverse the
neurological damage that has already been done. This research is not
only critical for A-T, but also for many other neurodegenerative
diseases including Parkinson's and Alzheimer's. This Congress has the
ability to make a tremendous impact on the future of modern medicine
and suffering of individuals and their families.
My friend Joe often refers to the time when he gets well. He knows
that the reality of his recovery is just around the corner. Right now,
funding means hope for all of these families. Hope that medical
research will produce a miracle in Joe's lifetime. For Joe, it will
mean a second chance at being a kid. For me, I intend to work with him
on his next karate belt as soon as research advances get him out of his
wheelchair. With your help, dreams will become reality.
______
Prepared Statement of Brad Margus
Mr. Chairman and Members of the Committee, thank you for giving me
the chance to tell you how a terrible disease has affected two of my
sons and how families like mine have tried to accelerate research
toward a cure. After describing my background to you, I would then like
to explain four specific actions your committee could consider taking
to increase the effectiveness of research--not only on my sons' brutal
disorder but on many other diseases as well.
my story
Not too long ago, in the early nineties, I knew nothing about the
Human Genome Project, nothing about serious health problems, and
nothing about how researchers in pharmaceutical companies, academic
institutions and government laboratories were trying to exploit
molecular biology to discover drugs and treatments for diseases. I knew
only about running a small, entrepreneurial business.
After graduating from business school in 1986, instead of going to
Wall Street or into venture capital or consulting, I went somewhere few
Harvard MBAs go--into the shrimp industry! There, I grew a successful,
but admittedly low-tech, seafood company. I also married a beautiful,
intelligent woman, and together we had had three sons within less than
four years. Vicki and I purchased our dream house on a tree-filled lot
in sunny Florida and imagined growing old watching our sons turn into
strong, healthy men someday. Life seemed perfect.
Then one day, everything changed. We suddenly lost control of our
perfect lives. In the spring of 1993, two of my young sons were
diagnosed with a terrible genetic disease known as ataxia-
telangiectasia (pronounced ``ayTACK-see-uh teh-LAN-jick-TAY-sha''), or
``A-T'' for short.
Our boys with A-T had seemed normal until about the age of two when
their walk had become a little ``wobbly'' and their speech had become
slurred. Doctors took nearly two more years, and we spent over $70,000
in tests to figure out what was wrong, and the final diagnosis was a
brutal one. We were told that by the age of nine or ten, our boys with
A-T would lose so much control of their muscles that they would need to
rely on wheelchairs. And, by their early teens, controlling eye
movement and throat muscles would make reading and swallowing extremely
difficult for them.
On top of hearing about the neurological progression, we were also
told that the boys each had a 40 percent chance of developing leukemia
or lymphoma and a 70 percent chance of having a weakened immune system
that would make common infections much more serious. Most children with
A-T, we were told, died in their late teens or early twenties. And, as
the diagnosis kept sinking in, we realized that the quality of their
lives would deteriorate long before then.
Devastated by the news about our boys, my wife and I did what many
parents do in similar situations. We started learning everything we
could about the disease. As I plunged into reading papers about A-T
published in scientific journals, I grew to realize that A-T--affecting
only about 600 children in the United States--was truly an ``orphan''
disease. No one with fame or money had ever had a child with this
disease and funds to support medical research were extremely limited.
Therefore, in the fall of 1993, we started a non-profit organization
called the A-T Children's Project.
I also realized that to have any effectiveness at all, I needed to
learn enough molecular biology so that I could comprehend the research
strategies being taken and could appreciate which scientists were
competent and which were not. I enlisted the help of several Ph.D.
scientists who tutored me every night by phone and fax.
At the same time, I made an effort to ask many scientists and
grant-giving organizations for their impressions about other non-
profits whom they believed were especially effective. I wanted to learn
from other model organizations so that I would avoid common pitfalls. I
could not afford to learn by trial and error. As a result of this
process, I immediately recruited a team of objective, first-rate
scientists and physicians to serve on my Scientific Advisory Board. I
didn't want to take any chance that a particular scientist or physician
might sway me too much (as often happens to parents desperately seeking
a cure for their kids' disease). I also began to visit the National
Institutes of Health regularly to learn how our government funded
research and to try to encourage increased interest in my kids' obscure
disease.
While continuing to manage my shrimp company, I learned how to
raise money by leading a grass-roots effort that organized walkathons,
dinners and diverse other events around the nation to support research.
We started by writing letters and gradually developed a base of
wonderful volunteers who helped us raise money. Events included
walkathons, celebrity golf tournaments, horse shows, races, dinner
dances, auctions, retail-level point-of-purchase ``heart'' sales, and
hundreds of other ideas . . . The funds we raised grew from a few
hundred thousand to over two million dollars per year.
Raising money for a rare disease with a name that is nearly
impossible to pronounce is not easy. And, because this disease is so
rare, we could never depend solely on the help of volunteers who have a
personal connection with an affected child in the way that
organizations for more common diseases can. Instead, we had to persuade
total strangers to reach out and help us.
Of course, besides raising money, it was critical to recruit first-
rate scientists and to persuade them to work on A-T. At least twice a
year, we orchestrated and sponsored scientific workshops that brought
together researchers from different disciplines to compare results,
generate new research approaches and form collaborations. At each of
these meetings, I worked hard to concoct the right mix of scientists
and to provide the perfect atmosphere so that they would candidly share
their latest, unpublished data and work cooperatively with each other
even after the meeting ended.
Our organization also played an important role in making sure
researchers had easy access to patient tissue samples. We set up an
international cell bank for blood and skin samples and a brain tissue
bank as well.
In the summer of 1995, the laboratory of a researcher at Tel Aviv
University in Israel, Dr. Yosef Shiloh, succeeded in finding the gene
that, when mutated, causes this disease. The NIH laboratory of Dr.
Francis Collins--who is also testifying at today's hearing--had
collaborated with the Israeli team, and we will always be thankful to
Dr. Collins for the contribution his group made to our gene hunt.
Having found our gene, we could not celebrate for long. Instead, we
quickly recruited geneticists who were experts in frogs, zebra-fish,
fruit flies, worms, yeast and fungus so that we could utilize their
experiences with similarly spelled genes in these lower organisms. We
also assisted several laboratories in developing strains of ``knock-
out'' mice that had the A-T gene disrupted so that we would have a
model of the disease in a mammal. We helped several scientists raise
antibodies against the A-T protein--an important tool for studying the
activity of the protein in various tissues. And then, we helped to make
sure these antibodies were freely shared with any new researcher who
became interested in our kids' rare disease.
Still other labs were encouraged to use bacteria to make
``recombinant'' A-T protein with which experiments could be performed,
and two groups succeeded at tagging the A-T protein so that its
movement could be followed in the cell. We also used various methods
such as yeast-two-hybrid screens and mass spectrometry to identify
other proteins and protein complexes that interacted with the A-T
protein.
Besides finding the A-T gene in 1995, we realized that year that we
needed one place in the world where a multidisciplinary team of
physicians were accumulating data on this disease (until then, most
physicians overseeing a child with A-T had never seen another case).
Therefore, after seeking proposals from many leading medical centers,
we established an A-T Clinical Center at Johns Hopkins Hospital in
Baltimore, Maryland. It included physicians covering every field
relevant to A-T (such as neurology, immunology, oncology,
ophthalmology, and pulmonary) as well as experts in brain imaging,
brain pathology, swallowing problems, physical therapy, occupational
therapy, speech therapy, and assistive technology.
About the same time, we set up an internet web site plus a list
server that provided a forum by which A-T families and caregivers
around the world could shares ideas about managing the disease day-to-
day and give each other emotional encouragement.
The scientific research continued to move swiftly as our sons' rare
disease became quite well known in biological research and especially
among cancer researchers. Because the A-T protein missing in my sons
was found to interact with a famous tumor suppressor gene called
``p53'' as well as a gene called BRCA-1 that is associated with breast
cancer, oncologists around the world became increasingly interested in
A-T. The A-T protein, known as ``ATM,'' was found to play an important
cellular role in sensing DNA damage and regulating the copy-and-divide
cycle of cells that when corrupted, leads to cancer or brain cell
death.
Other researchers published new findings that the A-T gene was
misspelled in the tumors of most patients with a particular form of
leukemia. And, the chromosomes inside the cells of A-T children were
also found to have shortened ends (or ``telomeres''), that are known to
shorten with age, making A-T an intriguing model of premature aging.
After studying how major medical progress had been made through
history, I realized that significant medical discoveries often have
roots in unrelated basic breakthroughs. Therefore, I concentrated on
surveying every area of science in hopes of finding new approaches and
brilliant investigators. I worked late into the night, struggling to
keep up with the science while sending faxes and e-mails in hopes of
engaging world-class scientists to study my sons' disease. I often
fantasized about a day when every scientist on the planet would be
aware of this disease. And gradually, researchers working on cancer,
neurodegeneration, immune deficiency and aging became involved.
In 1997, we thought for a moment that we had found a treatment! A
research team had discovered that in mice engineered to lack the A-T
protein, a certain type of brain cell was dying that was also known to
die in people who have Parkinson's disease. When the scientists
injected a common drug for Parkinson's Disease called ``L-dopa'' into
the mice, the animals seemed to improve a little. As a result, we
immediately organized a blinded clinical trial of L-Dopa in A-T kids,
but the results were disappointing (no significant improvement compared
with children receiving the placebo). Nevertheless, running our first
clinical trial helped us realize the important issues in designing drug
trials for children with A-T (such as establishing reliable,
quantitative, clinical end-points with which to measure and observe any
changes in the kids resulting from the drug).
Children with A-T have an extreme risk of developing cancer, and
because radiation is lethal to them, treating A-T children for cancer
is especially challenging. Therefore, in 1999, we established a cancer
clinic for A-T kids at St. Jude Children's Research Hospital in
Memphis, Tennessee where pediatric oncologists are now striving to
develop unique protocols that should improve the management of cancer
in children with A-T.
Besides running several scientific meetings each year that were
attended by M.D.s and Ph.D.s, we also organized and sponsored other
types of meetings that brought families of A-T children together with
doctors to learn about managing the symptoms of A-T and coping with the
exhausting lives they endured. We also published a manual that provided
a lot of practical information to physicians, parents and therapists
who took care of children with A-T.
Recently, much of the research we supported held promise for other
diseases besides A-T. For example, by this past year, we were funding
work on cultured neural stem cells that not only held the potential of
helping to ``reseed'' the brains of A-T kids, but might also help
patients with Alzheimer's, Parkinson's, ALS, spinal cord injury and
stroke. We were also funding work aimed at transferring and expressing
a healthy copy of the A-T gene into the brain cells of A-T children. If
this virus-based system of gene therapy worked, it could also be
applied to numerous other neurological disorders.
We were also supporting trials of new ``super antioxidant''
compounds on A-T mice that had been shown to extend the lives of worms
by 40 percent, and we were working with still other researchers to
combine gene targeting and nuclear transfer (cloning) techniques to
make animal models of A-T in monkeys, cows and pigs. We were even
checking to see if neural auto-antibodies, ion channel defects,
mitochondrial dysfunction, nuclear inclusions or cytokines were playing
roles in the disease, and whether growth factors might have therapeutic
potential.
In short, we had done our best to ``catch up'' with the efforts of
the big, well-known disease organizations. And many people therefore
said that we had made much progress. But we had not succeeded. We had
still not found a single way to slow the progression of this relentless
disease for even one day.
I received various accolades for our work, including invitations to
serve on advisory councils that directed the National Institutes of
Health and chances to tell Senate committees how I would improve the
government's funding of medical research. I was also given the
opportunity to serve as a board member of the Genetic Alliance--an
umbrella organization that represents over 300 genetic disease
organizations. Barbara Walters hosted an hour-long ABC News television
show in 1996 about our efforts. And this past year, I was given the
opportunity to become Chief Executive Offcer of a new Silicon Valley-
based biotech company called Perlegen Sciences that recently raised
$100 million in first-round financing from private investors (this
career move has allowed me to leave the food industry and to focus all
facets of my life on scientific research aimed at understanding and
treating diseases).
Yet, in spite of these votes of confidence, I am compelled every
day to realize that until now, I have still failed in finding a
treatment or cure for children with A-T . . .
Time has passed quickly, and A-T children like my boys have
continued deteriorating and dying. My son Jarrett is now twelve years
old, and Quinn is ten. Time is running out. Both boys now use power
wheelchairs and rely on full-time aides in school. Their minds are
unaffected by the disease, but they are trapped inside bodies that are
letting them down. As they become less able to share activities with
healthy friends, my wife and I struggle to figure out how we're going
to help them deal with their social isolation and physical limitations.
Of course, my fight to cure or treat A-T has now reached far beyond
merely fighting to save my own two sons. I have visited families of
hundreds of children who have A-T, some of whom have subsequently lost
their lives to this disease. My wife and I are no longer alone in this
fight but now share our mission with other families of A-T children
around the world who are doing whatever they can to raise money and
increase awareness. Several of those families are here in this room
today.
And, I cannot tell you how thrilled I am today that such a talented
and admired motion picture actor and Academy Award-winning screenwriter
has stepped forward to help us in our fight. Today, families like mine
across America are overwhelmed with joy, realizing that Ben Affleck is
not merely testifying before you today about A-T but--through his
friendship with thirteen year-old Joey Kindregan--truly knows what our
kids face.
steps you could take to accelerate research
The question I am most often asked is, ``What do you still need to
accomplish in order to find a cure or treatment for A-T?'' My answer
always includes the same four themes: ``translational research,''
``physicians willing and able to do clinical research,'' ``new tools
and technology,'' and ``a more involved NIH.'' Please allow me now to
explain four steps that you could take to help us in these areas:
Encourage the NIH to support translational research on diseases like A-
T
Even though my small organization, the A-T Children's Project, has
been able to support basic research conducted by academic laboratories
looking at the biological defect and the role of the A-T gene/protein
in cells, it has been exceedingly difficult for us to persuade clinical
researchers to conduct what is referred to as ``translational
research.''
Translational research seeks to apply the findings from basic
research in a clinical setting. This type of research is typically done
by pharmaceutical companies rather than by academics, and I am sure you
can imagine how difficult it is for us to persuade drug companies to
devote resources to a rare disease that represents a miniscule market
potential. Therefore, we really need the help of the National
Institutes of Health (NIH) in encouraging this kind of applied research
on A-T, even though it is a rare disease.
I know that from time to time, I have heard discussion in your
hearings about why there is a need for an intramural program at the
NIH. The best reason I have heard is so that research can be done there
that cannot be done anywhere else. It would be great if you could
encourage the NIH's intramural clinical researchers to focus more
attention on diseases like A-T. We cannot help hoping that the new
clinical center being built on the NIH campus might undertake some
clinical research projects involving A-T.
Provide for physicians to do more clinical research
Everyone who wants to find a treatment for a disease, and
especially families affected by pediatric neurological diseases, want
to see more physicians who are able to do clinical research. But over
the last few years, we have found that the time clinicians have for
doing clinical research on diseases like A-T at leading medical
centers--even at teaching hospitals--is quickly shrinking.
We need your committee to allocate more funds so that excellent
physicians with the talent to contribute as researchers can do so. Some
tactics tested by the NIH have already helped, such as repaying medical
school loans for physicians who agree to go into research, but we need
you to encourage the development of more solutions to this problem.
Important strides were recently made on this front through the passage
of the Clinical Research legislation in the last Congress, but it is
important that this aspect of our biomedical research infrastructure be
monitored carefully.
Encourage the development of new tools for ``downstream'' biological
research
The progress in creating new tools to accelerate research has not
been fast enough for families like mine who watch our kids slip a
little further from us each day. Keep in mind that researchers found
the gene that causes A-T over six years ago but there is still not a
single treatment available. Since then, the progress in understanding
the function and role of that gene in the human body has been
substantial but still not adequate. Just as breakthrough technologies
such as automated DNA sequencers and polymerase chain-reaction (PCR)
have super-charged the hunts for disease genes, we need new high-
throughput methods and tools for elucidating the protein pathways
directed by those genes in order to know what to do about the genetic
defect.
With your direction, the NIH and other government agencies could
scale-up their efforts and be more innovative in encouraging scientists
and engineers with inventive skills to create these technologies, even
when they have risky ideas for which venture capital funding may not be
possible or when they have approaches that would benefit only rare
diseases with limited markets.
Support greater interaction between NIH program directors and the
research and disease community
At each NIH institute, a different program director typically
oversees each specific area of research. This individual plays a
critical role in implementing the research priorities and strategic
plans that are conceived by NIH leaders and Congress. Program directors
must therefore represent first-rate talent and must be given ample
support.
My organization has found that when program directors are more
aware of the research activities on any particular disease, announced
requests for proposals are more appropriate, redundant research
projects are minimized, and fewer scientific opportunities are missed.
In other words: the NIH's funds are stretched much farther. These
individuals tend to be extremely dedicated to keeping up on
developments in their scientific areas, comparing notes with disease
advocate groups, and providing guidance to investigators preparing
grant proposals. But they are also spread very thin, and their travel
budgets to meet with researchers and patients are often restricted.
More program directors are needed, and their proactive involvement
in the research community needs to be encouraged. While allocating
funds to this ``administrative expense'' instead of toward direct
research grants may at first glance seem wasteful to you, in our
experience, having highly-qualified program directors with more time
and resources to keep on top of their areas would be tremendously
worthwhile. In addition, in order to encourage more translational
research, we feel it would be valuable for the NIH to take steps to
recruit more program directors who have clinical experience.
Mr. Chairman and Members of the Committee, as you can see, none of
the steps I have suggested requires you to set aside funds specifically
for my sons' disease. And yet, I am confident that these steps would
ultimately accelerate research progress on A-T as well as many other
diseases.
I would be happy to answer any questions you may have, and I would
also be eager to work with your staff to develop legislative language
for insertion in the appropriations bill to cover these areas of
concern.
Thank you.
Senator Harkin. Thank you very much, Mr. Affleck.
Joe, you have got a good friend there. He says he is going
to help you get your next belt.
Mr. Margus, welcome also. I understand you also have a
couple of children with A-T. Is that right?
Mr. Margus. Yes. Joe knows them. They are Jarrett and
Quinn. Quinn is 10 and Jarrett is 12. They also have A-T.
Senator Harkin. Is Joe's mother here? Do I understand that?
Hi, mom.
Ms. Kindregan. I am not allowed to speak.
Senator Harkin. You are not allowed to speak? You are
allowed to speak if you would like to speak.
Mr. Affleck. It was Joe that told her she was not allowed
to speak.
Senator Harkin. Well, Joe, where are you from?
Mr. Kindregan. Springfield, Virginia.
Senator Harkin. Oh, Springfield, Virginia. Oh, not too far
from here.
How did you two meet? At Dulles?
Mr. Kindregan. Yes.
Mr. Affleck. Yes. I was shooting ``Forces of Nature'' and
we were at Dulles and Joe was heckling me.
Mr. Affleck. I told him to clam up and we almost got in a
fist fight. It was an awkward thing, but then we made up.
Remember that?
Mr. Kindregan. Yes.
Senator Harkin. So, Joe, you went to the premiere of the
movie, ``Pearl Harbor''?
Mr. Kindregan. Yes.
Senator Harkin. That is pretty exciting. Did you see him in
``Good Will Hunting'' also?
Mr. Kindregan. Yes.
Mr. Affleck. Did your mom let you see that movie? The 143
swear words in that movie.
Some of the benefits of being in a wheelchair is mom lets
you watch the R-rated movies.
Mr. Kindregan. Some of them.
Senator Harkin. Well, Joe, we are really proud that you are
here and proud you brought your friend Ben here. If you had
anything that you wanted us to know or if you want to say
anything, by gosh, the floor is yours.
Mr. Kindregan. No.
Senator Harkin. Well, okay. Did Ben say it all for you?
Pretty much.
Mr. Kindregan. Yes.
Senator Harkin. Good. Well, we thank you for being here,
Joe, and I can assure you that these people who are sitting
down the table from you here, all these scientists and Dr.
Collins and Dr. Rich and Dr. Needleman and Dr. Murray, I know
that every day they go to work they think about you and they
think about the people out there that are going to be helped by
the research and the investment of time and their lives that
they have done. This is who they think about. I do not know
them all. Some of them I know better than others, but I know
that this is what they are about. I have a great deal of faith
in their abilities to get the research done and the
interventions and cures that we need for a lot of these
illnesses and especially for the one that is affecting you, A-
T.
I was not aware of it either until you came here today.
Believe me, I am now aware, and I am going to be asking more
and more questions of NIH of what they are doing to make sure
that we get more research into this area.
But I just turn to all of you, all the scientists who are
here. When I think of Joe and A-T--I do not know if any of you
are familiar with A-T. I sure was not, but Dr. Collins is. Tell
me what we are here for this morning in terms of the human
genome project and finishing it and moving ahead with it. Tie
that in with Joe Kindregan. How does that work for Joe?
Dr. Collins. Well, I will take a try at that. I think Joe's
situation is emblematic of hundreds of thousands of other folks
who have disorders that may not make the headlines but which
are very real every day for them and their families.
The genome project has, I think, a view that every gene
matters and therefore every disorder matters. In fact, the
ability to look at the whole thing is one of the best antidotes
against that tendency to only focus on common illnesses. When I
mentioned 50 disease genes had been found in the last couple of
years, most of those are for relatively rare conditions like A-
T. Wearing my research hat, I was honored to be part of the
team that found the A-T gene about 5 years ago, and part of the
team that helped develop this mouse model that Brad Margus
referred to.
Yet, now with those powerful tools we are poised to unravel
at the biochemical level why the single gene that is not
working in that condition causes the havoc that it does. We
still have several steps to traverse. That means understanding
this particular protein. It is a very large, complicated
protein. What is it normally there for and why, when it is not
doing its job, does this wide array of problems occur, the
immune system, the neurologic system, the risk of cancer?
I would give Mr. Margus a huge amount of credit for the way
in which his A-T Children's Project has worked very effectively
with NIH--and over the years Brad and I have grown to be good
friends--in a very productive, effective partnership to try to
get the best science applied to this problem. Most of the
scientists working on A-T today had not heard of it until
somebody like Brad came along and invited them to a conference.
So, I think it is fair to say this relatively rare
condition has now become the focus of a lot of scientific
interest, and it turns out that while inherited alterations in
this gene are relatively uncommon and afflict people like Joe,
that you can acquire a misspelling in this gene during your
lifetime. That plays a significant role in the risk of things
like lymphomia and leukemia. Once again, the study of a rare
condition sheds light on a much broader array of issues, in
this case cancer, and that in turn draws more people into the
area of interest.
But what we really need to understand now is what does this
protein do, what other proteins does it interact with, and how
can you compensate for it not working in a certain
circumstance, like what Joe lives with every day. I think the
tools to do that that are now marshaled, that attack the
problem, are profoundly more powerful than they were even 5
years ago. But complexity is still the norm in human biology,
and to unravel all that in the direction of an actual cure
takes a lot of steps, a lot of support, a lot of good science.
Senator Harkin. But can I tell Joe, sitting here today,
that there are more people working on unraveling this mystery
than there was a year ago or 2 years ago?
Dr. Collins. Absolutely, and I think Brad would agree with
that. We are getting to the point now where there may be more
people working on A-T than have the disease, and I think that
is great.
Senator Harkin. That is good.
Mr. Affleck. Correct me if I am wrong. My understanding
this is a disease which falls under a much, much larger
umbrella, the set of diseases which all could benefit from stem
cell research. These cells have been demonstrated, as I am sure
you know, Senator, when extracted and then reinserted into
brains and spinal cords of mice, to go to the place in the
brain that is deteriorating and regrow in the brain and to
regrow some spinal tissue. So, I think that is very important.
I think A-T would benefit enormously at least from that
research.
And the Federal Government plays an important role in that.
Being a Democrat, of course, I am a great fan of regulation.
So, I think it is research that needs to be regulated, and I
think it is one that needs to be supported by the Federal
Government. And I admire and appreciate your bipartisan support
of that.
Senator Harkin. Thank you very much, Mr. Affleck.
I am going to turn to Senator Landrieu. When Senator
Landrieu gets finished, I am going to come back to a question I
want you to ponder. I want you to tie together stem cell
research and genomic research for me.
Senator Landrieu, welcome. Again, Senator Landrieu
represents a number of highly respected national research
institutions in her State of Louisiana.
Senator Landrieu. Thank you, Mr. Chairman. Let me begin by
thanking you for your focus on this important work. I can see
from the numbers of people here and from the numbers of people
who are tuned into this hearing that it is a vitally important
issue for our Nation. There are many parents and doctors and
communities and children who are looking very carefully at the
policies that are laid out here to provide the kind of hope and
excitement that has been talked about this morning. So, I want
to thank all of you and thank you, Mr. Chairman, for keeping us
focused so that we can take the steps every week and every year
here in Congress whether through policies or appropriations to
further this important work.
Joe, I want to thank you so much for being so brave and so
wonderful to be such a good example to all of us to come here
to Washington, not the easiest place to get to and not the most
comfortable place sometimes to testify, but for your braveness,
being an example to children everywhere and to adults about the
ways that you can become a great advocate so we can continue to
do the kind of work that we do. To you, Ben, and to you, Mr.
Margus, for your stepping out.
Brad, I was not here for your opening statement. But what
could we do immediately to help you as you have done so
successfully to bring this particular disease to the forefront?
What could we do in Congress to help sort of multiply your
efforts in a faster, more direct way so that we can really
build on the great work that Joe has done and that Ben has
done?
There are many larger policy issues that this Congress is
going to grapple with and there will be some controversies
about these issues of morality and responsibility and
liability, et cetera. But there are some things that should not
at all be controversial about the Federal Government stepping
up to help you and these other ``orphan'' diseases to try to
expedite the good results. Could you just comment maybe
briefly? I think the chairman and I would both be interested.
Mr. Margus. I would love to give you a nice example of
something that is on our wish list that would not just benefit
A-T but would benefit a lot of diseases.
When we first started the A-T Children's Project, my kids
were diagnosed and there was really nothing going on, to speak
of, in A-T research. We reached out to do everything that had
been done for more common diseases. So, we said, why can we not
get our gene if cystic fibrosis has theirs? Why can we not do
mouse models or other animal models and other organisms like
Drosophila and fruit flies? But there were things that were
already being done for the more common diseases, and we said,
we deserve to have that for ours. That was kind of my spiel
with NIH and if I could run into any of you.
Today a lot of what needed to be done has been done, and a
lot of the obstacles we run into are the same ones that are for
more common diseases. I will not dig into all the more
controversial ones, but the one that is really clear Dr.
Collins mentioned. We have been really fortunate in that our
disease gene--the protein that is missing in Joe because the
gene is misspelled is a protein that plays a real critical role
in cell biology. It is involved in cancer. The protein actually
interacts with another protein called P53 that has been found
to be mutated or misspelled in the majority of all tumors. It
also interacts with another gene or protein called BRCA-1 that
is involved with breast cancer. So, it is really this hot,
popular protein in cell biology, even though most of you have
never heard of A-T. Because of that, there are a lot of great,
first-class scientists, basic biologists working on the
mechanism of the A-T protein and what it is doing.
The frustrating thing for parents like me and for kids like
Joe is that even though all this great science is being done
downstream from finding the gene--we found the gene 6 years
ago--it is not a treatment. If you look at how long it might
take to figure out the complete biological pathway of how that
one gene causes all these symptoms, it could be 20 or 30 years,
maybe longer.
If you look at the history of medical discovery and most of
the drugs that the drug companies are selling, I hate to say
it, but they do not develop them by this rational approach of
figuring it all out. Most of them have been chance discoveries
or discoveries that came about from looking for one thing and
something else became useful.
That may all change now because the tools have really
improved. The human genome project will change that
tremendously and there are a lot of other technologies coming
out that should accelerate molecular biology.
But what we really need is ways to apply it. So, how can we
get, even before we have all the answers, to something that we
can treat our kids with? I think one of the real obstacles that
maybe you can help us with is to get more clinicians, doctors
involved in research. We have some great scientists working on
the basic cell biology, but we do not have many doctors who are
trained neurologists and trained immunologists who are able or
willing to go into research.
Part of the reason is what Ben mentioned in his testimony;
that is, there are a lot of pressures on doctors today with
managed care and so on. Doctors have less and less time to
spend doing research. But we really need to find a way to find
really good physicians who can translate or take the basic
research and apply it in the clinic.
If A-T were a disease like it is but kids die a month after
they were diagnosed, then you would be going nuts doing
everything you could just applying things just the way they
treat really aggressive cancers, but because it is kind of over
time most of the time, scientists tell us, wait till we have
the answers completely figured out on the biology. And we
really cannot wait for that. What we need is more physicians
who are also able to go into research.
I know that the NIH has done some things recently, repaying
student loans for med school and things like that, to encourage
physicians, doctors to go into research.
Senator Landrieu. Mr. Chairman, could I follow up with one
question on this? Because I think you and I would be
particularly interested. Because children cannot wait and
neither can parents, I would like Dr. Collins or Dr. Murray to
follow up, adding to that some specific things that we could
take action on now that has limited or no controversy
associated with it, that we could expedite the treatment and
hope for Joe and for his family and for Mr. Margus and his
family. Is there something that you could add to the testimony
that could help us to really focus in this budget cycle on what
could be done along those lines?
Mr. Margus. You have a really great, huge clinical center
being built on the NIH campus I noticed. Obviously, there is a
big push now to do more clinical research. We just hope some of
that will be done on A-T.
Senator Landrieu. Anybody for the record?
Dr. Collins. Well, I think your question is very
appropriate. Certainly for myself as a physician, I have been
deeply concerned to watch, over the last 20 years, the number
of physicians doing clinical research gradually decline. That
decline got quite precipitous a few years ago, particularly
because with the advent of managed care, a physician who wanted
to do clinical research in a medical center out in one of our
great universities increasingly was under pressure not to do
the research but to be out there in the clinic or on the ward
seeing patients and getting reimbursements because all the
academic centers were struggling so much. This is a big part of
the dynamic, the way in which our change in reimbursement has
placed academic centers in a position of basically providing
disincentives for physicians to do research. And that issue is
far from resolved.
NIH has made a number of bold steps I think to try to
provide some backstopping of those who would like to do this.
And I think it has, to some degree, turned the tide so that
that steady decline has begun to reverse, but we are still way
behind where we need to be.
Certainly I am the first to agree, genomics is a wonderful
basic science, but it does not matter a whole lot if it does
not end up benefiting individuals, people with diseases. That
translational process requires people who understand the
practice of medicine, those clinical researchers, and we do not
have enough of them.
The loan repayment program may be a way to get rid of one
of the financial disincentives to people who come out of
medical school already owing $100,000 or more. Being a clinical
researcher will not make you rich. You will be driving a 10-
year-old car when your friends out there are getting their
second Mercedes of the year. It is not the sort of thing that
somebody without a great deal of personal commitment is going
to be able to do. Yet, there are ways I think that we could
make that financial situation a little less onerous and provide
some encouragement to those who do want to do this, that they
do not have to be forced into just delivering patient care for
reimbursement all the time the way their medical centers often
ask.
I would be glad to provide some more information for the
record about the programs that NIH has already put in place and
some ideas about other things that we could do that are even
more ambitious.
Senator Landrieu. That was very helpful and I appreciate
it.
[The information follows:]
Department of Health & Human Services,
National Institutes of Health,
National Human Genome Research Institute,
Bethesda, MD, August 7, 2001.
Hon. Tom Harkin,
Chairman, Subcommittee on Labor, Health and Human Services, Education,
and Related Agencies, Washington, DC.
Dear Senator Harkin: It was a pleasure to testify before your
committee on July 11, 2001. During that hearing Senator Landrieu asked
about efforts by the National Institutes of Health to promote clinical
research. Below is a description of some of the activities currently
underway at the NIH to promote clinical research.
In 1999, following a detailed analysis by a subcommittee of the
Advisory Committee to the NIH Director, the NIH launched three clinical
research programs: the Clinical Research Curriculum Award (K30), the
Mentored Patient-Oriented Career Development Award (K23) and the Mid-
Career Investigator in Patient-Oriented Research Award (K24). The K30
program provides support to institutions for the development and
conduct of didactic courses for clinical investigators to enhance their
fundamental knowledge in study design, biostatistic, ethical and
regulatory issues with clinical trials. The NIH has awarded a total of
55 K30 awards. The K23 program provides didactic training and mentored
research experience for investigators who are interested in doing
patient-oriented research. Since their inception, the NIH has funded
279 K23 awards. The K24 program provides protected research time and
mentoring opportunities to mid-career investigators by relieving them
of patient care and administrative responsibilities. The NIH has
awarded 158 K24 awards since 1999. These programs have been successful
and continue to attract enthusiastic response from the clinical
research community.
The NIH also sponsors a loan repayment plan (LRP) which assist in
increased participation in clinical research by young scientists. The
LRPs pay a maximum of $35,000 a year toward participants' outstanding
eligible educational debts. In return, participants must sign a
contract agreeing to conduct qualified research activities as NIH
employees. Participants in the LRP may apply for additional, 1-year
renewal contracts and continue to receive loan repayment benefits.
There are four different types of LRPs:
--The NIH AIDS Research Loan Repayment Program (AIDS-LRP) is designed
to attract highly qualified physicians, nurses, and scientists
to HIV/AIDS research and research training.
--The NIH Clinical Research Loan Repayment Program (CR-LRP) is
designed to recruit highly qualified physicians, nurses, and
scientists from disadvantaged backgrounds to serve as clinical
researchers.
--The NIH General Research Loan Repayment Program (General-LRP) is
designed to attract highly qualified physicians, nurses, and
scientists to conduct research at the NIH.
--The NIH General Research Loan Repayment Program for ACGME Fellows
(ACGME-LRP) is a pilot initiative of $5,000 per year in loan
repayment currently available to fellows employed by the NIH in
subspecialty and residency training programs accredited by the
Accreditation Council for Graduate Medical Education (ACGME).
Qualifying fellows must hold a three year appointment at the
NIH beginning July 2000, 2001, or 2002.
In 2000 Congress passed the Clinical Research Enhancement Act as
part of the Public Health Improvement Act (H.R. 2498). The legislation
instructs the director of NIH to expand the agency's role in clinical
research by awarding grants for the establishment of new General
Clinical Research Centers (GCRCs), creating new enhancement awards, and
expanding the NIH loan repayment program for clinical researchers to
include extramural investigators.
In addition to these programs, the NIH is currently developing a
program announcement to provide support to institutions to develop
degree-granting programs in clinical research. It is anticipated that
the National Center for Research Resources will take the lead in this
initiative and launch it in fiscal year 2002. We believe that these new
programs, along with the existing clinical career development awards,
e.g., K08, K12, etc, have gone a long way in addressing the need for
training more qualified physician scientists.
I hope this gives you an idea of the programs the NIH is working on
with regard to clinical research. Please let me know if you have any
further questions.
Sincerely,
Francis S. Collins, M.D., Ph.D.,
Director.
Senator Landrieu. Dr. Needleman.
Dr. Needleman. Senator, it occurs to me--what is the
distance between getting a drug to a patient and the
discoveries and what are some of the limitations? So, it is
really extremely important on the genomic end to understand all
the multiple implications of the expressed genes. The human
genome is like the Lewis and Clark trip. It did not tell us
what the country was. It was the map. We have to figure it out.
I will go to the back end. Maybe the NIH ought to think
about the development of genetic or biological markers that
enable assessment of clinical trials so clinical trials could
be done in patient populations that are diagnostic and help
invest the science because the regulatory environment is not
yet built for genetic markers and biomarkers. You might have to
do trials now till mortality. So, if you want to change a
chronic disease that slowly evolves, then I think a wise
investment, both in industry and in fundamental science, in how
to use genetic markers to see the progression of the disease
and the maintenance of its factors and the proofs that are
necessary to change the regulatory environment, then you could
truncate years off the process between a great idea, a lead
molecule, and when it is approved for use. No sacrifice of
safety. But we need a revolution in genetic and biological
markers.
Senator Landrieu. Thank you.
Dr. Murray. I would like to also follow up on Dr. Collins'
comments. I do think this question about the clinical research
is one that you do need to address right now. We are going to
lose a whole generation of physician scientists soon if we are
not careful. When I see young faculty coming into our own
university, it is impossible for them to be both researchers
and clinicians, the way Dr. Collins and myself and others were
when we started out 15 or 20 years a go. The financial demands
now on the clinicians force them to spend 100 percent of their
time seeing patients, with no opportunity for them to begin
these kinds of research projects, often that come directly from
the clinic. Just as Mr. Affleck met Joe here and became
interested and a friend of his, that is how clinicians get
interested in problems and then take them into the laboratory.
If the clinicians, especially beginning ones, do not have the
time and the resources, the protected time, to do that, they
will not be able to begin and start these projects that can
lead to the kinds of successes that we are hearing today. So, I
think you need to support through things like loan repayment,
through medical scientist training programs, through the full
reimbursement of the clinical people working in academic
centers to allow them opportunities to do this.
Senator Harkin. I look forward to working with you on this,
Senator Landrieu, to make sure that we can get those various
things implemented. This has bedeviled us for a few years now
and we have not worked our way out of it yet. But we really do.
The academic health centers have--well, I would not say they
have been forgotten, but they have been kind of pushed aside in
a number of ways, and we need to focus more on them and to
provide the kind of financial support to the academic health
centers whereby people do not have to see patients day after
day after day, where they can go back in the lab. But I tell
you, it is a real problem and we need your best thoughts on how
to solve it.
The tax thing, the forgiveness of the loans is one thing.
The other thing is also to make sure the academic health
centers get the kind of financial support they need to continue
this research. That comes right from here, and it has to do
with priorities and what we are spending our money on in this
country and things like that. With the budget constraints we
have right now, it is going to be tough to get that done. But
it has to be done and we are going to do everything we can on
this subcommittee to provide those funds.
I just had one last question. Then we need to wrap it up.
But I asked, before Senator Landrieu asked her questions, you
to tie together for me stem cell research and genomic research.
We have the human genome project. We have done the research.
You, Francis, talked about how we have got to keep going
forward on it. Now we have got the whole area of stem cell
research that hopefully we are going to get a favorable
decision on here soon. Tie the two together. Where do they
meet? How do they support one another?
Dr. Murray. One example that I think of that will really
bring this together really well. Unfortunately for the rest of
you, it comes from again Iowa. But 10 days ago, I went to a
party that was a celebration for a friend of my daughter who is
a 15-year-old girl who a year ago exactly on Sunday had
received a kidney transplant. Her family has a very unusual and
as-yet undefined genetic immunologic disorder. She has an older
brother with diabetes who would love to have a cure for that.
She received a kidney transplant a year ago from her father.
Her father turns out actually to be a pediatric surgeon and
loves his daughter just as much as mom loves her son and all of
us love our own children. And he made a tremendous sacrifice
for her to give her this kidney.
The genome project holds out the prospect for their
particular disorder to be identified and studied in the same
way that A-T is in many of the other disorders that we have
heard about today. But even once that has happened, we need to
convert that information into something that is useful for that
particular family. Certainly stem cell research and related
projects hold out the prospect of fathers in the future not
having to give up their own kidneys or organs to their children
or someone else doing that, but to be able to use those stem
cells to generate a kidney, an artificial organ on the outside,
which will now be compatible with that child that she could
receive herself. And it will be through those kinds of findings
we can do it.
Senator Harkin. Very good. Anything else? Does anyone want
to add anything?
Mr. Margus. I have a good example you might be interested
in. We have 18 mice that do not have the gene and therefore
have the same disease the kids have. We have, obviously, been
excited that stem cells could reseed the brains of these mice.
So, if you inject in those stem cells that have not decided
what kind of cells they are going to become yet and migrate to
different areas, hopefully they will have an affinity for the
areas that are damaged and that is where they will go and
produce growth factors and become wired.
The problem is it is a very exciting field that everyone
has hopped on, but it is really an early stage of the field.
There is not a lot known about what those stem cells really do.
So, one thing that a lot of stem cell researchers are doing
right now is they are looking at the genes that are turned on
or off in the environment inside the brain at different stages
of life. So, when you stick stem cells in an elderly person who
has a stroke, they may not do very much, and if you stick those
stem cells into a baby mouse, these stem cells seem to go to
the right place. Well, there must be other things turned on in
there at that stage of life that direct those stem cells.
So, one of the things a lot of researchers are doing is
using different technologies to find out which genes are turned
on and which ones are off so that they can really guide and
control those stem cells.
Now, once you have used those technologies to pull out
genes that are involved at different stages, you have to know
what those genes are. At that point, you can get on the
Internet today and probably find that gene in the human genome
project's data.
The reason I know this is because I explain it to families,
not just mine, but my wife, a lot of other families. We are all
hoping that stem cells may have great promise. But the thing I
warn them of is that what if it kind of works but not great. If
it worked perfectly, then, hurray, we have got a home run, and
we do not care if we know how those stem cells work. But
chances are it will almost work but not quite, and if you do
not know exactly what is going on, you cannot tweak it. You
cannot really perfect it. And the way to know what is going on
is by knowing those genes that are turned on and off. So, the
genome project and genetics really does enlighten and elucidate
what is going on when stem cells are doing their thing.
Senator Harkin. Thank you very much, Mr. Margus.
Does anyone else have anything to add?
Dr. Needleman. You do not know the traffic cops for stem
cells, so you really have to use genomics and proteins to say
when am I going to differentiate into a heart cell or a brain
cell. So, you really need a lot of fundamental discoveries yet.
It is not just taking a cell and growing it for an organ, but
we can take control some day of the direction of the cells even
in the body. So, you really need genomics and fundamental
studies to understand the traffic cops and when it is on and
when it off. It is like your red light.
Dr. Rich. Just one thing, reflecting on what Dr. Collins
said earlier, is that even though we are probably 99 percent
similar at our DNA level to other organisms, you can tell that
that little 1 percent or less than 1 percent is highly
variable. I am not much like Francis. He has a lot more hair
than I do for one thing.
But that means that there is a lot of variation in stem
cells potentially, and we need to have lots of stem cells to
track that variation. So, in a sense we need to have the
variation in the stem cell resource that we do in people to
help provide this information and decide what is the traffic
cop and how it works.
Dr. Collins. Senator, I think this group has described it
extremely well.
It always comes as a surprise to those who hear it for the
first time that we have the same instruction book, the same set
of DNA in a liver cell or a brain cell or a cell in the islet
of the pancreas or a cell in the muscle. They all have that
same instruction book, and one of the most amazing developments
of the last 3 or 4 years is the recognition of the plasticity
that seems to exist of how cells can reprogram themselves from
being a bone marrow cell to a heart muscle cell, as has
recently been demonstrated, or a variety of other such
examples.
That all has to come about because the genome, that set of
instructions, has the ability to be modulated down different
pathways, and the understanding of that is critical to our
medical applications of this really surprising set of new
biological insights.
Senator Harkin. Well, thank you all very much. This has
been terribly enlightening, and it has been great. I compliment
you all for moving these frontiers of knowledge. This committee
will do what it can to continue to provide the funding, and
hopefully we can get the money to do that.
Mr. Margus, thank you for being here. Mr. Affleck. Joe, do
you have any last thing you want to say to all these
scientists?
Mr. Kindregan. No.
Senator Harkin. How about I say for it for you? Hurry up.
CONCLUSION OF HEARING
Thank you all very much for being here, that concludes our
hearing.
[Whereupon, at 11:15 a.m., Wednesday, July 11, the hearing
was concluded, and the subcommittee was recessed, to reconvene
subject to the call of the Chair.]
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