[Senate Hearing 105-939]
[From the U.S. Government Publishing Office]
S. Hrg. 105-939
STEM CELL RESEARCH
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HEARINGS
before a
SUBCOMMITTEE OF THE
COMMITTEE ON APPROPRIATIONS UNITED STATES SENATE
ONE HUNDRED FIFTH CONGRESS
SECOND SESSION
__________
SPECIAL HEARING
__________
DECEMBER 2, 1998--WASHINGTON, DC
JANUARY 12, 1999--WASHINGTON, DC
JANUARY 26, 1999--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
TED STEVENS, Alaska, Chairman
THAD COCHRAN, Mississippi ROBERT C. BYRD, West Virginia
ARLEN SPECTER, Pennsylvania DANIEL K. INOUYE, Hawaii
PETE V. DOMENICI, New Mexico ERNEST F. HOLLINGS, South Carolina
CHRISTOPHER S. BOND, Missouri PATRICK J. LEAHY, Vermont
SLADE GORTON, Washington DALE BUMPERS, Arkansas
MITCH McCONNELL, Kentucky FRANK R. LAUTENBERG, New Jersey
CONRAD BURNS, Montana TOM HARKIN, Iowa
RICHARD C. SHELBY, Alabama BARBARA A. MIKULSKI, Maryland
JUDD GREGG, New Hampshire HARRY REID, Nevada
ROBERT F. BENNETT, Utah HERB KOHL, Wisconsin
BEN NIGHTHORSE CAMPBELL, Colorado PATTY MURRAY, Washington
LARRY CRAIG, Idaho BYRON DORGAN, North Dakota
LAUCH FAIRCLOTH, North Carolina BARBARA BOXER, California
KAY BAILEY HUTCHISON, Texas
Steven J. Cortese, Staff Director
Lisa Sutherland, Deputy Staff Director
James H. English, Minority Staff Director
------
Subcommittee on Departments of Labor, Health and Human Services, and
Education, and Related Agencies
ARLEN SPECTER, Pennsylvania, Chairman
THAD COCHRAN, Mississippi TOM HARKIN, Iowa
SLADE GORTON, Washington ERNEST F. HOLLINGS, South Carolina
CHRISTOPHER S. BOND, Missouri DANIEL K. INOUYE, Hawaii
JUDD GREGG, New Hampshire DALE BUMPERS, Arkansas
LAUCH FAIRCLOTH, North Carolina HARRY REID, Nevada
LARRY E. CRAIG, Idaho HERB KOHL, Wisconsin
KAY BAILEY HUTCHISON, Texas PATTY MURRAY, Washington
TED STEVENS, Alaska ROBERT C. BYRD, West Virginia
(Ex officio) (Ex officio)
Majority Professional Staff
Bettilou Taylor
Mary Dietrich
Minority Professional Staff
Marsha Simon
Administrative Support
Jim Sourwine and Jennifer Stiefel
C O N T E N T S
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Page
Wednesday, December 2, 1998
Statement of Harold Varmus, M.D., Director, National Institutes
of Health, Department of Health and Human Services............. 1
Opening remarks of Senator Arlen Specter......................... 1
Opening statement of Senator Tom Harkin.......................... 2
Prepared statement of Dr. Harold Varmus.......................... 8
Statement of John D. Gearhart, Ph.D., professor of gynecology and
obstetrics, Johns Hopkins University School of Medicine........ 11
Prepared statement........................................... 12
Statement of James Thomson, Ph.D., associate research animal
veterinarian, Wisconsin Regional Primate Research Center....... 14
Prepared statement........................................... 16
Statement of Michael West, Ph.D., president and chief executive
officer, Advanced Cell Technology.............................. 19
Prepared statement........................................... 20
Curing disease................................................... 26
Parkinson's disease.............................................. 27
Use of embryos................................................... 28
Federal ban on research on human embryos......................... 28
Treating age-related degenerative diseases....................... 31
Cloning.......................................................... 31
Parkinson's disease.............................................. 32
Diabetes......................................................... 33
Statement of Arthur L. Caplan, Ph.D., director, Center for
Bioethics, University of Pennsylvania.......................... 35
Prepared statement........................................... 37
Statement of Richard M. Doerflinger, associate director for
policy development, secretariat for pro-life activities,
National Conference of Catholic Bishops........................ 42
Prepared statement........................................... 44
Statement of Thomas B. Okarma, Ph.D., M.D., vice president of
research and development, Geron Corp........................... 51
Prepared statement........................................... 52
Statement of Eric Meslin, Ph.D., executive director, National
Bioethics Advisory Commission.................................. 66
Prepared statement........................................... 67
Fetus destruction................................................ 68
Prepared statement of Daniel Perry, on behalf of the Alliance for
Aging Research................................................. 76
Tuesday, January 12, 1999
Statement of Maria Freire, Ph.D., Director, Office of Technology
Transfer, National Institutes of Health, Department of Health
and Human Services............................................. 79
Opening remarks of Senator Arlen Specter......................... 79
Technology transfer legislation.................................. 80
Research tools................................................... 81
Prepared statement of Maria Freire............................... 82
Statement of Q. Todd Dickinson, J.D., Acting Assistant Secretary
of Commerce, and Acting Commissioner of Patents and Trademarks,
Department of Commerce......................................... 85
Prepared statement........................................... 87
Remarks of Senator Tom Harkin.................................... 91
Prepared statement........................................... 93
Time constraints................................................. 94
Statement of Lawrence Goldstein, Ph.D., professor of
pharmacology, Division of Cellular and Molecular Medicine,
University of California at San Diego.......................... 95
Prepared statement........................................... 97
Statement of Doug Melton, Ph.D., representing the Juvenile
Diabetes Association, Harvard University....................... 98
Prepared statement........................................... 100
Statement of Richard Pikunis, J.D., Parkinson's patient, Marlton,
NJ............................................................. 102
Prepared statement of the Biotechnology Industry Organization,
[BIO].......................................................... 104
Obtaining by ethical means....................................... 108
Patentability of research tools.................................. 110
Bayh-Dole Act.................................................... 110
University of Wisconsin research................................. 113
Bayh-Dole........................................................ 114
Tuesday, January 26, 1999
Statement of Harold Varmus, M.D., Director, National Institutes
of Health, Department of Health and Human Services............. 117
Opening remarks of Senator Arlen Specter......................... 117
Prepared Statement of Dr. Harold Varmus.......................... 121
Statement of Harriet Rabb, J.D., General Counsel, Department of
Health and Human Services...................................... 123
Remarks of Senator Tom Harkin.................................... 123
Statement of Eric M. Meslin, Ph.D., executive director, National
Bioethics Advisory Commission.................................. 128
Prepared statement........................................... 130
Statement of Richard M. Doerflinger, associate director for
policy development, secretariat for prolife activities,
National Conference of Catholic Bishops........................ 131
Prepared statement........................................... 134
Cells are units of organisms--organisms are units of life........ 142
STEM CELL RESEARCH
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WEDNESDAY, DECEMBER 2, 1998
U.S. Senate,
Subcommittee on Labor, Health and Human
Services, and Education, and Related Agencies,
Committee on Appropriations,
Washington, DC.
The subcommittee met at 9:34 a.m., in room SD-192, Dirksen
Senate Office Building, Hon. Arlen Specter (chairman)
presiding.
Present: Senators Specter and Harkin.
DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
STATEMENT OF HAROLD VARMUS, M.D., DIRECTOR
opening remarks of senator specter
Senator Specter. The Subcommittee on Labor, Health and
Human Services, and Education will now proceed.
Senator Harkin and I discussed our agenda for the year
several weeks ago and jointly decided that our initial hearing
ought to be on the highly charged, very important subject about
the use of human embryos and fetal tissue for medical research
and have accordingly scheduled this hearing today.
Before proceeding to the hearing, just a word or two about
reports of my own consideration for changing chairmanships of
subcommittees. I will be remaining as chairman of the
Subcommittee on Labor, Health and Human Services, and
Education. I had given some brief consideration to a change. I
was surprised, flattered, to hear so many people say that I
should stay.
These rumors have a way of appearing in print and sort of
out of control. But to put that matter to rest, I shall be
remaining as chairman of this subcommittee.
The subject matter on our hearing today arises from a
provision of the legislation reported out by this subcommittee
last year, which limits the use of Federal funds for research
on human embryos. That is an issue which has come into sharp
focus with very dramatic recent medical developments,
warranting a closer analysis or perhaps a reanalysis of that
question.
There is a curious dichotomy, really an inconsistency or an
arguable inconsistency, when Federal funds may be used on
research on fetal tissue, but not on human embryos. While there
are very substantial differences, the question is raised as to
whether that is a consistent policy.
The recent advances have shown that the stem cells have
potential to grow into any kind of bodily tissue and have, at
least reportedly, enormous potential on a wide variety of very
serious ailments--heart disease, diabetes, Alzheimer's, cancer,
spinal cord. We will get into a full range as we hear from our
expert witnesses today.
The problems with embryos are unique because the embryo has
the potential to create a new person under some circumstances,
and we shall explore that. There has been consideration raised
about the use of discarded embryos where couples using
fertility treatment discard embryos, another very complex and
controversial and very highly charged subject.
The discussion which we will be initiating today, or
carrying forward today, is one which will challenge ethicists
and theologians as well as Senators and members of the House.
The collateral question arises as to whether these procedures
may be patented. Some applications have already been made for
patents. So there are many, many questions which are raised on
this very, very important subject because of the potential to
treat illnesses of enormous importance and whether this is an
appropriate procedure.
That in a very brief statement, is an outline of some of
our parameters which we will expand during the course of
today's hearing and beyond. I now turn to my distinguished
colleague, the ranking member, Senator Harkin.
opening statement of senator tom harkin
Senator Harkin. Mr. Chairman, thank you very much for your
leadership of this committee. Thank you for holding this
important hearing to air the ethical and scientific issues
involved in stem cell research. I am pleased to have this
opportunity to hear directly from Dr. Varmus, our lead-off
witness, the distinguished scientists who have conducted this
ground-breaking research, as well as from the ethicists who
have examined the moral implications.
While the press has highlighted the exciting potential
benefits of Dr. Thomson and Dr. Gearhart's work, they have
spent much of their time documenting the controversy
surrounding their accomplishments. They have focused on the
Federal ban on human embryos research, the ethical implications
of advanced cell technologies research with human and bovine
cells, the President's request to the National Bioethics
Advisory Commission, and the scientific furor over the release
of ACT's unpublished research to the New York Times.
All of these issues deserve a full debate, and again I
thank you, Mr. Chairman, for bringing us together today. I also
want to thank you for continuing on and staying as chairman of
this subcommittee. I had heard these rumors and I thought if
they got very serious I was going to threaten you with great
bodily harm if you decided to leave. So I am grateful that you
did stay.
Senator Specter. That kind of bodily harm might not be
cured by stem cells, either. [Laughter.]
Senator Harkin. They would have to hurry up the research.
I want to thank Dr. West for his commitment to a public
discussion of the ethical implications of stem cells research
and to commend Doctors Thomson and Gearhart for their
groundbreaking accomplishments. From enabling the development
of cell and tissue transplantation to improving and
accelerating pharmaceutical research and development, to
increasing our understanding of human development and cancer
biology, the potential benefits of this work are awe-inspiring.
The cell lines they have isolated and kept alive could reduce
the demand for organ donors and pave the way for many life-
saving therapies.
They could help pharmaceutical companies improve the
testing of their products by providing an unlimited quantity of
normal human cells of any tissue. Therefore, rather than going
directly from animal testing to human testing, they could test
these new drugs for benefits and adverse effects on normal
human tissue.
And undoubtedly, a long-term benefit if their work will be
to enhance our understanding of human development, as
scientists may now be able to produce cells at specific stages
of human development that have previously been inaccessible to
research.
But all of these benefits could be delayed or even denied
to patients without a healthy partnership between the private
sector and the Federal Government. As many of you know, Senator
Specter and I are strong supporters of this partnership, and we
were pleased to be able to provide an historic increase for NIH
in this year's budget and will continue to work to double the
NIH budget in the next few years.
Now, while the market interest in stem cell technology is
strong and private companies will continue to fund the
research, the Government has an important role to play in
supporting the basic and applied science that underpins these
technologies. The problem is that early basic science is always
going to be underfunded by the private sector because this type
of research does not get products to the market quickly enough.
The only way to ensure that this research is conducted is
to allow NIH to support it. But unfortunately, as the American
Society for Cell Biology writes in a recent letter, the ban on
human embryo research ``has the effect of excluding the
majority of the Nation's most prominent researchers who are
supported by the NIH and limits the development of new
therapies.''
The key question that I hope will be addressed today is
whether under current law scientists can use Dr. Thomson's stem
cells for federally funded research. These stem cells do not
have the capacity to become a human being and, therefore, it is
my opinion, based upon a lot of study of this, that they do not
fall under the ban on human embryo research.
I know that NIH has asked the general counsel at the
Department to examine the law and make a determination. It is
my hope that this research will be allowed to go forward.
I would like to point out that Federal support is critical
to ensure that stem cell research using human embryos is
monitored and that consistent, up to date ethical guidelines
are followed. The research conducted by the distinguished
scientists sitting before us today holds such hope and such
potential for millions of people around the world who are sick
and in pain that I believe it is morally wrong for us to
prevent or delay our world-class scientists from building on
this progress.
However, I think it is right and proper for us as
policymakers to consider the ethical implications and demand
that consistent, up to date ethical and scientific guidelines
are established and followed.
We reach, I think, in the final analysis, the age-old
question: What are the limits of human knowledge? I have
responded consistently that I do not believe there are any
limits to human knowledge. There are ethical limits that
society may place on the use of that human knowledge.
But to limit this kind of research and to limit this kind
of expansion of human knowledge I believe in the final analysis
is really unhuman. As long as the research is conducted in an
ethically validated manner, it should be allowed to go forward
and it should receive Federal support.
Thank you, Mr. Chairman.
Senator Specter. Thank you very much, Senator Harkin.
In accordance with our regular practice, the 5-minute rule
will apply for opening statements by each witness. There will
be substantial time for questions and answers to elaborate upon
positions taken.
summary statement of dr. harold varmus
Senator Specter. Our lead witness is the distinguished
Director of the National Institutes of Health, Dr. Harold
Varmus, who has been at the job since November 1993, passing
the 5-year mark. At the University of California at San
Francisco he earned the Nobel Prize for his work on the
causative link between certain genes and cancer. A graduate of
Amherst, Harvard, and the Columbia Medical School.
Again, Dr. Varmus, we welcome you and the floor is yours.
Dr. Varmus. Mr. Chairman and Senator Harkin: Thank you very
much.
First let me express on behalf of the biomedical research
community and indeed the entire public our pleasure with your
official decision to remain as chairman of this committee. The
team you have formed with Senator Harkin here has been truly
extraordinary and the biomedical research community is
extremely grateful for your continued support.
I am also very pleased that you are holding this hearing--
--
Senator Specter. Did you like the $2 billion increase last
year? [Laughter.]
Dr. Varmus. We did, Senator, and we plan to use it well.
Senator Specter. We have quite a number of chairs where
staff sits. We have a lot of people standing. You are welcome
to come up and sit in these green chairs along the sidelines on
both sides. It should accommodate another 20 people. And you
may even sit in the first four seats on the Senators' dais, to
be replaced if you do not have an election certificate or if a
person arrives with a Senate election certificate. But you are
welcome to take the seats because of the overflow arrangements.
Dr. Varmus. Will these arrangements be subtracted from my
time, Senator?
Senator Specter. Yes.
Dr. Varmus. Thank you.
Senator Specter. We will give you all the time you need,
Dr. Varmus.
Dr. Varmus. Thank you. I am very pleased to have a chance
to join you at this hearing to discuss mainly the recently
published work by Dr. Jamie Thomson and Dr. John Gearhart that
has excited both the scientific community and the public. What
these scientists have done is to establish lines of pluripotent
human stem cells, cells that grow continuously in culture and
are capable of forming many different kinds of tissues. This
work does warrant public attention because of its scientific
and medical promise and because of the ethical concerns that it
raises.
I briefly would like to consider five questions. First,
what are stem cells, especially pluripotent stem cells? Second,
what are the potential uses of these stem cells? Third, what
methods have been used to make pluripotent stem cells? What is
the ethical status of pluripotent stem cells? And finally and
briefly, what is the role of NIH in these endeavors?
I am going to use some charts, Senator, to try to make
things clear.
[Chart.]
Let me begin by pointing out that there are many different
kinds of stem cells. Stem cells have the general properties of
being able to renew themselves, as indicated by these arrows,
to commit themselves to a higher degree of differentiation, a
higher, more specialized function, and to undergo this level of
commitment with time. Shortly after fertilization----
Senator Specter. Dr. Varmus, would you pull one of those
microphones over to you a little more closely. Thank you.
Dr. Varmus. Early in the process of the development of a
human being, after fertilization, cells are completely potent,
able to develop to give rise to a complete organism. Those
cells are called totipotent.
With time, cells become more highly specialized, resulting
in the formation of cells we call pluripotent, able to make
many different kinds of cells, but not give rise to an entire
organism.
Over the course of development, cells become yet more
specialized and develop into stem cells that are committed to
certain specific tissue lineages, like blood or muscle or liver
or nerve. Such stem cells, that can give rise to specific
tissues and are committed to those lineages, are found both in
the course of development in the fetus and in adults, and
you're no doubt familiar. For example, so-called blood or
hematopoietic stem cells were recently in the news as a result
of recent publications indicating that such stem cells can be
isolated, for example, from cord or placental blood and used as
a source of treatment in patients who are undergoing bone
marrow transplantation for cancer.
Indeed, there is a great deal of research going on with
these mature forms of stem cells that are committed to specific
lineages, and much of that research, supported by the NIH and
by industry, has achieved therapeutic status in the case of
bone marrow stem cells or blood stem cells, and much work is
going on with experimental animals to develop other kinds of
stem cells for various kinds of uses.
[Chart.]
But what are the great uses to which these so-called
pluripotent stem cells might be put? There are a variety of
venues for such research. First of all, since these cells are
relatively primitive in their place in the hierarchy, they can
be used to study the differentiation process that gives rise to
many different kinds of tissues, and this is going to hopefully
allow us to understand the origin of birth defects and to
understand many abnormalities of cell behavior, such as occur
in cancer, for example.
That, of course, goes on at the fundamental level. These
cells may also have many applied uses, for example in
identifying targets for development of new pharmaceuticals or
for carrying out simple means to assess the toxicity of
candidate pharmaceuticals.
In the realm of therapy, such stem cell lines that are
pluripotent in character may well be useful for developing
therapies that supply missing or defective tissues in a wide
variety of diseases--cells for patients with diabetes, heart
muscle cells for patients who have impaired cardiac function,
nerve cells for patients with a variety of neurodegenerative
diseases, like Parkinson's or Alzheimer's, and, of course, bone
marrow precursors for patients who have disorders of the blood-
forming system or have been treated for cancers.
Now, the assumption that all this work can be done is based
upon the fundamental research necessary to learn how to
efficiently differentiate pluripotent cells into the respective
lineages and to overcome the traditional problem of tissue
rejection due to the immune system.
How do we get to the point of obtaining such pluripotent
cells?
[Chart.]
Now, there are many ways that this can be done, but let me
focus on the two that will be the subject of discussions by
Doctors Gearhart and Thomson. I should mention that these
methods were developed with NIH funds to study how cells
develop in experimental animals, particularly the mouse.
Let me first remind you about the normal sequence of events
in a simple manner. Development begins, of course, with
fertilization of an egg by a sperm, shown here as occurs in a
test tube. That cell undergoes a series of divisions, still
producing cells that are fully capable of giving rise to an
embryo. But those cells go through further divisions and
undergo the first round of specialization, producing this sac-
like structure called a blastocyst, in which the cells that
will give rise to the mature individual are referred to as
cells within the inner cell mass.
The blastocyst then undergoes implantation in the womb and
eventually may give rise to a fetus, which eventually may give
rise to a newborn infant.
In the work conducted by Dr. Thomson, cells were taken from
the inner cell mass and placed into a petri dish under defined
conditions that he will describe for you and were then grown in
culture, producing what are referred to as pluripotent cells
and proved to be so by a variety of criteria.
In Dr. Gearhart's work, cells were taken from the gonadal
region of a fetus which was obtained from a terminated
pregnancy. These cells from the gonadal region, so-called
primordial germ cells, were cultured under specialized
conditions and proven by a variety of tests to be capable of
giving rise to a variety of tissues--hence this cell line was
also called pluripotent.
[Chart.]
Let me say a few words about the status of such cells.
There are many issues to be raised about the cells that we're
talking about today, but one of those questions is whether
these cells have the ability to give rise to a complete human
being. The answer to that from a scientific perspective is no.
I remind you that cells that are developed by
fertilization, cells early in development, or intact
blastocysts can, when reintroduced into a womb, give rise to an
infant, whereas cells removed from the inner cell mass or grown
as cultured pluripotent stem cells if reintroduced into a
uterus do not give rise to a new human being. Hence, these
pluripotent cells cannot be considered organisms and cannot be
considered to be embryos.
Now, let me turn at this point to a few additional
considerations. Despite what I have just told you about the
fact that pluripotent stem cells are not organisms and are not
embryos, because pluripotent stem cells are derived from human
organisms early in their development, the use of these cells
has raised legitimate public concerns and the cells do deserve
special ethical consideration.
As you will hear from the final panel of witnesses, there
is a wide range of views about the moral status of these cells
and the developmental states from which they are derived. These
views must, in my opinion, be taken into consideration in doing
research with such cells.
For example, in 1994 the NIH issued a report from its panel
on human embryo research that carefully reviewed the medical
benefits and the ethical quandaries that are presented by these
and other types of experiments. Then, 2 weeks ago President
Clinton asked the National Bioethics Advisory Commission to
give him further advice in the wake of recent publications.
Finally and briefly, what is the role of NIH in these
endeavors? Federal funds were not used in the experimental work
that you will hear about from Doctors Gearhart and Thomson
concerning human cells. The funding of Dr. Thomson's work by
the NIH was indeed forbidden by an amendment to our
appropriation bill. He used embryos that were remaining in an
in vitro fertilization clinic, donated by parents who had
successfully achieved pregnancy in a treatment for infertility.
Funding of Dr. Gearhart's work by the NIH would have been
possible under existing law, but he obtained support from
private industry instead.
Now, I cannot overemphasize that we at the NIH see enormous
promise in the work that is being discussed here today. We also
believe that it is beneficial, in general, for medical research
to be conducted in the public domain, with open dialog, with
careful oversight, and with maximum opportunity for
participation by the best minds in our country.
But, we also respect existing laws. We recognize the need
for public education about these complex issues, such as is
occurring today, and we insist on clear guidelines and careful
oversight for any research that might be carried out with these
cell lines or other controversial materials under Federal law.
prepared statement
Again, I thank you, Senator, for having the subcommittee
provide a venue for this important discussion, and I will be
very pleased to answer any questions that you might have.
Senator Specter. Thank you very much, Dr. Varmus. We have
turned off the red light to allow you to describe in somewhat
greater detail the specifics here.
[The statement follows:]
Prepared Statement of Harold Varmus M.D.
Mr. Chairman and Members of the Subcommittee, I am Harold Varmus,
Director of the National Institutes of Health. I am pleased to appear
before you to discuss recent published reports on the isolation and
propagation of the first human pluripotent stem cell lines. These
findings, reported by Drs. John Gearhart from Johns Hopkins University
and James Thomson from the University of Wisconsin, bring medical
research to the edge of a new frontier that is extraordinarily
promising. The development of human pluripotent stem cell lines
deserves close scientific examination, further evaluation of the
promise of the research, and careful consideration and open discussion
of the ethical and legal issues. I want to thank you for the
opportunity to discuss this important issue with you and the Members of
this Subcommittee.
Why the excitement? For the first time, scientists have obtained
human stem cells that can give rise to many types of cells in our body.
Let me briefly describe these experiments. Dr. Thomson and coworkers
derived stem cell lines from embryos donated by couples undergoing in
vitro fertilization (IVF) as part of treatment for infertility. These
cells were grown in culture and found to divide indefinitely and have
the ability to form cells of the three major tissue typesendoderm
(which goes on to form the lining of the gut), mesoderm (which gives
rise to muscle, bone and blood) and ectoderm (which gives rise to
epidermal tissues and the nervous system). The ability of the cells to
specialize into the three major tissues types is an important indicator
that these cells are pluripotent. Dr. Gearhart and his coworkers
derived pluripotent stem cells from fetal gonadal tissue destined to
form germ cells. When grown in culture, these cells resemble other
types of pluripotent stem cells in that they, like the cells from Dr.
Thomson's work, also can develop into cells of the three major tissue
types.
what are stem cells?
As policy makers proceed to consider the scientific, ethical and
societal issues raised by this research, it is absolutely essential to
clarify terms and definitions. There are many types of stem cells. In
general, they all have the ability to divide (and self renew) and to
commit to a more specialized function. There is a hierarchy of stem
cell types. Some stem cells are more committed than others. Some stems
cells--the pluripotent stem cell we are discussing today--have the
ability to become many, but not all, of the cells types in the human
body.
Through processes we are only beginning to understand, primitive
stem cells can be stimulated to become specialized, so that they are
precursors to any one of many different cell types such as muscle
cells, skin cells, nerve cells, liver cells. Unlike the stem cells from
which they are derived, these specialized cells are ``committed'' to a
particular function.
All stem cells have the capability of self-renewal, i.e., they can
continually reproduce themselves. Cells from the very earliest embryo
(up to about the 16 cell stage) are totipotent stem cells. They are
``totally potent'' or totally capable of forming all cells of the body,
including the cells required to support embryonic and fetal
development. Each cell of this early embryo has the potential to
develop into a human being.
After a few days of development, the early embryo forms a hollow
ball of cells, called a blastocyst. This is the next stage of embryonic
development. The clustered cells within this ball are called the inner
cell mass. The cells in the inner cell mass are not totipotent. Rather,
they are pluripotent. Pluripotent stem cells are more ``committed''
than totipotent stem cells. Unlike the fertilized egg, or the early
embryo, or the intact blastocyst, neither the disaggregated inner cell
mass nor the pluripotent stem cells derived from it (nor the
pluripotent stem cells derived from fetal germ cells) will produce a
human being even if returned to a woman's uterus. These cells do not
have the potential to form a human being, because they do not have the
capacity to give rise to the cells of the placenta or other
extraembryonic tissues necessary for implantation, nor can they support
fetal development in the uterus.
During fetal development, pluripotent stem cells become even more
committed, i.e, they have the capacity to form only one or a few
different kinds of cells. For example, hematopoietic stem cells can
form all the blood cells, but no other tissue types. The adult human
being continues to harbor many types of stem cells responsible for the
body's ability to repair some but not all tissues. Stem cells that
permit new skin growth and renewal of blood cells are two examples.
potential applications of pluripotent stem cells
There are several important reasons why the isolation of human
pluripotent stem cells is, indeed, important to science and for the
future of public health. At the most fundamental level, pluripotent
stem cells could help us to understand the complex events that occur
during human development. A primary goal of this work would be the most
basic kind of research--the identification of the factors involved in
the cellular decision-making process that determines cell
specialization. We know that turning genes on and off is central to
this process, but we do not know much about these ``decision-making''
genes or what turns them on or off. Some of our most serious diseases,
like cancer, are due to abnormal cell differentiation and growth. A
deeper understanding of normal cell processes will allow us to further
delineate the fundamental errors that cause these deadly illnesses.
Human pluripotent stem cell research could also dramatically change
the way we develop drugs and test them for safety and efficacy. Rather
than evaluating safety and efficacy of a candidate drug in an animal
model of a human disease, these drugs could be tested against a human
cell line that had been developed to mimic the disease processes. This
would not replace whole animal and human testing, but it would
streamline the road to discovery. Only the most effective and safest
candidate would be likely to graduate to whole animal and then human
testing.
Perhaps the most far-reaching potential application of human
pluripotent stem cells is the generation of cells and tissue that could
be used for transplantation, so-called cell therapies. Many diseases
and disorders result from disruption of cellular function or
destruction of tissues of the body. Today, donated organs and tissues
are often used to replace the function of ailing or destroyed tissue.
Unfortunately, the number of people suffering from these disorders far
outstrips the number of organs available for transplantation.
Pluripotent stem cells stimulated to develop into specialized cells
offer the possibility of a renewable source of replacement cells and
tissue to treat a myriad of diseases, conditions and disabilities
including Parkinson's and Alzheimer's disease, spinal cord injury,
stroke, burns, heart disease, diabetes, osteoarthritis and rheumatoid
arthritis. There is almost no realm of medicine that might not be
touched by this innovation. Let me expand on two of these examples.
Transplant of healthy heart muscle cells could provide new hope for
heart attack victims. The hope is to develop heart muscle cells from
human pluripotent stem cells and transplant them into the failing heart
muscle in order to augment the function of the heart. Preliminary work
in mice and other animals has demonstrated that healthy heart muscle
cells transplanted into the heart successfully repopulate the heart
tissue and integrate with the host cells. These experiments show that
this type of transplantation is feasible.
In the many individuals who suffer from Type I diabetes, the
production of insulin by the pancreas by specialized cells called islet
cells is disrupted. There is evidence that transplantation of either
the entire pancreas or isolated islet cells could mitigate the need for
insulin injections. Islet cell lines derived from human pluripotent
stem cells could be used for this critical research and, ultimately,
for transplantation.
While I have taken this opportunity to outline the promise of this
research, there is much to be done before we can realize these
innovations. First, we must do the basic research to understand the
cellular events that lead to cell specialization in the human, so that
we can direct these pluripotent stem cells to become the type(s) of
tissue needed for transplantation in great numbers. And before we can
use these cells for transplantation, we must overcome the well-known
problem of immune rejection. Because human pluripotent stem cells
derived from embryos or fetal tissue would likely be genetically
different from the recipient, future research would need to focus on
modifying human pluripotent stem cells to minimize tissue
incompatibility. Technological challenges remain before these
discoveries can be incorporated into clinical practice. These
challenges, though significant, are not insurmountable.
how are pluripotent stem cells produced?
There are several ways to produce human pluripotent stem cells.
These methods have been developed over the past 17 years by researchers
working with animals. The work you will hear about today builds on this
important basic animal research.
As I mentioned earlier, one method of creating these pluripotent
stem cells was described by Dr. Thomson and his coworkers. The
techniques they used were initially developed using mice. Dr. Thomson
first made stem cells from non-human primates. In the most recent work,
they used inner cell mass cells from blastocyst stage human embryos
that were created in the course of infertility treatment and donated by
couples for research to derive stem cells. The researchers allowed cell
division to continue in culture to the blastocyst stage and then
removed the inner cell mass, which was cultured to derive pluripotent
stem cells.
Pluripotent stem cells can also be derived from fetal tissue, as
was first done using primordial germ cells from mouse fetal tissue. Dr.
Gearhart and coworkers isolated human primordial germ cells, the cells
that will go on to become eggs and sperm, from 5-9 week old fetal
tissue obtained after pregnancy termination. When grown in culture,
these stem cells appear to be pluripotent.
It may also be possible to make human pluripotent stem cells by
using somatic cell nuclear transfer--the technology that received so
much attention with the announcement of the birth of the sheep, Dolly.
Although there has been no scientific publication of this to date,
presumably any cell from the human body (except the egg or sperm cell)
could be fused with an enucleated egg cell and stimulated to return to
highly immature, pluripotent and possibly totipotent state.
the role of the federal government
Federal funds were not used in either of the experiments that you
will hear about today. First, let me first address Dr. Thomson's work
in which cells were derived from embryos created by in vitro
fertilization but not used for infertility treatment. This work falls
clearly within the Congressional ban on human embryo research. NIH
could not, and did not, support Dr. Thomson's recent work developing
this cell line. The same restrictions do not apply to Dr. Gearhart's
work, although it may be governed by other laws and regulations. Dr.
Gearhart derived his pluripotent stem cells from fetal tissue from
terminated pregnancies. The Public Health Service Act authorizes
Federal funding of human fetal tissue research and provides safeguards
for its conduct. The department may conduct or support research on the
transplantation of human fetal tissue for therapeutic purposes if a
number of statutory requirements are met. Thus, if Dr. Gearhart's
research falls within these boundaries, NIH could have supported his
recent work deriving pluripotent stem cells from fetal tissue, as long
as he followed these Federal statutes and regulations. For the record,
NIH did not, however, support any of this research.
ethical issues
I have just described the science and the medical promise of
research on the pluripotent stem cell. But the realization of this
promise is also dependent on a full and open examination of the social
and ethical implications of this work. The fact that these stem cells
were produced from embryos and fetal tissue raises a number of ethical
concerns including, for example, the need to ensure that stem cell
research not encourage the creation of embryos or the termination of
pregnancies for research purposes. In strict accordance with the
President's 1994 directive, no NIH funds will be used for the creation
of human embryos for research purposes. We also will continue to abide
by relevant statutes.
The ethical and social issues associated with stem cell research
are complex and controversial and require thoughtful discourse in
public fora to reach resolution. To this end, the President has asked
the National Bioethics Advisory Commission to undertake a thorough
review of the issues associated with human stem cell research,
balancing all ethical and medical considerations.
summary
The development of cell lines that may produce almost every tissue
of the human body is an unprecedented scientific breakthrough. It is
not too unrealistic to say that this research has the potential to
revolutionize the practice of medicine and improve the quality and
length of life.
Mr. Chairman, I am grateful to you for providing a forum to present
information about this promising arena of science and medicine. I would
be pleased to answer any questions you might have.
NONDEPARTMENTAL WITNESSES
STATEMENT OF JOHN D. GEARHART, Ph.D., PROFESSOR OF
GYNECOLOGY AND OBSTETRICS, JOHNS HOPKINS
UNIVERSITY SCHOOL OF MEDICINE
Senator Specter. I think it would be useful--we have a very
long list of witnesses--if we invited at this time the next
three witnesses to join the panel because we will be talking
about very similar subjects, and then we will return to the
question and answer session. So let me call now for Dr. John
Gearhart, Dr. James Thomson, and Dr. Michael West to join us at
the panel.
Our first witness is Dr. John Gearhart, a professor of
gynecology and obstetrics at Johns Hopkins University. Dr.
Gearhart received his undergraduate degree from Penn State and
his Ph.D., from Cornell University in genetics, and has some
very fascinating results to report to us here this morning.
So we will begin with you, Dr. Gearhart. We would like to
observe the 5-minute time limit, leaving the maximum amount of
time for questions and answers. Thank you for joining us and
the floor is yours.
Dr. Gearhart. Thank you for the opportunity to appear
before the committee and to provide the committee with insight
into the research in which we have been engaged for the last 5
years. I feel strongly that the medical benefits of this
research will be enormous and that we are excited about its
potential.
Dr. Varmus has covered the salient features of embryonic or
pluripotent stem cells. I would like to reinforce a few points
and then I would like to tell you how we performed our
experiments.
The most important point I think to be reinforced is the
fact that, although these cells can form many different cell
types, they are unable by themselves to form an embryo or a
human being.
A bit of perspective. For the past 20 years I have been
involved in Down Syndrome research. This research has been
sponsored through the National Institutes of Health, and one of
the conclusions from our studies of 20 years is that many of
the events that lead to the abnormalities that one sees in Down
Syndrome occur very early during pregnancy, very early in
embryogenesis, at stages that we cannot have access to.
In studies from the mouse using embryonic stem cells, we
are able to look at very early developmental events utilizing
these cells, and thus our desire to establish human cells with
which we can study aspects of early development, focusing on
Down Syndrome.
[Chart.]
The procedure that we used in the laboratory is depicted on
the first placard. We obtained from autopsy material, fetal
autopsy material, this structure here--I hope I do not blind
somebody--which is a very small piece of tissue in which the
primordial germ cells reside from the period of 5 to 7 weeks
post-fertilization. This piece of tissue is dissociated, placed
in culture under certain conditions such that these cells will
grow, the germ cells, and will convert, for lack of a
scientific term, into a pluripotential stem cell.
I want to emphasize that this technology was first
developed in the mouse and we adapted it to the human. We did
not have to work it out in the human per se, just adapt it.
These cells, as depicted in our publication, have many of
the properties of embryonic stem cells. Our studies have
followed Federal, that is FDA and NIH, guidelines, State
guidelines, and institutional guidelines. Our research has been
rigorously reviewed annually by the Johns Hopkins School of
Medicine institutional review board, which considers not only
scientific merit but also ethical considerations of the work.
What of the application of this work? Well, we have
mentioned several times here its use in tissue transplantation,
birth defects studies, et cetera. My main interest coming into
this has been in aspects of birth defects, and directed
primarily to Down Syndrome.
[Chart.]
I would like to show you on the next placard, though, some
more recent results. What is depicted here are images of mature
human neurons that have been grown from embryonic stem cells in
culture. Embryonic stem cells have been grown for a period of 3
months and then treated over a period of 5 days so as to
encourage these cultures to form neurons. They are human, they
have the features of neurons, and this would go to show, I
think, some of the power of this technology from the standpoint
of being able to derive these different tissues in culture
which could perhaps then be used for tissue transplantation
studies.
prepared statement
In conclusion, I firmly believe that this research holds
the potential for treatments of catastrophic and debilitating
diseases and injuries that affect millions of Americans. What
is needed to realize this potential as soon as possible is
Federal support and oversight such as that that the NIH could
provide and that the investigators in this area not be
restricted in their endeavors, so that we may bring the
products of this technology to the patients as soon as
possible.
Thank you, Mr. Chairman.
Senator Specter. Thank you very much, Dr. Gearhart.
[The statement follows:]
Prepared Statement of John Gearhart
My name is John Gearhart and I am a Professor of Gynecology and
Obstetrics at the Johns Hopkins University School of Medicine. My
research interests are in how genes regulate the formation of tissues
and embryos. For the past 18 years my research has focused on Down
Syndrome in attempts to determine the causes of the birth defects
characteristic of this syndrome, with special emphasis on mental
retardation. As a result of our studies, it is apparent that the events
leading to the many birth defects characteristic of the syndrome occur
in the very early stages of the embryo's development, at stages not
accessible for study. Because of this limitation, I sought to develop
another approach that would enable us to study theses key events. The
approach I sought was to use human pluripotential stem cells (hPSC).
HPSCs will enable us to study the formation of specific tissues that
would reveal the cellular mechanisms resulting in the pathogenesis
found in Down Syndrome. Knowing how and when abnormalities arise will
enable us to design therapies to ameliorate the devastating effects of
developmental disabilities and enable individuals to have a better
quality of life.
In order to use human stem cells in the study of birth defects, the
first step was to culture hPSCs in the laboratory, something that had
not been done before we began our attempts in 1993. Over several years
I was able to put together a research team consisting of Drs. Michael
Shamblott, Peter Donovan, John Littlefield, Paul Blumenthal, and George
Huggins, with the excellent technical support of Elizabeth Bugg and
Joyce Axelman. This past year, Shunping Wang, a graduate student,
joined the team. On November 10th of this year we reported in the
Proceedings of the National Academy of Sciences our results on the
culturing of cells with properties of hPSCs. A copy of that paper is
submitted with this testimony.
I would like to place our recent work on hPSCs in perspective.
hPSCs are unique cells in that they have both the capacity to form any
of the over 200 different cell type in the body and to self-renew the
stem cell population. These properties can be realized in the
laboratory, that is, the stem cells can be grown indefinitely in tissue
cultures dishes and, under appropriate culture conditions, they will
form other cell types. It is important to note that while these cells
have the capacity to form a variety of cell types, they cannot form
embryos. Our laboratory used primordial germ cells (PGCs) as starting
material to derive the stem cells. PGCs are cells whose descendants are
sperm and eggs. PGCs were collected from autopsy material of
therapeutic pregnancy terminations and placed in tissue culture. Over a
period of two weeks in culture the PGCs develop into pluripotential
stem cells.
It has been well documented from animal studies that PSCs have full
developmental potential. Both in animals and in the culture dish, these
cells can form a wide variety of cell types including blood cells,
blood vessels, skeletal and cardiac muscle, and nerve tissue have been
shown to develop from these cells in the laboratory. I have presented
examples here today of nerve cells produced in the laboratory from the
human stem cells.
Although we can demonstrate a variety of cell types formed in the
laboratory from these cells, we do not yet know how to control which
cell types will form. This is one of the next challenges, to determine
how to direct all the stem cells in the culture dish to form specific
cell types, such as pancreatic islet cells, cholinergic neurons,
dopaminergic neurons, cardiac muscle, lymphocytes, etc. These cell
types are at risk in some of our more devastating diseases and a tissue
culture source would be ideal for therapies that are mentioned below.
The time frame for accomplishing this phase of the research will be
directly correlated to the research efforts of laboratories involved in
this research effort. Only a supportive research environment, both in
terms of policy and resources, will move this work forward rapidly.
What is to be gained from studies using hPSCs? I mentioned that my
group's initial motivation in attempting to isolate a human pluripotent
line was to provide a powerful tool for determining the bases of the
abnormalities seen in Down Syndrome, something we have been studying
for two decades. We have learned that the bases for many of the
features of this syndrome are initiated very early in the embryo.
Without a human pluripotential cell line, it would be impossible to
study the cells and tissue in which these features are initiated.
However, with this tool scientists may better understand mechanisms
behind the formation, and malformation, of distinct tissue types. With
this understanding, biomedical science may someday be able to alleviate
the worst of these features, such as mental retardation, in Down
Syndrome as well as other genetically based developmental
abnormalities. Without question, hPSCs will have the greatest impact on
medicine through their utilization in tissue transplantation therapies
in which tissues or cells are engrafted into organs, which have been
destroyed through disease or injury. Tissue transplantation therapy has
become increasingly important in the last two decades. Traditional
tissue transplantation therapies utilize such tissues as bone marrow,
bone, skin, etc. However, as each day passes, new therapies are
envisioned which tax current donation protocols. An example of such a
novel therapy is the use of tissue transplantation for the treatment of
Parkinson's Disease. This therapy began with the transplantation of the
patient's own dopaminergic adrenal medullary tissue into the
degenerating portions of the brain. The next development in the
treatment of Parkinson's was the utilization of fetal neural tissue
instead of adrenal tissue. The fetal tissue, due to its more plastic
state and its ability to grow and integrate into the host environment,
offers an effective treatment of Parkinson's disease.
With the rise of these novel tissue transplantation therapies,
equally novel graft resources have been sought. These include adult-
derived stem cells, such as those found in muscle; genetically
engineered graft tissue, non-human animal tissue, human fetal tissue
and, finally, the use of hPSCs. Eventually, through our abilities to
control what cell types are formed from the stem cells in the
laboratory and through the optimization of transplantation protocols,
the hPSCs will enable a panoply of new treatments. Along with
Parkinson's disease, it is likely that the symptoms of other
neurodegenerative disorders and injuries, such as Alzheimer's disease,
Huntington disease, stroke and spinal cord injury could be effectively
ameliorated and quality of life improved. Neurodegenerative disorders
are by no means the only conditions to which the use of human
pluripotent stem cells could apply. The bankable pluripotential stem
cells could be induced to form insulin-producing pancreatic b-cells to
make diabetics less dependent on insulin injection. Muscle stem cells
could also conceivably be produced from human pluripotential stem cells
in a large enough yield to help those with muscular dystrophies regain
better motor control. Cardiac muscle stem cell could be derived and
subsequently used to help in the treatment of degenerative heart
disease and perhaps decrease the necessity of more complicated and more
costly whole organ transplantation.
One of the major limitations of tissue transplantation is the issue
of graft rejection. The patient's immune system must be compromised to
allow for the presence of the graft. This generally involves the use of
powerful drugs with side affects. In animal studies, it has been found
that stem cells can be genetically manipulated so as to modify graft
rejection. It may eventually be possible to produce universal donor
cell lines in the laboratory through the use of hPSCs.
The capability of hPSCs to form a variety of cell types, their
ability to self-renew in the laboratory (and to be banked) and their
ability to be genetically manipulated to enhance their transplantation
efficiency, all support the contention that these cells will be an
invaluable resource in transplantation medicine.
Our research has been reviewed and approved annually by the
Institutional Review Board of the Johns Hopkins University School of
Medicine whose composition includes ethicists, religious leaders, lay
people, and doctors. This committee insures that we are in compliance
with all Federal, State and institutional requirements, from patient
consent, to record keeping, to safety. This committee considers ethical
issues as well as the scientific merit and research protocols. Our
research on stem cells has been supported through endowment funds to my
division in Gynecology and Obstetrics until last year, when we received
funding from Geron Corporation of Menlo Park, CA. My involvement with
Geron Corporation has been reviewed and approved by the Conflict-of-
Interest Committee for the Johns Hopkins University School of Medicine.
In conclusion, research with pluripotent human stem cells holds
enormous promise for treatments of catastrophic and debilitating
diseases and injuries affecting millions of Americans. To realize the
full medical potential of these cells, it is imperative that this work
goes forward in a supportive research environment with appropriate
overview and regulation. It is my opinion that this work should be
eligible for Federal funds and that the National Institutes of Health
should be given the responsibility to develop policy and guidelines,
review research applications, and award research grants on human
pluripotential stem cells. Only through the mechanism of NIH oversight
and support will the American people be assured that the medical
benefits of these cells for alleviating suffering will progress as
rapidly as possible and that any concerns that they may have will be
taken into account.
Thank you for the opportunity to address the committee on this
important issue.
This statement was prepared with the assistance of Brian Edwards.
STATEMENT OF JAMES THOMSON, Ph.D., ASSOCIATE RESEARCH
ANIMAL VETERINARIAN, WISCONSIN REGIONAL
PRIMATE RESEARCH CENTER
Senator Specter. We turn now to Dr. James Thomson,
Associate Research Animal Veterinarian at the Wisconsin
Regional Primate Research Center, a graduate of the University
of Pennsylvania in veterinary medicine, a Ph.D. in molecular
biology, author of numerous scientific publications in his
field.
Thank you for joining us, Dr. Thomson. The floor is yours.
Dr. Thomson. I would like to thank the committee for
inviting me. What I have to say overlaps a great deal with what
Dr. Varmus and Dr. Gearhart said, so I will be fairly brief.
My group has recently reported the derivation of human
embryonic stem cell lines. As you have heard, these are
undifferentiated cells. This means that they do not look like
the cells that make up the adult body. They are not yet
committed to become specific things. These undifferentiated
cells----
Senator Specter. People are straining to hear you in the
audience, so would you put the microphone closer, please.
Dr. Thomson. These undifferentiated cells can proliferate
in tissue culture indefinitely. That means we can make as many
of these cells as we want to and we know no biological limit to
the numbers of these cells we can make.
What is important about these cells is that, even after
prolonged culture for months and potentially years, they
maintain the ability to form many, if not all, of the cells
that make up the adult body.
Now, our cells differ in their source, where they came
from, compared to Dr. Gearhart's. Our cells were derived from
the pre-implantation embryo. They were derived from in vitro-
fertilized produced embryos, and these were produced for
clinical purposes, but they are in excess of the clinical needs
of the couples and the couples donated them specifically for
this project instead of actually discarding them. The informed
consent process was detailed and specified the purpose of the
research, its context, and its implications.
Now, as you have heard, human embryonic stem cells are
important because they could provide large purified populations
of human cells, such as muscle cells, pancreatic cells, or
neurons for transplantation therapies. Many diseases, including
diseases such as juvenile onset diabetes and Parkinson's
disease, result from the death or dysfunction of just one or a
few cell types, and the replacement of those cell types can
potentially offer life-long treatments.
These cells are also important because they will offer
insights in development events that cannot be studied directly
in the intact human embryo, but which have important
consequences in clinical areas, including birth defects and
fertility and pregnancy loss, and John Gearhart touched on Down
Syndrome, for example.
Screening tests that use specific ESL derivatives will
allow the identification of new drugs, the identification of
genes that could be used for tissue regeneration therapies, and
the identification of toxic compounds.
Although the long-term potential for human therapies
resulting from human ESL cell-line research is enormous, these
therapies will take years to develop. Significant advances in
developmental biology and transplantation medicine are
required, but I believe that therapies resulting from human ESL
research will become available within my lifetime.
How soon such therapies will be developed will depend on
whether there is public support of research in this area.
Private companies will have an important role in bringing new
ESL-related therapeutics to the marketplace. However, the
current ban in the United States on the use of NIH funding for
human embryo research discourages the majority of the best U.S.
researchers from advancing this promising area of medical
research.
Human pre-implantation embryo research was reviewed in
depth by the NIH human embryo research panel 1994. The NIH
panel recognized the therapeutic promise of human embryo
research, while recognizing that the human embryo warrants
serious moral considerations as a developing form of human
life. For these reasons the panel concluded in part:
Federal Funding and Regulation
It is in the public interest that the availability of
Federal funding and regulation should provide consistent
ethical and scientific review for this area of research. The
panel believes that, because the pre-implantation embryo
possesses qualities requiring moral respect, research involving
the ex utero pre-implantation embryo must be carefully
regulated and consistently monitored.
I agree with these conclusions.
prepared statement
This hearing on embryonic stem cell research is timely and
I hope that I can help you better understand the work we have
done and its medical and ethical implications. I would be
pleased to answer any of your questions.
Senator Specter. Thank you very much, Dr. Thomson.
[The statement follows:]
Prepared Statement of James A. Thomson
overview
My name is James Thomson and I'm a developmental biologist at the
University of Wisconsin-Madison. My group has recently reported the
derivation of human Embryonic Stem (ES) cells that can proliferate
indefinitely in tissue culture and yet maintain the potential to form
many, and possibly all, adult cell types. Human ES cells thus provide a
potentially unlimited source of specific differentiated cell types for
basic biological research, pharmaceutical development, and
transplantation therapies. These human ES cell lines were derived from
in vitro fertilized embryos before the formation of any fetal
structures. These embryos were produced by in vitro fertilization for
clinical purposes, but were in excess of clinical needs and were
donated after informed consent. The informed consent process was
detailed and specified the purposed of the research, its context, and
its implications.
Human ES cell lines are important because they could provide large,
purified populations of human cells such as heart muscle cells,
pancreatic cells, or neurons for transplantation therapies. Many
diseases, such as juvenile onset diabetes mellitus and Parkinson's
disease, result from the death or dysfunction of just one or a few cell
types, and the replacement of those cells by transplantation could
offer lifelong treatment. Human ES cells are also important because
they will offer insights into developmental events that cannot be
studied directly in the intact human embryo, but which have important
consequences in clinical areas, including birth defects, infertility,
and pregnancy loss. Screening tests that use specific ES cell
derivatives will allow the identification of new drugs, the
identification of genes that could be used for tissue regeneration
therapies, and the identification of toxic compounds.
Although the long-term potential for human therapies resulting from
human ES cell line research is enormous, these therapies will take
years to develop. Significant advances in developmental biology and
transplantation medicine are required, but I believe that therapies
resulting from human ES cell research will become available within my
lifetime. How soon such therapies will be developed will depend on
whether there is public support of research in this area. Private
companies will have an important role in bringing new ES cell-related
therapeutics to the marketplace; however, the current ban in the U.S.
on the use of Federal funding for human embryo research discourages the
majority of the best U.S. researchers from advancing this promising
area of medical research. Human preimplantation embryo research was
reviewed in depth by the National Institutes of Health (NIH) Human
Embryo Research Panel in 1994. The NIH Panel recognized the therapeutic
promise of human embryo research while recognizing that the human
embryo warrants serious moral consideration as a developing form of
human life. For these reasons, the panel concluded in part, ``It is in
the public interest that the availability of Federal funding and
regulation should provide consistent ethical and scientific review for
this area of research. The Panel believes that because the
preimplantation embryo possesses qualities requiring moral respect,
research involving the ex utero preimplantation human embryo must be
carefully regulated and consistently monitored.'' I agree with these
conclusions. This hearing on embryonic stem cell line research is
timely. I hope I can help you better understand the work we have done
and its medical and ethical implications, and I would be pleased to
answer any questions that you have.
what are human embryonic stem cells?
In the adult mammal, cells with a high turnover rate are replaced
in a highly regulated process of proliferation, differentiation, and
programmed cell death from undifferentiated adult ``stem cells''.
Tissues from which stem cells have been extensively studied include
blood, skin, and the intestine. In the human small intestine for
example, approximately one hundred billion cells are shed and must be
replaced daily. Although various definitions have been proposed,
characteristics of adult stem cells generally include: (i) prolonged
proliferation, (ii) self-maintenance, (iii) generation of large numbers
of progeny with the principle phenotypes of the tissue, (iv)
maintenance of developmental potential over time, and (v) the
generation of new cells in response to injury. Thus, stem cells in the
adult sustain a relatively constant number of cells and cell types.
Several properties of adult stem cells limit their therapeutic
potential. First, all adult stem cells are committed to becoming a
relatively restricted number of cell types. Second, although adult stem
cells can divide for prolonged periods, cell division can occur only a
finite number of times, so there is a limit to how much they can be
expanded in tissue culture. Third, the sustainable culture of adult
stem cells has not yet been achieved. And fourth, several tissues of
clinical importance, such as the heart, completely lack stem cells in
the adult. Thus, after a heart attack, when heart muscle dies, there is
no regeneration of heart muscle, only the formation of non-functional
scar tissue.
In contrast to the adult, embryonic cell proliferation and
differentiation elaborates an increasing number of cells and cell
types. In mammals, each cell of the cleavage stage embryo has the
developmental potential to contribute to any embryonic or
extraembryonic cell type, but by the blastocyst stage, cells on the
outside of the embryo (the trophectoderm) are committed to a particular
cell type found in the placenta (Figure 1). The cells on the inside of
the blastocyst (the inner cell mass) contribute to all the tissues of
the embryo proper. Soon after the blastocyst stage, cells of the inner
cell mass develop into cells that are developmentally restricted to
particular lineages. Because the cells of the inner cell mass
proliferate and replace themselves in the intact embryo for a very
limited time before they become committed to specific lineages, they do
not satisfy the criteria for stem cells that are applied to adult
tissues. In contrast, if the inner cell mass is removed from the normal
embryonic environment and dissociated under appropriate conditions, the
cells will remain undifferentiated, replace themselves indefinitely,
and maintain the developmental potential to contribute to all adult
cell types. Thus, these inner cell mass-derived cells satisfy the
criteria for stem cells outlined above, and they are referred to as
embryonic stem (ES) cells. The derivation of mouse ES cells was first
reported in 1981. We have recently described the isolation of human ES
cell lines that satisfy the following criteria for ES cells: (i)
derivation from the pre- or per-implantation embryo, (ii) prolonged
undifferentiated proliferation, and (iii) stable developmental
potential after prolonged culture to form differentiated derivatives of
all three embryonic germ layers (endoderm, mesoderm, and ectoderm)
which are the three basic lineages that give rise to all of the cells
of the adult. Cells we have already observed to differentiate from
human ES cell lines have included gut epithelium (endoderm), cartilage,
bone, and smooth and striated muscle (mesoderm); and neural epithelium,
embryonic ganglia, and stratified squamous epithelium (ectoderm).
why are human es cells important?
Human ES cell lines could offer insights into developmental events
that cannot be studied directly in the intact human embryo or in other
species, but which have important consequences in clinical areas,
including birth defects, infertility, and pregnancy loss. Particularly
in the early post-implantation period, knowledge of normal human
development is largely restricted to the description of a limited
number of sectioned embryos and to analogies drawn from the
experimental embryology of other species. Although the mouse is the
mainstay of experimental mammalian embryology, early structures
including the placenta, extraembryonic membranes, and the egg cylinder
all differ significantly from those of the human embryo. Human ES cell
lines will be particularly valuable for the study of the development
and function of tissues that differ between mice and humans.
Elucidating the mechanisms that control differentiation will
facilitate the directed differentiation of ES cells to specific cell
types. The standardized production of large, purified populations of
normal human cells such as heart muscle cells and neurons will provide
a potentially limitless source of cells for drug discovery and
transplantation therapies. For example, large purified populations of
ES cell-derived heart muscle cells could be used to find new drugs to
treat heart disease. Many diseases, such as Parkinson's disease and
juvenile onset diabetes mellitus, result from the death or dysfunction
of just one or a few cell types. The replacement of those cells could
offer lifelong treatment. In addition to Parkinson's disease and
juvenile onset diabetes, the list of diseases potentially treated by
this approach is long, and includes myocardial infarction (heart muscle
cells and blood vessels) atherosclerosis (blood vessels) leukemia (bone
marrow), stroke (neurons), burns (skin) and osteoarthritis (cartilage).
For the foreseeable future, these therapies will involve the repair of
organs by the transplantation of cells or simple tissues, but not the
replacement of entire organs.
Strategies to prevent immune rejection of the transplanted cells
need to be developed, but could include banking ES cell lines with
defined major histocompatibility complex backgrounds or genetically
manipulating ES cells to reduce or actively combat immune rejection.
Significant advances in basic developmental biology are required to
direct ES cells efficiently to lineages of human clinical importance.
However, progress has already been made in the in vitro differentiation
of mouse ES cells to neurons, hematopoietic cells, and cardiac muscle.
why is the derivation of human es cell lines controversial?
The derivation of human ES cells lines is controversial both
because of the use of human embryos, and because of the properties of
ES cell lines. We have derived human ES cell lines from in vitro
fertilized embryos at a stage before implantation (the blastocyst
stage) and before the formation of any fetal structures. These embryos
were produced by in vitro fertilization for clinical purposes, but were
in excess of clinical needs. Instead of discarding these embryos,
couples donated them specifically for ES cell derivation after informed
consent. The use of human embryos generated by in vitro fertilization
for any research purpose raises complex ethical issues, and it is
beyond the scope of this testimony to review the wide range of views on
this subject. Research on human preimplantation embryos has been
reviewed in depth by national panels in Britain, Canada, and the United
States. In Britain, some research on human preimplantation embryos is
allowed, but it is very carefully monitored and regulated, regardless
of whether public or private funds are used. The derivation of human ES
cell lines is already being publicly funded in Britain. In the U.S.,
the most recent and complete review of human preimplantation embryo
research was completed by the National Institutes of Health (NIH) Human
Embryo Research Panel in the fall of 1994. Although the guidelines
suggested by the NIH panel do not have the force of law, we followed
those guidelines in our derivation of human ES cell lines, as no other
Federal guidelines currently exist for privately funded human embryo
research. The derivation of human ES cell lines was specifically
addressed by the NIH Panel, and it was recommended as acceptable for
Federal funding, as long as embryos were not fertilized expressly for
that purpose. The subsequent ban on Federal funding for research on
human preimplantation embryos has prevented the NIH from funding the
derivation of human ES cell lines, and has prevented the NIH from
regulating and monitoring research in this area. The NIH Panel both
recognized the therapeutic promise of human embryo research and
recognized that the human embryo warrants serious moral consideration
as a developing form of human life. For these reasons, the panel
concluded in part, ``It is in the public interest that the availability
of Federal funding and regulation should provide consistent ethical and
scientific review for this area of research. The Panel believes that
because the preimplantation embryo possesses qualities requiring moral
respect, research involving the ex utero preimplantation human embryo
must be carefully regulated and consistently monitored.''
Human ES cell lines are not the equivalent of an intact human
embryo. If a clump of ES cells was transferred to a woman's uterus, the
ES cells would not implant and would not form a viable fetus. The
recent cloning of sheep and mice by the transfer of an adult cell
nucleus to an enucleated oocyte demonstrates that at least some adult
cells are totipotent (capable of forming an intact embryo that is
capable of developing to term). If nuclear transfer from adult cells to
enucleated oocytes allows development to term in humans, then the
transfer of a nucleus from an ES cell to an enucleated oocyte might
also result in a viable embryo. However, if someone wanted to clone a
specific famous or infamous individual, the transfer of a nucleus from
adult cell would have to be used, not a nucleus from an ES cell. One of
the major uses of mouse ES cells has been to genetically modify the
germ line (gametes) of mice in very specific ways. However, because of
the significant reproductive differences between mice and humans, and
the inefficiency of this method of modifying the germ line, human ES
cells do not increase the potential for modifying the human germ line.
As has already been demonstrated in domestic animal species such as the
cow and sheep, nuclear transfer techniques allow a much more efficient
way to modify the germ line of species with long generation times.
Thus, if someone wanted to genetically modify the human germ line,
there are already other approaches that would be quicker and more
efficient than using human ES cells. The NIH Human Embryo Research
Panel included recommendations against research involving nuclear
transfer to enucleated human oocytes or zygotes followed by transfer to
a uterus, and any formation of chimeras with human embryos; these
recommendations would effectively preclude the use of ES cells for
human cloning or modifying the human germ line.
STATEMENT OF MICHAEL WEST, Ph.D., PRESIDENT AND CHIEF
EXECUTIVE OFFICER, ADVANCED CELL TECHNOLOGY
Senator Specter. We now turn to Dr. Michael West, president
and chief executive officer of the Advanced Cell Technology.
Dr. West has a Ph.D., in cell biology from Baylor College of
Medicine and has recently noted the use of cloning techniques
to create an embryo out of human and cow cells.
We appreciate you joining us, Dr. West, and look forward to
your testimony.
Dr. West. Thank you, Mr. Chairman, members of the
subcommittee. I would like to just expand on a few salient
points. You have my written testimony.
First, I think it is important to emphasize what the aims
of this research we are discussing today is. The goal is to
solve unsolved problems in transplantation medicine. Currently
estimates are that upward of half of all health care
expenditures in the United States, so that is upwards of $400
billion, can in one way or another be attributed to costs
associated with transplantation. Even coronary artery bypass,
after all, is a transplantation procedure.
These costs are expected to be aggravated dramatically with
the aging of the population. As you know, our population is
greying at an alarming rate, such that perhaps up to a
sevenfold increase in the number of elderly between 1980 and
the year 2030 will occur. So with this is thought to be a dire
need for transplantable tissues. You may know that upwards of
ten people die every day awaiting a transplantable organ which
they do not receive. Many others die for lack of hope of a
transplant that could cure their disease. However, their
disease could be possibly treated with the technologies we are
discussing today.
The problem is two things. First is the availability of
tissues. They are simply not available. Many primitive
undifferentiated cell types that would be necessary to treat
disease like heart failure are not available. The discovery of
the human embryonic stem cells and the embryonic germ cell may
go a long ways toward supplying the unsupplied demand.
But a second problem is histocompatibility. The cells that
Dr. Gearhart and Thomson described have the potential to be
genetically engineered to be universal donor cells, so that
cells that they derive could potentially be used for all the
transplantation of the future. However, there is a distinct
risk that that is not a practically achievable goal. We simply
do not know today for sure a technology to make these cells
universal donor cells. They may indeed, for the foreseeable
future at least, require immunosuppressive therapies, drugs
that carry with them an inherent risk of rejection, despite
immunosuppression and life-threatening complications, including
death.
Now, a promising solution which could potentially
revolutionize transplantation medicine would be to combine this
embryonic stem cells technology with nuclear transfer
technology or cloning technology. Now, the concept here would
be that we would take the patient's own cell and fuse it with
an egg or oocyte cell that has had its nucleus removed. The
belief is that this nuclear transfer procedure can
dedifferentiate the cell, taking it back to this primitive
state where it can become any cell type, and in addition
actually rejuvenates the cell, makes the cell young again. So
for elderly patients with degenerative disease this procedure
may indeed provide some dramatic improvements in therapy.
The remaining problem, however, is that we simply cannot
practically achieve a means of sourcing human oocytes for a
large-scale solution to the problems of transplantation.
Sourcing human oocytes, we have potentially problematic and
cost issues, quality control, and risk to the donor.
So in 1996 Advanced Cell Technology began studies to
determine whether we could use an animal oocyte as a means of
dedifferentiating a human cell. Now, this is not cloning
technology. We are not cloning human beings. The intent is not
to clone human beings and we are against the cloning of a human
being.
The intent, however, would be to take an animal oocyte and
completely remove all genetic information by removing its
genomic nucleus that contains all of the DNA and, using that
oocyte stripped of its DNA, to reprogram a human somatic cell,
then making cells that would be fully compatible with the
patient.
prepared statement
This work was done in 1996. In 1997, as you know, there was
the announcement of the cloning of Dolly, and on March 4, 1997,
President Clinton asked for a voluntary moratorium in the
public and private sectors on human cloning. We felt that it
would be inappropriate for us to continue this research without
further guidelines and backed off from the research. However,
we recently announced these preliminary results in the hope of
stimulating debate, to hopefully receive guidelines to allow
this important technology to move forward. We believe that it
would be possible to address one of the most important,
significant, and life-threatening problems in medicine today
that could be addressed with transplantation.
Thank you.
Senator Specter. Thank you very much, Dr. West.
[The statement follows:]
Prepared Statement of Michael D. West
Mr. Chairman and members of the Subcommittee on Labor, Health and
Human Services and Education, my name is Dr. Michael D. West and I am
the President and Chief Executive Officer of Advanced Cell Technology a
biotechnology company based in Worcester, Massachusetts. A copy of my
curriculum vitae is presented in Appendix A.
introduction
I am pleased to testify today in regard to the new opportunities
and challenges associated with human embryonic stem (ES) cell and
nuclear transfer (NT) technologies. By way of introduction, I believe
it is important to bring to mind the context of these new
opportunities. We are approaching a period in our national history of
unparalleled growth of the elderly sector of the population. The aging
of the baby boom population along with a general increase in the number
of aged people is expected to increase the number of the elderly
sevenfold between 1980 and 2030 A.D. And since the aged use a
disproportionately high percentage of healthcare, this ``graying of
America'' is likely to greatly strain our national resources. It has
been estimated that transplantation procedures currently account for
nearly half of our health care expenditures, approaching $400 billion
annually. This is likely to grow even larger with the aging of our
population and result in a marked increase in the demand for
transplantation. The increased incidence of age-related degenerative
disease will likely lead to conflicts of economics, ethics, and
aesthetics as we struggle to find a humane and practical means of
treating the ailing. Concrete examples of tissues needed will likely
include: heart tissue for heart failure, arrhythmias, and ischemic
damage, cartilage for arthritis, neurons for Parkinson's disease,
kidney cells for kidney failure, liver cells for cirrhosis and
hepatitis, skin for burns and ulcers, and bone marrow transplantations
for cancer to name only a few. While current procedures are partially
successful in alleviating human suffering, these procedures are limited
by two major difficulties: (1) the availability of the needed cell or
tissue type, and (2) the histocompatibility of the transplanted
tissues. As a result, thousands of patients die every year for the lack
of transplantable cells and tissues and projections from the Bureau of
the Census suggest this shortage will worsen with the aging of our
population.
human es cells
Human ES cell technologies may greatly improve the availability of
diverse cell types. Human ES cells are unique in that they stand near
the base of the developmental tree. These cells are frequently
designated ``totipotent'' stem cells, meaning that they are potentially
capable of forming any cell or tissue type needed in medicine. These
differ from previously-isolated stem cells that are ``pluripotent''
that is, capable of forming several, but only a limited number, of cell
types. An example of pluripotent stem cells are the bone marrow stem
cells now widely used in the treatment of cancer and other life-
threatening diseases.
With appropriate funding of research, we may soon learn to direct
these cells to become vehicles of lifesaving potential. We may, for
instance, become able to produce neurons for the treatment of
Parkinson's disease and spinal cord injury, heart muscle cells for
heart failure, cartilage for arthritis and many others as well. This
research has great potential to help solve the first problem of tissue
availability, but the technologies to direct these cells to become
various cell types in adequate quantities remains to be elucidated.
Because literally hundreds of cell types are needed, thousands of
academic research projects need to be funded, far exceeding the
resources of the biotechnology industry.
As promising as ES cell technology may be, it does not solve the
second problem of histocompatibility. As shown in Figure 1, human ES
cells obtained from embryos derived during in vitro fertilization
procedures, or from fetal sources, are essentially cells from another
individual (allogeneic). Several approaches can be envisioned to solve
the problem of histocompatibility. One approach would be to make vast
numbers of human ES cell lines that could be stored in a frozen state.
This ``library'' of cells would then offer varied surface antigens,
such that the patient's physician could search through the library for
cells that are as close as possible to the patient. But these would
likely still require simultaneous immunosuppression that is not always
effective. In addition, immunospuppresive therapy carries with it
increased cost, and the risk of complications including malignancy and
even death.
Another theoretical solution would be to genetically modify the
cultured ES cells to make them ``universal donor'' cells. That is, the
cells would have genes added or genes removed that would ``mask'' the
foreign nature of the cells, allowing the patient's immune system to
see the cells as ``self''. While such technologies may be developed in
the future, it is also possible that these technologies may carry with
them unacceptably high risks of rejection or other complications that
would limit their practical utility in clinical practice.
Given the seriousness of the current shortage of transplantable
cells and tissues, the FDA has demonstrated a willingness to consider a
broad array of options including the sourcing of cells and indeed whole
organs from animals (xenografts) although these sources also pose
unique problems of histocompatibility. These animal cells do have the
advantage that they have the potential to be genetically engineered to
approach the status of ``universal donor'' cells, through genetic
engineering. However as described above, no simple procedure to confer
such universal donor status is known. Most such procedures are still
experimental and would likely continue to require the use of drugs to
hold off rejection, drugs that add to health care costs, and carry the
risk of life-threatening complications.
therapeutic cloning
A promising solution to this remaining problem of
histocompatibility would be to create human ES cells genetically
identical to the patient. While no ES cells are known to exist in a
developed human being and are therefore not available for treatment,
such cells could possibly be obtained through the procedure of somatic
cell nuclear transfer (NT). In this still largely theoretical
procedure, body cells from a patient would be fused with an egg cell
that has had its nucleus (including the nuclear DNA) removed. This
would theoretically allow the production of a blastocyst-staged embryo
genetically identical to the patient that could, in turn, lead to the
production of ES cells identical to the patient. In addition, published
data suggests that the procedure of NT can ``rejuvenate'' an aged cell,
restoring the proliferative capacity inherent in cells at the beginning
of life. Therefore, NT as applied to the production of therapeutic stem
cells could have valuable and important applications in the treatment
of age-related degenerative diseases.
The use of somatic cell nuclear transfer for the purposes of
dedifferentiating a patient's cells for purposes of obtaining
undifferentiated stem cells has been designated ``Therapeutic Cloning''
in the United Kingdom. This terminology is used to differentiate this
clinical indication from the use of NT for the cloning of a child which
in turn is designated ``Reproductive Cloning'' in the United Kingdom.
In the United Kingdom, the use of NT for therapeutic cloning is being
encouraged while legislation has been passed to prohibit reproductive
cloning. As promising as NT technologies may be in the arena of
therapeutic cloning, a remaining difficulty would be on a source of
human oocytes, both for research purposes, but also eventually for
large-scale clinical implementation. We believe there may be certain
advantages to the use of ``surrogate'' oocytes from animal sources.
Animal oocytes could be supplied in large numbers on an economical
basis, they could be ``humanized'' so as to provide fully human cells
with human, rather than animal, mitochondria, and they could also
potentially be engineered to be defective in producing a fetus even if
used in an inappropriate effort to clone a human being by implantation
in a uterus. Since these oocytes would be produced in cloned animals
(presumably cows), they could, in principle, offer two advantages: (1)
an economical and ethically acceptable source of oocytes for
therapeutic cloning, and (2) it is possible that they could be
engineered to be effective in dedifferentiating human cells and
allowing differentiation into specific lineages, but defective in
creating a human embryo if implanted into a uterus. This may prevent
the abuse of the technology in the event of an inappropriate use of the
technology in attempting to produce a pregnancy.
The NT technologies described above are not designed to be used for
the cloning of a human being. Advanced Cell Technology has no intent to
clone a human being, and we are opposed to efforts to clone a human
being. As of today, we see no clear utility in producing a child by NT,
and even if such uses were identified, NT would likely carry with it an
inappropriately high risks of embryonic and fetal wastage. However, we
believe that the production of genetically-engineered surrogate animal
oocytes may be an important resource for medical research, and may
solve certain practical and ethical problems associated with sourcing
human oocytes and the risks of abuse in human reproductive cloning.
It should be emphasized that the above-mentioned technologies are
still in the very earliest stages of development. It is not possible as
of today to determine whether the production of human ES cells through
sexual or asexual means will meet all the necessary requirements for
the development of human therapeutics. What is clear however, is that a
careful, informed, and reasoned public discourse would help insure that
these technologies could develop to the point where they could be used
in the clinic to treat human disease
ethical considerations
The problem of sourcing human cells and tissues for transplantation
raises numerous ethical dilemmas. Because developing embryonic and
fetal cells and tissues are ``young'' and are still in the process of
forming mature tissues, there has been considerable interest in
obtaining these tissues for use in human medicine. However, the use of
aborted embryo or fetal tissue raises numerous issues ranging from
concerns over increasing the frequency of elected abortion, to simple
issues of maintaining quality controls standards in this hypothetical
industry. Similarly, obtaining cells and tissues from living donors or
cadavers is also not without ethical issues. For instance, an important
and largely unresolved issue is whether it is morally acceptable to
keep ``deceased'' individuals on life support for long periods of time
in order to harvest organs as they are needed.
The implementation of ES-based technologies could address some of
the ethical problems described above. First, it is important to note
that the production of large numbers of human ES cells would not in
itself cause these same concerns in accessing human embryonic or fetal
tissue, since the resulting cells have the potential to be grown for
very long periods of time. Using only a limited number of human embryos
not used during in vitro fertilization procedures, biotechnology could
theoretically supply the needs of many millions of patients if the
problem of histocompatibility could be resolved. Second, in the case of
NT procedures, the patient may be at lower risk of complications in
transplant rejection. Third, the only human cells used would be from
the patient. Theoretically, the need to access tissue from other human
beings could be reduced.
On March 4, 1997 President Clinton asked for a, ``moratorium on the
cloning of human beings until our Bioethics Advisory Commission and our
entire nation have had a real chance to understand and debate the
profound ethical implications of the latest advances.'' Prior to this
1997 request and the cloning of Dolly, Advanced Cell Technology had
initiated research into the use of human somatic cell NT for human cell
therapy (therapeutic cloning) and had obtained preliminary results that
suggested the technology would be useful in treating disease. Following
the President's request, however, the Company tabled all research in
this area awaiting clarification of recommended guidelines. After
internal review in 1998, the Company decided that it did not have
sufficient data to assemble a scientific publication, but believed that
it was in the public interest to release the preliminary results to
promote an informed and reasoned public discussion of the issues. In
this regard, we are grateful for the President's request of November
14, 1998 asking the National Bioethics Advisory Commission to analyze
the issues surrounding this new technology.
In regard to the President's letter of November 14, 1998, we would
like to offer the following observations. First, we share the
President's concerns regarding the mixing of DNA across species. By way
of background, it is useful to recall the debate surrounding the
specter of mingling of human and non-human DNA in gene splicing
technologies in the 1970s. In addition to the general discomfort of
combining the genes of organisms across the plant and animal kingdoms,
there were more focused concerns raised concerning the deliberate
mixing of the genomes of viruses such as adenovirus and tumor viruses
such as SV40 or between SV40 and bacteria such as E. coli for fear that
new and virulent man-made pathogens may unintentionally result in a
major health risk. Shortly thereafter, there were again concerns voiced
over the mixing of antibiotic resistance genes in bacteria not then
possessing such resistance. The resolution of those concerns may guide
us in the consideration of these new technologies. The use of
attenuated strains of host organism, and other precautions have served
us well and allowed recombinant technology to advance and, in doing so,
to improve the human condition.
Concerns over the mixing of the genomes of differing species is
even of greater concern given newer technologies that allow the
transfer of entire chromosomes across species. Given justifiable
concerns that these technologies not be abused in medical research, we
join in asking for ethical debate of the issue of the mixing of genomic
DNA across species.
The mixing of DNA across species does not, however, bear on the
issue of NT. The research performed in 1996 resulted in human cells
with less than one millionth of the DNA being from a nonhuman (bovine)
source, and that DNA was for the mitochondria, an energy source for the
cell, not encoding species-specific traits such as eye color,
intelligence, or other distinctive features. In addition, it was, and
is, the intent of Advanced Cell Technology to produce fully-human stem
cells through the genetic modification of the bovine egg cell to
introduce human mitochondrial DNA.
The relevant issue is that the biotechnology industry is seeking
guidelines for the application of ES and NT technologies in medicine.
We believe that these new technologies, if properly applied, could lead
to significant medical advances with lifesaving potential. Poorly
constructed legislation, designed to prohibit the cloning of a human
being, could inadvertently interfere with urgent and ethical
applications of the technologies in medicine.
Prohibitions against humanized surrogate NT may also have serious
collateral consequences in addition to harming these new therapeutic
avenues. During various in vitro protocols, it is not unlikely that
human oocytes or embryos may be cultured in the presence of bovine
proteins, such as bovine fetal calf serum. It would be unwise to set a
precedent that the contact of a human embryonic cell with nonhuman
(bovine) proteins is to be prohibited. Proteins do not encode
hereditary information. The sensitivity remains in the area of mixing
genomes (DNA) of human and animal, likely not the mixing of proteins,
especially in the surrogate protocol under discussion wherein the
bovine proteins are rapidly replaced by human.
We therefore respectfully request that Congress be measured and
forward-thinking taking into full account the tools necessary for
medical researchers to apply these exciting new technologies in
clinical practice in the future.
[GRAPHIC] [TIFF OMITTED] T07DE02.003
______
Appendix A
michael david west, b.s., m.s., ph.d., curriculum vitae, september 1998
Personal
Date and Place of Birth: April 28, 1953; Niles, Michigan.
Citizenship: U.S.A.
Ethnicity: Caucasian.
Marital Status: Married, no children.
Home Address: 555 Bryant St., No. 280, Palo Alto, CA 94301.
Email: [email protected].
Education
Niles Senior High School; Niles, MI: 1971.
Rensselaer Polytechnic Institute; Troy, NY: B.S. Major: Psychology
1976; Minor: Management.
Andrews University; Berrien Springs, MI; M.S. Biology 1982.
Baylor College of Medicine; Houston, TX: Ph.D. Cell Biology 1989,
(Division of Molecular Virology)
Business Experience
West Motor Leasing Company, Inc., President, General Manager, 1976-
1982.
West Leasing Company, Inc., President, General Manager, 1978-1982.
West Motor Sales, Inc., President, General Manager, 1980-1982.
Geron Corporation, Founder, Director, Officer, 1990-1998.
Origen Therapeutics, Inc., Founder, Chairman, 1997-Present.
Advanced Cell Technology, Inc., President & CEO, 1998-Present.
Research and Professional Experience
1998-Present: President and CEO, Advanced Cell Technology, Inc.,
One Innovation Dr., Worcester, MA 01605.
1997-Present: Founder, Chairman, Origen Therapeutics, Inc., 651
Gateway Blvd., Ste. 980, South San Francisco, CA 94080.
1994-1998: Founder and V.P. of New Technologies, Geron Corporation,
200 Constitution Dr., Menlo Park, CA 94025.
1993-1994: Founder and V.P. of Business Development, Geron
Corporation, 200 Constitution Dr., Menlo Park, CA 94025.
1992-1993: Founder, VP, and Chief Scientific Officer, Geron
Corporation, 200 Constitution Dr., Menlo Park, CA 94025.
1990-1992: Founder, President and CEO, Geron Corporation, 200
Constitution Dr., Menlo Park, CA 94025.
1990-1992: Senior Research Scientist, Department of Cell Biology
and Neuroscience, Southwestern Medical School, 5323 Harry Hines Blvd.,
Dallas, Texas 75235, Laboratories of: Dr. Woodring E. Wright, Dr. Jerry
W. Shay.
1989-1990: Postdoctoral Research Fellow, Department of Cell Biology
and Neuroscience, Southwestern Medical School, 5323 Harry Hines Blvd.,
Dallas, Texas 75235, Laboratories of: Dr. Woodring E. Wright, Dr. Jerry
W. Shay.
1985-1988: Graduate Student (Ph.D.), Baylor College of Medicine,
Division of Molecular Virology, One Baylor Plaza, Houston, TX 77030.
1982-1985: Graduate Student (Doctoral Candidate), University of
Arkansas for Medical Sciences, Department of Biochemistry, 4301 W.
Markham, Little Rock, AR 72205.
1979-1982: Graduate Student (M.S.), Andrews University, Department
of Biology, Berrien Springs, MI 49104.
______
Bibliography
Patents
1. West, M.D. 1996. Trypsin-sensitive Agent Able to Reduce PAI-1
and beta-APP Expression in Senescent Cells and Increase the Ability of
Fibroblasts to Divide in Culture. U.S. Patent No. 5,482,838.
2. West, M.D., Shay, J., Wright, W. 1996. Therapy and Diagnosis of
Conditions Related to Telomere Length and/or Telomerase Activity. U.S.
Patent No. 5,489,508.
3. West, M.D. 1996. PADPRP Inhibitors to Treat Diseases Associated
with Cellular Senescence. U.S. Patent No. 5,589,483.
4. Shay, J., West, M.D., and Wright, W.E. 1997. Methods for Cancer
Diagnosis and Prognosis. U.S. Patent No. 5,639,613.
5. West, M.D., Harley, C.B., Strahl, C.M., McEachern, M.J., Shay,
J., Wright, W.E., Blackburn, E.H., and Vaziri, H. 1997. Therapy and
Diagnosis of Conditions Related to Telomere Length and/or Telomerase
Activity. U.S. Patent No. 5,645,986.
6. West, M.D., Shay, J., and Wright, W.E. 1997. Telomerase
Diagnostic Methods. U.S. Patent No. 5,648,215.
7. West, M.D., Shay, J., and Wright, W.E. 1997. Methods for
Screening for Agents which Modulate Telomere Length. U.S. Patent No.
5,686,245.
8. West, M.D., Shay, J., and Wright, W.E. 1997. Methods and
Reagents for Lengthening Telomeres. U.S. Patent No. 5,686,306.
9. Shay, J., West, M.D., and Wright, W.E. 1997. Methods for Cancer
Diagnosis and Prognosis. U.S. Patent No. 5,693,474.
10. West, M.D., Shay, J., Wright, W., Blackburn, E.H., and
McEachern, M.J. 1997. Telomerase Activity Assays for Diagnosing
Pathogenic Infections. U.S. Patent No. 5,695,932.
11. West, M.D. 1998. Method to extend life span and proliferative
capacity of cells--comprises administration of polyadenosine
diphosphate-ribose polymerase inhibitor to cells. WO 9827975.
12. Feng, J., Funk, W., Hirsch, K.S., Linskens, M.H.K.,
Villeponteau, B., and West, M.D. 1998. Identifying, isolating, and
regulating senescence-related genes--useful to ameliorate problems
associated with accumulation of senescent cells, e.g. age-related
lipofuscin accumulation in the retina and AIDS. U.S. Patent No.
5,744,300.
13. Blackburn, E.H., Shay, J., West, M.D., and Wright, W. Therapy
and Diagnosis of Conditions Related to Telomere Length and/or
Telomerase Activity. Australian Patent No. 688.262.
14. Linskens, M.H.K., Hirsch, K.S., Villeponteau, B., Feng, J.,
Funk, W., and West, M.D. 1998. Methods and Reagents for the
Identification and Regulation of Senescence-Related Genes. U.S. Patent
No. 5,744,300.
Scientific Publications
1. West, M.D., Pereira-Smith, O.M., and Smith, J.R. 1989.
Replicative Senescence of Human Skin Fibroblasts Correlates with a Loss
of Regulation and Overexpression of Collagenase Activity. Experimental
Cell Research, 184:138-147.
2. West, M.D. 1989. An Examination of Growth Factor Modulation of
Extracellular Matrix Metabolism in Human Skin Fibroblasts During
Cellular Senescence In Vitro, Ph.D. Dissertation, Baylor College of
Medicine, Houston, TX.
3. Shay, J.W., West, M.D., Wright, W.E. 1992. Re-expression of
Senescent Markers in De-induced Reversibly Immortalized Cells. Exp.
Gerontology. 27:477-492.
4. West, M.D. 1994. The Cellular and Molecular Biology of Skin
Aging. Arch. Dermatol. 130:87-95.
5. Harley, C.B., Kim, N.W., Prowse, K.R., Weinrich, S.L., Hirsch,
K.S., West, M.D., Bacchetti, S., Hirte, H.W., Counter, C.M., Greider,
C.W., Piatyszek, M.A., Wright, W.E., and Shay, J.W. 1994. Telomerase,
Cell Immortality, and Cancer. Cold Spring Harbor Symposium on
Quantitative Biology LIX: 307-315. Cold Spring Harbor Press. Cold
Spring Harbor, N.Y.
6. Kim, N.W., Piatyszek, M.A., Prowse, K.R., Harley, C.B., West,
M.D., Ho, P.L.C., Coviello, G.M., Wright, W.E., Weinrich, S.L., and
Shay, J.W. 1994. Telomerase Activity is Associated with Cell
Immortality and Advanced Human Carcinomas. Science, 266:2011-2014.
7. Feng, J., Funk, W.D., Wang, S-S, Weinrich, S.L., Avilion, A.A.,
Chiu, C-P., Adams, R., Chang, E., Allsopp, R.C., Siyuan Le, J-Y., West,
M.D., Harley, C.B., Andrews, W.H., Greider, C.W., Villeponteau, B.V.
1995. The RNA Component of Human Telomerase. Science. 269:1236-1241.
8. Linskens, M.H., Harley, C.B., West, M.D., Campisi, J., and
Hayflick, L. 1995. Replicative Senescence and Cell Death. Science
267:17.
9. West, M.D. 1995. Chromosome and Breakage. In The Encyclopedia of
Aging. 2nd Edition. Springer, NY. p179.
10. West, M.D., Shay, J.W., Wright, W.E., and Linskens, M.H.K.
1996. Altered expression of plasminogen activator and plasminogen
activator inhibitor during cellular senescence. Exp. Gerontol. 31:175-
193.
11. Effros, R.B., Allsopp, R., Chiu, C-P., Hausner, M.A., Hirji,
K., Wang, L., Harley, C.B., Villeponteau, B., West, M.D., and Giorgi,
J.V. 1996. Shortened telomeres in the expanded CD28- CD8+ cell subset
in HIV disease implicate replicative senescence in HIV pathogenesis.
AIDS 10:F17-F22.
12. Vaziri, H., West, M.D., Allsopp, R.A., Davison, T.S., Wu, Y-S.,
Arrowsmith, C.H., Harley, C.B., Poirier, G.G., and Benchiol., S. 1997.
ATM-dependent telomere loss in aging human diploid fibroblasts and DNA
damage lead to the post-translational activation of p53 protein through
poly (ADP-ribose) polymerase. EMBO J. 16:6018-6033.
13. West, M. D., and Hjelmeland, L. M. 1997. Replicative
senescence: A role in age-related macular degeneration? (Invited
review, manuscript in preparation).
14. West, M. D. 1997. Collagenase and Aging. In The Collagenases,
Springer Verlag, In Press.
15. Matsunaga, H., Handa, J.T., Aotaki-Keen, A., Sherwood, S. W.,
West, M.D., and Hjelmeland, L.M. 1998. Markers of Preplicative
Senescence in Human Retinal Pigment Epithelial Cells in vitro. Invest.
Ophthalmol. Vis. Sci. (In Press).
16. West, M.D. Telomere Length Assays in Gerontological Research.
1998. Invited Review, Manuscript in Preparation.
curing disease
Senator Specter. Dr. Varmus, we will begin the first round
of questioning with you. There has been considerable discussion
already about curing disease, dealing with life-threatening
ailments, Parkinson's, heart disease, cancer, Alzheimer's. Are
there any limitations as to the range of this kind of a
technique on curing diseases? Would it apply to everything?
Dr. Varmus. Well, Senator, it is a little difficult to
answer the question because it is very difficult to know what
science would be capable of producing. As you have heard from
the----
Senator Specter. But the basic point is you find a way of
replicating cells which are diseased. So would there be any
apparent limitation on the scope of these technologies to cure
any kind of a disease?
Dr. Varmus. There would be certain kinds of diseases; for
example, infections would not immediately be amenable to
therapies with these cells. But as you have heard, one of the
limitations that currently exists is that, while we know that
the cells in question can form many different kinds of tissues,
we do not yet have the knowledge that allows us to efficiently
differentiate them into the tissue of choice.
Moreover, as Dr. West just pointed out again and as others
of us have alluded to, we do not yet have a clear solution to
the problem of what we call histocompatibility, having tissues
that can be delivered to any individual and not rejected by
that individual's immune system. Indeed, the use of somatic
cell nuclear transfer methods does offer promise in this regard
and there is the potential for developing cell lines with
pluripotent potential using that methodology.
Indeed, in last year's discussion of the Human Cloning
Prohibition Act the President issued a statement of
administration policy in which he wanted to preserve the
ability to use somatic cell nuclear transfer with human cells
for the purpose of developing stem cells for exactly this
purpose. Of course, we view there to be a prohibition on that
kind of research at the moment due to the amendment that I
alluded to in our appropriation bill.
parkinson's disease
Senator Specter. Dr. Varmus, perhaps it would be helpful to
take a specific ailment and to run through how this approach
would, say, deal with Parkinson's. Could you use that
illustratively to tell us what could be done to treat someone
with Parkinson's?
Dr. Varmus. As you know, Senator, Parkinson's is a result
of loss of certain nerve cells in a region of the brain called
the basal ganglia. Those cells are responsible for producing
dopamine, an important neurotransmitter. There already are
methodologies in use that attempt to restore brain function,
for example by transplanting fetal cells to the brains of
individuals with this disease, or by attempting to inactivate
cells that usually inhibit the ability of other cells to
produce dopamine.
You saw, still can see, a picture of nerve cells derived in
Dr. Gearhart's experiments from his pluripotent stem cells. One
could imagine being able to induce cells that specifically make
dopamine and to introduce those cells using so-called
stereotaxic instrumentation into the appropriate place in the
brain to restore the function of that part of the nervous
system.
Senator Specter. Well, how will the stem cell technique
advance the current techniques used to deal with Parkinson's?
Dr. Varmus. Well, the objective would be to be able to
produce cells that are specifically designed to carry out the
function of the cells that have undergone deterioration in the
process of developing the disease. I cannot give you one, two,
three yet, because obviously there is work to be done. But the
point would be to have a large repertoire of cells that, rather
than having to go and identify and having to use many fetal
donors, essentially, one could have a bank of cells that is
known to respond to certain kinds of chemical instructions to
make the kinds of cells that would be useful in the
transplantation process.
Senator Specter. One of the questions which those of us on
this side of the panel always ask with respect to time line and
cures is how much appropriations will set you in motion to find
the answer. But illustratively, is it possible to give a
generalization, if this research were unleashed, how long it
would take to find a cure, say to Parkinson's or Alzheimer's?
Dr. Varmus. Well, remember, Senator, that I referred to the
fact that certain kinds of stem cells are already in use in
clinical practice, for example blood stem cells, and there are
experimental models, especially in mice, that indicate that
certain other tissues, like the heart, may be repaired by the
use of cells that have been converted from committed stem cells
to heart muscle cells using an appropriate recipe.
Given those precedents, it seems to me that within the
course of the next decade or two, with an appropriate cadre of
investigators, that many, many diseases would be at least
treated, if not entirely cured, by the kinds of cell therapies
we are talking about.
use of embryos
Senator Specter. My red light is on, but I am going to ask
one final question of Dr. Thomson with respect to the embryos.
There is the obvious concern of the use of embryos where an
embryo could be the start of a human life. In your research in
the use of embryos, how do you deal with this specific issue?
Dr. Thomson. The embryos that we used were specifically
made for clinical purposes, but they were beyond what the
patients could use. The majority of these embryos had been
frozen for a number of years and they had to decide what to do
with them. The option that they were considering was to discard
them, so it was a choice between discarding the embryos and
doing this research.
Senator Specter. So what you are saying is that none of the
embryos which you used had the possibility of being the start
of a human life?
Dr. Thomson. Because they would otherwise be discarded,
yes.
Senator Specter. Because?
Dr. Thomson. They would have otherwise been discarded.
Senator Specter. Otherwise been discarded.
Well, my time is up.
Senator Harkin.
federal ban on research on human embryos
Senator Harkin. Mr. Chairman, thank you.
Since we have a limited amount of time, I have two things I
want to kind of clear up. One kind of gets to the heart of the
matter, I hope, here on whether or not the use of these stem
cells are covered under the Federal ban that was placed here a
couple of years ago on research on human embryos. Now, let me
just read the law. It says: ``None of the funds made available
in this act may be used for: (1) the creation of a human embryo
or embryos for research purposes.'' We're not talking about
that here, is that clear? Is that right? ``(2) Research in
which a human embryo or embryos are destroyed, discarded, or
knowingly subjected to risk of injury or death greater than
that allowed for research on fetuses in utero under pertinent
sections of the Public Health Service Act.''
Is that included here? ``None of the funds made available
under this act may be used for research in which a human embryo
or embryos are destroyed, discarded, or knowingly subjected to
risk of injury or death greater than that allowed for research
on fetuses in utero under 45 CFR,'' et cetera, et cetera.
Now, let me read the next paragraph: ``B. For purposes of
this section, the term' human embryo or embryos' includes any
organism, not protected as a human subject under 45 CFR 46 as
of the date of enactment of this act, that is derived by
fertilization, parthenogenesis, cloning, or any other means
from one or more human gametes or human diploid cells.''
My point is this. It says: ``For purposes of this section,
the term' human embryo or embryos' includes any organism.''
Now, I heard someone say that these stem cells are not
organisms. Now, so I asked my staff to get me the dictionary. I
want to find out what an ``organism'' is. In this dictionary,
Random House--maybe it is different in some others--it says:
``Organism. 1. A form of life composed of mutually dependent
parts that maintain various vital processes.''
Now, to my limited scientific knowledge, that definition
does not meet a stem cell. It does not seem that a stem cell
contains ``mutually dependent parts that maintain various vital
processes.''
So my question is, getting back to the matter of whether or
not these are covered by the ban on Federal human embryo
research: One, are these organisms? Are these stem cells
organisms? I am just asking. Anybody? Dr. West?
Dr. West. The cultured cells I would say are not. If they
are, for instance, grown in a laboratory dish or transplanted
into a uterus, they will not form a human being. They have
never been observed to form a complete animal using the animal
equivalent of these cells.
Senator Harkin. Dr. Varmus.
Dr. Varmus. As a scientist, as I have testified here today
from the perspective that I bring to this from my professional
background, I agree that these are not organisms. The issue
that we are dealing with in the Government is complying with
the law, knowing the legal definition of an organism, and we
are struggling with this as part of the activities in the
Department and elsewhere in the administration to be sure that
any actions we take in response to these developments are in
compliance with existing law.
Senator Harkin. I understand.
Dr. Thomson, are these organisms?
Dr. Thomson. They are not organisms and they are not
embryos.
Senator Harkin. They are not organisms?
Dr. Thomson. Or embryos, no.
Senator Harkin. Or embryos.
Dr. Gearhart. No; they are not. They are not organisms.
Senator Harkin. They are not organisms.
Well, I may not be a very good scientist, but I am somewhat
of a lawyer and I do read the English language. It says: ``For
the purposes of this section, the term `human embryo or
embryos' includes any organism.'' If it is not an organism then
it is not included.
So that is why I made the statement that I did at the
opening of this session. From my reading of it and my
understanding of it, this is not covered by the Federal ban. If
someone has a different definition of ``organism'' I would like
to see it.
Second, during the debate last year on human cloning the
National Conference of Catholic Bishops cited a number of
alternative ways to conduct research using stem cells,
alternatives they said would not require the use of a human
embryo at all. They include: (A) stimulating proliferation and
differentiation of the quiescent stem cells which are known to
exist in many adult tissues and customizing those cells to each
individual patient; (B) collecting stem cells from bone marrow
or umbilical cord blood or collecting stem cells from fetal
bone marrow; (C) genetically engineering cells of different
kinds to repair damaged organs, perhaps by injecting them with
an oncogene.
Do any of you know of this research? Is it possible to
achieve the same therapies with these alternatives? I am not a
scientist. I do not understand this.
Dr. Varmus. Senator, in my testimony I alluded to the fact
that there was a tremendous amount of research already
supported by the NIH and by private industry and many other
countries on stem cells that exist in fetal and adult tissue
that has the potential to develop into specific types of cells.
We think this is very important research. Indeed, it has
produced many of the advances in transplantation of bone marrow
and reconstitution of bone marrow that is used daily in
hospitals. So we strongly endorse that approach.
What is at issue, though, is the tremendous potential for
working with cells that are earlier in that hierarchy of stem
cells that I described to you earlier. Certain fundamental
questions about how cells differentiate, how we become complex
organisms, how birth defects arise, what causes cancer, how
cells fail, tools for use in development of new
pharmaceuticals, the ability to expand the repertoire of cells
that can be used for tissue therapies, is in my view going to
have to be approached with cells that come from organisms
earlier in development.
Now, as I have also tried to indicate, research with such
cells does create ethical concerns and we need to address those
and balance those against the benefits.
Senator Harkin. I understand. I think what is important
here is that when I read the news accounts and the newspaper
stories they say stem cells as if every stem cell is exactly
the same.
Dr. Varmus. That is wrong.
Senator Harkin. That is wrong. We have to clear that up
here today for the public. When you are talking about stem
cells you are talking about a broad spectrum of stem cells.
Dr. Varmus. That is correct.
Senator Harkin. Yes?
Dr. West. We call them stem cells maybe in part because it
is a bit like a tree. The stem cells we are talking about today
are at the base of the development tree and can branch out into
all the different cells and tissues of the body. Some stem
cells are way out at the edges of the branches and can only
become a few different cell types. There are many cell types.
There are tissues in the body that have no stem cells.
Heart tissue, the leading cause of death in the United
States, there are no stem cells to repopulate the heart. They
simply do not exist. But, going back to the base of the
developmental tree, we believe we can potentially make heart
muscle cells that can be used to address the No. 1 cause of
mortality.
Senator Harkin. I thought that was important to clarify.
Thank you.
treating age-related degenerative diseases
Senator Specter. Thank you, Senator Harkin.
We are going to take another round here and try to hold it
just to the five and five, because we do have quite an array of
other witnesses.
Dr. West, you used the phrase that the technique would make
cells young and would certainly be a retarding of the aging
factor. Just how far could this go? Do we really have what
could be a realistic fountain of youth by the use of this
technique?
Dr. West. I think a fountain of youth may be a bit of a
stretch. But what we do have published information on is that
the process of nuclear transfer does impart back to an aged
cell the full proliferative capacity it had when it was born.
Dolly, after all, was born as a young lamb, not an old one.
Senator Specter. So what are the limitations which would
stop it from being a veritable fountain of youth?
Dr. West. I am excited about the possibilities of using
somatic cell nuclear transfer to treat age-related degenerative
disease. There is now growing evidence that in numerous
diseases associated with aging that there are cells that have
lost the potential to proliferate in the way that they did when
they were young, and so nuclear transfer could be used to treat
immunosenescence, the aging of our immune system. The elderly
increasingly find it difficult to fight infectious disease,
chronic pneumonias, and other things.
So the nuclear transfer has the potential to benefit
embryonic stem cell research in personalizing these cells--they
are genetically identical to you--eliminating actually many
ethical problems associated with sourcing cells and tissues
today. As you know, the FDA is reviewing possibilities of
making cells and tissues in animals, xenografts, taking pig
kidneys and pig heart valves and so on, and sourcing cells and
tissues from cadavers, keeping people alive to source cells and
tissues.
cloning
Senator Specter. Dr. West, let me just interrupt you, if I
might, because we have very limited time, and ask you this one
other question. Your company's technique has been characterized
as the use of cloning techniques to create an embryo out of
human and cow cells. Is that accurate with respect to the
characterization of cloning?
Dr. West. I think it is very inaccurate. Actually, the
cartoons that show the half-human, half-cow I think are science
fiction. The goal here is to use the proteins in the egg after
the genomic information is removed to reprogram a human cell.
Senator Specter. When you use the human and cow cells,
eyebrows are raised. What concerns do you have about the
joinder of human and cow cells?
Dr. West. I actually agree with the President's letter of
November 14, where he asked the National Bioethics Advisory
Commission to look into this issue of the mixing of species. It
has been a profound debate for years in the scientific
community. As you know, the recombinant DNA debate of the
1970's was a debate about the mixing of DNA across species, and
this is even more profound today. We have the ability today to
actually introduce whole chromosomes across species, not single
genes.
Parkinson's disease
Senator Specter. Dr. Gearhart, what kind of a time line do
you see on the kind of research you have done to provide
practical answers to problems like Parkinson's or Alzheimer's
or cancer?
Dr. Gearhart. Actually, I think Parkinson's will be one of
the first targets and one that we will see in a short period.
Senator Specter. How long is a short period?
Dr. Gearhart. Well now, let me back off.
Senator Specter. No, no; go on.
Dr. Gearhart. I will. I actually think within several
years, to be honest with you, because these neurons that I have
demonstrated here, we do not know, to be honest, since this is
new data, we do not know what neurons they represent, what
type, whether they are cholinergic, dopaminergic, etcetera.
But from what we have known from our colleagues' work who
are studying the differentiation of neurons in animals, the
dopaminergic neurons are one of the first ones that are
developed. We know more, I think, about what factors actually
result or will lead to the formation of a dopaminergic neuron.
Senator Specter. Dr. Gearhart, I want to get a fairly short
answer from doctor--did you want to say something?
Dr. Gearhart. I should have explained dopaminergic neuron,
which is the neuron that is deficient in Parkinson's.
Senator Specter. I want to get a brief answer from Dr.
Thomson and Dr. West on time line for practical application
before the red light goes on.
Dr. Thomson. There are practical applications even today,
not in therapeutics right away. But for example, for making
heart muscle cells, there are very simple techniques to do this
in mouse embryonic stem cells and they will probably transfer
fairly quickly to human embryonic stem cells.
Senator Specter. Applicable today?
Dr. Thomson. Applicable today, because you can use them for
drug screens.
Senator Specter. Illustratively, for Parkinson's how long?
Dr. Thomson. Parkinson's? I am going to say 5 to 10 years
more. It will be one of the first ones.
Senator Specter. Dr. West, what time line do you see?
Dr. West. I would estimate for the discovery of drugs,
using the cells simply to discover drugs in the laboratory, 3
to 5 years; for the first cell therapies, somewhere between 7
to 15 and 20 years; Parkinson's potentially beginning within 7
to 12 years.
Senator Specter. Thank you.
Senator Harkin.
Senator Harkin. That is very encouraging. What I hear you
saying is that if this basic research is allowed to go forward
that a minimal amount of understanding of how stem cells
develop will lead to a proliferation of knowledge, which then
can be used by a lot of scientists all over the field. Is that
sort of--am I thinking the right way?
Yet, if you block this basic understanding of how that stem
cell differentiates, that means that all those scientists out
there cannot then focus on how to apply it in that timeframe.
Am I close to it? Something like that?
So that is why I am grateful the chairman has called this
hearing, because of the misinformation I think is out there,
especially regarding the ES technologies, and the
misinformation as to whether or not this is really covered by
the law banning human embryo research.
Let me focus a little bit--now, you talked about this time
line that the chairman just laid down in terms of Parkinson's.
What I heard was that anywhere from 3 to 5 to 12 years,
somewhere in there we might be finding something. Is that
assuming the Federal ban continues and this research is not
allowed to go forward, or that it is federally funded and
only--hold on I need to back up.
You can do this research in the private field. NIH cannot
fund it. What I heard all of you say is that it would be
vitally important, to have NIH be able to fund it. If this
Federal ban is deemed to cover research on stem cells, does
your time line hold?
Dr. West. The time line I gave, 7 to 12 years for
Parkinson's, assumed that the NIH would be allowed to fund
research in differentiating these cells into cells for
Parkinson's.
Senator Harkin. So your answers were based on----
Dr. West. Yes.
Senator Harkin [continuing]. I should not say lifting the
ban because, you see, I do not think the ban applies.
Dr. West. Right.
Senator Harkin. So I have got to be careful about what I
say. So your time line is based upon an interpretation or
reading of this that the ban does not apply to stem cells?
Dr. West. Right.
Senator Harkin. Is that true of all of you?
Dr. Varmus. That is correct.
Dr. Thomson. That is correct, but also the number of
diseases likely to be treated by this will increase
exponentially if there is public funding. Industry can target
one or two or a couple and get it done in a reasonable time.
The more difficult ones will just be left undone.
diabetes
Senator Harkin. So you are saying, again, with this
research there could be all kinds of breakthroughs later.
Dr. Thomson. Take diabetes as an example. Take diabetes as
an example. That is caused by the death of a very particular
cell in the pancreas and it is a fairly difficult developmental
program to go from undifferentiated stem cell to beta islet
cell. That is likely to be a more difficult cell to derive from
embryonic stem cell. It requires a lot of basic research, and
the Government has the job of doing basic research.
Senator Harkin. Well, I think there is so much potential
here. But there is so much misinformation out there, the
cartoons of the half-horse and the half-human, going back to
Greek mythology. I think we have been burdened with Greek
mythology for far too long. [Laughter.]
Senator Harkin [continuing]. And we have to get past that.
But our job I think as legislators--and again I compliment
the chairman; I thank him for having this hearing--is to try to
get over these hurdles of misinformation that are out there.
And I can understand people having these fears based upon
inadequate knowledge and understanding of what you are doing.
I think our job is to make sure that we get that
understanding out there in a clear fashion.
So I compliment you all for the work you are doing. I
believe that if this research is allowed to go forward it is
the gateway to a lot more understanding of how we treat
illnesses, especially genetic illnesses. Now, how the proper
way is, whether it is NT-based, nuclear transfer-based, or the
ES-based, I do not know. That is way above my pay grade. But I
think in either case the Federal ban certainly does not apply.
I thank you for your work and I encourage you to press on,
and hopefully we will have a clearing up of this so that NIH,
Dr. Varmus, can move ahead very aggressively in this area. I
would close on that question: If, in fact, this is the case,
will NIH move ahead aggressively?
Dr. Varmus. We will certainly do so, with, of course, the
usual oversight. That is, we will have a panel, we will have
guidelines, we will have the review of grant applications, and
proceed as we did on previous topics, like recombinant DNA or
gene therapy and xenotransplantation, with due consideration of
the ethical issues and firm oversight of the science.
Senator Harkin. Thank you, Dr. Varmus.
Senator Specter. Thank you very much for your testimony,
gentlemen. I think that it has been very useful in shedding
light on the issue that the embryos which are used here are not
embryos which could produce life, that when we talk about fetal
tissue, as Dr. Gearhart has talked about it, it is discarded
fetal tissue, it is not related to any inducement of abortions
or any medical procedure to produce fetal tissue.
Dr. Gearhart. That is correct.
Senator Specter. But there is concern, as Dr. West has
described, for the cloning consideration and for the mixture of
cows and human cells, and, perhaps most importantly, the
projection as to when immediate practical application may be
present. Dr. Thomson points out that with certain heart cells
it is now.
It is obviously a heart-rendering situation to see people
with Alzheimer's. We just had a very difficult situation in a
Veterans Administration hospital in Coatsville, PA, where
people with Alzheimer's, veterans, who could not walk were
being excluded from treatment. We finally got that solved.
People with Parkinson's had a major event in Pittsburgh last
year with Muhamed Ali coming forward and people with the
Parkinson's ailment. One man has an hour glass that he measures
his time by.
And as we work through juvenile diabetes, and this
subcommittee is deluged with people who want more funding and
more answers and more responses to their medical problems. We
did the maximum last year with $2 billion. Senator Harkin and I
do not know what we can do for an encore this year.
But when you talk about medical research which may provide
very, very unique answers with all the people who are suffering
there, we want to see what the medical potential is. It appears
to be very, very promising for catastrophic illnesses.
We are now about to turn to a panel to deal with the
ethical considerations, the other side of the coin. So we very
much appreciate your coming, and now we will call panel two.
Senator Harkin. I am sorry, there is one other point I just
have to clear up. Could I just clear up one thing?
Senator Specter. One final question.
Senator Harkin. I have to clear up something. I want to ask
you a question. I am drafting a letter of my own to Dr.
Shapiro, but the letter that the President wrote said: ``I am
deeply troubled by this news of experiments involving the
mingling of human and nonhuman species.''
What you are saying, Dr. West, is that that is not
scientifically correct?
Dr. West. Well, I share his concern about the mingling of
genomic DNA. That is not what we are doing.
Senator Harkin. That is right. I would share that concern,
too, combining genomic DNA. I would share that, too. But you
are saying that that is not happening?
Dr. West. That is not what we are doing.
Senator Harkin. I just wanted to clear that up.
Dr. Varmus. We also want to focus on the question of
whether experiments are being conducted in cultured cells as
opposed to experiments that would involve any attempt to return
a potential embryonic cell to a womb to develop a mature
individual. That is a very important distinction that was
repeatedly made by my embryo research panel when they
considered these experimental approaches.
Senator Harkin. Thank you very much.
Thank you, Mr. Chairman.
Senator Specter. Thank you very much, gentlemen.
STATEMENT OF ARTHUR L. CAPLAN, Ph.D., DIRECTOR, CENTER
FOR BIOETHICS, UNIVERSITY OF PENNSYLVANIA
Senator Specter. We would now like to call Dr. Caplan, Dr.
Doerflinger, Dr. Okarma; and we are going to bring Dr. Meslin
in on the next panel, all together.
Our first witness is Dr. Arthur Caplan, first witness on
the second panel, who is director of the Center for Bioethics
at the University of Pennsylvania, had that position since
1994; also serves as the chairman of the advisory committee to
the Department of Health and Human Services Centers for Disease
Control and Food and Drug Administration on Blood Safety and
Availability. Ph.D., from Columbia, author of some 400 articles
in professional journals.
Welcome, Dr. Caplan. The 5-minute rule is in effect and the
floor is yours.
Dr. Caplan. Thank you, Senator.
I have to say, too, that you have made the people at the
legislative liaison office at the University of Pennsylvania
very happy with your announcement about staying on this
committee. They will be more interested in that than anything I
have to say here.
When I left this morning I was trying to look at some
books, as philosophers such as myself are wont to do, about
ethical ideas. I did look a little bit at the Greek myths. I am
not as skeptical as Senator Harkin that Greek mythology is
useless, since to some extent the Greeks kept going with great
zeal in trying to advance what we call science today, though
they tried to warn us about not being full of hubris and pride
when we did it.
I looked at some other ethics books on my shelf, but I
realized that the real source of my knowledge about what is
right and wrong is to ask my 14-year-old son. So I sat him down
and I said: Now, I am going down to Washington. The issue is,
if we try hard to respect human origins and try hard to respect
human embryos and try hard to understand the special nature of
procreation, if we have a technology that offers us benefits,
that might help the paralyzed, the disabled, people dying of
heart disease and other dread ailments, how do you think we
should trade this off?
My son said, ``Well, dad, it seems to me if you have got a
man in a wheelchair you owe that person something in the here
and now, as opposed to trying hard to respect what might be or
what could have been, what is potential.''
I think he is right. I think it is true that the goal of
our public policy should be to tell that person in a wheelchair
we are going to try and weigh tradeoffs morally, ethically,
between the hard choices that have to be made in using certain
tissues, certain cells as sources, dealing with certain
totipotent and pluripotent cells as points of origin for making
wondrous therapies, and that it is wrong in the end if we
cannot come up with a policy that says we will not hold that
person in a wheelchair hostage to our moral concerns about
tissues that will otherwise be destroyed, tissues that are not
going to be turned into human beings under any circumstances,
or cells and tissues that, because we misunderstand or
misdescribe them, are going to wind up being misclassified as
potential people or possible human beings.
We have heard about that in the first panel and I think
that is the goal that faces Congress and the executive branch,
is to try and get us into the right balance.
The other introductory thing I would like to say is just
that I find myself as a philosopher, someone interested in
ethics, amazed by these developments this past year, 2 years,
ranging from cloning and creation of origin cells, oocytes from
animals that might be places where animal sources can be used
to host the production of human proteins, and stem cell
developments.
It reminds me that we do not live in a world of moral
absolutes. Some of the bright lines that we think we can go to
are not so bright when the DNA of any cell can be converted
ultimately, potentially, to a human being by transfer and
technology that allows for nuclear cell cloning. We can no
longer say that we understand exactly when life begins, how to
respect life, depending upon certain properties that might
inhere in particular cells or tissues.
It seems to me in the end that what we have got to do is
this. We have to say that some principles ought guide us as we
move forward in this area, and I want to propose four, and I
think they are ones that guide all medical research.
The first is that we should seek to achieve the most good
or benefit with the least harm and destruction of things that
we value. I believe that we do value human procreation, human
origins, human embryos, and we want to try and minimize what we
have to do there to get benefit, but we must pursue benefit.
That tradeoffs to achieve progress in the struggle against
disease and disability are inevitable and they are ethical. We
do that every day, Senators, when we conduct human research and
understand that we put people at risk, that deaths will result
from some of the things that are tried, that we may hasten
death inadvertently. We understand that tradeoffs must be made,
and I think that applies in this area.
It seems to me that the creation of materials with the
capacity to become human life is a process that requires moral
guidance and humility. That is something that I think we are
going to have to inject in this debate.
The last principle I would like to advance is that it is
better to do things in this area that are accountable and
public than it is to ask them to become private and commercial.
If we continue the policies we have, we are not going to be
able to bring the nuanced supervision and oversight that this
area of stem cell research requires from us.
prepared statement
I want to end by saying again, I do not think we are in the
realm of absolutes. I think we need judgment. I think we need
virtues. That is why we need public funding, public
accountability, to make the right tradeoffs.
Senator Specter. Thank you very much, Dr. Caplan.
[The statement follows:]
Prepared Statement of Arthur L. Caplan
the ethics of human stem cell research
Why is stem cell research so important?
Tremendous fanfare has greeted the announcement of success in
identifying human embryonic stem cells. Fanfare is becoming an
increasingly common phenomenon in the world of science and biomedical
news. So there is a tendency to greet each weeks `breakthrough' with
some cynicism. But in the case of the isolation of pluripotent
embryonic stem cells the acclaim is surely merited.
The identification of human embryonic stem cells has been widely
acknowledged as of inestimable value because it will help scientists
understand basic mechanisms of embryo development and gene regulation.
It also holds the promise of allowing the development of techniques for
manipulating, growing and cloning these cells to permit the creation of
designer cells and tissues. The availability of immortal stem cell
lines will greatly aid drug discovery. The study of stem cells should
also shed light on the process of human fertility and growth and should
even open the door to techniques that could be used, someday, to permit
many forms of genetic engineering and transplant therapy for human
beings.
There are many in the biomedical community who, when confronting
such powerful and useful possibilities maintain that no steps or
actions should be taken to restrict, control much less prohibit this
important research from moving forward. There is even the suggestion
that anyone who raises questions about the ethics of human embryo stem
cell research is merely using the prospect of research in this area for
``political'' purposes.
Such objections are rhetorically powerful but not at all
persuasive. As many scientists, policy makers, religious leaders and
the American people have long understood, research that may lead to the
elucidation of the secrets of human reproduction and development, the
modification of the genetic makeup of future children and their
children, the creation of new forms of life and a bounty of therapies
that hold out the prospect of a longer and better life raises issues of
ethics and social policy that must be discussed and debated publicly.
It is very appropriate that these issues be raised and examined since
human embryonic stem cell research is in its infancy and there is still
time to shape and direct its course.
Ironically, the much of the work being done on human embryonic stem
cells is being done without the support of funding from American
governmental agencies. This is entirely due to ethical concerns about
any research involving human embryos and tissues derived from elective
abortions. Embryonic stem cell research has and may involve these
sources.
Many worry that to raise any questions about the ethics of stem
cell research is to sacrifice a crucially important and incalculably
valuable area of biomedical research on the alter of the abortion
controversy. They also despair that any dialogue can occur in our
society about the ethics of using materials derived or created from
embryonic sources given the horrid track record of social divisiveness
and violence that are the constant companions of any discussion of
abortion in this country,
But the reality is that unless some effort is made to address head
on the moral and social issues that embryo stem cell research raises it
is very likely that further advances in this area will be slowed as a
result of a lack of government support or because they will be
conducted completely under private auspices with little accountability
and relatively little accessibility to the community of biomedical
science. The value of embryonic stem cell research is simply too great
to permit a policy stance of inaction to be the response that our
government and other governments around the world offer to this
enormously promising domain of inquiry.
key ethical issues raised by stem cell research.
Sources
The most obvious and pressing issue raised by stem cell research is
the issue of the source of these cells. Stem cells can be obtained from
human embryos specially created for research purposes, they can be
obtained from aborted fetal tissues including both spontaneous and
elective abortions, they can be created by processes that involve the
transfer of genetic materials to either animal or human egg or embryo
hosts and they can be obtained from embryos created through various
means of artificial reproduction and then frozen either as no longer
wanted by the persons whose gametes created them, or, being held as
reserves for the future by couples seeking to have children. What is
fascinating about these many sources of human embryonic stem cells from
an ethical point of view is that they are not at all morally
equivalent.
Not all embryos are created equally
Specially created embryos
The moral problems with making embryos for research are that as a
society we do not want to see embryos treated as products or mere
objects for fear that we will cheapen the value of parenting, risk the
commercialization of procreation, and trivialize the act of
procreation. It is the moral framework that society wishes to construct
for procreation and reproduction, and the interests of those whose
gametes are involved in making embryos, that provide much of the moral
force for restricting or prohibiting the manufacture of embryos for
nonprocreative uses. This is especially so once it is realized that
most human embryos at the point of conception will not become human
beings even under the best of all possible developmental circumstances.
Those who study the problem of infertility are beginning to understand
what it is about certain eggs and embryos that make them unlikely or
unable to develop into fetuses and later babies. While it is true as a
matter of historical fact that all human life has begun with conception
it is not true that all conception is capable of becoming human life.
Nor will it be true for long that all human life must begin with
conception. These changing realities mean that much more fine-tuned and
nuanced conceptual framework is needed to keep pace with advances in
knowledge and manipulability of human gametes and embryos.
The moral problems with making embryos for research are that as a
society we do not want to see embryos treated as products or mere
objects for fear that we will cheapen the value of parenting, risk the
commercialization of procreation, and trivialize the act of
procreation. Society may or may not agree that a human conceptus is
deserving of full ethical standing and respect on a par with an adult
human being. But, surely we do have a broad consensus in American
society that the process of creating embryos that have the potential
and ability to become human beings requires special status and standing
within our law and our culture.
If that is so then the manufacture of embryos for stem cell
research will have the potential to become persons may be morally
suspect because it violates our desire to accord special standing and
status to human conception, procreation and sexuality. To do nothing in
this area it should be noted is to consign the practice of embryo
creation for generating stem cells to the marketplace which is to
completely abrogate any special standing or status to human conception
and procreation.
Spare embryos
One of the greatest ironies of current policies governing embryo
research in the United States is that it has created a situation in
which a huge industry has arisen to treat infertility with relatively
little oversight and accountability for its practices. It has also
created a situation in which the demand for clinical services is high
but the knowledge base of those providing techniques such as in vitro
fertilization (IVF) is not what it might be because of the lack of
Federal funds to support fundamental research. As a result, when
couples seek to use IVF they are required to create more embryos than
they or their doctors might wish in order to minimize the need to
create more should they fail to have a child and to help insure that at
least some embryos will be made that are capable of growth and
development. This means that some fortunate couples are lucky enough to
have the technique work on a first or second try but wind up with the
problem of what to do with remaining surplus or spare embryos. This
country now finds itself in a situation in which tens of thousands of
orphan embryos sit in liquid nitrogen unwanted and highly unlikely to
be used by anyone ever to try to make babies.
Recently the United Kingdom enacted legislation to permit the
destruction of unclaimed and unwanted embryos. The United States has
not done so but there are thousands of embryos that might be made
available for research and study for many purposes including stem cell
research if those who created them were given this option or if clinics
could make them available for this purpose after a waiting period of
say ten years.
There are some who would still object that these frozen embryos are
still potential persons. But that claim does not square with the facts.
If no woman is willing to have the embryos placed inside her bodies, if
clinics are reluctant to use embryos that have been stored for long
periods of time because their potential to become babies is diminished
or if couples do not want anyone else using their embryos then their
potential for becoming persons is zero.
There would be a moral problem if embryos were created solely for
the purpose of being frozen and then used for research. Such a practice
would demean human reproduction and sexuality in turning it into a
process of manufacture and mass production. But, it is very simple to
prevent such practices from occurring. If infertility clinic personnel
understood that it was illegal and punishable by fine and prison to
inquire if a couple or woman wanted to freeze embryos until an IVF
cycle had been completed, then there would be no incentive to create
embryos. Spare, unwanted or damaged embryos could then be made
available for stem cell research, storage with consent or future
utilization.
To those who say this is still permitting the use of human embryos
for a purpose that is disrespectful, research and the consequent
destruction of the embryo, it seems appropriate to ask why continued
freezing is not just as disrespectful. It is also appropriate to ask
why, even if regrettable and sad, it would not be worth permitting the
donation of spare embryos for research that might lead to cures and
benefits in much the same way that we allow families to donate their
loved ones organs and tissues under the most tragic of circumstances to
aid others? Spare embryos would seem to be a legitimate and morally
defensible source of human embryonic stem cells.
Constructions
Perhaps the most disturbing source of stem cells is from embryos
that are specially built or designed for this purpose. Chimeras, human-
animal mixtures believed capable of prolonged development from
conception, possibly to birth, fused cells using enucleating human or
animal eggs and genomic transfer, disabled oocytes or embryos made from
disabled sperm are but a number of possible ways in which scientists
might create new forms of embryos to generate embryonic stem cells. The
ethically positive side of this kind of construction is that it may be
possible to create useful stem cells without having to use embryos that
have any potential to become persons. The negative side is that the
creation of special embryonic constructs may involve the creation of
potential whose outcome is uncertain, unknown or would have the
potential to create a severely deformed and damaged living organism.
The complexities in this area require a nuanced moral response but it
does seem clear that a clear boundary line must be to prohibit the
creation of any living being that would with certain become or have the
potential to become a deformed, damaged, freakish or dying entity.
There are also other risk involved with some forms of construction that
take human genomic material into animal hosts or vice versa. These
include the danger of importing viral matter or sub-viral entities into
the human population. There are also risk that some material may then
be carried into stem cells made from such sources.
some possible moral principles to guide stem cell research
It might be helpful once it is recognized that there are no hard
and fast lines to be drawn with respect to the ethics of stem cell
research to try and advance some simple moral principles that might
help those charged with controlling or approving such research. I would
suggest the following as principles which are in evidence already in
other areas of biomedical research and therapy:
--Seek to achieve the most good or benefit with the Least harm and
destruction of things of value
--Tradeoffs to achieve progress in the struggle against disease and
disability are both inevitable and ethical
--The creation of materials with the capacity to become human life is
a process that requires moral guidance and humility.
--The complexity of the tradeoffs involved when research is being
conducted at the boundaries of human life requires
accountability and publicity.
Each of these principles is used to justify activity in biomedical
research and therapy that is known to be risky or even known to be
harmful but which has important benefits to individuals and society.
Our society is quite familiar with the concept of tradeoffs. Americans
recognize few moral absolutes and in the area of stem cell research
where the tradeoffs frequently involve the possibility of harm to
potential persons versus the reality of harm to real flesh and blood
persons it is hard not to use some of these principles to guide prudent
choices, albeit tragic ones. To be blunt it would be hard to honor
principles such as these and the role they play in biomedicine and many
areas of public life and still tell the persons paralyzed in a
wheelchair or immobile as a consequence of ALS or Muscular Dystrophy or
Parkinson's that they must remain in such states because of inviolate
moral concern for the moral standing of an unwanted frozen embryo.
public versus privately sponsored research
Perhaps the most neglected factor in weighing what to do with
respect to stem cell research is the reality that stem cell research
will proceed even without federal funding. It will proceed more slowly
but it will proceed. It will proceed with no accountability but it will
proceed. It will proceed cloaked in secrecy but it will proceed. And it
will proceed with an eye toward the commercially attractive rather then
basic knowledge or the public good but it will proceed. The importance
of the benefits to be garnered in this area makes it imperative that
speed, accountability, publicity, and the drive to understand shape as
much of the early course of stem cell research as is possible. Add to
this the fact that the world of embryo sources and the status of stem
cells themselves is complex and it becomes certain that it would be
better to see publicly sponsored research complement private activities
and publicly accountable oversight accompany the market ethos that soon
will prevail in the United States if no action is taken by government.
a brief history of policy response to the ethics of embryo research
Announced with great fanfare, the Acting Director of NIH
established a panel to recommend guidelines for the funding of
preimplantation embryo research in August 1993. The Human Embryo
Research Panel was composed of 19 members, including 11 researchers,
scientists and physicians, 4 ethicists, 2 lawyers and 2 public members.
It met in public six times from February to September 1994, when it
issued its final report. The panel's charge was to place potential
research involving the ex utero preimplantation human embryos into one
of three categories: (1) acceptable for federal funding; (2) warrant
additional review; and (3) unacceptable for federal funding.
Using the mechanism of majority vote, the panel concluded that
studies to improve chances of pregnancy; research on fertilization;
research on egg activation, maturation and freezing; preimplantation
genetic diagnosis; development of embryonic stem cells; and creation of
parthenotes were acceptable for federal funding. Unacceptable research
included cloning and use of fetal oocytes followed by transfer to a
female uterus, and cross-species fertilization. This panel's
recommendations have been more or less ignored by the NIH Director,
Congress and the President ever since.
The reason why is that the moral foundation for the panel's
recommendations about embryo research was not persuasive. Unless a
moral framework emerges that proponents and critics of embryo research
can accept, it is likely that policy recommendations about stem cell
research will meet the same fate. This ought not be allowed to happen
since the scientific, therapeutic and commercial benefits of stem cell
research are too enormous to reject or hinder simply as a result of an
inability to confront a tough ethical problem head on.
why was the moral framework used to support some embryo research
unsatisfactory?
The panel considered and rejected the moral stance that a human
embryo has rights that would completely prohibit its use in research.
To those who argue that an embryo is a human person from the moment of
conception, the panel responded that there is no single trait or
property present at conception that suffices to confer personhood, and
thus, rights, on an embryo.
Having rejected rights as the proper framework for thinking about
the moral status of the human embryo, the panel recommended the
adoption of what it termed ``a pluralistic approach.'' Embryos possess
``a variety of distinct, intersecting and mutually supporting
considerations such as ``genetic uniqueness, potentiality for full
development, sentience, brain activity, and degree of cognitive
development''. The panel argued that ``their developing presence in an
entity increases its moral status until, at some point, full and equal
protectability is required.'' In essence the panel recommended a `big
tent' solution.
But, the pluralistic framework was not and is not persuasive. Just
saying embryos have a lot of potential and many different emerging
properties leaves matters mysterious and unresolved. It is not clear
what properties of embryos confer moral standing or worth and which are
simply properties that are interesting but irrelevant to ethics.
Without more of an underlying rationale for why particular property or
set of properties are morally important, the panel's framework wound up
looking like it was constructed to rationalize a desired conclusion--
that some research on embryos ought to be permitted--rather than as a
conclusion which follows from an ethical analysis.
The failure to be persuasive about the moral status of the embryo
turned out to be a crucial failure of the report. Saying that embryos
have a combination of properties which somehow entitle them to respect
without explaining how those properties confer moral significance on
embryos or what it means to say an embryo ought to be treated with
respect leaves policy makers and ultimately biomedical scientists with
little to work with in terms of moral guidance.
What the earlier panel which took on the analysis of the ethics of
embryo research did not grasp is that the human embryo has moral
standing not so much for what it is at the moment of conception, but
because the embryo is the result of procreative activity which is
intended to produce or is at least capable of producing a child. This
means that for many embryos there are other human beings who have a
direct interest in the status and fate of the human embryo since their
gametes created it, it carries their genes and potentially could become
their child. It also means that the key moral characteristics of human
embryos are not their inherent properties but the potential that they
have to become persons and the intent that those who created them have
to permit those which can do so to do so.
The same analysis is true but only more so for human embryonic stem
cells. Some of these cells come from embryos which had the capacity to
become persons. Some may be located and studied in embryos that lack
any such capability. Some stem cells will originate in embryos which
have no prospect of becoming persons because they are slated for
immediate destruction. And still other stem cells might originate in
embryos which were intentionally created so as to lack the ability to
become a person under any circumstances. To simply ban all stem cell
research as immoral because it relies on human embryos of some sort as
the source of such cells is to conflate what are fundamentally
different embryos with different moral standing. And to equate stem
cells themselves with human embryos capable of becoming persons is to
commit the same conceptual mistake but only in a more flagrant form.
In order to understand what is and is not ethical with respect to
stem cell research it is necessary to know a great deal about the
nature of the human embryo where such cells must be identified and
isolated, something about the stem cells themselves, something about
the aims and goals of the research and something about the benefits
that are likely to eventuate from a particular research study. Simple
moral schemes of classification are not sufficient for negotiating this
dense biological terrain. It will take a committee or commission with
the time and expertise to review particular proposals from specific
researchers to make the judgements that are required.
what should be done?
I conclude with three recommendations based on my understanding of
the nature of the issues raised by stem cell research and the
complexity of ethical and social questions such research raises:
1. America needs to create a public forum where advances in biology
and genetics can be discussed by ethicists, philosophers, theologians
and other humanists and social thinkers so as to permit a richer set of
concepts and categories to emerge so as to enhance public and political
understanding of what it is to talk of the creation of human life, new
forms of life and potential life.
2. America needs to seek to allow the many benefits of stem cell
research to be secured. This does not however make moral discussion of
how to proceed simply political. Nor does it mean that concerns and
worries about the moral licitness of stem cell and embryo research must
always yield to the promise of benefits and new knowledge.
3. America needs to create an oversight body, committee or
commission with appropriate expertise to consider and approve requests
for research protocols involving stem cell and embryo research.
STATEMENT OF RICHARD M. DOERFLINGER, ASSOCIATE DIRECTOR
FOR POLICY DEVELOPMENT, SECRETARIAT FOR
PRO-LIFE ACTIVITIES, NATIONAL CONFERENCE OF
CATHOLIC BISHOPS
Senator Specter. Our next witness is Mr. Richard
Doerflinger, associate director for policy development for the
secretariat for pro-life activities, National Conference of
Catholic Bishops. During Mr. Doerflinger's 18 years of service
he has been responsible for the preparation of policy
statements and congressional testimony on a wide variety of
subjects, including abortion, euthanasia, reproductive
technologies, and other medical and moral issues for the
Bishops Conference. Master of arts in divinity from the
University of Chicago, widely published on ethical issues
relating to the dignity of human life.
Thank you for joining us, Mr. Doerflinger, and the floor is
yours.
Mr. Doerflinger. Thank you very much, Mr. Chairman.
I would ask that my longer statement be entered into the
record and I will summarize it briefly.
Senator Specter. The full statement will be made a part of
the record, as will all others, and you have the 5 minutes for
summarizing or as you choose.
Mr. Doerflinger. I think it is important in assessing these
experiments to know that when Congress decides to subsidize
various forms of human experimentation it is making a moral and
not just an economic decision. It is deciding that these are
kinds of research that are sufficiently valuable and also
sufficiently ethical to be done in the name of all Americans
and all American taxpayers. By making those funding decisions,
Government can make an important moral statement, set an
example for private research, and help direct research toward
avenues which are ethically appropriate as well as medically
useful.
Three kinds of experiments involving human embryos have
been discussed here. On one level, some of these experiments
advance the debate on human cloning in ways that I think are
interesting and productive, because they indicate that there
are ways of making useful stem cells other than the use of
human somatic cell nuclear transfer of cloning, and that in
fact human cloning could be banned without endangering such
research. There would be other avenues available.
At the same time, however, each of the experiments
discussed raise ethical and, yes, legal questions of its own.
Currently the drive for advances in fetal and embryonic
research are balanced against ethical considerations in three
different areas of law, the law on life fetal research which
has been in existence since 1975, which treats the embryo and
fetus, at least from the time of implantation, as a protectable
human subject that must be protected from harmful research.
I say that with emphasis because a number of people here
have talked about whether this kind of embryo or that is
capable of creating a human being, and we saw pictures of
little bouncing babies over here. But in the area of law we are
talking about, a human being, a human subject worthy of
protection, includes the human embryo.
There are also, of course, appropriations riders since 1995
which extend this to the pre-implantation human embryo, not
only to special creation of embryos for research purposes, but
also to harmful or destructive research on embryos already in
existence.
Finally, we have fetal tissue transplantation guidelines
which we, it will be no surprise to you, find inadequate
because we do not think that tissues should be obtained from
abortion victims at all. But those guidelines as well have some
guidelines on how any use of tissue, even from a dead fetus,
should be separated as much as possible from any decisions to
destroy that fetus, that the destruction should not be geared
toward the research or the timing and manner of it should not
be geared toward the use of the tissue.
Along those lines, I find that two of the three experiments
that have been discussed here are exactly the kind of thing
that the human embryo research ban was directed against. Dr.
West's experiment, with all due respect, does involve a use of
cloning to create human embryos, which are then harvested for
their stem cells and thus destroyed.
The fact is that the reason for using nuclear transfer here
is to produce a genetic match for each individual patient. So
for each individual patient who may need treatment, you would
need to be making some number of new human embryos and then
harvesting them for their tissues. This is a violation of both
provisions of the current human embryo research ban. It creates
embryos and then it destroys them.
The research from the University of Wisconsin also involves
destroying embryos, though it does not involve creating them
because it gets them from IVF clinics. Again, that violates the
embryo research ban.
I think the more interesting question is whether subsequent
use of the stem cells that have now been produced by that
tissue would be violating the Federal ban. I think there we
would have to look for precedent to the current fetal tissue
transplantation guidelines, which say that the tissue should
not be used if the manner of the destruction of the original
fetus or embryo was geared toward or related to the research.
It has to be done for unrelated reasons. it cannot be linked
with the research.
It seems to me that the way in which these cells are
obtained, thus destroying the original embryo, is very much
geared toward the banking of those tissues, and it raises an
ethical problem that I think is parallel to the question that
was already resolved by Congress with its guidelines on fetal
tissue transplants.
Finally, in conclusion, I think it would be sad if
Congress' attention were to focus chiefly on those avenues of
research which garner front page news precisely because they
are ethically problematic. Congress has an opportunity to use
its funding power to advance medical research in ways that
fully respect human life as well as promoting medical progress.
prepared statement
I believe that some of the aspects of Dr. Gearhart's
research are very intriguing in this regard. We would like to
explore it further, especially if the tissue that can be
obtained can be obtained from sources other than abortion
victims, because it does not seem, though there is some
ambiguity here, that that research does not involve creating
embryos which are then destroyed for cells.
Thank you very much for allowing me to testify.
Senator Specter. Mr. Doerflinger, we appreciate your being
with us and thank you.
[The statement follows:]
Prepared Statement of Richard M. Doerflinger
I am Richard M. Doerflinger, Associate Director for Policy
Development at the Secretariat for Pro-Life Activities, National
Conference of Catholic Bishops. I am grateful for the opportunity to
present the Catholic bishops' ethical concerns regarding new
developments in embryo research.
In discussions of human experimentation, the researcher's
temptation is to think that if something technically can be done it
ethically should be done--particularly if it may lead to medical
benefits or advances in scientific knowledge. A civilized society will
appreciate the possibilities opened up by research, but will insist
that scientific progress must not come at the expense of human dignity.
When this important balance is not maintained, abuses such as the
Tuskegee syphilis study or the Cold War radiation experiments become a
reality.
In deciding whether to subsidize various forms of human
experimentation, legislators are not merely making an economic decision
to allocate limited funds. On behalf of all citizens who pay taxes,
they are making a moral decision. They are declaring that certain kinds
of research are sufficiently valuable and ethically upright to be
conducted in the name of all Americans--and that other kinds are not.
By such funding decisions, government can make an important moral
statement, set an example for private research, and help direct
research toward avenues which fully respect human life and dignity as
they seek to help humanity.
Three kinds of experiments involving human embryos or embryonic
cells have recently come to public attention. On one level, some of
these experiments advance the ethical and legal debate on human
cloning. They indicate that cloning is not necessary for promising stem
cell research, and thus that it may be banned without endangering such
research. At the same time, however, each of these experiments raises
ethical problems of its own.
Currently, the drive for advances in human fetal and embryonic
research is balanced against ethical considerations in three
significant areas of federal law. It is important to review these to
address the question: What moral principles are reflected in these
enactments that can help us to make a moral judgment on new experiments
that may not have been anticipated before?
1. Live fetal research is governed by federal regulations on the
protection of human subjects first issued in 1975 (now codified at 45
CFR Sec. 46.101 et seq.). Federal regulations on fetal research treat
the prenatal human being as a human subject worthy of protection, from
the time of implantation in the womb (about one week after
fertilization) until a child emerges from the womb and is found to be
viable. Essentially the same standard is applied here as in regulations
protecting live-born children: Since the unborn child is a helpless
subject incapable of giving informed consent to experimentation,
federally funded research involving this child is permissible only if
(a) it could be therapeutic for that particular child (as with prenatal
surgery to correct congenital defects), or (b) it is necessary to
obtain important information and will not subject the child to
significant risk of harm.\1\ In 1985 Congress further clarified this
standard through an amendment to the National Institutes of Health
reauthorization act: In assessing research on live fetuses in utero,
protection from risk must be ``the same for fetuses which are intended
to be aborted and fetuses which are intended to be carried to term''
(42 USC Sec. 289g). No matter what fate may be planned for the
developing human being by others, the government must still make its
own moral decision to respect life--it cannot single out certain lives
as disposable, or as uniquely fit for harmful research, simply because
someone else plans to show disrespect for those lives.
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\1\ 45 CFR 46.208(a). Such research may only pose a ``minimal
risk,'' which means that ``the probability and magnitude of harm or
discomfort anticipated in the research are not greater in and of
themselves than those ordinarily encountered in daily life or during
the performance of routine physical or psychological examinations or
tests.'' 45 CFR Sec. 46.102(i).
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2. Embryo research involving human embryos outside the womb--such
as embryos produced in the laboratory by in vitro fertilization (IVF)
or cloning--has never received federal funding. Originally this was
because the federal regulations of 1975 prevented funding of IVF
experiments unless such experiments were deemed acceptable by an Ethics
Advisory Board--and after the first such board produced inconclusive
results in 1979, no Administration chose to appoint a new board. In
1994, after this regulation was rescinded by Congress, a Human Embryo
Research Panel recommended to the National Institutes of Health that
certain kinds of harmful nontherapeutic experiments on human embryos
receive federal funding--but the Panel's recommendations were rejected
in part by President Clinton, then rejected in their entirety by
Congress. Since 1995, three successive Labor/HHS appropriations bills
have prevented federal funding of experiments which involve (a)
creating human embryos for research purposes, or (b) subjecting human
embryos in the laboratory to risk of harm or death not permitted for
fetuses in utero under the regulations on protecting human subjects.
Since 1997 this rider has explicitly banned funding of experiments
involving embryos produced by cloning using human body cells.\2\
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\2\ The current funding ban is Section 511 of the Labor/HHS
appropriations bill for fiscal year 1999, enacted as part of Public Law
105-277, the Omnibus Consolidated and Emergency Supplemental
Appropriations Act for fiscal year 1999 (p. 399).
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3. Fetal tissue transplantation research has been a matter of
extended controversy. Such research could receive federal funds during
the Bush Administration only if the tissue was obtained from sources
other than induced abortion. The possible use of ovaries from aborted
fetuses to create research embryos provoked more controversy within the
NIH Human Embryo Research Panel than perhaps any other proposal; in the
end the Panel decided to defer any possible funding of such research
until further discussion could take place. Under current federal
funding policy, human fetal tissue--defined as ``tissue or cells
obtained from a dead human embryo or fetus after a spontaneous or
induced abortion, or after a stillbirth,'' (42 U.S.C. Sec. 289g-1(g))--
may be used for ``therapeutic purposes'' only if various safeguards are
followed to ensure that the researcher avoids participating in an
abortion and has no effect on the ``timing, method, or procedures used
to terminate the pregnancy'' (42 USC Sec. 289g-1(b)(2)).
In our view, current safeguards on the use of fetal tissue are
inadequate. The only sure way to prevent federally funded research from
collaborating in and providing legitimacy for abortion is to forbid
abortion as a source for potentially ``therapeutic'' tissue. Certainly,
it would be wrong for Congress to apply to early human embryos any
policy less protective than that now applied to the later embryo and
fetus. Existing law explicitly applies to human embryos, and destroying
or discarding an embryo in the laboratory is the moral equivalent of
abortion. As Congress has already done in the case of live fetal
research, it should make clear in this area of research that the same
standards apply to human embryos whether inside or outside the womb.
Current law on live fetal and embryonic research is no mere
political compromise. It is a reflection of universally accepted
ethical principles governing experiments on human subjects--principles
reflected as well in the Nuremberg Code, the World Medical
Association's Declaration of Helsinki and other statements. Members of
the human species who cannot give informed consent for research should
not be the subjects of an experiment unless they personally may benefit
from it, or the experiment carries no significant risk of harming them.
Only by such ethical principles do we prevent treating people as
things--as mere means to obtaining knowledge or benefits for others.
Some will be surprised that such protections can exist under the
U.S. Supreme Court's abortion decisions. But the Court has never said
that government may not protect prenatal life outside the abortion
context. It has even allowed states to declare that human life begins
at conception, and that it deserves legal protection from that point
onward--so long as this principle is not used to place an undue burden
on a woman's ``right'' to choose abortion before viability.\3\ Although
states may not place meaningful restrictions or prohibitions on
abortion under current Supreme Court jurisprudence, harmful experiments
on human embryos are illegal in ten states regardless of how they are
funded.\4\ Public sentiment also seems even more opposed to public
funding of such experiments than to funding of abortion.\5\
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\3\ Webster v. Reproductive Health Services, 492 U.S. 490 (1989).
\4\ See testimony and documentation provided by Lori Andrews, J.D.,
to the NIH Human Embryo Research Panel, February 3, 1994. Ms. Andrews
cites ten states whose laws on fetal research generally prohibit
experiments on human embryos ex utero: Louisiana, Maine, Massachusetts,
Michigan (which in 1997 also enacted a ban on creating human embryos by
cloning), Minnesota, New Hampshire, North Dakota, Pennsylvania, Rhode
Island and Utah.
\5\ A national Tarrance poll in 1995 showed 18 percent support for
using tax dollars for experiments that would involve destroying or
discarding live human embryos in the first two weeks of development.
Seventy-four percent of the Americans in the survey opposed such
funding, with 64 percent strongly opposed. Press release, ``Poll Shows
Strong Opposition to Embryo Research Funding,'' United States Catholic
Conference, July 25, 1995.
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Moreover, a scientific consensus now recognizes the status of the
early human embryo, and the continuity of human development from the
one-celled stage onward, to a greater extent than was true even a few
years ago. In the 1970s and 1980s, some embryologists spoke of the
human embryo in its first week or two of development as a ``pre-
embryo'' and claimed it deserved less respect than embryos of later
stages. But most embryology textbooks have now dropped the term, and
some texts openly refer to it as a ``discarded'' and ``inaccurate''
term.\6\ The Human Embryo Research Panel and the National Bioethics
Advisory Commission have both rejected the term; they describe the
human embryo, including the one-celled zygote, as a living organism and
``a developing form of human life.'' \7\
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\6\ See Ronan O'Rahilly and Fabiola Muller, ``Human Embryology and
Teratology,'' 2nd edition (New York: Wiley-Liss 1996) at 8, 12.
Professor Lee Silver of Princeton University, a proponent of cloning
and embryo research, recently declared that the term ``pre-embryo'' was
embraced by IVF researchers ``for reasons that are political, not
scientific'' in an effort to ``allay moral concerns'' about their
research. Lee M. Silver, ``Remaking Eden: Cloning and Beyond in a Brave
New World'' (New York: Avon Books 1997), 39.
\7\ See: National Bioethics Advisory Commission, ``Cloning Human
Beings'' (June 1997), appendix-2 (``embryo'' as ``the developing
organism from the time of fertilization''); National Institutes of
Health, ``Report of the Human Embryo Research Panel'' (September 1994),
at 2 (``the preimplantation human embryo warrants serious moral
consideration as a developing form of human life'').
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How is this human life treated in each of the three most recent
developments in human embryo research?
university of wisconsin: stem cells from an ivf embryo
The University of Wisconsin proposal seems to be exactly the kind
of experiment that the federal funding ban was consciously directed
against. Researchers obtained 36 live human embryos from IVF clinics,
grew them to the blastocyst stage, and then destroyed them for their
stem cells; cells from 14 of the embryos were placed in culture, and
``cell clusters'' from five were successfully cultured to grow tissue.
The researchers report that the inner cells were ``isolated by
immunosurgery'' from the rest of the embryo.\8\ The effect is the same
as if one were to ``isolate'' the heart and lungs from an adult human--
the being from whom the cells are taken is killed.
---------------------------------------------------------------------------
\8\ James A. Thomson et al., ``Embryonic Stem Cell Lines Derived
from Human Blastocysts,'' 282 Science 1145-7 (6 November 1998) at 1147
n. 6.
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This kind of experiment was recommended for federal funding in 1994
by the Human Embryo Research Panel, but rejected by Congress every year
from 1995 to the present. In this respect it does not present a new
issue, for Congress has already decided that even so-called ``spare''
embryos from IVF clinics should not be subjected to destructive
experiments using federal funds.\9\
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\9\ On July 11, 1996, an amendment was offered by Rep. Nita Lowey
(D-NY) to drop the ban on funding research involving ``spare'' embryos,
while retaining the ban on special creation of ``research embryos'';
the amendment was defeated 256-to-167.
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Two new issues have been raised regarding this experiment, however.
First, could the embryonic cells that are removed from these human
embryos, once isolated, be seen as human embryos themselves? The
question arises because these inner cells are often described as the
cells that would ultimately form the ``embryo proper'' as development
continues. If removed from the original embryo but transferred to the
nurturing environment of the womb, would each cell or each cluster of
cells begin to develop as a new organism? Is a special environment
provided by researchers to suppress such development and divert it
toward undifferentiated growth as tissue instead? Certainly such
diversion of embryonic development by use of molecular signals has been
proposed by some researchers.\10\ If that were at work here--if the
experiment creates new embryos and then suppresses their development--
funding such an experiment might also violate the current ban on
creating human embryos for research purposes.
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\10\ See Lee M. Silver, supra note 6, at 128 (such molecular
signals can be used as a way of ``tricking'' an early embryo into
expanding as undifferentiated tissue, instead of undergoing normal
growth and differentiation as an organism).
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Second, what of the prospect of funding research that would use
this tissue for supposedly therapeutic purposes after it has been grown
in culture? Here, the ethical principles reflected in current law on
fetal tissue argue against funding the research. One must refer here to
the principles rather than to the exact letter of the law because,
while it applies to embryos as well as fetuses, it speaks of induced
abortion rather than of destroying embryos by dissection. But there
seems to be no reason why the same ethical standard should not apply.
Human embryos are destroyed precisely to obtain this tissue, and the
timing and manner of the destruction are tailored to obtaining this
kind of tissue. An effective separation between the destructive act and
the harvesting of the tissue, which federal law requires in the case of
tissue from an induced abortion, does not seem to exist here.
One positive development, however, is that this line of research
has put to rest the claim made last year by some biotechnology
companies that production of human embryos by cloning (somatic cell
nuclear transfer) is necessary to develop therapies based on embryonic
stem cells. Such claims assumed that adults could not be treated with
such cells unless the embryos were produced by cloning to create a
genetic ``match'' and avoid tissue rejection. But in his commentary on
the Wisconsin experiment, John Gearhart has cited three other avenues,
some of which were also cited by the National Bioethics Advisory
Commission last year: Stem cells can be banked from multiple cell lines
to prevent such reactions; they can be genetically altered to produce a
universal donor line; or they can be customized using the relevant
histocompatibility genes from the intended recipient.\11\
---------------------------------------------------------------------------
\11\ John Gearhart, ``New Potential for Human Embryonic Stem
Cells,'' 282 Science 1061-2 (6 November 1998) at 1061.
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Whatever else may be said of this research, then, it means that
proposed federal bans on human cloning need no longer be held hostage
to the debate on stem cell research. But the experiment itself is
unethical and should not be funded. Instead, as the National Bioethics
Advisory Commission has already observed,\12\ avenues should be
explored for creating stem cell lines without creating or destroying
human embryos.
---------------------------------------------------------------------------
\12\ National Bioethics Advisory Commission, supra note 7, at 30-
31. See NCCB Secretariat for Pro-Life Activities, ``Would a Ban on
Human Cloning Block Stem Cell Research?'' (Fact sheet, 4/20/98;
www.nccbuscc.org/prolife/issues/bioethic/fact498.htm).
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johns hopkins: stem cells based on primordial germ cells from induced
abortion
Presumably the Johns Hopkins University study could not be funded
unless it follows the provisions of current law regarding fetal tissue
from induced abortions. We wish to reiterate here that we find the
existing policy inadequate and would support federal funding only if
the cells can be obtained from sources other than induced abortion.
The new question raised here is this: Are the primordial germ cells
obtained from abortion victims being used to create human embryos,
which are then destroyed or suppressed to provide tissue. Even the NIH
Human Embryo Research Panel did not recommend funding such an
experiment, and it would clearly be forbidden by the current embryo
research ban.
There is some ambiguity in current reports of the new research,
because the researchers speak of collecting ``embryoid bodies'' from
these cultures and finding ``derivatives of all three embryonic germ
layers'' in the culture. They add that some of these bodies form
``complex structures closely resembling an embryo during early
development,'' and that they ``appear to recapitulate the normal
developmental processes of early embryonic stages and promote the cell-
cell interaction required for cell differentiation.'' \13\
---------------------------------------------------------------------------
\13\ Michael J. Shamblott, et al., ``Derivation of pluripotent stem
cells from cultured human primordial germ cells,'' 95 Proceedings of
the National Academy of Sciences 13726-13731 (November 1998) at 13726,
13729.
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However, if this research is now conducted--or could be conducted--
to establish useful cell lines without creating early human embryos, it
would avoid some of the serious ethical problems associated with other
experiments in this field. In that case the only remaining ethical
problem is the use of cells from induced abortion, which does not seem
necessary to the nature of the research. We urge that the use of cells
from spontaneous abortions, ectopic pregnancies or other sources be
explored instead.\14\
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\14\ See Peter J. Cataldo and Albert S. Moraczewski, O.P. (eds.),
``The Fetal Tissue Issue: Medical and Ethical Aspects'' (Braintree, MA:
Pope John Center 1994).
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advanced cell technology: human cloning using cows' eggs
While this third type of experiment has not been fully reported in
the medical literature it seems to pose a relatively new question--that
of human/animal hybrids--as well as an old one, that of somatic cell
nuclear transfer (cloning) to make human embryos for research purposes.
Even the Human Embryo Research Panel opposed funding the former; the
current ban on embryo research rightly forbids funding the latter.
The National Bioethics Advisory Commission, in its November 20
letter to President Clinton commenting on this experiment, rightly
draws attention to the special ethical problems raised by combining
human and animal cells to initiate embryonic development. On the one
hand, this experiment does not create a hybrid in the sense of a being
that is half human and half cow. All the nuclear genetic material comes
from a human body cell; the cow egg contains some mitochondrial DNA,
but this seems to be quickly taken over and directed by the human
nucleus. On the other hand, proteins from the cow egg must be directing
the remodeling of the chromosomes and thus the very earliest stages of
development in this new being, and the ultimate effect of this is not
known.
However, even if this experiment in one sense does not create a
human/animal hybrid, it presents a new twist on the use of cloning to
create human embryos for research purposes. Oddly, defenders of such an
experiment must simultaneously argue that it is promising because it
can produce genetically matched, fully human tissue for
transplantation--and that it is not covered by the ban on embryo
research because fusing a human nucleus and a cow egg does not really
produce a human embryo.
Cows' eggs are apparently being used not to make hybrids as such,
but to avoid one of the remaining practical obstacles to unlimited mass
production of identical human embryos by cloning: the fact that human
eggs are difficult to obtain in large numbers, and cannot be harvested
in quantity without posing health dangers to women. Therefore this
experiment not only poses ethical problems in its own right but could
set the stage for further mistreatment of human life as an object of
experimentation on a large scale. Funding for such an experiment should
be, and is, banned by current law, which forbids creating a new
organism from ``one or more'' human gametes or body cells by
fertilization or cloning.
In its new letter the Commission seems very uncertain as to whether
this experiment creates an embryo. But this is partly due to the
Commission's own truncated approach to what constitutes an embryo. Its
assumption seems to be that the new being is an embryo only if it can
be proved capable of growing and developing into a new ``human being,''
by which it means a live-born infant. But this is too narrow a
standard. In many circumstances--especially those involving laboratory
manipulation of new life--embryos are created in such a fatally damaged
condition that they will not survive to live birth. This does not mean
that they were never embryos. One might as well say that an infant born
with a fatal disease, who will not survive to adulthood, was never an
infant. This strange standard seems to grow out of the Commission's
earlier attempts to propose that no ``human cloning'' has taken place
so long as any human embryos created by cloning are ultimately
discarded or aborted instead of being implanted to attempt a live
birth.\15\ We believe the relevant question here is whether the new
one-celled entity with a human nucleus begins, even for a brief time,
to grow and develop as an early organism of the human species. If so,
the experiment should be seen as involving the creation and destruction
of human embryos and, as such, should not be funded.
---------------------------------------------------------------------------
\15\ For a critique of this approach see Testimony of Cardinal
William Keeler before the House Commerce Subcommittee on Health and
Environment, February 12, 1998; reprinted in 27 Origins 597-601
(February 26, 1998).
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Each of these new developments poses ethical questions, and none
should be pursued by the federal government unless and until ethical
questions have been satisfactorily answered.
A remaining question involves the other avenues for advancing stem
cell research, or for advancing the medical goals to which this
research is directed, without exploiting developing human beings. Last
year, for example, we proposed to Congress that there may be nine
promising alternatives to the use of cloning to provide stem cell
lines--and eight of these seem to involve no use of embryonic stem
cells at all.\16\ In the same few weeks that these embryo experiments
garnered such national attention, significant advances were reported in
two of these areas: The use of growth factors to help hearts grow new
replacement blood vessels, and the use of stem cells from placental
blood to treat leukemia and other illnesses.\17\
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\16\ See NCCB Secretariat for Pro-Life Activities, supra note 12.
\17\ See: ``Gene Therapy Helps Mice Grow New Blood Vessels,''
Business Wire, November 20, 1998; ``Injected Genes Help Grow Heart
Bypasses,'' Washington Post, November 10, 1998 at A3; ``Stem Cells
`Grow' in Value: Potential Benefits of Umbilical Cord Banking Further
Validated,'' PRNewswire, November 27, 1998; Pablo Rubinstein et al.,
``Outcomes among 562 Recipients of Placental-Blood Transplants from
Unrelated Donors,'' 339 New England Journal of Medicine 1565-77
(November 26, 1998); Robertson Parkman, ``The Future of Placental-Blood
Transplantation,'' 339 New England Journal of Medicine 1628-9 (November
26, 1998). In light of some researchers' zeal for use of cloning by
nuclear transfer to ensure an exact genetic match between tissue and
recipient, it is worth noting that placental blood transplants seem to
be more effective in treating leukemia if they are not too close a
genetic match. Rubinstein et al. at 1573.
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It would be sad indeed if Congress's attention were to focus
chiefly on those avenues of research which garner front-page news
precisely because they are ethically problematic. Instead, Congress has
an opportunity to use its funding power to channel medical research in
ways which fully respect human life while advancing human progress.
None of the new proposed experiments change in any way the ethical
principle grounding current restrictions on human embryo research: In
trying to serve humanity we should not support actions that are
fundamentally wrong. Even a good end does not justify an evil means.
______
Would A Ban on Human Cloning Block Stem Cell Research?
Some biotechnology companies claim that a ban on producing human
embryos through cloning would stall important research in generating
``stem cells'' to cure a variety of diseases [Cong. Record, 2/5/98,
S425]. To put this claim in perspective:
1. Cloning is desired as a source of ``customized stem cell lines''
which would be an exact genetic match to each individual patient with a
given disease. But this would require each individual patient to
undergo somatic cell nuclear transfer to produce one or many living
human embryos who genetically are the patient's identical twin sisters
or brothers. These embryos would then be destroyed to provide embryonic
stem cells.
Two methods of obtaining the cells have been described. In one, the
embryo is allowed to develop normally for a week or two to the
blastocyst stage, at or after the usual time of implantation in the
mother's womb; then this embryo, consisting of hundreds of cells, is
dissected for its stem cells. The other method is to introduce
molecular signals into the embryo's environment to ``trick'' its cells
into departing from normal development and instead producing ``a mass
of undifferentiated tissue,'' which can then be reprogrammed into
various kinds of cells [Lee Silver, ``Remaking Eden: Cloning and Beyond
in a Brave New World'' (Avon Books 1997), p. 128]. In either case, the
living embryo is destroyed.
2. This avenue for providing medical benefits has been described
even by supporters as ``largely conjectural'' (J. Kassirer and N.
Rosenthal, in ``New England Journal of Medicine,'' March 26, 1998, p.
905). President Clinton's National Bioethics Advisory Commission called
it ``a rather expensive and far-fetched scenario.'' The Commission
observed: ``Because of ethical and moral concerns raised by the use of
embryos for research purposes it would be far more desirable to explore
the direct use of human cells of adult origin to produce specialized
cells or tissues for transplantation into patients.''
The Commission outlined three alternative avenues for promising
research using stem cells that do not involve human cloning, two of
which do not use human embryos at all (``Cloning Human Beings: Report
and Recommendations of the National Bioethics Advisory Commission,''
June 1997, pp. 30-31).
the commission's alternatives
The alternatives outlined by President Clinton's Commission are as
follows:
1. Generating ``a few, widely used and well characterized human
embryonic stem cell lines, genetically altered to prevent graft
rejection in all possible recipients.'' This would raise its own
ethical objections because it may involve producing and destroying some
human embryos at the outset; but it does not require somatic cell
nuclear transfer, or the creating and destroying of genetically related
embryos for each individual patient.
2. Stimulating ``proliferation and differentiation of the quiescent
stem cells which are known to exist in many adult tissues, including
even the nervous system.'' Such stem cells could be ``customized'' to
each individual patient and would not be from embryonic sources.
3. Identifying ``methods by which somatic cells could be `de-
differentiated' and then `re-differentiated' along a particular path.''
This would permit ``the growth of specialized cells compatible with a
specific individual person for transplantation.'' While at present this
option is considered speculative, its feasibility is now enhanced by
the central finding of the research that produced ``Dolly'' the sheep:
An adult body cell can be ``de-differentiated'' surprisingly easily and
regressed all the way back to a stage at which it can provide the
nucleus for a new developing embryo. The question is: Can this
regression be done to a point short of this, so an adult cell becomes
the basis for cells that are like embryonic stem cells but never came
from an embryo?
other alternatives (not explicitly cited by the commission)
4. There are other promising sources of pluripotent (not embryonic)
stem cells for treatment of disease. One example is hematopoietic
(blood cell producing) stem cells from bone marrow or even from the
umbilical cord blood in live births. These cells are already widely
used in cancer treatment and in research on treating leukemia and other
blood diseases. Their versatility was recently found to be even greater
than once thought. For example, given the right environment bone marrow
cells can be used to regenerate muscle tissue, opening up ``a whole
avenue of potential therapies that didn't exist before'' for muscular
dystrophies (``Bone Marrow Cells May Provide Muscle Power,'' Science, 6
March 1998, p. 1456).
5. An enormously promising new source of stem cells is fetal bone
marrow, which is ``23 times more effective than adult marrow and eight
times better than umbilical cord blood.'' Recent studies show that
``miscarriages can provide enough cells for transplantation if we would
collect them effectively and store them in banking'' (``Fetal marrow
transplants promising against disease,'' Detroit News, May 4, 1997). A
stem cell line from such sources could provide a continuous supply of
stem cells for research. It seems fetal bone marrow cells do not
provoke the same immune reactions as adult or even newborn infant
cells. This is true whether the unborn child is the donor or the
recipient--that is, fetal cells can be used to treat adults, or adult
bone marrow cells can be used to treat a child in the womb, without
harmful immune reactions (see Jack Goldberg, ``Fetal stem cell
therapy,'' in Jauniaux et al. (eds.) Embryonic Medicine and Therapy
[Oxford U. Press 1997], pp. 474-80).
6. Other approaches to tissue regeneration involve the growth
factors (activators and inhibitors of cell division and growth)
responsible for the development of various cell types and tissues.
These factors may be used to manipulate the cells of a tissue along the
spectrum of differentiation, without the need to create stem cells
first. Use of these factors has already shown promise in the clinical
setting, as a vascular growth factor has been successful in saving the
legs of three patients who had potentially lethal blood clots requiring
amputation: Application of the growth factor allowed new vessels to
grow around the clots and restore circulation to the legs (see
Circulation, 3/31/97, pp. 1114 ff.). Now such factors have been used to
generate new blood vessels to human hearts in 20 patients (``Drug
Stimulates Growth of Heart Blood Vessels,'' Washington Post Health,
Feb. 24, 1998, p. 5).
7. Cells of different kinds are now being genetically engineered to
repair damaged organs, especially by injecting them with an
``oncogene'' (a type of gene that causes cancer cells to reproduce
rapidly). Heart cells produced with this gene can ``survive and beat
like normal heart muscle cells'' when transferred to a damaged heart
(``Study: Cells Repair Heart Damage,'' Associated Press, March 17,
1998).
8. Methods are being developed for growing entire replacement
organs, to treat children before or after birth. Cells of the needed
variety are extracted from the child and cultured, then grown into
organs in the laboratory using biodegradable scaffolds. The researchers
say they hope to receive FDA approval for routine use of the technology
within five years. They add that ``there are no ethical concerns doing
this treatment, as there are about some other procedures [such as human
cloning]'' (``Doctors grow animal organs,'' Washington Times, July 23,
1997, pp. A1, A18; also see Ben Bova, ``Lost a lung? Grow your own,''
in USA Today, Feb. 24, 1998).
9. Promising avenues have been opened up in research on cancer and
diseases of aging by studies of telomerase, dubbed by some ``the
immortality enzyme.'' It protects and rebuilds telomeres, the
protective caps on the ends of chromosomes which deteriorate as we age.
It is now believed that telomerase activity is required for the
uncontrolled growth of most cancerous tumors. Mastering this enzyme may
enable researchers to (a) inhibit its activity in cancer cells and
reduce or stop tumor growth, and (b) to use telomerase itself in a
controlled way to help rejuvenate and regenerate damaged tissues and
organs. (J. Madeleine Nash, ``The Immortality Enzyme,'' Time, Sept. 1,
1997).
In short: The claim that human embryo cloning is needed to advance
promising medical research in cancer, degenerative diseases, etc. is
simply false.
Even if the use of somatic cell nuclear transfer to create and
cannibalize human embryos were to enable more rapid development of some
limited branches of research (a proposition for which there is no firm
evidence), the words of Professor Patricia King, co-chair of the NIH
Human Embryo Research Panel, would remain valid:
The fertilization of human oocytes for research purposes is
unnerving because human life is being created solely for human use * *
*. In particular, the public should be assured that embryos will not be
created because such creation is the most convenient means of answering
important scientific questions that can be answered--perhaps more
slowly--in other ways.'' [Final Report of the Human Embryo Research
Panel (NIH, Sept. 27, 1994), p. 97].
STATEMENT OF THOMAS B. OKARMA, Ph.D., M.D., VICE
PRESIDENT OF RESEARCH AND DEVELOPMENT,
GERON CORP.
Senator Specter. We turn now to Dr. Thomas Okarma, Vice
President of Research and Development of Geron Corporation.
Since 1991 Dr. Okarma has served as a clinical associate
professor of medicine at Stanford, authored over 100
publications, and has a dozen U.S. patents, a Ph.D., and M.D.
from Stanford.
Thank you for joining us, Dr. Okarma, and the floor is
yours.
Dr. Okarma. Thank you for the invitation this morning.
We have heard ample testimony prior to my time validating
the significance of the discoveries here, so I will not waste
our time repeating those, and turn directly to why Geron chose
to fund this research. Clearly, the therapeutic potential, as
we have heard, is extraordinary. The potential, however, is
realizable and portions of it can be reduced to practice based
upon prior knowledge gained from animal stem cell work and the
convergence of available complementary technologies developed
by both the biotech industry and the academic community.
For example, Geron's demonstrated ability to use the
telomerase gene to convey unlimited replicative capacity to
differentiated cells is a key synergistic technology for
developing the therapeutic applications we have been talking
about today. Simply stated, as we learn to control the pathways
that take stem cells down the road to neurons, blood vessels,
and heart cells, we can immortalize them by telomerase gene
transfer, so that sufficient quantities of these cells can be
grown for transplant applications.
Geron's corporate mission is to develop treatments for
chronic degenerative disease. These two technologies,
telomerase gene transfer and human pluripotent stem cells,
combine to make possible the repair of degenerating organs with
young, healthy, and fully functional cells.
Now, why the NIH should participate in the development of
these applications. As we have heard, the scientific frontier
opened up by the derivation of these cells is vast. However,
industry will only explore that part of the frontier that may
lead to products. Yet, much of this frontier is early basic
research that would otherwise be underfunded by the private
sector, thereby delaying and reducing the full impact of the
discovery.
Basic mechanisms of early human cellular differentiation,
intercellular communication, gene expression, and development
biology are accessible to vigorous study for the first time. We
must seize this opportunity and allow the most sophisticated
biotechnology community in the world full access to these cells
and appropriate levels of support to increase our understanding
of the fundamental mechanisms that control our own development.
Last, I would like to summarize the position of Geron's
ethics advisory board on the ethical justification of this kind
of work. The company formed an ethics advisory board to advise
us on the ethical issues associated with this research. The
board, composed of medical ethicists of diverse religious
traditions, carefully deliberated the issues and unanimously
agreed that research on human pluripotent stem cells can be
conducted ethically if performed within certain guidelines,
which briefly are: treating the cells with appropriate respect
due to early developmental tissue; obtaining full and informed
consent from donors of the tissue; no reproductive cloning of
human beings; accord for accepted norms of animal research;
concern for global justice and the use of best efforts to
develop and utilize the technology for all peoples; and last,
participation by an independent ethics advisory board, in
addition to an institutional review board, to assess the
appropriateness of each research protocol.
Geron has and will continue to follow these guidelines. I
have submitted the ethics board's report to this hearing and a
full publication of these guidelines and their ethical
foundations will be published by the board in conjunction with
the Hastings Center.
prepared statement
In conclusion this morning, the therapeutic applications of
this technology are real and near term. The benefits to society
are clear, and their development appropriately falls under the
purview of the National Institutes of Health. The ethical
implications of the research, while requiring continual
oversight as the technology matures, are nevertheless
compelling today and argue strongly for the development and
application of this technology for the improvement of health
care.
Senator Specter. Thank you very much, Dr. Okarma.
[The statement follows:]
Prepared Statement of Thomas Okarma
executive summary
First, I would like to thank the committee for inviting my
testimony on behalf of Geron Corporation on the implications of human
stem cell research. My comments will briefly cover (l) the significance
of the discovery, (2) why Geron chose to support this research, (3) why
the NIH should participate in the development of biomedical
applications of this research and (4) the view of Geron's Ethics
Advisory Board on the ethical justification for research on the human
pluripotent stem cell.
I respectfully request that my comments and submitted background
materials be incorporated into the record of this hearing.
1. The significance of the discovery.--The human pluripotent stem
cell has the potential to dramatically impact clinical medicine by
introducing fundamentally new therapeutic technologies. No other human
cell has the potential to (1) enable the development of cell and tissue
transplantation therapies and gene therapy, (2) retool pharmaceutical
research and development, and (3) accelerate research in human
developmental biology, cellular differentiation mechanisms and cancer
biology.
These cells are immortal in their undifferentiated state--they will
grow indefinitely in culture, thereby providing a continuous source of
homogeneous starting material for the production of uniform
transplantable cells.
These cells are pluripotent, capable of forming all cells of the
human body, making them a potential source of replacement cells for any
failing organ. This would reduce the demand for organ donors, and more
importantly, enable therapies to treat conditions that otherwise must
be addressed by whole organ transplants such as:
--Heart muscle cells to restore the failing hearts of the five
million Americans with congestive heart failure.
--Blood forming cells to provide hematologic support for the over one
million new cases of invasive cancer in the US each year.
--Cells to line the inside of blood vessels to treat atherosclerosis
which contributes to 650,000 deaths in the US each year.
--Insulin producing islet cells which could cure the 1.4 million US
patients with Insulin Dependant Diabetes Mellitus.
--Nerve and brain cells for the one million Parkinson's disease
patients, the 500,000 stroke victims or the four million
Americans with Alzheimer's disease.
2. Why Geron chose to fund this research.--Clearly, the therapeutic
potential is extraordinary. This potential is realizable and portions
of it can be reduced to practice based upon prior knowledge gained from
animal stem cell work, and the convergence of available complimentary
technologies developed by both the biotechnology industry and the
academic biomedical community. For example, Geron Corporation's
demonstrated ability to use the telomerase gene to convey unlimited
replicative capacity to differentiated cells is a key synergistic
technology for developing therapeutic applications of human pluripotent
stem cells. As we learn to control the pathways that take stem cells
down the road to neurons, blood vessels, and heart cells, we can
immortalize them by telomerase gene transfer so that sufficient
quantities of these cells can be grown for transplant applications.
Geron's mission is to develop treatments for chronic, degenerative
disease. These two technologies, telomerase gene transfer and human
pluripotent stem cells, combine to make possible the repair of
degenerating organs with young, healthy and fully functional cells.
3. Why the NIH should participate in the development of biomedical
applications of this research.--The scientific frontier opened up by
the derivation of human pluripotent stem cells is vast. Industry will
only explore that part of the frontier that may lead to products. Yet
much of this frontier is early, basic research that will be otherwise
underfunded by the private sector, thereby delaying and reducing the
full impact of this discovery. Basic mechanisms of early human cellular
differentiation, intercellular communication, gene expression and
developmental biology are accessible to vigorous study for the first
time. We must seize this opportunity and allow the most sophisticated
biomedical research community in the world full access to these cells
and appropriate levels of support to increase our understanding of
these fundamental mechanisms that control our own biological
development.
4. The position of Geron's Ethics Advisory Board on the ethical
justification of research on human pluripotent stem cells.--Geron
formed an Ethics Advisory Board to advise the company on the ethical
issues associated with this research. The board, composed of medical
ethicists of diverse religious traditions, carefully deliberated the
issues and unanimously agreed that research on human pluripotent stem
cells can be conducted ethically if performed within certain
guidelines:
(1) Treating the cells with respect appropriate to early
developmental tissues. As stated by the Human Embryo Research Panel in
their 1994 report, while deserving moral consideration due any human
tissue, the early blastocyst (from which the stem cells are derived)
does not warrant the same moral status as infants or children because
of the absence of individuation and the lack of even the possibility of
sentience and other qualities relevant to the moral status of persons.
Therefore the use of such cells for the purpose of saving or healing
human life constitutes appropriate respect for these cells.
(2) Full and informed consent for tissue donation.
(3) No reproductive cloning of human beings or creation of chimeras
(live animal combinations of two different species).
(4) Accord for accepted norms for animal research.
(5) Concern for global justice and the use of best efforts to
develop and utilize the technology for all peoples.
(6) Participation by an independent ethics advisory board in
addition to an Institutional Review Board to access the appropriateness
of each research protocol.
Geron has and will continue to follow these guidelines. I have
submitted the EAB's report to this hearing. A full publication on these
guidelines and their ethical foundations will be published by the Board
in conjunction with the Hastings Center.
In conclusion, the therapeutic applications of this technology are
real and near term. The benefits to society are clear and their
development appropriately falls under the purview of the NIH. The
ethical implications of this research, while requiring continual
oversight as the technology matures, are nevertheless compelling and
argue strongly for the development and application of this technology
for the improvement of health care.
the first derivation of human embryonic stem cells
A Scientific Breakthrough for Transplantation Medicine, Pharmaceutical
Research and Development, and Human Developmental Biology
The Breakthrough
Dr. James Thomson and colleagues at the University of Wisconsin,
Madison, have for the first time successfully derived human embryonic
stem cells (hES cells) and maintained them in tissue culture. Human
embryonic stem cells are different from every other human stem cell
previously isolated in that they have (i) an unlimited ability to
divide and (ii) the capability to turn into any and all cell types and
tissues in the body. These cells, licensed worldwide to Geron
Corporation, hold great promise as a potentially universal source of
replacement cells for transplantation and for use in screens for
pharmaceutical research and development. Further, this promise is
enhanced by Geron's cell immortalization technology which can
potentially increase the lifespan of the differentiated cells produced
from hES cells. The combined technology positions Geron to potentially
supply an unlimited number of young cells and tissues for every organ
in the body. In addition, hES cells will improve our understanding of
reproductive and developmental biology. This could lead to better
treatments for infertility and the discovery of new gene products to
treat a wide variety of diseases.
Characteristics of Human Embrvonic Stem Cells
Derived from in vitro fertilized (IVF) blastocysts by a patentable
laboratory process (US claim allowed) and donated under informed
consent, hES cells have all the following characteristics which make
them useful for multiple new therapeutic, pharmaceutical, and
scientific applications.
1. Pluripotency.--hES cells can form virtually any cell in the
body. Specifically they have the potential to form derivatives of all
three cellular layers, including the gut epithelium (endoderrn);
cartilage, bone, and smooth and striated muscle (mesoderm); and neural
epithelium, embryonic ganglia and stratified squamous epithelium
(ectoderm). Other later stage human stem cells have only a limited
capability to form certain cell types such as blood cells (CD34+ stem
cells) or connective tissue (mesenchymal stem cells).
2. Self-renewing capacity.--Under appropriate in vitro conditions,
the hES cells repopulate themselves while remaining in the
undifferentiated state. Therefore, they may be a continuous source of
normal pluripotent human stem cells. We expect they can be scaled-up to
commercial manufacturing levels for transplantation therapies. It has
not been possible to maintain long term self-renewing capacity of other
human stem cells in culture. The ability of hES cells to propagate
indefinitely in the undifferentiated state without losing pluripotency
is a characteristic that distinguishes them from all other
``multipotent stem cells'' discovered to date in humans. Among other
benefits, the availability of scaled-up hES cell-derived cells and
tissues for transplantation therapies could greatly reduce future
reliance on primary human fetal and animal derived tissue.
3. Telomerase expression.--Telomerase is an RNA-dependent DNA
polymerase demonstrated by Geron Corporation and its collaborators to
be the enzyme which, when reactivated in normal cells, allows their
continual proliferation. hES cells normally express the enzyme
telomerase. The continual steady state activity of telomerase in hES
cells conveys replicative immortality. Other stem cells express
telomerase at low levels or only periodically and therefore age and
stop dividing with time.
4. Normal chromosome structure (karyotvpe).--hES cells maintain a
structurally normal set of chromosomes (including the sex chromosomes,
XX or XY) even after prolonged growth in vitro. They do not, for
example, have any additions, deletions or rearrangements in their
chromosomal structure as is characteristic of cell lines immortalized
by viruses.
Because of these characteristics, hES cells are unique. No other
cell has the potential of hES cells to (i) enable development of
transplantation therapies, (ii) re-tool pharmaceutical research and
development practices, and (iii) accelerate research in human
developmental biology. Moreover, hES cells should provide an immediate,
alternative source and industrial supply of starting material,
relieving the need to continually resource primary human fetal-derived
tissues. Much of the research necessary for product development work
can be performed on the hES cells now made available by Dr. Thomson's
breakthrough discovery. This research will be challenging and take
time, yet holds vast biomedical and therapeutic potential. Geron
Corporation has provided funding and support for Dr. Thompson's work
and holds worldwide rights to his discovery.
Benefits to Science and Medicine
The derivation of hES cells is a fundamental discovery that holds
promise for three major areas of biomedicine: (1) Transplantation
medicine, (2) Pharmaceutical research and development and (3) Human
developmental biology.
1. Transplantation Medicine.--The potential therapeutic impact of
hES cells in transplantation medicine is enormous because of their
expected capability to produce virtually unlimited quantities of any
cell in the body. In addition, they have the potential to be
genetically engineered to prevent their immune rejection by the
transplant recipient. Examples of medically relevant cells that could
be developed and tested for transplantation therapies in humans include
the following:
(i) Cardiomyocytes.--Heart muscle cells do not proliferate during
adult life. When heart muscle is damaged by injury or ischemia,
functional heart muscle is replaced with non-functional scar tissue.
Congestive heart failure, a common consequence of heart muscle or valve
damage, affects nearly 5 million people in the United States, with
400,000 new cases diagnosed each year. In addition, about 1.5 million
people each year suffer myocardial infarction, the primary cause of
heart muscle damage, and about one third of them die.
Mouse cardiomyocytes derived from mouse embryonic stem cells have
been prepared and injected into the hearts of recipient adult mice. The
injected cardiomyoctes repopulated the myocardial tissue and stably
integrated with host myocardial tissue (Klug, et al., 1996, J Clin
Invest 98:216-224). These results suggest that the development of hES
cell-derived cardiomyocytes for cellular transplantation therapy of
congestive heart failure and myocardial infarction in humans is
technically feasible.
(ii) Hematopoietic stem cells.--Bone marrow transplantation is a
life saving procedure used in pediatric and adult cancers. In 1995,
there were approximately 4,500 allogeneic (donor) and 8,000 autologous
(self) blood and bone marrow transplants performed in North America.
The number of procedures performed dramatically under-serves the
medical need. The main factor which limits the number of procedures is
tissue or donor availability.
Blood-forming stem cells could be developed from hES cells as has
been done using mouse embryonic stem cells (Kennedy, et al., 1997,
Nature 386:488-492). This would increase the availability of these
cells and reduce reliance on donors. Further, hES cell-derived
hematopoietic stem cells potentially could be genetically engineered to
resist infection by such agents as the HIV virus and used in a
transplant setting for the treatment of AIDS, or possibly used for the
treatment of patients with sickle cell anemia.
(iii) Endothelial cells.--(blood vessel forming cells). Endothelial
cells have been observed in hES-derived teratomas in mice and mouse
endothelial cells have been derived from mouse ES cells (Vittet, et
al., 1996 Blood 88:3424-3431). These blood vessel forming cells could
be generated from hES cells and used to re-line blood vessels for the
purpose of treating atherosclerosis, a condition which contributes to
over 650,000 deaths annually in the US. hES-derived endothelial cells
could also be used for generating new blood vessels in ischemic regions
of the heart, brain, or lower extremities to treat angina, stroke and
arterial insufficiency.
(iv) Islet cells.--The 1.4 million U.S. patients with Insulin
Dependant Diabetes Mellitus potentially could be treated with islet
cells derived from hES cells and isolated for this use. Such human
cells are unavailable today and could provide a lifelong cure for this
disease.
(v) Neurons.--It has been demonstrated that mouse neurons can be
derived from mouse embryonic stem cells (Bain, et al., 1995, Dev Biol
168:342-357). Neurons derived from hES cells potentially could be
prepared for the treatment of (i) the over 1 million individuals in the
United States who suffer from Parkinson's disease, (ii) the 500,000
U.S. citizens who suffer a stroke each year, and (iii) even Alzheimer's
disease, which now affects over four million Americans.
(vi) Fibroblast and keratinocyte skin cells.--of mice have been
observed in cultures of differentiated mouse ES cells (Bagutti, et al.,
1996, Dev Biol 179:184-196). We expect that comparable human skin cells
could be produced from hES cells and used for wound healing and the
treatment of burns.
(vii) Chondrocytes.--cartilage forming cells, also observed in hES-
derived teratomas in mice, could potentially be generated from hES
cells for cartilage replacement in osteoarthritis which affects over 16
million Americans, or rheumatoid arthritis which affects over two
million persons in the United States.
2. Pharmaceutical research and development.-- The potential to
produce and supply unlimited quantities of normal human cells of
virtually any tissue type could have a major impact on pharmaceutical
research and development. Until now, the only cell lines available for
this work were either animal in origin or abnormal transformed human
cells. Permanent, stable sources for normal human differentiated cells
may be developed for drug screening and testing, drug toxicology
studies, as well as new drug target identification. Further, because
hES cells express telomerase and can therefore undergo multiple rounds
of a sophisticated type of genetic engineering called gene targeting,
cellular models of human disease could be developed for use in drug
development. Finally, cell lines derived from hES cells may be useful
for developing screens for teratogens (drugs causing birth defects),
extending the capability of current assays based on bacterial and
murine systems.
3. Human reproductive and developmental biology.--Unraveling the
biology of hES cells as they differentiate into functional cell types
in vitro offers a unique platform to understand and harness nature's
mechanisms of embryonic development, tissue differentiation and repair.
Such understanding has potential for contributing to (i) the treatment
of fertility disorders which affect one out of every six couples in the
U.S. trying to become pregnant, (ii) the prevention of premature
pregnancy loss, estimated to be 15 percent of recognized pregnancies in
the US, and (iii) the diagnosis and prevention of birth defects which
afflict 3 percent of live births in the US.
Until now, the early developmental events which naturally occur
during human embryogenesis have been inaccessible to direct study. The
availability of hES cells may facilitate a molecular understanding of
how specific human tissues and organs develop without conducting
research on human embryos or fetuses. Further, it is possible that
novel genes which fundamentally control tissue differentiation could be
identified by the application of genomic technologies to cultured hES
cells as they differentiate into a variety of functional cell types.
These new gene products may have potential to be developed into
therapeutic proteins with possible applications including wound
healing, stroke, myocardial infarction, spinal cord injury, and tissue
regeneration.
These potential clinical applications would utilize suspensions of
hES cell-derived differentiated cells administered by injection. With
further technical development, complex multi-cellular solid tissues and
organs potentially could be developed for application in organ support
therapies for lung, kidney, liver, cardiac and brain diseases. While
the biomedical and therapeutic promise of hES cells is vast, it should
be emphasized again that the additional research and development
required to realize this potential is significant.
This Breakthrough is Enhanced by Geron's Technology
Geron's focus is on identifying and modifying for therapeutic
purposes the molecular mechanisms that control cellular aging and
replication. The company and its collaborators have cloned the enzyme
telomerase which extends the replicative capacity of cells. The
application of telomerase gene transfer technology to hES cells is part
of Geron's ongoing work in cell and gene therapy and flows from its
published results on extending cellular replicative potential as
reported in Science earlier this year (Bodnar, et al., 1998, Science
349-352). Telomerase activity is quickly down-regulated after hES cells
differentiate. The ability to reactivate telomerase in differentiated
cells derived from hES cells could prolong their replicative lifespan
indefinitely and thereby make them the preferred cells for applications
in transplantation medicine because they should be long-lived and form
a durable graft.
The History of hES Cell Derivation
Work to derive and maintain undifferentiated pluripotent cell lines
dates back to the 1960s with the demonstration that certain cancer-
derived mouse cells were capable of forming multiple tissue types.
These cancerous cells proved to be of limited research utility, and
efforts continued to derive non-cancerous, self-renewing, pluripotent
stem cells from mouse embryos. Eventually, the successful derivation of
murine embryonic stem cells from the inner cell mass of mouse
blastocysts in 1981 allowed culture conditions to be defined that
supported their unlimited propagation. These cells were soon shown to
be totipotent and capable of contributing to the germ line in mice
(passed on from generation to generation). The use of murine embryonic
stem cells in gene targeting experiments has resulted in development of
numerous mouse models of human disease (knock-out mice) and has
provided valuable insights into developmental biology, much of which
has been applied to human medicine. However, these experiments also
demonstrated that there are major differences in developmental biology
between mice and humans. These fundamental differences formed a
rationale to pursue the derivation of embryonic stem cells from higher
mammals.
Methods developed for deriving mouse embryonic stem cells were
applied toward deriving embryonic stem cell lines from other animals
such as sheep (1987), hamster (1988), pig (1990), and rabbit (1993).
The first non-human primate embryonic stem cell was described by Dr.
James Thomson at the University of Wisconsin, Madison in 1995. The
derivation process for primate embryonic stem cells differed from
methods developed for the mouse and other non-primate species.
Furthermore, there are differences between primate ES cells and other
ES cells. For example, currently, primate embyonic stem cells have a
absolute requirement for feeder layers of irradiated fibroblasts in
order to propagate in the undifferentiated state in vitro. They also
differ from mouse ES cells in colony appearance and biochemical surface
markers.
Like other mammalian embryonic stem cells, however, primate
embryonic stem cells differentiate and form tissues of all three
cellular layers when injected into immunodeficient mice, proving their
pluripotency. Published reports show that these primate embryonic stem
cells have been maintained in culture for more than a year, during
which time they have retained their pluripotency, self-renewing
capacity, and their normal karyotype (Thomson, et al., (1995), PNAS
92:7844-7848).
Dr. Thomson subsequently applied his primate embryonic stem cell
derivation technology to voluntarily donated in vitro fertilized human
blastocysts. He now reports the first successful derivation and
propagation of human embryonic stem cells which, like the primate
embryonic stem cells derived earlier, are pluripotent,\1\ self
renewing, and telomerase positive with a normal karyotype (Thomson, et
al., (1998) Science, in press).
---------------------------------------------------------------------------
\1\ hES cells are referred to as pluripotent. All non-human ES
cells are referred to as totipotent (capable of developing into the
whole organism). The only way to prove totipotency is to derive an
organism from the cell. This has been done with animal ES cells but
will not be done with hES cells for ethical reasons.
---------------------------------------------------------------------------
The Derivation of Human Embryonic Stem Cells
In vitro fertilized preimplantation stage blastocysts, produced
initially but not used for clinical purposes, were donated voluntarily
with conformed consent, by clients undergoing in vitro fertilization
procedures. The derivation protocols were approved by the University of
Wisconsin Institutional Review Board. After culturing to the blastocyst
stage, the inner cell masses were recovered and cultured on irradiated
mouse embryonic fibroblast feeder layers. After about two weeks in
culture, the hES cells were dissociated and replated on fresh feeder
layers. The hES cells were thereafter maintained for months in the
undifferentiated state by serially sub-culturing onto fresh, irradiated
mouse embryonic fibroblast feeder layers (Fig 1).
The Demonstration of Pluripotency
The capability of hES cells to differentiate into virtually any
cell in the body was demonstrated by experiments in which the hES cells
were injected into severe combined immunodeficient (scid) mice. Each of
the injected cell lines produced non-malignant tissue masses
(teratomas) that contained a wide range of human differentiated cells
and tissues, including gut epithelium (endoderm); cartilage, bone,
smooth and striated muscle (mesoderm); and neural epithelium, embryonic
ganglia and stratified squamous epithelium (ectoderm). These three
cellular layers (endoderm, mesoderm and ectoderm) have the potential to
form all the cells in the body (Fig 2).
The Significance of Telomerase Expression in hES Cells
In general, cells that express telomerase have the ability to
divide indefinitely. Cells not expressing telomerase (most cells of the
body) have a limited replicative capacity. hES cells express telomerase
and therefore have infinite replicative capacity.
Telomerase is an enzyme, cloned by Geron and collaborators, that
maintains the length of the telomeric regions (ends) of chromosomes and
thereby prevents cell senescence. In fact, telomerase expression is
highly correlated with replicative immortality in certain human cells.
Similarly, re-introduction of telomerase by gene transfer into normal
telomerase-negative cells confers replicative immortality (Bodnar, et
al., 1998, Science 349-352). Telomerase activity is continuously
present in adult male reproductive tissue and is present in human fetal
heart, liver, and kidney cells but only for the first 11-15 weeks of
embryonic development.
The benefits of telomerase expression in hES cells are twofold.
First, the cells are immortal, enabling the production of an unlimited
supply of undifferentiated pluripotent cells. Second, the cells are
amenable to a sophisticated type of genetic engineering called gene
targeting which allows the insertion of new genes to specific sites on
the chromosome to enhance their expression and control.
Geron's Intellectual Property Position in hES Cells
Geron's intellectual property estate in the embryonic stem cell
field consists of:
1. A worldwide license to the stem cell patent estate of Dr. James
Thomson and the Wisconsin Alumni Research Foundation. Licensed patent
applications include primate and human embryonic stem cells and related
diagnostic and therapeutic products. A broad claim has already been
allowed in the US from this estate covering primate embryonic stem
cells with the characteristics described in the Thomson Science paper
just published.
2. A worldwide license to the stem cell patent estate of Dr. John
Gearhart and the Johns Hopkins University. This license includes all
applications of human embryonic stem cells including diagnostic and
therapeutic products.
3. A worldwide license to patent applications of Dr. Roger Pedersen
and the Regents of the University of California covering diagnostic and
therapeutic products based on hES cells.
4. A license of the Genpharm patents on genetic modification of
human and primate embryonic stem cells by homologous recombination
(gene targeting). This estate consists of four issued US patents and
eight pending US patent applications.
5. Geron-owned patent applications including screens for hES cell
growth factors, media formulation and preferred growth conditions, and
also relating to telomerase gene transfer and recombinant telomerase
expression in embryonic stem cells and their derivatives.
The Ethical Considerations in hES Cell Product Development
These hES cells are derived from in vitro fertilized blastocysts.
IVF clinic patients voluntarily donated the blastocysts with informed
consent. The University of Wisconsin-Madison Institutional Review Board
approved all of the research protocols. Geron's intended hES cell
research as well as that of its collaborators is conducted within the
suggested guidelines of the 1994 report by the NIH Human Embryo
Research Panel.
Human embryonic stem cells are obtained from in vitro fertilized
human blastocysts and capable of differentiating into virtually any
cell in the body. However, hES cells are derived from the blastocyst
inner cell mass by a laboratory process and are not the cellular
equivalent of an embryo.
The small cluster of cells (inner cell mass) within the in vitro
fertilized blastocyst from which the hES cells are derived have not yet
differentiated and are unspecialized. The inner cell mass does not form
discrete parts of an individual embryo as one or more of these inner
mass cells can be removed from the blastocyst (for preimplantation
diagnosis) without affecting subsequent fetal development after
transfer to the uterus. If hES cells were to be transferred to a
uterus, the hES cells would not form an embryo because other cells
necessary for implantation and embryogenesis have been lost in the
derivation process.
Geron has adopted the conclusion of the NIH Human Embryo Research
Panel in its 1994 report. The cells will not be used for (i) cloning
humans, (ii) transfering to a uterus, or (iii) generating human-human
or human-animal chimeras (live animal hybrids produced by mixing
embryonic stem cells of different individuals or species).
Geron has formed an independent Ethics Advisory Board composed of
prominent bioethicists to advise the company on the ethical
implications of hES cell product development strategies. The Board has
unanimously agreed that research on hES cells can be conducted
ethically if performed within the guidelines adopted by Geron
Corporation and its collaborators. To complement its internal research
and development, Geron Corporation maintains sponsored research
collaborations with Dr. James Thomson, Dr. John Gearhart and Dr. Roger
Pedersen, nationally prominent investigators in human stem cell
research whose protocols have all been reviewed and approved by their
respective Institutional Review Boards.
The Next Steps in hES Cell Research and Development
Now that the major bottleneck in developing hES cell-derived cells
and tissue for transplantation has been eliminated with the derivation
of hES cells, Geron plans to develop other supporting technologies
including:
(i) Human embryonic stem cell production, scale up and genetic
engineering.--A standardized process will need to be developed for
large-scale production of hES cell-derived differentiated cells for
transplantation. Quality control criteria will need to be developed for
the feeder lines, culture media, growth factors, sterility assays and
phenotypic markers used for the clinical production of hES cells.
Protocols will need to be developed and optimized for genetically
engineered hES cells. Techniques of gene targeting \2\ (homologous
recombination) will need to be optimized.
---------------------------------------------------------------------------
\2\ Gene targeting is a sophisticated technique of genetic
engineering which allows the gene of interest to be ``targeted to'' a
specific and desired location in the chromosome, thereby allowing the
gene of interest to be controlled by the normal regulators of that
gene's expression. Because gene targeting requires several rounds of
selection, each requiring multiple cycles of cell division, only
immortalized cells have sufficient replicative capacity to be suitable
for this form of genetic engineering.
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(ii) Differentiation control.--Technologies using tissue-specific
promoters and drug selection strategies will need to be developed to
direct the differentiation of these cells towards the desired final
cell and tissue product. Other methods of cell purification such as
cell sorting will also need to be explored. Factors useful to drive
cells toward specific differentiation states will need to be identified
and used in conjunction with drug selection-enrichment technologies.
Techniques will need to be developed to prevent the rejection of hES
cell derived tissues by transplant recipients.
(iii) Primate model development.--Human therapeutic products
derived from hES cells will require in vitro and animal testing. With
Geron's license to the non-human primate embryonic stem cells of
monkeys (also identified by Dr. Thomson at the University of Wisconsin-
Madison), Geron has the capability to develop and test its proposed
therapeutic products in a highly useful primate model.
This continuing research and development activity will constitute
Geron Corporation's hES cell technology development program. Geron has
work plans in place with Drs. Thomson, Gearhart and Pedersen, and will
seek to collaborate with other academic centers and biotechnology and
pharmaceutical companies in developing these therapeutic opportunities.
The availability of pluripotent, self-renewing hES cells that can
be differentiated into bulk-manufactured, functional, youthful cells
and tissues will potentially usher in a new era of therapeutic
opportunities in transplantation medicine, pharmaceutical research and
development, and developmental biology that could positively impact
many millions of patients worldwide.
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glossary
First Derivation of Human Embryonic Stem Cells
Allogeneic: When describing transplantation biology, the donating
individual is of the same species, but not one's self.
Angina: A condition with severe and constricting pain, usually
referring to the heart.
Autologous: When describing transplantation biology, the donating
individual is one's self.
Blastocyst: In mammalian embryology, the preimplantation embryo
consisting of a sphere of cells with an outer cell layer, a fluid-
filled cavity, and a cluster of cells on the interior that is the inner
cell mass.
Cardiomyocytes: Mature, differentiated heart muscle cells.
Chondrocytes: Mature, differentiated cartilage cells chromosomes:
Composed chiefly of DNA, they are the carrier of genes, the hereditary
information.
Cloning: A term that is applied to genes, cells or entire organisms
that are derived from, and are genetically identical to, a single
common ancestor gene, cell, or organism, respectively.
Differentiate: To undergo a cellular progression to a more
specialized type.
Embryo (human): An organism at its earliest stage of development
which has the potential, if transferred to a uterus, to develop in the
normal course of events into a living human being.
Embryogenesis: The process of embryo formation.
Feeder layers of irradiated mouse fibroblasts: mouse cells which
have been treated to prevent their division, but which produce
important growth factors allowing ES cells to repopulate.
Fibroblast cells: Cells that give rise to connective tissue.
Keratinocytes: Cells that synthesize keratin as in the skin, hair,
and nails.
Gene targeting: The insertion of DNA into specific sites or genes
within the genome of selected cells to alter gene expression for
therapeutic applications.
Genome: The genetic material (complete set of chromosomes) of an
organism.
Genomic technology: Sequencing genes and their expression products.
Hematopoietic: Pertaining to the formation of blood cells.
hES cells: Human embryonic stem cells, they are immortal (self-
renewing), telomerase positive, and pluripotent.
Homologous recombination: A process whereby a specific gene
sequence within the genome is replaced with a related gene sequence
using the cellular recombination enzymes.
Inner cell mass: The cluster of cells within the blastocyst from
which hES cells are derived.
Implantation: Attachment of a blastocyst to the endometrium.
In vitro: Performed in an artificial environment such as a test
tube.
In vivo: Performed in a living organism.
In vitro fertilization (IVF): An assisted reproduction technique in
which fertilization is accomplished outside of the body.
Ischemia: Deficiency of oxygen in a tissue due to obstruction of a
blood vessel.
Islet cells: Cells of the pancreas that produce and secrete
insulin; degeneration of islet cells is the cause of Insulin Dependent
Diabetes Mellitus.
Karyotype: The chromosomal characteristics of a cell.
Knock-out mice: Mice that have had one or both copies of a specific
gene deleted or inactivated Page Three/First Derivation of Human
Embryonic Stem Cells.
Murine: Of or relating to the rodent family.
Myocardial infarction: Heart attack.
Pluripotent: The ability to develop into multiple cell types
including all three embryonic lineages forming the body organs, nervous
system, skin, muscle, and skeleton.
Severe combined imunodeficient (scid) mice: Mice with the majority
of their immune defenses not functioning.
Telomerase: An enzyme composed of a protein and an RNA template
which synthesizes telomeric DNA at the ends of chromosomes and confers
replicative immortality to cells.
Telomeres: The ends of chromosomes.
Teratoma: A non-malignant tumor consisting of different types of
tissue caused by the growth of embryonic stem cells at an abnormal site
in the body.
Totipotent: The ability of a cell to give rise to all cells and
tissues in the body including the reproductive organs.
Undifferentiated: Having no limited or specialized function or
structure, as in stem cells.
Zygote: Cell formed by union of two gametes--male and female germ
cells.
______
Questions and Answers
Science/Technical
Question. What is the relationship between human ES cells and other
human stem cells?
Answer. First, under appropriate in vitro conditions, hES cells
repopulate themselves while remaining in the undifferentiated state.
They are, therefore, a potentially continuous source of pluripotent
human stem cells which could be developed to generate specific cells or
tissues and scaled-up to commercial manufacturing levels for
transplantation therapies. It has not been possible to maintain in
vitro long term self-renewing capacity in the undifferentiated state
with any other human stem cell. The ability of hES cells to propagate
indefinitely in the undifferentiated state without losing pluripotency
is one of the characteristics that distinguishes them from all other
stem cells discovered to date in humans.
Second, other human stem cells have only a limited capacity to form
differentiated cell or tissue types such as blood cells (CD34+ stem
cells) or connective tissues (mesenchymal stem cells). hES cells, in
contrast, have the unique capability to form any and all cell and
tissue types in the body.
Question. Could these cells be used to grow entire organs?
Answer. Human Embryonic Stem cells form differentiated tissues with
organ-like features when injected into immuno-compromised mice. Under
appropriate laboratory conditions and with the development of
supportive technologies, it may be possible to grow multicellular
tissues and perhaps whole organs in a laboratory environment for
subsequent therapeutic applications in humans.
Question Will additional hES cells be derived?
Answer. Although much of the basic research and developmental work
required to translate this discovery into products of medical value can
be performed on the hES lines already isolated by Dr. Thomson, other
hES lines will be isolated to support product development. Because the
cells are believed to be immortal and pluripotent, and are amenable to
sophisticated forms of genetic engineering, we envision the possibility
of producing multiple types of transplantable tissues from single hES
lines, reducing the necessity to routinely generate new ES cell lines
for each application.
Question. How does this technology relate to cloning human beings?
Answer. As has been documented with animals, the basic technology
required to clone mammals is already available, although not at this
point reduced to reliable practice. Dolly was one success in 278
attempts. To our knowledge, Dolly and all other animals cloned to date,
were cloned using nuclear transfer procedures which utilize adult cell
nuclei and enucleated egg cell cytoplasm, not embryonic stem cells.
Using nuclear transfer procedures, it might be possible in the future
to clone human beings, without use of hES cell technology.
However, Geron fully supports the current ban in the State of
California on cloning human beings for reasons outlined in the 1997
report of the National Bioethics Advisory Commission on human cloning.
Medical Potential
Question. What are the hurdles to developing therapeutic
applications of this technology--for example, growing heart muscle
cells for heart disease patients?
Answer. Many lessons have been learned from animal experiments with
heart muscle, nerve and certain blood cells. For example, heart muscle
cells have been derived from mouse embryonic stem cells and have been
injected into hearts of adult mice where they were shown to
functionally integrate into the heart muscle. In order to accomplish
this, the mouse embryonic stem cells were genetically modified using
procedures that allowed the selection of only cardiomyocytes from the
differentiating cultures. These genetically-based differentiation
technologies will need to be tested in primate and hES cells in an
attempt to produce cardiomyocytes of sufficient purity.
Question. How long will it take before you begin any human clinical
trials using this technology?
Answer. Many technologies will need to be developed to realize the
full potential of the clinical applications of hES cells. Furthermore,
these applications, once developed, will need to be tested in primate
models. It is therefore difficult to predict how soon human clinical
trials using this technology could begin.
Question. Would it be easier--and just as effective--to work with
stem cells further downstream, that have already differentiated into
specific cell types?
Answer. There are several approaches now in human clinical trials
that utilize mature, multipotent stem cells (blood-forming cells,
neuron-forming cells and cartilage-forming cells). These human trials
will provide valuable insights toward the use of stem cells in
transplantation procedures. However, each of these approaches requires
that an individual donor (or the patient) be used as the source of the
cells which are then subsequently processed in a laboratory and
transplanted. These procedures, necessary to address tissue sourcing
constraints and immune system rejection, are costly, time consuming,
and inefficient. These downstream stem cells have already
differentiated and are therefore more difficult to modify to make them
tissue compatible.
Telomerase positive hES cells, on the other hand, are believed to
be self-renewing and therefore scalable. One culture line can produce
many different tissues thereby improving production efficiency. We also
believe that hES cells, because they are more primitive and
developmentally upstream, could be more likely to develop into fully
functional integrated tissues once transplanted. Further, these hES
cells potentially can undergo multiple rounds of sophisticated genetic
engineering to become tissue compatible, thereby eliminating the need
to identify compatible donors as a source of the cells.
Business Issues
Question. How is Geron involved in this breakthrough?
Answer. We have funded Dr. Thomson's research for three years and
collaborated with his lab on the characterization of the hES cells he
derived. Geron also has a worldwide license to this discovery.
Question. What evidence is there to support that there will be any
viable commercial uses based on this discovery?
Answer. Several of the proposed hES cell-based therapeutic
applications have already been demonstrated in mice with murine ES
cells. Geron believes it is likely that these technologies will be
transferable with appropriate modifications. We believe that results
achieved in animals potentially can be extended and developed into
viable therapeutic strategies for humans.
Furthermore, there are commercial applications of hES technology
that could be reduced to practice before the cells become available for
tissue transplantation. We expect to collaborate with one or more
genomics companies to identify novel genes that could be used to
generate therapeutic proteins to help regenerate tissue in such
conditions as spinal cord injury, stroke, or heart attacks.
Also, cells derived from hES cells may also be commercialized as a
technology for use in drug screening, drug target identification or
even identifying teratogens (drugs that cause fetal abnormalities) and
therefore make the pharmaceutical research and development process more
efficient.
Question. What will Geron's sustainable advantage be in competing
with other stem cell companies?
Answer. Human embryonic stem cell technology fits in extremely well
with Geron's telomere and telomerase technology platform. Geron and its
collaborators have cloned the telomerase enzyme and demonstrated its
utility in immortalizing cells for potential therapeutic applications.
Telomerase gene transfer technology, being developed by Geron, could be
important for the development of compatible, transplantable tissues
derived from hES cells that result in durable, long lasting grafts.
Further, hES cells are the earliest, most upstream pluripotential stem
cells and the only human stem cell thus far shown to self-renew in the
undifferentiated state. These characteristics provide unique
capabilities to these cells which, we believe, will likely translate
into technical and commercial competitive advantages.
Question. What about differentiated stem cells: are there issued or
pending patents on these later-stage cells by other companies or
institutions?
Answer. There are issued patents and pending patent applications on
later stage differentiated stem cells and non-primate embryonic stem
cells held by other companies or institutions. It is possible that
Geron may determine it advantageous to negotiate a license certain of
these technologies. However, the human embryonic stem cell occurs
developmentally upstream from all other stem cells and a broad claim
covering these cells has already been allowed by the US patent office.
Importantly, we will also attempt to patent genetically engineered
downstream cells derived from hES cells. Geron will continue to
aggressively pursue worldwide protection for this technology and
subsequent related inventions.
Question. What about growth and differentiation factors: does Geron
need to license this technology?
Answer. Geron may need to in-license certain technologies to enable
the development of the full therapeutic potential of hES cells,
including certain vector technologies, genetic differentiation
technologies, and growth factors. We will attempt to accomplish this
via licensing agreements and other forms of partnerships.
Question. Isn't there a business risk that work in this field will
someday be prohibited by the government?
Answer. Geron Corporation believes that the potential benefits to
medicine we have described are enormously important. Geron, and the
scientific and medical communities, generally support appropriate
scientific and ethical guidelines for conducting research in the field.
All product applications will, as is the case for all new therapeutics,
be carefully evaluated by the FDA. We anticipate that follow-on
research and development from breakthrough discoveries in science such
as hES cells will continue to be encouraged.
Question. Why should any one company be permitted to own the rights
to something as potentially important and valuable as the hES cell?
Answer. hES cells that exist outside the body in culture are
derived by a specific and novel laboratory process, and do not exist in
nature, so are therefore patentable. Geron will continue to invest in
product development based on this discovery. Academic researchers will
also work with the cells to develop other potential therapeutic uses
for them.
Ethical/Social Issues
Question. Is it possible that using ES cells will eliminate or
reduce the need to rely on controversial methods of research?
Answer. hES cells are expected to provide an immediate source of
material for the development of cells and tissues for application in
transplantation therapies. As such, hES cells could help relieve the
need to continually resource primary human fetal-derived tissues.
Question. Who should control and regulate the use of this
technology?
Answer. The US Food and Drug Administration is the appropriate
regulatory body to supervise the clinical testing of all therapeutic
products derived from hES cell technology.
statement on human embryonic stem cells by the geron ethics advisory
board
Background
Human embryonic stem (hES) cells have been derived and subsequently
maintained in tissue culture. The hES cells are isolated from donated
preimplantation embryos (technically, from the inner cell mass within
the blatocyst) produced through In Vitro Fertilization for clinical
purposes. Institutional Review Boards (IRBs) have approved the
research. All the cell research is conducted within the guidelines of
the 1994 report of the NIH embryo research panel and the 1997 National
Bioethics Advisory Committee report.
What makes the hES cells unique and important is that they are:
1. Pluripotent
2. Self-renewing
3. Expressive of the enzyme telomerase
4. Normal in chromosomal structure
Because of these features, these hES cells have the potential to
make distinctive contributions to:
1. Understanding developmental biology (e.g., how tissues
differentiate)
2. Pharmaceutical research (e.g., drug discovery and testing)
3. Transplantation medicine (e.g., generation of heart muscle
cells, bone marrow, etc.)
There is no intention to use the hES cell lines for cloning a human
person, transfer to a uterus (they could not develop into a fetus), or
generating human-human or human-animal chimeras (mixing cells of
different individuals or species).
statement of the geron ethics advisory board:
An Ethics Advisory Board, whose members represent a variety of
philosophical and theological traditions with a breadth of experience
in health care ethics, was created by Geron Corporation in July 1998.
The Board functions as in independent entity, consulting and giving
advice to the Corporation on ethical aspects of its work. The process
of the Board's deliberations has included sessions informing the Board
of the scientific, technical, and product development work of the
Corporation. Members of the Board have no financial interest in Geron
Corporation.
The Geron Ethics Advisory Board is unanimous in its judgment that
research on hES cells can be conducted ethically. In order for such
research to be conducted ethically in the current context, some
conditions must pertain. In addition, further public discourse will be
needed on a range of ethically complex questions generated by this
research.
1. The blastocyst must be treated with the respect appropriate to
early human embryonic tissue. Members of the Board are unanimous in
taking a developmental view of the moral status of the developing human
being. However, we also hold that, as human tissue, the blastocyst is
to be treated with moral seriousness. Research use of the blastocyst
requires justification; that justification is found in research that
aims ultimately to save or heal human life. This means that such tissue
is to be used only when there is an overriding good to be derived from
the research. In the view of the Board, the three purposes of research
(understanding developmental biology, pharmaceutical research, and
transplantation medicine) qualify as such goods.
2. Women/couples donating blastocysts produced in the process of In
Vitro fertilization must give full and informed consent for the use of
the blastocysts in research and in the development of cell lines from
that tissue. The consent process must be undertaken with care, in
recognition that donors undergoing In Vitro Fertilization are often
vulnerable. Donors should understand the potential market implications
of the research, and should be advised as to whether or not there are
any proprietary rights in the tissue.
3. The research will not involve any cloning for purposes of human
reproduction, any transfer to a uterus, or any creation of chimeras.
4. Acquisition and development of the feeder layer necessary for
the growth of hES cell lines in vitro must not violate accepted norms
for human or animal research.
5. All such research must be done in a context of concern for
global justice. One of the reasons the Ethics Advisory Board supports
this research is its potential to contribute to widespread accessible
medical interventions to alleviate human suffering. Accordingly, in the
development of this research and its applications, attention must be
paid to how technologies can be developed and utilized fairly for all
people.
6. All such research should be approved by an independent Ethics
Advisory Board in addition to an Institutional Review Board.
This analysis applies only to the isolation of hES cells from in
vitro fertilized blastocysts. The Ethics Advisory Board has not yet
considered the implication of emerging research on other stem cells
isolated from fetal tissues.
STATEMENT OF ERIC MESLIN, Ph.D., EXECUTIVE DIRECTOR,
NATIONAL BIOETHICS ADVISORY COMMISSION
Senator Specter. Our final witness on this panel is Dr.
Eric Meslin, executive director of the National Bioethics
Advisory Commission, Ph.D. in philosophy from the Kennedy
Institute of Ethics at Georgetown 1989, authored and coauthored
some 40 book chapters and articles on bioethics, and is a
senior research fellow at Georgetown University.
We appreciate your joining us, Dr. Meslin, and look forward
to your testimony.
Dr. Meslin. Thank you very much and good morning, Mr.
Chairman. I am pleased to appear before you and offer some
brief remarks on the subject of human stem cell research. Since
I only learned late yesterday afternoon that I would be
testifying, with your permission I will submit my written
testimony for inclusion in the written record soon after this
hearing is complete.
Senator Specter. Yes; that would be fine. We appreciate
your coming. We had called upon the chairman of the commission
and we did give late notice. When we reviewed our witness list,
we thought that we ought to hear from you since the President
had written to you and you had responded. So we thank you for
coming on short notice.
Dr. Meslin. My pleasure.
Mr. Chairman, as you know, on Thursday, November 14,
President Clinton wrote to Dr. Harold Shapiro, chair of NBAC,
expressing concern about the report of an apparent experiment
that involved the fusion of a human cell with a cow egg. The
President requested that NBAC ``consider the implications of
such research at your meeting next week and to report back to
me as soon as possible.'' The President also requested that
NBAC undertake a thorough review of the issues associated with
human stem cell research, balancing all ethical and medical
considerations.
NBAC met 3 days later on November 17 for a regularly
scheduled meeting and, in response to the President's first
request, included on its agenda a discussion of the human cell-
cow egg experiments. I must say that the commission was aided
in these discussions greatly by consultations via telephone
with Dr. Ralph Brinster of the University of Pennsylvania. Also
in attendance at this meeting was Dr. West, from whom you have
already heard.
Following the commission's discussions, Dr. Shapiro
prepared a letter which he sent to President Clinton on
November 20, a copy of which NBAC has made available to this
subcommittee and is, I might add, available on our website at
www.bioethics.gov.
Mr. Chairman, now that the commission has responded to the
first of the two requests made in President Clinton's initial
letter, we are now turning our attention to preparing a
comprehensive report on the ethical, legal, scientific, and
medical issues arising from research involving human stem
cells. We intend to complete this report as quickly as possible
and very likely by early spring.
The commission next meets on January 19 and 20 of the
coming year and we have already decided to devote the majority
of our meeting to this subject. As with all commission reports,
we intend to consult widely with the public, with scientists,
with health professionals, with bioethicists, with industry,
Government officials, and others who can provide us with the
benefit of their wisdom.
prepared statement
In particular, NBAC looks forward to working with you and
your subcommittee in the coming months, and I would be
delighted to extend my staff's offer to work with your staff
and to brief them on our work as we seek their input.
Thank you very much, Mr. Chairman, for the opportunity to
appear before you this morning.
Senator Specter. Thank you. Thank you very much, Dr.
Meslin.
[The statement follows:]
Prepared Statement of Eric M. Meslin
Good morning Mr. Chairman and distinguished members of this
subcommittee. My name is Eric Meslin. I am the Executive Director of
the National Bioethics Advisory Commission, also known as NBAC. I am
pleased to appear before you this morning and offer some brief remarks
on the subject of human stem cell research. However, since I only
learned late yesterday afternoon that I would be testifying, with your
permission, I will submit my written testimony for inclusion in the
written record soon after this hearing is complete.
Mr. Chairman, as you know, on Thursday, November 14, 1998,
President Clinton wrote to Dr. Harold T. Shapiro, Chair of the National
Bioethics Advisory Commission, expressing concern about the report of
an apparent experiment that involved the fusion of a human cell with a
cow egg. The President requested that NBAC ``consider the implications
of such research at your meeting next week, and to report back to me as
soon as possible.'' The President also requested that NBAC ``undertake
a thorough review of the issues associated with * * * human stem cell
research, balancing all ethical and medical considerations.'' A
specific time frame was not given for this latter study.
NBAC met three days later, on November 17, 1998 for a regularly
scheduled meeting, and in response to the Presidents first request,
included on its agenda a discussion of the human cell/cow egg
experiments. [The Commission was aided in these discussions by
consultations via telephone with Dr. Ralph Brinster. Also in attendance
at this meeting was Dr. Michael West, of Advanced Cell Technology, who
was given an opportunity to answer questions.]
Following the Commission's discussions Dr. Shapiro prepared a
letter, which he sent to President Clinton on November 20, 1998, a copy
of which NBAC has made available to this subcommittee.
Mr. Chairman, now that the Commission has responded to the first of
the two requests made in President Clintons letter, we are now turning
our attention to preparing a comprehensive report on the ethical,
legal, scientific and medical issues arising from research involving
human stem cells. We intend to complete this report by late spring
1999. The Commission next meets on January 19-20, 1999 and will devote
the majority of our meeting to this subject. As with all Commission
reports, we intend to consult widely with the public, with scientists,
health professionals, academics, industry, government officials and
others who can provide us with the benefit of their wisdom. In
particular, NBAC looks forward to working with you and your
subcommittee in the coming months. I would be delighted to work with
your staff to brief them on our work and seek their input.
Thank you very much Mr. Chairman for the opportunity to appear
before you this morning.
Fetus destruction
Senator Specter. Mr. Doerflinger, you stated that the fetus
destruction should not be geared toward research. If fetal
material is available, then, in a manner which does not arise
from being geared toward research, do you find that research
acceptable?
Mr. Doerflinger. For Federal funding?
Senator Specter. Yes.
Mr. Doerflinger. We do not, though I understand that is the
current law. I have no reason to believe that Dr. Gearhart's
experiment would not have qualified under that part of the law
in terms of obtaining the tissue only after the abortion and
not getting involved in the informed consent process of the
woman and so on.
Senator Specter. Why do you make the distinction, as you
did in your testimony, that there is a difference, as I
understood your testimony, where there is fetal destruction
geared toward research contrasted with fetal destruction which
is not geared toward research? You think there is a significant
distinction there?
Mr. Doerflinger. I think the law recognizes a distinction,
because it requires that if the tissue research is going to be
federally funded there cannot be any influence upon the timing,
manner, or method of the abortion on the part of the
researcher. This is designed as a way of creating a kind of
wall of separation between the research on the subsequent
tissue and the actual abortion.
We think that wall is rather porous. We believe that when
Government requisitions tissue from abortions generally it
collaborates with an industry we do not think it should be
collaborating with, and it tends to legitimize abortion as a
way to produce useful material. We also think that the avenues
for getting these tissues from other sources, such as
miscarriages and ectopic pregnancies, have not been
sufficiently explored. The Bush Administration began to fund a
project in exploring those avenues, but that was shut down by
the Clinton Administration before it produced any results.
I think the issue, though, is also raised with regard to
the use of the stem cell lines from the Wisconsin experiment,
because even though it does not involve what we would
ordinarily call an abortion, it does involve destroying embryos
to get the stem cells. The current fetal tissue law does cover
embryos as well as fetuses, but it speaks in terms of induced
abortion instead of in terms of destruction in the laboratory.
I think that nobody was thinking of this then when they framed
the law.
But the question is whether these embryos were destroyed in
a certain way, in a manner and timing that is geared toward
producing these cell lines. If that is the case, then does it
not violate that wall of separation that the Congress was
trying to create between the motives for destroying the embryo
and the motives for using the subsequent tissue?
Senator Specter. Well, I think you raise a very valid point
when you raise the porous issue if there is a subterfuge here.
You think there may be some line, as fetal tissue from
miscarriages where, as you put it, it would not be a porous
line, but one which could be determined that the fetal tissue
was not obtained for experimental purposes, but happened in the
natural course where the fetus could not survive?
Mr. Doerflinger. Well, that is right. If the tissue is
available because of death by accident, there is no question of
mixed motives or collaborating with the decision to destroy. I
should mention that it is footnoted in my longer statement that
the National Catholic Bioethics Center did a book-length study
of this in league with Dr. Maria Macheta of Georgetown
University and was able to determine that Catholic hospitals
would be willing to provide the resources for obtaining tissue
of that kind that is not from induced abortion and of banking
it so that cell lines could be developed that might be useful
in these areas.
Senator Specter. Mr. Doerflinger, you also made a
distinction between embryos at, I think you said, implantation
contrasted with pre-implantation. Was that your testimony?
Mr. Doerflinger. That is a distinction that is in the
current regulations. The current regulations, the Code of
Federal Regulations, protects the embryo from implantation
onward. The effect of the appropriations riders that have been
in effect for the last 3 years was to extend similar protection
to the embryo in the laboratory who has not been implanted in
the womb.
Senator Specter. Well, that raises the question which Dr.
Caplan testified to, and I appreciate your view on it, where he
characterized the situation as tissues to be otherwise
destroyed or tissues not to become human beings. If you take
his definition on an embryo, where it is not to become a human
being and it is to be otherwise destroyed, do you see an
ethical objection to using the embryo in that circumstance?
Mr. Doerflinger. Yes; I think the nature of the moral
argument here--and it is something Congress debated at some
length in 1995--is because someone else in the private sector
ultimately plans to discard this embryo, why do we not destroy
it ourselves? To be quite frank, Mr. Chairman, I think you
could leave as chairman of this committee and close down the
committee if that is the basis on which this committee is going
to make decisions, if you are going to just fund something that
anybody else in the private sector is going to do anyway.
But what we think is that when Congress appropriates funds
it decides there are certain things out there that, even though
other people are going to do them anyway, we are not going to
do with the taxpayers money. That is why we have bans on
abortion funding even though abortion is legal.
The analogy limps a bit here because in this case two of
these three experiments I believe would not be legal in your
home State of Pennsylvania. They would be felonies.
Senator Specter. Well, this committee or subcommittee is
not, No. 1, about to close down; No. 2, not about to make
decisions----
Mr. Doerflinger. I hope you do not.
Senator Specter. What we are going to do is ask some
questions and try to figure some things out. Then, if we think
we know enough, then we will consider making some decisions.
Mr. Doerflinger. Could I add one point on that, because it
is something that came up 3 years ago quite a bit. When the
effort was made in the congressional debate to protect only
against the special creation of embryos for research and to
allow harmful research on so-called spare embryos, we found a
number of statements from people who run the IVF clinics who
were willing to say that the distinction was meaningless.
Basically, if you allow the research on spare embryos, then
when they do the IVF work, the in vitro fertilization work,
they will just make more of them up front and make sure that
they will have spares left after the fact.
In Australia and the United States, people who run these
clinics are saying this. So it is an ineffectual distinction to
make in terms of funding policy, I think.
Senator Specter. Well, I can understand that, and if you
are dealing with subterfuges that is something that you have to
deal with. But before we get to the subterfuge, which I think
we would all agree is inappropriate what I am trying to get are
your views on some of the basic points.
You think that an embryo ought not to be used for research
even if it is going to be destroyed under circumstances which
have integrity, where you do not make more than you need or you
are not having a subterfuge, but there is a genuine
fertilization issue and embryos have been created and now they
are not to be used, but are to be destroyed? If that is
factually true, would you say that in the private sector it is
unethical to use those embryos for research purposes?
Mr. Doerflinger. Yes; I do not think the fact that someone
else plans to mistreat human life creates any moral burden on
you to go ahead and mistreat that life yourself. I believe that
that is the principle that Congress has enacted in various ways
in the course of debates on fetal research.
Senator Specter. I am making a distinction now between
public funding and private funding.
Mr. Doerflinger. I understand.
Senator Specter. I asked you the question as to private
funding. Do you think that----
Mr. Doerflinger. I am just making an ethical point which
would apply to either.
Senator Specter. Which would apply to both?
Mr. Doerflinger. Yes; It seems to me that one of the things
that Congress did in 1985 to clarify the Federal regulations
was to say, even if it is crystal clear that someone is
intending to have an abortion, the fetus that is going to be
subject to that abortion should not be treated by the
Government as deserving any less protection from research harm,
research risk, than an embryo or fetus intended to be carried
to term.
So this was a statement of moral principle. People make
individual decisions out in the private sector. There are times
when you cannot do anything about that. But even when that
child has been abandoned by his or her own parents, that does
not give the Government a moral warrant to go and do harm by
itself.
Senator Specter. Thank you very much.
Senator Harkin.
Senator Harkin. Thank you very much, Mr. Chairman.
I want to ask the scientists who are here. Again, I want to
focus back on the issue that I brought up with the other panel
initially, and that is whether or not under the reading of the
ban on embryo or embryo research--you were here, you heard me
read it. I will read it again. Section 511: ``None of the funds
made available in this act may be used for the creation of a
human embryo or embryos for research purposes; research in
which a human embryo or embryos are destroyed, discarded, or
knowingly subject to risk of injury or death greater than that
allowed for research on fetuses in utero under'' other sections
of the law. ``For purposes of this section, the term human
embryo or embryos includes any organism, not protected as a
human subject under 45 CFR 46.''
I asked all of the scientists who were here before the
question of whether or not these stem cells are organisms. And
I believe the record will show they all said no, it is not an
organism.
Would that be your view, Dr. Meslin?
Dr. Meslin. I cannot speak on behalf of the commission
since we did not deliberate about the ban during the several
hours that we devoted to our discussion----
Senator Harkin. You did not go to the law and look at that?
Dr. Meslin. Not in the 2 hours that we spent deliberating
in response to the President's request. We considered it as an
issue that we felt was important to raise in the context of our
longer study and we intend to look at that very carefully in
the coming months.
Senator Harkin. Dr. Okarma.
Dr. Okarma. My view is that these cells are clearly not
organisms. They are highly derived by a laboratory process that
took years to develop, and, in fact, as we have said, are not
the cellular equivalent of an embryo. Were these cells to be
implanted, they would not form a conceptus nor develop.
Senator Harkin. Dr. Caplan.
Dr. Caplan. Absolutely not an organism. Stem cells lack the
capacity to become viable, independent, interrelated,
functioning entities, so they are not organisms.
Senator Harkin. Let me ask the nonscientist. Mr.
Doerflinger?
Mr. Doerflinger. Thank you. Stem cells are not organisms.
However, two of the three experiments that were discussed here
were not experiments on stem cells. They were experiments to
get stem cells, by in one case creating and then destroying
embryos, organisms, and in the other case taking embryos
already in existence and destroying them.
In the Gearhart experiment, the question is whether what he
has created in that tissue culture is only stem cells or in
some cases is organized enough to be an embryo. He says in his
study that these bodies in the tissue were forming ``complex
structures closely resembling an embryo during early
development,'' and that ``they appear to recapitulate the
normal developmental processes of early embryonic stages.''
So I think that it is an open question with regard to Dr.
Gearhart's experiment whether in the course of this experiment
he is actually creating some early embryos in the culture. I
think the answer is no, but I do not know and I do not know
that anyone knows.
The other experiments clearly involve the laboratory
manipulation and destruction of human embryos, which are
protected organisms.
Senator Harkin. What was that last thing you said? The
other ones are not?
Mr. Doerflinger. The other two experiments, the
Massachusetts and Wisconsin experiments, clearly involve the
destruction of human embryos, which are organisms, in order to
obtain from them stem cells, which are not organisms.
Senator Harkin. I did not think that was true of the
Massachusetts.
Dr. Caplan. I do not think it is true, either, in the sense
in which----
Senator Harkin. It was not true. Mr. Doerflinger, you may
be closer on the other one, but certainly not Massachusetts.
Mr. Doerflinger. Massachusetts, because it is a cow cell?
Senator Harkin. No, no, no.
Mr. Doerflinger. I could cite you----
Senator Harkin. Dr. West, where did you get your cell from,
your stem cell? Was it from an embryo?
Dr. West. Well, it was from an aggregation. It was the
product of somatic cell nuclear transfer, creating a small
group of cells. Its status as an embryo would be a matter of
debate. I think it is impossible to answer at this point.
Mr. Doerflinger. I think it has been answered. We have a
fact sheet which I would be happy to append to my testimony, in
which most of the leading scientists involved in somatic cell
nuclear transfer say that when you put a somatic cell nucleus,
properly prepared, into an enucleated egg what you produce is
an embryo. It is only because it produces an embryo that we are
here debating human cloning at all.
Dr. Caplan. Just as a quick comment about what is in the
dish, which is what we are talking about now, it would be
optimistic for anybody to say that what was created in the
Massachusetts report, No. 1, is not published; No. 2, is not
verified. But more to the point, we do not know actually what
the capacity or what will happen if that particular creation or
construct, if someone attempted to grow it out.
When I was testifying before, I suggested that humility
rather than bright lines might be what we want to bring to this
discussion. It is possible that someone in Massachusetts could
culture out something from what was in that dish. We have no
idea.
Senator Harkin. It seems to me, then, that looking back on
where we have been on fetal tissue research, which was banned
for a number of years and then it was lifted. We had the ban
and then it became I think clear to a lot of us in the Congress
and in the administration and in the scientific community--I
heard for years about the problems that this ban was causing.
So we lifted the ban, but we replaced it with very strong
Federal guidelines. So maybe that is what we are looking at
here--not a ban but putting down strict guidelines as to what
can be done with this.
Dr. Caplan. If you were headed in my direction, I would say
it does seem to me that the two key moral categories of what we
are talking about this morning are what are the sources of stem
cells and where do they come from. There are issues there about
the use of embryos. I tried to suggest in my oral and written
testimony that it is wrong to say that all embryos are alike.
I will repeat what Senator Specter drew out of my
testimony: It does not seem to me ethically sound to treat
embryos destined for destruction, that no one wants to use, or
embryos derived from tissues that have already been destroyed,
from fetal gametes, as on a par with specially created human
embryos at the IVF clinic that you intend to make a baby from.
I do not believe the same moral framework ought to be applied
there.
It does seem to me that if we want to understand how best
to responsibly use stem cell research technology, the more
public, the more accountable, the more oversight we have got,
that is the way we are going to be able to make the judgments.
If we let it just stay private, not only will it be slow, it
will be hidden, it will be secret, and we will not know what
people are doing with these materials. I think that is not the
desirable outcome from a public policy point of view.
Mr. Doerflinger. I do not know, if I can respond to that
question as well. I think guidelines may be appropriate in
cases where you are dealing with tissue that is already tissue,
it is already from someone who is already dead. What they are
talking about is setting guidelines for how and when to make
and destroy human embryos, and I do not think guidelines alone
are sufficient for that.
I just want to note that in Dr. West's testimony he said
that the purpose of his experiment is to allow for ``the
production of a blastocyst-staged embryo genetically identical
to the patient who donated the nucleus, which then is harvested
for its stem cells.'' If you ask are the stem cells an
organism, the answer is no. If you take my heart out, it is not
an organism, either. But the question is the experiment
involves ripping out the cells from what was before a living
organism.
Senator Harkin. Well, we can go into this for a long time.
The fact is is that we have thousands of embryos now all over
the United States that are frozen in nitrogen and they are
obviously going to be destroyed. Let us face it, OK. You are
not going to keep them forever and ever and ever.
So if there is a potential of getting the stem cells from
those and using those for the research, what is wrong with
that? Why should we not?
Dr. Caplan. It is not actually thousands; it is tens of
thousands.
Senator Harkin. I do not know how many.
Dr. Caplan. They seem to be wards of the utility company at
this point, as long as the electricity holds out.
Senator Harkin. If these stem cells are indeed--I do not
know what the proper word--self-replicating, they can keep
growing----
Dr. Caplan. Immortal, immortal.
Senator Harkin. Immortal. Then it would seem to me that we
already have, Mr. Doerflinger, a source that is already going
to be destroyed, that were not produced for this purpose
because this purpose did not exist before.
Dr. Caplan. Senator, just to add two points about that.
One, these are embryos that were not created with any eye
toward exploitation of research.
Senator Harkin. Exactly, exactly.
Dr. Caplan. And I have talked before coming here today with
as many in vitro fertilization clinic personnel as I could, and
they say that after a prolonged period of time, say 4 or 5
years, they are not going to use these embryos. They do believe
there is a diminishment in their ability to become anything. So
not only are we talking about embryos that are fated not to be
put into any human being, we are talking embryos that
specialists would not use in any human being.
So it does seem to me again morally a different status
applies here. I know we have debated this in the past and will
undoubtedly revisit it again, but I want to say it does seem to
me that that source for stem cells is very different from a
specially created circumstance where we head out to make them
to use them.
Senator Harkin. This may be a topic for another hearing,
Mr. Chairman, and I know you want to wrap this up.
There is one other area, I am just going to make a
statement on it, but I believe it is going to really compel us,
Mr. Chairman, to have some further hearings on this. It has not
to do with ethical and moral implications of what we are doing
here. It has to do with the legal implications, of patent laws.
The article in the Post this morning pointed out that, even
if Congress resolves the ethical issues, there is a dispute
over patents. I notice that in your testimony, Dr. Okarma, you
talked about Geron's intellectual property position, saying
that:'' Geron's intellectual property estate in the embryonic
stem cell field consists of ''--dah-dah-dah-- ``a worldwide
license to the stem cell patent estate of Dr. John Gearhart and
the Johns Hopkins University. This license includes all
applications of human embryonic stem cells, including
diagnostic and therapeutic products.''
Whew, man. I take a little issue with that one. You may not
think so, and again this may take us a whole other hour and we
do not have the time.
Senator Specter. Senator Harkin, you may be about to start
a subsequent hearing.
Senator Harkin. Well, I think, Mr. Chairman, we are going
to have to have a hearing on this.
Senator Specter. Well, I think there are many questions
which we cannot answer in the parameter of a 2-hour hearing,
and we had targeted conclusion for 11:30 a.m., which is just 2
minutes away.
Senator Harkin. I just wanted to throw it out there.
Dr. Okarma. May I have the courtesy of a response?
Senator Harkin. Pardon?
Dr. Okarma. May I have the courtesy of a response?
Senator Harkin. Sure.
Dr. Okarma. First of all, as you may know, the bulk of
patent applications, for example, in new gene sequences come
not from the industry, but from academia, academic centers.
Like that, the applications that we have taken license to were
originated by Johns Hopkins and University of Wisconsin.
In terms of the exclusivity and the applications issue that
you raised, this is a starting point. We recognize that Geron
by itself could never commercialize all of the opportunities we
have heard elegantly testified to today. So it is our
commercial intent to create partnerships with other companies
to further the development of these life-saving applications.
Furthermore, if I may use what we have done with our
telomerase discovery in January of this year, where we
published in Science the ability to immortalize cells, since
that publication we have received and responded to over 250
requests from laboratories around the world to receive that
gene, which we have sent to them and allowed, under appropriate
constraining guidelines, the kind of work that could be funded,
is funded by the NIH in cellular immortalization. And we would
propose to perform the same kind of academic collaboration with
these cells were they fundable by the NIH.
Senator Specter. Thank you very much for that answer, Dr.
Okarma.
Senator Harkin. We need another hearing.
Senator Specter. Senator Harkin suggests another hearing
and I think there is a need for further hearings on this issue
and others. We are on a very, very deep and complex subject and
in the course of the 2 hours we cannot cover it totally.
I just want to cover one more point with you, Dr. Okarma,
and that is your view on the importance of having NIH be free
to engage in this kind of research. Is the private sector,
illustrated by your company, sufficient to undertake this
research, or do you think it is desirable to have NIH involved
as well?
Dr. Okarma. It is imperative, essential, that the NIH be
involved in the development of these applications.
Senator Harkin. We have Mr. Doerflinger's view on that. Dr.
Caplan, what is your view on the issue of having NIH involved?
Dr. Caplan. If the NIH is not involved, the research will
go more slowly, the research will be driven solely by
commercial practicality, the patent policies will be locked
down on basic science, which should not happen, and there will
be very little accountability. The substitute virtue will be
secrecy. I think it would not be sound public policy.
Senator Specter. Dr. Meslin, do you care to offer an
opinion on that subject?
Dr. Meslin. My own view is that it is absolutely essential
that NIH play a leading role. They have been thinking about
ethical issues as well as the scientific issues for many years,
and we are anxious to get their views as we deliberate on our
own report.
Senator Specter. Mr. Doerflinger, I think you have
expressed yourself on this, but I want to give you an
opportunity to comment further, and perhaps with some focus on
the question which I do not think you have addressed, raised by
others, about the desirability of having regulations and
oversight, which you do not have with the private companies,
although we could legislate that as well. Would you care to
supplement your views on the question of NIH involvement?
Mr. Doerflinger. I think funding and regulation are often
very appropriate to distinguish acceptable research from
possible abuses. My problem with some of the experiments
discussed here is that I believe they are themselves the
abuses, so I do not see any point in funding them in order to
regulate how they are done.
I think the argument about it being done in secrecy would a
fortiori apply to the fact that in eight or nine States, as I
mentioned earlier including Pennsylvania, they are illegal
already anyway. So I suppose there would be an argument for
also dropping all of those criminal statutes against
experimenting on embryos, but I do not think that is going to
be convincing to those who think that these statutes are really
protecting human life.
Prepared statement of Daniel Perry, on behalf of the Alliance for Aging
Research
We have received a statement from Daniel Perry, on behalf
of the Alliance for Aging Research, it will be inserted into
the record at this point.
[The statement follows:]
Prepared Statement of Daniel Perry
Chairman Specter, Senator Harkin and Members of the Committee:
Thank you for the opportunity to address the matter of embryonic stem
cell research. As the head of a not-for-profit group eager to find
cures and preventions for the diseases of aging and overall better
health and vitality for the elderly, my views on research are dictated
by the medical needs of the growing population of older Americans. The
Alliance for Aging Research, which I represent, works to stimulate
academic, governmental and privately sponsored research into the
chronic diseases of human aging. I am here to express the Alliance's
view that any legislation which stops or restricts stem cell research
could seriously impede highly promising research which will greatly
benefit older Americans, their families and the nation as a whole.
The United States and much of the world is experiencing a profound
and wholly unprecedented demographic shift toward greater longevity for
human beings. Every day in our nation another 6,000 people celebrate a
65th birthday and America's Baby Boomers are entering their 50s in even
greater numbers.
In the decade between ages 50 to 60, the risks to the average
person of being diagnosed with hypertension, arthritis or diabetes more
than triple. Over the next 30 years, the United States population over
age 65 will double to at least 70 million people. Their risks to
disease including cancer, stroke, macular degeneration, Parkinson's and
Alzheimer's diseases are doubling every five years. The cost of these
disorders--just in purely economic terms--is staggering. If you add up
the costs of eight of the major diseases of aging--osteoporosis,
stroke, depression, arthritis, Alzheimer's, diabetes, cancer and heart
disease--the total is $573 billion annually. Only new discoveries from
biomedical research hold the hope of delaying or preventing altogether
these debilitating conditions, potentially saving the nation billions
of dollars.
Unless scientists discover better ways to treat, postpone and
possibly prevent such disabling conditions, the burden on Medicare and
private insurance will be crushing as the Baby Boom generation moves
into the high-risk years. Without research breakthroughs and their
applications, we will be left with the equivalent of very expensive
hand holding for sick older people. In truth, today's drugs and other
remedies for age-related diseases are not good enough. Even the better
versions of current pharmaceuticals are designed to treat only the
symptoms of heart failure, arthritis, and cancer, not the root causes.
The good news is that there are signs of an historic shift in drug
development. Advances in genetics research are taking us towards
personalized medicines that exactly match each person's unique needs
and biochemical profile. Personalized medications would be far more
effective in promoting health, and far less likely to carry side
effects and complications that too often make matters worse, not
better, for older people.
Part of the revolution in drug discovery is that some of the
largest pharmaceutical companies are ready to invest billions to
produce drugs that work by postponing the onset of diseases, or prevent
them entirely by shutting off their genetics switches. This has
enormous potential for the geriatric population. Even a brief delay in
the onset of age-related disability can translate into dramatic savings
for the economy and for the nation. For example, we estimate that
postponing physical dependency among older American by just one month
would save the U.S. at least $5 billion a year in health care and
nursing home costs. Postponing the average onset of Alzheimer's disease
by just five years would eventually save $50 billion a year in health
care costs by eliminating half of all cases of that disease.
With emerging research, there is now good reason to hope that
scientific understanding may some day permit new approaches to
disabilities driven by the aging process itself. As the committee
knows, earlier this month at the University of Wisconsin, researchers
reported they had successfully derived human embryonic stem cells with
the potential to be transplanted into any part of the body for
therapeutic use. The Wisconsin researchers believe these cells have the
potential to supply unlimited quantities of normal cells of virtually
any tissue type. The unique qualities of human embryonic stem cells
will give researchers powerful new tools to understand mechanisms of
cell division and cell repair.
The long range benefit of this kind of research is not the unlikely
possibility of greatly extended lifetimes, but the plausible use of
this technology to restore damaged tissues, using self-renewing,
plenipotent human cells to treat blindness, coronary artery damage,
diabetes, and other diseases. The ability to maintain long-lived
colonies of human cells could lead directly to cell transplantation
techniques in a few years to treat Parkinson's, breast cancer, heart
disease, and possibly even Alzheimer's disease. Scientists involved in
this research say that embryonic stem cell technology has the potential
to be used to generate an unlimited supply of healthy cells and tissues
for repair or replacement in a vast range of medical uses. To deny our
aging population the opportunity to benefit from this research would be
a tragic reversal of dramatic recent biomedical progress toward
permanent cure of diseases that compromise quality of life and which
account for so much of our nation's health care expenditures.
At the Alliance for Aging Research, we view recent advances in
human stem cell research as a major step toward development of ``gero-
technology.'' Gero-tech is medical science harnessing the mechanics of
the aging process itself in order to develop novel processes and
therapies. Ultimately these research techniques could help cure,
postpone or prevent age-related diseases. The more we learn about the
mechanisms of aging and the more scientific interest that goes to
aging, more new discoveries will be made that could improve the health
and functional independence of older Americans. It would be unwise to
put barriers in the way of such research.
The Alliance supports responsible and sound biomedical research,
including emerging cellular technologies, that could lead to the
development of therapies for scores of age-related diseases and
disabilities. At this very moment millions of older Americans are
suffering from Alzheimer's, Parkinson's, cancer, diabetes and other
chronic health problems of aging. Not only are they suffering, but
their families and care givers are suffering too, and hoping that
scientists will find cures for these devastating disease and other
conditions while there is still time.
Our chances of finding new ways to prevent and cure debilitating
diseases will stifled unless bio-medical research into aging matters,
including stem cell research, is allowed to proceed without hindrance.
Certainly, policymakers, ethicists, scientists and patient groups must
discuss and debate, but in the end, it is important that we arrive at
public policies that allows stem cell and other promising biomedical
research to go forward.
Mr. Chairman, it is likely we will continue to be confronted with
scientific advances that pose difficult social and ethical questions.
The vast majority of Americans strongly support the advancement of
biomedical research through the application of their tax dollars.
Indeed, surveys consistently show the American people want to see even
greater efforts against serious and life-threatening diseases. The
present momentum in the life sciences, and the profound implications of
what we are learning, will inevitably raise public concerns.
It is entirely appropriate that as the legislative body which
appropriates much of the funds for medical research, and as the forum
for debate over public issues, the Congress exercise its right and
responsibility to set public policies concerning medical research.
Surely, Congress is at its best when its actions are informed and
enriched by slow and careful debate, by advice from expert sources, and
when taken in respect for minority opinion.
In the case of proposals to limit any of the tools for scientific
and medical research, the need for prudence is powerful, due to the
complexity of the issues and the consequences for public health and
well-being. Ultimately, however, I believe that it is far better for
the Congress and the rest of the federal government to maintain an
constructive role in the ongoing research, rather than taking any
action which seeks to block it. Only in this way, can the Congress
ensure that the views of the American people are heeded in the research
process.
On this point, it is worth noting that the research on stem cell
development was carried out in the private sector without any federal
funds and without any federal involvement or oversight. It is likely
that private interest in, and support for, this research will proceed
ahead. We believe the federal government should be actively supporting
and advancing research that hold promise for healthier aging, including
the stem cell and related technologies. That support should include the
development of guidelines by the appropriate federal agencies to assure
the ethical conduct of this sensitive but important research.
Mr. Chairman, on behalf of the Alliance for Aging Research, I thank
the committee for its consideration of this vital issue and for the
opportunity to present the Alliance's views on it.
subcommittee recess
Senator Specter. Thank you all very much for being here,
the subcommittee will stand in recess.
[Whereupon, at 11:32 a.m., Wednesday, December 2, the
subcommittee was recessed, to reconvene subject to the call of
the Chair.]
STEM CELL RESEARCH
----------
TUESDAY, JANUARY 12, 1999
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 a.m., in room SD-192, Dirksen
Senate Office Building, Hon. Arlen Specter (chairman)
presiding.
Present: Senators Specter and Harkin.
DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
STATEMENT OF MARIA FREIRE, Ph.D., DIRECTOR, OFFICE OF
TECHNOLOGY TRANSFER
DEPARTMENT OF COMMERCE
STATEMENT OF Q. TODD DICKINSON, J.D., ACTING ASSISTANT
SECRETARY OF COMMERCE, AND ACTING
COMMISSIONER OF PATENTS AND TRADEMARKS
Opening remarks of senator arlen specter
Senator Specter. Good morning, ladies and gentlemen. The
hour of 9 a.m., having arrived we will proceed with the hearing
of the Appropriations Subcommittee on Labor, Health and Human
Services, and Education.
Today we are going to move forward with the second hearing
on the issue of stem cells, focusing on the provision of law
which appears to bar the National Institute of Health from
engaging in embryo research.
We held our first hearing on December 2, and today we are
going to move ahead with the patent aspects of the issue and
more testimony on the potential of stem cell research.
We regret the scheduling difficulties, where we have been
constrained to make some adjustments because of the Senate's
consideration of the impeachment issue, and today's hearing had
been set for 9:30 a.m., but yesterday Senator Lott scheduled a
meeting at 10 o'clock which made it desirable to move the
hearing to 9 a.m., this morning, and we are going to do our
best to conclude by 10 o'clock.
The focus of our hearing today will center on a number of
issues. One of them is whether stem cells are defined as an end
product, which may be the contention of the companies who seek
patent protection, contrasted with a classification of stem
cells as a research tool, which would be a designation to
promote freer dissemination among researchers.
I am a little disappointed that the Geron Corp., declined
to testify today, and a number of other major associations have
considered it too soon to come forward at this hearing because
their public policy committees have not yet taken a position on
stem cell research. It is my hope that we might move
legislation to lift the ban at a very early stage because of
the urgency involved here with the potential for stem cell
research, which deals with so many serious diseases.
I think every day that we lose on lifting the NIH ban costs
lives, perhaps every hour that we lose costs lives, so I want
to see if we cannot move this legislation. That is why we held
the hearing in December, shortly after the research discoveries
were announced, moving ahead at this early date to be ready,
and the Congress moves to the legislative agenda.
I want to now call our first panel, Dr. Maria Freire,
Director of the Office of Technology Transfer at NIH, and Mr.
Todd Dickinson, Acting Commissioner of Patents and Trademarks,
if you would step forward.
Dr. Freire is the Director of the Office of Technology
Transfer for NIH, and oversees the patenting and licensing
activities for NIH and the development and implementation of
technology transfer policies and procedures.
She received her Ph.D., in biophysics at the University of
Virginia. Full statements will be made a part of the record. We
are going to observe the 5-minute rule to allow the maximum
amount of time for questions and answers. Thank you for joining
us, Dr. Freire, and the floor is yours.
Summary statement of maria freire
Dr. Freire. Good morning, Mr. Chairman. I appreciate the
opportunity of being here today, and I am here to address how
intellectual property considerations affect basic science and
the future development of products for public benefit.
This morning I will focus on three issues, first how
technology is transferred from the not-for-profit to the
private sector, second, how this applies to stem cells and stem
cell technology, and third, the implications for basic
research.
Technology transfer legislation
Let me start briefly by describing two laws enacted 20
years ago that encourage universities and Government
laboratories to commercialize their research. These laws are
the Bayh-Dole Act and the Stevenson-Wydler Act, including one
of its amendments, the Technology Transfer Act. In general,
these laws allow the laboratories and the recipients of
Government funding to elect title to their inventions. They
also impose certain obligations, to promote utilization, to
encourage commercialization, and to ensure public availability.
In the biomedical arena, the impact of these statutes has
been, indeed, dramatic, and many experts believe that it is the
close relationship between the academic sector and the private
sector that has spawned the biotechnology industry. Value to
the public is also very important as new drugs, vaccines,
diagnostics, and medical devices of course result from this
close interaction.
These activities have also stimulated economic development,
and they have generated jobs in the United States.
The University of Wisconsin provides a very good example of
how the Bayh-Dole Act is implemented. Early work by Dr. Thomson
on nonhuman primates, such as rhesus monkeys, was federally
funded. In accordance with the law, the invention was disclosed
by the university to the NIH, the university filed a patent
application, and the technology was licensed to a small
company.
Because Federal funds were used, the Government has a
nonexclusive royalty-free right to use patented cells by or on
behalf of the Government. This allows Government laboratories
and their contractors the right to use patented cells for
further research.
In contrast, when research is funded entirely by the
private sector, as is the case of Dr. Gearhart's work, the
Government has no license, and it is strictly a private matter
whether and under what terms new intellectual property is made
available to others.
Research tools
Let me point out that the fact that there exists a patent
is usually not what raises concerns in the biomedical community
but, rather, it is the way the patent holder chooses to
exercise his or her rights on the patent.
For example, the discovery may be a research tool or a new
procedure, primarily useful as a means to conduct further
research. Such discoveries are commonly known as research
tools. These tools may be patentable and, indeed, they have
economic value for the holder of the patent.
In our view, however, the value to society is greatest when
research tools are made widely available to scientists. But,
therein lies the quandary. What is a research tool to one is a
product to another.
Those of us working in this field strive to promote the
balance between commercial interests and the public interest.
For example, research tools can also be therapeutic products.
Licenses can be crafted by scope and field to allow research
uses without destroying commercial incentives.
The NIH, indeed, has been concerned with this issue for a
good while, and Dr. Varmus put in place a national work group
to study the issue and make recommendations. We will set forth
guidelines for public comment in February in the Federal
Register.
So how does this relate to the pluripotent stem cells? Stem
cells are research tools today, and hopefully they will also be
developed into therapeutic products in the future. We
understand that both Johns Hopkins and Wisconsin licenses to
Geron are exclusive at this time, but may allow for use of
these cells by nonprofit researchers under certain terms and
conditions.
There is no direct role of the NIH in these negotiations
and these agreements. However, it is our view that these
licenses can be crafted to ensure commercial and research
purposes be both preserved.
prepared statement
For example, licenses can be crafted nonexclusively and
they should be negotiated whenever possible to allow and assure
that the research tools are available for researchers as well
as preserve the commercial applications. It is important to
reiterate, however, that when only private funding is involved
the NIH has very little ability to obligate the universities to
abide by these guidelines.
Mr. Chairman, I would be pleased to answer any questions.
Senator Specter. Thank you very much, Dr. Freire.
[The statement follows:]
Prepared Statement of Maria C. Freire, Ph.D.
Mr. Chairman and members of the subcommittee, I am Maria Freire,
Director of the Office of Technology Transfer at the National
Institutes of Health (NIH). I am pleased to appear before you today to
address how intellectual property considerations affect basic science
and the future development of products for public benefit.
I understand that the subcommittee is particularly interested in
how patent rights and commercialization strategies operate in the
context of the recent findings on pluripotent stem cells reported by
Drs. John Gearhart from Johns Hopkins University and James Thomson from
the University of Wisconsin. You have previously heard from a panel of
experts, including the Director of NIH, Dr. Harold Varmus, on the
scientific implications of these findings. Given the complexity of
these issues, it is important to understand how the transfer of
federally funded technology from the not-for-profit sector--be it
university or Federal laboratory--to the private sector, is
accomplished. To do so, I direct you to the successful process
established by Congress in the 1980's that governs the
commercialization of federally funded biomedical research.
The Bayh-Dole Act, Stevenson-Wydler Technology Innovation Act of 1980,
and amendments, including the Federal Technology Transfer Act
of 1986 (FTTA)
Nearly twenty years ago, Congress enacted a series of laws that
encourage government owned and government funded research laboratories
to pursue the commercialization of the results of their research. These
laws are the Bayh-Dole Act of 1980, the Stevenson-Wydler Innovation Act
of 1980, including one of its amendments, the Federal Technology
Transfer Act of 1986 (FTTA). The Bayh-Dole Act addresses intellectual
property rights in federally funded grants, contracts and cooperative
agreements, while Stevenson-Wydler and the FTTA address intellectual
property of government laboratories. The goal of these laws is to
promote economic development, enhance U.S. competitiveness and benefit
the public by encouraging the commercialization of technologies that
might otherwise not be developed into products due to the lack of
incentives. Generally, these laws allow government laboratories and the
recipients of government funding to elect to retain title to their
inventions. They also impose certain obligations: promoting
utilization, encouraging commercialization and ensuring public
availability of these technologies.
I am pleased to say that these goals have been achieved and
expectations have been surpassed. Indeed, in the biomedical arena, the
impact of these statutes has been dramatic. Many experts believe that
the biotechnology industry was spawned from the close interaction
between academia and industry. The Bayh-Dole Act and the FTTA continue
to contribute to the global leadership of the U.S. biomedical
enterprise. New products developed under this system benefit patients
daily and provide hundreds of scientists with the tools required for
further discovery in support of our public health mission. The NIH
intramural program alone has over 150 products on the market, including
diagnostic kits, vaccines, therapeutic drugs and dozens of antibodies,
cell lines and other research tools. Statistics on the remarkable
success of university-based technology transfer activities are also
available and I have submitted a recent survey for the record.
To accomplish the transfer of technology, universities have relied
on authorities granted to them by the Bayh-Dole Act. The Act permits
the grantee to retain title to intellectual property developed with
federal funds and to license its rights to for-profit entities. Patents
provide the right to exclude others from making, using, or selling a
new invention for the life of the patent. This is society's reward to
the owner for teaching others how to make and use the invention claimed
in the patent. In the biomedical field, patents are extremely valuable
to companies, particularly small companies. They provide a means of
securing investment income by establishing the company's preeminence in
a particular area of technology. Parties interested in practicing an
invention, in which they have no ownership, may obtain rights to the
invention by entering into a licensing agreement with the patent owner.
A license is a contract with binding commitments on each party, usually
involving compensation. A license does not grant title to the
invention. Licenses can be exclusive, when only one party is permitted
to benefit from the use of the technology, or non-exclusive, when more
than one party is allowed to benefit from such rights.
As this subcommittee well knows, new drugs and vaccines are costly
to develop; companies will not invest in further research and
development without some promise of future product exclusivity. When
Congress gave federal grantees the ability to patent and exclusively
license government-funded inventions, the private sector turned its
attention toward publicly supported research as a new source of
potential products. The value to the public resides in the generation
of new drugs, vaccines, and medical devices. These activities have also
stimulated economic development and the creation of new jobs in the
United States.
The University of Wisconsin provides us with a good example of how
the Bayh-Dole Act is implemented. Early work by Dr. Thomson on non-
human primates, such as Rhesus monkeys, was federally funded and
therefore, the patent obtained on stem cells arising from this work is
governed by this Act. In accordance with the law, the invention was
disclosed to the NIH, a patent application was filed by the University,
through the Wisconsin Alumni Research Foundation (WARF), and WARF
licensed the technology to a small company (Geron). Because federal
funds were used for this non-human primate work, the government has a
non-exclusive, royalty-free right to use the patented cells by or on
behalf of the government. This would allow the government laboratories
and contractors the right to use the patented cells for further
research. In addition, in handling this invention the University must
ensure that the goals of the Bayh-Dole Act--utilization,
commercialization, and public availability--are implemented.
When research is funded entirely by the private sector, the
government has no license, and it is strictly a private matter whether,
and under what terms, new intellectual property is made available to
others for commercial or research purposes. This is the case for the
Geron sponsored work conducted by Dr. Gearhart on human pluripotent
stem cells derived from fetuses.
It is usually not the existence of a patent that raises concern for
the biomedical research community. The concern arises when the patent
holder chooses to exercise its rights through licensing in a manner
inconsistent with the advancement of basic research. For example, many
new inventions are not final products. The discovery may be a research
material or a new method or procedure, primarily useful as the means to
conduct further research. Such discoveries are commonly known as
research tools. There is little doubt that these research tools may be
patentable and that they are of economic value to the holder of these
rights. There is also little doubt that the value to society is
greatest when such research tools are widely available to scientists.
Mr. Chairman, I cannot emphasize this point strongly enough.
Preserving research uses is extremely important to the advancement of
science. A license that provides complete exclusivity to a technology
that is also a research tool may result in some product development in
the short-term, but it will close off opportunities to advance science
and develop other products in the long-term. The only way to maximize
the benefit to the public is to ensure that both research use and the
potential for commercial development are preserved.
The professionals working in the specialized field of biomedical
licensing strive to promote a balance between commercial interests and
the public interest. In those instances where a research tool can also
become a therapeutic product, licenses can be, and are, carefully
crafted by scope, application and field to allow use by the research
community without destroying a company's commercial incentive to
develop the product. Careful licensing that preserves this balance,
however, has not always been the case. The NIH has been concerned for
some time about the potential adverse effects of restrictive licensing
practices on access to research tools. Dr. Varmus convened a national
workgroup to study the issue and make recommendations to the NIH. The
report of the workgroup is on the NIH web site (www.nih.gov./news/
researchtools/index.htm), and NIH expects to publish guidelines for NIH
supported investigators this spring, in accordance with the report.
Stem Cell Research
How does this relate to pluripotent stem cells? Pluripotent stem
cells provide the research community a springboard to launch numerous
inquiries into the most fundamental processes of cellular growth and
differentiation that underlie human development. Elucidating these
mechanisms provides the foundation for the next generation of
biomedical discovery. Such discoveries will be directed toward
treatment of human developmental abnormalities, regulation of
uncontrolled cellular growth associated with cancer, a source of
differentiated cells and tissues for transplantation therapy, and a
means to identify new drug targets and test potential therapeutics,
among others. Realizing the fullest potential from this new stem cell
technology for the American people deserves and requires further
inquiry.
Stem cells are a research tool today; hopefully, they will also be
developed into therapeutic products in the future. The issuance of
patents on these new discoveries by the Patent and Trademark Office may
not necessarily have an adverse effect on continuing research, provided
that the patent owners devise a licensing strategy that will allow
basic research to continue unencumbered while preserving commercial
value. We understand that both the Johns Hopkins and Wisconsin licenses
to Geron are exclusive at this time, but may allow for the use of these
cells by non-profit researchers under certain terms and conditions.
These terms and conditions would be set forth in an agreement commonly
called a Material Transfer Agreement, or MTA.
MTAs are vehicles used to transfer proprietary materials between
and among the for-profit and not-for-profit sectors. While most MTAs
are simple, 1- to 2-page agreements, MTAs can sometimes pose problems
due to the type of obligations or restrictions imposed by the provider
of a material on the recipient. Such obligations can stifle the broad
dissemination of new discoveries, slow the technology transfer process
and limit future avenues of research and product development. Examples
of such obligations include so-called ``reach-through'' provisions that
may: (1) give the provider of a material ownership of new inventions
developed by the recipient; (2) require royalty payments by the
recipient to the provider on inventions discovered by the recipient
that are not covered by the provider's patent; or, (3) require options
to exclusive rights to any new intellectual property arising from
recipient's use of the material. The NIH has minimal authority with
regard to the stem cell patent and patent applications at issue today,
and it would be inappropriate for me to try to comment on specific
terms and conditions that may be imposed by these parties under the
MTAs contemplated.
At NIH, our view is that conditions imposed by patent owners--
whether in a license or an MTA--can be crafted to ensure both research
uses and commercial development. For example, our strategy is to
negotiate non-exclusive licenses whenever possible. This allows more
than one company to develop products using a particular technology,
products that may ultimately compete with each other in the
marketplace. We recognize that companies need an exclusive market to
offset the risk, time, and expense of developing biomedical diagnostic
or therapeutic products. However, companies do not necessarily need to
achieve that position solely by exclusively licensing a government
technology used to develop the product. Instead, companies are
frequently able to add their own proprietary technologies to the
invention licensed from the government to ultimately achieve some level
of uniqueness and exclusivity for the final product.
If non-exclusive licensing does not provide enough incentive for
the company to develop a product, and it often does not for a potential
therapeutic application, NIH will award exclusivity for specific
indications or fields of use, based on the license applicant's
commercial development plans at the time of the application. NIH also
requires exclusive licensees to grant sublicenses to broaden the
development possibilities when necessary for the public health.
Finally, NIH insists on the continuing unencumbered availability of the
licensed technology to not-for-profit scientific community for further
research.
Experience over the last 20 years has shown that to maximize public
health benefit, the balance between exclusivity and access must be
carefully maintained and research uses of new technologies must be
preserved. These concepts form the basis for the licensing policies of
the NIH, as well as for the proposed guidelines for our grantees
mentioned above.
Summary
Congress has enacted legislation for recipients of federal funding
that encourages the utilization, commercialization and public
availability of federally funded inventions. Grantees have exercised
broad discretion and appropriately seek to achieve these goals through
the patenting and licensing of new inventions that arise through the
use of federal funds. If the research is entirely funded by the private
sector, the government has no license and is not involved in patenting
or licensing decisions. Exclusive licensing, without regard to research
uses, can impede rather than enhance utilization and public
availability of certain types of inventions, such as research tools.
Strategic licensing can alleviate potential problems. Indeed, many
grantees provide for the continuing availability of exclusively
licensed subject matter to researchers in order to ensure progress of
biomedical research. The NIH has urged, and will continue to urge,
patent owners and exclusive licensees to ensure continuing availability
under terms that do not limit basic research or encumber future
products.
Mr. Chairman, I am grateful to you for providing a forum to present
information about the effects of patents and licenses on this promising
new area of science and medicine. I would be pleased to answer any
questions you may have.
summary statement of q. todd dickinson
Senator Specter. We now turn to Mr. Todd Dickinson, who is
actually a doctor also, J.D., appears after his name--lawyers
become doctors--Acting Assistant Secretary of Commerce, Acting
Commissioner of Patents and Trademarks, B.S., degree in
chemistry from Allegheny College, law degree from the
University of Pittsburgh Law School, and he moved from
northwestern Pennsylvania, to western Pennsylvania, to
Philadelphia, to practice with the very fine law firm, Deckert,
Price, & Rose, my old firm.
Mr. Dickinson, we welcome you here, and look forward to
your testimony.
Mr. Dickinson. Thank you, Senator. I want to thank you and
the committee for providing the opportunity to discuss the
patent system, more specifically the patenting of biotechnology
that affects particularly stem cells.
It is my understanding you have been recently considering
the scientific implications of this research and are now
interested in investigating the patent and technology transfer
implications.
The history of the U.S. patent system is a long and
distinguished one. It is grounded in the Constitution. The
first Patent Act was passed in the 1790's by the first Congress
sitting in Philadelphia.
The premise on which the patent system is based is a simple
one. In exchange for a full and complete disclosure of an
invention, the Government grants a limited right in the
invention to an inventor. It is not a monopoly right to own an
invention as is sometimes suggested, but rather it is the right
to exclude others from making, using, or selling it, and at the
patent owner's discretion that right may or may not be
exercised.
The public benefits from this arrangement, because full
disclosure permits others to improve that technology by either
developing alternative solutions or finding a better alternate
species invention within the broad genus of the patent claim.
This expands mankind's technological base.
Additional benefits include preventing wasteful duplication
of R&D, a comprehensive teaching of the technology, and an
indexing of the technology through our patent classification
system.
The current patent statute dates from 1952 and specifies
that to obtain a patent the applicant must meet basic statutory
requirements: that the claimed invention be statutory subject
matter; that it be novel, or new, that means it was not
invented before; that it not be obvious to a person having
ordinary skill in the art to which it pertains; and that it be
fully and unambiguously disclosed in the text of the
application sufficient to enable the skilled practitioner to
practice it.
It is also important to remember it is a limited grant in
time. The patent term runs for 20 years from the date the
application is filed. After it expires anyone is free to use
it. This brings me to the specific matter of biotechnology we
talked about today. Biotechnology generally and broadly
encompasses any technique that uses living organisms or their
components to make or modify products, to improve plants or
animals, or to use microorganisms for specific usage.
As has been, I think, testified to many times,
biotechnology has begun to affect our daily lives in ever-
increasing ways. It is opening new pathways in the treatment of
disease, and showing promising alternatives to less traditional
methods.
A serious downside of research and development in
biotechnology is that it is voraciously expensive, and often
requires substantial time periods for commercial development.
Moreover, many lines of research eventually prove to have been
fruitless, yet the successful results, once known, are often
not difficult to replicate by others.
Other factors, including public perception regarding things
that are new and different, often keep many biotechnology
inventions from reaching their full market potential.
Consequently, very few biotechnology companies are profitable
at this time. Many continue to require substantial additional
investment to maintain their operations.
As a consequence, the biotechnology industry has a
demonstrated need for patent protection to act as an effective
incentive for innovation and to serve as a tangible asset for
investment purposes.
One exciting development in biotechnology research has been
the isolation and purification of a particular type of
undifferentiated cells that can give rise to specialized
functional cells. These are known as stem cells and are
currently the subject of intensive research. Although most
cells can only divide a limited number of times, the division
of stem cells can be unlimited, so they serve as a useful tool.
In addition, some are known as pluripotent stem cells and can
be developed into a variety of specialized cells.
Since stem cells are both living and found in nature, a
question may be legitimately raised whether they constitute
patentable subject matter under section 101 of our laws.
Although the question of the patentability of living organisms
was answered as long ago as 1873 when Louis Pasteur got a
patent on a type of yeast, 20 years ago the Supreme Court
answered that question very firmly in the case of Diamond v.
Chakrabarty, where they found that genetically engineered
living bacteria were patentable.
They cited the congressional reports stating Congress
intended statutory subject matter to include anything under the
sun that is made by man. Many commentators feel this was a
major factor in the growth of the biotechnology research
industry.
Second, although stem cells do indeed occur in nature, they
are always mixed with other cell types and do not occur in
isolated or purified forms. Purified and isolated cells lines
as well as methods for their purification and isolation
represent important technological advances.
They may also have novel or unexpected properties or uses.
A long line of case law, therefore, suggests that they may
indeed result in a patent. In another regard, concerns have
been raised about licensing of technology in the biotechnology
area, specifically in the context of availability of research
tools.
While the PTO does not normally concern itself with these
issues, we have some experience in these matters and are asked
to comment.
Senator Specter. Mr. Dickinson, will you summarize?
prepared statement
Mr. Dickinson. I will do that.
Licensing can occur in a variety of ways, royalty-bearing,
royalty-free, exclusive or nonexclusive. Some have speculated
that licensing may adversely affect these research tools. It
has been my experience that the realities of the marketplace
and the goodwill of researchers very often resolve this problem
very efficiently.
Senator Specter. Thank you very much, Mr. Dickinson.
[The statement follows:]
Prepared Statement of Q. Todd Dickinson
Mr. Chairman and Members of the Subcommittee: I am Q. Todd
Dickinson, Acting Assistant Secretary of Commerce and Acting
Commissioner of Patents and Trademarks. I want to thank you for
providing me with this opportunity to discuss the patent system, more
specifically the patenting of stem cells, and the licensing of
technology. It is my understanding that you have recently been
considering the scientific implications of research into these cells
and are now interested in investigating the patent and technology
transfer implications.
Background
The history of the U.S. Patent System is a long and distinguished
one. Grounded in Article 1, Section 8 of the Constitution, the Patent
Act of 1790 was one of the first statutes passed by the First Congress
sitting in Philadelphia. The first patent was granted that same year to
Samuel Hopkins, also of Philadelphia, for a method of making potash, a
chemical useful for fertilizer and gunpowder--critical technologies for
a new, agriculturally based nation. The application was examined by the
first patent examining board: Secretary of State Thomas Jefferson,
Attorney General Edmund Randolph and Secretary of War Henry Knox. The
patent itself was personally signed by the President of the United
States, George Washington.
The system has evolved in many ways since that auspicious
beginning, and continues to serve the primary function it was intended
to serve by the Founding Fathers: as an incentive to technological
innovation and economic growth. From the cotton gin to the computer,
America has been a model for technological development throughout its
history, and patents have provided protection for the fledgling
enterprises that were based on that innovation. For example, Thomas
Edison still holds the record as the individual inventor holding the
most patents, and his efforts led to the General Electric Co., one of
the most successful and valuable corporations in the United States.
The premise on which the system is based is a simple one: in
exchange for a full and complete disclosure of an invention, the
government grants a limited right in that invention to the inventor or
his or her assignee. It is not a monopoly right to own an invention, as
is sometimes suggested, but rather the right to exclude others from
making, using, or selling it. Moreover, at the patent owner's
discretion, this right may or may not be exercised.
The public benefits from this arrangement since full disclosure
permits others to improve that technology by developing alternative
solutions, or to find a better, unexpected species invention within the
broad genus of the patent claim, thereby expanding mankind's
technological base. Additional benefits include preventing wasteful
duplication of research and development; a comprehensive teaching of
the technology, permitting it to be used efficiently after the patent
term expires; and the creation of indexed databases of technology in
the form of the patent classification system which permit easier and
more comprehensive searching.
Studies have consistently shown that many important industries rely
on a strong and effective patent system. University of Pennsylvania
economist Edwin Mansfield surveyed 100 U.S. corporations chosen
randomly in six industries. \1\ In each case, he asked senior
management if strong intellectual property laws were a significant
consideration for different kinds of investment the corporation would
make in a particular country. The survey found that approximately 60
percent of companies investing in final product manufacturing
facilities said that intellectual property rights had a ``strong
effect'' on whether direct investment would be made. In chemical,
pharmaceutical, or electrical equipment manufacturing, the percentages
were even higher, between 74 and 87 percent. Even more telling, when
executives were asked if they would invest in research and development
facilities (the top end of wealth creation in an economy), 80 percent
said that the strength or weakness of intellectual property rights in a
country would have a strong effect on whether the company invests
there.
---------------------------------------------------------------------------
\1\ E. Mansfield; ``Intellectual Property Protection, Foreign
Direct Investment and Technology Transfer''; International Finance
Corporation, Discussion Paper Number 19, The World Bank, 1994.
---------------------------------------------------------------------------
Non-profit research institutions also benefit financially from
strong intellectual property protection. The largest public university
system in the United States is the University of California with over
7,000 faculty members among its 9 campuses. In 1997, the University had
2,943 active inventions. Revenues on those patent and technology
licenses produced $74.7 million for the University in 1997. Carnegie
Mellon University in Pittsburgh recently assigned a patent claiming
spidering technology used to search the World Wide Web to Lycos for a
reported $500,000 in cash, 20 percent equity in the start-up and an
unspecified percentage of royalties.
In the biotechnology field, this effect is even more apparent. I
recently participated in a conference hosted by members of the European
Parliament who were finally successful in passing a new biotechnology
patent law for Europe after more than ten years of effort. (It is
reputed to be the most extended debate ever about a piece of
legislation before the European Parliament.). Speaker after speaker
bemoaned the fact that the absence of such legislation in Europe, and
the presence of strong biotechnological patent protection in the U.S.,
had caused significant research and development funds, manufacturing
investment, and large numbers of research scientists to relocate to the
United States.
U.S. Patent Law
The current patent statute, title 35 of the United States Code,
dates from 1952, and specifies that to obtain a patent the applicant
must meet four basic statutory requirements: that the claimed invention
be statutory subject matter (35 U.S.C. Sec. 101); that it be novel,
i.e., that it was not invented before (35 U.S.C. Sec. 102); that it not
be obvious to a person having ordinary skill in the art to which it
pertains (35 U.S.C. Sec. 103); and that it be fully and unambiguously
disclosed in the text of the patent itself, sufficient to enable the
skilled practitioner to practice the claimed invention (35 U.S.C.
Sec. 112). If the patent application and its claims do not meet these
requirements, it is rejected. These requirements are not easy hurdles
to overcome. Section 103 non-obviousness, in particular, requires a
careful review of the state of the art and often very skillful crafting
of claims to avoid it. In the biotechnology field, the section 112
enablement requirement is often a major stumbling block.
It should also be noted that the claims are the only legally
operative portion of the patent itself. Readers of patents often
incorrectly assume that the teaching of the detailed description or
background of the invention found in the body of the patent in some way
defines the metes and bounds of the protected invention, or that the
``concept'' of the invention taught in the claims is what is covered.
This is incorrect. Furthermore, while the applicant may be his or her
own lexicographer and define terms, undisclosed meanings not apparent
in the text cannot be read into a claim and inferences cannot be drawn;
the plain language of the claim alone defines the parameters of the
invention. This means that claim interpretation is a difficult and
often semantic art.
It is also important to remember that the patent grant is a limited
right in time. The patent term runs for twenty years from the date that
the application is filed. After it expires, anyone is free to use it.
Furthermore, owners of patents do not necessarily have to enforce their
rights: they can and do dedicate them to the public. Since a patent may
not be granted on an invention known to the public for more than a
year, inventors may also dedicate their inventions to the public
through public disclosure without filing applications
Biotechnology and Stem Cell Research
Biotechnology generally encompasses any technique that uses living
organisms or their components to make or modify products, to improve
plants and animals, or to use microorganisms for specific uses.
Biotechnology has begun to affect our daily lives in ever-increasing
ways. It is opening new pathways in the treatment of incurable diseases
and is showing promising alternatives to less effective traditional
treatments. In the field of nutrition, biotechnology makes ever-greater
headway to improve food production and plant breeding in a manner that
one could only dream about a decade ago. In the field of genetics, the
use of new techniques is beginning to open substantial and wide-ranging
benefits for human and animal health, the protection of the environment
and the potential for productivity gains in food, agricultural and
pharmaceutical industries.
A serious downside of research and development in the biotechnology
area is that it is voraciously expensive and often requires substantial
time periods for commercial development. Moreover, many lines of
research eventually prove to have been fruitless. Yet, the successful
results, once known, are often not difficult to replicate by others.
Other factors, including public perception regarding anything new and
different, also keep many biotechnology inventions from reaching their
full market potential. Consequently, very few biotechnology companies
are profitable at this time. Many continue to require substantial
additional investment to maintain operations. As a consequence, the
biotechnology industry has a demonstrated need for patent protection to
act as an effective incentive to innovation and to serve as a tangible
asset for investment.
One exciting development in biotechnology research has been the
isolation and purification of particular types of undifferentiated
cells that can give rise to a succession of specialized functional
cells. These are known as stem cells, and are currently the subject of
intensive research. Although most non-cancerous cells can divide only a
limited number of times, the division of stem cells can be unlimited
and may serve as a useful tool in solving many previously intractable
medical conditions. In addition some stem cells are ``pluripotent''
cell lines, meaning they can be made to develop into a variety of
different specialized cells.
Patentability
Since stem cells are both living and found in nature, however, a
question that may legitimately be raised is how they can constitute
patentable subject matter under Sec. 101 of our patent law. Although
the question of the subject matter patentability of living organisms
may have been answered as long ago as 1873, when Louis Pasteur was
granted a United States patent on yeast, it was most firmly addressed
by the Supreme Court almost twenty years ago in the famous case Diamond
v. Chakrabarty \2\. In that case, Chief Justice Burger, writing for the
Court, found that genetically engineered bacteria useful for cleaning
up oil spills by ingesting hydrocarbons were themselves patentable. As
noted by the Court (citing the Congressional Report accompanying the
1952 Act \3\), ``Congress intended statutory subject matter to include
anything under the sun that is made by man''. Many commentators believe
that this case was a major factor in the phenomenal growth of the
biotechnology industry. And it should also be noted that the PTO has
long issued patents to living plants under the provisions of the Plant
Patent Act of 1930.
---------------------------------------------------------------------------
\2\ 447 U.S. 303, 65 L.Ed.2d 144, 100 S.Ct. 2207, 206 U.S.P.Q. 193
(1980).
\3\ S. Rep. No. 1979, 82nd Cong., 2d Sess., 5 (1952); H.R. Rep. No.
1923, 82nd Cong., 2d Sess., 6 (1952).
---------------------------------------------------------------------------
Moreover, although stem cells do indeed occur in nature, most
evidence indicates that they are always mixed with other cell types and
do not occur in an isolated and purified form. Purified and isolated
cell lines, as well as methods for their purification and isolation,
represent important technological advances. They may also have novel or
unexpected properties or uses, and may therefore result in a patent.
\4\ As stated by the Supreme Court, ``To obtain a patent for a product
made from raw material, it must possess a new or distinctive form,
quality, or property.''\5\
---------------------------------------------------------------------------
\4\ See generally Bozicevic, ``Distinguishing `Products of Nature'
from Products Derived from Nature,'' 69 Journal of the Patent and
Trademark Office Society 415 (1987).
\5\ American Fruit Growers, Inc. v. Brodex Co., 283 U.S. 1, 11, 8
U.S.P.Q. 131, 133 (1931).
---------------------------------------------------------------------------
The patentability of biologically pure compositions has been the
law for over twenty years. In In re Bergy (1977) \6\, the Court of
Customs and Patent Appeals (the predecessor court to the Court of
Appeals for the Federal Circuit (CAFC), the appeals court to which PTO
appeals are taken) ruled that a biologically pure bacterial culture was
patentable, and not a ``product of nature'', since the culture did not
exist in nature in its pure form and could only be produced in a
laboratory under carefully controlled circumstances. \7\ This has been
extended since that time to ```purified and isolated' DNA sequences
encoding human erythropoietin (EPO)'', \8\ and a preparation of Factor
VIII: C, used for treating hemophilia. (``Although Factor VIII: C
molecules occur in nature, a purified and concentrated preparation of
Factor VIII: C as claimed in the patent constitutes a new form or
combination not existing in nature, and hence is patentable under 35
U.S.C. Sec. 101.'') \9\
---------------------------------------------------------------------------
\6\ 568 F.2d 1031, 195 U.S.P.Q. 344 (ccpa 1977).
\7\ The Supreme Court granted certiorari, but summarily remanded to
the CCPA in light of another related case. The CCPA later affirmed its
earlier opinion.
\8\ Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 13 USPQ2d 1737,
aff'd in part, rev'd in part, vacated in part, 927 F.2d1200, 18 USPQ2d
1016 (Fed Cir. 1991), cert. denied, 112 S. Ct. 169 (1991).
\9\ Scripps Clinic & Research Foundation v. Genentech Inc., 666
F.Supp. 1379, 1389 n.6, 3 USPQ2d 1481, 1487 n6. (N.D. Calif. 1897),
aff'd.in part, rev'd in part, vacated in part and remanded, 927 F.2d
1565, 18 USPQ2d 1001.
---------------------------------------------------------------------------
Accordingly, it is the present position of the Patent and Trademark
Office that purified and isolated stem cell lines are patentable
subject matter under 35 U.S.C. Sec. 101.
Licensing
Concerns have also been raised regarding the licensing of
technology in the biotechnology area, specifically in the context of
the availability of research tools. While the Patent and Trademark
Office does not normally concern itself with access issues, we do have
responsibility for intellectual property policy generally, and, as
such, have some experience in these matters.
A traditional way to exploit one's patent is to license it to
others, under a wide variety of possible terms: exclusive or non-
exclusive; royalty-free or royalty bearing. Patent owners may also
choose not to license, for a variety of reasons, such as a desire to
preserve exclusivity or maintain competitive advantage. This right is
fundamental to the patent grant.
While some speculate that patent owners who refuse to license or
exclusively license others may adversely affect access to
biotechnological research tools, it has been my experience that market
realities and/or good will almost always resolve this problem. One
famous example may prove illustrative.
Almost two decades ago, Stanford University was granted a patent on
a method covering basic recombinant DNA technology, the so-called
Cohen-Boyer patent, U.S. Patent Number 4,237,224. Because of the
fundamental nature of the technology, great public concern was raised
that biotechnology research would be blocked, or that Stanford would
charge such exorbitant royalty rates that research would be priced out
of reach. In reality, nothing of the sort occurred. Stanford quickly
developed a reasonable and widely available licensing program and
alternative technologies were developed to compete with it. Because the
licenses were offered at reasonable rates to all who sought them,
technology was not stymied. Improvements to the technology also arose
resulting in a moderating cross-licensing program.
Another question which has been raised concerns specific additional
grants or limitations contained in certain licensing agreements. These
include such provisions as a requirement that any improvements in the
licensed technology be licensed back to the patent holder, commonly
known as grant-backs. Provisions such as this are fairly common in
commercial technology licenses, although they are also often the
subjects of significant negotiation.
It is also important to note that many of these aspects of
intellectual property licenses may be subject to antitrust scrutiny.
See, for example, the Antitrust Guidelines for the Licensing of
Intellectual Property, recently promulgated by the Antitrust Division
of the Justice Department and the Federal Trade Commission.
In the context of these licensing considerations, it is also
important to define specifically what ``research tools'' are being
implicated in these concerns. Many of the instruments, chemicals and
equipment used daily in research have patented technologies associated
with them. A license to practice under those patents, and the related
royalties, are often captured in the purchase price.
Last, and significantly, it should be noted that restrictions on
licensing or subject matter patentability must also comply with United
States international obligations. Through protracted negotiations, the
U.S. has convinced many of our trading partners of the great value of
intellectual property protection and has been able to reach agreement
with them to provide strong intellectual property protection. In fact,
we were able to incorporate our position on intellectual property
protection into the Uruguay Round Trade Agreements of GATT. The
Agreement on Trade-Related Aspects of Intellectual Property Rights
(TRIPS) requires the United States and all other members of the World
Trade Organization to provide similar patent protection for all
patentable subject matter.
We have encouraged strong pharmaceutical patent protection by our
trading partners and must continue to provide strong patent protection
for biotechnological inventions, such as cell lines. That protection
should not be diminished by inappropriate incursions into the rights of
the patent owner. In fact, U.S. patent policy toward our trading
partners strongly discourages compulsory licenses or any other such
limitations on a patent holder's rights.
While we certainly share concerns about access to technology, and
would highly recommend that oversight of potential abuses be
maintained, the balance of interests in this area is currently a
carefully calibrated one, and should not be upset absent strongly
reasoned analysis and demonstration of actual harm.
Summary
The United States leads the world in biotechnology research and
development. We also lead the world in intellectual property
protection. It is imperative to the former that we maintain the latter.
As stated long ago by President Abraham Lincoln, a patent holder
himself: the patent system has ``added the fuel of interest to the fire
of genius.'' Our continued success as the most technologically advanced
nation in the history of the world demands that we honor that system
and the benefits it brings.
Thank you.
remarks of senator tom harkin
Senator Specter. Let me turn, before we go to a round of
questioning, to my distinguished colleague, the ranking member,
Senator Harkin.
Senator Harkin. Thank you very much, Mr. Chairman. I
apologize for being a little bit late, and I thank you for
convening this very important hearing. I just had a couple of
statements, if I might make them here.
This really is going to help us get a much better
understanding of the patenting and licensing issues,
particularly as they apply to the recent discovery of human
embryonic stem cells.
Last month we heard the Department of Health and Human
Services General Counsel's Office was examining whether the
current ban on human embryo research, whether NIH-funded
scientists could conduct research on the stem cells lines
isolated by Dr. Thompson and Dr. Gearhart.
As I recall, at our last hearing, every scientist present
stated their belief that the stem cells are not organisms and,
therefore, cannot fall under the Federal ban.
Shortly after the hearing last month, I sent a letter to
Secretary Shalala requesting her timely decision on this issue,
and I must say I am very disappointed that this has not yet
been done and the decision has not yet been made by HHS. It
seems obvious to me and every scientist who testified here last
month that this research can be federally funded.
Now, with or without Federal funding, some of the research
community have questioned the availability of these cells
lines, questioning whether or not they can be available to
nonprofit scientists. They believe the content of the licensing
agreements and what some perceive to be overly broad patent
claims can hinder others from using these cells lines.
Now, again, I do not pretend to know the answer to these
questions. I am pleased that we have the people here today to
testify on this.
I must say that I am disappointed that we did not have here
today witnesses from one or more of the private companies
involved in this to hear their side of the story, although I do
understand, Mr. Chairman, that--at least my staff tells me that
they are going to submit a statement for the record. Can you
enlighten me on that?
Senator Specter. Well, it is pretty hard just to have a
statement for the record. It is pretty hard to have a hearing
without witnesses.
Senator Harkin. Well, I agree with you. I wish they had
shown up. I would like to have questioned them.
Senator Specter. Or a trial without witnesses.
Senator Harkin. Well, it depends on what kind of trial you
are talking about. [Laughter.]
Are you talking about a courtroom trial?
Senator Specter. We can agree on a hearing with witnesses.
[Laughter.]
Senator Harkin. We can agree on a hearing with witnesses.
[Laughter.]
Senator Specter. Senator Harkin, they have submitted a
draft statement, but I commented before you arrived that I was
a little disappointed that Geron did not appear.
Senator Harkin. Well, I am, too.
Senator Specter. Because, without mentioning impeachment,
we really need to be able to ask them questions and have a
dialog, and their absence here does not help the subcommittee
on moving ahead with its conclusions. We have a draft
statement, and perhaps we can hear them at a later time. I
think the parties are even subject to subpoena under a variety
of rules in our Senate.
Senator Harkin. Well, I am sorry, Mr. Chairman. I do not
know what you want to do with that statement, whether you want
to make it a part of the record. That is fine with me.
Senator Specter. We will make it a part of the record for
whatever value it has, but I concur with you that we need them
here to respond to questions.
Senator Harkin. Well, I agree. I am glad we agree on that,
Mr. Chairman, but at least we have the people who are here
today and some other scientists to talk about applications of
this in terms of health care. My interest in this hearing today
was to get a better understanding of the Bayh-Dole Act, the
Stevenson-Wydler Act, and how these apply in genetics and in
the stem cell areas particularly, and what that means in terms
of licensing arrangements under the patents that they hold.
I remember in 1980, when Bayh-Dole was passed, I was in the
House and I was chairing the subcommittee that had jurisdiction
over the National Science Foundation, and I remember at that
time the problems that we had with private entities coming in,
putting the money into research, and not being assured that
they could have a patent or something for future recompense for
the money that they had invested. That was a big stumbling
block.
I remember an invention that had been developed at Iowa
State University. I am searching my memory for exactly what it
was, but because of the inability to obtain a patent on it, a
Japanese company had come in and taken it and was manufacturing
it and selling it in this country.
prepared statement
So that propelled us in 1980 to pass this bill to try to
strike a balance between the public interest and the need to
raise the private moneys to engage in this kind of expensive
research so that people could be guaranteed they would get some
return on that investment and to bring these products to
market, to get them out of the lab and get them to market.
Our first witness said something about a dilemma. I will
not go into that. I will just ask that the rest of my statement
be made a part of the record.
[The statement follows:]
Prepared Statement of Senator Tom Harkin
Thank you, Chairman Specter, for convening this important hearing.
I had requested this hearing in order to get a better understanding of
patenting and licensing issues, particularly as they apply to the
recent discovery of human embryonic stem (hES) cells.
Last month, we heard that the Department of Health and Human
Services' General Counsel's office was examining whether, under the
current ban on human embryo research, NIH-funded scientists could
conduct research on the hES cell lines isolated by Dr. Thomson at the
University of Wisconsin and Dr. Gearhart of Johns Hopkins. As I recall,
at our last hearing every scientist present stated their belief that
hES cells are not organisms, and therefore cannot fall under the
federal ban. Shortly after the hearing last month, I sent a letter to
Secretary Shalala requesting her timely decision on this issue, and I
must say I am very disappointed that she has not yet been able to make
a decision on this. It seems obvious to me--and to every scientist who
testified here last month--that this research can be federally-funded.
But with or without federal funding, there are some in the research
community who question the availability of these cell lines to non-
profit scientists. They believe that the content of the licensing
agreements, and what some perceive to be overly broad patent claims,
could hinder others from using these cell lines. I don't pretend to
know the answer to these questions, so I am very pleased that we have
an opportunity to hear from patent and technology transfer experts
Maria Freire from the NIH and Todd Dickinson from the Patent and
Trademark Office (PTO), to get their views on the matter.
I am also glad to hear today from cell biologist Dr. Lawrence
Goldstein, Mr. Richard Pikunis, who suffers from Parkinson's disease,
and Dr. Douglas Melton on behalf of the Juvenile Diabetes Association.
We learned a great deal from the hearing last month about the
technology and methods for isolating hES cells, now is our chance to
learn from the second panel about the hope this new technology offers
to the millions of Americans who suffer from these diseases, and the
critical need for federal funding of this research.
The ground breaking research done by Dr. Thomson and Dr. Gearhart
shows tremendous promise. From enabling the development of cell and
tissue transplantation, to improving and accelerating pharmaceutical
research and development, to increasing our understanding of human
development and cancer biology, the potential benefits of their work
are truly awe-inspiring.
Therefore, my primary goal for this hearing is to make sure
Congress is doing what it can to ensure that research moves forward,
without unreasonable impediments or delays. However, I want to make it
clear that I do not believe that research should be done solely for
research's sake. We must continue to ensure that incentives are in
place for promising inventions to get to market. That is why we have
invested all we have in biomedical research--so that these inventions
can be used to cure and treat the diseases affecting the American
people. To this end, I believe the patent system and the Bayh-Dole law
have been very successful.
However, as I stated earlier, some in the research community have
raised concerns about their access to ``research tools,'' which I
understand include these new stem cell lines. They say that dealing
with the required bureaucratic paperwork slows down their research, and
that the cost of access to these tools increases the overall cost of
research, which leads to higher and higher costs of the product for the
eventual consumer.
Others in the research community maintain that the system works
well and should not be changed. They say that without intellectual
property rights, the biotechnology industry would have little incentive
to invest in the time-consuming and expensive research and development
(R&D) required to bring a product to market.
I believe it would be a travesty if the potential benefits of stem
cell research--or any research for that matter--are delayed or denied
to patients for any reason: Whether it is because the add-on cost of
access to research tools is too expensive, or because companies lack an
incentive to bring a product to market. It is therefore critical that
we maintain a healthy balance of incentives between the federal
government, non-profit research institutions and the private sector.
I hope today's hearing will help clarify this debate.
Time constraints
Senator Specter. In light of our time constraints, I said
to Senator Harkin before you arrived that Senator Lott had
scheduled the session on the impeachment issue at 10 o'clock,
which is why we had moved the hearing to 9 o'clock.
Senator Harkin. We are in session at 10 o'clock?
Senator Specter. No; it is not in session, it is a meeting
among Republican Senators.
Senator Harkin. An open meeting? [Laughter.]
Senator Specter. I think only the closing statements are
open, Senator Harkin. [Laughter.]
If you missed Senator Harkin on C-SPAN last night, he was
not quite as erudite as this morning, but very erudite.
[Laughter.]
In the interests of time we are going to call the next
panel, and if you would stay where you are, and then we will
move to questions among all five of the witnesses.
NONDEPARTMENTAL WITNESSES
STATEMENT OF LAWRENCE GOLDSTEIN, Ph.D., PROFESSOR OF
PHARMACOLOGY, DIVISION OF CELLULAR AND
MOLECULAR MEDICINE, UNIVERSITY OF
CALIFORNIA AT SAN DIEGO
summary statement
Senator Specter. Our first witness on the second panel is
Dr. Lawrence Goldstein, professor of pharmacology at the
Division of Cellular and Molecular Medicine, University of
California. He serves as an investigator for Howard Hughes
Medical Institute at the University of California at San Diego,
Ph.D., from the University of Washington. Welcome, Dr.
Goldstein, and the floor is yours for the next 5 minutes.
Dr. Goldstein. Thank you, Senator.
Mr. Chairman and members of the subcommittee, I am Lawrence
Goldstein and I am here today as a representative of the
American Society for Cell Biology. The society represents over
9,000 biomedical researchers throughout the United States and
the world, most of whom work in our Nation's leading research
universities and institutes.
As you said, my own research is conducted in the Division
of Cellular and Molecular Medicine at the University of
California San Diego School of Medicine.
Before moving to San Diego, I was on the faculty in the
Department of Cellular and Developmental Biology at Harvard
University for 10 years. My research work concerns molecular
and genetic analysis of protein motors and their roles in
cellular growth, function, and development.
I speak today on the need to ensure life-saving progress in
medical research while simultaneously protecting ethical and
moral decency. As you know, scientific advances are emerging at
a blinding pace. These advances present Congress with a serious
challenge. You must find a balance between on the one hand
assuring the public that new knowledge will not be misused and
that the ethics of such work will be carefully considered,
while on the other hand ensuring that critical medical research
is not impeded because of unnecessary fear or insufficient
information.
The specific issue today concerns human stem cells, which
have extraordinary potential to revolutionize the treatment and
cure of devastating human diseases. Already, in the short time
since the generation of these cells was announced, we can
conceive of many important applications in the treatment of
heart disease, diabetes, Parkinson's disease, and Alzheimer's
disease. In fact, the list of possible therapeutic uses is
almost endless.
These broad applications are likely, because it may be
possible to coax stem cells to become the many types of cells
often lost to the ravages of disease.
My colleague, Nobel Laureate Dr. Paul Berg of Stanford
University, stated in a recent letter to you that currently
only scientists who receive private, non-Federal funding may
pursue stem cell research. This has the effect of excluding the
majority of the Nation's most prominent researchers, who are
supported by the NIH and NSF, and are based at universities and
nonprofit institutions throughout the country.
The current exclusion limits the development of new
therapies, and relies exclusively on the commercial sector to
reap the benefits of scientific insights originally developed
with the generous support of the Federal Government.
Recent work with stem cells from fetal tissue is
permissible under current Federal guidelines. However, we first
seek to persuade this committee and the Congress to make the
informed and courageous decision to ensure that those
scientists who are most prepared and best-qualified to conduct
safe, ethical, and invaluable embryonic stem cell research be
allowed to do so.
Allowing peer-reviewed Federal funds to be used for this
type of research is our best guarantee the quality of the work
will be high, and the results can be best used to serve the
public good.
Senator Harkin went to great lengths at your last hearing
to point out that the current ban on embryo research does not
expressly prohibit federally funded scientists from conducting
the research using human embryonic stem cells. We agree with
the Senator's understanding, and await the Department of Health
and Human Services' interpretation of the current law.
In any discussion of this issue, however, it is essential
to define clearly and to distinguish among varying types of
human stem cells, and there are at least two kinds.
First are totipotent stem cells, which have the theoretical
and perhaps real potential to become any kind of cell and could
perhaps, under appropriate conditions, such as implantation in
a uterus, become an entire individual.
Second are pluripotent stem cells, such as those that can
be obtained from an early stage embryo, which have a more
limited potential in that they can only form certain kinds of
cells such as muscle, nerve, or blood. Thus, pluripotent stem
cells that are derived from the inner cell mass of a blastocyst
are not capable on their own of embryological development, or
the creation of a human being.
It may, though, be possible to induce these cells to form
certain specialized cell types that make up important human
tissues such as those of the liver, pancreas, skin, heart, and
nerves, and it is this potential which makes these stem cells
such an important resource to develop for therapeutic uses.
To this end, the society supports the elimination of the
existing prohibition of Federal funding for research with human
embryos and specialized cells derived from them. Research with
human embryos obtained by ethically validated means and
specialized cells derived from them should be allowed to
proceed in a way that would assure the public that the cloning
of a human being is prohibited, and that ethical considerations
are guaranteed.
In closing, the society enthusiastically supports your
efforts to highlight for the public and your colleagues in the
Senate the potential value of modern scientific techniques for
improving human health.
prepared statement
Stem cell research in particular has enormous potential for
the effective treatment of human disease. Thus, we believe
there is a moral imperative to do it in an ethically validated
manner. We must not close off scientific opportunity to those
most qualified to make dramatic strides in the cure of disease
through the use of stem cells.
Mr. Chairman, thank you for the opportunity to present my
thoughts today.
Senator Specter. Thank you very much, Dr. Goldstein.
[The statement follows:]
Prepared Statement of Lawrence S. B. Goldstein, Ph.D.
Mr. Chairman and members of the Subcommittee: I am Lawrence
Goldstein. I am here today as a representative of the American Society
for Cell Biology. The Society represents over 9,000 basic biomedical
researchers throughout the United States and the world, most of whom
work in our Nation's leading research universities and institutes.
My own research is conducted in the Division of Cellular and
Molecular Medicine and the Department of Pharmacology at the University
of California, San Diego School of Medicine. I am also an Investigator
of the Howard Hughes Medical Institute. Before moving to San Diego I
was on the faculty in the Department of Cellular and Developmental
Biology at Harvard University for 10 years. My research work concerns
molecular and genetic analysis of protein motors and their roles in
cellular proliferation, function, and development.
I speak today on the need to ensure life-saving progress in medical
research, while simultaneously protecting ethical and moral decency. As
you know, scientific advances are emerging at a blinding pace. These
advances present Congress with a serious challenge. You must find a
balance between assuring the public that new knowledge will not be
misused and that the ethics of such work will be carefully considered,
while ensuring that critical medical research is not impeded because of
unnecessary fear or insufficient information.
The specific issue today concerns human stem cells, which have
extraordinary potential to revolutionize the treatment and cure of
devastating human diseases. Already, in the short time since the
generation of these cells was announced, we can conceive of many
important applications in the treatment of heart disease, diabetes,
Parkinson's disease, Alzheimer disease, spinal cord injury; in fact,
the list of possible therapeutic uses is almost endless. These broad
applications are possible because it may be possible to coax stem cells
to differentiate into the many types of cells often lost to the ravages
of disease.
My colleague, Nobel Laureate Dr. Paul Berg of Stanford, stated in a
recent letter to you that:
Currently, only scientists who receive private (non-federal)
funding may pursue [stem cell] research. This has the effect of
excluding the majority of the Nation's most prominent researchers who
are supported by the NIH and NSF and are based at universities and non-
profit institutions throughout the country. The current exclusion
limits the development of new therapies and relies exclusively on the
commercial sector to reap the benefits of scientific insights developed
with the generous support of the federal government.
Recent work with stem cell from fetal tissue is permissible under
current federal guidelines. We further seek to persuade this Committee
and the Congress to make the informed and courageous decision to ensure
that those scientists who are most prepared and qualified to conduct
safe, ethical and invaluable stem cell research be enabled to do so.
Allowing peer-reviewed federal funds to be used for this type of
research is our best guarantee that the quality of the work will be
high and that the results can be best used to serve the public good.
Senator Harkin went to great lengths at your last hearing to point
out that the current ban on embryo research does not expressly prohibit
federally-funded scientists from conducting research using human stem
cells. We agree with the Senator's understanding and await the
Department of Health & Human Services' interpretation of the current
law.
In any discussion of this issue, it is essential to define clearly
and to distinguish among various types of human stem cells. There are
at least two kinds of stem cells:
--Totipotent stem cells have the theoretical, and perhaps real,
potential to become any kind of cell, and under appropriate
conditions, such as implantation in a uterus, could become an
entire individual.
--Pluripotent stem cells, such as those that can be obtained from an
early stage embryo, have a more limited potential, including
those which are more committed, in that they can form only
certain kinds of cells, such as muscle, nerve or blood cells,
but they cannot form a whole organism.
Pluripotent stem cells that are derived from the inner cell mass of
a blastocyst are not capable on their own, however, of embryological
development or the creation of a human being. It may, though, be
possible to induce these cells to form certain specialized cell types
that make up important human tissue, such as those of the liver,
pancreas, skin, heart, and nerves. It is this potential which makes
stem cells such an important resource to develop for therapeutic uses.
To this end, the Society supports the elimination of the existing
prohibition on federal funding for research with human embryos and
specialized cells derived from them. Research with human embryos
obtained by ethically validated means, and specialized cells derived
from them, should be allowed to proceed in a way that would assure the
public that the cloning of a human being is prohibited, and that
ethical considerations are guaranteed.
The Society enthusiastically supports your efforts to highlight for
the public and your colleagues in the Senate the potential value of
modern scientific techniques for improving human health. Stem cell
research, in particular, has enormous potential for the effective
treatment of human disease. Thus we believe that there is a moral
imperative to pursue it in an ethically validated manner. We must not
close off scientific opportunity to those most qualified to make
dramatic strides in the cure of disease through the use of stem cells.
Mr. Chairman, thank you for the opportunity to present my thoughts
today. I would be pleased to answer any questions.
STATEMENT OF DOUG MELTON, Ph.D., REPRESENTING THE
JUVENILE DIABETES ASSOCIATION, HARVARD
UNIVERSITY
Senator Specter. We now turn to Dr. Douglas Melton,
chairman of the Department of Molecular and Cellular Biology at
Harvard University, who also serves as an investigator for the
Howard Hughes Medical Institute, and associate member of the
Children's Hospital in Boston. Dr. Melton is here today on
behalf of the Juvenile Diabetes Association and has an extra
special interest in the issue, since his 7-year-old son was
diagnosed with the disease at the age of 6 months.
Welcome, Dr. Melton. The floor is yours.
Dr. Melton. Good morning, Chairman Specter and Senator
Harkin. As you noted, I am the chairman of the Molecular
Biology Department at Harvard, but I am here today both as a
researcher and a father of a 7-year-old type I diabetic. I am
here because I feel I can speak to you both about the human
burden of diabetes and the scientific potential of stem cell
research.
Mr. Chairman, before I begin my remarks on the subject of
today's hearing I want to take this opportunity to thank you
and other members of the subcommittee for your role, your
leading role in last year's historic increase in HIH funding.
The strong bipartisan support for that increase gives renewed
hope to those of us who are struggling with chronic diseases on
a daily basis.
Founded nearly 30 years ago by parents of children with
diabetes, the JDF is a voluntary health organization that is
dedicated to finding a cure for diabetes through research and,
in fact, this year the foundation expects to commit nearly $65
million directly toward diabetes research.
Diabetes, as you know, is an insidious disease, and remains
widely misunderstood by the public, because many people wrongly
think that insulin is a cure when it is, in fact, merely life
support.
Diabetes is the leading cause of new adult blindness,
kidney disease, and nontraumatic amputations, and it costs this
country nearly $100 billion a year. That is billion, not
million; 60 million Americans suffer from diabetes and, on
average, a person with the disease can expect to live 15 fewer
years than those without it.
In addition, and particularly poignant to me, is that it is
among the most chronic diseases affecting children, and this is
a group upon which its effects are especially devastating.
Before I discuss the exciting potential of stem cell
research, allow me to speak briefly to you as a parent. The
daily regimen of my son Sam's blood checks and insulin
injections, up to five of them a day, are coupled with our need
to balance his diet and exercise. This is, as you might expect,
a serious challenge in dealing with a 7-year-old soccer player.
The medical troubles for Sam are compounded by the
vigilance and worry that extracts a heavy toll on the rest of
my family. For example, my wife is regularly up late in the
night doing blood checks while Sam sleeps and we wonder, is his
blood sugar too low, will he go into a coma during the night.
I am sorry to say that I cannot recall a night of peaceful
sleep since Sam was diagnosed nearly 7 years ago, and I am
unwilling to accept the enormity of the medical and
psychological burden, and am personally devoted to bringing it
to an end for my son Sam and for all type I diabetics. I
implore you to continue to make it possible to cure diabetes
for diabetics and their families.
Let me now turn to the main subject of today's hearing.
That is, the potential cure for diabetes as it relates to human
stem cell research. As Dr. Goldstein mentioned, based on recent
discoveries it is now foreseeable that human stem cells could
be stimulated to develop into a number of cell types, notably
pancreatic islets. These are the cells that are destroyed in a
type I diabetic.
These stem cells then have the potential to develop into
any tissue organ in the body, and they could no doubt be
directed to make pancreatic islet or beta cells.
One of the most promising ways of curing diabetes is to
restore biologically the function of the missing islet cells,
and this could occur through islet transplantation, or through
engineering cells such as these human stem cells.
The availability of human stem cells which could be turned
into beta cells would solve two important problems, No. 1, that
of insufficient islet supply, which presently plagues the field
and, No. 2, the recurrence of the autoimmune response.
My written testimony details how it solves the autoimmune
problem, but let me just say that by engineering stem cells it
would be possible to avoid the requirement for the
immunosuppressive drugs.
I would like to conclude by noting the important ethical
considerations which your subcommittee has, of course,
considered. The JDF and I well understand that stem cell
research has important ethical considerations that need to be
addressed. However, we feel that appropriate safeguards can and
should be established to ensure that this important research
can be conducted using Federal funding.
The 1994 Human Embryo Research Panel, which included both
scientists and ethicists, studied the ethical issues raised by
this type of research, and it is important to note that they
concluded that stem cell research involving preimplantation
human embryos is acceptable for Federal funding.
We believe that that panel's report provides a scientific
and ethical basis to justify Federal funding for stem cell
research on human material, and this report could also serve as
the basis for the establishment of a set of safeguards that
would ensure that this research was conducted ethically in both
public and private settings while still allowing for
significant advances in the fight to cure diabetes.
prepared statement
I will conclude, Mr. Chairman, by thanking you for the
opportunity to speak today and saying that the opportunities
presented by human stem cell research offer us the promise of
truly significant advances and perhaps a cure for diabetes. A
world without diabetes for all the children and adults who
suffer from the devastating impact of this disease is the goal
of the JDF, and we urge you to ensure that Federal policies
allow this research to continue to speed our path to cure this
disease.
Thank you.
Senator Specter. Thank you, Dr. Melton.
[The statement follows:]
Prepared Statement of Doug Melton, Ph.D.
Good morning Chairman Specter, Senator Harkin and other members of
the subcommittee. My name is Doug Melton and I appear before you today
on behalf of the Juvenile Diabetes Foundation International and the
millions of families in this country touched by diabetes. I am Chairman
of the Department of Molecular and Cellular Biology at Harvard
University, but more importantly for today's discussion, I am here
today because my 7-year-old son, Sam, has had Type 1 (or insulin-
dependent) diabetes since he was 6 months old. I am here this morning
as a father and a researcher, as someone who can speak to you about the
human burden of diabetes and the scientific potential of stem cell
research.
Mr. Chairman, before I begin my remarks on the topic of this
morning's hearing, I want to take this opportunity to thank you and the
other members of this subcommittee for your leading role in last year's
historic increase in NIH funding. The strong bipartisan support for NIH
exhibited last year provides renewed hope for those of us struggling
with chronic disease on a daily basis.
Founded nearly 30 years ago by parents of children with diabetes,
JDF is a voluntary health agency dedicated to finding a cure for
diabetes through the support of research. JDF gives more money to
diabetes research than any other nonprofit, non-governmental
organization in the world. This year, the Foundation expects to commit
nearly $65 million directly to diabetes research.
Diabetes is an insidious disease, and remains widely misunderstood
by the general public. Insulin is not a cure for diabetes, it is merely
life support. Diabetes is the leading cause of new adult blindness,
kidney disease, and non-traumatic amputations, costing this country
nearly $100 billion annually. Sixteen million Americans suffer from
diabetes. On average, a person with diabetes can expect to live 15
fewer years than someone who does not have the disease. In addition, it
is one of the most common chronic diseases affecting children, a group
upon which it has an especially devastating impact.
Before discussing the exciting potential of stem cell research,
allow me to speak briefly as a parent. The daily regimen of Sam's blood
checks and insulin injections (up to 5 per day) are coupled with our
need to balancing his diet and exercise: a serious challenge in dealing
with a 7-year-old soccer player. The medical troubles for Sam are
compounded by the vigilance and worry that extract a heavy toll on the
rest of the family. For example, my wife is regularly up in the late
hours of the night doing blood checks while Sam sleeps: we wonder is
his blood sugar too low? Will he find the middle ground between a
``low'' or coma and being too ``high'' in the morning? I can't recall a
night since Sam was diagnosed when we slept peacefully, free of the
worry that the balance between his food, insulin and exercise was not
good enough. I'm unwilling to accept the enormity of this medical and
psychological burden and I am personally devoted to bringing it to an
end for Sam and all type I diabetics. I implore you to continue to make
it possible to cure diabetes, for diabetics and their families.
Human Stem Cell Research: A Potential Cure for Diabetes
I would like to commend the Subcommittee for holding these
important hearings on stem cell research. The recent discoveries in the
field hold the potential to end all of this and finally find a cure for
diabetes.
Based on these discoveries, it is now foreseeable that human stem
cells could be stimulated to develop into pancreatic islet cells to
replace those that have been destroyed in individuals with Type 1
diabetes. Stem cells have the potential to develop into any tissue or
organ in the body and yet cannot develop into a full human being.
Moreover, these cells could be engineered in such a way that people who
receive them might not need highly toxic immunosuppressive drugs, which
prevent the body from rejecting ``foreign'' tissue--currently a major
obstacle to successful islet transplantation.
One of the most promising ways of curing diabetes is to restore
biologically the function of islet cells. This could occur either
through islet cell transplantation or through engineering of cells to
restore the insulin-secreting function. In both instances, the
availability of stem cells would significantly expedite research
progress.
Islet cell transplantation has been largely unsuccessful for two
important reasons:
--Insufficient islets available for transplantation; and
--Recurrence of the autoimmune response that attacks the islets after
transplantation.
The problem of insufficient supply of islet cells could potentially
be solved through additional stem cell research. Because the cells
being studied are so early in their developmental stage, we are hopeful
that we will be able to one day direct their development into any human
tissue or organ. If and when scientists can specialize these cells to
become insulin-producing islet cells, cell lines could be developed to
produce an unlimited number of islet cells. This would effectively
solve the islet cell supply problem.
In addition, in most cases, the immune system of a person with Type
1 diabetes will not tolerate an islet cell transplantation, even when
an individual is given anti-rejection medications (which themselves can
cause serious problems). Because stem cells are primordial all-purpose
cells from which all tissues of the body develop, it may be possible to
alter them genetically so that they will not be susceptible to an
immune attack. This would negate the need for immunosuppression.
Ethical considerations
JDF understands that stem cell research raises important ethical
considerations that need to be addressed. However, we feel that
appropriate safeguards can and should be established to ensure that
this important research can be conducted using federal funding.
The 1994 Human Embryo Research Panel, which included scientists and
ethicists, studied the ethical issues raised by this type of research
and concluded that stem cell research involving ``preimplantation''
human embryos is acceptable for federal funding. We believe that the
Panel's report provides a scientific and ethical basis to justify
federal funding for human stem cell research. This report could also
serve as the basis for the establishment of a set of safeguards to
ensure such research is conducted ethically, in both public and private
settings, while still allowing for significant advances in the fight to
cure diabetes.
Summary
Mr. Chairman, the opportunities presented by human stem cell
research offer us the promise of significant advances--and perhaps a
cure--for diabetes. A world without diabetes for all of the children
and adults who currently suffer from its devastating impact continues
to be our goal, and we urge you to ensure that federal policies allow
this research to continue to speed our path to cure this disease.
STATEMENT OF RICHARD PIKUNIS, J.D., PARKINSON'S
PATIENT, MARLTON, NJ
Senator Specter. We now turn to Mr. Richard Pikunis, also a
lawyer and a doctor, J.D., diagnosed with Parkinson's disease 3
years ago at the age of 27, having exhibited symptoms since the
age of 24. He persevered and received his law degree in May of
last year at Widener University School of Law. He lives in
Marlton, NJ, a suburb of Philadelphia, if I may say. Many of us
consider Marltons Philadelphians. [Laughter.]
He has one child and one on the way, and is anxiously
awaiting a resolution of the political issues for medical
research on Parkinson's.
We welcome you here today and look forward to your
testimony.
Mr. Pikunis. Thank you, sir. My name is Richard Pikunis. I
wish to thank Senator Specter and the other members of this
committee for allowing me the opportunity to discuss my
experiences with Parkinson's disease with you.
I am not a scientist, nor do I hold myself out as an expert
in the field of stem cell and fetal tissue research. What I can
share with you today is my perspective as a young person with
the terrible debilitating disease known as Parkinson's.
Parkinson's disease is a progressive neurological disorder
caused by the degeneration of brain cells that produce
dopamine, a neurochemical that controls motor function. By the
time symptoms of stiffness, tremor, and slowness of movement
begin to exhibit themselves, the brain has already lost about
80 percent of its dopamine-producing cells.
Of course, I did not know any of this for a long time.
Dopamine meant as much to me as planning for my retirement, and
science had no bearing on my life. However, today I look to
science praying it will be able to save my life.
When I was 24 years old, my symptoms were apparent, but
because of my age and general overall good health it went
undiagnosed. I had the symptoms associated with a typical
Parkinson's patient, slowness and loss of movement, postural
instability, resulting in frequent falls, a distorted gait and
muscle rigidity. I remember not going on a family vacation
because my body ached so bad, I was so stiff and rigid, that
walking consumed all my energy.
Because of a common misconception that Parkinson's diseases
is a geriatric disorder, the diagnosis was not as obvious as it
should have been. Besides, I do not exhibit the most prominent
telltale symptom of Parkinson's, the tremor. In fact, according
to the American Parkinson's Disease Association, tremors only
occur in about 70 percent of patients, and it is usually these
tremors that bring a patient to the doctor.
However, after years of knowing something was wrong, but
not quite able to put my finger on it, my mind was finally put
at ease when the doctor told me I had Parkinson's. Yes, at the
ripe old age of 27 years, and after three medical opinions, it
was conclusive. I did have Parkinson's disease.
I was just starting out in life, the same age as my friends
who were getting married and buying houses. They were enjoying
life, as I felt life was slowly being drained from my body.
Not knowing what Parkinson's was was probably why I was not
as upset as my parents upon hearing the diagnosis. I remember
my mother abruptly leaving the doctor's office, only to find
her moments later in the car sobbing.
Since then, I have learned a lot about Parkinson's, and I
am here to tell you that I hate it with a passion. Parkinson's
has robbed me of my youth. Parkinson's has been there for every
major event of my adult life, and overshadows everything I do,
and fights me every chance it gets. Parkinson's walked down the
aisle with me at my wedding. It made my life hell as I attended
law school. As if the stress of law school was not bad enough,
I had to constantly be reminded by my stiff, aching body that
Parkinson's was still with me.
I had always hoped to have a career in Federal law
enforcement when I graduated from law school, but now I am
finding it difficult to even enjoy a walk with my family.
I can accept all this, but what scares me the most about
Parkinson's disease is that it holds my future in its hands. My
son celebrated his first birthday and is learning to walk as I
am slowly losing my ability to do so. I wake up every morning
barely able to move until my medication kicks in.
I am currently taking L-dopa to replace the dopamine that
my body can no longer produce, but it is becoming less
effective at the current dosage. I know L-dopa will not be able
to adequately treat my symptoms forever, and it really scares
me when I think about how my life will be in a few years if we
do not find a better treatment or a cure for Parkinson's. I
wonder if I will be able to teach my children how to ride a
bike, or dance at their weddings.
I am scared about forced retirement before I am financially
stable. I just graduated from law school. Believe me, I cannot
afford not to work, but I know the choice may not be mine to
make, because with an increase in L-dopa comes the debilitating
side effects such as involuntary body movements and motor
fluctuations. Sometimes these side effects are just as bad as
the disease.
It is imperative that now, right now, we expand the
research into Parkinson's diseases. Preliminary scientific
evidence indicates investment in Parkinson's research, into
areas involving stem cells and fetal tissue, have the potential
to produce viable treatments and cures not only for Parkinson's
disease but for heart failure, diabetes, stroke, Alzheimer's,
and spinal cord injuries, to name a few.
Researchers are on the cutting edge of discoveries that
will change immeasurably the lives of millions. Please make it
possible for the scientific community to explore these avenues
of research. Congress has taken steps in the right direction,
the enactment of the Morris K. Udall Parkinson's Research Act,
but my Government is still falling short in the eyes of
millions who desperately need their help.
We want the money authorized by the Udall act to actually
be spent on research. Start investing the millions it will take
to cure us rather than the billions to care for us. Please help
me and others like me live our dreams and maintain our dignity.
prepared statement
Only you can help put an end to the human suffering
associated with Parkinson's disease. Do not let me become a
burden to my loved ones and society. Let me live my dream of an
optimistic future with my wife and family.
Thank you.
[The statement follows:]
Prepared Statement of the Biotechnology Industry Organization (BIO)
executive summary
Pluripotent stem cells research provides the hope of a new
generation of therapeutics. Using cell transplants instead of drugs,
biologics and other current therapies, provides new hope for patients
with cancer, spinal cord injury, stroke and degenerative diseases. As
the federal government has not to date provided funding for pluripotent
stem cell research, the biotechnology industry has taken the lead in
funding it. For industry to continue to fund this research, and for
this research to be developed into products at the bedside for
patients, patent protection must be available. For the vital
partnership between industry and academic biomedical researchers to
remain strong, the terms of technology transfer agreements must be
commercially reasonable.
statement
The Biotechnology Industry Organization (BIO) represents 832
companies, state and affiliated organizations engaged in biotechnology
research on medicines, diagnostics, agriculture, pollution control and
industrial applications. BIO appreciates the leadership of the
Subcommittee in providing strong support for research on pluripotent
stem cells and for this opportunity to participate in this hearing.
Pluripotent stem cell research is a very exciting, cutting-edge
area of scientific research whose promise has captured the imagination
of the research community, patient advocates, and the American public.
We urge the Subcommittee to continue to lead the way in supporting this
research and the policies that will speed it to market for the benefit
of patients.
Over the last 50 years, the only constant in medical innovation has
been that scientists are constantly trying to treat human diseases
through new approaches. The newest approach which we are here today to
discuss is using embryonic or pluripotent stem cells (early human
cells) to treat degenerative cell based diseases. (We have attached to
the end of this document two figures to help explain stem cells' place
in embryonic development and the new method of generating these cells).
Stem cell research is intended to find treatments which do not depend
on chemical compounds, rather they use living cells as the treatment or
cure.
It is anticipated that these cells will be differentiated into
blood, skin, heart, or brain cells and may be able to treat cancers,
spinal cord injuries, heart disease and potentially many other
diseases.
The science of stem cells
There are 200 different kinds of cells that make up most of the
human body. These cells are differentiated, which mean that they have a
distinct morphology (shape and size), and have achieved a specialized
function such as carrying oxygen or transmitting ``nerve'' signals. For
years scientists have known about ``blood stem cells'' (cells that can
become one of several different blood cells such as white blood cells
or red blood cells) and the potential uses of umbilical cord blood.
However, late last year the Geron Corporation announced that its
research had, for the first time, successfully derived human embryonic
stem (ES) cells and maintained them in tissue culture. This was a great
step forward in this area of research.
Stem cells are the earliest precursor of human differentiated
cells. These cells come from an embryo, and, therefore, have been
defined as embryonic stem cells (ES). These cells, ES cells, have the
capacity to become virtually any cell or tissue in the body. These
cells are ``pluripotential''--that is these cells can be used to form
almost any tissue. These cultured ES cells are special as they have the
capacity for self-renewal, meaning they can produce more of themselves
without limit.
The excitement in the research and patient community is
understandable. There are two ways that ES cells are an advancement:
first, as a research tool to study developmental biology; and second,
as the starting point for therapies to create cures to some of the most
deadly diseases. The excitement and promise of this advancement is seen
in the letter that 52 patient and medical professional societies sent
to Members of the Senate on December 2, 1998, which supported stem cell
research and development (letter attached).
Although many see the benefits of stem cell research, we understand
that for some people this new area of research raises ethical issues.
These issues range from the ethics of conducting research on human
fertilized eggs to patenting research procedures.
Stem cell research
In compliance with current law requirements and concerns of the
public and the use of public funds to support research projects that
raise ethical concerns, the federal government has not sponsored
research to derive pluripotent stem cells. Now that these stem cells
have been derived, the government is determining whether it can and
should fund research on these cell lines.
Recent studies have documented that government funded basic
research is an important precursor to innovation by the
biopharmaceutical industry. \1\ In addition, public funding stimulates
additional investment by the drug companies and enhances the
effectiveness of their Research and Development expenditures as well.
\2\ According to a study of connections between pharmaceutical firms
and publicly funded scientists in academia and government, these
relationships have a large impact, raising the level of private sector
research productivity by as much as 30-40 percent. \3\ (See ``Federal
Funding for Biomedical and Related Life Sciences Research, fiscal year
1999,'' by Federation of American Societies for Experimental Biology.)
In addition, research that is funded by the Federal government is
subject to a variety of oversight mechanisms.
---------------------------------------------------------------------------
\1\ Andrew A. Toole, ``The Impact of Federally Funded Basic
Research on Industrial Innovation: Evidence from the Pharmaceutical
Industry,'' Madison, Wisconsin: Lauritis R. Christensen Associates
(1997).
\2\ Andrew A. Toole, ``Public Research, Public Regulation, and
Expected Profitability: The Determination of Pharmaceutical Research
and Development Investment,'' Madison, Wisconsin: Lauritis R.
Christensen Associates (1997).
\3\ Iain Cockburn and Rebecca Henderson, ``Public-private
interaction and the productivity of pharmaceutical research,'' National
Bureau of Economic Research (1997).
---------------------------------------------------------------------------
Technology partnership mechanisms
Technology transfer is a process by which amorphous areas of
scientific research are defined (generally through patents), then sold
or licensed to others. This process promotes the commercial development
of products as it is designed to provide for the capturing of the value
of basic research by the basic researcher (generally a non-profit
university researcher), and the shifting of the research to
organizations that are better able to assume the financial risk
associated with developing a commercial product (generally a
corporation).
In biotechnology, technology partnerships take a number of forms
depending on whether they involve the NIH, NIH-funded research, or in
the case of stem cell research, non-government support of research. In
each case the biotechnology industry pays royalties for the patent
rights to medical technologies. For your information, the principal
technology partnership mechanisms are listed below:
Cooperative Research and Development Agreement (CRADA).--A CRADA is
an agreement through which researchers at the NIH and private companies
negotiate terms for cooperative research and define the rights of the
parties to use licenses for any patents which might be created as a
result of the research. CRADAs are the cornerstone of the basic
biomedical research partnerships between the NIH and the biotechnology
and pharmaceutical industries. In many cases the corporate partner
provides funding and other resources to conduct research at the NIH.
This corporate partner will then take the new technology and develop a
marketable product.
Bayh-Dole agreements.--Bayh-Dole Agreements are agreements between
universities or medical institutes and biotechnology companies or
pharmaceutical companies in which the parties define the licensing
rights to patents and agree on how to share funds and materials.
Similar agreements exist between intramural government researchers and
licensees.
Technology licensing.--In the absence of federal funds,
organizations are free to license technology as they see fit, without
oversight of any Federal office. This freedom to license insures that
research organizations are able to capture the value of the research.
Generally these agreements are in accord with the mission of the
organizations involved. Anti-trust considerations sometimes play a
role.
Licensing of patents
The partnerships that are formed are based upon the licensing of
patents to basic biomedical research discoveries. These licenses are
critical to the relationship between biotechnology and pharmaceutical
companies and their research partners. Without patents to protect the
taking of an invention by a competitor, a company cannot justify its
research investment. For instance, any company would be competitively
disadvantaged by investing in stem cell research if other companies
could freely acquire it. It is crucial that the basic research
institution secures patents on their inventions so companies that
invest money in developing these inventions can benefit from their
investment. These licenses generally require companies to make royalty
payments to the proprietary owner of the license, or licensor, based on
any sales of products attributed to the licensed patent. These
arrangements allow the research organization to gain a benefit from the
research while not bearing the risk associated with the continued and
expensive research and development program. While protecting investment
and rewarding risk-taking, patents also act as a powerful spur to
competitors to improve on the patented technology or provide
alternatives.
In this regard, the biotechnology industry anticipates the
assumption of the risk and hopes to pay royalties as a part of a
license agreement. Companies frequently license technology from one
another and the norm is to include royalty payments. Restrictive future
licensing provisions will merely diminish the value of the licensed
technology. Logically, in some cases, restrictive practices would
prevent the licensing of some technology and thereby prevent its
development.
Patents and stem cells
Prior to the licensing of technology, the nebulous boundaries of a
technology must be defined so that the intangible assets can be handled
by the U.S. business and our legal system. In general that is done
through the patent system. A U.S. patent is defined by claims that
provide sharply defined borders to technology. These boundaries give
clear notice to others so that the area can be avoided or licenses can
be taken to practice what is defined. The claims can be directed to
products and compositions of matter. Once boundaries are established
and claims granted in an exciting field such as stem cells, patents
provide a powerful stimulus to competitive academic groups and
companies to improve on technologies and/or find new routes to achieve
the same effects. In this way, patents increase the range of effective
products available to treat intractable diseases and improve social
welfare.
There may be no industry which is more sensitive to patent
protection than the biotechnology industry. The rate of investment in
research and development in this industry is higher than in any other
industry. Any law which undermines the ability of biotechnology
companies to secure patent protection undermines funding for research
on deadly, disabling and costly diseases. Capital will not be invested
in biotechnology companies if they are not able to secure intellectual
property protection to recoup the substantial investments they must
make in developing a product for market.
Our industry's position on patents follows from one simple fact
about the biotechnology industry; most of our firms fund research on
deadly and disabling diseases from equity capital, not revenue from
product sales. Without investors taking the risk of buying the stock of
our companies, much of our vital research would end. Almost without
exception our industry cannot borrow capital. Our principal, and for
most of us, our only source of capital, is equity capital.
Intellectual property protection is critical to the ability of the
biotechnology industry to secure funding for research because it
assures investors in the technology that they will have the first
opportunity to profit from their investment. Without adequate
protection for biotechnology inventions, investors will not provide
capital to fund research. There is substantial risk and expense
associated with biotechnology research and investors need to know that
the inventions of our companies cannot be pirated by their competitors.
Our industry's general position on patents is identical to our
industry's position on stem cell patents. In regard to stem cell
research, patents are vital and they should be freely transferable.
These patents are essential to the continuation of stem cell research.
No money has yet been made from selling stem cell products. It is
unreasonable to expect any money to be made for many years to come from
this research.
Research exemptions
This position is entirely consistent with the continued existence
of a ``research exemption'' \4\. (This exemption is different from the
statutory Bolar \5\ exemption that provides additional protections for
non-patent holders. Bolar is not relevant to stem cell research at this
time as no therapeutics are nearing submission for regulatory
approval). The courts and BIO recognize that it is important that
patents do not block academic research that move a field forward and
which do not compete in the marketplace. Accordingly, the courts have
created the ``research exemption'' as a defense against patent
infringement for academic research--the type of research typically done
by universities. The biotechnology industry supports this exemption.
The industry benefits from the knowledge that is created by the
research being done on technology that the industry has patented. This
judicially created doctrine and the support of the doctrine from the
biotechnology industry has in having no biotechnology company ever
suing a university for performing academic research on patented
technology.
---------------------------------------------------------------------------
\4\ Popenhusen v. Falke, S.D.N.Y. 1861, 19 Fed.Cas. 1048, Northill
Co. V. Danforth, D.C.Cal. 1943, 51 F.Supp. 928, Chesterfield v. U.S.,
1958, 159 F.Suppl 371, 141 Ct.Cl. 838, Norfin, Inc. v. International
Business Mach. Corp. D.C. Colo., 1978, 453 F.Supp. 1072, affirmed 625
F.2d 357, Ares-Serono v. Organon Int. B.V., D.Mass.1994, 862 F.Supp.
603.
\5\ Roche v. Bolar Pharmaceutical Co., Fed. Cir 1984, 733 F.2d. 858
and see 35 U.S.C. 271(e).
---------------------------------------------------------------------------
In large part due to the patentability of new areas of research
like stem cell research and the transferability of patents, the United
States leads the world in biomedical research. The competitiveness of
the U.S. biotechnology industry means that the most vulnerable U.S.
patients have hope. It means that they can look to American biotech
companies to develop the therapies and cures which will ease their
suffering.
Summary of Commercial Development Issues Regarding Stem Cell Technology
The partnerships between NIH and NIH-funded grantees and the
biotechnology and pharmaceutical industries stand at the center of the
world's most productive biomedical research enterprise. Following is a
summary of BIO's views on the commercial development issues associated
with stem cell and other biomedical research.
--NIH and NIH-grantees have entered into a broad array of research
agreements and licenses. These agreements and licenses
typically provide that intellectual property generated by NIH
and NIH-grantees is licensed or sold to biotechnology and
pharmaceutical companies in exchange for royalty payments on
any sales.
--Central to these relationships are patents which ensure that the
results of the university and industry investments are not
misappropriated by those who did not make the investments.
Without patent protection no company can persuade its investors
to put their capital at risk, and NIH and its grantees would
have nothing to license. The patentability of inventions is
determined by the Patent and Trademark Office under well
established guidelines.
--Universities filed over 3,000 new patent applications in fiscal
year 1997 in the expectation that they could generate revenues
in the form of licenses and royalties. The availability of
patents--which grant an inventor 17 years of protection from
competitors--leads to an intense competition in the development
of life-saving drugs, biologics and devices. Patients in need
of new medicines and devices are the beneficiaries of this
competition.
--Patents do not block university researchers from conducting
research on patented inventions. These researchers are
protected from a patent infringement action by an
``experimental use'' exemption from an infringement action
because they are not competitors with a commercial motivation.
--Licenses can be exclusive or non-exclusive (i.e., sold to one, or
more than one entity). Each type of license may be appropriate
depending on the circumstances. About 10 percent of NIH's
licenses are exclusive. Academic researchers not engaged in
research for commercial use are not affected by the existence
of an exclusive license. The Association of University
Technology Managers (AUTM) Licensing Survey, fiscal year 1997,
found that universities executed 2,665 licenses and options of
which 1,377 were exclusive (52 percent) and 1,288 were non-
exclusive (48 percent); U.S. hospitals and research institutes
executed 361 licenses and options, of which 208 were exclusive
(58 percent) and 153 were non-exclusive (42 percent); and
Canadian institutions executed 198 licenses and options, of
which 139 were exclusive (70 percent) and 59 were non-exclusive
(30 percent).
--An exclusive license gives a company a greater incentive to invest
its resources in the development of technology and this means
that the companies are able and willing to pay a higher royalty
rate to the NIH or an NIH-grantee. Exclusive licenses are
particularly appropriate in cases where substantial risk and
expense are involved in the development of basic research into
a marketable product.
--In 1997 NIH received approximately $40 million (1,000 licenses) and
its grantees approximately $300 million (5,000 licenses) in
royalties from its licenses to biotechnology and pharmaceutical
companies. This income helps to fund additional research.
--In 1997, of all federally funded grantees, the top ten recipients
of royalty income include: University of California System
($67.3 million), Stanford University ($51.7 million), Columbia
University ($50.3 million), Florida State University ($29.9
million), Massachusetts Institute of Technology ($21.2
million), Michigan State University ($18.3 million), University
of Florida ($18.2 million), W.A.R.F/University of Wisconsin-
Madison ($17.2 million), Harvard University ($16.5 million),
Carnegie Mellon University ($13.4 million). This income helps
to fund additional research.
--In 1996, separate from licensing royalties, industry sponsored $1.5
billion in research at U.S. universities, hospitals and
research institutes, the overwhelming portion of which is in
biomedical research (such as conducting clinical trials,
including $41 million at Massachusetts General Hospital and $26
million at the Mayo Clinic). This income is vital to the
biomedical research efforts of these institutions.
--From 1980 through 1997 these technology partnerships between
federal government agencies and university-based research were
reported (many aren't reported) to have led to the founding of
1,521 U.S. companies.
--These technology partnerships, and the patents on which they are
based, are particularly important to small biotechnology
companies. These companies tend to focus their research on
breakthrough technologies that come from basic biomedical
research. They also must have strong patent protection to
justify the risks they take. Most of these companies have no
revenue from product sales to fund research, thus, they depend
on venture capital and public market investors. In 1997, the
biotechnology industry lost $4.1 billion. Previous years have
had similar financial losses (1996, $4.5 billion loss; 1995,
$4.6 billion loss; 1994, $4.2 billion loss). The biotech
industry hasn't ever had a profitable year.
Conclusion
BIO appreciates the opportunity to present these views on this
important issue. We look forward to working with the Subcommittee to
support policies that will speed the development of pluripotent stem
cell research into products for the benefit of patients.
obtaining by ethical means
Senator Specter. Thank you very much, Mr. Pikunis, for that
very moving statement, and we will start now 5-minute rounds of
questioning.
Your testimony goes to the point that I made in my opening
about the sense of urgency. There appears to be a ban--Senator
Harkin may be right that there really is no ban, but NIH is
treating it as a ban, and instead of importuning interpretation
and litigation we have the way to resolve it with legislation
that came out of this subcommittee.
The purported ban, we can lift that ban, and when you talk
about your personal situation, that is precisely the sense of
urgency which I think ought to move the Congress to get this
done.
Let me ask you the first question, Dr. Goldstein. Picking
up on your statement about obtaining by ethical means, the
embryo is a sperm-fertilized egg and will grow into a fetus
upon implantation in the uterus.
What we have here are discarded embryos, so there is no
possibility of the embryos which are used for stem cell
research to be implanted and to produce a person, is that a
correct scientific statement?
Dr. Goldstein. Yes; that is our understanding of the
situation, Senator. In addition, we presume--I presume
personally these embryos may be damaged in handling. You may
not want to implant them into women. Actually, to implant them
would itself be unethical.
Senator Specter. The long and short of it is that it is
ethical to take these discarded embryos, which are not going to
be used for implantation, to produce a human being for medical
research?
Dr. Goldstein. Yes; we believe so.
Senator Specter. I want to turn to you, Mr. Dickinson, on
the question of patent applicability, and again I am sorry that
Geron is not here to give us their view of the issue.
If the stem cell is defined as an end product, then it is
subject to patent protection, but if it is considered to be a
research tool, then in that situation--or is there any other
interpretation where it would not be subject to patent
protection?
Mr. Dickinson. Senator, patent claims are a very arcane and
very semantic type of----
Senator Specter. That is why we have you here.
Mr. Dickinson. Thank you. I think it would be not
appropriate necessarily for me to comment on or speculate on
what the breath of a claim might look like that we do not have
before us at this time.
The claims that are directed to stem cells, as you point
out, are directed to stem cells which have been isolated and
purified and, as such, from a long line of case law are subject
to patent protection.
Senator Specter. Well, if they are a research tool are they
subject to patent protection?
Mr. Dickinson. They can be, yes.
Senator Specter. Under what circumstance might they not be?
Mr. Dickinson. We have a four-part test, as I mentioned,
for patentability, and if they are outside that test--for
example, if they are not subject matter which is patentable by
statute, which is a very broad statute, or if they are not new,
if they have been known before, or if they are obvious in view
of what has been known before, they would not be patentable.
Senator Specter. So we might have to change the law to move
them outside of patent protection?
Mr. Dickinson. That is always a possibility, Senator.
Senator Specter. Well, Congress can do that.
Mr. Dickinson. Yes, sir.
Senator Specter. Dr. Freire, the patent contains 11 claims,
some of which use the term, primate to identify the Wisconsin
work. Primate might be construed as to cover humans, although
the term is not--the term human is not presented among the
claims. Could that be interpreted to have any implication for
producing human stem cells?
Dr. Freire. Yes, Senator. We checked with the holder of the
patent and they told us that they have prosecuted the patent to
include humans, although none of the research supported by NIH
was for humans. It was all for the monkeys.
Senator Specter. Does that bear upon the issue of human
cloning?
Dr. Freire. Well, the claims as they are right now on stem
cells and their production are from primates. As you point out
and, as such, humans are primates.
Senator Specter. My red light is on. I will pick up on my
first question to Dr. Melton in my next round.
Senator Harkin.
patentability of research tools
Senator Harkin. Thank you, Mr. Chairman. My first question
would be to you, Dr. Freire. You mentioned, and I caught it
when I sat down here when I came in a little bit late, a
dilemma. Would you expand upon what you meant by that dilemma?
Dr. Freire. Yes; it actually bears on the question that
Senator Specter asked Mr. Dickinson, whether or not research
tools are patentable. They are, indeed, patentable, so the
question is, how do you enforce those patent rights? We are
very respectful of the patent holder's right to extract value
from his or her invention. The concern arises when the value is
extracted, from our perspective, at a very early stage, at the
research stage, as we are being asked to do at this point. The
patent, of course, as Mr. Dickinson pointed out, allows for the
making, using, or selling, precluding others from making,
using, or selling, and our scientists are making and using many
of these research tools.
When obligation is tied to these very early discoveries by
the patent holder, at the end of the day we have a very
encumbered potential drug or therapeutic that may never see the
market because of these very complicated obligations.
On the other hand, it is of value to the owner of the
patent, and we certainly cannot diminish that value. We have
learned very many lessons from the 20 years. Your recollection
on Bayh-Dole is exactly correct. It was an economic development
effort. But one of the lessons we have learned is that while we
grant that protection we should be able to separate the way we
license this technology to ensure that the rights to maintain
unencumbered research continue while we extract the value for
the commercial partner. That was not something we thought about
doing early on.
bayh-dole act
Senator Specter. Under Bayh-Dole, if the Federal Government
is involved in any of the funding for the basic research, as I
understand it--correct me if I am wrong--the Federal
Government, NIH, retains the right to use those findings. Even
though they are patentable and patented, they are able to use
those as research tools intramurally.
Dr. Freire. Well, we actually retain the right to use--we
have a royalty-free right to use the patent. We have a license
to all of those patents for Government purposes, that is, the
intramural scientists at NIH.
Senator Harkin. A nonexclusive right?
Dr. Freire. That is correct.
Senator Harkin. And it is not--well, it is not something
that you pay for, that we pay for. The Government retains that
right.
Dr. Freire. Correct.
Senator Harkin. But you can only use that for intramural--
--
Dr. Freire. Or for Government purposes, contractual
Government purposes, like if we have a contract and the
contractor is doing work for the Government, that is one of the
retained rights.
Normally, these Government rights that are retained are not
interpreted to ensure to our grantees. Our grantees are not
considered part of the Government user rights.
Senator Harkin. And you think that should be allowed? I
mean, you raise that as a problem.
Dr. Freire. Yes; I think that we would very much like to
see the ability of our funded researchers to use these research
tools unencumbered, yes.
Senator Harkin. And if they use them unencumbered, then let
us assume that they find an application--they are able find a
means of developing that stem cell into muscle tissue or
something, and you get to the Parkinson's Disease, for example,
who has the right to that patent?
Dr. Freire. Well, the new invention, if it is in fact a new
invention, could be patentable by the grantee.
Senator Harkin. Well, would the grantee then have to pay a
licensing fee to the original patent holder of the stem cell?
Dr. Freire. Well, what normally happens is, the grantee
would license to company X. Company X would have to ensure that
they have the rights to practice the invention for commercial
purposes. Company X will go back to the companies that hold
other rights and establish licensee agreements with the other
commercial partners to ensure that they can move forward.
Senator Harkin. I just want to be clear on this. My time is
up. If the Federal Government retains the right to be able to
use these research tools as a means of enabling our grantees--
say another university--to be able to use these as a research
tool, that grantee is not paying any license rights to the
initial patent holder, is that correct? That is right.
And then the licensee develops a strain from that, and they
then want to patent that strain and obtain the recompense for
that. How, then, do we ensure that it gets back to the original
patent holder that they also would retain some right in that?
Dr. Freire. Well, the original patent holder, if they have
a dominant patent, would be approached by the licensee who
wants to bring the product to commercialization. Otherwise they
would be infringing the patent of the original holder.
Senator Harkin. I see. They could use the line for any kind
of research, but when they take the step to commercialize it,
then they have to go back to the original patent holder to
obtain some rights?
Dr. Freire. Let me clarify, Senator. In the pharmaceutical
and biotechnology industry the research exemption really does
not exist, per se, which is what you are getting at. We really
do not have a very solid research exemption.
Companies have, in fact, come back to the NIH and said, you
need to take a license because you are making or using patented
technology. But the pharmaceutical and biotechnology industry
have worked with the academic sector in a hand-shake type
agreement, because they understood the importance of basic
science. But, we are seeing companies come back and exercising
their rights this way.
Senator Harkin. Thank you, Mr. Chairman.
Senator Specter. Dr. Melton, you have extraordinary
credentials here, with your chairmanship of the Molecular and
Cellular Biology Department at Harvard University, and you have
equally impressive personal interest with your 7-year-old son.
Tell us what would the key processes be to develop stem
cells into cells that produce insulin, or otherwise deal with
diabetes?
Stated differently, how close are we to using stem cells to
solve the diabetes problem for your son?
Dr. Melton. That is a very good question, Mr. Chairman.
What I can tell you with some confidence is that the work with
mouse stem cells is so encouraging that one is within a few
years of being able to get those cells, or direct them to
become pancreatic cell types in culture, and that is why I
think it is so imperative that we immediately begin to transfer
that information, to test our knowledge, in the case of the
human cells to determine whether there are any significant
differences.
I was very encouraged by that questioning, because it is
clear that you and Senator Harkin are trying to free up Federal
funding so that this sort of research can continue.
Senator Specter. Well, as you know, there were many
millions of dollars added by this subcommittee last year, but
it does not do a whole lot of good if the NIH is barred from
using that on this very dramatic breakthrough.
Dr. Melton. What I can see, speaking from the scientist's
point of view in the trenches, is that there are many people
with very good ideas, novel ideas about how to actively pursue
this research, and we are anxious for Federal funding.
Senator Specter. Your few years is very helpful. We do not
have a whole lot of time, so I am going to move on to Mr.
Pikunis.
On Parkinson's, there have been very effective advocacy
groups. With the Udall legislation last year, that sort of took
the Congress by storm on the difficult matter of having
Congress establish priorities, which are characteristically
left for NIH.
Just how pressing is it for you personally, Mr. Pikunis, in
terms of your daily activities, to have the assurance that NIH
will move forward, the Federal Government will move forward?
How does that impact on your daily life?
Mr. Pikunis. I think it is very important, because right
now under current medication-type treatments for Parkinson's
Disease I am fine as long as I am on the medication, but I
notice if the dosage goes too high I start exhibiting the side
effects of the involuntary body movements, and that is at a
slightly increased dose from what I am on now.
As long as I am on the current dose, I am fine, but I know
that the current does is not going to last me forever.
Senator Specter. Dr. Goldstein, you identified a range of
other ailments in your testimony, heart disease, Alzheimer's--
does this have application for cancer as well?
Dr. Goldstein. Yes; we believe it does. Many of the
therapies that are involved in cancer chemotherapy wipe out
many types of cells in the body that need to be replenished.
Often, they are done by bone marrow transplants. Stem cells
could, in fact, be a much better source of these vital cells.
Senator Specter. Dr. Melton gives us a few years, as he
says, with respect to diabetes. Would you give us a ball park
figure with respect to Alzheimer's?
Dr. Goldstein. Alzheimer's is a very tough problem,
Senator, and I do not think we have a very good sense of how
long it will be. I guarantee you that every day we delay is
another day that the clock ticks and we are not making progress
using this vital research need.
Senator Specter. People in Congress like to have figures,
even ball park figures. Let me press you on the question, and
very seriously, this business of advocacy is a very tough
issue.
The first thing we have to do is disabuse many of the
notions that using embryos is somehow related to destroying
human lives. That is a very, very big political issue, and you,
ladies and gentlemen, a pretty good-sized group here, ought to
be aware of that in terms of your advocacy. You have got to
approach a lot of people to disabuse that notion.
And then if you talk in terms of being close, and what the
dollars will do, then you start to create an impetus for it, so
I want to give you just a little insight into advocacy.
My red light is on, but yours is, and for a very short
answer, how long?
Dr. Goldstein. Maybe 5 to 10 years, Senator, where we could
see some hope. We can turn these cells into neurons now, but
the question is whether we can turn them into the right sorts
of neurons.
Senator Specter. Senator Harkin, as is not unusual, has the
last word. [Laughter.]
University of Wisconsin research
Senator Harkin. Again, Dr. Freire, in your testimony you
mentioned that because the Government funded earlier research
on rhesus monkeys at the University of Wisconsin the Government
has a ``nonexclusive royalty-free right to use the patented
cells by or on behalf of the Government.'' Do those patented
cells include human embryonic stem cells?
Dr. Freire. The owner of the patent would argue that they
do include human embryonic stem cells.
Senator Harkin. The owner of the patent?
Dr. Freire. Wisconsin.
Senator Harkin. That they do?
Dr. Freire. Yes; that the claims to that patent do include
human embryonic stem cells. The word human does not appear in
the claims. The word primate appears in the claim, and primate
encompasses humans. That is the way the owner of the patent
prosecuted this application, from what we have been able to
discuss with them.
Senator Harkin. Do you agree with that?
Dr. Freire. Yes.
Senator Harkin. Mr. Dickinson, some in the research
community argue the Patent Office is issuing biotechnology
patents that are too broad. What is your response to that?
Mr. Dickinson. Well, the matter of the breadth or the
narrowness of the claim is a matter, again, of matching it up
against those four statutory requirements that I mentioned.
It has been my experience that when patents issue of a
certain breadth in a new technology there is often concern
about that breadth, but what happens in reality is that
additional patents, what may be called a genus patent, what
often happens, very quickly, is the people develop species
patents, new and not obvious claims in new patents that would
be patentable over that original broad patent.
This is something we have dealt with historically. It has
been dealt with effectively.
Senator Harkin. You do not think they are too broad?
Mr. Dickinson. Not in general, no. The nature of the
breadth of a patent is measured by the prior art.
Bayh-Dole
Senator Harkin. My time is up. One final question for all
of you. Do we need to readdress Bayh-Dole?
I have heard that it has been a success, but like anything
that is 18 or 19 years old, it may need to be readdressed. Do
we need to make some changes, because the biotech industry had
not really started--it was in its embryonic stage when we
passed Bayh-Dole.
Do we need to make any changes in Bayh-Dole, Dr. Freire?
Dr. Freire. When I discuss this with my colleagues at
universities the president of the Association of University
Technology Managers Karen Hersey said publicly that perhaps 20
years later we could go back and look and see how some of these
things have worked, so it would not be a full rewriting but an
assessment. I think it would be responsible to take a look at
what those items are.
Senator Harkin. Well, I for one, just speaking as an
individual, am open to any suggestion from you or anyone else
in the audience about suggestions for modifications if
modification is needed. I have not made that decision yet.
Mr. Dickinson, what say you?
Mr. Dickinson. I am not an expert on the Bayh-Dole Act. It
is probably not my place to comment on whether it is working or
not.
Senator Harkin. Dr. Goldstein, how about you? What do you
say?
Dr. Goldstein. I am sorry, Senator, I am not a lawyer, but
I can certainly point out that it is always worthwhile
reviewing past actions after 20 years have passed.
Senator Harkin. Dr. Melton, do you have any views on that?
Dr. Melton. I agree with Mr. Goldstein that the rapid
changes in the biotech industry were not foreseen when that act
was constructed and I think it is worth revisiting it.
Senator Harkin. Mr. Pikunis, do you have any views on this?
Mr. Pikunis. No, sir; I do not.
Senator Harkin. I am just trying to figure out--and again,
the dilemma is, we want the research, we want the money
invested, we want private moneys invested, and we also want to
make sure that they are able to get a return on that investment
and that they are able to patent it, but we also want to make
sure the research is broadly and widely available to others,
and that we are not hindered by a broad patent that is issued
that hinders further research that may be utilized. That is the
dilemma.
But I do not know what we will do on the Bayh-Dole Act, Mr.
Chairman. I do not know if it needs to be looked at or not.
Like I say, I have personally made no decision on that.
Senator Specter. Senator Harkin, it may be we will have to
take a look at it, and we will have to take a look at the
patent laws, or it may be that if Congress takes a look at the
patent laws in the Judiciary Committee, that there will be a
little more generosity on licensing, and having research going
forward. You never can tell how those issues are going to
interact.
subcommittee recess
Thank you all very much for being here, that concludes our
hearing. The subcommitee will stand in recess subject to the
call of the Chair.
[Whereupon, at 10 a.m., Tuesday, January 12, the hearing
was concluded, and the subcommittee was recessed, to reconvene
subject to the call of the Chair.]
STEM CELL RESEARCH: HHS LEGAL RULING
----------
TUESDAY, JANUARY 26, 1999
U.S. Senate,
Subcommittee on Labor, Health and Human
Services, and Education, and Related Agencies,
Committee on Appropriations,
Washington, DC.
The subcommittee met at 9:03 a.m., in room SD-138, Dirksen
Senate Office Building, Hon. Arlen Specter (chairman)
presiding.
Present: Senators Specter, Harkin, and Hollings.
DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
STATEMENTS OF:
HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH
HARRIET RABB, J.D., GENERAL COUNSEL, DEPARTMENT OF HEALTH AND
HUMAN SERVICES
NONDEPARTMENTAL WITNESSES
STATEMENTS OF:
ERIC M. MESLIN, Ph.D., EXECUTIVE DIRECTOR, NATIONAL BIOETHICS
ADVISORY COMMISSION
RICHARD M. DOERFLINGER, ASSOCIATE DIRECTOR FOR POLICY
DEVELOPMENT, SECRETARIAT FOR PRO-LIFE ACTIVITIES, NATIONAL
CONFERENCE OF CATHOLIC BISHOPS
opening remarks of senator specter
Senator Specter. Good morning, ladies and gentlemen. The
Subcommittee on Labor, Health and Human Services will proceed.
We have scheduled this hearing on stem cells, which is the
third in reasonably rapid succession, given the hearing
schedules of the subcommittee, this subcommittee or any
subcommittee, because of the importance of stem cells research,
where there is such enormous potential for medical advances.
The request has been made that the subcommittee not proceed
to initiate legislation on the subject because that might
complicate the use of stem cells under an opinion which has
just been rendered by legal counsel for the Department of
Health and Human Services, and we want to work with HHS and NIH
to see to it that the most appropriate course is followed here.
The definition of ``organisms'' and ``stem cells'' and the
entire medical lexicon is extraordinarily complicated. We have
noted that NIH researchers will only be allowed to work on stem
cells obtained by private sources. No NIH-supported researchers
will be allowed to conduct direct work on a human embryo, even
to obtain stem cells, consistent with the existing ban.
That is an advance, but it is limited, obviously, on the
face. There are a series of NIH caveats in that NIH will not
fund any human cell research until such time as special
guidelines are developed addressing relevant ethical and moral
issues. So that is a constraint.
NIH plans to convene a special oversight group to review
all research grant applications involving human stem cells in
addition to the regular scientific review process, which is
another limitation. NIH has asked the National Bioethics
Advisory Board for additional guidance.
I appreciate the thinking of NIH on all these very complex
subjects. The hearing today will focus on to what extent that
may delay research, and there is a question as to whether
additional legislation is needed, which we will be addressing.
These are very, very difficult legal problems, and that only
begins to scratch the surface of the ethical problems which
underlie them.
The question is in my mind as to whether legislation is
necessary or desirable. Maybe we should not have any
legislation. My preliminary thinking is, as I expressed it in
the second hearing, after studying the issue from our initial
hearing, was that we really ought to utilize this kind of
research, and if it requires legislative change then I think we
ought to proceed in an expeditious way, but in a careful way.
So Dr. Varmus, that is a very, very brief outline of some
of the problems running through my thinking on it. We welcome
you here again today. I know that there are scheduling problems
among the panel and there is a scheduling problem with the
subcommittee. We have advanced the hearing, as you know, to 9
o'clock because we have a caucus on the impeachment case, which
is very time-consuming. But it is my firm view that we ought to
be taking care of other problems as well. So whatever time we
have to meet to do that, however, we can proceed in an
appropriate but expedited fashion, we intend to do that. I know
you are experienced at that, Dr. Varmus.
We thank you for coming. We compliment you again on the
outstanding work you have done at NIH over the years. We have
put the government's money where our praise is, to paraphrase a
famous statement. The floor is yours, Dr. Varmus.
SUMMARY STATEMENT OF DR. HAROLD VARMUS
Dr. Varmus. Mr. Chairman, thank you very much.
Senator Specter. I would like you to limit the opening
statements to 5 minutes, to leave maximum time for questions.
Dr. Varmus. I appreciate your attention to these issues
despite conflicting demands on your time.
My purpose today is threefold. I want to just say a couple
of words to remind you about the scientific prospects here,
review the legal decision that you have alluded to, and outline
the next steps that the NIH proposes to take to pursue our
intention to support research with these new stem cells.
I remind you that human pluripotent stem cells were
recently isolated by two methods: first from fetal tissue after
elective abortion; and from embryos that were donated after
treatment of infertility. Neither of these events were
supported with Federal funding.
Now, human pluripotent stem cells can divide in culture for
long periods. That is part of their usefulness--good morning,
Senator--and they have the potential to form virtually any kind
of tissue. The research applications of these cells are various
and important. They include attempts to understand human
development, efforts to develop drugs and test for drug
toxicity in new ways, and the potential for developing cell
therapies for many diseases, injuries, and conditions.
We discussed in December at your hearing the issue of
Federal support for this science and indeed other kinds of
science as well. As you heard from the panelists at that time,
there are several advantages to receiving Federal support in
this area: the open exchange and the more intense and
accountable oversight, the greater number of dollars and the
more talent recruited to these problems, and the ultimate goal
of faster progress toward public health goals.
We at the NIH respect and recognize many ethical and legal
concerns about human pluripotent stem cells and the modes by
which they are derived. We are firm in our conviction that
Federal funds should not be used for this purpose until both
the legal concerns and these ethical concerns have been
addressed and many constituencies, including Congress and the
public, have been consulted.
As a first step, I asked the General Counsel, Harriet Rabb,
who is sitting with me today, for a legal opinion about the
Federal funding of research with these cells, distinguishing
carefully between the use of the cells and their derivation. In
other words, can we support work with the established human
pluripotent stem cells in view of the appropriation law that
you alluded to that bans the use of Federal funds for embryo
research.
The essence of her opinion, which you have been given, is
that: first, yes, we can fund work with human pluripotent stem
cells derived from nonliving fetuses under the existing
statutes that govern fetal tissue research; secondly, that we
can fund work with human pluripotent stem cells that are
derived from embryos because the cells themselves are not
organisms, they cannot become organisms, and hence they are not
embryos as defined by law. Indeed, at your December hearing,
prompted by Senator Harkin, all witnesses who expressed an
opinion agreed with this definition.
Now, under the appropriation law it is also the case that
we cannot use these stem cells to make an embryo, for example
by somatic cell nuclear transfer, and of course we cannot fund
work to derive such cells from embryos, although we can do so
from fetal tissue.
I presented these views at a meeting of the National
Bioethics Advisory Commission on January 19. That meeting was
held on this topic in response to a presidential request that
the entire area of stem cells research be reviewed in view of
the promises of recent work, because he felt that recent
advances had indicated that there was a need to reassess the
balance between the ethical concerns about such work and the
promise for medical research.
We welcome the review by NBAC. We specifically seek prompt
guidance with respect to the ethical considerations that will
allow us to carry out appropriate oversight on this research.
What are our next steps? Well, first, as I have made clear
on many occasions, no immediate funding is occurring until we
have our guidelines and process in place. This has been
communicated to all of our investigators, both intramurally and
extramurally, through memos and Internet postings and news
reports.
Second, I am establishing a working group of my advisory
committee to the Director which has ad hoc members from all the
relevant specialties. That working group will work with NIH
staff to compose guidelines for the conduct of research on
these cells. The guidelines will address the work to be done
with the cells, how the cells were derived, and how the
starting materials were obtained.
There are important frameworks that will make this
formulation of guidelines easier. There are Federal rules for
work with fetal tissue that will be helpful. Some years ago, in
1994, a human embryo research panel issued recommendations that
were extremely thoughtful and will be important guides in the
development of guidelines.
Finally, the group will also be consulting with the NBAC,
with Congress, with the public. We will be publishing a draft
of our guidelines in the Federal Register for comment. We
expect to have the guidelines written and presented to the
public in the course of the next couple of months. We will then
promulgate those guidelines and then, in a manner to be
determined by the working group, an oversight group will ensure
that all who do this work are actually in compliance with the
guidelines.
We expect that the vast majority of applications will be
mostly routine. That is, they will be applications to work with
the existing cells that have been described and whose
provenance is well understood. Any uncertainties will be
referred to further public discussion and we will carry out
annual reporting to Congress and the public about the status of
the science, the number of investigators, and any change
proposed for the guidelines.
Before I conclude these remarks, let me just make a
personal comment, that since I made my presentation to NBAC
last week my staff and I have received many, many, thoughtful,
interesting, perplexing questions. Let me just address two of
those that I think will help inform our discussion.
First, we have been asked, is not working with these stem
cells like using stolen goods because some of them were derived
from embryos in that embryo research is forbidden? No, no. It
is not illegal to derive human pluripotent stem cells. What is
forbidden is the use of Federal funds to derive them from
embryos.
In this sense, it is like many legal activities for which
Federal funding is not permitted. No Federal funds were used,
no laws were broken, in producing these stem cells, and we have
determined that no laws would be broken if Federal funds are
used to support work with them once they have been derived.
The second question we frequently hear is, will not Federal
funding for human pluripotent stem cells create a demand to
create additional human embryos? Again the answer is no. There
are thousands of embryos, indeed probably tens of thousands of
embryos, that are frozen and discarded in the United States in
vitro fertilization clinics each year because they are in
excess of the number required for successful treatment of
infertility.
In contrast, human pluripotent stem cells derived from very
few embryos can be used by many investigators for hundreds of
experiments because it is usually possible to keep these cells
growing for many generations, that is for many cell doublings.
PREPARED STATEMENT
Furthermore, Federal guidelines that protect against
coercion in the procurement of fetal tissue are likely to be
emulated in the construction of our guidelines for work with
human pluripotent stem cells.
Mr. Chairman, no doubt you and Senator Harkin have other
questions. I would be pleased to answer them now. Thank you
very much.
Senator Specter. Thank you very much, Dr. Varmus.
[The statement follows:]
Prepared Statement of Harold Varmus, M.D.
I would like to thank you for the opportunity to discuss the recent
decision by the Department of Health and Human Services concerning HHS
funding for research utilizing human pluripotent stem cells. In
testimony to this Subcommittee on December 2, 1998, I presented the
exciting science of human pluripotent stem cells and described how the
isolation of these cells could radically change the landscape of
biomedical research. At that time, the NIH was awaiting a legal opinion
from DHHS to determine whether or not the NIH could fund research
utilizing these cells. The legal opinion is now available and states
that research utilizing human pluripotent stem cells can be supported
with Federal funds. What then are the next steps?
First, let me say that we understand and respect the different
points of view that have been expressed about the important ethical and
moral issues involved in this research. In developing the important
safeguards that will govern funding for this research, NIH intends to
consult with those representative of a broad range of views. We welcome
the input of Congress as we move forward in this area.
Today, I would like to very briefly review some features of human
pluripotent stem cells--how they are derived and the promises they hold
for medical research and practice. I will then describe the legal
opinion and the plans for the development of guidelines and oversight
that will be in place before NIH would fund research with these cells.
We are committed to proceeding in a careful and deliberate manner that
recognizes the ethical, societal, and scientific issues of this area of
research.
I refer you to my previous testimony for a fuller description of
the scientific aspects of this research. Stem cells are cells that have
the ability to reproduce themselves and to give rise to other more
specialized types of cells. Totipotent stem cells--such as the product
of fertilization of an ovum and its progeny--are stem cells that have
total potency, which means that they have the ability to form an entire
mature organism, e.g., a human being, although only if placed in a
woman's uterus. In contrast, human pluripotent stem cells, which are
under discussion today, do not have total potency, and hence cannot
form an entire organism under any known condition. But pluripotent stem
cells can give rise to all of the different types of specialized cells
in the body.
The methodologies for deriving human pluripotent stem cells are not
really new; pluripotent stem cells have been derived from mice since
the early 1980s and, since then, from non-human primates and other
animals. The first reports of deriving human pluripotent stem cells
were published in November 1998 by Dr. John Gearhart and Dr. James
Thomson. Neither of these investigations were supported with DHHS
funds, although Dr. Gearhart's work could have been supported with
Federal funds, because he and his colleagues derived human pluripotent
stem cells from primordial gonadal tissue which was taken from a non-
living fetus. Federal laws and regulations already exist that govern
research on fetal tissue. Dr. Thomson and his co-workers derived
pluripotent stem cells from the blastocyst stage of an early embryo--
the embryos used were donated by couples who were receiving infertility
treatment; this derivation of stem cells from the embryo does fall
under the ban on Federal funding in the HHS/Labor/Education
Appropriations Bill. The pluripotent stem cells derived by each of
these means appear to be very similar or identical in structure,
function, and potential; but it will take more research to verify this.
The isolation and culturing of human pluripotent stem cells opens
certain avenues of research for the first time. Let me mention just
three potential applications of human pluripotent stem cells. The first
is research focused on how stem cells differentiate into specific types
of cells. The goal is to identify the genetic and environmental signals
that direct the specialization of a stem cell to develop into specific
cell types. Studying normal cell and tissue development will provide an
understanding of abnormal growth and development which, in turn, could
lead to the discovery of new ways to prevent and treat birth defects
and even cancer.
A second and more practical application of research using these
cells is in pharmaceutical development. Use of human pluripotent stem
cells could allow researchers to study the beneficial and toxic effects
of candidate drugs in many different cell types and potentially reduce
the numbers of animal studies and human clinical trials required for
drug development.
The third and most obvious potential application of these human
pluripotent stem cells is to direct the specialization of the cells
into cells and tissues that could be transplanted into patients for the
purpose of repairing injury and pathological processes. A number of
such examples are described in my December testimony, but two are worth
mentioning here.
(i) Transplantation of healthy heart muscle cells could provide new
hope for patients with heart disease. The hope is to develop heart
muscle cells from human pluripotent stem cells and then transplant them
into the failing heart muscle in order to augment the function of the
heart. Preliminary work in mice and other animals has demonstrated that
healthy heart muscle cells transplanted into the heart successfully
repopulate the heart tissue and integrate with the host cells. These
experiments show that this type of transplantation is feasible.
(ii) In many individuals with Type I diabetes, the production of
insulin in the pancreas by specialized cells called islet beta cells is
disrupted. There is evidence that transplantation of either the entire
pancreas or isolated islet cells could mitigate the need for insulin
injections. Islet cell lines derived from human pluripotent stem cells
could be used for this critical research and, ultimately, for
transplantation.
Because human pluripotent stem cells continue to replicate
robustly, stem cells derived from a few embryos or from a few fetuses
could potentially be used in hundreds of individual research protocols.
Briefly, that is the science and the promise. We are here today to
discuss the role of the Federal Government in the future of this area
of research.
There are a number of advantages to using public funding for
research. Perhaps the most important reason is the fact that Federal
involvement creates a more open research environment--with better
exchange of ideas and data among scientists--more public engagement and
more oversight. In addition, Federal support increases the fiscal
resources and expands the pool of talented investigators--particularly
in academia--both of which accelerate the tempo of scientific
discovery.
In response to the recent announcements concerning the isolation of
human pluripotent stem cells, I requested an opinion from DHHS on the
legality of using DHHS funds to support or conduct research that
utilizes these cells, in light of existing restrictions on human fetal
tissue research and the amendment in our Appropriations bill governing
human embryo research.
On January 15, 1999, DHHS delivered the following opinion. DHHS
funds can be used to support research utilizing human pluripotent stem
cells that are derived from human embryos: the statutory prohibition on
human embryo research does not apply to research utilizing human
pluripotent stem cells because human pluripotent stem cells are not
embryos. The statute that bans the use of Federal funds for embryo
research defines embryo as an organism derived by fertilization and
other means. The statute does not, however, define organism. Therefore,
the legal opinion relied on the broadly accepted science-based
definition of organism: an individual constituted to carry out all life
functions. By this definition--and as you heard from all the witnesses
that responded to that question at your hearing on this matter on
December 2, 1999--pluripotent stem cells are not and cannot develop
into organisms. Therefore, human pluripotent stem cells are not embryos
and are not covered by this prohibition on Federal funding. In
addition, the legal opinion states that DHHS funds can be used for
research using human pluripotent stem cells that were derived from
fetal tissue if the existing laws and regulations governing fetal
tissue research are obeyed.
Now that the legal opinion has been rendered, what are the next
steps? The approach will be careful and deliberative, recognizing the
important ethical concerns that surround this area of research. I want
to emphasize that NIH will not use Federal funds for research using
human pluripotent stem cells until guidelines and procedures to oversee
the research are developed. Let me describe the process that we have
planned to ensure that any research involving human pluripotent stem
cells is appropriately and carefully conducted. And as I mentioned
earlier, we are interested in hearing a broad range of views.
First, all researchers currently receiving NIH support have been
notified, via the NIH web site, that they cannot use DHHS funds to
begin research using human pluripotent stem cells until further notice.
We have made every effort to include this policy in all of our public
statements. In addition, NIH program staff have been requested to
notify those grantees who are most likely to have an interest in this
work about this present policy. The Deputy Director for Intramural
Research has also notified intramural scientists of these requirements.
Second, I will convene a subcommittee of the Advisory Committee to
the Director (ACD) to develop Guidelines that specify what work using
these cells can and cannot be supported with DHHS funds and outline
restrictions on the use of such funds in the derivation of the cells.
They will also be asked to develop an oversight mechanism to review
research proposals seeking to conduct research utilizing these
pluripotent stem cells. The subcommittee will meet in public session
and will be composed of scientists, the lay public, ethicists, and
lawyers; former members of the Human Embryo Research Panel may be asked
to participate. They will be asked to consider advice from the National
Bioethics Advisory Commission (NBAC), the newly established Council of
Public Representatives (COPR), the public, and the Congress. NIH
already has two thoughtful sets of Guidelines which will inform these
efforts--the 1994 Report of the Human Embryo Research Panel and the
regulations regarding Research on Transplantation of Fetal Tissue
(section 498A of the Public Health Services Act). Once developed,
Guidelines for research utilizing human pluripotent stem cells will be
published in the Federal Register for public comment. We hope the
Guidelines and oversight process will be operational within the next
several months.
In conclusion, the promise of human pluripotent stem cell research
is great. And we are committed to addressing important issues
surrounding this research in a deliberative and careful process to
ensure that this research is conducted in an ethical, scientifically
valid, and legal manner.
This concludes my statement. I would be pleased to respond to any
questions you may have.
SUMMARY STATEMENT OF HARRIET RABB
Senator Specter. Before yielding to my distinguished
colleague, we are going to turn to Dr. Rabb. We appreciate your
being here, Dr. Rabb. You served as General Counsel for the
Department of Health and Human Services since May 1993, a very
substantial tenure; former director of clinical education of
Columbia Law School, vice dean of the law faculty in 1992. We
appreciate your joining us and the floor is yours, Dr. Rabb.
Dr. Rabb. Thank you, Senator.
I wanted to spend the time today answering your questions,
if I may. You have my legal opinion. It is available to you for
any questioning you would like to put to us. I felt we should
save the time if you do not mind.
Senator Specter. I understand you are waiving your opening
statement?
Dr. Rabb. If you do not mind.
Senator Specter. Okay. Let me turn at this point to my
distinguished colleague, Senator Harkin.
REMARKS OF SENATOR TOM HARKIN
Senator Harkin. Thank you, Mr. Chairman. Again, thanks for
holding this follow-up hearing. This is an area that captured
my imagination and I think it is one of the most exciting new
realms that we have in science, that just holds so much
promise. That is why I am just delighted that we got your
decision, Dr. Rabb, on this that this research could proceed
apace.
I congratulate you, Dr. Varmus, on setting up the
subcommittee to do this in a careful procedural, open way so
that the public is aware of what we are doing. There is, as you
know, a lot of concern about this. There are ethical
considerations. I do not downplay those at all. As I have said
before on many occasions, I believe that science, especially in
this area, holds so much promise for alleviating human
suffering and debilitating disease that we have to move ahead
aggressively, although, again as I have said, we have to be
careful about the ethical considerations.
I believe that scientists working with ethicists and
lawmakers together, getting good public input, I believe we can
craft--I believe we have, I believe you have, Dr. Varmus. I
think we have a great structure to this.
As I understand it, your guidelines will be out in a couple
of months. That was the first question I had, but you answered
it. In a couple of months you will have these guidelines ready
to go. I assume then that funding could then proceed after
that, I would hope.
Dr. Varmus. We will submit for public comment, Senator. We
will submit for public comment, for 30 days of public comment.
Senator Harkin. I see. I am just wondering. Do you have any
idea right now--I am certain requests must be coming in as we
sit here.
Dr. Varmus. Yes, correct.
Senator Harkin. What sort of backlog do you see out there,
requests coming in for this kind of thing?
Dr. Varmus. Well, I have only indirect information. Recall
that there will be three ways at least to support this
research. Some investigators already have grants and they may
be working in this general area, but want to shift their
emphasis to work with human stem cells. There will be others
who may want to supplement existing grants by a small research
application. Others may want to initiate a new grant. In
addition, we have intramural investigators who may be
interested.
The only way we have to gauge the level of interest at this
point is to ask Doctors Thomson and Gearhart, who have made
these cell lines, how many requests they have received. We know
they have received on the order of 50 to 100 requests from
various investigators for these cells to be worked with. But
the investigators have been informed that at this point NIH
funding is not to be used until we have our procedures in
place. We hope, as I say, that that will be within the next few
months.
Senator Harkin. Well, I appreciate that. Again, I am
grateful for your opening statement in terms of addressing
head-on this issue of encouraging the creation of embryos. I
have heard a lot about that. But as you point out, because of
in vitro fertilization we have a lot of those, plus the fact
that the cells can continue on. So I do not think there is any
problem there at all. I am happy that you addressed that issue.
I just, I guess I have less than a question. I just
encourage you, Dr. Varmus--I do not think you need any
encouragement in this area, but--to really push ahead in it. I
mean, the more reading I do on this--I am not a scientist, but
the more reading I do on this, this holds so much promise, and
it could be in not too long a time for people suffering from
Parkinson's or heart disease, just understanding cancer cell
biology for example, things like that, that we just have not
had that grasp on right now.
I just again hope that you will proceed apace and keeping
in mind the guidelines, the need for public input and openness,
ethical guidelines. All that taken into account, I just hope
you will do everything you can to get the funding out to the
researchers. If we need to do anything here in the
subcommittee--I know Senator Specter has gotten us a whole lot
more money to put into medical research this year. So if you
need any more of that money, we can maybe help out.
I am putting you in a tough spot. But I hope we can get
more. We are working together on that. I think the budget from
the administration is going to be woefully inadequate to meet
the needs that we have out there and I am hopeful that we can
get more.
So any information that you have on the need for this for
the members and our responsibilities here for funding, I
encourage you to let us know.
Dr. Varmus. I will do that, Senator. Thank you.
Senator Harkin. Thank you, Dr. Varmus.
Thank you, Dr. Rabb, for the issuing of the opinion in a
timely manner.
Senator Specter. Dr. Varmus, I begin with a baseline
question. Just what is the extent of the potential, in your
professional opinion, from the stem cells? We have heard very
extraordinary comments about potential on Alzheimer's and
Parkinson's and diabetes, cancer, heart ailments, a whole range
of human medical problems. You are the great expert, Director
of NIH. Is that potential accurately stated?
Dr. Varmus. Well, no doubt, as in all realms of discussion
of this topic, there may be some hyperbole. But much of it is
in my view accurate. We have experience with similar work done
in experimental animals, for example in mice, and we know that
it is possible--we have had a long experience now, nearly 18
years or so, working with the parallel types of cells,
pluripotent stem cells from mice, and we know that those cells
can be induced to differentiate into certain kinds of cells and
those cells can be used to replenish diseased or impaired or
missing cells in mouse models of disease, that the prospects
for repairing damaged hearts and treating congestive heart
failure, for example, for returning missing components of the
blood system, are all very real.
There will be difficulties in treating more complex
diseases, like Alzheimer's. I do not think we should minimize
the challenge there. However, in conditions like diabetes,
where we know one specific type of cell is missing and that
that cell produces a product which circulates in the body, I
think the prospects are great.
As I emphasized last time, there are two major impediments
to using these cells in cell therapy. One is that we have a
still very limited idea of how to take mass cultures of these
cells and direct them efficiently into one cell lineage. But
that information will come as we study the way in which these
cells undergo their changes in program that allows them to
select a cell type to become.
The second problem is one of rejection, histocompatibility,
the classic problem in transplantation. We know that those
problems may be at different levels of severity with different
tissues. We also know that there are ways to manipulate cells
in culture to make them seem less foreign to the host.
Furthermore, there are new methodologies that are in
development that could obviate these problems in other ways,
for example by using our understanding of how cells work and
their apparent plasticity to take one kind of cell from the
patient himself or herself and to remodel that cell to make it
able to replace diseased or absent tissue.
Senator Specter. Dr. Varmus, you say that diabetes--you
single that out as one which is closer to solution. I know from
time to time we press you unduly as to a time frame, maybe not
unduly but we press you, because that is a very strong argument
with our colleagues to get additional funding if you can put it
in a time frame.
Could you give us a ballpark figure as to, say diabetes,
when this research might produce the cure?
Dr. Varmus. Well, as you know, Senator, I tend to be more
conservative than some of my colleagues in making these
predictions. But in the case of type one diabetes, where we
know that replenishment of the beta cell, of the Islets of
Langerhans in the pancreas, does have an important positive
effect in some patients who have been treated, for example,
with pancreatic transplantation.
In that setting, where we know what we need to do, the
major challenge is to figure out a way to make a pluripotent
cell become a beta cell.
Senator Specter. Could you give us a ballpark figure as to
how long?
Dr. Varmus. I would say certainly no sooner than 5 years,
but beyond that I am guessing.
Senator Specter. Let me ask you now about when these
guidelines will be out and when you will be able to start using
funds for research. You have a whole series of preliminaries,
the special guidelines, the oversight group, additional
guidance from the National Bioethics Advisory Board, a comment
period.
When? I approach this question with a sense of urgency
because, and I do not think it is hyperbole to say, that every
day lost human lives are lost. So when?
Dr. Varmus. I share your concern, Senator. But I do think
it is important to have an open and fair process because of the
many concerns that are felt and the feeling that the public and
Congress want to have a chance to express their opinions.
I am currently assembling the group that will work with us
to establish the guidelines. In the case of the existing cell
lines, the cell lines that have been made, reported, we know
all the details about how the tissues were obtained, I think it
is going to be very straightforward. We have a legal opinion,
we have the human embryo research panel guidance, we have
regulations with regard to fetal tissue research that are very
useful.
I believe that in the course of the next couple of months a
clear set of guidelines governing work on those cells can be
generated. I have asked Dr. Shapiro, the chairman of the
National Bioethics Advisory Commission, if they would attempt
to give us some preliminary information about this specific
issue in the course of their larger evaluation of embryo
research in general.
I hope we will have our guidelines out for public comment
within a couple of months. There will be a 30-day public
comment period. At that point we can begin to allow our
investigators to use Federal funds.
Senator Specter. You say a couple of months, to April 1,
and a 30-day comment period, and then that brings us to May 1?
Dr. Varmus. Now, I do not want to prejudge exactly how my
advisory committee will do its work and I do not know exactly
how they will segregate the different domains of research,
because they may find that some things are very cut and dried
and we can move very quickly and that other issues, for example
what to do in response to another set of cell lines----
Senator Specter. Dr. Varmus, we understand you have the
problems and we are pressing on the date so we can figure out
the time parameters and we know how to respond. We do not want
to schedule the next hearing prematurely.
My red light is on. Let me yield to Senator Harkin.
Senator Harkin. I just wanted to just follow up on one
thing. Getting back to the time frame on how things work out,
when can we expect results? For 23 years I have served on
committees in the House and the Senate that deal with the
National Science Foundation and now NIH. It has been my
experience through those years that when you are dealing in
basic research--and this is sort of basic and applied; there is
kind of a fuzzy boundary here on this one--that sometimes you
put a time frame, but sometimes serendipitous things happen in
science. But they will not happen unless you start moving down
the pathway.
So you can talk about 5 years or something, but you never
know. Maybe in a year from now or something some scientist
working someplace, something happens and you come up with
something. That is why I think it is so important to move ahead
aggressively in this because, like I say, you never know.
I just wanted to make that point, that a lot of times in
science things just happen like that.
Dr. Varmus. Well, I appreciate being castigated for my
conservative position. I am usually thought of as too
impetuous, so I appreciate your comments, Senator.
Senator Harkin. Thank you, Dr. Varmus.
Senator Specter. We are going to ask you to stay with us,
Dr. Varmus and Dr. Rabb.
I had announced at the outset that there are caucuses at 10
o'clock, at least a Republican caucus at 10 o'clock. Yours too?
Senator Harkin. Yes.
Senator Specter. Also with Senator Harkin, the caucus of
the Democratic Senators.
We are going to move now to panel two. We are going to
conclude the hearing by 10 a.m. We have not gotten Dr. Rabb
into the definitions, but we do have your very learned opinion,
and if you would stand by for some dialog and questions and
answers.
SUMMARY STATEMENT OF DR. ERIC MESLIN
We would like to call now Dr. Eric Meslin and Mr. Richard
Doerflinger. Dr. Meslin is the executive director of the
National Bioethics Advisory Commission and received his
bachelor of arts degree from York University, Toronto, M.A. and
Ph.D., in bioethics and philosophy at the Kennedy Institute of
Ethics at Georgetown University, and author of some 35 academic
articles and book chapters and peer reviewed literature.
We welcome you here, Dr. Meslin, and look forward to your
testimony. As I say, the clocks are set at 5 minutes to leave
maximum time for questions and answers.
Dr. Meslin. Thank you very much, Senator, and good morning.
Good morning to you, Senator Harkin.
I was privileged to appear before your subcommittee on
December 2nd to offer some brief remarks on the subject of
human stem cells research. At that hearing, Mr. Chairman, I
informed the subcommittee that in his November 20 letter to
President Clinton the NBAC chair, Dr. Harold Shapiro, addressed
only the immediate issue of the purported experiment involving
the fusion of a cow egg and a human cell and that NBAC would
devote a majority of its next meeting to the broader issues
raised by President Clinton in his November 14 letter to the
commission, namely that NBAC undertake a thorough review of the
issues associated with human stem cells research, balancing all
ethical and medical considerations.
Just this past week NBAC met for the 26 time since being
established by President Clinton. The commission devoted the
entire day, January 19, to the topic of human stem cells
research, hearing testimony from a number of leading
scientists, bioethicists, theologians, legal scholars, and the
public. The purpose of this meeting was to provide NBAC with a
deeper understanding of the ethical, scientific, legal, medical
and policy issues that are raised by this important area of
research.
While the commission did not reach any immediate
conclusions at that meeting, nor were they expecting to, it may
be helpful to describe the range of issues that were discussed
and then to describe our timetable for completing this report
since I understand how important it is to you.
In our view, an understanding of the legal status regarding
the use of Federal funds to conduct human stem cells research
provides an important context for fully understanding the
ethical issues. At our recent meeting we were very interested
to learn of the Office of the General Counsel's--that the
Office of the General Counsel has rendered an opinion regarding
whether Federal funds may be used for research conducted with
human pluripotent stem cells.
We are planning to carefully review this opinion as quickly
as possible since it provides one of the many pieces of
valuable information we will rely on to fully address the
bioethical issues involved in this area of research.
In testimony before us, Mr. Chairman, we heard some
compelling arguments in favor of permitting research on human
stem cells, based principally on the very promising results of
previous animal studies. Several beneficial uses of these cells
are anticipated and you have heard those from Dr. Varmus
already.
It was also clear that a number of important scientific
issues must be resolved before any actual therapies can be
developed or tested in human beings. These include how to
specifically direct stem cells to differentiate into specific
types such as cardiac, muscle, or nerve cells, how to overcome
the problem of immune rejection of such transplanted tissue,
and other items.
We also heard some words of caution and objection to all
forms of research involving the human embryo, the human fetus,
or the cells or tissues derived from these sources
respectively. Some of these concerns related to the potential
for complicity in the use of cells derived from spare or excess
embryos. Other concerns related to more fundamental objections
to the use of human fetal or embryonic material irrespective of
their source or potential for benefit.
Mr. Chairman, the focus of the NBAC effort is to develop
sound public policy proposals based on appropriate scientific,
medical, ethical, and legal considerations. In this respect, we
hope to use the experiences from a number of former
deliberative bodies. As with all NBAC reports, our
deliberations, agendas, transcripts, and working papers will be
available on our website.
In reviewing a working draft outline of the report prepared
by my staff, the commission at its meeting expressed a strong
interest in developing a report that was focused on a set of
answerable and timely questions, but that would also be able to
anticipate certain issues. The specific issues our report will
address are now being developed for NBAC's consideration, but
they will likely focus on some of the following points:
Is there an ethically relevant distinction between research
using human stem cells derived from fetal material versus
research using human stem cells obtained from existing embryos?
How should considerations about the source of human stem
cells be incorporated into the analysis?
Is it ethically acceptable to produce new human embryos as
a source of stem cells for research?
Finally, what is the appropriate role of the Federal
Government in overseeing research of this kind?
NBAC would hope that one of the results of its
deliberations on this topic would be to identify the bioethical
issues that ought to be considered when supporting such
research or developing guidelines for reviewing research in
this area.
Now let me say a word about our timetable. As you know, Mr.
Chairman, NBAC is subject to the Federal Advisory Committee
Act, which you helped cosponsor. This requires that we conduct
all of our business in public and come to conclusions in
public. This means that any commission decisions, be they
interim conclusions or final recommendations, can only occur at
NBAC meetings.
We are committed to completing this report by June 1999 or
thereabouts, so NBAC and its staff have mobilized to work as
expeditiously as possible. Additional meetings have now been
scheduled. In fact, we will be meeting next Tuesday and
Wednesday, February 2 and 3, in Princeton, NJ, and monthly
thereafter.
pREPARED STATEMENT
I should note, however, that the commission is also
preparing for the possibility of being able to provide to the
President conclusions on certain issues within the next few
months. We are keenly aware of NIH's interest in moving forward
with human stem cell research and Dr. Shapiro has already
indicated to Dr. Varmus separately that if NBACreaches any
interim conclusions they will be shared with NIH and others
after they are transmitted to the President. Naturally, Mr.
Chairman, we will be pleased to provide you and your staff with
an update on our work as it proceeds.
I would be pleased to answer any questions you may have.
Senator Specter. Thank you very much, Dr. Meslin.
[The statement follows:]
Prepared Statement of Eric M. Meslin, Ph.D.
Good morning Mr. Chairman and members of the subcommittee, my name
is Eric Meslin, I am Executive Director of the National Bioethics
Advisory Commission.
I was privileged to appear before your subcommittee on December 2,
1998 to offer some brief remarks on the subject of human stem cell
research. At that hearing, Mr. Chairman, I informed the subcommittee
that in his November 20th letter to President Clinton, the NBAC Chair,
Dr. Harold Shapiro, addressed only the immediate issue of the purported
experiment involving the fusion of a cow egg and a human cell, and that
NBAC would devote a majority of its next meeting to the broader issue
raised by President Clinton in his November 14, 1998 letter to the
Commission, namely that NBAC ``undertake a thorough review of the
issues associated with . . . human stem cell research, balancing all
ethical and medical considerations.''
Just this past week NBAC met for the 26th time since being
established by President Clinton. The Commission devoted the entire
day, January 19, to the topic of human stem cell research, hearing
testimony from a number of leading scientists, bioethicists,
theologians, legal scholars, and the public. The purpose of this
meeting was to provide NBAC with a deeper understanding of the ethical,
scientific, legal, medical, and policy issues that are raised by this
important area of research. While the Commission did not reach any
immediate conclusions--nor were they expecting to--it may be helpful to
describe the range of issues that were discussed, and then to describe
our timetable for completing this report.
In our view an understanding of the legal status regarding the use
of federal funds to conduct human stem cell research provides an
important context for fully understanding the ethical issues. At our
recent meeting, NBAC was interested to learn that the Office of the
General Counsel of the Department of Health and Human Services has
rendered an opinion regarding whether federal funds may be used for
research conducted with human pluripotent stem cells derived from
embryos created by in vitro fertilization or from primordial germ cells
isolated from the tissue of non-living fetuses. We are planning to
carefully review this opinion since it provides one of the many pieces
of valuable information we will rely on to fully address the bioethical
issues involved in this area of research.
In testimony before us, we heard some compelling arguments in favor
of permitting research on human stem cells, based principally on the
very promising results of previous animal studies. Several beneficial
uses of these cells are anticipated, including: understanding basic and
developmental biology; the development of transplantation therapies for
the treatment of diseases such as Parkinson's disease and diabetes; the
discovery of new drugs; and the study of infertility and birth defects.
It was also clear that a number of important scientific issues must
be resolved before any actual therapies can be developed or tested in
human beings. These issues include: how to specifically direct stem
cells to differentiate into specific types, such as cardiac muscle or
nerve cells; how to overcome the problem of immune rejection of such
transplanted tissue; and how stem cells derived from fetal primordial
germ cells (KG cells) differ from stem cells derived from embryonic
sources (ES cells), and whether these differences have any functional
importance.
We also heard some words of caution, and objection to all forms of
research involving the human embryo, the human fetus, or the cells or
tissues derived from these sources respectively. Some of these concerns
related to the potential for complicity in the use of cells derived
from spare or ``excess'' embryos. Other concerns related to more
fundamental objections to the use of human fetal or embryonic material,
irrespective of their source or potential for benefit.
The focus of the NBAC effort is to develop sound public policy
proposals based on appropriate scientific, medical, ethical, and legal
considerations. In this respect, we hope to use the experiences from
former deliberative bodies including the National Commission for the
Protection of Human Subjects of Biomedical and Behavioral Research, the
DHHS Ethics Advisory Board, the Fetal Tissue Transplantation Research
Panel, and the NIH Director's Embryo Research Panel. We will also be
contacting a variety of public, professional, scientific and other
organizations seeking their views on these issues. And, as with all
NBAC reports, our deliberations, agendas, transcripts and working
papers will be available on our website at www.bioethics.gov.
In reviewing a working draft outline of the report prepared by my
staff, the Commission expressed an interest in developing a report that
was focused on a set of answerable and timely questions, but that would
also be able to anticipate certain issues. The specific issues our
report will address are now being developed for NBAC's consideration,
but they will likely focus on some of the following points:
--Is there an ethically relevant distinction between research using
human stem cells derived from fetal material vs. research using
human stem cells obtained from existing embryos?
--How should considerations about the source of human stem cells be
incorporated into the analysis?
--Is it ethically acceptable to produce new human embryos as a source
of stem cells for research?
--What is the appropriate role of the federal government in
overseeing research of this kind?
NBAC would hope that one of the results of its deliberations on
this topic would be to identify the bioethical issues that ought to be
considered when supporting such research, or developing guidelines for
reviewing research in this area.
Now let me say a word about our timetable. As you know, Mr.
Chairman, NBAC is subject to Federal Advisory Committee Act (1972)
which requires that we conduct all of our business in public, and come
to conclusions in public. This means that any Commission decisions--be
they interim conclusions or final recommendations--can only occur at
NBAC meetings. We are committed to completing this report by June 1999,
or thereabouts, so NBAC and it staff have mobilized to work as
expeditiously as possible. Additional meetings have been scheduled--we
will be meeting next week, February 2-3, in Princeton, New Jersey, and
monthly thereafter. I should note, however, that the Commission is
preparing for the possibility of being able to provide to the President
conclusions on certain issues within the next few months. We are aware
of NIH's interest in moving forward with human stem cell research, and
Dr. Shapiro has indicated to Dr. Varmus that if NBAC reaches any
interim conclusions they will be shared with NIH and others after they
are transmitted to the President. Naturally, Mr. Chairman, we will be
pleased to provide you and your staff with an update on our work as it
proceeds.
I would now be pleased to answer any questions you may have.
SUMMARY STATEMENT OF RICHARD M. DOERFLINGER
Senator Specter. We now turn to Mr. Richard Doerflinger,
associate director for policy development at the Secretariat
for Pro-Life Activities, National Conference of Catholic
Bishops. Welcome, Mr. Doerflinger. We appreciate your coming
back, and the floor is yours.
Mr. Doerflinger. Thank you, Mr. Chairman.
I want to begin by noting that a point I made in my
December 2d testimony on this same matter has received new
support from recent events. Since then two startling scientific
breakthroughs have made it even more clear that destructive
embryo research is unnecessary. Advances in the use of
telomerase to promote regeneration of human tissues and the new
discovery that adult stem cells may be far more versatile than
was once thought offer the promise that embryonic stem cells
may simply be irrelevant to future medical progress.
At the December 2d hearing Dr. Varmus noted that, while
adult stem cells can be obtained from bone marrow, cord blood,
and so on, they are of limited use compared to embryonic cells
because they cannot form other kinds of tissues such as nerve
and skin. The most recent issue of ``Science'' suggests that
this judgment may well have been premature, that in fact stem
cells at a later stage of development can cross over these
boundaries and be adapted to perform the use of any different
kind of cell.
This subcommittee has now held three hearings on one narrow
avenue of research, precisely the avenue that raises the most
obvious moral and legal problems, so far to the exclusion of
all other alternatives, even when those avenues may be more
promising. The use of adult stem cells, for example, is said to
promise the complete avoidance of the tissue rejection problems
that Dr. Varmus has noted still need to be solved using
embryonic cells.
I would urge the subcommittee to expand its vision, to
explore the alternatives that will advance medical progress and
the wellbeing of patients without demeaning human dignity.
Turning now to the legal memorandum prepared by the
Department of Health and Human Services, in its effort to find
that Federal funding of embryonic stem cell research is
consistent with Congressional intent HHS has overlooked some
rather obvious facts and created its own arbitrary definition
of a human embryo and, even more striking, of a human being
that have no basis in biology or Federal law.
First looking at current laws on embryo and live fetal
research. HHS now claims that current law on embryo research
does not pose a barrier to embryonic stem cells research
because the law protects only the embryo, which is an organism,
and a stem cell, obtained by destroying embryos, is not an
organism. HHS even cites me on this point.
But they ignore other parts of my testimony and, more
importantly, ignore two important aspects of current law.
First, as I noted on December 2nd, there is a factual
uncertainty as to exactly what happens to the stem cells that
Dr. Gearhart of Johns Hopkins University has cultured from
fetal germ cells after abortions.
After being cultured, some of these stem cells have a
tendency to come back together and show signs of developing as
an early embryo. Whether the formation of early embryos does
take place in such a culture and whether that can be prevented
by adapting the research is a scientific question, cannot be
answered by attorneys. A stem cell is not an organism, but the
possibility must be explored that groups of stem cells may
recongregate in some of this research to form an entity that
is, however briefly, a living organism, in which case this
research could not be funded.
HHS seeks to avoid this factual inquiry by inventing its
own narrower definition of an embryo, which is not found in
Federal law. Such an entity, HHS argues, cannot be an embryo
because, even if implanted in a womb, it could not become a
``human being.'' Oddly enough, the key phrase ``human being''
is not defined, but from the context it seems to refer to a
live-born infant. In Dr. Varmus' testimony, I noted he said a
human being is a mature organism. So I am beginning to wonder
whether my 6 year old son qualifies.
Embryology textbooks, however, tell us that in biological
terms to embryo is a human being, and the current Federal law
treats the embryo as a human subject. Since 1975, it has
treated the human embryo as a human subject, to be protected
from harmful research from implantation onwards, and the
current embryo research rider is intended to extend that
protection back before implantation, to the embryo in the
laboratory.
Second, HHS seems to misread the embryo research rider
itself rather obviously by saying that this research can be
funded as long as Federal funds are not used for the actual
destruction of the embryo. They can be used for all subsequent
work with the stem cells so derived.
But Congress knows how to write a rider that says you
simply cannot use Federal funds for that act. It wrote the
rider that way when it dealt with creation of human embryos. It
said Federal funds cannot be used for creation of embryos. Then
it said Federal funds cannot be used for research in which a
human embryo or embryos are destroyed or discarded or subjected
to risk of harm. Obviously, that means if this is an integral
part of the research protocol, even if it is not directly
funded by Federal funds, the destructive harvesting of embryos
is not supposed to be something that is part of a research
project funded by Congress.
Finally, HHS ignores the possibility that the fetal tissue
transplantation guidelines now in law apply also to the
destruction of embryos in the laboratory. The statute clearly
says that it covers tissue derived from embryos or fetuses, and
it only allows the use of that tissue if the subject was dead
before the tissue was obtained and only if the destruction was
not altered in its method or timing by the needs of the
research.
Well, in all of the research in which embryos are destroyed
here, the destructive process is geared exactly toward
obtaining usable research tissue and toward nothing else. When
embryos are discarded in an IVF clinic, they do not use
immunosurgery to dissect the inner cell mass from the
trocoblast. They simply throw them away. Everything about the
harvesting procedure is altered to obtain usable tissue, and it
is the harvesting procedure that is itself the abortion or the
destruction.
PREPARED STATEMENT
In conclusion, if Congress wishes to insulate its funding
of medical advances from the destruction of innocent life,
there is a very simple way to do just that. It should devote
its funds to stem cells techniques and other promising avenues
of research that in no way depend upon such destruction. In
that way our government will truly serve all the people by
showing that it will not promote the destruction of one human
being to serve another or the development of treatments that
millions of Americans would find it morally abhorrent to use.
Thank you.
[The statement follows:]
Prepared Statement of Richard M. Doerflinger
I am Richard M. Doerflinger, Associate Director for Policy
Development at the Secretariat for Pro-Life Activities, National
Conference of Catholic Bishops. I am grateful for the opportunity to
present the Catholic bishops' concerns about efforts to justify the use
of cells from deliberately destroyed human embryos in federally funded
research.
I must begin by noting that a point I raised in my December 2
testimony before this subcommittee has received new support from recent
events. I said then that the goals some wish to serve by killing human
embryos for their stem cells can be achieved in other, morally
acceptable ways. Even at that time, one of the advances cited by
supporters as a future benefit of embryo research--the ability to grow
new blood vessels in the heart--was already in clinical use in human
patients with no need for embryonic cells.\1\ In the six weeks that
have elapsed since then, however, two startling scientific
breakthroughs have made it even more clear that destructive embryo
research is unnecessary. The use of telomerase to promote regeneration
of human tissues,\2\ and the new discovery that adult stem cells may be
far more versatile than was once thought,\3\ offer the promise that
embryonic stem cells may simply be irrelevant to future medical
progress.
---------------------------------------------------------------------------
\1\ See: ``Technique grows new heart vessels,'' MSNBC Health, 11/9/
98; ``Injected Genes Help Grow Heart Bypasses,'' Washington Post, 11/
10/98, A3.
\2\ C, Morales et al., ``Absence of cancer-associated changes in
human fibroblasts immortalized with telomerase,'' 21 Nature Genetics
115-8 (January 1999); see comments in Ruth Larson, ``Scientists find
new life for old cells,'' Washington Times, 12/29/98, Al.
\3\ C. Bjornson et al., ``Turning Brain into Blood: A Hematopoietic
Fate Adopted by Adult Neural Stem Cells in Vivo,'' 283 Science 534-7
(22 January 1999). See comments in: Evelyn Strauss, ``Brain Stem Cells
Show Their Potential,'' 283 Science 471 (22 January 1999); Paul Recer,
``Patient's Cells May Grow New Organs,'' Associated Press, 1/21/99
(``If such a technique also worked in humans, embryos may not be needed
for such research''); Nicholas Wade, ``Cell Experiment Offers Hope for
Tissue Repair,'' New York Times, 1/22/99, A21 (the technique avoids the
``ethical considerations'' arising from embryonic cells, as well as the
``immune rejection problems'' they can pose); Lee Bowman, `` `Master
cells' offer repair kits,'' Washington Times, 1/22/99, A9 (``it could
mean that stem cells don't have to come from embryos to generate
specialized cells'').
---------------------------------------------------------------------------
At the December 2 hearing, responding to our proposed list of
promising alternatives to embryonic stem cell research, National
Institutes of Health director Harold Varmus said that while adult stem
cells can be obtained from bone marrow, cord blood and so on, they are
of limited use because they cannot form other kinds of tissue such as
nerve and skin. The most recent issue of Science suggests that this
judgment was premature.
This subcommittee has now held three hearings on one narrow avenue
of research--precisely the avenue that creates the most obvious moral
and legal problems--to the exclusion of all other alternatives, even
when those avenues may be more promising. I urge the subcommittee to
expand its vision, to explore the alternatives that will advance
medical progress and the well-being of patients without demeaning human
dignity.
I would like to turn now to the legal memorandum prepared by the
General Counsel of the Department of Health and Human Services (``HHS
memo''). In its effort to find that federal funding of embryonic stem
cell research is consistent with congressional intent, HHS has
overlooked some obvious facts, and created its own arbitrary definition
of a human embryo that has no basis in biology or federal law.
Specifically, the HHS memo ignores key aspects of the current
appropriations rider on embryo research (Section 511 of the Labor/HHS
appropriations bill for fiscal year 1999), statutory and regulatory
provisions on live fetal research (42 U.S.C. Sec. 289g; 45 CFR
Sec. 46.201 ff.), and statutory law on fetal tissue transplantation
research (42 U.S.C. Sec. 289g-1).
Laws on Embryo Research and Live Fetal Research
HHS claims that current law on embryo research does not cover
embryonic stem cell research, because the law protects only the embryo,
which is an ``organism''--and a stem cell obtained by destroying an
embryo is not an ``organism.'' HHS even cites my December 2 testimony
for the proposition that a stem cell is not an organism--but the
authors overlook other parts of my testimony. More importantly, they
ignore two important aspects of current law.
(1) Distorted definitions of ``embryo'' and ``human being.''--
First, as I noted on December 2, there is some uncertainty about the
status of the cells that Dr. Gearhart of Johns Hopkins University has
cultured from fetal germ cells after abortions. After being cultured,
some of these stem cells may have a tendency to come back together and
develop as an early embryo.\4\ Whether the formation of early embryos
takes place in such a stem cell culture, and whether it can be
prevented, is a scientific question. It demands a scientific answer,
before federal funds are spent on the research--because these funds by
law cannot be used, even inadvertently, to create embryos which briefly
develop and then die in culture. In other words, a stem cell is not an
organism--but the possibility must be explored that groups of stem
cells may recongregate to form an entity that is, however briefly, a
living organism.
---------------------------------------------------------------------------
\4\ In Dr. Gearhart's experiment, ``embryoid bodies'' had formed
``complex structures'' in culture ``closely resembling an embryo during
early development''; these structures ``appear to recapitulate the
normal developmental processes of early embryonic stages and promote
the cell-cell interaction required for cell differentiation.'' M.
Shamblott et al., ``Derivation of pluripotent stem cells from cultured
human primordial germ cells,'' 95 Proceedings of the National Academy
of Sciences 13726-13731 (November 1998) at 13726, 13729. These remarks
were cited in my December 2 testimony, at note 13.
---------------------------------------------------------------------------
HHS seeks to avoid this factual inquiry by inventing its own
definition of an ``embryo''--a definition with no basis in science or
law. Such an entity, HHS argues, could not be an embryo because, even
if implanted in a womb, it could not become a ``human being.'' The
phrase ``human being'' is left undefined, but from the context it seems
to refer solely to a liveborn infant.
Is ``human being'' intended here as a scientific term? Clearly not,
since embryology textbooks tell us that in biological terms, the embryo
is a human being.\5\ Even the NIH's Human Embryo Research Panel, whose
recommendations for federal funding of embryo experiments were found
morally unacceptable by President Clinton and Congress, called the
early embryo ``a developing form of human life.''\6\
---------------------------------------------------------------------------
\5\ See: Keith Moore and T.V.N. Persaud, The Developing Human:
Clinically Oriented Embryology (W.B. Saunders 1998)(6th edition), p. 2
(``A zygote is the beginning of a new human being''); T.W. Sadler,
Langman's Medical Embryology (Williams and Wilkins 1995)(7th edition),
p. 3 (``The development of a human being begins with fertilization'');
William J. Larsen, Human Embryology (Churchill Livingstone 1997)(2nd
edition), p. 1 (``the male and female sex cells or gametes . . . will
unite at fertilization to initiate the embryonic development of a new
individual'').
\6\ National Institutes of Health, Report of the Human Embryo
Research Panel (November 1994), 2.
---------------------------------------------------------------------------
Is it, then, a legal term? No, since the phrase ``human being'' is
not used in this part of federal law. Instead, since 1975, federal
regulations have defined the human embryo, from implantation in the
womb onward, as a ``human subject'' to be protected from harmful
experiments, regardless of whether it is expected to survive to live
birth.\7\ Current law on fetal research explicitly demands that a fetus
to be aborted have the same protection as the fetus intended for live
birth (42 U.S.C. Sec. 289g(b)).
---------------------------------------------------------------------------
\7\ ``Human subject,'' in turn, is defined as a ``living
individual'' subjected to research (45 CFR Sec. 46.102(f)); Subpart B
of Part 46 provides special protections for fetuses as human subjects.
``Fetus'' includes ``the product of conception from the time of
implantation'' (45 CFR Sec. 46.203(c)). Through appropriations riders,
Congress since 1995 has extended this same protection to all human
embryos not previously protected as human subjects.
---------------------------------------------------------------------------
Moreover, federal law on fetal tissue refers to the use of tissue
from embryos and fetuses after a ``spontaneous or induced abortion'' or
a stillbirth (42 U.S.C. Sec. 289g-1(g)). The HHS memo's definition
would make this provision self-contradictory: A fetus that has
spontaneously aborted did not have the ability to become what HHS calls
a ``human being,'' and so (by the HHS approach) cannot be called an
``embryo'' or ``fetus'' at all.
The current appropriations rider on embryo research is crystal
clear. To determine whether an entity is an ``embryo'' we need only
determine whether it is a living organism here and now (Section 511
(b)). Section 511 says nothing about restricting this term to embryos
that can be shown to have the ``potential to develop'' to live birth.
In any case, testing an embryo's ability to become a born ``human
being'' is clearly impossible once one has used such a definition to
justify destroying that embryo in the laboratory.
HHS's strange and arbitrary digression on the phrase ``human
being'' does not serve the goal of understanding federal law, but the
very different goal of justifying harmful experiments. Some researchers
have actually offered to engineer lethal defects in advance into the
embryos they create and destroy with federal funds--so that one could
argue that these embryos would never become ``human beings'' and so are
exempt from current law.\8\
---------------------------------------------------------------------------
\8\ ``The goal is to create a developing mass of mostly human cells
that's crippled enough to prevent its development into a person, yet
healthy enough during the first week of existence to produce the
crucial `stem cells' that scientists want to collect.'' Rick Weiss,
``Can Scientists Bypass Stem Cells' Moral Minefield?'', Washington
Post, 12/14/98, A3.
---------------------------------------------------------------------------
Moreover, at this subcommittee's January 12 hearing, the theory was
offered that unwanted or frozen embryos from fertility clinics can
ethically be used for destructive research, because in any case they
would not have produced a ``human life.'' This did not refer to any
defect in the embryos, but simply to the fact that parents have chosen
not to let them survive. Such an approach makes a mockery of the
current law, which was intended to protect such ``spare'' embryos from
being harmed by the federal government regardless of what harm may be
intended by others in the private sector. HHS would reduce current laws
against harmful experiments on prenatal human life to this: Whenever
someone wants to discard or destroy human embryos or fetuses instead of
allowing them to survive, that very choice excludes them from the scope
of the law's protection. Prenatal human beings would be protected by
federal regulations only when they are in no need of such protection.
(2) Misreading the embryo research rider.--HHS's second error
arises from a misreading of the appropriations rider. The HHS memo
narrows its focus to the question whether a stem cell is an embryo, as
though what had to be done to an embryo to obtain the stem cell is
irrelevant. The implication here is that, so long as federal funds are
not used for the specific act of destroying a human embryo, such funds
may be used for all subsequent research on the resulting cells and
tissues. But this contradicts the plain words of the appropriations
rider. It does indeed ban the use of federal funds for ``the creation
of a human embryo or embryos for research purposes'' (apparently
leaving open the possibility that federal funds might be used to do
life-saving or therapeutic research on an embryo that was already
created without federal funds) (Sec. 511(a)(1)). But the provision goes
on to say that federal funds may not be used for ``research in which a
human embryo or embryos are destroyed, discarded, or knowingly
subjected to risk of injury or death . . .'' (Sec. 511(a)(2)). Clearly,
if Congress wished to say merely that federal funds may not be used for
destroying and discarding embryos, it knew how to say that; instead it
used this broader phrase that is not used in the parallel clause on
creating embryos.
How do we interpret the phrase ``research in which?'' A reasonable
reading is that federal funds may not be used for research for the
purpose of which human embryos were harmed or destroyed. Or, that
federal funds may not be used for research that cannot be done without
the prior harming or destroying of human embryos; or that such funds
may not be used for research if such destruction is part of the
researcher's protocol.\9\ Only one interpretation is impossible,
because Congress went out of its way to exclude it--the interpretation
that this rider bans only the direct use of federal funds for the
destructive harvesting of cells itself. That impossible interpretation
is the one that HHS seems to accept.
---------------------------------------------------------------------------
\9\ By these interpretations, both Dr. West's experiment (relying
on the destructive harvesting of cells from embryos created by somatic
cell nuclear transfer [cloning]) and Dr. Thomson's (relying on
destructive harvesting of cells from ``spare'' embryos from fertility
clinics) are barred from receiving federal funds. A mere bookkeeping
distinction between funds used to destroy the embryo and funds used to
work with the resultant cells is not sufficient.
---------------------------------------------------------------------------
Current Law on Fetal Tissue Research
HHS notes that ``some'' of the proposed research may implicate
current law on fetal tissue research, citing Dr. Gearhart's experiment
using fetal tissue from abortions as an example. Hinted at, but not
explored by HHS, is the possibility that other proposed experiments--
those relying on the destruction of human embryos in the laboratory--
may also be governed by these provisions.
In fact, the law explicitly covers tissue obtained from a ``human
embryo or fetus'' (42 USC Sec. 289g-1(g)). And since ``fetus'' is
defined in this area of law to include any product of conception from
implantation in the womb onward, the separate word ``embryo'' here can
only refer to the unimplanted embryo--the embryo in the laboratory. In
that case, the word ``abortion'' in this provision should be construed
to include the direct destruction of an embryo in the laboratory--for
otherwise the word ``embryo'' in the law would have no application
whatever.
If this interpretation is correct--if the use of tissue harvested
from embryos in the laboratory is governed by current guidelines on
fetal tissue research--then such tissue cannot be used for federally
funded tissue transplantation research. For such use would violate the
guideline demanding that the ``timing, method or procedures'' for the
abortion must not be altered ``solely for the purposes of obtaining the
tissue'' for a federal research project (42 U.S.C. Sec. 289g-
1(b)(2)(A)(ii)). Clearly, the destructive method used to obtain stem
cells from these embryos--the use of immunosurgery to extract the inner
cells--is never used to discard ``spare'' embryos in fertility clinics,
but is employed solely to obtain usable tissue for research.\10\
---------------------------------------------------------------------------
\10\ Among the inadequacies in current compromise provisions on
fetal tissue is the inclusion of the word ``solely'' here. It does not
adversely affect the issue at hand, but could be used to justify
federal collaboration with practitioners of the grotesque partial-birth
abortion technique to obtain brain tissue for research purposes. Since
the technique already involves killing a partly born child by
suctioning out his or her brain tissue before completing delivery, it
need not be altered ``solely'' to obtain usable tissue. Congress has
repeatedly voted to make partial-birth abortion a federal crime, so
presumably did not intend to state a preference for this procedure as a
source of material for federally funded research.
---------------------------------------------------------------------------
To be sure, this guideline's meaning is somewhat unclear, because
it refers to influencing the timing and method for ``terminat[ing] the
pregnancy.'' Ordinarily such a phrase would not be used to describe the
destruction of an embryo in the laboratory. However, one must recall
what Congress was trying to prevent by enacting this provision. Members
had learned of a procedure in Sweden, for example, in which the unborn
child intended for abortion was killed by suctioning out its brain
tissue for research on Parkinson's disease, and only afterward expelled
from the womb.\11\ Here, the harvesting procedure was itself the
``abortion,'' in the sense that it caused the death of the unborn
child. Such abuses were to be prevented in federally funded research in
the United States by this ban on altering the timing and method of
abortion. The destructive harvesting of stem cells to cause an embryo's
death, before it is discarded by a researcher or fertility clinic,
provides a very close analogy to such abuses which Congress sought to
prevent.
---------------------------------------------------------------------------
\11\ O. Lindvall et al., ``Human Fetal Dopamine Neurons Grafted
Into the Striatum in Two Patients With Severe Parkinson's Disease,'' 46
Archives of Neurology 615, 616 (June 1989).
---------------------------------------------------------------------------
Indeed, this law clearly was intended to permit only the use of
tissue that had been ``obtained from a dead embryo or fetus''--one that
died of other causes before tissue was harvested (42 USC Sec. 289g-
1(g)). Even in such cases, the guidelines were intended to prevent any
influence by researchers upon the decision to abort. The idea of using
tissue harvested in a way that itself destroys the embryo or fetus was
not proposed by any member of Congress.\12\
---------------------------------------------------------------------------
\12\ The provision's chief sponsor said: ``This issue . . . is not
about abortion . . . This is about what happens after an abortion takes
place: Will the tissue be discarded or will the tissue be used for
research . . . ?'' (Rep. Waxman, Cong Record, 3/10/93, H1131; emphasis
added). Harvesting of embryonic stem cells is not done after the embryo
is killed; it is precisely what kills the embryo.
---------------------------------------------------------------------------
Conclusion
In short, there is no clear support in any relevant provision of
federal law and regulations for the HHS opinion on using stem cells
from deliberately destroyed human embryos--in fact, one can find much
that is contrary to that opinion. The HHS memo ignores the explicit
language of the current appropriations rider on embryo research;
creates its own arbitrary and unsupported approach to defining a
``human being''; and overlooks the possible relevance of current law on
fetal tissue to the destructive harvesting of cells from human embryos.
In a broader view, it seems clear that all these laws and
regulations enacted over the past 24 years were intended to ensure that
the federal government never encourages the destruction of prenatal
life as a source for research material. The HHS opinion would
eviscerate this longstanding policy. Researchers who destroy human
embryos would receive direct federal rewards for such destruction,
since their lethal harvesting of tissue would make them uniquely
eligible for federal grants for research on embryonic stem cells. The
fact that such economic incentives would reward such destruction after
the fact, instead of being bestowed in advance to pay directly for such
destructive harvesting, is of no great significance.
If Congress wishes to insulate its funding of medical advances from
the destruction of innocent life, there is a simple way to do just
that. It should devote its funds to stem cell techniques and other
promising avenues of research that in no way depend upon such killing.
In that way our government will truly serve all the people, by showing
that it will not promote the killing of one human being to serve
another, or the development of treatments that millions of Americans
would find it morally abhorrent to use.
(Attachments: Reports of recent developments in alternatives to
embryonic stem cell research)
______
[From the Washington Post, January 21, 1999]
Patient's Cells May Grow New Organs
(By Paul Recer)
A patient's own cells might someday be used to grow new organs--a
development suggested by a breakthrough lab experiment that found the
building-block cells that normally make brain tissue in adult mice
could be changed into blood-making cells.
These so-called stem cells, the foundation source of the body's
tissue, have been identified as a way to make new skin, liver and other
organs. But in previous research the cells were harvested from embryos,
a technique that set off a storm of ethical objections.
The new research suggests that even mature stem cells, such as from
the adult brain or bone marrow, can change into the progenitor cells
for other types of tissue. If such a technique also worked in humans,
embryos may not be needed for such research.
``You may be able to use your own stem cells to make new tissue,''
said Angelo L. Vescovi, head of a team that conducted the mouse
experiment. ``As a concept, I don't see any problem in adult stem cells
being used to make new skin, for instance.''
The research shows ``there are alternative strategies'' to
harvesting stem cells from embryos, said Dr. Ronald McKay, a National
Institutes of Health researcher and a pioneer in stem cell studies.
Stem cells are the mortar and brick for growing all of the body's
tissues. In a developing embryo, they produce the cells that become the
body parts. After birth, some stem cells are specially programmed to
replenish some tissues such as blood and skin.
Researchers earlier had isolated stem cells from human embryos or
from aborted fetuses, and grew the cells in a lab. When treated with
specific proteins, the cells began to grow different types of tissue
cells.
That work set off a frenzy of studies. But the research was
shadowed by ethical concerns because it was thought that only stem
cells from embryos retained the ability to grow into a variety of
organs. Many groups objected to medical experimentation with human
embryos and Congress forbade federal money for such studies.
It also led President Clinton to order his National Bioethics
Advisory Commission to consider the moral issues of such research.
Earlier this week, NIH director Harold Varmus said his agency concluded
that research with lab-grown stem cells didn't violate the
congressional mandate, even though the cells originated from human
embryos.
But Vescovi's work with mice suggests that any stem cell even from
an adult can be reeducated to make any type of tissue.
Vescovi, of the National Neurological Institute in Milan, Italy, is
senior author of a study to be published Friday in the journal Science.
``This shows that the mature stem cells are a lot more plastic than
we imagined . . . they can produce a lot more cell types than was
previously thought,'' said Christopher Bjornson, a researcher at the
University of Washington, Seattle, on the team.
``A bone marrow stem cell might be able to produce tissue for the
brain . . . and the skin stem cell might be able to make other cell
types,'' Bjornson said.
In the experiment, researchers used mouse neural stem cells, which
normally would develop into three types of brain and nerve tissue.
They injected the cells into the blood stream of a second group of
mice whose bone marrow had been killed with radiation. The cells
migrated naturally to the void left by the killed bone marrow.
Once there, they transformed from neural stem cells into blood-
making cells a complete change from their original role.
But just what caused the change is unknown.
And it's unclear if adult neural stem cells have been isolated in
humans, although mature stem cells for intestines, skin and blood have
been identified, Vescovi said. McKay said his lab and one other had
found mature human neural stem cells.
Bjornson emphasized that the new work involves only mice and that
``huge steps are needed'' before stem cell technology can ever be used
for humans.
One key problem is learning how to direct stem cells to grow a
specific organ. Although researchers at Johns Hopkins University and
the University of Wisconsin, Madison, had earlier prompted stem cells
to start making a variety of tissue cells, the growth was not guided
toward a specific cell type.
If that problem can be solved, researchers believe it's
theoretically possible that stem cells could be used to grow new livers
or skin, make cells to renew a failing heart, or replace nerve cells
killed by Alzheimer's.
______
[From the Washington Times, January 22, 1999]
``Master Cells'' Offer Repair Kits; Study Suggests They Could be
Transplanted to Form Tissue
(By Lee Bowman)
A new study suggests that adult ``master cells'' can be
transplanted to form a number of types of tissue, a capability that
could mean humans carry their own built-in tissue repair kits.
Until now, scientists have only been able to experimentally use
immature stem cells cultivated from embryos and aborted fetuses for
such transplants.
But if the study reported today in the journal Science can be
confirmed and expanded to humans, it could mean that stem cells don't
have to come from embryos to generate specialized cells. Instead, they
can be moved around between different organ systems within the body.
A team led by Angelo Vescovi of NeuroSpheres Ltd. of Calgary,
Alberta, and the National Neurological Institute of Italy used neural
stem cells from the central nervous systems of mice in a transplant
that allowed them to assume the job of bone marrow ``master cells''
that produce the different varieties of blood cells in a second group
of mice.
``If they behave similarly to their mouse counterparts, human
neural stem cells may provide a renewable source of cells that could be
used in blood system reconstitution in various blood diseases and
disorders,'' and potentially other diseases, Mr. Vescovi said.
Normally, the neural stem cells generate replacements for the major
cells found in the adult brain, neurons and their support cells. Mr.
Vescovi and his colleagues took some of these cells from one group of
mice, genetically labeled them and injected them into the bloodstream
of a second group of rodents whose bone marrow had been destroyed by a
nearly fatal dose of radiation.
Once in the blood stream, the neural cells seeded the mice's bone
marrow and spleen, another point for blood production, and took over
the job of the destroyed blood stem cells within two weeks and produced
a range of blood cells and important immune-system cells within 20 to
22 weeks.
``It took us a while to believe our own data. The tissue of the
body has always been seen as unchangeable,'' Mr. Vescovi said.
As a comparison, researchers injected another group of irradiated
mice with donated blood system stem cells from mice. They, too, took
over the job of the stem cells that had been destroyed, but produced
blood cells an average of three weeks faster than did the transplanted
brain cells.
``This extra time required suggests that the neural stem cells
undergo additional steps of fate determination, differentiation and
maturation than do the blood stem cells'' to take over the same job,
Mr. Vescovi said.
But that they do eventually adapt themselves to work in a new
system means that adult stem cells are still versatile and not
genetically predestined to work only with the brain, blood, skin or
intestines, for instance.
The promise of embryonic stem cells has been that they have the
potential to become any type of tissue within the body as long as they
are given the proper genetic signals. Scientists haven't yet figured
out how to turn that switch by inserting some or all of the DNA from
the cells that they want to replicate, but it had been assumed that
stem cells from adults were already too set in their ways to assume new
tasks.
The new study suggests that reactivating dormant genetic coding in
stem cells may not require DNA transfers.
______
[From the Washington Times, December 29, 1998]
Scientists Find New Life For Old Cells
rejuvenated tissue could aid burn victims, fend off wrinkles
(By Ruth Larson)
Aging without wrinkles? It could become a reality with a new
technique for ``immortalizing'' human cells, Texas researchers say.
Lab cultures of human cells injected with an anti-aging enzyme have
lived four times longer than their normal lifetimes. More importantly,
they have shown no sign of developing cancer, as some researchers had
feared.
``At long last we've learned how to put cellular aging on hold,''
said Jerry Shay, professor of cell biology and neuroscience at the
University of Texas Southwestern Medical Center in Dallas. His research
will be published today in the journal Nature Genetics.
Introducing an enzyme called ``telomerase'' into the cells
effectively resets their biological clocks, enabling them to live and
divide like young, vigorous cells.
``This doesn't mean that we're going to be able to get a whiff of
telomerase and then live forever,'' Mr. Shay cautioned. ``We're still
going to die, because this won't solve all our problems. There will
still be car accidents and shootings,'' and health problems unrelated
to cellular aging.
Still, the ability to rejuvenate specific cells in the body opens
up a dazzling array of possibilities. Doctors could grow skin grafts
for burn victims using their own skin, insulin-producing cells for
diabetics, or muscle tissue for sufferers of muscular dystrophy. And
yes, they might even help combat wrinkles.
``Women--and some men--spend lots of money to get rid of
wrinkles,'' Mr. Shay said in a telephone interview. As individuals age,
their skin cells produce less of the connective tissue collagen, so the
skin becomes thinner, less elastic and more susceptible to wrinkles.
``Someday it might be possible to take one of a lady's skin cells,
inject it with telomerase, and rejuvenate her skin so she can make her
own collagen again,'' he said. ``It's speculative right now, but it's a
very real possibility in the future.''
The biotech firm Geron Corp., based in Menlo Park, Calif., has been
granted the right to commercialize the technique. Geron researchers
have implanted telomerase-treated human cells into mice, to see if they
would form tumors in the animals. They did not.
``Even though they were immortalized, these cells behaved just like
normal cells,'' said Calvin Harley, Geron's chief scientific officer.
The cells responded to normal growth regulators that prevent runaway
cell growth.
Geron is looking into several possible gene therapy applications,
but Mr. Harley stressed that human applications could be years away,
and only after their safety and effectiveness are proved.
Nevertheless, the Texas researchers say they have crossed a major
hurdle toward such clinical applications, now that they have shown that
the technique does not transform healthy cells into cancerous ones, as
some critics had initially suggested.
Unlike most normal cells, which have finite lives, cancer cells can
divide and reproduce indefinitely. One of the markers for cancerous
activity is the enzyme telomerase.
``All cancer cells have figured out a way to become immortal,'' Mr.
Shay explained. ``Because of that, some researchers have mistakenly
taken that to mean that if cells are immortalized, they will become
cancerous.''
Cancer, he said, is like a runaway car: ``The brakes are
malfunctioning, the accelerator is stuck, the steering wheel is coming
off in your hands, and you have a full tank of gas.''
By contrast, aging cells are like a car that has simply run out of
gas. ``All we've done is to put a little fuel in the gas tank; the
brakes, the accelerator and the steering wheel are all still OK.''
``Telomerase won't cause cancer; it won't lead to cancer,'' he
said.
Mr. Shay's colleague, Woodring Wright, said, ``The abnormalities
seen in cancer cells are due to other mutations; telomerase merely
allows the cells to keep dividing.''
Indeed, further research might help scientists find a way to
inhibit the telomerase enzyme in cancerous cells. ``That could be a
potent anti-cancer agent, because it would mean the cancer cells
couldn't divide,'' Mr. Shay said.
In January, Mr. Shay and his colleagues showed that structures
called ``telomeres''--short pieces of DNA at the ends of chromosomes--
are the biological timers that govern how many times a cell is
programmed to divide in its lifetime.
Each time a cell divides, its telomeres shorten, like the fuse of a
lighted firecracker. When the telomeres run out, the cell begins to
die.
``It's very clear that telomeres are the key timing mechanism,''
Mr. Shay said.
But adding the enzyme telomerase to cells actually lengthens the
telomeres, effectively giving them a new lease on life. Mr. Shay uses
the term ``immortal'' to mean that a cell has lived at least twice its
normal lifetime.
One promising application is producing healthy human cells for use
in developing and testing new drugs, or screening for genetic diseases.
A single, healthy human cell, dividing indefinitely, could provide an
unlimited supply of cells, thereby reducing the number of animals
required for lab experiments.
``This is literally changing the way we study various diseases,''
Mr. Shay said.
______
[From the New York Times, January 22, 1999]
Cell Experiment Offers Hope For Tissue Repair
(By Nicholas Wade)
In a bizarre experiment that demonstrates the surprising plasticity
of the body's cells, scientists have converted mice's brain cells into
blood cells.
The transformation has medical significance because if the human
body's tissues should prove to be as interconvertible, patients'
tissues might be repaired from their own cells.
The result in the mice was obtained with neural stem cells, which
have the ability to form the three main types of cell found in the
brain. Each organ of the body is thought to have its own brand of stem
cells that generate all the organ's specialized cell types.
But until now, the stem cells were thought to be committed to their
own organ type and unable to cross over.
A team of Italian and Canadian scientists, led by Angelo L. Vescovi
of the National Neurological Institute in Milan, has now found that the
neural stem cells can metamorphose into the blood-making stem cells of
the bone marrow.
Dr. Vescovi's team gave mice sublethal doses of radiation to
destroy their own blood-making cells, and then injected neural stem
cells from other mice whose cells carried an identifying genetic tag.
The neural stem cells found their way to the mice's bone marrow and
started producing various types of blood cells bearing the genetic tag
of the donor mouse, the scientists report in today's issue of Science.
The conversion of neural stem cells into blood cells is
particularly surprising because brain and blood come from different
germ layers created in the early embryo. Almost the first visible
structures in animal embryos are three primary sheets of cells, known
as the ectoderm, mesoderm and endoderm, from which all the tissues of
the adult body develop. The brain develops from the ectoderm and blood
from the mesoderm. Dr. Vescovi's work defies the widely held assumption
that cells in the three lineages are permanently committed to their
fate.
``It is that trinity that is now being challenged,'' said Ronald
McKay, a brain cell expert at the National Institutes of Health. Dr.
McKay said the new result showed that differentiation, the commitment
of a cell to a specific fate, is not irreversible.
Dr. Vescovi said he did not know the chemical signals to which the
neural stem cells were responding but assumed they were influenced by
local cues in the devastated bone marrow calling for more cells.
Biologists who work with stem cells hold high hopes for using them
in medicine. Stem cells, after all, are the natural source of new cells
when a tissue needs to repair itself.
The human embryonic stem cells whose first isolation was reported
last November have been seen as a promising source of new tissue. The
embryonic stem cells can give rise to all 250 cell types of the body
and in particular to the lower-level stem cells that generate each
organ of the body.
But there are ethical considerations in using embryonic stem cells
because the cells are derived by destroying an embryo. Also, the cells
would not be immunologically compatible with a patient unless
manipulated in ways that have yet to be devised.
Dr. Vescovi's work suggests that ordinary stem cells, from the skin
or blood perhaps, could be acquired from the patient, thus avoiding any
immune rejection problems.
``We think you can use skin stem cells to make other cells,'' Dr.
Vescovi said. If so, skin stem cells could be harvested from a patient,
and inserted into the bone marrow to make blood cells.
Dr. Vescovi believes a new branch of medicine is about to develop
from stem cell biology. ``The resource to heal a sick body lies in the
body itself,'' he said.
The recent cloning of animals like mice and sheep is also an
example of the new plasticity being recognized in cells. In those
cases, the nucleus of a fully specialized cell was reprogrammed after
being inserted into an egg cell. In Dr. Vescovi's work, the body's own
local signals apparently converted the neural stem cells to a new role.
The plasticity of all these cells is possible because every cell
contains a full set of the human genes or genome. Each type of cell
presumably activates its own subset of genes, with all the others being
switched off.
Biologists have long assumed the off-switches were put in place
early in an organism's development. It now seems that the state of a
stem cell's differentiation is more of a dynamic matter, depending on
whatever mix of signals it receives in its local environment.
Stem cells have become accessible to study only in the last 10
years or so. Distinguishing them from other cells required finding
markers on their cell surface for which an immune-based tag could be
developed. Once isolated, the cells have proved extremely unstable,
either dying or developing into specialized cell types. In the body,
their behavior is determined by the many cells surrounding them, a fact
that must be taken into account in cultivating them.
______
[From CNN Interactive, November 9, 1998]
Heart Researchers Replace Blocked Vessels by Growing New Ones
Doctors and researchers meeting at the American Heart Association's
annual conference are considering an experimental treatment called
angiogenesis, in which scientists use either medication or gene therapy
to grow new blood vessles in the heart.
As with most experimental treatments, researchers caution that it's
still too early for heart patients to get excited about the process.
But some patients already have experienced positive results.
Take real estate developer Gil Gilman.
``I could not walk across the street without suffering heart pains
or angina,'' Gilman said. Standard drug treatments, bypass surgery and
angioplasty were not successful in ending his pain.
Then doctors at Emerory University in Atlanta offered Gilman
angiogenesis. Since the treatment, Gilman said, he's gotten stronger,
and can ``go back to doing basically anything I want to do.''
Emory researchers have done safety tests of their angiogenesis
procedure on 58 patients and say they are pleased with the results.
But scientists say the treatment is still in the early stages of
development. One concern is that new blood vessels could grow in places
where they are not wanted, like the eyes and kidneys.
Encouraging results from Tufts study
A team at Tufts University in Boston use gene therapy on 16 male
patients with severe blockages. Researchers told the AHA meeting Monday
the men had less chest pain after the treatment and had to take fewer
drugs.
The treatment involved injecting a gene that controls production of
VEGF, or vascular endothelial growth factor, which instructs the body
to grow new blood vessels.
The 16 volunteers, aged 53 to 71, all had suffered heart attacks.
All had blocked arteries, and all had had either bypass surgery or
angioplasty to stretch open their clogged blood vessels--many of them
several times.
Yet each time the blockages came back. Most of the men had such bad
chest pain they could not live normal lives.
After having the VEGF injected into their hearts, all but one of
the patients reported the reduction in chest pain was ``marked,''
starting just 10 days after treatment.
Again, researchers stressed that more research is needed, but they
said the potential for treatment is huge.
Dr. Jeffrey Isner said about 250,000 patients a year have ischemia,
or blocked blood flow, for which bypass surgery, angioplasty or drugs
have not worked.
``For these patients there is currently no other treatment
option,'' he told a new conference.
Surgeon says valve repair can extend lives
Also at the AHA meeting Monday, University of Michigan surgeon
Steven Bolling said surgical repair of a heart valve can greatly extend
survival rates for patients with congestive heart failure, which claims
about 250,000 lives each year in the United States.
Bolling developed the new procedure as an alternative for patients
whose only other hope was a heart transplant.
Cells are units of organisms--organisms are units of life
Senator Specter. Thank you, Mr. Doerflinger.
Dr. Rabb, the opinion which you have rendered focuses on
the proposition that, while cells are units of organisms,
organisms are units of life. Except for unicellular life, a
cell does not equal an organism, which is recognized as an
animal or plant, not a collection of unicells but a
multicellular cooperative with the emergent properties of a
whole organism.
Now, in that context how would you respond to what Mr.
Doerflinger said, that stem cells may re-cogenerate into what
could be a whole organism? Is that a possibility?
Dr. Rabb. I cannot respond on the science, Senator Specter.
The question that was asked of me was whether, if one were
dealing with an entity that was not an organism, would one
violate the human embryo ban, and the answer to that is no, one
would not violate the ban if one were doing research with an
entity that was not an organism.
If the question is whether one can do research with an
organism that would otherwise be subject to the human embryo
ban, the answer then again would be no, one could not do such
research. But the science was not in my domain, the law was;
and we did not create our own definition of an embryo. The
definition we used was the one in the statute. As Senator
Harkin pointed out, the statute defines ``human embryo'' in
terms of an organism, and that was the question for my office.
The answer we found through science was that these stem cells,
not being organisms, are not subject to the ban.
Senator Specter. So when Mr. Doerflinger says that the
destructive harvesting of embryos is indispensable, would your
response be that stem cells can be obtained for this kind of
research without the destructive harvesting of embryos?
Dr. Rabb. That is a science question again, Senator
Specter. What I can say is that, however derived not using
Federal funds, once derived stem cells are not organisms and
therefore are not subject to the ban.
Senator Specter. Well, since it is a science question, Dr.
Varmus, you enter center stage here. Is it possible to have
these--acquire these stem cells for the research without having
the destructive harvesting of embryos?
Dr. Varmus. At this point, Senator, no. The cells derived
from embryos do require the destruction of the embryo.
Obviously, in derivation from fetal tissue the tissue comes
from a fetus which has already died.
Let me make a point about the issue that Mr. Doerflinger
raised with respect to whether pluripotent stem cells in
culture can become organisms. It is true that sometimes these
cells can aggregate and may appear like one of the early phases
in the development of a normal embryo. But to my mind nothing
would be less ethical than to attempt to ascertain whether or
not this was indeed a precursor to an organism, a viable
embryo; that that would require returning that mass of cells to
a uterus to ask whether it had potential to develop into a
fetus and a newborn, and the prospect for developing a severely
impaired individual would be enormous and to my mind a
reprehensible means of doing research.
Senator Specter. Dr. Rabb, you made a comment that, except
for the unicellular life, a cell does not equal an organism.
Would you explain what you mean by the exception of the
unicellular life.
Dr. Rabb. I am going to try. This gets to be science again.
An organism is, as it has been explained through the science,
is an individual constituted to carry out all life functions.
There are some unicellular animals. For those animals, the full
potential of their lives inheres in a single cell. We are human
beings. It is the complex interrelationship of all of the human
systems that make up the organism.
Senator Specter. Dr. Varmus, I have one final question for
you. When Mr. Doerflinger makes the point that we have ignored
other new developments which might lead us to the same avenues
as stem cells, are you pursuing the kinds of lines of inquiry
that Mr. Doerflinger suggests at NIH?
Dr. Varmus. Absolutely, Senator. I am glad you brought that
up. Many of us were pleasantly surprised by the report that
appeared in ``Science'' this week, a copy of which I have given
to your staff, that shows that stem cells taken from the mouse
brain and grown in culture can be returned to a mouse and
produce blood cells.
This indicates a level of plasticity that was unexpected
and of course a very promising area of research. But I must
emphasize, this is one report carried out in one way with one
strain of mice. Whether this formulation or this approach will
be applicable in other strains of mice, other animals, with
other types of cells, whether we can identify what is
responsible for reprogramming the cell, all matters of
conjecture.
My view is, yes, we should be pursuing this and many other
lines of investigation with relation to many kinds of stem
cells. But to say that we should put our eggs in one basket and
not in all the available baskets would be a serious mistake.
Senator Specter. So you are saying that NIH has eggs in
those other baskets?
Dr. Varmus. Absolutely.
Senator Specter. Senator Harkin.
Senator Harkin. Thank you, Mr. Chairman.
Mr. Doerflinger, I was just reading an article you had
written here for the ``National Right to Life News'' which I
found interesting. Let me just ask you, in vitro fertilization
is not illegal, is it?
Mr. Doerflinger. No.
Senator Harkin. Is it immoral?
Mr. Doerflinger. In Catholic teaching there are moral
problems with it, yes. There is a good bit of research,
however, involving in vitro fertilized embryos that is illegal
in various States.
Senator Harkin. I do not think the church has taken a
position that an infertile couple cannot engage in in vitro
fertilization. I do not--maybe I am wrong.
Mr. Doerflinger. Catholic teaching does not accept in vitro
fertilization as a solution for infertile couples. It urges
them to pursue fertility treatments that will help their sexual
union to be procreative if that is what they want, rather than
to substitute a laboratory procedure for that.
Senator Harkin. Well, I will have to check, but I did not
think that they had taken an absolute position against in vitro
fertilization. So I have in vitro fertilization----
Mr. Doerflinger. I am pretty close to that situation,
Senator.
Senator Harkin. Huh?
Mr. Doerflinger. Working for the National Conference of
Catholic Bishops, I am fairly close to that situation.
Senator Harkin. Well, I am sure you would be. I would hope
so. But I still, I did not think that they had taken a position
that said that you cannot use in vitro fertilization. Maybe I
am wrong. I do not know.
Mr. Doerflinger. I will be glad to send you the document on
it.
Senator Harkin. Am I wrong? Have they taken an absolute
position on it?
Mr. Doerflinger. I never like to say that up front to a
Senator, but I think so, Senator. I will send you the documents
on it.
Senator Harkin. Well, I do not know. I mean, you are the
authority on that. I do not know. Send it to me.
Mr. Doerflinger. Among the concerns that have been raised
beyond the Catholic Church about the procedure is the prospect
for abuses to the embryos that come out of the procedure, the
culling of high quality embryos, the discarding of embryos, the
selective reductions that are proposed when too many of the
embryos implant. These are all part of the----
Senator Harkin. So we have got in vitro fertilization. At
least it is not illegal. We have a lot of it going on, and
obviously there are a lot of leftovers that are frozen. What
happens to them?
Mr. Doerflinger. Some are frozen indefinitely. Some are
ultimately used for later attempts at having a child, and some
are experimented upon and some are thrown away.
Senator Harkin. Some are destroyed. Well, if in fact this
is not illegal and they are in fact, some are destroyed, why
not use them to get the pluripotent cells that we need to do
the kind of research that may help us in the future alleviate
human suffering? I do not understand why we cannot do that.
Mr. Doerflinger. Well, Senator, I think that is the
question that we explored a little bit at the last hearing.
There are lots of things that go on in the private sector that
are going to go on anyway that Congress has decided not to add
its encouragement to by giving Federal funds, abortion being an
excellent example. It is not only legal--I mean, it is more
legal than destructive embryo research, which is a felony in
several States. It is defined as a constitutional right. But
Congress has decided we are not going to use Federal funds to
give our endorsement to it.
I think you could just as well say, if you are walking down
the street and you find a bunch of big tough guys beating up an
old man, the question arises whether before they are done with
him you could take his liver because you need it, thus killing
him a little earlier. I do not think whatever somebody else is
doing out there in the private sector that they are going to do
anyway has much influence on what Congress has to decide in its
policy decision on what to promote.
See, in this case, this is not a case analogous to the
fetal tissue situation where the abortion has been done and, as
Henry Waxman said in 1993 in the House floor, the only question
left is whether to throw away the tissue that is left after the
fetus is dead or make use of it. Here is a case where the
researchers' harvesting procedure does the destruction itself.
That is a very different moral proposition.
Senator Harkin. But it is going to take place, as I said,
anyhow.
Mr. Doerflinger. It is going to take place anyway. Senator,
you and every other Senator in the Senate voted in 1997 to
reject Federal funding of euthanasia, even though all of those
people are going to die pretty soon anyway. But it makes a
difference whether they are going to die of some other cause or
whether the government is going to help kill them.
Senator Harkin. Well, as you said here in this article, you
said that such experiments that we are talking about here
create new human life. I thought we got through that.
Organisms, these are not organisms. They cannot develop into
full human life. Every scientist I have ever asked that
question to says that. Yet you seem to want to bring it back
across that boundary line again, and I just do not understand
that.
Mr. Doerflinger. I think what I was saying, Senator, was
there is a factual uncertainty about one of these experiments,
Dr. Gearhart's, which can be settled in a factual way. It is an
uncertainty he himself has. The answer that Dr. Varmus has
given is intriguing, because if we really do not know and there
is no ethical way to find out, that might answer the question
in the direction of saying we cannot fund it then.
But my broader question was simply that HHS gave an answer
to that question which is probably right as far as it goes, but
it is the wrong question, because the embryo research rider was
not intended only to say that you cannot use Federal funds for
the destructive act itself. It was designed to prevent Federal
funding of an entire research project in which these are
destroyed, even if they are destroyed with private funds.
Senator Harkin. Well, I disagree with that interpretation.
I adamantly disagree. That may be your interpretation. I do not
believe Congress--you would have to show me report language or
anything else that indicates that we intended it to be that
broad and that encompassing. I do not believe that.
Mr. Doerflinger. You have two clauses there right next to
each other. The first one says you cannot use Federal funds for
creation of embryos. If your interpretation is right, I cannot
think of a blessed reason why they did not just say Federal
funds cannot be used for destroying embryos. They did not say
that. Instead they said--they used an entirely different phrase
right next to the first one saying, cannot be used for research
in which embryos are destroyed or discarded.
Now, that cannot mean the same thing as the first clause
because it is very deliberately written more broadly.
Senator Harkin. I have to think. You lost me on that one.
Mr. Doerflinger. If you want to rewrite the rider, then we
can have a debate about that.
Senator Harkin. This is it right here. ``None of the funds
made available by Public Law 104-91 may be used for: [1] the
creation of a human embryo or embryos for research purposes or
[2] research in which a human embryo or embryos are destroyed,
discarded, or knowingly subjected to risks of injury or death
greater than that allowed for research on fetuses in utero
under 45 CFR,'' etcetera.
``For the purposes of this section,'' I will read one more
time, ``the phrase' human embryo or embryos' shall include any
organism not protected as a human subject under 45 CFR 46 as of
enactment of this act,'' etcetera, etcetera, etcetera.
Now again, I think that is the essence of the finding at
HHS. It is clear that these are not organisms----
Mr. Doerflinger. That the stem cells are not organisms.
Senator Harkin (continuing). and as such cannot be covered
by that law, Mr. Doerflinger. Now, if you want to change the
law----
Mr. Doerflinger. I am not talking about the stem cell being
an embryo. I am talking about the stem cell that you have to
kill to get the stem cells----
Senator Harkin. Wait a minute.
Mr. Doerflinger [continuing]. as an integral part of that
research protocol.
Senator Harkin. You are saying stem cell you have to kill
to get the stem cells. I do not understand that, what you just
said. You said the stem cell you have to kill to get the stem
cell.
Mr. Doerflinger. No, I said the embryo you have to kill to
get the stem cells. The stem cells are simply the inner cell
mass of an embryo. The way the stem cells is obtained is by
doing microsurgery on an embryo and sucking out the inner cell
mass to provide stem cells for culture.
What I am saying is the destruction of that initial embryo
in two of the three experiments we are talking about, because
Dr. Gearhart's experiment is using fetal tissue, but in Dr.
West's and Dr. Thomson's experiments an integral part of the
research protocol is you must arrange for these embryos to be
destroyed by the harvesting of these cells. It is not after the
embryo is dead. It is what kills the embryo. It seems to me
that that is what Congress was intending to prevent.
Senator Specter. Senator Harkin, do you have further
questions?
Senator Harkin. No, thank you very much, Mr. Chairman.
Thank you, Mr. Doerflinger.
Senator Specter. Thank you.
Senator Hollings.
Senator Hollings. Would you care to comment, Dr. Varmus.
Dr. Varmus. I think the point is the law to our minds reads
quite clearly, and it is not our job to try to discern intent
when intent is not described by report language or other means
of discernment. So our view is that there is a very clear
distinction to be made between research in which stem cells
that have been developed in one laboratory by one procedure are
then used by other investigators to support other kinds of
research that is not research in which an embryo, an organism,
is subjected to risks greater than those that are dictated by
other statutes.
Senator Hollings. Thank you, Mr. Chairman.
Senator Specter. Thank you, Senator Hollings.
We are now slightly past 10 o'clock, so we are going to
have to adjourn. We thank you very much for coming again today,
and this is obviously going to be an ongoing matter of great
public interest as we pursue the steps which are set up. We
appreciate your participation, Mr. Doerflinger, to give us your
analysis. You have immunity here when you criticize Senators.
You can say Senators are wrong. That comes under----
Senator Hollings. We hear that every day.
CONCLUSION OF HEARINGS
Senator Specter. Senator Hollings is accurate about that.
But you have a privilege to make those statements. We are here
to have an exchange, and we appreciate your incisiveness and
your study and your knowledge of the field.
We thank you, Dr. Varmus, Dr. Rabb, and Dr. Meslin, and
stay tuned. Thank you all very much for being here, that
concludes our hearing. The subcommittee will stand in recess
subject to the call of the Chair.]
[Whereupon, at 10:02 a.m., Tuesday, January 26, the hearing
was concluded, and the subcommittee was recessed, to reconvene
subject to the call of the Chair.]
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