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Mr. Chairman, distinguished Members of the
Subcommittee, thank you for the opportunity to testify today at this
important hearing regarding stem cell research.
The use of federal funds to support human embryonic stem
cell research is illegal, unethical, and unnecessary. Research using stem cells not derived from human embryos has
confirmed what prior evidence had long suggested: that adult stem cells
(and other "post-natal" stem cells)
have vast biomedical potential to cure diseases such as diabetes,
Parkinson's, heart disease, and other degenerative diseases. This biomedical potential is as great as or greater than
the potential offered by human embryonic stem cell research. Simply stated, adult stem cell research is a preferable alternative
for progress in regenerative medicine and cell-based therapies for disease
because it does not pose the medical, legal, and ethical problems
associated with destructive human embryonic stem cell research.
Among the justifications stated in the Guidelines for
pursuing human embryonic stem cell research was the allegedly limited
potential of adult stem cells as compared to the purportedly enormous, yet
speculative, potential of embryonic stem cells. In particular, NIH's response to comments urging the benefits of
adult stem cell research highlighted four alleged shortcomings related to
the biomedical potential of adult stem cells. 65 Fed. Reg. 51976. The
agency stated that adult stem cells (1) had not been found in all cell
types, (2) appear in limited numbers and can be difficult to harvest and
grow in time for treatment, (3) are likely to pass on genetic defects, and
(4) may not have the capacity to multiply as do "younger cells." Id. Recent
scientific developments now support the contention, however, that these
claims about the shortcomings of adult stem cells are not true, are not
relevant to their therapeutic potential, and/or overstate the differences
between adult stem cells and embryonic stem cells. Significantly, human adult stem cells can be pluripotent and have
the ability to transform from one cell type into another, a fact largely
unrecognized by the Guidelines. The
scientific record now indicates that the supposed shortcomings NIH
perceived in adult stem cell research either are illusory or can be
overcome.
Moreover, an impressive volume of scientific literature
attests to the fact that human adult stem cells -- unlike human embryonic
stem cells -- are currently being used successfully in clinical trials to
combat many of the very diseases that embryonic stem cells only
prospectively promise to treat. Animal
research strongly suggests that more therapeutic applications of adult
stem cell research will follow.
Finally, the potential biomedical application of human
embryonic stem cell research faces risks that are unique to embryonic stem
cells, such as the tendency toward tumor formation, as well as instability
in gene expression. In
addition, embryonic stem cells face the very real possibility of immune
rejection, while use of a patient's own adult stem cells is free from
this problem. Consequently,
adult stem cells have several advantages as compared with embryonic stem
cells in their practical therapeutic application for tissue regeneration.
Thus, contrary to the suggestions by supporters of
destructive human embryonic stem cell research, federal funding of such
research is not a necessary, or even a wise, use of limited federal
research dollars. Other forms
of stem cell research are more promising, are demonstrably more successful
at producing beneficial treatments that are actually in use today, and do
not present the significant problems and uncertainties (to say nothing of
the ethical and legal problems) posed by destructive human embryonic stem
cell research.
1. Adult stem cells have been located in numerous cell and tissue
types and can be transformed into virtually all cell and tissue types,
including functional tissues
Although it is true that human adult stem cells have not
been found in every cell type, they have been found in many cell
and tissue types including, but not limited to: brain (and other nervous
system),
muscle,
retina,
pancreas,
bone marrow and peripheral blood,
cornea,
blood vessels (endothelial cells),
fat,
dental pulp,
spermatogonia,
and placenta. In essence, where scientists have devoted time and resources to the
identification of human adult (and other non-embryonic) stem cell types,
they have generally found them.
Moreover, experiments using animals have recently
isolated many additional adult stem cell and tissue types, including, but
not limited to: skin,
liver,
and mammary gland. Given the impressive pace of adult stem cell identification in the
past few years -- which invariably followed the pattern of (1)
identification and isolation of the stem cell in animals, followed by (2)
identification and isolation of the stem cell in humans -- the imminent
identification and isolation of the human adult stem cells of these cell
and tissue types is highly likely.
Even more important than the identification of human
adult stem cells in most cell types is the fact that adult stem cells can
regenerate healthy tissue and many can transform from one cell type into
another. Thus, many types of
human adult stem cells -- including stem cells from fat -- exhibit the
ability to transform from one tissue type into many others. For example, plentiful adult stem cells from fat have been
transformed into cartilage, muscle, and bone.
Readily accessible human adult bone marrow stem cells have been
transformed into smooth muscle,
cardiac tissues,
neural cells,
liver,
bone,
cartilage,
and fat.
Human adult neural stem cells have been reprogrammed to form
skeletal muscle,
and have the ability to form all neural types.
Human adult stem cells from skeletal muscles can be coaxed into
forming skeletal myotubes, smooth muscle, bone, cartilage, and fat.
Human adult stem cells from human dental pulp can be induced to
differentiate into tooth structures.
And stem cells from placenta are reported to have been induced to
form bone, nerve, cartilage, bone marrow, muscle, tendon, and blood
vessels.
(Please see Appendix C for a graphical representation of some adult
stem cells discovered and potential transformations into other tissue
types based on the literature.)
In fact, animal research indicates that adult neural and
bone marrow stem cells may be able to generate virtually all adult
tissues, including heart, lung, intestine, kidney, liver, nervous system,
muscle, and the gastrointenstinal tract (including esophagus, stomach,
intestine, and colon).
Clarke suggests that "stem cells in different adult tissues may .
. . have a developmental repertoire close to that of [embryonic stem]
cells."
The recent rapid pace of discovery of adult stem cells for a
variety of tissue types, combined with their ability to form many, if not
all, adult tissues, suggests that adult stem cells will ultimately be
found in or be capable of transforming into every significant tissue type.
In particular, the Guidelines evince concern that no
pancreatic or cardiac adult stem cells had been identified. 65 Fed. Reg. 51976. In
fact, however, human pancreatic and cardiac stem cells have been
identified. Indeed,
scientists have actually reversed diabetes in mice using the animal's
own adult pancreatic stem cells. This animal research has led to evidence of adult human pancreatic
stem cells, which have been grown in culture and induced to differentiate
into insulin-producing cells.
In fact, in 1999, well before the NIH published the Guidelines, the
NIH was funding research involving insulin-producing adult human
pancreatic stem cells.
These cells are available for use in potential technologies to
reverse diabetes in humans.
Recent evidence also indicates the ability of stem cells
to transform into heart cells. Added
to the numerous studies done in animals since 1995, these reports indicate
that adult stem cells from skeletal muscle, bone marrow, liver, and the
heart itself have the capacity to regenerate cardiac tissue and repair
heart damage. More recently, new evidence has emerged suggesting the existence of
a human heart stem cell. This research promises potential biomedical application to treat
heart disease. In fact,
myoblast transplantation has already been used in the first successful
clinical application of human adult stem cells for treatment of cardiac
damage.
Contrary to the impression created by advocates of
destructive human embryonic stem cell research, these results for adult
stem cell research are far more promising than any results obtained
thus far through embryonic stem cell research. Indeed, researchers have yet to publish any evidence that
human pancreatic cells can be generated from human embryonic stem cells,
and have yet to show any evidence that human cardiac cells generated from
embryonic stem cells in culture can form functional tissue in the body. The case for diverting scarce research dollars away from
promising avenues of research and instead into human embryonic stem cell
research in order to "cure" diabetes or heart disease is weak indeed.
2. Adult stem cells can be reproduced to create a "virtually
limitless" supply
Contrary to the assumptions expressed in the Guidelines,
recent scientific evidence indicates the ability of adult stem cells to
rapidly expand and implies that adult stem cells can be produced in ample
quantities for biomedical applications. To be sure, adult stem cells are present in finite amounts
throughout the human body, but the supply of human adult stem cells
immediately available is much greater than previously thought.
Moreover, the number of available adult stem cells can be expanded
greatly in culture. In March
of 2000, researchers identified the conditions necessary to allow for a
large-scale expansion (a billion-fold in a few weeks) of adult stem cells
in culture.
Other researchers have confirmed the ability to rapidly and
significantly expand the numbers of adult stem cells in culture, so that
sufficient numbers of a variety of adult stem cells can be produced for
clinical applications.
Thus, scientific reports make clear that adult stem
cells are readily accessible, can create a "virtually limitless"
supply, and can even be transformed into other tissue types with use of a
simple protocol.
Indeed, animal studies indicate that a single stem cell is
sufficient to repopulate adult bone marrow,
generate nerves,
and participate in tissue repair in a variety of tissues throughout the
body.
In a nutshell, the arguments for federal funding of
destructive human embryonic stem cell research rely on an outdated
understanding that markedly underestimates the number of adult stem cells
present in an adult human and the efficiency with which those cells can be
reproduced. Studies published
since the close of the Guidelines' comment period indicate that there
will be no shortage of adult stem cells for clinical use.
3. The pluripotent nature of adult stem cells alleviates concerns
about the difficulty of harvesting neural stem cells from humans
As discussed above, adult stem cells show great
potential to transform from one tissue type into multiple other tissue
types. Thus, at least some
adult stem cells can be pluripotent in the sense that they can develop
into cells and tissues of the three primary germ layers -- the ectoderm,
the mesoderm, and the endoderm. For
example, as noted above, human adult bone marrow stem cells have the
capacity to transform into the following tissue types: muscle, cardiac
blood vessels, neural cells, liver, bone, cartilage, and fat. See supra, § 1. Animal
research suggests that the bone marrow stem cell could transform into
virtually all tissue types. Such research also indicates that adult neural stem cells have the
ability to transform into virtually all tissue types.
The Guidelines evinced a concern that adult neural stem
cells were impracticable in clinical application because neural cells
would be difficult to harvest. A
finding of pluripotency for adult stem cells would make this and similar
concerns irrelevant. If
neural stem cells can easily be created from readily accessible adult bone
marrow stem cells in human beings,
it will not matter whether the harvesting of neural cells directly from
adult humans would require difficult procedures such as surgery.
Aside from creating neural cells through a
transformation of cell type, adult brain cells have also been isolated at
locations that are more accessible and safer to harvest.
Indeed, researchers have determined that human adult neural stem
cells can be isolated from cadavers.
Thus, as with other concerns discussed above, the suggestion that
adult stem cell research and clinical applications suffer from a lack of
adequate supply is not supported by the available evidence.
4. Treatments using adult stem cells will not be prohibited by risks
of "duplicating genetic error"
The Guidelines asserted that adult stem cells are likely
to be ineffective at combating genetic diseases because the patient's
own stem cells would likely contain the same genetic error, making cells
from the patient inappropriate for transplantation.
But evidence from clinical studies to date belies this assertion.
The first successful human gene therapy used "remedied" adult
stem cells -- not embryonic stem cells -- to cure severe combined
immunodeficiency syndrome.
Not only can genetic error be remedied while adult stem cells are
in culture, but in many cases the correction of the genetic defect may not
be necessary to effect a cure with adult stem cells.
For example, patients with systemic lupus have been treated with
their own adult bone marrow stem cells which repaired organ damage that
was previously considered permanent.
This repair occurred without correcting the genetic defect present
in the bone marrow cells.
In sum, a patient's genetic deficiency does not
preclude the use of his or her own stem cells for therapeutic purposes.
In fact, as discussed below, the use of one's own stem cells is
medically and scientifically preferable to the use of embryonic stem cells
derived from another human being, because the transplantation of embryonic
stem cells may carry with it a severe risk of immune rejection and tumor
formation.
5. Adult stem cells have been used in many clinical trials with great
success
Contrary to the impression created by advocates of
destructive human embryonic stem cell research, the biomedical potential
of embryonic stem cells remains entirely speculative, because such cells
have never been successfully used in clinical applications with
human patients. See infra,
§ 7. By contrast, adult
stem cells already have been used in a variety of human clinical trials
and applications with considerable success.
Indeed, because researchers have found that stem cells in the bone
marrow were the chief therapeutic agent in whole marrow transplants, many
treatments which previously relied on transplant of unfractionated bone
marrow now use transplants of bone marrow stem cells instead.
Such treatments include applications for various types of cancer,
including but not limited to: brain tumors,
retinoblastoma,
ovarian cancer,
various solid tumors,
testicular cancer,
multiple myeloma and leukemias,
breast cancer,
neuroblastoma,
non‑Hodgkin's lymphoma,
and renal cell carcinoma.
Adult stem cells have also been used in treatment of autoimmune
diseases such as multiple sclerosis, systemic lupus, rheumatoid arthritis,
and juvenile rheumatoid arthritis,
immunodeficiencies and anemias,
stroke,
and cartilage and bone diseases.
Adult stem cells have been used to regenerate corneas, restoring
sight to previously blind patients,
and also to combat blood and liver diseases.
Recently the positive results from the first successful human
trials of adult stem cells to treat cardiac damage were published.
Simply stated, adult stem cells are already being used
in a wide array of human clinical trials, with many therapeutic
applications having moved well beyond the experimental stage.
Thus, adult stem cells are presently providing the results only
promised by advocates of destructive embryonic stem cell research.
There can be little doubt that as we learn more about adult stem
cells, they will be even more successfully employed to fight the diseases
noted above and to combat other diseases and conditions, such as diabetes
and paralysis.
6. Adult stem cells have been used successfully in treatment of
numerous animal models of disease
The scientific record provides
strong evidence for the conclusion that adult stem cells will be applied
to biomedical technologies to treat a host of other human diseases and
conditions. Adult and other
non-embryonic stem cells have already been used successfully in treatment
of various animal models of disease, including nerve and spinal cord
damage,
retinal damage,
Parkinson's disease,
heart damage,
muscular dystrophy,
diabetes,
stroke,
and liver disease.
Adult stem cells also appear to possess an ability to "home" to
sites of damaged tissue in the body, repairing damaged tissue and even
attacking tumors.
There is every reason to believe that these studies will
yield positive results in human application as well.
As these studies move from animal models to clinical application,
adult stem cells will be our best hope for fighting those diseases in the
near term.
7. By contrast, human embryonic stem cells have never
successfully been used in clinical trials, have had lackluster success in
combating animal models of disease, and carry significant risks, including
immune rejection, tumor formation, and genomic instability
Human embryonic stem cells have never been used
successfully in clinical trials. Thus,
unlike adult stem cells, their biomedical potential is purely speculative.
And any speculative clinical use remains a distant hope.
Indeed, in contrast to human adult stem cells, human embryonic stem
cells have not been successfully coaxed to transform into pure populations
of most cell and tissue types, even in treatment of animal models of
disease.
Although human embryonic stem cells may exhibit
impressive plasticity due to their potency, this plasticity has proven to
be a double-edged sword, as embryonic stem cells have been difficult to
control in laboratories.
The inability to successfully control embryonic stem cells in the
controlled atmosphere of a laboratory does not suggest that they have a
high probability of successful use in therapeutic treatments.
In contrast, adult stem cells have proven to be relatively easy to
control.
Fetal tissue transplants provide a cautionary example of
the potential for problems using developmentally-young cells such as
embryonic stem cells, which are difficult to direct along specific and
controlled developmental pathways. In
one instance, fetal tissue derived from early fetuses was transplanted
into an individual's brain, resulting in no viable neurons but instead
producing non-specific differentiation into numerous non-brain tissues
within the patient's brain.
Moreover, in the most extensive controlled study of
fetal brain tissue transplantation for Parkinson's disease, the
transplants showed little or no benefit to most patients.
Fetal brain tissue was transplanted into the brains of patients to
regenerate or replace the cells missing or damaged due to Parkinson's
disease, the theory being that these young cells would take over
production of the missing brain chemical dopamine.
However, there were horrific results for some patients, with
transplanted fetal cells going out of control and producing irreversible
and devastating changes in the patients' brains.
Significantly, embryonic stem cells also face a
substantial risk of immune rejection, similar to the risks present in
organ transplantation.
These risks include the rejection of the transplanted tissue, as
well as the possibility of the transplant attacking the host, or even
forming tumors.
In stark contrast, the re-transplantation of a patient's own
adult stem cells carries with it no risk of immune rejection since the
cells are the patient's own.
Scientists have not developed an effective strategy to
combat the problems of tumor formation and immune rejection. Until they do, human embryonic stem cells have no realistic
potential to be used for therapeutic purposes.
Indeed, advocates of destructive embryonic stem cell
research have recently stated that embryonic stem cell regenerative
technologies will, by themselves, be unable to provide effective
therapeutic treatments. Instead,
they claim, embryonic stem cell technology must be applied to human
embryos produced by cloning if it is to achieve biomedical application.
The reason is simple: although human embryonic stem cells exhibit
tremendous plasticity, they lead to immune rejection.
A cloned embryo, however, has the same genetic code as the donor,
and thus transplantation of a pluripotent cell from this embryo into its
"original" may "avoid complications due to immune response
rejection."
Thus, embryonic stem cell research may be merely a tool to understanding
how pluripotent cells function, a stepping stone to open the door for what
some call "therapeutic cloning."
But this door is closed, providing further confirmation
that the NIH should not waste precious research dollars funding
speculative embryonic stem cell research that will never result in
effective medical treatments. The
Bush Administration has announced its opposition to human cloning for any
purpose, including research purposes.
If the ultimate goals and hypothetical applications of human
embryonic stem cell research depend on cloning, which is directly contrary
to the position of this Administration, it would be wholly inappropriate
-- and directly contrary to the Administration's policy on cloning -- to
fund embryonic stem cell research.
Finally, the Guidelines assert that adult stem cells may
be more difficult to grow and may contain more DNA abnormalities than
younger, embryonic stem cells. Although
these assertions are of questionable merit, it is important to note that
embryonic stem cells in fact suffer from these defects that the Guidelines
attribute to adult stem cells alone.
As demonstrated above, adult stem cells have proven to
be relatively easy to grow. See
supra, § 2. In
contrast, even proponents of embryonic stem cell research have noted that
embryonic stem cells are "tedious to grow," and that "simply keeping
human embryonic stem cells alive can be a challenge."
Not only is there difficulty in consistently coaxing human
embryonic stem cells to differentiate into the desired cell and tissue
type, but there is the more fundamental problem of keeping embryonic stem
cell lines alive.
In addition, embryonic stem cells face the risk of
mutation with every successive generation.
Thus, "[c]ells derived from stem cells that have replicated
through many generations will have accumulated mutations and be
susceptible to cancer or have decreased viability."
The phenomenon of mutation is controlled by the number of divisions
a cell line has undergone, and not its chronological age.
Thus, an embryonic stem cell line, kept alive in a lab for
successive generations, has an equal or greater chance of exhibiting
undesirable characteristics compared to the adult stem cells harvested
from a patient for purposes of autologous transplantation.
Moreover, a study published in the July 6th
issue of the journal Science points to potentially significant
problems with the possibility of using embryonic stem cells for
"therapeutic" treatments.
In the study, mice were cloned from mouse embryonic stem cells, and
even apparently healthy cloned animals had abnormalities that would be
difficult to detect but could lead to disastrous disorders later in life.
The abnormalities could be traced back to the embryonic stem cells
themselves; gene expression of the embryonic stem cells "was found to be
extremely unstable", even in the laboratory culture dish.
It was noted that the problems likely reflect changes that occurred
during culture even from a single embryonic stem cell.
This instability in gene expression suggests that using embryonic
stem cells to treat health disorders may not work nearly so well as some
scientists have suggested, and would likely limit any use of embryonic
stem cells in clinical applications.
Conclusion:
Compared with embryonic stem cells, adult stem cells have at least
as great, if not greater, potential for biomedical application, but
without the medical risks or the ethical controversy
The biomedical potential of adult stem cells is
enormous. Adult stem cells
have already been used successfully in treatments for diseases such as
multiple sclerosis, lupus, renal cell carcinoma, and breast cancer, with
encouraging results. Moreover,
animal models using adult stem cell treatments indicate that therapeutic
treatments for pernicious diseases such as diabetes, heart disease,
Parkinson's, and stroke are well within the vast therapeutic
capabilities of adult stem cells.
Additionally, science is continuing to discover human
adult stem cells for an increasing number of cell and tissue types.
Furthermore, studies of the pluripotent nature of human adult stem
cells as readily accessible as stem cells from fat or bone marrow are
yielding impressive results, and strongly suggest that some adult stem
cells have the capacity to transform into all significant cell and tissue
types. This transformative
power of adult stem cells, unrecognized by the Guidelines, has caused one
reviewer to remark that "[r]ecent studies have revealed that much of
this remarkable developmental potential of embryonic stem cells is
retained by small populations of cells within most tissues in the
adult."
In this respect, recent evidence indicates overlapping genetic
programs in hematopoietic and neural stem cells, leading some researchers
to propose that some genes are functionally conserved "to participate in
basic stem cell functions, including stem cell self-renewal."
One recent review proposes that "rather than referring to a
discrete cellular entity, a stem cell most accurately refers to a
biological function that can be induced in many distinct types of cells,
even differentiated cells."
The authors liken the circulatory system to a "stem cell
highway" in which adult stem cells may migrate from tissue to tissue,
taking "on-ramps" and entering tissues to generate appropriate cell
types in response to homing and growth signals ("billboards") as
required, with all choices reversible.
Critics of adult stem cell research have attempted to discredit the
findings, claiming that adult stem cell studies are published in journals
that are not peer-reviewed. This
is simply false. The
remarkable achievements with adult stem cells are published in the most
prestigious scientific and medical journals in the world, as well as
peer-reviewed scientific specialty journals; indeed, these are the same
journals in which proponents of embryonic stem cell research have
published their own findings (please see Appendix D for a sample listing
of journals.)
Whereas human adult stem cells continue to surpass the
Guidelines' expectations and amaze observers, embryonic stem cells have
yet to live up to their billing as the new fountain of youth.
Embryonic stem cells have proven to be difficult to work with, and
carry with them significant risks that cast doubt upon their therapeutic
viability.
Indeed, some now say that human cloning might be necessary if
embryonic stem cells could ever have clinical application to human beings
-- a result that is directly contrary to the stated policy positions of
this Administration. The
shortcomings of embryonic stem cells, contrasted with the capability of
adult stem cells, have led scientists to conclude that "adult stem cells
have several advantages as compared with embryonic stem cells in their
practical therapeutic application for tissue regeneration."
Finally, it is worth noting that the National Bioethics
Advisory Commission ("NBAC"), which recommended federally funding
research using embryonic stem cells under the assumption that embryonic
stem cells "offer greater promise of therapeutic breakthroughs," noted
that "the derivation of stem cells from embryos . . . is justifiable only
if no less morally problematic alternatives are available for advancing
the research."
There can be little doubt at this time that adult stem cells
provide equal, if not greater, potential for biomedical application as
compared with embryonic stem cells. Thus, applying NBAC's own standard, the scientific record
indicates that federal funding of destructive human embryonic stem cell
research is not justifiable. Indeed,
less morally problematic alternatives for advancing the research are available,
due to the stunning promise of research using adult stem cells.
Mr. Chairman, distinguished
Members, I thank you for the opportunity to provide testimony on this
important issue, and I would be pleased to answer any questions.
APPENDIX A
Selected References Documenting the Scientific
Advances in Stem Cell Research using Stem Cells which are not
derived from embryos.
The majority of the sources
cited in this reference list are articles published in peer-reviewed
scientific and medical journals. Some
are reviews of scientific research. This
document is organized by subject area, so some references may appear more
than once.
Current
Clinical Applications of Adult Stem Cells
Potential
Applications of Adult Stem Cells
Appendix
B
Sources of Stem Cells
and their Potentials
Appendix
C
Post-Natal
(non-embryonic) Stem Cells and their Known or Possible Derivatives (not
an all-inclusive list) (as suggested by the
peer-reviewed scientific literature; for placenta by company press
releases)
Appendix
D
Sampling of the
Peer-Reviewed Scientific and Medical Journals in which Adult Stem Cell
Research Achievements have been Published (not an all-inclusive list)
|
Annals
of Thoracic Surgery
|
Journal
of Neuroscience
|
|
Biochemical
and Biophysical Research Communications
|
Journal
of Neuroscience Research
|
|
Blood
|
Journal
of Thoracic and Cardiovascular Surgery
|
|
Bone
Marrow Transplant
|
The
Lancet
|
|
British
Journal of Haematology
|
Nature
|
|
British
Medical Journal
|
Nature
Biotechnology
|
|
Cancer
|
Nature
Immunology
|
|
Cell
|
Nature
Medicine
|
|
Diabetes
|
Nature
Neuroscience
|
|
Experimental
Cell Research
|
Neurology
|
|
Hepatology
|
Neurosurgery
|
|
Journal
of Biological Chemistry
|
New
England Journal of Medicine
|
|
Journal
of Cell Biology
|
Proceedings
of the National Academy of Sciences USA
|
|
Journal
of Clinical Investigation
|
Science
|
|
Journal
of Clinical Oncology
|
Tissue
Engineering
|
Disclosure of federal grants, contracts, or
subcontracts received in the current and preceding two fiscal years:
National
Institutes of Health
Indiana University School of Medicine, Indiana University-Purdue
University at Indianapolis
(collaborative research sub-contract with Dr. David A. Williams); 1
January 2000-31 July 2000; $11,000; "Molecular and Functional
Characterization of a Novel Mutation in Murine Stem Cell Factor"
National
Institutes of Health
Indiana University School of Medicine, Indiana University-Purdue
University at Indianapolis
(collaborative research sub-contract with Dr. David A. Williams); 1 August
2000-30 June 2001; $16,000; "Molecular and Functional Characterization
of a Novel Mutation in Murine Stem Cell Factor" (renewal)
National Institutes of Health
Indiana University School of Medicine, Indiana University-Purdue
University at Indianapolis
(collaborative research sub-contract with Dr. David A. Williams); 1 July
2001-31 December 2001; $13,000; "Molecular and Functional
Characterization of a Novel Mutation in Murine Stem Cell Factor" (renewal)
See Appendix B for a graphical representation of sources of stem cells
and their potentials.
See, e.g., T.D. Palmer et al., "Progenitor
cells from human brain after death," 411 Nature
42 (May 3, 2001) (neural stem cells isolated and grown from
human cadavers); S. Pagano et
al., "Isolation and Characterization of Neural Stem Cells from
the Adult Human Olfactory Bulb," 18 Stem Cells 295 (July 2000)
(identifying neural stem cells in a more accessible portion of the
brain); Barnett et al.,
"Identification of a human olfactory ensheathing cell that can
effect transplant-mediated remyelination of demyelinated CNS axons,"
123 Brain 1581 (Aug. 2000) (identifying human "olfactory ensheathing
cell," the cell type which has been used successfully in animals to
repair spinal cord damage); C.B. Johansson et al., "Neural
stem cells in the adult human brain"; 253 Exp. Cell Res. 733 (Dec.
1999) (discussing different regions in the adult brain in which stem
cells have been isolated); see also, C.J. Hodge, Jr. and M.
Boakye, "Biological Plasticity: The future of science in
neurosurgery," 48 Neurosurgery 2 (Jan. 2001) (reviewing science
regarding the plasticity of neural cells in humans and animals);
see generally, App. A, Refs. 113-143 (collecting published papers
using non‑embryonic neural stem cells from human adults and
animals).
See, e.g., P. Manasché et al. "Myoblast
transplantation for heart failure," 357 Lancet 279 (Jan. 27. 2001)
(using isolated human muscle cells in a clinical trial); J. T.
Williams et al., "Cells
isolated from adult human skeletal muscle capable of differentiating
into multiple mesodermal phenotypes," 65 Am. Surg. 22 (Jan. 1999); see
generally, App. A, Refs. 146-161 (collecting published papers
using non-embryonic muscle stem cells from humans and animals).
Tropepe et al., "Retinal stem cells in the adult
mammalian eye," 287 Science 2032 (Mar. 17, 2000) (identifying
retinal stem cells in humans and other mammals).
See, e.g., V. Gmyr et
al., "Adult human cytokeratin 19-positive cells reexpress
insulin promoter factor 1 in vitro: Further evidence for pluripotent
pancreatic stem cells in humans," 49 Diabetes 1671 (Oct. 2000); S.
Bonner-Weir et al., "In vitro cultivation of human islets
from expanded ductal tissue," 97 Proc. Natl. Acad. Sci. USA 7999
(July 5, 2000); see also P. Serup, O.D. Madsen, and T.
Mandrup-Poulsen; "Islet and stem cell transplantation for treating
diabetes"; 322 British Medical Journal 29 (Jan. 6, 2001) (reviewing
animal and human stem cell developments for biomedical potential to
treat diabetes).
See e.g., A. A. Kocher et al.,
"Neovascularization of ischemic myocardium by human
bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis,
reduces remodeling and improves cardiac function," 7 Nature Medicine
430 (April 2001) (experiment using bone marrow cells); see
generally, App. A, refs. 169-219 (collecting papers using
non-embryonic human and animal adult bone marrow and peripheral blood
stem cells).
See R. J-F. Tsai et al.; "Reconstruction of damaged corneas by transplantation of
autologous limbal epithelial cells," 343 New England J. of Medicine
86 (2000); I. R. Schwab et al.;
"Successful transplantation of bioengineered tissue replacements in
patients with ocular surface disease," 19 Cornea 421 (July 2000); K.
Tsubota et al.; "Treatment of severe ocular-surface disorders with corneal
epithelial stem-cell transplantation," 340 New England J. of
Medicine 1697 (June 3, 1999); see generally, App. A, Refs.
67-74 (collecting published papers using non-embryonic human corneal
stem cells).
See, e.g., T. Asahara et
al., "Isolation
of Putative Progenitor Endothelial Cells for Angiogenesis," 275
Science 964 (Feb. 14, 1997).
See P.A. Zuk et al., "Multilineage cells from
human adipose tissue: Implications for cell-based therapies," 7
Tissue Engineering 211 (2001).
See S. Gronthos et al., "Postnatal human dental
pulp stem cells (DPSCs) in vitro and in vivo," 97 Proc. Natl. Acad. Sci.
USA 13625 (Dec. 5 2000).
See F. Izadyar et al., "Spermatogonial stem
cell transplantation" 169 Mol. Cell Endocrinology
21 (Nov. 27 2000); D.S. Johnston et al., "Advances in
spermatogonial stem cell transplantation," 5 Rev. Reprod. 183 (Sept.
2000) (reviewing advances in spermatogonial stem cell transplantation
since 1994).
Based on press releases from AnthroGen indicating that
scientists have isolated stem cells in placenta that have been induced
to form bone, nerve, cartilage, bone marrow, muscle, tendon, and blood
vessel. This press
release is available at <http://www.mcpf.org/
AnthroGen%20Discovery.htm>. AnthroGen
has also posted articles based on that press release at
<http://www.anthrogenesis.com/page411559.htm>.
See, e.g., H. Oshima et al.,
"Morphogenesis and renewal of hair follicles from adult multipotent
stem cells," 104 Cell 233 (Jan. 2001) (studies showing that the
skin/hair follicle cell is multipotent and can form epidermis, hair
follicles, sebaceous glands, and all structures of the hairy skin).
See, e.g., N. N. Malouf et al., "Adult-derived
stem cells from the liver become myocytes in the heart in vivo," 158
American Journal of Pathology, 1929 (June 2001); see generally, App.
A, refs. 220-225(collecting papers discussing liver stem cells).
See N. D. Kim, "Stem cell characteristics of
transplanted rat mammary clonogens, 260 Exp. Cell Res. 146 (Oct. 10.
2000).
See P.A. Zuk et al., supra at n. 8.
O. N. Koc and H. M. Lazarus, "Mesenchymal stem cells: heading
into the clinic," 27(3) Bone Marrow Transplant 235-239 (Feb. 2001).
D. Orlic et al., "Bone marrow cells regenerate
infarcted myocardium," 410 Nature 701 (Apr. 5 2001).
J.Sanchez-Ramos et al., "Adult bone marrow stromal cells differentiate into neural
cells in vitro," 164 Experimental Neurology 247 (Aug. 2000); D.
Woodbury et al., "Adult rat and human bone marrow stromal
cells differentiate into neurons," 61 J. Neuroscience Research 364
(Aug. 15, 2000); E. Mezey and K. J. Chandross, "Bone marrow: a
possible alternative source of cells in the adult nervous system,"
405 Eur. J. Pharmacol. 297 (Sept. 29, 2000).
N. Theise et al.,
"Liver from bone marrow in humans," 32 Hepatology 11 (July 2000).
M. F. Pittenger et al., "Multilineage potential of adult human mesenchymal stem
cells," 284 Science 143 (Apr. 2, 1999).
R. Galli et al.,
"Skeletal myogenic potential of human and mouse neural stem
cells," 3 Nature Neuroscience 986 (Oct. 2000).
S. Gronthos et al., supra at n. 9.
See AnthroGen press release, supra at n. 11.
See D.L. Clarke et al.; "Generalized potential of adult neural stem cells" 288
Science 1660 (June 2, 2000); D.S. Krause et al.,
"Multi-Organ, Multi-Lineage Engraftment by a Single Bone
Marrow-Derived Stem Cell," 105 Cell 369 (May 4, 2001).
Clarke et al., supra at n. 28.
See V. K. Ramiya et al., "Reversal of insulin-dependent diabetes using islets
generated in vitro from pancreatic stem cells," 6 Nature Medicine
278 (March 2000).
See references cited in n. 4,
supra.
See Grant Number 5R21DK57173-02 to Lawrence K. Olson,
Michigan State University, "Pluripotent Human Pancreatic Ductal
Cells," Project Start Date, September 30, 1999 (available at NIH
website).
See, e.g., B. Pouzet et al., "Factors
affecting functional outcome after autologous skeletal myoblast
transplantation," 71 Ann Thorac Surg 844 (Mar. 2001); B. Pouzet et
al., "Intramyocardial transplantation of autologous myoblasts :
can tissue processing Be optimized?," 102 Circulation 210 (Nov. 7,
2000); M. Scorsin et al., "Comparison of the effects of fetal
cardiomyocyte and skeletal myoblast transplantation on postinfarction
left ventricular function," 119 J. Thorac. Cardiovasc. Surg. 1169
(June 2000); P.D. Kessler and B.J. Byrne, "Myoblast cell grafting
into heart muscle: cellular biology and potential applications," 61
Ann. Rev. Physiol. 219 (1999); K. A. Jackson et al., "Regeneration of ischemic cardiac muscle and
vascular endothelium by adult stem cells," 107 Journal of Clinical
Investigation 1395 (June 2001); D. Orlic et al., supra
at n. 17; J-S. Wang et al., "Marrow stromal cells for
cellular cardiomyoplasty: Feasibility and potential clinical
advantages," 120 The Journal of Thoracic and Cardiovascular Surgery
999 (Nov. 2000).
See A. P. Beltrami et al., "Evidence That Human
Myocytes Divide After Myocardial Infarction," 344 New England
Journal of Medicine 1750 (June 7, 2001) (research indicating that the
adult human heart may have its own stem cell).
See P. Menasché et al., "Myoblast
transplantation for cardiac repair," 357 Lancet 279 (Jan. 27, 2001);
P. Menasché et al., ["Autologous skeletal myoblast
transplantation for cardiac insufficiency.
First clinical case."], 94 Arch Mal Coeur Vaiss 180 (Mar.
2001) (Original title and article in French).
See, e.g., , J. D. Cashman and C. J. Eaves, "High
marrow seeding efficiency of human lymphomyeloid repopulating cells in
irradiated NOD/SCID mice," 96 Blood 3979 (Dec. 1 2000).
D. Colter et al., "Rapid Expansion of recycling stem
cells in cultures of plastic-adherent cells from human bone marrow,"
97 Proc. Natl. Acad. Sci. USA 3213 (Mar. 28, 2000).
See, e.g. Cashman, supra at n. 36; L. Kobari et
al., "In vitro and in vivo evidence for the long-term
multilineage (myeloid, B, NK, and T) reconstitution capacity of ex
vivo expanded human CD34(+) cord blood cells," 28 Exp. Hematol. 1470
(Dec. 2000); G. L. Gilmore et al., "Ex vivo expansion of
human umbilical cord blood and peripheral blood CD34(+) hematopoietic
stem cells," 28 Exp. Hematol. 1297 (Nov. 2000); G. Bhardwaj et
al., "Sonic hedgehog induces the proliferation of primitive
human hematopoietic cells via BMP regulation" 2 Nature Immun. 172
(2001); A. Villa et al.,
"Establishment and properties of a growth factor-dependent,
perpetual neural stem cell line from the human CNS," 161 Exp.
Neurol. 67 (Jan. 2000); D. Woodbury et
al., supra at n. 18; T. Ueda et
al., "Expansion of human NOD/SCID-repopulating cells by stem
cell factor, Flk2/Flt3 ligand, thrombopoietin, IL-6, and soluble IL-6
receptor" 105 J. Clin. Invest. 1013 (April 2000).
D. Woodbury, supra at n. 18.
See D.S. Krause et al., "Multi-Organ,
Multi-Lineage Engraftment by a Single Bone Marrow-Derived Stem
Cell," 105 Cell 369 (May 4, 2001); M. Yagi et
al., "Sustained ex vivo expansion of hematopoietic stem cells
mediated by thrombopoietin," 96 Proc. Natl. Acad. Sci. USA 8126
(July 1999).
See N. Uchida et al., "Direct isolation of
human central nervous system stem cells," 97 Proc. Natl. Acad. Sci.
USA 14720 (Dec. 19, 2000); S. Shihabuddin et al., "Adult
spinal cord stem cells generate neurons after transplantation in the
adult dentate gyrus," 20 J Neuroscience 8727 (Dec. 2000).
See generally, App. A, refs. 160-207.
Even the staunchest supporters of embryonic stem cell research
concede that "[b]one marrow stem cells probably can form any cell
type." G. Vogel, "Can
Adult Stem Cells Suffice?" 292 Science 1820 (June 8, 2001)
(quoting Dr. Douglas Melton).
See, e.g., Clarke, supra at 28.
See, e.g., D. Woodbury, supra at n. 18.
M. Cavazzana-Calvo et al., "Gene therapy of human
severe combined immunodeficiency (SCID)-X1 disease," 288 Science 669
(Apr. 28, 2000).
A.E. Traynor et al., "Treatment of severe systemic
lupus erythematosus with high-dose chemotherapy and haemopoietic
stem-cell transplantation: a phase I study," 356 Lancet 701 (Aug.
26, 2000).
See P. Menasché, supra at n. 35; see
generally, App. A, Refs. 78-82 (collecting reports regarding
clinical treatment of heart damage using non‑embryonic human
stem cells).
App. A. at refs. 116, 125, 126, 131, 136, 137, and 215.
Id. at refs. 148-150, 152-153, 159-161, 170-172,
and 178.
Id. at refs. 151, 155, 156.
Id. at refs. 173, 174, 246.
Id. at refs. 118, 151, 169, 173, 180, 181, and 246.
In fact, these experiments have yielded disastrous results, as
implanted embryonic stem cells have literally killed the cells of
their host after transplantation.
See, e.g., G. Vogel, "Stem Cells: New excitement,
persistent questions," 290 Science 1672 (Dec 1, 2000) (describing an
experiment performed at Geron Corp. implanting human embryonic stem
cells into rats, where the implanted embryonic stem cells "did not
readily differentiate," and instead caused the neural cells "near
them . . . to die"). In stark contrast, experiments in which human adult bone
marrow stem cells were injected into rat brains to repair damaged
brain tissue -- experiments performed over 3 years ago -- yielded
remarkably successful results. See,
e.g., S.A. Azizi et al., "Engraftment and migration of
human bone marrow stromal cells implanted in the brains of albino
rats-similarities to astrocyte grafts," 95 Proc. Natl. Acad. Sci.
USA 3908 (March 1998) (reporting that human bone marrow stromal cells
had the ability to repair damaged rat brain tissue without
inflammatory response or rejection).
See, e.g., M. Schuldiner et al.,
"Effects of eight growth factors on the differentiation of cells
derived from human embryonic stem cells," 97 Proc. Natl. Acad. Sci.
USA 11307 (Oct. 10, 2000) (study using human embryonic stem cells
indicated that "none of the eight growth factors tested directs a
completely uniform and singular differentiation of cells"); G.
Vogel, supra at n. 42 ("And so far, reports of pure cell
populations derived from either human or mouse ES cells are few and
far between -- fewer than those from adult cells.").
R. D. Folkerth, R. Durso, "Survival and proliferation of
nonneural tissues, with obstruction of cerebral ventricles, in a
parkinsonian patient treated with fetal allografts," 46 Neurology
1219 (May 1996).
See C. R. Freed et al., "Transplantation
of embryonic dopamine neurons for severe Parkinson's disease," 344
New England Journal of Medicine 710 (Mar. 8, 2001); G. Kolata,
"Parkinson's Stem Cell Implants Yield Nightmarish Side Effects,"
New York Times (March 8, 2001).
See, for discussion, Serup, supra at n. 4; J.
Thomson et al., "Embryonic Stem Cell Lines Derived from Human
Blastocysts," 282 Science 1145 (Nov. 6, 1998) (noting that
strategies need to be developed to "prevent immune rejection of
transplanted [embryonic stem] cells");
see also, Thomas Okarma, Prepared Witness Testimony
before the Subcommittee on Health (hearings regarding H.R. 1644, Human
Cloning Prohibition Act of 2001) (June 20, 2001) (noting the
"need" for cloning, given the risks of immune rejection that
embryonic stem cells face when implanted into a host), available at
http://energycommerce.house.gov/107/hearings/06202001Hearing291/Okarma450print.htm.
See, e.g., Johns Hopkins Medical Institutions Office of
Communications and Public Affairs, "New Lab-Made Stem Cells May Be
Key To Transplants," (Dec. 25, 2000) (quoting embryonic
stem-cell researcher Dr. Michael Shamblott as stating, when
"coaxing [embryonic stem cells] to differentiate -- to form nerve
cells and the like -- you risk contaminating the newly differentiated
cells with the stem cells. . . . Injected into the body, stem cells
can produce tumors"); G. Vogel, "Can Adult Stem Cells Suffice?,"
supra at n. 42 ("E[mbryonic ]S[tem] cells have a disturbing
ability to form tumors, and researchers aren't yet sure how to
counteract that").
See Okarma, supra at n. 79 ("Somatic cell
nuclear transfer [i.e., cloning] is essential if we are
to achieve our goals in regenerative medicine.") (emphasis added).
Mr. Okarma explains the process as follows: "Once we fully
understand re-programming[, the process of making a differentiated
cell a pluripotent cell,] we will be able to develop specific cells[,
using the knowledge that will be acquired from studying embryonic stem
cells,] for transplantation without immune rejection."
Id. Thus,
advocates of destructive human embryonic stem cell and cloning
research seek to learn technologies from cells created through the
destruction of human embryos that then can be applied to technologies
using clones -- individuals who will necessarily be destroyed as they
are used for research purposes -- all in an attempt to avoid immune
rejection and tumor formation, side effects to regenerative
therapies that are already avoidable by employing effective autologous
transplants using adult stem cells.
See, e.g., Azizi, supra at n. 75.
Claude Allen, Prepared Witness Testimony before the
Subcommittee on Health (hearings regarding H.R. 1644, Human Cloning
Prohibition Act of 2001) (June 20, 2001) (speaking on behalf of the
administration, stating that "we oppose the use of human somatic
cell nuclear transfer cloning techniques either to assist human
reproduction or to develop cell- or tissue-based therapies," because
cloning "would pose deeply troubling moral and ethical issues for
humankind").
G. Vogel, "Stem cells: New excitement, persistent
questions," supra at n. 75 (quoting Dr. Peter Andrews of
University of Sheffield, England).
L. Roccanova, P. Ramphal, P. Rappa III, "Mutation in
Embryonic Stem Cells," 292 Science 438 (Apr. 20, 2001).
Id. (citing J. Smith, O. M. Pereira-Smith, 273 Science
63).
D. Humpherys et al.; "Epigenetic Instability in ES Cells and
Cloned Mice"; 293 Science 95 (July 6, 2001).
M. S. Rao and M. P. Mattson, "Stem cells and aging: expanding
the possibilities"; 122 Mech. Ageing Dev. 713 (May 31, 2001)
Terskikh AV et al.; "From hematopoiesis to neuropoiesis:
Evidence of overlapping genetic programs"; 98 Proc. Natl. Acad. Sci.
USA 7934 (July 3, 2001).
Blau et al.; "The Evolving Concept of a Stem Cell: Entity or
Function?"; 105 Cell 829 (June 29, 2001)
See generally, G. Vogel, "Stem cells: New excitement,
persistent questions," supra at n. 75.
T. Asahara, C. Kalka, and J. M. Isner, "Stem cell therapy and
gene transfer for regeneration," 7 Gene Ther. 451 (March 2000); see
generally, Do No Harm: The Coalition of Americans for Research
Ethics, "Stem Cell Report: Advances in Alternatives to Embryonic
Stem Cell Research," available at
<http://www.stemcellresearch.org/stemcellreport.htm> (collecting
press reports and scientific articles that suggest adult stem cell
research is scientifically preferable to embryonic stem cell
research).
National Bioethics Advisory Commission, "Ethical Issues in
Human Stem Cell Research," at 53 (Sept. 1999) (emphasis added).
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