[Senate Hearing 108-949]
[From the U.S. Government Publishing Office]
S. Hrg. 108-949
ADVANCES IN ADULT AND NON-EMBRYONIC
STEM CELL RESEARCH
=======================================================================
HEARING
before the
SUBCOMMITTEE ON SCIENCE, TECHNOLOGY,
AND SPACE
of the
COMMITTEE ON COMMERCE,
SCIENCE, AND TRANSPORTATION
UNITED STATES SENATE
ONE HUNDRED EIGHTH CONGRESS
FIRST SESSION
__________
JUNE 12, 2003
__________
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SENATE COMMITTEE ON COMMERCE, SCIENCE, AND TRANSPORTATION
ONE HUNDRED EIGHTH CONGRESS
FIRST SESSION
JOHN McCAIN, Arizona, Chairman
TED STEVENS, Alaska ERNEST F. HOLLINGS, South
CONRAD BURNS, Montana Carolina, Ranking
TRENT LOTT, Mississippi DANIEL K. INOUYE, Hawaii
KAY BAILEY HUTCHISON, Texas JOHN D. ROCKEFELLER IV, West
OLYMPIA J. SNOWE, Maine Virginia
SAM BROWNBACK, Kansas JOHN F. KERRY, Massachusetts
GORDON H. SMITH, Oregon JOHN B. BREAUX, Louisiana
PETER G. FITZGERALD, Illinois BYRON L. DORGAN, North Dakota
JOHN ENSIGN, Nevada RON WYDEN, Oregon
GEORGE ALLEN, Virginia BARBARA BOXER, California
JOHN E. SUNUNU, New Hampshire BILL NELSON, Florida
MARIA CANTWELL, Washington
FRANK R. LAUTENBERG, New Jersey
Jeanne Bumpus, Republican Staff Director and General Counsel
Robert W. Chamberlin, Republican Chief Counsel
Kevin D. Kayes, Democratic Staff Director and Chief Counsel
Gregg Elias, Democratic General Counsel
------
SUBCOMMITTEE ON SCIENCE, TECHNOLOGY, AND SPACE
SAM BROWNBACK, Kansas, Chairman
TED STEVENS, Alaska JOHN B. BREAUX, Louisiana, Ranking
CONRAD BURNS, Montana JOHN D. ROCKEFELLER IV, West
TRENT LOTT, Mississippi Virginia
KAY BAILEY HUTCHISON, Texas JOHN F. KERRY, Massachusetts
JOHN ENSIGN, Nevada BYRON L. DORGAN, North Dakota
GEORGE ALLEN, Virginia RON WYDEN, Oregon
JOHN E. SUNUNU, New Hampshire BILL NELSON, Florida
FRANK R. LAUTENBERG, New Jersey
C O N T E N T S
----------
Page
Hearing held on June 12, 2003.................................... 1
Statement of Senator Brownback................................... 1
Prepared statement........................................... 2
Witnesses
Barsh, Steven L., Merion Station, Pennsylvania................... 40
Prepared statement........................................... 42
Hess, David C., Professor and Chairman, Department of Neurology,
Medical College of Georgia..................................... 3
Prepared statement........................................... 6
Kurtzberg, M.D., Joanne, Director, Pediatric Stem Cell Transplant
Program, Duke University Medical Center........................ 11
Prepared statement........................................... 15
McDonald, M.D., Ph.D., John, on behalf of the Coalition for the
Advancement of Medical Research................................ 23
Prepared statement........................................... 25
Peduzzi-Nelson, Ph.D., Jean D., Department of Physiological
Optics, University of Alabama at Birmingham.................... 26
Prepared statement........................................... 28
Penn, Keone, Snellville, Georgia................................. 47
Prepared statement........................................... 48
Rubinstein, M.D., Pablo, Director of Placental Blood Program, New
York Blood Center.............................................. 9
Prepared statement........................................... 15
Sprague, Stephen R., Staten Island, New York..................... 44
Prepared statement........................................... 45
Appendix
Testimony of the American Academy of Physician Assistants........ 55
ADVANCES IN ADULT AND NON-EMBRYONIC STEM CELL RESEARCH
----------
THURSDAY, JUNE 12, 2003,
U.S. Senate,
Subcommittee on Science, Technology, and Space,
Committee on Commerce, Science, and Transportation,
Washington, DC.
The Subcommittee met, pursuant to notice, at 2:46 p.m. in
room SR-253, Russell Senate Office Building, Hon. Sam
Brownback, Chairman of the Subcommittee, presiding.
OPENING STATEMENT OF HON. SAM BROWNBACK,
U.S. SENATOR FROM KANSAS
Senator Brownback. The hearing will come to order. I want
to thank everybody for being here today, particularly the
witnesses that traveled some distance. We have a couple of
really special ones--not that all of you aren't special, but I
think you're going to find these just particularly heartening
stories of incredible things that have taken place.
Today, we'll be conducting a hearing on some of the
exciting new advances being made in the fields of adult and
non-embryonic stem cell research. As I'm sure many of you know,
the field of regenerative medicine offers great hope to those
suffering from this disease. Much of the research that is
providing new hope to those who are currently suffering is
moving along at a fast pace and is doing so without
questionable or morally controversial techniques.
At this hearing, we will examine some of these advances.
This hearing is not about human cloning or destructive human
embryonic stem cell research. Rather, it is about some of the
other important scientific discoveries that are being made
using noncontroversial techniques that rely on adult or non-
embryonic stem cells. And these are some processes that only a
year-and-a-half ago, we'll recall, were being called ``junk
science.'' And yet you're going to hear today from people that
have been cured. So there's been amazing work, fabulous work,
that has really resulted in people's lives being changed.
In particular today, we will hear from cord-blood stem cell
researchers, as well as others, who are working hard in the
field of regenerative medicine to find the cures to the
diseases that plague humanity. At this hearing, we will discuss
not only some of the research that is being conducted, but also
some of the treatments that are currently being offered. And we
will hear from some of the patients who are benefiting from
this important life-saving research. The stories that we will
hear from some of the patients will truly be astounding. They
are miraculous. We all agree on the need to work hard toward a
cure for the diseases that plague humanity, and we're going to
be listening to some of that success here today.
Now, rather than discussing this, I'd like to take
advantage of the panels that we have here today to testify. I
want to turn to our first panel of people to testify. And they
are Dr. David Hess, M.D., Chairman and Professor, Department of
Neurology, Medical College of Georgia, in Augusta, Georgia; Dr.
Joanne Kurtzberg, M.D., Director of the Pediatric Stem Cell
Transplant Program at Duke University Medical Center, in
Durham, North Carolina--being a KU grad, I'm familiar with
Duke----
[Laughter.]
Senator Brownback.--and a very good school, other than in
basketball----
[Laughter.]
Senator Brownback.--Dr. John W. McDonald, M.D., Ph.D.,
Washington University School of Medicine, Department of
Neurology, in St. Louis, Missouri; Dr. Jean Peduzzi-Nelson,
Ph.D., University of Alabama at Birmingham; and Dr. Pablo
Rubinstein, M.D., Director of Placental Blood Program, New York
Blood Center, New York, New York.
I'm delighted to have such a distinguished panel here with
us today to testify. I look forward to your testimony. If you
would, we will run the clock on 7 minutes. We will take your
full testimony into the record. I think it's always best for
people to summarize somewhat in putting it forward, so it can
save time, as well, for questions afterwards.
We do have an active floor running today. We may have to
have recesses periodically, for me to go over and vote. Other
members will probably be joining us, as well, so there may be
some people stepping in.
[The prepared statement of Senator Brownback follows:]
Prepared Statement of Hon. Sam Brownback, U.S. Senator from Kansas
Thank you for coming to our hearing today.
Today, we will be conducting a hearing on some of the exciting new
advances being made in the fields of adult and non-embryonic stem cell
research.
As I am sure many of you here know, the field of regenerative
medicine offers great hope to those suffering from disease. Much of the
research that is providing new hope to those who are currently
suffering is moving along at a fast pace and is doing so without
questionable or morally controversial techniques.
At this hearing we will examine some of these advances.
This hearing is not about human cloning, or destructive human
embryonic stem cell research.
Rather, it is about some of the other important scientific
discoveries that are being made using non-controversial techniques that
rely on adult or non-embryonic stem cells.
In particular, today we will hear from cord blood stem cell
researchers as well as others who are working hard in the field of
regenerative medicine to find the cures to the diseases that plague
humanity.
At this hearing we will discuss not only some of the research that
is being conducted but also some of the treatments that are currently
being offered.
And, we will hear from some of the patients who are benefitting
from this important life-saving research. The stories that we will hear
from some of the patients will truly be astounding.
Regardless of how the members of this committee feel on the
controversial issues of human cloning and destructive human embryonic
stem cell research, certainly, we can all agree on the need to work
hard toward a cure for the diseases that plague humanity.
Now, rather than describe some of the advances being made I would
like to turn to our first panel.
Senator Brownback.With that, Dr. Hess, I'd like to invite
your testimony, and we will move on down this panel list.
STATEMENT OF DAVID C. HESS, PROFESSOR AND CHAIRMAN, DEPARTMENT
OF NEUROLOGY, MEDICAL COLLEGE OF GEORGIA
Dr. Hess. Thank you, Senator Brownback.
I'm David C. Hess. I'm Professor and Chairman of the
Department of Neurology at the Medical College of Georgia. I am
a physician and neurologist, and that's a specialist that cares
for people with neurological diseases.
Many neurological diseases, such as strokes, spinal-cord
injury, Alzheimer's disease, Parkinson's disease, and Lou
Gehrig's disease, are formidable foes, resistant to treatment,
and take an enormous toll in suffering, like you mentioned. A
week will not pass when I do not receive an e-mail or a call
from a suffering patient asking for a stem cell injection to
help them recover their ability to walk or to speak. Some
patients are so desperate that they offer up themselves to be
the first patient to try the stem cells. I can't blame them.
There are few effective treatments for their diseases, and they
are looking for any ray of hope.
As you mentioned, Senator Brownback, there is some
foundation for their hope. The field of regenerative medicine
is taking off, and there are new regenerative-medicine and stem
cell institutes and centers being established all over the
country.
Many scientific dogma have been slain in the past 5 years.
One dogma was that we don't make new brain cells in our brain,
in adults. In other words, you steadily lose what you have.
However, in a set of clever experiments, it has recently been
shown that humans, even in their 60s and 70s, can make new
nerve cells in their hippocampus, a comforting fact for all of
us.
Adult stem cells can be obtained from a variety of organs,
ranging from the brain's so-called neural stem cells to the
skin. However, the best study is that most accessible adult
stem cells are in the bone marrow. Bone marrow is a rich source
of stem and progenitor cells. I will briefly review the
potential of adult stem cells derived from the bone marrow.
As a physician, my motivation is to see some of these cells
used to treat these devastating neurological diseases that I
see every day. And as a physician researcher, I'm trying to
make some small contribution to the stroke-recovery field,
thanks to past support from the American Heart Association and,
presently, the NIH.
Let me explain. Bone marrow contains two major types of
stem or progenitor cells, and maybe many more. The two major
types are the hematopoietic stem cells and the mesenchymal stem
cells, or what are often called marrow stromal cells.
Hematopoietic stem cells have been used for years in bone-
marrow transplants and have cured thousands of patients with
leukemias and other forms of cancer. These hematopoietic stem
cells have the ability to circulate throughout the whole body
and reach every organ in the body. Their plasticity--that is,
their ability to turn into other cell types of cells, such as
nerve cells, liver cells, and pancreas cells that produce
insulin--is still hotly debated; however, there is evidence
that these cells can turn into Purkinje cells in the brain, a
very sophisticated type of nerve cell. And this phenomena is
not just restricted to rodents. There is now autopsy evidence
from humans that bone-marrow cells can form new neurons in the
brain. There may also be other bone-marrow-derived cells that
circulate in the peripheral blood, with stem cell or progenitor
cell qualities.
Recently, the progeny, or the daughter, of the
hematopoietic stem cell, so to speak, circulating blood
monocytes, have been shown to be able to differentiate into
nerve cells and blood-vessel cells called endothelial cells.
This is potentially of great clinical relevance, as monocytes
are easy to isolate from human blood and could be a rich source
of replacement cells.
There are also bone-marrow cells that do not normally
circulate in the bloodstream, but, instead, reside in the bone
marrow and service supporting cells for the hematopoietic stem
cells. These cells are called mesenchymal stem cells, or marrow
stromal cells. It is these cells that are the source of much
excitement in the field of regenerative medicine.
Some of the most exciting research, in terms of an eventual
human clinical application, are the multipotent adult
progenitor cells isolated by Catherine Verfaillie. These can be
isolated from both rodent and human bone marrow. They are able
to turn into cells of all three germ layers. That is, they can
turn into endothelial cells, which line the blood vessels,
liver cells, and nerve cells. And, importantly, they don't just
do this in a petri dish; they are also able to do it in the
live animal. Moreover, they do not die prematurely, and,
importantly, they do not form teratomas, or tumors, like
embryonic stem cells tend to do.
Dr. Walter Low, a collaborator of Dr. Verfaillie, has
recently shown that these MAPCs can aid in brain repair after
stroke in a rodent. The obvious advantage of these cells for
regenerative medicine is that they can be easily isolated from
human bone marrow and the potential for a patient to be cured
or treated with their own cells, without any fear of rejection.
A closely related cell type is the marrow stromal cell.
Marrow stromal cells have been shown to be involved in brain
repair after stroke and traumatic brain injury, by Dr. Michael
Chopp, at Henry Ford Hospital, and to repair the injured spinal
cord, by Dr. Darwin Prockop's group at Tulane. Like many other
adult stem cells, these cells can be delivered intravenously,
and they can home to the injured tissue, almost like a guided
missile. There appear to be chemical signals released by
injured tissue that attract these cells. Marrow stromal cells
are easy to culture, easy to expand; and, since they can be
autologous, they would not be rejected.
How, exactly, these cells repair injured tissue is not
clear. While, in some cases, there is actual replacement of
injured cells, it seems more likely that these cells serve as
growth-factor factories and aid the tissue to repair itself.
There's also another type of circulating bone-marrow-
derived cell, the so-called endothelial progenitor cell that
has attracted much recent interest. EPCs circulate in the
bloodstream and form new endothelial cells in blood vessels. We
now know that these EPCs contribute to organ repair after
cutting off blood supply to the heart, the limbs, and the
brain. This is critically important, as cardiovascular disease
and stroke are two of the three biggest killers in the United
States. We have learned that by giving animals extra doses of
these EPCs, we can improve their outcome from heart attack and
salvage their limbs that are starved for blood.
The field is moving very, very fast. Bone-marrow-derived
cells are already being tested in small numbers of patients
with heart attacks. The TOPCARE trial was a trial published in
the journal, The Lancet. And, in this, bone-marrow cells,
harvested from the patient's own bone marrow or their blood,
were delivered via a catheter in the coronary artery to these
patients. The procedure was safe, and the initial results were
encouraging, though this was a very small trial.
Another type of bone-marrow blood stem cell, which you're
going to hear about later, is the human umbilical cord stem
cell. These are derived from umbilical cords that are normally
discarded after a delivery. Umbilical cord blood is a rich
source of stem cells. These have already been exploited as a
source of bone-marrow transplants in the cancer field and in
sickle-cell anemia.
These umbilical cord stem cells also have great potential
as a treatment for neurological disease. When delivered
intravenously to a rodent with a stroke, they help improve the
outcome of that stroke in that rodent.
Despite these hopeful signs, much work needs to be done.
Before we are able to treat humans safely and effectively, we
need to define the optimal dosing of these cells, the optimal
type of bone-marrow populations to use, and the timing of when
to administer them. And then how should we administer them?
Should we give them directly into the tissue, like into the
heart or the brain? Should we deliver them intravenously, or
should we give them in an artery? There's multiple avenues that
we could give them. We also need to learn more about how these
bone-marrow cells and other adult stem cells home or go to the
damaged tissue.
The major advantages of bone-marrow-derived stem cells are
that they are autologous, with the exception of umbilical cord
stem cells, and, therefore, they are less likely to be
rejected. They can be easily isolated from bone-marrow
aspirates, which are done clinically, and they avoid the
ethical concerns that many have with embryonic stem cells.
However, we have to keep in mind that repairing the central
nervous system is a daunting task. Neurons make tens of
thousands of connections with other nerve cells. Some of them
send projections, or axons, from meters--feet, literally--and
it's very important that they connect up to the other cell.
In most of the experiments, so far, we have little evidence
that any stem cell delivered into an adult will be able to make
all these connections and become fully functional. It is likely
that most of the cell transplants in the brain work by
stimulating the brain to actually repair itself. We need to
learn more about enhancing these self-repair processes.
In the growing field of cell therapy, we will need to
target diseases with specific cell types and approaches. One
size will not fit all. We may need to treat some of these
diseases with a combination of both cells and different growth
factors. The treatments we develop for Parkinson's disease will
probably be vastly different from those we develop for stroke.
There are no magic bullets; only painstaking research and more
funding will allow us to advance.
Thank you.
[The prepared statement of Dr. Hess follows:]
Prepared Statement of David C. Hess, Professor and Chairman, Department
of Neurology, Medical College of Georgia
I am David C. Hess M.D., Professor and Chairman of the Department
of Neurology at the Medical College of Georgia. I am a physician and
neurologist, a specialist that cares for people with neurological
diseases. Many neurological diseases such as stroke, spinal cord
injury, Alzheimer's disease, Parkinson's disease, and Amyotrophic
Lateral Sclerosis (Lou Gehrig's disease) are formidable foes, resistant
to treatment and take an enormous toll in suffering. A week will not
pass when I do not receive an e-mail or a call from a suffering patient
asking for a stem cell injection to help them recover their ability to
walk or speak.. Some patients are so desperate that they offer up
themselves to be the first patient to try the stem cells. I can't blame
them; there are few effective treatment for their diseases and they are
looking for any ray of hope. They have also been influenced by
exaggerations in the media.
Yet there is some foundation to their hope. The field of
``regenerative medicine'' is taking off and there are new
``Regenerative Medicine'' and ``Stem Cell'' institutes and centers
being established all over the country. Many scientific dogma have been
slain in the past 5 years. One dogma was that new neurons are not born
in the brains of humans-in other words, you just steadily lose what you
have as you age. However, in a set of clever experiments by Drs.
Ericksson and Gage in1998 it was shown that humans even in their 60s
can make new nerve cells in their hippocampus, a comforting fact for
all of us. Moreover, mice make more new neurons if they are kept in an
``enriched'' environment and exercise (Kempermann, 2002). If we can
extrapolate these findings to humans, it suggests that by keeping our
minds active we are less likely to lose them. We also now know that new
neurons can be made in response to a brain injury in other parts of the
rodent brain, not just the hippocampus. For example, after a stroke,
new neurons are born and travel to the damaged tissue and appear to aid
in its repair (Arvidsson, 2002). Now we have to learn how to enhance
and stimulate these natural repair mechanisms.
Adult stem cells can be obtained from a variety of organs ranging
from the brain (so called neural stem cells) to the skin. However, the
best studied and most accessible adult stem cells are in the bone
marrow. Bone marrow is a rich source of stem and progenitor cells. I
will briefly review the potential of adult or non-embryonic stem cells
to treat human disease. I will focus on bone marrow stem cells. As a
physician my perspective is on the clinical potential of these advances
and my motivation is to see some of these cells used to treat these
devastating neurological diseases that I see every day. As a physician-
researcher, I am trying to make some small contributions to the stroke
recovery field thanks to past support from the American Heart
Association and currently the NIH.
Bone marrow contains two major types of stem or progenitor cells
and maybe many more. The two major types are the hematopoietic stem
cells and the mesenchymal stem cells or marrow stromal cells.
Hematopoieitc stem cells have been used for years in bone marrow
transplants and have cured thousands of patients with leukemias and
other forms of cancer. These hematopoietic stem cells and their
progeny-the white blood cells, red blood cells and platelets-have the
ability to circulate throughout the bloodstream and reach every organ
in the body. Their plasticity, that is, the ability of these cells to
``turn ``into other cell types such as nerve cells, liver cells and
pancreas cells that produce insulin, is still hotly debated. However,
there is evidence that these cells can rarely differentiate into
Purkinje cells in the brain, a very sophisticated type of neuron. The
phenomenon is not restricted to rodents; there is now autopsy evidence
from humans that bone marrow cells are involved in the formation of
neurons at a low level (Mezey, 2003)
Some recent evidence had suggested that cell fusion was responsible
for some of the plasticity that had been described for bone marrow stem
cells (Terada, 2002; Wang, 2003; Vassilopoulos, 2003). In cell fusion,
the bone marrow cells would not actually ``turn into'' another cell
type-they would just fuse with the mature cell giving it twice the
number of chromosomes and thereby making it potentially unstable.
However, while cell fusion may indeed account for some of the
``plasticity'' of bone marrow cells, particularly in the liver, it does
not seem to account for all of it. In recent work, bone marrow cells
have been shown to become functional insulin-secreting cells in the
pancreas of mice without any evidence of cell fusion (Ianus, 2003).
There may also be bone marrow-derived cells that circulate in the
peripheral blood with ``stem cell'' or ``progenitor cell'' qualities.
Recently the progeny of the hematopoietic stem cell, a subpopulation of
circulating blood monocytes, have been shown to be able to
differentiate into nerve cells and blood vessel cells called
endothelial cells (Zhao, 2003). This is potentially of great clinical
relevance as monocytes are easy to isolate from human blood and could
be a rich source of replacement cells.
There are also bone marrow cells that do not normally circulate in
the bloodstream but instead reside in the bone marrow and serve as
supporting cells for the hematopoietic stem cells. These cells are
called mesenchymal stem cells or marrow stromal cells. It is these
cells that are the source of much excitement in the field of
regenerative medicine. Some of the most exciting research, in terms of
an eventual human clinical application, are the Multipotent adult
progenitor cells (MAPC) isolated by Catherine Verfailie and described
comprehensively in the July 2002 issue of Nature (Jiang, 2002). These
cells can be isolated from rodent and human bone marrow. They are able
to differentiate into cells of all three germ layers (endoderm,
mesoderm and ectoderm) that is they can from endothelial cells or blood
vessel lining cells, hepatocytes (liver cells), and nerve cells. They
not only do this in the petri dish, they also do it in the live animal.
Moreover, they do not senesce or die prematurely and importantly they
do not form teratomas or tumors like embryonic stem cells tend to do.
Dr. Walter Low a collaborater of Dr. Verfaillie has shown that these
MAPCS can aid in brain repair after stroke in a rodent (Zhao, 2002).
The obvious advantages of these cells for regenerative medicine is
their easy isolation from human bone marrow and the potential for a
patient to be their own donor without fear of rejection.
A closely related cell type is the marrow stromal cell. Marrow
stromal cells have been shown to be involved in brain repair after
stroke and traumatic brain injury by Dr. Chopp at Henry Ford Hospital
and to repair the injured spinal by Dr. Darwin Prockop's group at
Tulane. Like many other adult stem cells, these cells can be delivered
intravenously and then ``home'' like a guided missile to the injured
tissue. There are chemical signals released by injured tissue that
attract these cells. Marrow stromal cells are easy to culture, easy to
expand, and since they are autologous they would not be rejected. How
exactly these cells repair injured tissue is not clear. While in some
cases this is actual replacement of damaged cells, it seems more likely
that these cells serve as growth factor ``factories'' and aid the
tissue to repair itself by reactivating latent developmental programs.
There is also another type of circulating bone marrow-derived cell,
the endothelial progenitor cell (EPC) that has also attracted much
recent interest. Endothelial cells are cells that line all the blood
vessels of the body. Besides being mere conduits for blood, we now know
that they play an active and necessary role in the development and
sustenance of the body's organs. Bone marrow cells that can circulate
in the bloodstream and form new endothelial cells and blood vessels
were first described and characterized in 1997 (Asahara). We now know
that these EPCS contribute to vessel and organ repair after ischemia to
the heart, limbs and brain (Rafii, 2003). This is critically important
as cardiovascular disease and stroke are two of the three biggest
killers in the U.S. We have learned that by giving animials extra doses
of these EPCS, we can improve their outcome from heart attack and
salvage their limbs that are starved for blood.. Also, these EPCs can
be mobllized from the bone marrow and into the peripheral blood with
drugs and different growth factors . Some of these growths such G-CSF
are already approved by the FDA for other indications
The field is moving fast. Bone marrow-derived stem cells are
already being tested in small numbers of patients with heart attacks.
In the TOPCARE trial, bone marrow cells harvested from the same
patient's bone marrow or their blood were delivered via a catheter in
the coronary artery to injured heart tissue (Assmus, 2002). The
procedure was safe and initial results were encouraging. There is also
a trial using bone marrow cells in patients with congestive heart
failure (Perin, 2003).
Another type of bone marrow or blood stem cell is the human
umbilical cord stem cell. These are derived from umbilical cords that
are normally discarded after a delivery. Umbilical cord blood is a rich
source of stem cells. These have already been exploited as a source of
bone marrow transplants in the cancer field. These umbilical cord stem
cells also have great potential as a treatment for neurological
diseases. When delivered intravenously to a rodent with a stroke, they
help improve the recovery from the stroke (Chen, 2001).
Despite these hopeful signs, much work needs to be done. Before we
are able to treat humans safely and effectively, we need to define the
optimal dosing of these cells, the optimal type of bone marrow
populations to use, the timing of when to administer, and the best
route of administration (inject directly into the organ, intravenously,
intra-arterially). We also need to learn more about how they these bone
marrow cells and other adult stem cells home to damaged tissue so we
can exploit this therapeutically.
The major advantages of bone marrow derived stem cells are: 1) they
are autologous (except for umbilical cord stem cells) and will not be
rejected; 2) they can be easily isolated from bone marrow aspirates;
and 3) they avoid the ethical concerns that many have with embryonic
stem cells. However, we also have to keep in mind that repairing the
nervous system is a daunting task. Neurons make tens of thousands of
connections with other neurons. Some send their projections (axons) for
meters and then connect to another cell. In most of the experiments so
far we have little evidence that stem cells delivered into an adult
will be able to make all these connections and become fully functional.
It is likely that most of the cell transplants in the brain work by
stimulating the brain to repair itself. We need to learn more about
enhancing these endogenous (self) repair processes. In this growing
field of ``Cell Therapy'', we will need to target diseases with
specific cell types and approaches-one size will not fit all. We may
need to treat some of these diseases with a combination of both
``cells'' and growth factors. The treatments we develop for Parkinson's
disease will be different from those we develop for stroke. There are
no magic bullets-only painstaking research will allow us to advance.
References
Arvidsson A., Collin T., Kirik D., Kokaia Z., Lindvall O. Neuronal
replacement from endogenous precursors in the adult brain after stroke.
Nat Med. 2002 Sep; 8(9):963-70.
Asahara T., Murohara T., Sullivan A., Silver M., van der Zee R., Li
T., Witzenbichler B., Schatteman G., Isner J.M. Isolation of putative
progenitor endothelial cells for angiogenesis. Science. 1997 Feb 14;
275(5302):964-7. Assmus B., Schachinger V., Teupe C., Britten M.,
Lehmann R., Dobert N., Grunwald F., Aicher A., Urbich C., Martin H.,
Hoelzer D., Dimmeler S., Zeiher A.M.; Transplantation of Progenitor
Cells and Regeneration Enhancement in Acute Myocardial
Infarction.Transplantation of Progenitor Cells and Regeneration
Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation.
2002 Dec 10; 106(24):3009-17.
Chen J., Zhang Z.G., Li Y., Wang L., Xu Y.X., Gautam S.C., Lu M.,
Zhu Z., Chopp M. Intravenous administration of human bone marrow
stromal cells induces angiogenesis in the ischemic boundary zone after
stroke in rats. Circ Res. 2003 Apr 4; 92(6):692-9
Chen J., Sanberg P.R., Li Y., Wang L., Lu M., Willing A.E.,
Sanchez-Ramos J., Chopp M.Intravenous administration of human umbilical
cord blood reduces behavioral deficits after stroke in rats. Stroke.
2001 Nov; 32(11):2682-8.
Eriksson P.S., Perfilieva E., Bjork-Eriksson T., Alborn A.M.,
Nordborg C., Peterson D.A., Gage F.H.. Neurogenesis in the adult human
hippocampus. Nat Med. 1998 Nov; 4(11):1313-7
Hofstetter C.P., Schwarz E.J., Hess D., Widenfalk J., El Manira A.,
Prockop D.J., Olson L. Marrow stromal cells form guiding strands in the
injured spinal cord and promote recovery. Proc Natl Acad Sci USA. 2002
Feb 19; 99(4):2199-204.
Ianus A., Holz G.G., Theise N.D., Hussain M.A.. In vivo derivation
of glucose-competent pancreatic endocrine cells from bone marrow
without evidence of cell fusion. J Clin Inest 2003 March 111(6): 843-50
Jiang Y., Jahagirdar B.N., Reinhardt R.L., Schwartz R.E., Keene
C.D., Ortiz-Gonzalez X.R., Reyes M., Lenvik T., Lund T., Blackstad M.,
Du J., Aldrich S., Lisberg A., Low W.C., Largaespada D.A., Verfaillie
C.M. Pluripotency of mesenchymal stem cells derived from adult marrow..
Nature 2002 Jul 4; 418(6893):41-9
Kempermann G., Gast D., Gage F.H. Neuroplasticity in old age:
sustained fivefold induction of hippocampal neurogenesis by long-term
environmental enrichment. Ann Neurol. 2002 Aug; 52(2):135-43.
Li Y., Chen J., Chen X.G., Wang L., Gautam S.C., Xu Y.X.,
Katakowski M., Zhang L.J., Lu M., Janakiraman N., Chopp M.. Human
marrow stromal cell therapy for stroke in rat: neurotrophins and
functional recovery. Neurology. 2002 Aug 27; 59(4):514-23 Mezey E., Key
S., Vogelsang G., Szalayova I., Lange G.D., Crain B. Transplanted bone
marrow generates new neurons in human brains. Proc Natl Acad Sci USA.
2003 Feb 4; 100(3):1364-9 Perin E.C., Geng Y.J., Willerson J.T. Adult
stem cell therapy in perspective. Circulation. 2003 Feb 25; 107(7):935-
8.
Rafii S., Lyden D. Therapeutic stem and progenitor cell
transplantation for organ vascularization and regeneration. Nat Med.
2003 Jun; 9(6):702-12.
Terada N., Hamazaki T., Oka M., Hoki M., Mastalerz D.M., Nakano Y.,
Meyer E.M., Morel L., Petersen B.E., Scott E.W.. Bone marrow cells
adopt the phenotype of other cells by spontaneous cell fusion. Nature.
2002 Apr 4; 416(6880):542-5 Vassilopoulos G., Wang P.R., Russell D.W..
Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003
Apr 24; 422(6934):901-4 Wang X., Willenbring H., Akkari Y., Torimaru
Y., Foster M., Al-Dhalimy M., Lagasse E., Finegold M., Olson S., Grompe
M.. Cell fusion is the principal source of bone-marrow-derived
hepatocytes. Nature. 2003 Apr 24; 422(6934):897-901
Zhao L.R., Duan W.M., Reyes M., Keene C.D., Verfaillie C.M., Low
W.C.. Human bone marrow stem cells exhibit neural phenotypes and
ameliorate neurological deficits after grafting into the ischemic brain
of rats. Exp Neurol. 2002 Mar; 174(1):11-20. Zhao Y., Glesne D.,
Huberman E. A human peripheral blood monocyte-derived subset acts as
pluripotent stem cells. Proc Natl Acad Sci USA 2003 Mar 4; 100(5):2426-
31
Senator Brownback. What you're describing is exciting and I
hope this is a field that we can put much additional research
funding into.
Dr. Rubinstein, thank you very much for joining us today.
STATEMENT OF PABLO RUBINSTEIN, M.D., DIRECTOR OF PLACENTAL
BLOOD PROGRAM, NEW YORK BLOOD CENTER
Dr. Rubinstein. Thank you very much, Senator. We are
grateful for the opportunity to address this Committee.
The work I will describe refers to the stem cells that are
present in cord blood. This work, which will be presented by
both myself and Dr. Kurtzberg, has taken place over a number of
years, as I will describe.
The first evidence that there were stem cells in cord blood
was reported in 1974. From that time to the present, the most
important elements in this history are the first cord-blood
transplant that occurred in 1988. During the intervening years,
there was a lot of research done that allowed this to happen.
From 1988, where the first patient was transplanted by--a
patient from Duke University, a patient of Dr. Kurtzberg's.
The next big element was the setting up of a cord-blood
program for treating patients without sibling donors, where we
collect cord blood from unrelated donors, with informed
consent, and this blood is frozen and then is available for use
on anyone who needs them. The first unrelated cord-blood
transplant from our repository at New York Blood Center was
performed by Dr. Kurtzberg at Duke in 1993.
And the next step in this story is the exemption granted by
the FDA for us to continue this research and to expand the
range of documented indices of the activities of these
transplants. This year, there have been more than 3,500
transplants performed worldwide, so far, with cord blood. Of
these, more than 2,000 have been in the United States, and
1,370 from our own cord-blood bank.
The NIH has recognized the importance of this work and has
created a second study, the COBLT study, which Dr. Kurtzberg
participated, both of the transplanted and as a banker, to
produce more of these transplants for patients in need. Dr.
Kurtzberg will also report beautiful results that have been
obtained with patients with cord-blood transplants that
repaired, or at least helped to repair, tissues other than the
blood and the immune system, which are a direct province of the
stem cells in the cord blood.
How is cord blood prepared and used? After the birth of a
healthy baby, the placenta is removed, with the major segment
of the cord, and the baby goes one way; the placenta is taken
out. Normally, this placenta, with the segment of the cord, is
discarded. In our case, we drain the blood that is left in the
placenta, and we take it to the laboratory, process it, freeze
it down, and, as the slide shows, we have special containers
that allow us to freeze it in liquid nitrogen. At the
temperature of liquid nitrogen, this blood will be available
for transplantation for many years, without attrition. The
blood is stored in special containers, which maintain control
and information, directly in the same device.
Results that have been obtained in the clinical use of this
cord blood over the years allow us to compile a list of
advantages that cord blood offers to clinicians and patients,
in comparison with bone marrow. There are, first of all, no
risks to the donors. There is no donor attrition. The blood
will stay frozen until it's used. If it is processed correctly,
it will be available for many years. We don't know how many,
because it's longer than has been used, so far over 15 years.
Grafts are available on short notice. They can be produced, and
routinely are produced, in our case, within days, not months or
years. There are fewer latent viral infections in cord blood
than in adult bone marrow.
But the main reason why this blood is so important is
because the immune reaction that the donor's cells exert
against the recipient's tissues, which is a problem with bone-
marrow transplantation, is much weaker in the case of cord
blood; probably reflecting the biological status of that blood
that comes from an organism in which the mother and the child
have to tolerate each other. This advantage allows us to
perform transplants with some mismatches. In bone-marrow
transplantation, the more mismatches, the more problems occur
for the patient; not just immediate, but for a long time for
those patients who are successfully treated.
That allows us, therefore, to find matches for people who
have very much difficulty finding matches, people with rare
types and people of ethnic minorities in which the
opportunities to find a donor among those in the volunteer
donor groups is much less, simply because there are fewer of
them in the population.
Another important result, which is now being shown in the
slide, has been obtained in cooperation with the International
Bone Marrow Transplant Registry. Several hundred patients
transplanted with bone marrow were compared with cord-blood
recipients for the same disease and the same age groups. The
cord blood with no more than one mismatch, and the bone marrow
with no more than one mismatch, as you can see offer exactly
the same long-term transplant survival. What you're not seeing
here is that the clinical condition of the patients is
different. The cord-blood recipients usually have a much easier
time, with much fewer chronic graft versus host disease than
the bone marrow.
Another thing the slide doesn't show is that the average
result for all types of transplants that are taking place. And
in the case cord blood, there is an additional influence. In
addition to the matching is the cell dose. You can see, in the
panel on the left, that people transplanted with small cell
doses have a lower probability of long-term survival. But if we
can eliminate, from our transplantation, the need to use those
small cord bloods, we can shift the whole curve up and offer an
overall larger probability of success.
To terminate, I would just like to show you two slides,
which refer to the need. It has been reported by the GAO, in
October last year, the situation with bone-marrow
transplantation that reflects the fact that in this country, at
the moment, for people who need unrelated transplants, the
opportunity to get the transplant is estimated at about 9
percent of the total. For the period 1997 to 2000, of an
estimated 44,000 patients who needed transplant, 4,056 got
them--10 percent of the need, and about a quarter of all of
those patients that went all the way to search officially.
Finally, the other aspect of cord blood is, because of its
tolerance of mismatches, it's possible to transplant patients
of the different minority populations in our country with
appropriate transplants. And, in this slide, you can see four
populations--Asians, African Americans, Hispanic, and
Caucasians. The African American is highlighted as an example.
You will see, in the first part of the slide, that the
proportion of African Americans, among all those who search, is
about 12 percent, which reflects very closely with the size of
the African American community in the national scope. However,
the donors that were transplanted with bone-marrow transplants
by the NMDP is only 6 percent, so only half as much chance as
is available if they were equally--if they have equal access to
the transplants. With cord blood, however, the probability is
19 percent. And the reason for that is twofold. One is that we
can make transplants that are less well matched. And, second,
that we can select our donors by harvesting the cord blood in
places where we can collect effectively, cord blood from
members of these ethnic, and all the ethnic, groups. And, as a
result, we can improve the access of these patients to
transplantation.
This is my part of the presentation. And now Dr. Kurtzberg
will continue.
Senator Brownback. Thank you very much, Dr. Rubinstein.
And, Dr. Kurtzberg, I look forward to your testimony here
today.
STATEMENT OF JOANNE KURTZBERG, M.D., DIRECTOR,
PEDIATRIC STEM CELL TRANSPLANT PROGRAM,
DUKE UNIVERSITY MEDICAL CENTER
Dr. Kurtzberg. We're going to have a little technical
switch here.
Senator Brownback. All right.
Dr. Kurtzberg. OK.
Well, thank you very much for listening to our story today
about cord blood. I'm going to continue by talking about the
clinical applications of cord-blood transplantation, today and
in the future.
We've been very excited about cord-blood transplantation,
because, as a transplant physician, I, and all others, are
faced with patients who need the therapy and don't have donors.
And cord blood has filled the niche for those patients, because
it can be used without complete matching.
Now, the child shown in this slide was the first recipient
ever of a cord-blood transplant. He's from Salisbury, North
Carolina, and was transplanted in 1988 with cord blood from his
baby sister. And his transplant was extremely important,
because there was no way to really demonstrate or prove, in
animal model or in a test tube, that cord blood contains
sufficient numbers of stem cells to reconstitute a patient. And
there were many skeptics, and most people believed it wouldn't
work. But this family was very courageous and allows his baby
sister's cord blood to be used for his transplant for a rare
genetic diseased, called Fanconi anemia. And he's shown----
Senator Brownback. What was the disease?
Dr. Kurtzberg. Fanconi anemia, which is an inherited
disease that causes death in the first decade of life. It's a
defect in DNA repair. And it affects all cells in the body; but
first, the blood. And it leads to bone-marrow failure, or
leukemia, causing death in the first decade of life.
Senator Brownback. Thank you.
Dr. Kurtzberg. This boy was successfully transplanted,
successfully engrafted, is shown 15 years later, in the right-
hand panel, and is doing well; well, has a durable graft.
Again, one of the questions a transplanter would have is,
``Will the cells not only grow back at the beginning, but will
they stay there, and will they remain and grow with the patient
who received them?'' And he is the longest living survivor of a
cord-blood transplant, the first recipient of a cord-blood
transplant. And, at least at 15 years, we can say that this is
a durable graft, without causing any late problems.
Now, after his transplant, there were other related
transplants performed in small numbers over the next 5 years,
but the real breakthrough in cord-blood transplantation came
when Dr. Rubinstein's bank was established and there was a pool
of donors in the unrelated setting. And it's now been shown
that cord blood can be used for all the applications of bone
marrow and that includes those listed in the slide--hematologic
malignancies, immune deficiencies, like the ``bubble boy''
disease, marrow-failure syndromes, hemoglobinopathies. And
you'll hear from a sickle-cell anemia patient later, who has
had his disease corrected with a cord-blood transplant.
And then a very interesting category of diseases called the
``inborn errors of metabolism,'' where babies are born missing
enzymes that are necessary for development of the brain or the
muscles or the heart or the skeletal system; and where, without
therapy, they generally die in infancy or early childhood.
Now, I only have time to show you a little bit of data from
patients transplanted with cord blood; and I chose the genetic
diseases to focus on, because I think they really illustrate
lessons that we can learn to move into the field of
regenerative medicine.
This slide shows our results transplanting children with
genetic immunodeficiency syndromes--where their immune system
is absent at birth. And there are multiple forms of this
disease. It's fatal in childhood, without treatment, either
because of infection or cancer. And transplant is the only
therapy that's curative.
This little boy was transplanted at 18 months of age, when
he was critically ill with a fungal infection, and really no
one thought he would even make it through the transplant. And
he's shown 3 years after transplant, successfully corrected
with a normal immune system.
Overall, in about 30 patients with this disease, we have an
80 percent event-free survival, which is shown in that curve.
And what that means is these children are alive, well,
engrafted, and they have a recovered immune system that
functions normally.
Senator Brownback. And the children would have all died.
Dr. Kurtzberg. They would have all died, yes. These are
lethal genetic conditions.
Another example is an inborn error called Hurler syndrome,
where children are born missing an enzyme that's necessary for
development of the brain, the liver, the bones, the cornea, and
the cartilage. And this little girl is an example of a child
transplanted with Hurler in infancy. These children generally
die by the age of five to 10 years. And although they have
severe mental retardation, they actually die of atherosclerotic
heart disease because of deposits that fill up the coronary
arteries and cause damage to the heart muscle. And transplant,
again, will correct this disease. And, in our hands,
transplanting now over 25 children, the event-free survival is
90 percent. That means these children are engrafted, corrected.
And I just showed you one example of a child transplanted at 5
months of age, now 6 years old, with a normal IQ--actually, a
high IQ--and she's a reflection, not an exception. All the
children we've treated have had normal development and regained
skills that they had lost.
Senator Brownback. And normal IQ development.
Dr. Kurtzberg. Yes, they are in the normal range.
We also know that their bones have corrected, and that they
have not developed coronary artery disease, which probably has
implications for adult coronary artery disease, although the
pathogenesis is different.
A third disease that really falls into a category called
leukodystrophy, where there's, again, children born with
defects in myelination. Myelin is the covering of the nerve
sheath in the white matter of the brain. And without that
covering, the brain neurons are damaged and die. Krabbe disease
is the most severe leukodystrophy, with the earliest onset, and
children who have this disease generally develop normally for
the first few months of life and then regress and are
vegetative by a year of age, and die between one and two years
of age.
Now, the little boy in the picture lost a sibling to Krabbe
disease, and the sibling died at 13 months of age. He's shown
at 2 years of age, but he was transplanted at 3 weeks of age,
because we knew, the cause of his sibling's death we know to
look for the disease. And when he was diagnosed, we were able
to mobilize a cord blood within a few days. We tested that cord
blood to make sure that cord blood didn't carry the disease,
and then go forward with a transplant in the first month of
life. There have now been ten children treated in the United
States with that same approach, and all ten are doing very well
anywhere from one to 6 years later.
The survival curves that are portrayed on the graph show
you that the newborn transplants, which is the top of the line
and is straight, at 100 percent, all are surviving, doing well,
and developing normally. Children in the middle line, that goes
down and evens out at about 40 percent, are children who had no
family history. There was no way to know to look for the
disease. They were diagnosed after they had symptoms, and they
had some brain damage at that point. And those children have a
40 percent event-free survival, and they are left with some
disability, sometimes severe and sometimes mild.
Senator Brownback. So the age that you catch this is very
significant.
Dr. Kurtzberg. Well, it's either the age or the amount of
damage or both, and it's hard to know.
And then the other line, that goes all the way down to
zero, shows you the natural history of the disease in untreated
children. In this case, there are 156 in the curve. And these
are children whose families contacted us, and we evaluated, but
we felt were too advanced with the disease for the procedure,
and so they were not treated, and the disease ran its natural
course.
Now, this is an MRI picture. Now, I know it's a little
complicated, but it shows the brain of a different child, who
was also transplanted, with Krabbe, in the first 3 weeks of
life. And what's interesting here is, this is her scan--moving
into it with my arrow--at 1 year of age, the smaller brain; and
then, on the left-hand panel, 2 years of age. And at 1 year of
age, she has some fluffy stuff around the ventricles, which is
inflammation, which is abnormal. But, at 2 years of age, that
has regressed and has gone away. And, in addition, these gray
lines show myelination, which is normal for age. Now, this
child would not have been able to myelinate her brain if she
had not been transplanted. And, in fact, she probably would not
have survived to this age. But this shows actual repair on a
scan in a child who is doing well.
This last slide of this Krabbe story shows brain tissue
from a child who died. The child was a girl, and she received a
transplant from a boy. And these are nuclei of brain cells in
the white matter and in something called the choroid plexus,
which are the cells lining the ventricles. All the cells that
have blue or green dots are male cells, donor cells, that have
traveled to this child's brain and distributed throughout the
brain. In fact, we found that 30 to 40 percent of the cells in
her brain came from the donor, and we're investigating what
kinds of cells they are.
But, again, as you think of repairing neurologic damage,
this is a hint that maybe these cells have the capacity to do
that, and they certainly need to be examined further.
Finally, I want to just end with a few comments about
sickle-cell anemia and hemoglobinopathies. Sickle-cell anemia,
as you'll hear later, can be cured by hematopoietic stem cell
transplantation, either from bone marrow or from cord blood.
But many patients don't have donors. And we have transplanted a
few patients with sickle-cell disease and leukemia, and cured
both diseases.
The little boy in the picture here is a surgeon's son, who
has thalassemia, which is another kind of hemoglobinopathy, and
he was the first recipient of a cord-blood transplant for
hemoglobinopathy, at two-and-a-half months of age, before the
disease had caused any damage to any of his organs. And he is
going well, at 5 years of age, without any symptoms or problems
from the disease.
Personally, I believe that we should be taking the same
approach for sickle cell, using the transplant very early in
childhood or infancy, where the transplant survival rates are
better. This graph shows you event-free survival after related
cord-blood transplants, and they are 90 percent survival, and
80 percent of event-free survival in thalassemia and sickle-
cell disease, respectively. And so this works and is better
than much of the morbidity that much of the patients who suffer
with this disease later will experience.
Also, cord blood has a role here for African American
patients, who otherwise can't find donors very quickly.
Cord blood has a lot of applications right now, in the
diseases I mentioned and others. It also has applications, I
think, in the future for cellular therapies, along with other
stem cell sources. And our real request here is to continue to
be able to bank cord blood in the public setting.
And very briefly, Dr. Rubinstein told you the history, but
the NHLBI had funded both his first public cord-blood bank, and
then a second group of banks, under a program called COBLT.
Those banks and Dr. Rubinstein's bank have proven that this is
an important resource. But now there's no continued funding to
take this resource, where really about $20 million was already
expended to build it up and continue it. It needs to transfer
over to the service sector and be supported through federal
dollars.
So our proposal is to establish a national cord-blood
program, which will provide grafts for patients in need now and
provide an inventory of cells for research and future cellular
therapies, and we need to have funding to create a network of
four to six banks in the United States that will network
together to build an inventory of about 100 to 150,000 units,
which are the numbers needed to solve the problems that Dr.
Rubinstein illustrated with cell dose and matching.
I'll stop there. Thank you.
[The prepared statement of Dr. Rubinstein and Dr. Kurtzberg
follow:]
Cord Blood
A Source of Stem and Progenitor Cells for Patients in Need ofBone
Marrow Transplantation and Other Cellular Therapies
Pablo Rubinstein, M.D., New York Blood Center and Joanne Kurtzberg,
M.D., Duke University
Cord Blood Research Progress
1974: First Report on Stem/Progenitor Cells in
Human Cord Blood
1988: First Cord Blood Transplant (Sibling)
1992: First Public Cord Blood Bank
(Unrelated Donors. NIH-sponsored Research)
1993: First Unrelated Cord Blood Transplant
1996: First FDA IND + NIH Sponsored COBL T Study
2003: More than 3500 Cord Blood Transplants
Worldwide, 2000 in U.S.
2003: Donor-type Cells of Non-Blood or Immune
Lineages and Evidence of Myelin
Regeneration in Patients with lysosomal
storage diseases after Cord Blood
Transplant
______
______
______
______
______
______
______
Senator Brownback. Is there legislation introduced to do
that, on either the House or the Senate side? Do you know?
Dr. Kurtzberg. There is one in progress, but it has not
been introduced yet.
Senator Brownback. OK.
Dr. Kurtzberg. There's a draft of a bill.
Senator Brownback. All right. Because we'll sure want to
get that out and do that for you. This is very encouraging. And
if you were one of the parents of one of those children, this
is the hope you've been looking for.
Dr. Kurtzberg. I've personally treated over 500 patients,
and I have seen this work in children with otherwise fatal
diagnoses. So it's very important to be able to continue the
work.
Senator Brownback. I'm sure that parents are absolutely
ecstatic when they see that and see you. You're----
Dr. Kurtzberg. Sometimes.
Senator Brownback.--an angel to them.
Dr. McDonald, thank you very much for joining us and for
being here today.
STATEMENT OF JOHN W. McDONALD, M.D., Ph.D.
DEPARTMENT OF NEUROLOGY, WASHINGTON UNIVERSITY
SCHOOL OF MEDICINE
Dr. McDonald. Good afternoon, Mr. Chairman.
I'm Dr. John W. McDonald, and I'm an Assistant Professor at
the Department of Neurology and Neurological Surgery and
Director of the Spinal Cord Injury Program, at Washington
University School of Medicine, in St. Louis. I'm also a staff
physician at Barnes-Jewish Hospital, the Rehab Institute of St.
Louis and St. Louis Children's Hospital.
I'm here today on behalf of the Coalition for the
Advancement of Medical Research, a coalition of over 75
patient, scientific, and university organizations dedicated to
ensuring that all forms of stem cell research be allowed to be
explored here in the United States.
The Coalition started 2 years ago to ensure that stem cell
research receives the same sorts of funding that all other
research receives from the Federal Government. The group also
is dedicated to ensuring that critical cutting-edge research is
not criminalized.
As the Director of the Spinal Cord Injury Program, I see
thousands of children and adults with devastating neurologic
injuries, including spinal-cord injuries. These patients really
have no practical alternatives for recovery of function after
the injury has already occurred, such simple things as recovery
of bowel and bladder control, or simply feeling a loved-one's
embrace. And only some of the 11,000 people who are injured
every year recover any substantial function with traditional
rehabilitation, which assumes that recovery is only possible
after 6 months to 2 years.
I'm currently working on a variety of ways to treat
patients with spinal-cord injury or disease. And shown now is
an example of a T2 weighted MRI image, the spinal cord is in
the middle, if you see, down to the red box, it actually shows
where the injury is. A really minute injury at this point in
the nervous system becomes a really devastating problem. And I
mentioned that there's 11,000 people injured each year. There's
a quarter of a million living with spinal-cord injury, and
another four to five times that many with medical causes of
spinal-cord injury, such as multiple sclerosis or ALS.
I've been working on a variety of ways to treat patients
with spinal-cord injury and disease. For example, I've seen
significant improvements in a very small group of patients,
using activity-based therapy. This is a therapy that relies on
providing pattern activations for someone who's completely
paralyzed, like putting a paralyzed person on a functional
electrical stimulation bike, with this idea that the nervous
system requires optimal activity in order for new cells to be
born to optimize regeneration, now that we understand that the
adult nervous system does have some limited capacity for
regeneration.
Shown here on this graph is the results of a patient that
participated in this. Now, let me preface this by saying that
this individual was completely paralyzed, from the neck down,
from just below C-2 down, unable to breathe, move, or feel
below that level, for the first 5 years. Traditional history
would say that there's no opportunity, absolutely, that this
individual could regain any substantial function. And this
individual began to recover substantial motor function, being
able to move most of the joints in his body, to about 20
percent of normal on the scale. Of more importance was the
recovery of sensation, which was about 70 percent of normal.
Again, over the first 5 years, there was very limited recovery,
and then a progressive recovery over the last 3 years, after
institution of the activity-based recovery program, in the
middle of 1999.
We've done additional research now in animals that
demonstrates that this type of activity actually mobilizes the
stem cells that are present in the spinal cord below the level
of the injury. What happens, below the level of the injury, in
a chronic situation, is that the number of stem cells are
reduced, unable to be there to be able to replace cells that
are lost. And this activity appears to be repleting those cells
so that they're available, inasmuch as a stem cell transplant
would allow.
Senator Brownback. By the physical stimulation that's
taking place.
Dr. McDonald. Right.
Now, while adult stem cells have potential for
significantly improving clinical treatment of a wide range of
diseases, I believe it's critical that we also explore the use
of embryonic stem cells.
If you compare stem cells to a tree, adults stem cells have
already developed and specialized down a particular path, or
limb. On the other hand, embryonic stem cells are still at the
base of the trunk, ready to be guided down any number of limbs.
It's, therefore, much more feasible to try to encourage
embryonic stem cells to develop into whatever cell type is
needed.
As you can see from this video, this is an animal that's
treated, 9 days after a spinal-cord injury, with embryonic stem
cells that have been induced to become neuro progenitors. This
is an animal that's just a control; treated identically, except
no cells. You can see it has great difficulty moving its hind
limbs, raising his tail, and basically drags his behind.
The next slide is a similar animal, but it's been
transplanted with embryonic stem cells, and you can see,
really, a marked improvement in its ability to walk, stand on
its hind limbs, and lift his tail. And the stage at which these
cells were transplanted were neuro progenitors similar to those
that can be derived from ESLs.
So, as you can see from the video, we have already found
encouraging support for the use of embryonic stem cells to cure
or treat some of the most debilitating diseases. The two rats
that you have just seen have the same injury, but the rat that
received the transplanted embryonic stem cells has recovered
significantly more use of its hind limbs and tail.
My hope is that one day the patients that I see in the
Spinal Cord Injury Program will also be able to regain
movement, just like that rat in this video.
And as a scientist, I cannot guarantee that embryonic stem
cells will lead to cures and treatments. I can tell you,
however, that they hold great promise. Science is a process in
which we knock on 20 doors; 19 open, with nothing behind them;
one opens to reveal a pot of gold. We can't predict which door
will be the magic door.
The field of stem cell research, whether it be embryonic,
adult, cord-blood stem cells, is extremely new. It's entirely
too early to rule out any one of these areas of research in
favor of another. But my wheelchair-bound patients should not
have to wait for us to explore each possibility one at a time.
In the years that have been spent debating the issues here
in Washington, research that could 1 day lead to cures and
treatments for so many diseases has been held back. Some senior
researchers have either left the United States to work
elsewhere or have decided to work in other areas of biomedical
research. And, more importantly, many of the next generation of
researchers have decided to stay away from these areas because
of the uncertain political environment.
Mr. Chairman, please allow all forms of stem cell research
to move forward--adult, cord blood, and embryonic--so that we
can continue to look for medicine's pot of gold.
Thank you.
[The prepared statement of Dr. McDonald follows:]
Prepared Statement of John McDonald, M.D., Ph.D. on behalf of the
Coalition for the Advancement of Medical Research
Good afternoon Mr. Chairman and members of the Committee. I am Dr.
John W. McDonald and I am an Assistant Professor in the Departments of
Neurology, Neurological Surgery, Anatomy and Neurobiology and Director
of the Spinal Cord Injury Program at Washington University School of
Medicine in St. Louis. I am also a staff physician at Barnes-Jewish
Hospital, the Rehabilitation Institute of St. Louis and St. Louis
Children's Hospital.
I am here today on behalf of the Coalition for the Advancement of
Medical Research,* a coalition of over 75 patient,
scientific and university organizations dedicated to ensuring that all
forms of stem cell research be allowed to be explored here in the
United States. The Coalition started two years ago to ensure that stem
cell research receives the same sorts of funding that all other
research receives from the Federal government. The group also is
dedicated to ensuring that critical, cutting-edge research is not
criminalized.
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\*\ The Coalition is comprised of nationally-recognized patient
organizations, universities, scientific societies, foundations, and
individuals with life-threatening illnesses and disorders, advocating
for the advancement of breakthrough research and technologies in
regenerative medicine--including stem cell research and somatic cell
nuclear transfer--in order to cure disease and alleviate suffering.
---------------------------------------------------------------------------
As the director of the Spinal Cord Injury Program, I see thousands
of children and adults with devastating spinal cord injuries. These
patients have no real hope for recovering functions most of us take for
granted, from bowel and bladder control to simply feeling a loved one's
embrace. And only some of the 11,000 people who get injured each year
recover with traditional rehabilitation, which assumes that recovery is
only possible after six months to 2 years.
I am currently working on a variety of ways to treat patients with
spinal cord injury or disease. For example, I've seen significant
improvements in a very small group of patients using activity-based
therapy, which relies on electrical stimulation to help patients
exercise their paralyzed limbs. While significant, even those successes
are minimal and extremely preliminary--it's still unclear whether these
techniques can help most spinal cord injuries, and to what extent they
alone can restore function. We need to examine other promising
approaches, and I believe that embryonic stem cells have the most
potential.
While adult stem cells also have potential for significantly
improving clinical treatment of a wide range of diseases, I believe it
is critical that we also explore the use of embryonic stem cells. If
you compare stem cells to a tree, adult stem cells have already
developed and specialized down a particular path, or limb. On the other
hand, embryonic stem cells are still at the base of the trunk, ready to
be guided down any of a number of limbs. It's therefore much more
feasible to try to encourage embryonic stem cells to develop into
whichever type of cell is needed.
As you can see from the video, we have already found encouraging
support for the use of embryonic stem cells to cure or treat some of
the most debilitating diseases. The two rats you see have the same
injury, but the rat that received transplanted embryonic stem cells has
recovered significantly more use of its hind legs and tail.
My hope is that one day the patients I see in the Spinal Cord
Injury Program will also be able to regain movement, just like the rat
in this video.
As a scientist, I cannot guarantee that embryonic stem cells will
lead to cures and treatments. I can tell you, however, that they hold
great promise. Science is a process in which we knock on 20 doors:
Nineteen open with nothing behind them; One opens to reveal a pot of
gold. We cannot predict which door will be that magic door. The field
of stem cell research, whether it be embryonic, adult or cord blood
stem cells, is still extremely new. It is entirely too early to rule
out any one of these areas of research in favor of any other. My
wheelchair bound patients should not have to wait for us to explore
each possibility one at a time.
In the years that have been spent debating the issue here in
Washington, research that could one day lead to cures and treatments
for so many diseases has been held back. Some senior researchers have
either left the United States to work elsewhere or have decided to work
in other areas of biomedical research. And many of the next generation
of researchers has decided to stay away for these areas because of the
uncertain political environment. Mr. Chairman, please allow all forms
of stem cell research to move forward, adult, cord-blood and embryonic,
so that we can continue to look for medicine's pot of gold.
Senator Brownback. Thank you, Dr. McDonald. And thank you
for your passion and your heart and your work to help others be
able to walk.
Dr. Peduzzi-Nelson, we have 12 minutes, I think, they're
just telling me, left in the vote. So I think we'll try to get
your testimony in before I head over to vote.
But I'm delighted to have you here, and please proceed with
your testimony.
STATEMENT OF JEAN D. PEDUZZI-NELSON, Ph.D.
DEPARTMENT OF PHYSIOLOGICAL OPTICS
UNIVERSITY OF ALABAMA AT BIRMINGHAM
Dr. Peduzzi-Nelson. What I'm going to show is that these 20
doors are partially opened. We can see what doors contain the
pots of gold and what doors contains gremlins that we need to
close permanently. I agree with Dr. McDonald that we're not
knocking on these doors equally. Even with the Federal ban, the
vast majority of studies are still using embryonic animal stem
cells and human stem cell lines. The ban does not affect animal
stem cell research. Using a person's own stem cells is the area
of research that's being neglected.
I would like to quickly review the results of some clinical
and pre-clinical trials that clearly shows where the pots of
gold are and where the gremlins are. We've already heard some
testimony that there's definitely pots of gold for a number of
children, using human umbilical cord blood, and also that the
work that Dr. Hess presented, using bone marrow, and also Dr.
McDonald's work with rehabilitative therapy--are all very
viable, wonderful areas to pursue.
In terms of spinal-cord injury, I'd like to present the
results of two clinical trials and show their results using an
exact same test. In these trials, they were using tissue,
neural tissue. And how this relates to the stem cell issue is,
if you put this tissue--transplant it into the brain or spinal
cord, the cells that survive are the stem cells, or the early
derivatives of these stem cells.
In a clinical trial that took place at the University of
Florida that began in 1997, minced fetal spinal-cord tissue was
used. The results of the first two patients have been published
and are presented on the left side of the first three graphs.
Their finding was that there was very little change in their
condition. However, in another study that's an ongoing trial in
Portugal, person's own olfactory mucosa was used. All of the
patients in this study, as you can see in the first graph, in
the light-touch ASIA scores, and in the next graph, using the
pin-prick ASIA scores, and in the next graph, using the motor
scores, that there was some improvement in actually all the
patients that received the transplant by the first month after
the transplant of their own olfactory mucosa.
And furthermore, the first patient that was treated, after
15 months after--16 months after the treatment, regained
bladder control. And I don't if many people in the audience
know this, but this is a very severe problem with people with
spinal-cord injury. And this woman no longer needs catheters at
all.
What's interesting is, at the Portuguese studies, they had
no rehabilitative methods available to them. There was no rehab
therapy at all. The improvement was all what just happened
naturally. And much greater improvement might have occurred if
they had resources to have rehab therapy.
I'd like to move on to--in the next graph, to the results
of two Parkinson's trials. These are clinical trials that
clearly show some difference in the results. In a study by
Freed and Associates done several years ago, human fetal stem
cells were injected into the brain. And, on the left, you see
the results of that study. There was a 28 percent improvement
in the younger patients. ``Younger,'' in this study, which I
like, means less than 60 years old. However, at about 1 year
after the transplant, there was a very devastating result in 15
percent of the patients. They got significantly worse because
of overgrowth of these embryonic cells that were placed in the
brain, and they were much worse in function than they had been
previously.
However, there's been another clinical trial in
Parkinson's, and this was using the person's own stem cells
from their brain. And this was a study done by Dr. Michel
Levesque, in California. In this case, in this patient, there
was an 83 percent improvement, and the patient had the
treatment 2 years, and no detrimental side effects have been
observed.
The experimental studies, animal studies, also provide
indication of what is behind the doors. First, in the next
slide, it's true, maybe you can't make a whole tree from adult
neural stem cells, the cells that are from the brain. However,
there's lots of other stem cells in the body. So why would you
even try to make every stem cell from an adult neural stem
cell?
Also, we know that you can make neurons, muscle cells,
blood cells, from the stem cells in the adult brain. Also, you
can get neurons or nerve cells or support cells to develop from
bone, as Dr. Hess has mentioned, from skin, from blood, and my
favorite, from fat stem cells.
Second, the experimental studies that have been done using
embryonic stem cells, as do the clinical trials, show that
embryonic stem cells are dangerous, especially in terms of
overgrowth. And studies by Bjourland and also by Dr. Gage and
others have found tumor formation and sometimes blockage of the
ventricular system can occur using embryonic stem cells.
Third, my own work in rats with chronic severe spinal-cord
injury show that adult stem cells can lead to a functional
improvement.
I think that it really gets down to a very basic question.
If you or your loved one had a serious disease or injury, would
you like them, or yourself, to receive your own stem cells or
fetal, embryonic, or cloned stem cells? I think you don't have
to be a scientist to answer that question. But the answer to
the question is also supported by the clinical trials and the
pre-clinical animal trials that have been done so far.
I would like to end by saying that the reason I'm here is
that the victims of terrible diseases and injuries are again
becoming victims to support a therapy that's not in their best
interest. With only a limited amount of funding available, more
focus is needed in directing research in areas that can help
people in the next five to 10 years, not several lifetimes
away.
Thank you.
[The prepared statement of Dr. Peduzzi-Nelson follows:]
Prepared Statement of Jean D. Peduzzi-Nelson, Ph.D., Department of
Physiological Optics, University of Alabama at Birmingham
``The Y in the Road''
Thank you Senator Brownback and Senator McCain and distinguished
senators of the subcommittee for the invitation to present to you
today. Stem cells are a major medical breakthrough with tremendous
potential but we are now at a ``Y in the road'' as far as the future of
medicine. In deciding our course, the way is clouded by opposing
ethical views, vested interests of certain scientists & the biotech
community, political allegiances and celebrities. I would like the
members of the subcommittee and the audience to set aside all those
factors for just a few minutes. I ask you now to think about a very
basic question: If your loved one was suffering from a terrible injury
or disease, what type of stem cell treatment do you think would work
the best: (1) their own cells or (2) cells derived from embryos,
fetuses or cloned embryonic cells? I don't think you need to be a
scientist to answer that question. It also turns out that if you look
at the scientific evidence, not speculation about the future by
prominent scientists on either side of the issues, but just the facts
of where we are today based on clinical and preclinical trials, the
logical choice in medical treatment is also the best medical treatment.
I would now like to review the scientific data that prove that an
intuitively obvious concept is also supported by the results of recent
clinical trials and preclinical trials (experimental animal studies).
First, I would like to review the clinical trials using stem cells and
their derivatives in spinal cord injury and Parkinson's disease. Two
clinical trials using fetal tissue have been done in the U.S. and one
on-going clinical trial in Portugal using a person's own tissue. All of
these spinal cord injury trials are important to the question of stem
cell research because the cells that survive after the tissue
transplant are the stem cells and their early derivatives. The mature
cells in the tissue except for some support cells would die off. The
first study using fetal tissue was done at the University of Florida,
beginning in 1997, in the treatment of syringomelia--a condition in
which a large cavity forms in the spinal cord. Minced spinal cords (SC)
from 4-8 different human fetuses taken from elective abortions were
grafted into the cavity in the spinal cord. At 18-month follow-up of
the first 2 patients, the condition of the patients was not very
different.\1\ Another study was performed more recently using pig fetal
tissue at Washington University and SUNY/Albany. There have been no
further announcements regarding this study although the first patient
was done in April 2001.\2\ The study in Portugal has had impressive
results using a person's own olfactory mucosa.\3\ The olfactory mucosa
lines the upper nasal cavity and contains stem cells and cells that
encourage growth of nerve cell processes called olfactory ensheathing
cells. Patients with severe (complete) spinal cord injuries were
operated at 6 months following the injury. Other patients in this study
(not reported below) were up to 7 years post-injury with similar or
better results. On the next page are the charts comparing the results
from the first 2 patients from each of the 2 different trials. In
comparing the results of using embryonic tissues or using one's own
tissue:
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\1\ Wirth E.D. 3rd, Reier P.J., Fessler R.G., Thompson F.J., Uthman
B., Behrman A., Beard J., Vierck C,J., Anderson D.K. Feasibility and
safety of neural tissue transplantation in patients with
syringomyelia.Journal of Neurotrauma. 18(9):911-29, 2001.
\2\ http://www.diacrin.com/SCI%20Albany%20Surg.htm
\3\ Parks, D. Birmingham, News, Sunday, December 8, 2002, Olfactory
nerves could help mend spinal injuries. http://www.scsnw.com/
Nerves%20in%20nose%20may%20repair%20spinal%20
cord%20injuries.htm
(1) There was little change in the condition of the patients using
the embryonic tissue. There appeared to be no massive rejection
even though 4-8 different embryos were used for each patient in
the University of Florida trial and no reports of rejection in
the trial using pig cells used in Washington University and
---------------------------------------------------------------------------
SUNY/Albany.
(2) In the Portuguese study, there were increases in motor and/or
sensory scores by 1 month in almost all the patients receiving
their own olfactory mucosa suggesting that a person's own
tissue is more effective. The first patient done regained
bladder control at 16 months after the treatment and no longer
uses catheters. The second patient that had less improvement
was the patient that had the largest lesion (6 cm) of all of
the patients done so far.
The changes observed might have been greater for the patients
treated in Portugal if rehabilitative therapy was available there.
The clinical trials in Parkinson's disease had dramatic differences
in their findings depending on the original source of the cells:
fetuses or the person's own cells. In both cases, the cells were
matured in culture before being transplanted into the patient. A
clinical trial was done by Dr. Freed and colleagues in which 19
patients received cells derived from 4 different fetuses with abortions
at 7-8 weeks after conception.\4\ The patients that were under 60 years
showed about a 28 percent improvement in the Unified Parkinson's
Disease Rating Scale (UPDRS). About 15 percent of these patients showed
severe decline in function at 1 year after treatment. In another
Parkinson's study done by Dr. Michel Levesque, the patient who was 57
years old at the time of treatment, received cells derived from his own
brain stem cells.\5\ This patient showed an 83 percent improvement in
the UPDRS. Below is a chart that summarizes the percentage improvement
in the 2 clinical trials.
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\4\ Freed C.R., Greene P.E., Breeze R.E., Tsai W.Y., DuMouchel W.,
Kao R., Dillon S., Winfield H., Culver S., Trojanowski J.Q., Eidelberg
D., Fahn S. (2001) Transplantation of embryonic dopamine neurons for
severe Parkinson's disease. New Engl. J. Med.. 344:710-9.
\5\ Levesque, M.F. and T. Neuman Autologous transplantation of
adult human neural stem cells and differentiated dopaminergic neurons
for Parkinson's disease: one year post-operative clinical and
functional metabolic results. AANS31, 2002.
The greater improvement and lack of harmful late effects using a
person's own cells is primarily due to the fact that the cells were
derived from an adult as opposed to fetuses. Of lesser contribution to
the overall improvement probably was that the cells were genetically
identical and not rejected. There was no evidence of massive rejection
in any of the studies using fetal cells/tissues, even when pig cells
were used without long-term immune-suppressing drugs to prevent
rejection. However, better results were obtained using person's own
adult cells. The study by Freed and colleagues also suggests that the
primary problem with the fetal cells is not rejection. Using cells
derived from fetuses, the severe functional deterioration seen in
several patients was due to overgrowth of the cells derived from
fetuses, not a lack of cell survival.
It is rather ironical that the qualities cited for the superiority
of embryonic or fetal stem cells are actually responsible for causing
problems. Rapid growth is not always a desirable quality as clearly
seen with weeds in a garden or cancer in the body. In the Parkinson's
study, cells derived from the embryo and the adult were both allowed to
mature in culture, but the end result was quite different. As the graph
demonstrates, the patient's own cells markedly improved and no
debilitating side effects were observed. A possible explanation for
these findings is that adult stem cells are the natural components of
the adult body and endogenous mechanisms exist to control their growth
and maturation to replace damaged neurons.\6\ The cells from the adult
may have certain molecules on their surface (ligands or receptors) that
keeps the cells from uncontrolled growth. Both studies allowed the stem
cell to mature before implantation. If maturation of stem cell is a
necessary safety step, then the fact that embryonic cells are so
immature is a disadvantage. It would be possible and simpler to have
large-scale commercialization of cells derived from embryos or fetuses
but the end product would be grossly inferior for the recipients. There
are many types of adult human stem cells that are readily available
that lack the problems of overgrowth, rejection, and disease
transmission. Most people do not need a total body replacement. Even if
costly and complicated procedures of cloning are done to produce the
human stem cells (not technically possible yet), the cells will not be
genetically identical because of the mitochondrial DNA and improper
imprinting. There is evidence that the debate is raging in the
scientific community. A recent scientific article describing a clinical
trial included an opinion that the authors, although using a patient's
own blood stem cells, in no way support a ban on using human embryonic
stem cells.\7\
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\6\ van Praag H. Schinder A.F. Christie B.R. Toni N. Palmer T.D.
Gage F.H. Functional neurogenesis in the adult hippocampus. Nature.
415(6875):1030-4, 2002.
\7\ Janson C.G., T.M. Ramesh, M.J. During, P. Leone and J. Heywood
2001 Human intrathecal transplantation of peripheral blood stem cells
in amyotrophic lateral sclerosis. J Hematotherapy & Stem Cell Res
10:93-915.
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Preclinical Trials: Preclinical trials (experimental animal
studies) not only provide the basis for future clinical trials
described above, but also support the same conclusion that is reached
in reviewing the clinical trials. There is abundant evidence that adult
stem cells can be used as a therapy and are readily available in
people. The conclusion from the preclinical studies is that adult stem
cells work just as well, if not better, than embryonic stem cells and
are probably safer.\8\ There is no need for embryonic stem cells
especially cloned ones.
---------------------------------------------------------------------------
\8\ Bjorklund L.M.. Sanchez-Pernaute R.. Chung S.. Andersson T..
Chen I.Y.. McNaught K.S.. Brownell A.L.. Jenkins B.G.. Wahlestedt C..
Kim K.S.. Isacson O. Embryonic stem cells develop into functional
dopaminergic neurons after transplantation in a Parkinson rat model.
[comment]. [Journal Article] Proceedings of the National Academy of
Sciences of the United States of America. 99(4):2344-9, 2002.
---------------------------------------------------------------------------
Ten years ago, it was discovered that stem cells exist in the adult
brain and spinal cord and can be readily isolated.\9\ \10\ Many initial
ideas about adult stem cells in the brain were wrong. For example, the
cells were first thought to only be present in rodents, but later found
in people.\11\ It was once thought that only embryonic stem cells have
the capacity to become many different cell types. More recently, it has
been found that neural stem cells from adults have this potential.\12\
Stem cells and their cellular derivatives may be useful in many ways.
In the nervous system, they can be replacement neurons, source of
growth factors, or a substrate of growth. Another misconception was
that adult stem cells might not be functional in their ability to
transmit a signal to another neuron. There is recent evidence that
adult stem cells can mature and form functional connections with other
neurons in culture.\13\ \14\ A surprising finding was that many cells
in the adult (not just the cells in the brain and spinal cord) have the
potential to be neurons. Sources of adult human stem cells that are
capable of forming neurons include the brain,\15\ \16\ olfactory mucosa
in the upper nose,\17\ \18\ cornea,\19\ choroid and sclera \20\ of the
eye, teeth,\21\ bone marrow.\22\ \23\ and skin.\24\ Further evidence
that bone marrow can be a source of neurons for the brain is supported
by findings in the patients' brains who have received bone marrow
transplants.\25\ There is no reason to use embryonic/fetal tissue or to
clone people to obtain genetically similar embryonic stem cells when
there is a ready supply of stem cells in adult humans.
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\9\ Reynolds B.A., Wiess S. 1992. Generation of neurons and
astrocytes from isolated cells of the adult mammalian central nervous
system. Science 255:1701-1710.
\10\ Richards, Lric T.J., Bartlett P.F. 1992. De nonv generation of
neuronal cells from the adult mouse brain. Proc. Natl Acad Sci USA
89:8591-8595.
\11\ Eriksson P.S., Perfilieva E., Bjork-Eriksson, T., Alborn A.M.,
Nordborg C., Peterson D.A., Gage F.H. 1998. Neurogenesis in the adult
human hippocampus. Nat Med. 4:13113-1317.
\12\ Gritti A., Vescovi A.L., Galli R. Adult neural stem cells:
plasticity and developmental potential. Journal of Physiology-Paris.
96(1-2):81-90, 2002.
\13\ Toda H., Takahashi J., Mizoguchi A., Koyano K., Hashimoto N.,
Neurons generated from adult rat hippocampal stem cells form functional
glutamatergic and GABAergic synapses in vitro. Experimental Neurology.
165(1):66-76, 2000.
\14\ Song, H-j, C.F. Stevens, F.H. Gage, Neural stem cells from
adult hippocampus develop essential properties of functional CNS
neurons. Nature Neuroscience5: 438-445, 2002.
\15\ Suslov O.N., Kukekov V.G., Ignatova T.N., Steindler D.A.
Neural stem cell heterogeneity demonstrated by molecular phenotyping of
clonal neurospheres. Proceedings of the National Academy of Sciences of
the United States of America. 99(22):14506-11, 2002.
\16\ Akiyama Y., Honmou O., Kato T., Uede T., Hashi K., Kocsis J.D.
Transplantation of clonal neural precursor cells derived from adult
human brain establishes functional peripheral myelin in the rat spinal
cord. Experimental Neurology. 167(1):27-39, 2001.
\17\ Murrell W., Bushell G.R., Livesey J., McGrath J., MacDonald
K.P., Bates P.R., Mackay-Sim A. Neurogenesis in adult human.
NeuroReport. 7(6):1189-94, 1996.
\18\ Feron F.. Perry C., McGrath J.J., Mackay-Sim A. New techniques
for biopsy and culture of human olfactory epithelial neurons. Archives
of Otolaryngology--Head & Neck Surgery. 124(8):861-6, 1998.
\19\ Seigel G.M., Sun W., Salvi R., Campbell L.M., Sullivan S.,
Reidy J.J. Human corneal stem cells display functional neuronal
properties. Molecular Vision. 9:159-63, 2003.
\20\ Arsenijevic Y., Taverney N., Kostic C., Tekaya M., Riva F.,
Zografos L., Schorderet D., Munier F. Non-neural regions of the adult
human eye: a potential source of neurons?. Investigative Ophthalmology
& Visual Science. 44(2):799-807, 2003.
\21\ Miura M., Gronthos S., Zhao M., Lu B., Fisher L.W., Robey
P.G., Shi S. SHED: Stem cells from human exfoliated deciduous teeth.
Proceedings of the National Academy of Sciences of the United States of
America. 100(10):5807-12, 2003.
\22\ Deng W., Obrocka M., Fischer I., Prockop D.J. In vitro
differentiation of human marrow stromal cells into early progenitors of
neural cells by conditions that increase intracellular cyclic AMP.
Biochemical & Biophysical Research Communications. 282(1):148-52, 2001.
\23\ Hung S.C., Cheng H., Pan C.Y., Tsai M.J., Kao L.S., Ma H.L. In
vitro differentiation of size-sieved stem cells into electrically
active neural cells. Stem Cells. 20(6):522-9, 2002.
\24\ Toma J.G., Akhavan M., Fernandes K.J., Barnabe-Heider F.,
Sadikot A., Kaplan D.R., Miller F.D. Isolation of multipotent adult
stem cells from the dermis of mammalian skin. Nature Cell Biology.
3(9):778-84, 2001.
\25\ Mezey E., Key S., Vogelsang G., Szalayova I., Lange G.D.,
Crain B.Transplanted bone marrow generates new neurons in human brains.
Proceedings of the National Academy of Sciences of the United States of
America. 100(3):1364-9, 2003.
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There are several studies that support the usefulness of adult stem
cells. Stem cells obtained from adult spinal cord have been shown to
survive and mature into neurons when transplanted into the brain.\26\
Transplantation of stem cells from adult human brain causes myelination
to occur in a focally demyelinated spinal cord of the rat.\27\
Demyelination is common in spinal cord injury and disease states such
as Multiple Sclerosis, and interferes with signal conduction between
the neurons. Human cells from adult have been used to treat animal
models of disease states . For example, human cells led to functional
improvement in animal models of Parkinson's disease using human bone
cells \28\ or using neural stem cells.\29\ Human brain adult stem cells
can even be obtained after death \30\ so if a person's own stem cells
are not used; there are other less objectionable alternatives. Another
alternative to the use of embryonic stem cells is human umbilical cord
blood. Human umbilical cord blood has the potential to form
neurons,\31\ \32\ as well as other cell types.\33\ Human umbilical cord
blood injected IV caused a functional improvement when injected into
experimental animals with traumatic brain injury or stroke.\34\ \35\ In
the case of genetic defects, there are several other alternatives to
cloning. One is gene therapy that has been successfully used in mice
\36\ and humans. More recently stem cells have been used as vehicle to
deliver genes to the brain.\37\ \38\ \39\ \40\. Bone marrow stromal
cells from adult rats promote functional recovery after spinal cord
injury in rats when given 1 week after injury,\41\ even when the cells
are injected intravenously.\42\ Bone marrow stromal cells also will
migrate to site of a head injury when given IV and caused a functional
improvement.\43\
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\26\ Shihabuddin L.S., Horner P.J., Ray J., Gage F.H. Adult spinal
cord stem cells generate neurons after transplantation in the adult
dentate gyrus. Journal of Neuroscience. 20(23):8727-35, 2000.
\27\ Akiyama Y., Honmou O., Kato T., Uede T., Hashi K., Kocsis
J.D.: Transplantation of clonal neural precursor cells derived from
adult human brain establishes functional peripheral myelin in the rat
spinal cord. Exp Neurol 167:27-39, 2001.
\28\ Hou L.L., Zheng M., Wang D.M., Yuan H.F., Li H.M., Chen L.,
Bai C.X., Zhang Y., Pei X.T.[Migration and differentiation of human
bone marrow mesenchymal stem cells in the rat brain].Sheng Li Hsueh
Pao--Acta Physiologica Sinica. 55(2):153-9, 2003.
\29\ Liker M.A., Petzinger G.M., Nixon K., McNeill T., Jakowec M.W.
Human neural stem cell transplantation in the MPTP-lesioned mouse.
Brain Research. 971(2):168-77, 2003.
\30\ Palmer T.D., Schwartz P.H., Taupin P., Kaspar B., Stein S.A.,
Gage F.H. Cell culture. Progenitor cells from human brain after death.
Nature. 411(6833):42-3, 2001.
\31\ Sanchez-Ramos J.R., Song S., Kamath S.G., Zigova T., Willing
A., Cardozo-Pelaez F., Stedeford T., Chopp M., Sanberg P.R. Expression
of neural markers in human umbilical cord blood. Experimental
Neurology. 171(1):109-15, 2001.
\32\ BuzaAska L., Stachowiak E., Stachowiak M., DomaAska-Janik K.
Neural stem cell line derived from human umbilical cord blood--
morphological and functional properties.Journal of Neurochemistry. 85
Suppl 2:33, 2003.
\33\ Goodwin H.S., Bicknese A.R., Chien S.N., Bogucki B.D., Quinn
C.O., Wall D.A. Multilineage differentiation activity by cells isolated
from umbilical cord blood: expression of bone, fat, and neural markers.
Biology of Blood & Marrow Transplantation. 7(11):581-8, 2001.
\34\ Lu D., Sanberg P.R., Mahmood A., Li Y., Wang L., Sanchez-Ramos
J., Chopp M. Intravenous administration of human umbilical cord blood
reduces neurological deficit in the rat after traumatic brain
injury.Cell Transplantation. 11(3):275-81, 2002.
\35\ Sanberg P.R., Chopp M., Willing A.E., Zigova T., Saporta S.,
Song S., Bickford P., Garbuzova-Davis S., Newman M., Cameron D.F.,
Sanchez-Ramos J. Potential of umbilical cord blood cells for brain
repair.Journal of Neurochemistry. 81 Suppl 1:83, 2002.
\36\ Shen J.S., Watabe K., Ohashi T., Eto Y. Intraventricular
administration of recombinant adenovirus to neonatal twitcher mouse
leads to clinicopathological improvements. Gene Therapy. 8(14):1081-7,
2001.
\37\ Schwarz E.J., Reger R.L., Alexander G.M., Class R., Azizi
S.A., Prockop D.J. Rat marrow stromal cells rapidly transduced with a
self-inactivating retrovirus synthesize L-DOPA in vitro. Gene Therapy.
8(16):1214-23, 2001.
\38\ Nakano K., Migita M., Mochizuki H., Shimada T. Differentiation
of transplanted bone marrow cells in the adult mouse brain.
Transplantation. 71(12):1735-40, 2001.
\39\ Park K.W., Eglitis M.A., Mouradian M.M. Protection of nigral
neurons by GDNF-engineered marrow cell transplantation. Neuroscience
Research. 40(4):315-23, 2001.
\40\ Ehtesham M., Kabos P., Gutierrez M.A., Chung N.H., Griffith
T.S., Black K.L., Yu J.S. Induction of glioblastoma apoptosis using
neural stem cell-mediated delivery of tumor necrosis factor-related
apoptosis-inducing ligand. Cancer Research. 62(24):7170-4, 2002l.
\41\ Hofstetter C.P., Schwarz E.J., Hess D., Widenfalk J., El
Manira A., Prockop D.J., Olson L. Marrow stromal cells form guiding
strands in the injured spinal cord and promote recovery. Proceedings of
the National Academy of Sciences of the United States of America.
99(4):2199-204, 2002.
\42\ Akiyama Y., Radtke C., Honmou O., Kocsis J.D. Remyelination of
the spinal cord following intravenous delivery of bone marrow cells.
[Journal Article] GLIA. 39(3):229-36, 2002.
\43\ Lu D., Mahmood A., Wang L., Li Y., Lu M., Chopp M. (2001)
Adult bone marrow stromal cells administered intravenously to rats
after traumatic brain injury migrate into brain and improve
neurological outcome. Neuroreport 12:559-63.
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Below is a brief summary (in italics) of recent findings using
other treatments besides stem cell for injuries and diseases of the
nervous system. This summary is meant to make 2 major points:
(1) Other treatments used alone or in combination with adult stem
cells may hold the greatest promise in treating spinal cord
injury and other damage to the nervous system.
(2) While there is no ban on animal cloning, a review of recent
literature revealed more than 40 articles of promising
treatments other than stem cells for spinal cord injury but
only 1 or just a few articles showing any therapeutic benefit
of therapeutic cloning. The one article that received
significant press coverage attempted to show a benefit of
cloning in an animal study also revealed some of the
difficulties with this procedure.\44\
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\44\ Rideout W.M. III, Hochedlinger K., Kyba, M. Daley Q., and
Jaenisch R. Correction of a genetic defect by nuclear transplantation
and combined cell and gene therapy Cell 109:17-27
Other cell types: Other cell types that do not form neurons also
help in recovery. After selective demyelination in rat spinal cord,
olfactory ensheathing cells myelinated axons \45\ and led to greater
motor and somatosensory evoked potentials and a better functional
outcome.\46\ Olfactory ensheathing cells promote locomotor recovery in
the transected cord after delayed transplantation.\47\ These cells were
also found to stimulate growth of motor axons.\48\ Olfactory
ensheathing cells when used with methylprednisolone promoted functional
recovery and axonal regeneration after lesioning of the corticospinal
tract.\49\
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\45\ Kato T., Honmou O., Uede T., Hashi K., Kocsis J.D.
Transplantation of human olfactory ensheathing cells elicits
remyelination of demyelinated rat spinal cord. GLIA. 30(3):209-18,
2000.
\46\ VerdA E., GarcA-a-AlA-as G., ForA(C)s J., LA pez-Vales R.,
Navarro X. Olfactory ensheathing cells transplanted in lesioned spinal
cord prevent loss of spinal cord parenchyma and promote functional
recovery GLIA. 42(3):275-86, 2003.
\47\ Lu J., Feron F., Mackay-Sim A., Waite P.M. Olfactory
ensheathing cells promote locomotor recovery after delayed
transplantation into transected spinal cord. Brain 125:14-21, 2002.
\48\ Ramon-Cueto A., Cordero M.I., Santos-Benito F.F., Avila J.
Functional recovery of paraplegic rats and motor axon regeneration in
their spinal cords by olfactory ensheathing glia. Neuron 2000
Feb;25(2):425-35.
\49\ Nash H.H., Borke R.C., Anders J.J. Ensheathing cells and
methylprednisolone promote axonal regeneration and functional recovery
in the lesioned adult rat spinal cord. Journal of Neuroscience.
22(16):7111-20, 2002.
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Growth Factors: With the discovery of new growth factors such as
neurotrophic factors and cytokines that influence the survival and
growth of neurons, it was hoped that spinal cord injury could soon be
treated. Brain-derived neurotrophic factor (BDNF) reduces the necrotic
zone and supports neuronal survival after spinal cord hemisection in
adult rats \50\ and suppresses apoptosis of oligodendrocytes.\51\ Also
neurotrophin-3 (NT-3) enhances sprouting of corticospinal tract after
adult spinal cord lesion \52\ even in chronic SCI.\53\ Basic fibroblast
growth factor (bFGF) reduced the pathology observed in spinal cord
injured rats receiving bFGF via the CSF following a spinal cord
injury.\54\ Acidic fibroblast growth factor (aFGF) promote axonal
growth between spinal cord slices \55\ and when combined with
peripheral nerve segments led to improved locomotor function after
spinal transection.\56\ Insulin growth factor 1 (IGF-1) stimulates
myelin formation in the nervous system \57\ and also stimulates the
production of neurons and synapse formation.\58\ In our own lab studies
using cells derived from adult stem cells to treat rats with severe,
chronic spinal cord injuries, significant functional improvement was
observed when the factors (diff media) used for stem cells maturation
are used alone. Further improvements are found when adult stem cell
(SC) or IGF-1 is added to the treatment suggesting the benefit of
combination treatments.
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\50\ Novikova L., Novikov L., Kellerth J.O. Brain-derived
neurotrophic factor reduces necrotic zone and supports neuronal
survival after spinal cord hemisection in adult rats. Neuroscience
Letters. 220(3):203-6, 1996.
\51\ Koda M., Murakami M., Ino H., Yoshinaga K., Ikeda O.,
Hashimoto M., Yamazaki M., Nakayama C., Moriya H. Brain-derived
neurotrophic factor suppresses delayed apoptosis of oligodendrocytes
after spinal cord injury in rats. Journal of Neurotrauma. 19(6):777-85,
2002.
\52\ Schnell, L., R. Schneider, R. Kolbeck, Y.A. Bard and M.E.
Schwab (1994) Neurotrophin-3 enhances sprouting of corticospinal tract
during development and after adult spinal cord lesion. Nature 367:170-
173.
\53\ Tuszynski M.H., Grill R., Jones L.L., Brant A., Blesch A.,
L.A. w K., Lacroix S., Lu P. NT-3 gene delivery elicits growth of
chronically injured corticospinal axons and modestly improves
functional deficits after chronic scar resection. Experimental
Neurology. 181(1):47-56, 2003.
\54\ Liu W.G., Luo Y.X. The early protective effects of basic
fibroblast growth factor on acute spinal cord injury in rats.
[Chinese]Chung-Kuo Hsiu Fu Chung Chien Wai Ko Tsa Chih/Chinese Journal
of Reparative & Reconstructive Surgery. 13(5):291-4, 1999.
\55\ Lee Y.S., Baratta J., Yu J., Lin V.W., Robertson R.T. AFGF
promotes axonal growth in rat spinal cord organotypic slice co-
cultures. Journal of Neurotrauma. 19(3):357-67, 2002.
\56\ Lee Y.S., Hsiao I., Lin V.W. Peripheral nerve grafts and aFGF
restore partial hindlimb function in adult paraplegic rats. Journal of
Neurotrauma. 19(10):1203-16, 2002.
\57\ Brooker G.J., Kalloniatis M., Russo V.C., Murphy M., Werther
G.A., Bartlett P.F. Endogenous IGF-1 regulates the neuronal
differentiation of adult stem cells. J. Neurosci. Res. 59(3):332-41,
2000.
\58\ O'Kusky J.R., Ye P., D'Ercole A.J. Insulin-like growth factor-
I promotes neurogenesis and synaptogenesis in the hippocampal dentate
gyrus during postnatal development. Journal of Neuroscience.
20(22):8435-42, 2000.
Another cytokine, transforming growth factor-beta (TGF-beta) caused
a decrease in the lesion size following SCI.\59\ Yet another cytokine,
glial cell line-derived neurotrophic factor (GDNF) when incorporated in
a fibrin glue promotes dorsal root regeneration into spinal cord.\60\
Metabolites such as inosine also appear to encourage growth of spared
axons and possibly injured axons following spinal cord injury.\61\ The
spinal cord distal to the injury consists of cells that are shrunken
and appear unhealthy. One possibility is that this natural metabolite
especially when used as part of a combination treatment may stimulate
the growth of these cells. Many recent studies have used a combination
of growth factors. The combination of EGF and bFGF showed better
functional recovery than vehicle or either factor alone.\62\ Insulin-
like growth factor (IGF) and epidermal growth factor (EGF) rescued
motor neurons better than each individually even when delivered after
4-week delay.\63\ Although significant stimulation of axonal growth is
observed with growth factors, problems in delivery, penetration, and
down-regulation or truncation of receptors \64\ have perhaps kept their
full potential from being realized.
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\59\ Tyor W.R., Avgeropoulos N., Ohlandt G., Hogan E.L. Treatment
of spinal cord impact injury in the rat with transforming growth
factor-beta. Journal of the Neurological Sciences. 200(1-2):33-41,
2002.
\60\ Iwakawa M., Mizoi K., Tessler A., Itoh Y. Intraspinal implants
of fibrin glue containing glial cell line-derived neurotrophic factor
promote dorsal root regeneration into spinal cord. Neurorehabilitation
& Neural Repair. 15(3):173-82, 2001.
\61\ Benowitz L.I., D.E. Goldberg, J.R. Madsen, D. Soni and N.
Irwin Inosine stimulates extensive axon collateral growth in the rat
corticospinal tract after injury. PNAS 96: 13486-13490, 1999.
\62\ Kojima A., Tator C.H. Intrathecal administration of epidermal
growth factor and fibroblast growth factor 2 promotes ependymal
proliferation and functional recovery after spinal cord injury in adult
rats. Journal of Neurotrauma. 19(2):223-38, 2002.
\63\ Bilak M.M., Kuncl R.W. Delayed application of IGF-I and GDNF
can rescue already injured postnatal motor neurons. Neuroreport.
12(11):2531-5, 2001.
\64\ Liebl D.J., Huang W., Young W., Parada L.F. Regulation of Trk
receptors following contusion of the rat spinal cord.Experimental
Neurology. 167(1):15-26, 2001.
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Gene therapies: To overcome the problem of the growth factors
actually reaching the affected neurons, two strategies have been taken.
First, certain cell types have been modified to produce growth factors
then grafted into the injury site. Second, endogenous cells have been
genetically modified primarily using virus vectors. Fibroblasts
genetically modified to produce BDNF \65\ or NGF \66\ support regrowth
of chronically injured axons. The in vivo transfer of GDNF cDNA can
promote axonal regeneration and enhance locomotion functional
recovery.\67\ Neurotrophin-secreting Schwann cell implants improved
urinary bladder structure after spinal cord contusion.\68\ NT-3 gene in
an adenoviral vector was delivered to the spinal motoneurons by
retrograde transport through the sciatic nerve, causing induced growth
of axons from the intact corticospinal tract across the midline to the
denervated side.\69\ Another approach is to actually stimulate one of
the intracellular pathways that play a role in neurite outgrowth. Viral
delivery of vectors carrying the mutated form of MEK1 that activates of
the extracellular-signal-regulated kinases (ERKs) induces axonal
regeneration across the transection site of the spinal cord in young
rats.\70\ Newer approaches that direct transient production of growth
factors specifically in motor neurons also hold great promise.\71\
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\65\ Jin Y., Tessler A., Fischer I., Houle J.D. Fibroblasts
genetically modified to produce BDNF support regrowth of chronically
injured serotonergic axons.Neurorehabilitation & Neural Repair.
14(4):311-7, 2000.
\66\ Grill R.J., A. Blesch and M.H. Tuszynski (1997). Robust growth
of chronically injured spinal cord axons induced by grafts of
genetically modified NGF-secreting cells. Exper. Neurol. 148:44-452.
\67\ Lu K.W., Chen Z.Y., Jin D.D., Hou T.S., Cao L., Fu Q. Cationic
liposome-mediated GDNF gene transfer after spinal cord injury. Journal
of Neurotrauma. 19(9):1081-90, 2002.
\68\ Sakamoto K., Uvelius B., Khan T., Damaser M.S. Preliminary
study of a genetically engineered spinal cord implant on urinary
bladder after experimental spinal cord injury in rats. Journal of
Rehabilitation Research & Development. 39(3):347-57, 2002.
\69\ Zhou L., Baumgartner B.J., Hill-Felberg S.J., McGowen L.R.,
Shine H.D. Neurotrophin-3 expressed in situ induces axonal plasticity
in the adult injured spinal cord.Journal of Neuroscience. 23(4):1424-
31, 2003.
\70\ Miura T., Tanaka S., Seichi A., Arai M., Goto T., Katagiri H.,
Asano T., Oda H., Nakamura K. Partial functional recovery of paraplegic
rat by adenovirus-mediated gene delivery of constitutively active
MEK1.Experimental Neurology. 166(1):115-26, 2000.
\71\ Jackson, C.A., C. Cobbs, J.D. Peduzzi, M. Novak and C.D.
Morrow (2001) Repetitive Intrathecal injections of Poliovirus Replicons
result in gene expression in neurons of the central nervous system
without pathogenesis. Human Gene Therapy, 12:1827-1842.
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Substrate or Matrix: There have been several studies that provide a
substrate for growth is useful. Self-assembling peptide scaffolds
support differentiation as well as extensive neurite outgrowth in
culture.\72\ When a collagen tube is implanted into hemisected adult
rat spinal cord, there is growth of the rostral spinal axons into the
caudal ventral roots.\73\ Growth factor-treated nitrocellulose implants
that bridge a complete transection lesion of adult rat spinal cord
caused regrowth of ascending sensory axons across the traumatic spinal
cord injury site.\74\ Implants using poly-beta-hydroxybutyrate (PHB) as
carrier scaffold and containing alginate hydrogel, fibronectin, and
Schwann cells can support neuronal survival and regeneration after
spinal cord injury.\75\ Using a polymer scaffold seeded with stem cells
led to better functional recovery in hemisected SC and appeared to
encourage the growth of corticospinal axons.\76\ When a hydrogel is
implanted into the injury site of a rat with chronic, severe SCI, there
was improved function and evidence of blood vessels, and axonal
growth.\77\
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\72\ Holmes T.C., de Lacalle S., Su X., Liu G., Rich A., Zhang S.
(2000) Extensive neurite outgrowth and active synapse formation on
self-assembling peptide scaffolds. PNAS 97:6728-33.
\73\ Liu S., Said G., Tadie M. Regrowth of the rostral spinal axons
into the caudal ventral roots through a collagen tube implanted into
hemisected adult rat spinal cord. Neurosurg. 49:143-50, 2001.
\74\ Houle J.D. and M.K. Ziegler (1994) Bridging a complete
transection lesion of adult rat spinal cord with growth factor-treated
nitrocellulose implants. J. Neural Transplant. & Plast. 5:1115-124.
\75\ Novikov L.N., Novikova L.N., Mosahebi A., Wiberg M., Terenghi
G., Kellerth J.O. A novel biodegradable implant for neuronal rescue and
regeneration after spinal cord injury. Biomaterials. 23(16):3369-76,
2002.
\76\ Teng Y.D., Lavik E.B., Qu X.. Park K.I., Ourednik J.,
Zurakowski D., Langer R., Snyder E.Y. Functional recovery following
traumatic spinal cord injury mediated by a unique polymer scaffold
seeded with neural stem cells. Proceedings of the National Academy of
Sciences of the United States of America. 99(5):3024-9, 20.
\77\ Woerly S., Doan V.D., Evans-Martin F., Paramore C.G., Peduzzi
J.D. Spinal cord reconstruction using NeuroGel implants and functional
recovery after chronic injury.Journal of Neuroscience Research.
66(6):1187-97, 2001.
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Modifying the Immune System: The immune system plays an important
role in spinal cord injury. Many cytokines and other factors released
by immune cells also influence neural cells. Several studies suggest a
benefit of activated macrophages or specific T cells in reducing the
amount of secondary injury and stimulating growth after spinal cord
injury in rats.\78\ Recent clinical trials using activated macrophages
are being conducted in Israel.\79\ However, others have found that
activation of macrophages in a normal cord can actually cause axonal
injury and demyelination \80\ and suggests inherent danger of
activating the immune system after SCI.\81\ IL-10 is neuroprotective
after a spinal cord injury.\82\ Another study found that IL-10 and MPS
reduce the amount of damaged tissue but do not change functional
outcome.\83\
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\78\ Hauben E., Agranov E., Gothilf A., Nevo U., Cohen A., Smirnov
I., Steinman L., Schwartz M. Posttraumatic therapeutic vaccination with
modified myelin self-antigen prevents complete paralysis while avoiding
autoimmune disease. Journal of Clinical Investigation. 108(4):591-9,
2001.
\79\ http://www.biospace.com/company_profile.cfm?CompanyID=4350
\80\ Popovich P.G., Guan Z., McGaughy V., Fisher L., Hickey W.F.,
Basso D.M. The neuropathological and behavioral consequences of
intraspinal microglial/macrophage activation. Journal of Neuropathology
& Experimental Neurology. 61(7): 623-33, 2002.
\81\ Jones T.B., Basso D.M., Sodhi A., Pan J.Z., Hart R.P.,
MacCallum R.C., Lee S., Whitacre C.C., Popovich P.G. Pathological CNS
autoimmune disease triggered by traumatic spinal cord injury:
implications for autoimmune vaccine therapy. Journal of Neuroscience.
22(7):2690-700, 2002.
\82\ Bethea J.R., Nagashima H., Acosta M.C., Briceno C., Gomez F.,
Marcillo A.E., Loor K., Green J., Dietrich W.D. Systemically
administered interleukin-10 reduces tumor necrosis factor-alpha
production and significantly improves functional recovery following
traumatic spinal cord injury in rats. [Journal Article] Journal of
Neurotrauma. 16(10):851-63, 1999.
\83\ Takami T., Oudega M., Bethea J.R., Wood P.M., Kleitman N.,
Bunge M.B. Methylprednisolone and interleukin-10 reduce gray matter
damage in the contused Fischer rat thoracic spinal cord but do not
improve functional outcome. Journal of Neurotrauma. 19(5):653-66, 2002.
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Inhibitors and Scar: For many years, Schwab and colleagues explored
the potential of the IN-1 antibody to block myelin associated
inhibitory molecule, Nogo, after SCI. IN-1 caused improvement in
function if given shortly after injury.\84\ Other myelin-associated
inhibitors such as MAG have been described. Blockers of Nogo and MAG
appear to cause functional improvement.\85\ Many suggest that the scar
inhibits \86\ and have tried various inhibitors such as iron
chelators.\87\ Beta-aminopropionitrile treatment that inhibits the
formation of glial scar accelerates recovery of mice after spinal cord
injury.\88\ Other efforts involve implantation of a collagen tube to
interfere with scar formation.\89\ The semaphorins may be important
contributor to the inhibitory effects of the scar.\90\
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\84\ Merkler D., Metz G.A., Raineteau O., Dietz V., Schwab M.E.
Fouad K.Locomotor recovery in spinal cord-injured rats treated with an
antibody neutralizing the myelin-associated neurite growth inhibitor
Nogo-A.Journal of Neuroscience. 21(10):3665-73, 2001.
\85\ GrandPre T., Li S., Strittmatter S.M. Nogo-66 receptor
antagonist peptide promotes axonal regeneration. Nature. 417(6888):
547-51, 2002.
\86\ Hermanns S., Klapka N., Muller H.W. The collagenous lesion
scar--an obstacle for axonal regeneration in brain and spinal cord
injury.Restorative Neurology & Neuroscience. 19(1-2):139-48, 2001.
\87\ Hermanns S., Reiprich P., Muller H.W. A reliable method to
reduce collagen scar formation in the lesioned rat spinal cord.Journal
of Neuroscience Methods. 110(1-2):141-6, 2001.
\88\ Gilad G.M., Gilad V.H. Beta-aminopropionitrile treatment can
accelerate recovery of mice after spinal cord injury.European Journal
of Pharmacology. 430(1):69-72, 2001.
\89\ Spilker M.H., Yannas I.V., Kostyk S.K., Norregaard T.V., Hsu
H.P., Spector M. The effects of tubulation on healing and scar
formation after transection of the adult rat spinal cord. Restorative
Neurology & Neuroscience. 18(1):23-38, 2001.
\90\ Pasterkamp R.J., Anderson P.N., Verhaagen J. Peripheral nerve
injury fails to induce growth of lesioned ascending dorsal column axons
into spinal cord scar tissue expressing the axon repellent
Semaphorin3A.European Journal of Neuroscience. 13(3):457-71, 2001.
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Rehabilitation: There has been tremendous progress in the field of
rehabilitation with use of weight-supported treadmills,\91\ functional
electrical stimulation and biofeedback. In our own lab, we found a
statistically significant improvement in rats with a moderate degree of
spinal cord injury that are placed in an enriched environment compared
to standard caging.\92\ An enriched environment consists of a social
environment where there is free access to novel items that include
exercise equipment.
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\91\ 6. Edgerton V.R., Roy R.R., Hodgson J.A., Prober R.J., de
Guzman C.P., de Leon R. Potential of adult mammalian lumbosacral spinal
cord to execute and acquire improved locomotion in the absence of
supraspinal input. J. Neurotrauma. 9 Suppl 1:S119-28, 1992.
\92\ Fischer, F.R. and J.D. Peduzzi. Functional improvement in rats
with chronic spinal cord injuries after exposure to an enriched
environment. Soc. Neurosci. Abstr., 23:2188, 1997.
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My primary reason for being here today is that I don't want victims
of injuries and diseases to again become victims. The best chance of
cellular treatment for them is using their own stem cells. Victims of
injuries and diseases are again being used to justify a treatment that
is not in their best interest. Both the clinical trials and pre-
clinical trials suggest that adult stem cells and/or using one's own
stem cells is a more effective treatment for diseases and injuries. The
data just keep accumulating that this is the direction to go despite
the fact that most of the research is being done using embryonic stem
cells in experimental animals or human cell lines.\93\ The least funded
area is still `bench to bedside' research using one's own stem cells or
using adult stem cells. Despite the fact that there are much fewer
experimental studies using adult stem cells, amazing progress has been
made as evidenced by the clinical trials. The idea that we should look
to cloning for a treatment for diseases or injuries is way in the
future. Despite all the claims of its promise there has been only 1 or
2 experimental animal study to suggest that this is a promising
direction.\94\ We have at least 200 experimental animal studies in the
field of spinal cord injury alone that show that a particular cellular,
growth factor, or other treatment causes a functional or anatomical
improvement and only 1 or 2 in the field of cloning despite the fact
that there is no ban on performing animal cloning. With only a limited
amount of funding available, more focus is needed in directing research
funds to areas that can help people in the next 5-10 years and not
several lifetimes away.
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\93\ Neil Munro. SCIENCE: Petri-Dish Politics. National Journal,
04-19-2003.
\94\ Rideout W.M. III, Hochedlinger K., Kyba M., Daley Q. and
Jaenisch R. Correction of a genetic defect by nuclear transplantation
and combined cell and gene therapy Cell 109:17-27.
Senator Brownback. Thank you, Dr. Peduzzi.
We have a vote on. First, I want to announce that I'll be
joining other Members in a letter to promote and push for the
funding for a national cord-blood bank system and the funding
that you were talking about, Dr. Kurtzberg, that's going to be
needed to do this. I know Senator Hatch is going to be joining
in this letter, and I think we'll have several others. And
we'll also be helping with legislation on a national cord-blood
banking program. I think this has extraordinary opportunities,
and I really applaud your work and Dr. Rubinstein's work that
you're doing in this field that really holds so much promise.
It's beautiful, beautiful work. And we'll be pushing for that
to see if we can't get that mature on forward.
This is very interesting to see and to hear, and exciting.
I appreciate all of your passions and your help and your work
that each of you are doing in this field.
We've got a vote on that I'm going to move over for. And
then what I think we'll do is, we'll bring the next panel up
while I recess this for a period of time, and then bring that
next panel up.
But I hope, in the next year-and-a-half, we make as much
progress as we made in the past year-and-a-half. I think you
will see a fascinating array of people being treated and helped
if we're able to put in the resources here, if we're able to
really move forward in these fields of regenerative medicine.
The adult work, the cord blood, has been beautiful in its
successes and are really exciting to see these moving forward.
We will be in recess for approximately 15 minutes. If I
could have the next panel ready to go when I get back, and then
we'll move forward.
Thank the panelists for being here today.
We're in recess for 15 minutes.
[Recess.]
Senator Brownback. Call the hearing back to order.
I want to apologize for making it over and back so fast, I
didn't have as much time to spend with those who wanted to
visit with me.
We've got an exciting next panel that I would like to call
up. And the last panel was very informative, as well. These are
patients, who have been working on and been involved in some
really incredible things. Mr. Steven L. Barsh, from
Pennsylvania; Mr. Keone Penn, from Snellville, Georgia; and Mr.
Stephen R. Sprague, from Staten Island, New York, the people
that will be testifying, and we look forward to hearing your
comments and the testimony.
I would say to each of you, we have your written testimony
in the record, so you can summarize, if you'd like or you can
go all go off this testimony, whichever you would like, or you
can submit your written testimony for the record and then say
what you please here. And then I look forward to being able to
question each of you for a little bit, if possible.
I thank you all very much for coming here, appreciate your
being willing to attend. And, Ms. Penn, I appreciate you being
willing to come, accompanying your son, here today, as well.
Mr. Barsh, delighted to have you.
STATEMENT OF STEVEN L. BARSH,
MERION STATION, PENNSYLVANIA
Mr. Barsh. Thank you, Senator Brownback. And, by the way,
do we have 5 minutes or 7 minutes for our testimony?
Senator Brownback. I'm going to run the clock at 7 minutes,
just to give you some guidance.
Mr. Barsh. No problem.
Senator Brownback. As you can see, it's not a hard and fast
rule, but it gives you a little bit of guidance.
Mr. Barsh. It's greatly appreciated. Unfortunately I'm not
a patient; I'm a parent. Our son, Spencer, couldn't be here
today. He's three and a half. It was too much for him to come
down from Philadelphia, and he had some therapy this morning.
So I'm just the parent of a patient. But good afternoon.
Thank you for the opportunity to testify today on the very
important topic of cord blood, and why a national cord-blood
stem cell bank network should be provided for to save the lives
of some of this great nation's most severely ill children and
adults.
We first learned, a little over 2 years ago, that our one-
year-old son, Spencer, had ALD, or adrenoleukodystrophy. In 50
percent of ALD children, more and more of their brains vanish
due to this rare neurodegenerative disease, leading to loss of
function and death by age ten. The remaining 50 percent have a
severe-to-deadly form as adults. A parent's worst nightmare,
or, in this case, a day-mare, because you actually have to live
through it. This is the disease behind the film, Lorenzo's Oil,
if you're familiar with that film. As a matter of fact,
Lorenzo's father is in this room today, a very great man.
Senator Brownback. Would he care to stand so we could
recognize him?
Mr. Barsh. Oh, he's just stepped out. Augusto Odone. I'm
sorry.
Senator Brownback. Well, we'll try to recognize him when he
comes back.
Mr. Barsh. I apologize. He is present today. A very great
man.
Spencer, our son, started to have repeated MRI brain
studies. In February of last year, these MRI studies showed
changes had started in his brain, indicating that the deadly
brain deterioration had begun.
Cord-blood and bone-marrow transplants are the only
accepted therapies when this ALD brain deterioration begins and
is caught in time, as Dr. Kurtzberg referenced. You need to
catch these diseases in time.
Via the National Marrow Donor Program, or the NMDP, we
searched for a perfect six-out-of-six bone-marrow match, and
couldn't find one. And, as some of the doctors or researchers
alluded to earlier, finding a good match is really important.
Otherwise, particularly in bone marrow, it doesn't work real
well and it has a pretty poor outcome, to put it mildly. Plus,
we were looking at nearly 6 months before we could even get
Spencer to transplant, while his brain would continue to break
down and deteriorate, because going the bone-marrow route takes
a lot of time.
See, even if you find someone on the National Marrow Donor
Program donor list, it doesn't mean you can get to them
quickly. It's a heartbreaking and gut-wrenching process of
calling in potential donors that they identify through their
network, having them screened, confirming that they'll go
through surgery to remove some of their bone marrow, et cetera.
You lose precious time waiting. And in these neurodegenerative
diseases, it's a time issue. You really need to transplant
very, very quickly. Worse yet, more than 50 percent of people
are turned away by the NMDP, told there's no suitable donor for
them. So about, you know, 50 to 60 of every 100 people that
knock on their door looking for a solution are told, ``Sorry,
we can't help you.''
ALD, like many metabolic diseases, can move very quickly
along its destructive path, and horrifying changes can often be
seen daily in your child. This is particularly true for rare
metabolic diseases discussed earlier, such as Hurlers, MLD, or
metachromatic leukodystrophy, Tay-Sachs, and others--all
diseases that can now be treated by a cord-blood transplant.
In metabolic diseases, lessening the time to transplant
equals less deficits and a better transplant outcome. As
discussed, time is enemy number one. And, in cord blood, the
unit has already been typed, checked, prepped, and is waiting
in a freezer right now. There just needs to be more of it.
Spencer's pre-transplant work-up testing started just 4
weeks after we found a bad MRI of his brain, and only 5 days
after my wife and I made the decision that he should be
transplanted. There was no 6 months of waiting. We held on
tightly to our two-and-a-half-year-old son, Spencer, while he
was in a pediatric isolation and intensive-care unit for nearly
40 days. There, he received his cord-blood stem cell
transplant, preceded by highly toxic medications, including
massive, massive chemotherapy. He was lucky. He had what's been
considered and characterized an ``easy course of transplant.''
At the same time, we saw kids who didn't make it, as the
procedure proved too toxic. While core-blood stem cells work
for most of their very, very fortunate recipients, more
research needs to be done. More and higher-quality cord-blood
units need to be available, not only for transplantation, but
for research purposes. And stem cell research, in general,
needs to be carefully and properly further explored to harness
all of its life-saving potential. Those greater units and
greater research, particularly in cord blood, would come about
by passage of this bill.
Spencer's cord-blood transplant was just 14 months ago. But
who's counting? He's doing extremely well. As a matter of fact,
I'm happy to say he starts summer camp in 2 weeks. It'll be his
first time he ever goes to camp, school, nursery school,
anything, in his entire life. And he'll walk into that camp as
a normal little boy.
We see improvements and problem reversal on a weekly basis.
At only 6 months post-transplant, physicians began to see
improvements in Spencer's brain MRI, as well as his clinical
presentation. It appears that Spencer is actually re-
myelinating, meaning that the cord-blood stem cells are
repairing his brain. The early progenitor stem cells from the
cord blood are differentiating into other cell types.
The MRI and clinical observations have been confirmed both
at Duke and by a diverse team at Children's Hospital of
Philadelphia, or CHOP. I believe the non-technical word they
have used is ``amazing,'' going on to say, ``We've never seen
anything like this. We don't usually see brain MRIs improve.''
Cord blood works. With only one-tenth of the funding
provided to the National Marrow Donor Program today, cord blood
from a national cord-blood stem cell bank network is a solution
for more than the 50 percent of people who the NMDP turns away.
These treatment options must be available to the children and
adults who have these devastating diseases, including malignant
diseases, such as leukemias.
In closing, it's important to remember that you can get to
transplant with cord blood extremely quickly, which is very,
very critical with many diseases. The early progenitor stem
cells in Spencer now appear to be differentiating into other
cell types and are repairing problems in his brain. ``Just
amazing'' is the term we hear time and again.
At only one-tenth of the funding provided to the NMDP, a
national cord-blood stem cell bank network can be provided so
that this life-saving technology, that works today, can be
available to everyone in need.
We now have a normal and healthy 3-year-old son. His name
is Spencer Barsh. And cord blood saved his life.
Thank you for your time and thoughtful consideration on
this matter.
[The prepared statement of Mr. Barsh follows:]
Prepared Statement of Steven L. Barsh, Merion Station, Pennsylvania
Good afternoon.
Thank you for the opportunity to testify today on the very
important topic of cord blood and why a National Cord Blood Stem Cell
Bank Network should be provided for to save the lives of some of this
great nation's most severely ill children and adults.
We first learned a little over 2 years ago that our one year old
son Spencer had ALD or Adrenoleukodystrophy. Fifty percent of ALD
children have a deadly cerebral onset of this rare neurodegenerative
disease leading to loss of function and death by age 10. The remaining
50 percent have a severe to deadly form as adults. A parent's worst
nightmare, this is the disease behind the film Lorenzo's Oil.
Spencer started to have repeated MRI brain studies and in February
of last year, MRI studies showed changes had started in his brain
indicating a deadly cerebral onset had begun.
Cord blood and bone marrow transplants are the only ``accepted''
therapies when a cerebral onset of ALD has begun and is caught in time.
Via the National Marrow Donor Program (NMDP) we had already been
searching for a perfect 6/6 bone marrow match and couldn't find one.
Plus, we were looking at nearly 6 months before we could even get to
transplant while Spencer would be deteriorating.
Even if you find someone on the NMDP donor list, it doesn't mean
you can get to them quickly. It's a heartbreaking and gut-wrenching
process of calling in potential donors, having them screened,
confirming they will go through surgery, etc. You lose precious time,
waiting. Worse yet, more than 50 percent of people are turned away told
there is no suitable donor for them.
ALD, like many metabolic diseases, can move very quickly along its
destructive path and deficit changes can sometimes be seen daily. This
is particularly true for rare metabolic diseases such as Hurler's, MLD,
Tay-Sachs, and others--all diseases that can now be treated by a cord
blood transplant.
In metabolic diseases, lessening the time to transplant equals less
deficits and a better transplant outcome. Time is enemy #1. In cord
blood, the unit has already been typed, checked, prepped, and is
waiting in a freezer right now.
Spencer's pre-transplant work-up testing started just 4 weeks after
his bad MRI (only 5 days after my wife and I made the decision that he
should be transplanted). There was no 6 months of waiting.
We held on tightly to our 2\1/2\-year-old son Spencer while he was
in a pediatric isolation and intensive care unit for nearly 40 days.
There he received his cord blood stem cell transplant preceded by
highly toxic medications including massive chemotherapy. He was lucky.
He had what was considered an ``easy course of transplant.''
At the same time, we saw kids who didn't make it as the procedure
proved too toxic. While cord blood stem cells work for most of their
very fortunate recipients, more research needs to be done. More and
higher quality cord blood units need to be available not only for
transplantation, but for research purposes; and stem cell research in
general needs to be carefully and properly further explored to harness
all of its life saving potential.
His cord blood transplant was just 13 months ago, but who's
counting?
He is doing extremely well.
We see improvements and deficit reversal on a weekly basis. At only
6 months post transplant, physicians began to see improvements in
Spencer's MRIs as well as clinical presentation.
It appears that Spencer is actually re-myelinating as the early
progenitor stems cells from the cord blood are differentiating into
other cells types in his brain.
The MRI and clinical observations have been confirmed both at Duke
and by a diverse team at the Children's Hospital of Philadelphia
(CHOP). I believe that the non-technical word they have used was
``amazing'' going on to say ``They've never seen anything like this. We
usually don't see MRIs improve.''
Cord blood works.
With only \1/10\ of the funding provided to the NMDP today, cord
blood from a National Cord Blood Stem Cell Bank Network is a solution
for the more than 50 percent of people who the NMDP turns away.
These treatment options must be available to the children and
adults who have these devastating diseases including malignant
diseases.
In closing:
It's important to remember that you can get to transplant
with cord blood extremely quickly which is very, very critical
with many diseases.
The early progenitor stem cells in Spencer now appear to be
differentiating into other cell types that are repairing
problems in his brain. ``Just amazing'' is the term we hear
time and again.
At only 1/10th of the funding provided to the NMDP, A
National Cord Blood Stem Cell Bank Network can be provided for
so that this life saving technology, that works today, can be
available to everyone in need.
We now have a normal 3 year old son.
His name is Spencer Barsh.
Cord blood, saved his life.
Thank you for your time and thoughtful consideration.
Senator Brownback. Thank you for being here, Mr. Barsh. You
know, when you talk about him going to summer camp, you amaze
at the simple pleasures and what they truly mean. That's a
beautiful story.
Mr. Barsh. We cherish every day.
Senator Brownback. Mr. Sprague, thank you very much for
joining us here today, and I would turn to you next.
STATEMENT OF STEPHEN R. SPRAGUE,
STATEN ISLAND, NEW YORK
Mr. Sprague. Thank you, Senator.
I certainly am personally fortunate to have an opportunity
to speak with you today; not in medical terms, but from a
patient's perspective. I know you can't tell, but you're
looking at an aging baby-boomer. And I was already a medical
veteran before I got my leukemia diagnosis. That was 7 years
ago. I was 47 years old. I was a diabetic. I had survived a
heart attack and bypass surgery, all in 1993. In spite of all
that medical training, I was totally unprepared for a battle
with cancer.
This was in November 1995. In those days, chemotherapy only
stalled the inevitable for long-term survival, and that was, of
course, the traditional bone-marrow transplant. ``The cure that
can kill,'' we like to call it.
Although CML, which was my diagnosis, usually progresses
slowly, in May 1997, only 18 months after my initial diagnosis,
I found myself in blast crisis, the end-stage of the disease.
Meanwhile, my oncologist began what would quickly become a
very frustrating marrow-donor search. I soon discovered that
less than a third of those seeking transplant have a matching
sibling, the best and most obvious donor source. I was an only
child. I needed to find an unrelated donor if a transplant were
even to be an option for me.
To make a very long story short, I was not one of the lucky
ones to find a match in any of the marrow-donor registries.
``Enjoy your remission for as long as you can. Get your affairs
in order,'' I remember them telling me, ``while we keep looking
and try to figure something else out.''
This sad predicament is still all too familiar for many
adult leukemians. Even now, far too many patients are unable to
proceed to transplant due to the complexity, as you've heard
already earlier--the complexity of antigen matching, as well as
the problems inherent in tracking down, collecting the matching
marrow from a hopefully still willing and still available
marrow donor.
Fortunately, as I was, unfortunately, beginning to lose my
remission, my doctor was planning to begin one of the very
first clinical trials for end-stage adult CML'ers using
neonatal stem cells, those from cord blood. A perfect cord-
blood match was found for me within days, from the New York
Blood Center's world-renowned Placental Blood Program, as it
was known back at that time. And in life-or-death struggles
like these, days do matter.
Incredibly, some still anonymous New York City mother had
decided to do what few mothers were doing back then, and that
was to donate her newborn cord blood to a public cord-blood
bank. It was that donation, from that newborn baby girl, that
just happened to be my one and my only stem cell match.
I entered the hospital October 30, 1997. Magic and miracles
happened. And, by the grace of God, I was discharged 40
treacherous days later, but with a new, working immune system,
no trace of leukemia. And no hair.
[Laughter.]
Mr. Sprague. Here I am today, 5 years, 7 months, and 12
days later--and, believe me, I count every one of them--with a
100 percent donor cells, all female chromosomes, just like my
donor, completely cancer free. Still not much hair.
[Laughter.]
Mr. Sprague. In my post-transplant years as a patient
advocate, I've come to learn a lot of things--about myself,
about life and death, about perspectives, about appreciations
and priorities, but, most importantly, about hope. Part of that
hope, for desperate patients seeking transplant, patients like
I was, involves options. Heading down the transplant trail is a
risky endeavor, even in the best of circumstances, but that
critical first step can't ever be taken without first finding
the right stem cell match. Cord blood remains a largely
untapped, non-controversial, readily available alternative
source of non-embryonic stem cells.
That's the good news. That most of it continues to be
trashed as medical waste instead of finding its way into a
public cord-blood bank, that remains the problem. But it's a
solvable problem, as you've heard.
Registering the good intentions of prospective volunteer
marrow donors has been one solution to providing stem cells to
patients in need. Collecting and preserving the actual cord
blood, thanks to new parents who are willing, who are eager, to
donate at the time of delivery, may be a better solution, or at
least a viable option.
As cord blood finds its way into the medical mainstream,
it's my personal hope, shared by my cancer companions--the
lucky ones like me, as well as the less fortunate ones, who
have died waiting while searching for their elusive marrow
match--that an infrastructure to assist patients nationwide can
be created, regulated, funded to take better advantage of this
natural and precious gift of life.
If more of those estimated 4 million new parents each year
have a better opportunity to donate their newborn's cord blood,
an important new donor bank can be created quickly,
conveniently, without pain and without controversy. And it
certainly remains my privilege to serve as living proof of the
promise of cord blood for the adult leukemia community.
You know, we think of leukemia as a children's disease, but
90 percent of all leukemia cases are diagnosed in middle-aged
adults, like me, like some of you. Regardless of age, cord
blood is a proven alternative for saving lives, that needs your
support to become more readily available.
Again, I thank you for the privilege of telling my story
and sharing my concerns.
[The prepared statement of Mr. Sprague follows:]
Prepared Statement of Stephen R. Sprague, Cord Blood Crusader,
Staten Island, New York
Mr. Chairman and Members of the Subcommittee:
My name is Stephen Sprague and I am personally fortunate to have
the opportunity of speaking with you today. In a life before leukemia,
I've appeared before lots of committees, but never about matters
affecting life or death. Today, I'm here wearing a proud new hat . . .
that of a long-term adult cord blood transplant survivor, and my
remarks are much more critical . . . for those like me in the cancer
community, and I hope, for you who have an opportunity to help us now .
. . not with more research, but by supporting proven patient
applications.
While you probably can't tell, I'm an aging baby boomer and was
already a medical veteran before I got my leukemia diagnosis 7 years
ago at age 47. I'm a diabetic and had survived a heart attack and
quadruple bypass surgery in 1993. In spite of that, I was totally
unprepared for a battle with cancer. This was November 1995. In those
days, and even today with new experimental wonder drugs for cancer,
chemotherapy only stalled what was inevitable for long-term survival. .
.the traditional bone marrow transplant. ``The Cure That Can Kill'' as
some of us have learned to call it. Since CML is usually a slowly-
progressing, manageable cancer, I continued to seek a decent quality-
of-life while mentally preparing for transplant . . . the only option.
For whatever reason, in May 1997, only 18 months after my initial
diagnosis, I found myself in blast crisis, the end-stage of this
disease.
After a rigorous few months in the hospital, my oncologist, Dr.
Andrew Pecora, got me into my first remission while we began what would
quickly become a frustrating marrow donor search. I soon discovered
that less than a third of those seeking transplant have a matching
sibling, the best and most obvious donor source. Since I was an only
child, I needed to find an unrelated matching donor if a transplant
were to even be an option for me. To make a very long and complicated
story short, I was not one of the lucky ones to find an acceptable
match in any of the marrow donor registries. ``Enjoy your remission for
as long as you can and get your affairs in order'' I was told, ``while
we keep looking and try to figure something else out.''
This sad predicament is still an all-too-familiar one for many
adult leukemians. Even now, far too many patients referred for a
primary marrow donor search are unable to actually proceed to
transplant due to the complexity of antigen matching, as well as the
problems inherent in tracking down and eventually collecting the
matching marrow from a hopefully still-willing and still-available
donor. Fortunately for me, there soon came a series of events that, to
this day, I find difficult to understand or describe.
Just as I was beginning to lose my remission, my doctor, who
directs Hackensack (NJ) University Medical Center's prestigious Stem
Cell Transplant Program, was planning to begin one of the very first
clinical trials for end-stage adult CMLers using neonatal stem cells
obtained from umbilical cord blood. And equally astonishing, a perfect
cord blood match was found for me within days, from the New York Blood
Center's world-renowned Placental Blood Program, as it was known at the
time. And in life-or-death struggles like these, days matter.
Incredibly, some still-anonymous New York City mother had decided to do
what few new mothers were doing back in those days . . . donating their
newborn's cord blood to a public cord blood bank. It was that donation
from a newborn baby girl that happened to be my one and only match.
I entered the hospital on October 30, 1997. Magic and miracles
happened, including a pioneering treatment using cord blood. And by the
grace of God, I was discharged 40 treacherous days later, December 8,
1997, with a new, working immune system and no trace of leukemia. And
no hair. Fast-forward a bit and here I am today . . . 5 years, 7 months
and 12 days later . . . with 100 percent donor cells, all-female
chromosomes just like my donor, completely cancer-free and in
relatively good health. And still not much hair.
In my post-transplant activities as a patient advocate volunteer, I
have come to learn a lot of things. . .about myself, about life and
death, and about perspectives, appreciations and priorities. And most
importantly, about hope.
My point is simply this. Part of that hope for desperate patients
seeking transplant . . . patients like I was . . . involves options.
Heading down the transplant trail is a risky endeavor, even in the best
of circumstances. But that critical first step can't ever be taken
without first finding the right stem cell match.
As you will come to appreciate, umbilical cord blood remains a
largely untapped, non-controversial and readily available alternative
source of non-embryonic, neonatal stem cells. That's the good news.
That most of it continues to be trashed as medical waste instead of
finding its way into a public cord blood bank remains the problem. A
solvable problem. Registering the good intentions of prospective
volunteer marrow donors has been one solution to providing stem cells
to patients in need. Collecting and preserving the actual cord blood
thanks to new parents willing and eager to donate at the time of
delivery may be a better one. Or at least another viable option.
As cord blood finds its way into the medical mainstream, it is my
personal hope, shared by my cancer companions . . . the lucky ones as
well as the less fortunate ones who have died searching for their
elusive marrow match . . . that an infrastructure to assist patients
nationwide can be created, regulated and funded to take better
advantage of this natural and precious ``gift of life.'' If more of
those estimated 4 million new parents each year have a better
opportunity to donate their newborn's cord blood, an important new
donor bank can be created quickly, conveniently, without pain, and
without controversy. And it remains my privilege to serve as living
proof of the promise of cord blood for the adult leukemia community.
Although we think of it as a children's disease, 90 percent of all
leukemia cases are diagnosed in middle-aged adults. But regardless of
age, cord blood is a proven alternative for saving lives that needs
your support to become more readily available.
Thank you for the opportunity to share my concerns with you and I
would be happy to answer questions at the appropriate time.
Stephen R. Sprague,
Cord Blood Crusader.
Senator Brownback. And thank you. What an encouraging
story.
Have you done any public-service announcements? Because
you've got a natural gift here.
[Laughter.]
Mr. Sprague. Oh, thank you, Senator. In a former life, life
before leukemia, I appeared before lots of committees, but
never on something about life or death. It was always about all
the unimportant stuff. So I appreciate this opportunity.
Senator Brownback. We spend a lot of time on unimportant
stuff. But we do spend some time on important things, as well.
And you're sitting next to quite a star.
Mr. Penn, you've received quite notoriety, I know, already,
you're quite a remarkable young man. Will you tell us your
story?
STATEMENT OF KEONE PENN, SNELLVILLE, GEORGIA
Mr. Penn. My name is Keone Penn. Two days ago, I turned 17.
Five years ago, they said I wouldn't live to be 17.
I was born with sickle-cell anemia. My mother said I was a
crying baby. She didn't realize I was in pain.
I had a stroke when I was 5 years old. The teacher called
my mom from preschool and said that I had been acting funny all
day. My mother knew the symptoms, because she had seen it with
my grandparents.
They had to do a blood exchange of my whole body. I had
brain damage to the right side of my brain. I couldn't walk or
talk for a long time. I had to relearn everything.
Things got worse after that. My life was full of pain
crises, blood transfusions, and more times in the hospital than
I can count. I was never able to have a normal life. I couldn't
play sports, like basketball or football.
And I had a tube in my chest, and some kids bullied me and
threatened to hit me in my chest, and I felt like an outsider,
like I wasn't a normal kid. And it was just hard.
And I was suicidal then. Every day I'd go to school and
people would pick on me. I couldn't take it any more. One day,
I came home from school with a sad look on my face. My sister
got home after me, and my mom had went to work. I went in my
room, sat on my bed, and cried. I had suicide on my mind.
Then I thought about my family, how they would miss me. I
thought about my mom, my sister, my aunt, and my cousin, how
they would cry if I, you know, would die. I held my head up and
dried my eyes. My mother always said we have to do what we have
to do, and that you have to deal with the life you are given.
The year before I had the transplant, I was in the hospital
13 times. I knew everybody in the hospital and had been in just
about every room on the floor.
Then my mom, one day when I was in the hospital, she came
into the room, looking all depressed, because I had had a pain
crisis. And she was really sad, and she just looked at me, and
said, ``Keone, they want to try something. They want to do a
cord-blood transplant. They said if you don't do it in the next
5 years, you're going to have another stroke that could be
fatal. And this is experimental, and, you know, we have to work
together on this.'' And she said, ``So what do you think? Do
you want to do it?'' And I was thinking I'd rather go out
fighting than just wait and know you're going to die, you know,
because nobody wants to die. So I said yes, and we did the
cord-blood transplant.
My cord-blood transplant wasn't easy, but I thank God I'm
still here. I had a lot of problems, like graft versus host
disease, which is a rejection of the new cells.
I thought the coolest part about my transplant was that my
blood type has changed from O to B.
[Laughter.]
Mr. Penn. I missed a lot of school, and I had to do a
couple of years of home-schooling. But I still made all A's and
B's. I made B's this year.
[Laughter.]
Mr. Penn. Next year, I will graduate from high school. My
family will be so proud to see me graduate, because they
thought I wouldn't live long enough to graduate. Before I had
my transplant, they said I wouldn't live another 5 years.
My graduation will mark a big victory in my life. I want to
become a chef. I plan to go to a good culinary arts school in
Georgia. I cook for my family all the time. I think I'm pretty
good at it.
[Laughter.]
Mr. Penn. My life, with sickle cell, was very rough. I have
been through more things than most grownups can only imagine.
But sickle cell is a part of my past. One year after my
transplant, they pronounced me cured of sickle-cell anemia.
Cord blood saved my life. Now I can look forward to a brighter
future.
Thank you.
[The prepared statement of Mr. Penn follows:]
Prepared Statement of Keone Penn, Snellville, Georgia
My name is Keone Penn. Two days ago, I turned 17 years old. Five
years ago, they said I wouldn't live to be 17. They said I'd be dead
within 5 years. I was born with sickle cell anemia. Sickle cell is a
very bad disease. I had a stroke when I was 5 years old. Things got
even worse after that. My life has been full of pain crises, blood
transfusions every two weeks, and more times in the hospital than I can
count. The year before I had my stem cell transplant, I was in the
hospital 13 times. I never was able to have a normal life. My stem cell
transplant was not easy, but I thank God that I'm still here. I will
graduate from high school this year. I want to become a chef because I
love to cook. I think I'm pretty good at it. Sickle cell is now a part
of my past. One year after my transplant, I was pronounced cured. Stem
cells saved my life. Thank you.
Senator Brownback. Thank you.
Those are very impressive statements and very impressive
comments.
Mr. Barsh and Mr. Sprague, I'm curious--and you may want to
involve any of the researchers that can comment on this, as
well.
Senator Brownback. You have commented that timing is
critical determining the need for cord blood. Every minute,
every day counts on this.
Mr. Barsh, you were right on top of this at an early phase.
How do we catch these earlier? What's your advice on how we
catch these to be able to intercept as fast as possible, number
one? And I want to ask you, as well, is this the sort of thing
if you catch it right at birth, you're likelihood of success is
far greater than if it drags on for a period of time?
Mr. Barsh. Senator, they're all excellent questions, and
thank you for asking me, and I'll just comment.
One way that these types--or many, but not all--of the
neurodegenerative diseases can be caught is by better prenatal
testing--or testing, immediately after birth, like PKU testing,
which is mandated today for every baby born. It's done on a
state-by-state basis, but not a Federal basis. In about a year,
there's going to be a test for adrenoleukodystrophy, so it
could be screened and caught earlier.
Ours was caught in a very unfortunate circumstance, where
one of Spencer's oldest cousins is in a persistent vegetative
state from ALD today. There were three boys in our family that
had it, because it's X-linked and gets passed down. So Oliver
was the martyr and won't be able to recover, but he saved two
other kids in the family.
But better testing----
Senator Brownback. I'm sorry----
Mr. Barsh. Yes?
Senator Brownback.--Mr. Barsh----
Mr. Barsh. Yes.
Senator Brownback.--let me back up on this a bit. What time
was it caught in him?
Mr. Barsh. He was about, I would say, seven or 8 years old,
and he had been seeing physicians for about four or 5 years for
some type of problem that had been misdiagnosed as everything--
ADD, ADHD, Asperger's Syndrome--which is very common with our
type of disease.
So I'd say I think the other thing that Congress could do
would be to pass legislation, from a healthcare point of view--
and I'll just talk to one narrow area, which is children.
Children that display some type of mental delay, or some type
of symptom that wants to be diagnosed as ADD or ADHD--a very
simple, painless MRI can be performed on their brains just to
make sure it's nothing else.
In certain countries in Europe today--I believe, in
France--it's actually mandated. If a child has developmental
delay, they do an MRI to check. That's how you could catch a
lot of these diseases, because they slip through.
A typical pediatrician, our pediatrician, that has Spencer
as a patient, that had ALD, she'll never see another child in
her career with the disease. Around one in 10-13,000 kids has
ALD. And it's so rare a single pediatrician would see it.
So I think better education for physicians, and laws
mandating that children that have some type of developmental
delay be screened. Again, screening right after birth for a
number of these diseases--you know, West Virginia screens for
two diseases. Pennsylvania screens for about 26. It differs
state by state.
Senator Brownback. Can you screen before birth for ALD?
Mr. Barsh. Yes, you can. You can screen at CVS testing. You
can screen during amniocentesis. It's not typically screened
today, because, the genetic testing labs will tell you, ``You
can't screen for everything. Otherwise, we'll be screening for
forever.'' So they do it--if there's a family history, they can
absolutely screen for it today.
Senator Brownback. Are there treatments, even before birth?
Are there in-utero treatments?
Mr. Barsh. Not really. One of the things I believe some
researchers are looking toward the future of doing in-utero
cord-blood transplants, which, to me, is staggeringly
interesting. But, yes, you could absolutely, if you knew.
And that technology--it's not there today, I believe. And I
think Dr. Kurtzberg could address that specifically. But----
Senator Brownback. Dr. Kurtzberg, would you mind sitting up
here? I know this isn't the way we normally proceed. And if any
of the other researchers want to pitch in, but I really would
like to get at this point, about at what age and stage can cord
blood can be the most successful.
Dr. Kurtzberg. Well, newborn screening could be available
for most of these diseases. But it is not available on a
routine basis or a mandatory basis. And even when parents
request it, most of the time their pediatricians think it's not
indicated. But if it was part of the standard newborn screening
panels, it would be wonderful.
And what would be needed for that is, you know, an RFP to
invite proposals to develop simple technology on dot-blot
testing for newborn screening for these metabolic diseases.
Senator Brownback. Which do not exist today.
Dr. Kurtzberg. Well, I mean, there are researchers working
on the technology. It does exist, but it is not implemented in
the United States, and it should be. Because all of these
diseases would fare better if they were treated early in life.
And regardless of what disease you're treating, children do
better with transplant earlier in life. We don't have to use
quite as much chemotherapy. They tolerate the procedure better.
I don't know if you remember, but our young Krabbe kids
have 100 percent survival because they're healthier. And even
though they have that bad disease, the rest of them can
tolerate the therapy and the medicines easier.
Senator Brownback. What about in-utero diagnosis and
treatment?
Dr. Kurtzberg. Well, yes, there are--diagnosis is certainly
possible. Parents can also be screened to see if they're
carriers so they know whether or not they would be possibly
conceiving a child with the disease. There's something called
pre-implantation diagnosis, which allows selection of a healthy
embryo. More commonly, people use CVS or amnio, as Steve
mentioned, to make an in-utero diagnosis.
In-utero treatment is more complicated. There have been
transplants tried in the second or third trimester. You
obviously can't give a fetus chemotherapy. And most of the time
they're either rejected because the fetus has enough of an
immune system to not retain the cells; or there are too many
cells, and the balances are off.
What probably would work and has been demonstrated in
animals is that if you did the transplant in the first
trimester of pregnancy, which would require diagnosis by CVS,
those cells would probably be tolerated by the fetus because
it's in a state called a pre-immune state. But no one knows
that for sure, and a lot more research has to be done to prove
that. But, theoretically, and in animals, that looks like the
way to go.
Senator Brownback. We're looking to set up a hearing on in-
utero treatments, because there's a burgeoning field of
treatments that--some spina bifida is being successfully
treated in utero--that are really, really fantastic.
Dr. Kurtzberg. Well, you would a 10- to 12-week fetus and
inject cord-blood cells into the belly, or the forming abdomen,
and those cells would induce tolerance so that, later, they
could be boosted, after birth, without chemo.
Senator Brownback. Well, that's interesting.
Dr. Kurtzberg. But you have to know that the baby has the
diagnosis, and that, again, has been done in animals, but not
in people.
Senator Brownback. This procedure you've described has not
been performed on people.
Dr. Kurtzberg. No.
Senator Brownback. But it has been successful in an animal
model.
Dr. Kurtzberg. Correct. And there are people talking about
implementing it in people. But it takes a lot of things to come
together. I mean, you have to know there's a risk, someone has
to have a CBS, and then you have to be able to mobilize the
donor in a week, which you could do with cord blood.
Senator Brownback. Mr. Sprague, in your treatment and the
situation you're in, what advice do you give to patient groups?
You said you speak quite a bit. Is it early screening? Do we
have to do more in the cord-blood field? Is it to look at the
option of cord blood, which a lot of people don't know about,
instead of bone marrow?
Mr. Sprague. Early detection is kind of interesting for
blood cancers. There are few symptoms. Usually the diagnosis is
a total shock, because you don't feel like you have cancer. You
know you have a blood cancer, by a simple blood test. So one of
the easiest things for everybody to do is just check your oil
once in awhile. Get a blood test and make sure that everything
is OK. Some of us do that religiously; some of us seldom do it.
Once you've been diagnosed with a blood cancer, while
chemotherapy will only keep the disease manageable--and, in
some cases, for many, many years--it's just known that the only
cure--and leukemia is one of the few cancers that people can
look you in the eye and tell you you're cured--is a successful
stem cell transplant. The problem, as I said earlier, is if you
can't find a stem cell match, then you have no cure, and you
sit home, and you wait to die.
When you compare having to go through a marrow search with
the ability to find a cord-blood match sitting on the shelf
somewhere--already typed, already collected, already screened,
already matched to your particular type--I mean, that's going
to save you months, sometimes more than months. And usually
when patients decide to go to transplant, they're in the
serious stages of the disease.
When you're feeling pretty good and you've been early
diagnosed with the leukemia, transplant is something you think
is way down the line. So if you can improve the time to find a
match by having an inventory of stored cord blood, as opposed
to a bunch of people who have, out of the goodness of their
heart, said, ``I'll be a donor if I match somebody and if you
can find me when the time comes to get my marrow,'' that's
going to save an awful lot of lives of blood cancer patients
who are in distress to the point where if something doesn't
happen quick, then they're going to die.
Senator Brownback. Mr. Penn, you've got quite a remarkable
story that you've put forward in being cured of sickle cell
anemia. What's your advice to others that have suffered under
the same disease that you've gone through? Is it to really seek
to find cord blood that can match and that can do this and at
earlier ages?
Mr. Penn. Yes. Because, I mean, I can only imagine how hard
it is on other people. And I'm just one kid with sickle cell. I
mean, you could walk up to anybody today, and they could have
sickle cell. They probably wouldn't tell you, but--and there's
probably a lot of people in the world who have sickle cell and
who are looking for a cure. And this could really help them.
And if I could help them, I would like to. I mean, I'd do
all I can to make sure nobody goes through what I went through.
Senator Brownback. How many years ago did you go through
the procedure?
Mr. Penn. Five years ago.
Senator Brownback. Five years ago.
Mr. Penn. Yes, it'll be 5 years on December 11.
Senator Brownback. And it was very difficult for you at
that time, going through the chemotherapy and----
Mr. Penn. Yes.
Senator Brownback. Now, if this had been caught earlier and
tried earlier, would that have been easier?
Mr. Penn. Probably. Because your body's more healthy when
you're a baby, so your body's able to accept the chemotherapy
when you have to do the chemo. And since my body had aged, my
body really didn't accept it that much. The cells either--since
the cells had been in my body so long, they were fighting it
off. That's probably why I got graft versus host disease, too.
Senator Brownback. Dr. Kurtzberg, is this one that could
have been--if you know and have a family history--diagnosed in
utero, the procedure started that you had described?
Dr. Kurtzberg. Certainly with the appropriate research on
the procedure. But most states have screening programs for
sickle cell in newborns, so it is pretty universally diagnosed
at birth now. And medical therapy, like antibiotics and extra
visits to the pediatrician and education of parents about
crises, et cetera, is started in the first year of life. If
those babies were transplanted in the first year of life, one,
they would tolerate it better, they would have a higher
survival. They wouldn't have damage to their tissues that
sickle cell, itself, causes or the transfusions cause. So the
whole process is easier. And, hearing Keone's story, how he had
to miss school and how, socially, he had issues because he was
sick and he couldn't attend school normally, are avoided when
you transplant a newborn. Because by the time they recover,
they're two or one and a half, and they're at a point where
they really haven't missed out on school or other social
developmental things that older children need to have.
Senator Brownback. Is this being done regularly now in
sickle cell diagnosis? Is the cord blood?
Dr. Kurtzberg. The diagnosis is regular. Cord blood
transplant is not regular.
Senator Brownback. Why not?
Dr. Kurtzberg. Because, I think, the hematology community
worries about the mortality risks. And there is a natural study
of sickle cell disease, which is ongoing, which shows that not
all patients will have a severe course. Some do and some don't.
And there have yet to be predictors identified that say which
of the patients will be having strokes as children, et cetera.
And so, because of that, there's been a reluctance to recommend
that all children with the disease are treated.
And thalassemia, which is another hemoglobin problem where
children don't make red cells effectively at all and are
dependent on transfusions from the age of about five or 6
months, there's more acceptance to doing it in infancy because
it's known that that disease, because if iron buildup, will be
fatal in usually the second or third decade of life.
Senator Brownback. Now, in Keone's case, where at age five,
had a stroke, he would be clearly be somebody that you would
say we need to do the cord blood, with the knowledge that we
have now.
Dr. Kurtzberg. Right. Correct. And that is starting to
happen. Yes.
Senator Brownback. Good.
Dr. Kurtzberg. But, you know, just as a point, in some
states, Medicaid won't cover HLA typing for a sickle cell
patient. That's the tissue typing that you need to have to
know: Do you have a donor in your family or do you need to look
for an unrelated donor? So that's not even a universal health
care benefit, and it certainly should be.
The other thing I wanted to say about genetic diseases is
that parents are a huge resource, and they are huge advocates
for their children. And as much as it's important to educate
pediatricians, of which I am one, I think that the parents can
be empowered, in large part, to do a lot to get their children
screened and to use tests that might be made available to them.
And that parental education about some of these diseases would
help make things happen. And with the Internet, there's a huge
tool now to bring about some programs that would be beneficial
to all, and not that expensive to implement.
Senator Brownback. Ms. Penn, do you have anything to tell
us about your experience with this?
Ms. Penn. Well, there's quite a few things I could actually
tell you. In Keone's experience, his life has been pretty
difficult with sickle cell. And, like he said earlier, if
there's a opportunity or a chance that another child doesn't
have to go through things that my child has been through,
that's a gift from God, and hopefully, this will bring about
some change.
Senator Brownback. Yes. Hopefully, it will.
Thank you very much. This has been a very encouraging
group, all of you. You've been very thoughtful.
I hope all of you do public service announcements, get the
word out. I hope there's lots of comments and quotes that are
attributed to you, because I think this is the sort of thing we
need to build a lot of knowledge and exposure to. This is a
truly remarkable set of developments that--areas we hadn't
thought we had much hope--and a whole new alternative to be
able to go with.
I'm very heartened by this and by your comments. That's
another area for us to look at, is the Medicaid coverage on the
sickle cell blood typing.
Dr. Kurtzberg. HLA typing. Tissue typing or HLA typing.
Senator Brownback. OK.
Well, thank you. God bless you all for coming forward.
Thanks for being here. And hopefully we'll make some good
progress in this area.
The hearing is adjourned.
[Whereupon, at 4:33 p.m., the hearing was adjourned.]
A P P E N D I X
Testimony of the American Academy of Physician Assistants
On behalf of the more than 46,000 clinically practicing physician
assistants in the United States, the American Academy of Physician
Assistants is pleased to submit comments in response to the
Subcommittee's June 12 Hearing on Advances in Adult and Non-Embryonic
Stem Cell Research.
The Academy applauds the wonderful advances in adult and non-
embryonic stem cell research that were highlighted in the
Subcommittee's hearing of June 12. The field of regenerative medicine
does indeed offer great hope to individuals who are suffering from
disease. However, to fully realize the enormous potential benefits in
medical research and human healing, the AAPA believes that the use of
human embryonic stem cell research, including the use of nuclear
transplantation techniques (also known as non-reproductive, research or
therapeutic cloning), must also be fully supported. The promises of
human embryonic stem cell research are, through its eventual
application in the hospital and office, to ease human suffering, save
lives and harness fundamentally novel avenues for patient care.
Physician Assistants (PAs)
Physician assistants are legally regulated in all states to
practice medicine as delegated by and with the supervision of a
physician. Physicians may delegate to PAs those medical duties that are
within the physician's scope of practice and the PA's training and
experience, and are allowed by law. A physician assistant provides
health care services that were traditionally only performed by a
physician. Forty-seven states, the District of Columbia, and Guam
authorize physicians to delegate prescriptive privileges to the PAs
they supervise. An estimated 170 million patient visits were made to
PAs and approximately 213 million medications were prescribed or
recommended by PAs in 2001.
PAs work in virtually every area of medicine and surgery and are
covered providers of physician services through Medicare, Tri-Care, and
most private insurance plans. Additionally, PAs are employed by the
Federal Government to provide medical care, including the Department of
Veterans Affairs, the Department of Defense, and the Public and Indian
Health Services.
American Academy of Physician Assistants (AAPA)
The American Academy of Physician Assistants was founded in 1968
and is the only national organization representing physician assistants
(PAs) in all medical specialties. The Academy educates the general
public about the PA profession, assures competency of PAs through
active involvement in the development of educational curricula and
accreditation of PA programs, provides continuing education, and
conducts PA-related research. The mission of the Academy is to promote
quality, cost-effective health care, and the professional and personal
growth of physician assistants.
AAPA Policy on Stem Cell Research
The AAPA's policy on stem cell research is based on the desire to
promote the intense, vigorous, and responsible scientific research that
will be necessary to realize the potential medical benefits of using
stem cells to treat disease and repair tissue damaged by disease or
trauma. The research holds tremendous promise for the development of
new treatments for a wide range of serious illness and injury, such as
Parkinson's disease, Alzheimer's disease, cancer, diabetes, heart
disease, arthritis, neurodegenerative and immunodeficiency diseases,
and spinal cord injury.
The AAPA policy on stem cell research was adopted by the Academy's
House of Delegates in 2002 and 2003. Four principles are core to the
Academy's collective policy--
Federal funding must be used to support embryonic stem cell
research.
Productive research requires a larger source of stem cell
lines than those in existence on August 9, 2001, necessitating
the isolation of new embryonic cell lines.
The cloning of human beings for the purpose of reproduction
must be prohibited.
The use of nuclear transplantation techniques should be
promoted as a desirable means to create embryonic stem cells
for research purposes.
The AAPA believes the Federal government is the single, best source
for the large and sustained financial investment needed to move the
research forward. The Federal government must play an important role in
providing public review, approval, and monitoring of the research, as
well as insuring the scientific and ethical appropriateness of the
research.
Concerns regarding the age, quality, ownership, and racial and
ethnic variability of the cell lines available on or before August 9,
2001 led the AAPA to support the isolation of new embryonic cell lines.
Questions about whether appropriate informed consent from the donors of
embryos that had been used to develop the earlier cell lines further
substantiated the need to support the isolation of new embryonic cell
lines.
In developing its support for embryonic stem cell research, the
Academy addressed difficult ethical considerations, which led to policy
being adopted to safeguard the use of donated embryos, including the
appropriate use of excess, abandoned, or non-transferable frozen
embryos currently stored at in vitro fertilization clinics.
In 2003, the AAPA affirmed and strengthened its opposition to the
inappropriate use of human embryos by adopting policy to support a
legally enforceable ban on the cloning of human beings for the purpose
of reproduction.
The creation of stem cells by nuclear transplantation is supported
as an ethically responsible means of isolating new embryonic stem cell
lines, because the procedure does not involve implantation of a
blastocyst in a uterus, nor is it intended to lead to the birth of a
cloned human being. The stem cells that are produced are unspecialized
cells that can renew themselves indefinitely and, under the right
conditions, develop into more mature cells with specialized functions.
Furthermore, the cells are created with the express permission of the
donor and the express understanding that the tissue will be used for
stem cell derivation only, not for implantation and reproduction.
The AAPA believes that stem cell research and nuclear
transplantation hold tremendous potential to ease human suffering
through advanced therapies. The Academy applauds the Subcommittee's use
of the June 12 hearing to showcase the remarkable advances in medicine
that have been made in the fields of adult and non-embryonic stem cell
research. However, the Academy also urges the Subcommittee to consider
the appropriate and responsible use of embryonic stem cell research. No
other current avenue of medical research holds the promise of human
embryonic stem cells.
Thank you for the opportunity to submit the comments of the
American Academy of Physician Assistants to the Hearing Record.