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 types endoderm (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.
