[Senate Hearing 108-249]
[From the U.S. Government Publishing Office]



                                                        S. Hrg. 108-249
 
                 FEDERAL FUNDING FOR STEM CELL RESEARCH
=======================================================================

                                HEARING

                                before a

                          SUBCOMMITTEE OF THE

            COMMITTEE ON APPROPRIATIONS UNITED STATES SENATE

                      ONE HUNDRED EIGHTH CONGRESS

                             FIRST SESSION

                               __________

                            SPECIAL HEARING

                      MAY 22, 2003--WASHINGTON, DC

                               __________

         Printed for the use of the Committee on Appropriations













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                      COMMITTEE ON APPROPRIATIONS

                     TED STEVENS, Alaska, Chairman
THAD COCHRAN, Mississippi            ROBERT C. BYRD, West Virginia
ARLEN SPECTER, Pennsylvania          DANIEL K. INOUYE, Hawaii
PETE V. DOMENICI, New Mexico         ERNEST F. HOLLINGS, South Carolina
CHRISTOPHER S. BOND, Missouri        PATRICK J. LEAHY, Vermont
MITCH McCONNELL, Kentucky            TOM HARKIN, Iowa
CONRAD BURNS, Montana                BARBARA A. MIKULSKI, Maryland
RICHARD C. SHELBY, Alabama           HARRY REID, Nevada
JUDD GREGG, New Hampshire            HERB KOHL, Wisconsin
ROBERT F. BENNETT, Utah              PATTY MURRAY, Washington
BEN NIGHTHORSE CAMPBELL, Colorado    BYRON L. DORGAN, North Dakota
LARRY CRAIG, Idaho                   DIANNE FEINSTEIN, California
KAY BAILEY HUTCHISON, Texas          RICHARD J. DURBIN, Illinois
MIKE DeWINE, Ohio                    TIM JOHNSON, South Dakota
SAM BROWNBACK, Kansas                MARY L. LANDRIEU, Louisiana
                    James W. Morhard, Staff Director
                 Lisa Sutherland, Deputy Staff Director
              Terrence E. Sauvain, Minority Staff Director
                                 ------                                

 Subcommittee on Departments of Labor, Health and Human Services, and 
                    Education, and Related Agencies

                 ARLEN SPECTER, Pennsylvania, Chairman
THAD COCHRAN, Mississippi            TOM HARKIN, Iowa
JUDD GREGG, New Hampshire            ERNEST F. HOLLINGS, South Carolina
LARRY CRAIG, Idaho                   DANIEL K. INOUYE, Hawaii
KAY BAILEY HUTCHISON, Texas          HARRY REID, Nevada
TED STEVENS, Alaska                  HERB KOHL, Wisconsin
MIKE DeWINE, Ohio                    PATTY MURRAY, Washington
RICHARD C. SHELBY, Alabama           MARY L. LANDRIEU, Louisiana
                                     ROBERT C. BYRD, West Virginia (ex 
                                         officio)
                           Professional Staff
                            Bettilou Taylor
                              Jim Sourwine
                              Mark Laisch
                         Sudip Shrikant Parikh
                             Candice Rogers
                        Ellen Murray (Minority)
                         Erik Fatemi (Minority)
                      Adrienne Hallett (Minority)

                         Administrative Support
                             Carole Geagley















                            C O N T E N T S

                              ----------                              
                                                                   Page

Opening statement of Senator Arlen Specter.......................     1
Statement of Elias Adam Zerhouni, M.D., Director, National 
  Institutes of Health, Department of Health and Human Services..     2
    Prepared statement...........................................     4
Opening Statement of Senator Tom Harkin..........................     9
Statement of Ronald McKay, Ph.D., Senior Investigator, National 
  Institute on Neurological Disorders and Stroke, National 
  Institutes of Health, Department of Health and Human Services..    19
    Prepared statement...........................................    20
Statement of John A. Kessler, M.D., Boshes Professor and 
  chairman, Davee Department of Neurology, Northwestern 
  University Medical School......................................    21
    Prepared statement...........................................    23
Statement of Roy Ogle, Ph.D., associate professor of neurosurgery 
  and cell biology, University of Virginia Medical School........    25
    Prepared statement...........................................    27
Statement of James Cordy, founder, Parkinson's Alliance, on 
  behalf of the Coalition for the Advancement of Medical Research    29
    Prepared statement...........................................    31
Questions Submitted to Dr. Zerhouni..............................    37
Questions Submitted to Dr. Von Eschenbach........................    39















                 FEDERAL FUNDING FOR STEM CELL RESEARCH

                              ----------                              


                         THURSDAY, MAY 22, 2003

                           U.S. Senate,    
    Subcommittee on Labor, Health and Human
     Services, and Education, and Related Agencies,
                               Committee on Appropriations,
                                                    Washington, DC.
    The subcommittee met at 9:47 a.m., in room SR-418, Russell 
Senate Office Building, Hon. Arlen Specter (chairman) 
presiding.
    Present: Senators Specter and Harkin.


               opening statement of senator arlen specter


    Senator Specter. Good morning, ladies and gentlemen. The 
Appropriations Subcommittee on Labor, Health and Human 
Services, and Education will now proceed. This morning's 
hearing is on the subject of the determination as to whether 
the current stem cell policy is adequate on moving research 
toward cures of so many maladies, and we are going to be 
looking into the adequacy of the existing stem cell lines.
    Until Monday of this week the conclusive information, 
consistent information, presented to this subcommittee and more 
broadly was that there were insufficient stem cell lines and 
that they were contaminated with mouse feeders. On Monday I was 
informed by staff that Dr. Zerhouni had just called to say that 
he believed there were stem cell lines which were not 
contaminated with mouse feeders, which was more than a 
surprise; it was a shock.
    I sat down with Dr. Zerhouni on Tuesday afternoon to go 
into the matter in some greater detail. The reason that the 
issue was so startling was that this subcommittee has been 
consistently advised that the eligible stem cell lines have all 
been grown with mouse feeder cells. That information was given 
to us, by the Secretary of HHS Thompson; Dr. Alan Spiegel, the 
director of the National Institute on Diabetes, Digestive, and 
Kidney Diseases, which has principal responsibility on the stem 
cell issues; by Dr. James Battey, chairman of the NIH Stem Cell 
Task Force, all from NIH, and from other scientists as well--
Dr. Roger Pederson from Cambridge, Dr. George Daley from MIT.
    There is a considerable body of additional authority for 
the proposition that the existing cell lines, stem cell lines, 
are contaminated with mouse feeders, but I will not take the 
time to go into them now. We had a delay of about 15 minutes in 
commencing this hearing because the President addressed the 
Members of the Senate and the House on a meeting which was just 
scheduled late last night, and he just concluded a few moments 
ago. I came directly from that meeting in the Capitol to this, 
to this hearing.
    There is concern about the--putting this is somewhat 
delicate, but--the objectivity of the information which this 
subcommittee is getting and whether there is a politicization 
of the process. This subcommittee had a direct confrontation 
with Secretary Thompson when we sought information some time 
ago about stem cells and the information was requested from all 
of the directors and the information was edited before it came 
to us, which was out of line. And the subcommittee is concerned 
as to what is happening on a continuing basis.
    The disparity between funding an NIH for human embryonic 
stem cells and adult stem cells raises real questions, to put 
it without hyperbole. Stem cell research has $10.7 million in 
2002 and $17.1 in 2003. Adult stem cell research has $147.6 
million in 2002 and $155.7 million in 2003.
    There have been very strong reasons advanced for additional 
stem cell lines: first, genetic diversity; second, proper 
comparison of lines grown using mouse feeders and lines grown 
without mouse feeders; and third, the need for lines grown 
without feeders for use in treatment.
    This is the 16th stem cell hearing which this subcommittee 
has had and we have focused a great deal of our time and energy 
on the subject because we think it is so important. It is very 
important that we get the scientific opinions without 
politicization, without shading. These issues are too 
important.
    The President responded by allowing some 63 lines in his 
speech at 9 o'clock on August 9, 2001, after some 76 Senators 
had expressed themselves in favor of Federal funding on stem 
cells. The hands of the scientists should not be tied in any 
way. We ought to be finding out what the facts are and 
proceeding on them, and this subcommittee intends to do that. 
We have great respect for the new director, Dr. Zerhouni, but 
we intend to find out what the facts are.
STATEMENT OF ELIAS ADAM ZERHOUNI, M.D., DIRECTOR, 
            NATIONAL INSTITUTES OF HEALTH, DEPARTMENT 
            OF HEALTH AND HUMAN SERVICES
ACCOMPANIED BY JAMES BATTEY, M.D., DIRECTOR, NATIONAL INSTITUTE ON 
            DEAFNESS AND OTHER COMMUNICATION DISORDERS, NATIONAL 
            INSTITUTES OF HEALTH, DEPARTMENT OF HEALTH AND HUMAN 
            SERVICES

    Senator Specter. Our first witness is Dr. Elias Adam 
Zerhouni, the 15th Director of NIH. Prior to becoming director, 
Dr. Zerhouni has had an extraordinarily distinguished career: 
executive vice dean of Johns Hopkins, received his medical 
degree from the University of Algiers. Dr. Zerhouni is 
accompanied by Dr. James Battey.
    Dr. Zerhouni, the floor is yours. We are looking forward to 
your testimony.
    Dr. Zerhouni. Thank you, Mr. Chairman. I am pleased to 
appear before you and I will make my comments short as the full 
testimony is available for the record.
    Senator Specter. Your full statement will be made a part of 
the record without objection.
    Dr. Zerhouni. I am pleased to testify for you about the 
progress we have made over the past year and since the last 
hearing on human embryonic stem cell research. There are more 
than 60 investigators at 48 institutions that have received NIH 
awards and are working on embryonic stem cell research. There 
are 78 lines that are fully eligible for Federal funding in 
various stages of development.
    In the last year alone, NIH support has helped increase the 
number of widely available lines to any researcher from one in 
April of 2002 to five at our last hearing in September to 11 
today, and more are being developed and will be available in 
the near future.
    I can report to you that we are as diligently as possible 
implementing the policy promulgated by the President August 9, 
2001, which has enabled the field of embryonic stem cell 
research to advance. Prior to that date, no funding had been 
spent on the field of embryonic stem cell research and we are 
trying to accelerate funding as fast as we can over the past 18 
months since we have developed our strategy at NIH to support 
this field.
    So we continue to acquire new knowledge about human 
embryonic stem cells at a rapid pace. Recently, NIH-supported 
researchers have succeeded in replacing a stretch of DNA within 
a stem cell and this is a very important advance as it opens 
the door to scientists who want to study the function of 
specific genes and also provide a way to modify derived tissues 
for use in treating patients.
    Scientists are currently working to identify those genes 
that are involved in the differentiation of human embryonic 
stem cells as well as those genes that permit embryonic stem 
cells to self-renew, and this is an important scientific 
prerequisite for progress to be made. Until recently, all human 
embryonic stem cells were expanded after derivation on mouse 
feeder layers.
    Now scientists are discovering and establishing conditions 
that allow these cells to grow in the presence of human feeder 
cell layers. NIH-supported scientists in the United States, 
using approved NIH-available cell lines, tested the ability of 
human feeder cells to sustain these lines and are now learning 
as fast as they can the molecular signals that will allow us 
eventually to expand and grow human embryonic stem cells 
without any feeder layers.
    Since I arrived at NIH about a year ago, I have been 
working hard to promote stem cell research based on 
recommendations received from the research community and by the 
NIH stem cell task force, which I established in August 2002, 
with scientists from within NIH and from the extramural 
community.
    The newest effort, for example, is the establishment, after 
recommendation of the NIH stem cell task force, of an NIH 
characterization unit at NIH under the direction of Dr. Ron 
McKay. This unit will be located on our campus in Bethesda and 
this unit will provide what is missing right now in the field 
of embryonic stem cell research, reliable, standardized data 
derived from assays performed on human embryonic stem cell 
lines, so that we can make available for widespread 
distribution lines that are fully characterized so that 
scientists can compare results across experiments.
    Again, I want to assure the committee of NIH's commitment 
to pursuing embryonic stem cell research vigorously, as well as 
continuing our advances in the field of adult stem cell 
research. The President's policy has provided us the 
opportunity to be at the forefront of new discoveries about 
stem cells and we are exploiting it as fully as we can.
    As I said, over the past year I have been actively working 
on providing open discussions and open access to all the 
scientists who have ideas about how to promote the field. I 
have established processes to do so.

                           prepared statement

    In echoing your own statement, Mr. Chairman, at my 
confirmation hearing I stated the fact that it was very 
important for the NIH director to be factual and provide 
accurate factual information to the maximum extent possible at 
the time needed to inform policy decisions, and this is what I 
will do.
    Thank you, Mr. Chairman.
    [The statement follows:]
                  Prepared Statement of Elias Zerhouni
    Mr. Chairman, Senator Harkin, and Members of the Subcommittee, I am 
pleased to appear before you today to testify about the progress of 
human embryonic stem cell research. In fiscal year 2002, NIH spent 
approximately $11 million for human embryonic stem cell research to 
increase the availability of stem cell lines for federal research, 
train scientists how to use these technically-challenging cells, and 
conduct basic, pre-clinical research that represents the first steps 
toward understanding how stem cells might be used to treat injuries and 
diseases.
    More than 60 investigators at 48 institutions have received NIH 
awards, including 14 investigator-initiated grants and 44 
administrative supplements. The administrative supplements allow 
investigators to rapidly incorporate research on human embryonic stem 
cells into their ongoing work. As you know, there are 78 lines fully 
eligible for Federal funding, in various stages of development. NIH 
support has helped increase to 11 the number of human embryonic stem 
cell lines that are widely available for all researchers. More lines 
will become available in the future, as we help the scientific 
community capitalize on this opportunity. I can report to you today 
that NIH's implementation of the policy set by the President on August 
9, 2001 has enabled the field of stem cell research to advance. We 
continue to acquire new knowledge about human embryonic stem cells 
(hESCs). Some of the significant discoveries include the following 
research findings.
  --NIH-supported researchers at the University of Wisconsin recently 
        succeeded in replacing a specific stretch of DNA in human 
        embryonic stem cells. This technique, called homologous 
        recombination, opens the door to scientists who want to study 
        the function of specific genes within these cells and also 
        provides a way to modify hESC-derived tissues in a very precise 
        matter for use in treating patients.
  --Scientists at NIH have been able to demonstrate that differentiated 
        mouse embryonic stem cells can be directed to become 
        specialized cells in order to repair damage when transplanted 
        into the brain or spinal cord. This finding could lead to the 
        development of replacement therapy for cells that are destroyed 
        through injury or disease, such as stroke, Parkinson's disease 
        or Alzheimer's disease.
  --In vitro studies have produced more specialized cells from human 
        embryonic cells that might be used for blood cell 
        transplantation therapies for patients with blood malignancies 
        such as leukemia or myeloma.
  --Scientists are currently working to identify those genes that are 
        involved in the differentiation of hESCs, as well as those 
        genes that permit embryonic stem cells to self-renew. This 
        knowledge, along with research involving gene transfer 
        techniques, potentially will allow scientists to coax hESCs 
        into becoming insulin-producing beta cells to treat insulin-
        dependent diabetes.
  --Until recently, all hESCs were grown on mouse feeder layers. Now 
        scientists are establishing conditions that allow hESCs to grow 
        in the presence of human feeder cell layers. NIH-supported 
        scientists in the United States, using stem cells eligible for 
        federal research, have tested the ability of human feeder cells 
        derived from fetal or adult tissues to support the growth of 
        human embryonic stem cell lines. Both fetal and adult human 
        feeder cells were able to support and maintain the cells in an 
        undifferentiated state. Also, we have seen published research 
        on the existence of one cell line, developed in Singapore, that 
        was created and developed using human feeder layers. However, 
        the Food and Drug Administration has informed NIH that, given 
        the complexity of this area of research, it is difficult to 
        predict whether newly derived human embryonic stem cells grown 
        exclusively on human feeder cells would result in clinical 
        trials sooner than the existing eligible cell lines either 
        grown exclusively on mouse feeder cells or adapted to human 
        feeder cells.
    At the same time, we continue to learn more about other types of 
stem cells, including adult and those derived from umbilical cord 
blood.
  --An NIH-supported researcher at the University of Minnesota isolated 
        multipotent adult progenitor cells from human bone marrow. 
        These cells demonstrate the potential to differentiate beyond 
        bone marrow stem cells into other cell types, including liver, 
        neurons and blood vessels.
  --In a laboratory of the National Institute of Dental and 
        Craniofacial Research, NIH intramural scientists have recently 
        characterized a population of stem cells found in the dental 
        pulp of deciduous, or ``baby'' teeth. These stem cells have the 
        potential to become cells expressing molecular markers 
        characteristic of dentin, bone, fat and nerve cells and may 
        provide an accessible source of stem cells to repair damaged 
        teeth, regenerate bone, and treat nerve injury or disease.
  --Scientists established a number of years ago that umbilical cord 
        stem cells can repopulate the bone marrow of a small child. 
        Umbilical stem cells can be used today to treat certain 
        childhood disorders such as Fanconi's anemia. With the current 
        technology, however, these cord blood stem cells can only be 
        harvested in small numbers, which limits their clinical 
        utility. We are seeking methods to expand these cells in the 
        laboratory to generate very large numbers of the cells needed 
        for many other clinical applications.
    Human embryonic stem cell research is still in its nascent stages, 
and there are many basic research studies that will be required before 
we can begin to plan clinical trials. NIH is supporting preliminary 
research to understand how to direct differentiation along specific 
pathways, to establish techniques for isolating specific cell types, to 
control cell proliferation, and to control interactions between the 
host immune system and transplanted cells that might mediate graft 
rejection.
    Research using hESCs offers the potential to inform us about the 
earliest molecular and cellular processes that regulate normal 
development, and provides a tool to discover how a cell is able to be 
both pluripotent and indefinitely self-renewing. In addition, research 
using hESCs will help the scientific community to understand the 
molecular signals that specify differentiation into specific cell 
types, some of which may ultimately be useful for cell-based treatment 
of disorders, such as Type 1 diabetes or Parkinson's disease, that 
involve loss of a specific cell type.
    As we continue our work with the research community to fund new 
research and facilitate the availability of additional stem cell lines, 
the NIH Stem Cell Task Force is continuously and vigorously evaluating 
the state of the science to lead the implementation of a vigorous 
research program envisioned by the President. Attaining basic knowledge 
about the characteristics and potential use of stem cells remains the 
immediate challenge before the research community today. Until we 
understand the basics, we cannot know with certainty the future 
research requirements for advancing into clinical trials using 
embryonic stem cells. The NIH will continue to monitor the state of the 
science and assimilate the body of research evidence in order to make 
informed, evidence-based recommendations on this important issue.
    We are working hard to promote stem cell research, based on 
recommendations received from the research community by the NIH Stem 
Cell Task Force. The newest effort is the establishment of the NIH 
Characterization Unit, located on our campus in Bethesda, Maryland. 
This unit will provide reliable and standardized data derived from 
assays performed on human embryonic stem cell lines available for 
shipment to the research community. The unit will provide a direct 
side-by-side comparison to be made among the cell lines, and will 
facilitate comparison with adult stem cells. These data will be 
publicly available and will arm the scientific community with state-of-
the-art information, so scientists can make an informed choice when 
ordering one or more of the available cell lines. In response to 
additional recommendations from the research community, we continue our 
efforts to recruit new scientists to the field, to help mid-career 
investigators begin studies on embryonic stem cells, to monitor the 
state-of-the science through the NIH Stem Cell Task Force, to fund 
investigator-initiated grants, to disseminate information about the 
science and initiatives via the NIH Stem Cell Task Force website and to 
plan for a symposium that will bring together two hundred stem cell 
researchers from all over the country and several foreign universities.
    Again, I want to assure the committee of NIH's commitment to 
pursuing embryonic stem cell research, as well as continuing our 
advances in the field of adult stem cell research. The President's 
policy has provided us the opportunity to be at the forefront of the 
latest groundbreaking discoveries in the culturing, characterization 
and differentiation of stem cells, and I am confident that NIH will 
keep its premier place in this field for years to come.

    Senator Specter. Dr. Zerhouni, this subcommittee has 
repeatedly requested that NIH recommend a non-NIH scientist to 
testify in support of your position that additional stem cell 
lines are not required. But NIH did not recommend a non-NIH 
scientist. Was that because you could not find one who would 
support you?
    Dr. Zerhouni. Senator, I was not actually aware of this 
particular request.
    Senator Specter. Dr. Battey, are you aware of the request?
    Dr. Battey. Yes, I am.
    Senator Specter. Why didn't NIH submit to this subcommittee 
a non-NIH scientist to back up the NIH position? Could you not 
find one?
    Dr. Battey. We knew of no individual who was willing to 
testify.
    Senator Specter. Dr. Zerhouni, why is it that so many 
authoritative spokesmen for NIH have told this subcommittee 
that all of the eligible stem cell lines were grown on mouse 
feeder cells, such as the Secretary himself, Dr. Spiegel, Dr. 
Battey, and on September 5, 2001 Secretary Thompson stated that 
categorically. On September 26, 2001, in response to my request 
NIH prepared a paper entitled ``The Development of Embryonic 
Stem Cell Lines'' and, among other things, concluded, quote, 
that ``Although a major focus of their work at present''--this 
is referring to Goteburg--``is to develop a culture system that 
is free of mouse feeder layers, this has not yet been 
applied.''
    Why is it that the subcommittee was informed that all of 
the existing lines were on, developed on mouse feeders, until 
Monday of this week when you contacted staff and Tuesday when 
you had the meeting with me?
    Dr. Zerhouni. Well, I was not there to know exactly what 
happened at NIH during those periods of time, but I take your 
point. There are inconsistencies in the responses that you have 
received over time. After I asked myself issues related to the 
new findings of human feeder cell layers being supportive of 
growth of human stem cells, that finding which was reported by 
Johns Hopkins scientists was important enough in my mind to 
make sure that we had a review of the field. Prior to that 
date, there was no other technique used to grow stem cells 
besides mouse feeder cells.
    So it was very important, I thought, that we made sure we 
had a complete inventory. But I understand your point and I 
have reviewed those statements and your staff actually provided 
me with some of those. I cannot explain why. I can only tell 
you one thing, which is that I am absolutely committed to 
providing you with the most accurate information at the time it 
happens. This field is fast evolving. It is a new field. We 
have only been funding this field for less than 18 months, and 
this is the commitment I have for you. And I will be happy to 
be on the record reviewing the entire data set and provide you 
information on the record, Senator. But I take your point.
    Senator Specter. Dr. Zerhouni, they are not 
inconsistencies. It is a flat-out contradiction, from night to 
day, from black to white, from yes to no. It is not an 
inconsistency, just flat-out different.
    Dr. Battey, how about it? You are one of those who said all 
the stem cell lines were grown with mouse feeders.
    Dr. Battey. At the time I was asked the question, I knew of 
no cell line on the NIH registry that had not been grown on a 
mouse feeder cell line. I learned differently earlier this 
week, and I apologize for promulgating misinformation. It was 
not done deliberately on my part.
    Senator Specter. Dr. Zerhouni, when we met on Tuesday you 
told me that you had a suspicion that there might be some stem 
cell lines not grown with mouse feeders and that it was that 
suspicion that led you to pursue the matter and led you to 
inform the subcommittee to the contrary. When did you first get 
that suspicion?
    Dr. Zerhouni. Actually, Senator, as I told you, for those 
who have been involved in this field--and I should remind you 
that in my previous job I had been very involved in developing 
an Institute for Stem Cell Engineering, so I had a lot of 
contacts with scientists. And even at that time, many 
scientists were saying that they would freeze and preserve some 
of their lines until they learned more about optimal culture 
conditions beyond the mouse feeder cells.
    Everybody wanted to discover, develop methods that would 
not require mouse feeder cells for future use. So from the 
contacts that I had with people, some informal conversations, 
for example from the Karolinska Institute, led me to believe 
that not everybody was growing cell lines, but they were 
preserving them prior to exposure perhaps. But I did not know 
that for a fact, Senator. I only focused on that issue----
    Senator Specter. When did you suspect it?
    Dr. Zerhouni. When the Johns Hopkins paper came out, it 
became an important scientific issue. You yourself raised the 
issue as well, which was appropriate, and we decided--I decided 
to, and the NIH staff decided, to have a laser focus on this 
issue to provide you with the best answer.
    Senator Specter. My question, Dr. Zerhouni, is when you 
first had a suspicion and what happened in the interval between 
then and Monday?
    Dr. Zerhouni. About 5 weeks ago, I believe. When the paper 
from Johns Hopkins was published, it became important for us to 
determine what were the conditions of growth. And we knew from 
descriptions of derivations versus growth that there were 
multiple steps there.
    Senator Specter. Was that the first time you had a 
suspicion that there might be some stem cell lines not grown 
with mouse feeders?
    Dr. Zerhouni. I knew before that there were some of the 14 
private lines--and remember, these are private lines, so we do 
not always get access to the information. We are only provided 
voluntary information. Some had frozen them.
    Senator Specter. I am trying to find out when.
    Dr. Zerhouni. When did I know that----
    Senator Specter. It seems to me that as soon as you had a 
suspicion I would ask why you did not make an inquiry then, or 
at least at the time you became director or perhaps prior to 
that time, when you and I discussed the matter. I am looking 
for the sequence of events as to why this was not determined 
earlier. That bears on the authenticity.
    Dr. Zerhouni. I appreciate your point. Let me be very 
clear. We knew--I knew, I suspected, and I think we knew at 
various time points that people had frozen cell lines that they 
were keeping in reserve. I knew that over several months and 
before I even came to NIH.
    Whether or not--the specific question, which is whether or 
not any of those frozen lines had or had not been exposed to 
mouse feeder cells, became relevant about 4 or 5 weeks ago when 
the Johns Hopkins paper was published, and this is when I 
started to question our knowledge about the specific growth 
conditions of these not yet de-frozen lines.
    Senator Specter. Dr. Zerhouni, I do not agree with you. I 
think it became relevant before the Johns Hopkins paper about 5 
weeks ago. If there is ever an inkling that there are some stem 
cell lines out there not grown on mouse feeders, that is a big 
deal, is it not?
    Dr. Zerhouni. Yes and no----
    Senator Specter. That is a major, a major matter.
    Dr. Zerhouni. Yes and no, Senator, because at the time 
prior to that there was no known technique to grow these cells 
other than on mouse feeder cells. So the question becomes 
relevant when you have someone describing a viable technique. 
That is why, Senator.
    Senator Specter. You are saying it only becomes relevant 
when there is some technique to grow them other than on mouse 
feeder cells? Well, Dr. Zerhouni, I do not--I do not agree with 
that, either, because techniques are developed and you never 
know when a technique is going to be developed if you have 
researchers and you have the wherewithal to develop techniques 
or new breakthroughs.
    It is a major matter if stem cell lines are in existence 
which are not grown on mouse feeders to make that 
determination, you might say in anticipation, but not really in 
anticipation, because the scientists anticipate everything. You 
never know where science is going to lead. Every stone you turn 
over may lead to something else.
    So you are saying that at some time before you came to NIH 
you had a suspicion, as you put it, that there might be some 
stem cell lines which were not grown or not contaminated with 
mouse feeders?
    Dr. Zerhouni. No, no. Let me just be very specific. I knew 
that scientific groups were freezing their lines, waiting for 
better knowledge about how to grow their lines more 
effectively. At that point I did not focus my attention 
personally on mouse feeders or others because there was no 
other technique known.
    Five weeks ago, with the report of a very specific method 
that was able to wean NIH-available lines from mouse feeder to 
human feeder, then it became very important to know. So I may 
have missed a turn, but frankly the point became of acute 
relevance when finally a technique was publicly described that 
could do that. That is my approach to it.
    Senator Specter. Well, I have your points and I have noted 
my disagreement as to the relevance of technique as a critical 
factor.
    Senator Harkin says I should go ahead. I have quite a lot 
more to say, but I do not like to go over the time, even though 
I am the chairman. I am going to defer to Senator Harkin.

                OPENING STATEMENT OF SENATOR TOM HARKIN

    Senator Harkin. This is very important, and I back you 
wholeheartedly on this thing. I did not want to interrupt you.
    Senator Specter. Okay, you have talked me into it.
    Senator Harkin. But I do want to have a couple of 
questions, but I just did not want to interrupt you.
    Mr. Chairman, first of all, thank you very much for having 
this hearing. I listened very closely to your line of 
questioning and we have talked about this. I think what we are 
finding out here is very upsetting. It is very upsetting as we 
try to get the correct information on which we can base our 
decisions here, because we are getting contradictory 
information.
    Now, there may be reasons for that, but you can understand 
that when things like this come out it makes us question 
whether or not we are really getting correct information. It 
makes me wonder if the information process at NIH has been 
politicized.
    Senator Specter. Permit me to interrupt you for just 1 
second. I have to be at the Judiciary Committee markup for a 
moment or two and this is a good time for me to break, leaving 
the questioning with you, and I will return very shortly.
    Senator Harkin [presiding]. Okay.
    So it just makes me wonder if the information process has 
been politicized at NIH, and I hope that that is not the case 
because we have to get to the science without political shading 
on this thing.
    Now, I wanted to just talk a little bit about what has 
happened with this recent sort of revelation. I understand 
there is a lot of debate in the field about the best way to 
grow human embryonic stem cells. It is possible that these 
cells might grow differently depending on whether you use mouse 
feeder cells, human feeder cells, or no feeder cells at all.
    Studying these differences is important, scientists tell 
me, because before you use stem cells in a human you have got 
to make sure they are safe. There is a contamination problem of 
those cells coming in contact with mouse feeder cells or other 
human feeder cells. But as I understand it, all 11 stem cell 
lines that are currently available to federally-funded 
researchers were grown using mouse feeder cells; is that 
correct?
    Dr. Zerhouni. That is correct.
    Senator Harkin. Thank you. Now, apparently scientists in 
Sweden have grown four or five--I wish I knew; I have heard 
four and I have heard five--lines without feeder cells; is that 
correct?
    Dr. Zerhouni. There is no published paper. This is a verbal 
communication of that fact. Yes, that is a statement, that is 
correct.
    Senator Harkin. So you do not know whether they really have 
or have not grown four or five cell lines without using 
feeders?
    Dr. Zerhouni. They are asserting that they have. I have no 
peer-reviewed fully published method and paper to be 
categorical about it, but this is what they have told us.
    Dr. Battey. Mr. Harkin, nor do we know how well 
characterized those cells are, growing in a feeder-free state. 
We do not know whether or not they can differentiate into all 
the major lineages. We do not know whether or not they can be 
continually self-renewed. We do not know whether or not they 
will remain karyotypically normal in their genome, in their 
karyotype, over long periods of time.
    All those are issues that need to be addressed. So that is 
why Dr. Zerhouni refers to peer-reviewed papers and that is why 
that is the gold standard for the scientific community, and we 
need a gold standard because otherwise we will end up mired in 
controversy and contradictory information, which has been an 
issue that you and Senator Specter have raised.
    Senator Harkin. Okay. Accepting that, then would it not be 
helpful to scientists to be able to compare these four or five 
lines with the 11 lines that they have available? Would it be 
helpful to scientists to compare that or not?
    Dr. Zerhouni. You know, the issue in stem cell lines is 
always to try to expand them reliably so they are available to 
the scientific community at large. We have funded studies by 
NIH of scientific groups to find and discover ways of growing 
cell lines without human feeder--without mouse feeder layers. 
We have funded that. We are currently funding----
    Senator Harkin. With human feeder cells?
    Dr. Zerhouni. With human or even trying not to have any 
cell whatsoever to support the growth. So your statement is 
correct, we need to discover the molecular factors that control 
that growth and keeps those cells growing vigorously, but at 
the same time not differentiating into lines of cells that we 
desire or not desire.
    So the answer is we are pushing the research. The question 
is, as you well know, it is difficult to grow cell lines. It 
took us a year to be able to expand them. We are working to 
expand those other lines so that we can have them.
    Senator Harkin. It does take time. It takes a year.
    Dr. Zerhouni. It takes a year to expand a line, yes, it 
does.
    Senator Harkin. So you have got 11 now?
    Dr. Zerhouni. Right.
    Senator Harkin. They have all been contaminated--well, that 
is the word I use. They have come in contact with mouse feeder 
cells.
    Dr. Zerhouni. Come in contact, right.
    Senator Harkin. To the best of our knowledge here at this 
committee, I know of no lines that have been developed in this 
country that have been developed without using either mouse 
feeder cells or human feeder cells. Is that correct, Dr. 
Battey?
    Dr. Zerhouni. There is a study--there is a scientific group 
at Johns Hopkins who just reported about 5 weeks ago a 
validated technique, well-described technique, where they have 
been able to take human stem cells that had been initially 
grown on mouse feeder cells, these are NIH-available lines----
    Senator Harkin. And they separated them out.
    Dr. Zerhouni [continuing]. And then they separated them 
out. But you know, Senator----
    Senator Harkin. I know that. But still, they separated them 
out, but we still do not know whether or not they might carry 
some contamination with them.
    Dr. Zerhouni. Well, we do not know that. But the key, the 
key element here, is that until these papers appeared, no one 
had discovered the way to do it.
    Senator Harkin. I think, Dr. Zerhouni, the key element here 
is if in fact, which I do not know, but if in fact there are 
four or five lines in Sweden, lines that have been developed--I 
do not mean they are still in the frozen blastocyst stage, but 
have been developed----
    Dr. Zerhouni. Right, right.
    Senator Harkin [continuing]. Without using any kind of 
feeder cells, it would seem to me that we would want to jump on 
that, get those lines out, get them to researchers in this 
country as fast as possible, to start comparing them and to see 
whether or not we can develop those even further on, because, 
as you just stated, it takes another year. It takes a year. And 
you know, when we have got people who--that is another year of 
time. Why not use those four or five lines that we have in 
Sweden? Why not?
    Dr. Zerhouni. We do not have those lines. They are in very 
early stages of defining a technique. Even the Swedes 
themselves have not published their methods. They are asserting 
that they are in the early stages of thinking that they have 
made some advances that will allow them to define the 
technique.
    At this point it is very preliminary and it is not 
scientifically established. So we want to encourage them. We 
have funded that group to find out what are the conditions. We 
have funded many groups, including the group at Hopkins and 
other grants, to try to accelerate our understanding of how you 
grow these cells without mouse feeder cell lines.
    Senator Harkin. But you do not know whether they have 
actually done that or not?
    Dr. Zerhouni. We do not know that they have been 
successful. They claim that they are seeing early signs that 
they are able to do that, but with the caveats that Dr. Battey 
mentioned. They are not characterized, we do not know whether 
they are differentiated or not. There are lots of steps, 
Senator, that really--I can certainly provide for the record 
the steps that are necessary.
    Senator Harkin. Is it safe to say that they are further 
along than we are, though?
    Dr. Zerhouni. No, I think not necessarily, because I do not 
know how--well, again, I think we should be factual and facts 
in science mean you publish the paper, it is peer-reviewed, the 
method is duplicated. The only two sources that we know have 
done that is Johns Hopkins with their recent paper and a source 
in Singapore that has claimed to have grown human feeder cells. 
But those cells have not been expanded and made available to 
the research community that we know of after a year of 
describing that advance.
    Senator Harkin. Again, my understanding--you can correct me 
if I am wrong--but that these lines that have been developed in 
Sweden, however far they have been developed--now you have 
raised a question in my mind as to how far they have been 
developed, but it has been my information that they have been 
developed a lot further than anything in this country has ever 
been done without using feeder cells. That is what I am talking 
about, okay, that they have taken this process a lot further 
than what we have here.
    Dr. Zerhouni. Right. Again, you are asking me to comment on 
a sentence, a verbal description, without really having the 
ability to have the scientific process look at it, Senator. So 
I think we need to really be very watchful. What I can tell you 
is that I and NIH are absolutely on every single piece of 
information that we can get to try to accelerate the field. But 
it is a difficult field. It is not easy.
    Senator Harkin. If those four or five lines were derived 
after August 9, 2001, does that limit you? I mean, I understand 
they were derived after August 9, 2001, Dr. Zerhouni.
    Dr. Zerhouni. Right, and those would not be eligible for 
Federal funding.
    Senator Harkin. But you just told me that you had people 
investigating this.
    Dr. Zerhouni. We are----
    Senator Harkin. But they are not eligible for Federal 
funding. Okay, now we are getting to where I want to get.
    Dr. Zerhouni. Okay.
    Senator Harkin. You are right. These cell lines which have 
been developed much further than anything we have done here in 
terms of not using feeder cells----
    Dr. Zerhouni. ``Much further than anything we have done,'' 
I would not be sure about the statement because we do not know 
what they have done. They have not published, they have not 
shared that information, publicly.
    Senator Harkin. Well, if it were true, if in fact they have 
been developed further, would you not want to compare them with 
what we have here?
    Dr. Zerhouni. Right, and the strategy is multi-pronged. You 
cannot just rely on one technique or one source. My prodding of 
our own strategy is to really fund multiple groups of 
investigators. Now, what the Swedes are doing is they are 
trying to discover what we are trying to discover, a reliable 
technique to grow these cells without feeder layers. They say 
they have made some progress. We are looking forward for them 
making as much progress as possible, because we have heard 
about progress before that did not materialize.
    Once that is done, the cells that are not yet expanded will 
hopefully be expanded with those new methods successfully at 
the same success rate that we have had with mouse feeder cells. 
That is the strategy, Senator.
    Senator Harkin. If it were true that they have developed 
these further and you wanted to federally fund researchers in 
this country to compare these cells, these cell lines, with 
what we have now, you would not be able to do it.
    Dr. Zerhouni. No, not necessarily, Senator, because we have 
a characterization unit that I have just described in my oral 
statement, which compares all the lines, the ones that are 
available currently, the 11 lines. If they were to develop a 
reliable method, which we are really seeking and actively 
promoting and pushing scientists to do, as soon as that method 
is available they will expand their frozen, 16 frozen lines 
that have not seen any----
    Senator Harkin. I am talking about the lines in Sweden, Dr. 
Zerhouni.
    Dr. Zerhouni. Right.
    Senator Harkin. Listen, I think we are getting off on the 
16 lines that are frozen here.
    Dr. Zerhouni. You are asking me----
    Senator Harkin. I am not talking about those. Those were 
frozen before August 9, 2001.
    Dr. Zerhouni. That is right.
    Senator Harkin. It is my understanding that the ones that 
have been developed not using feeder lines were developed from 
lines derived after August 9, 2001.
    Dr. Zerhouni. Correct.
    Senator Harkin. And I am saying if you wanted to compare 
those with what we have done here, you would not be able to do 
it under the guidelines.
    Dr. Zerhouni. We will be able to fund any of the eligible 
lines, including----
    Senator Harkin. Eligible lines.
    Dr. Zerhouni. Can I finish? Including the ones that they 
could develop that were derived before August 9, 2001, with 
Federal funds. Any researcher can use other funds to compare, 
if those lines were available, compare those lines to the 
federally funded lines. We are not preventing that from 
happening.
    Senator Harkin. Okay, those were the 16 lines that you are 
talking about that were developed before August 9.
    Dr. Zerhouni. Right. In other words, we will fund the 
Swedish researchers once we know that they have a reliable, 
scientifically-established technique to develop lines on human 
feeder cells that will then go to the registry that we have in 
the characterization unit to provide what you are asking for.
    Senator Harkin. Okay.
    Dr. Zerhouni. And no scientist is prevented in this country 
from doing that, and we are not preventing anyone from using 
federally funded lines as well as non-federally funded lines 
and still be funded by NIH.
    Senator Harkin. What is the difference between the four or 
five cell lines that we have heard about, that you are saying 
you do not have good scientific data on, the four or five lines 
that we have heard about in Sweden, that have been developed to 
some point--I do not know where they are, at what point on the 
spectrum they are--the four or five lines that have been 
developed without using any feeder cells, what is the 
difference between those, using those, and taking the 16 that 
are still frozen and developing those?
    Dr. Zerhouni. Well, first, again----
    Senator Harkin. What is the difference?
    Dr. Zerhouni. The difference is that this is hearsay and we 
do not know that that information is valid, nor is it clear to 
us that the methods that they are exploring are going to be 
effective eventually. If proven effective and efficient, then 
we certainly would want to see these methods transported to the 
16 cell lines that are eligible for Federal funding and fund 
those.
    But this is hearsay at this point. We cannot, as you 
mention yourself--I want to be factual and solid in terms of 
what we know, rather than--and avoid any----
    Senator Harkin. How long will it take you to find out 
whether or not those four or five lines have been developed and 
the status of them? How long will it take you to find that out?
    Dr. Zerhouni. Obviously, researchers are to publish their 
results, to submit their methodology. It is really not in my 
hands. It is in the hands of the Swedish researchers to 
demonstrate the validity of their claim, the hearsay claim. But 
at this point I am looking forward and encouraging them to 
promote--to make those findings public so that we can exploit 
them as quickly as we can.
    Senator Harkin. Okay. I guess there is a hypothetical I am 
asking here and maybe that is not fair for me to do that. But I 
am asking a hypothetical, that if in fact--I will just make the 
point. I will not ask the question. I will make the point. If 
in fact those cell lines were derived and developed without 
using feeder cells and they are viable for further, for further 
differentiation, what I hear you saying is that, we will take 
that information and then we can apply that to the 16 that are 
still frozen, and then we can use Federal funds to take that 
information and apply it to those 16 lines.
    Well, it seems to me that then what you are saying is you 
are basically wasting 1 year, maybe 1\1/2\ years or more, of 
time, because it is going to take you 1 year to develop those 
16 lines. The only difference, Dr. Zerhouni, between those four 
or five lines that may be there and may be developed, ready for 
differentiation, and the 16 that are frozen, the only 
difference is August 9, 2001. That is the only difference.
    I ask you as a scientist, is that a scientific basis?
    Dr. Zerhouni. The Federal funding decision that the 
President made on August 9, 2001, is obviously a policy 
decision that is based on more than scientific considerations.
    Senator Harkin. Right.
    Dr. Zerhouni. He made the decision based on moral and 
ethical considerations, allowing for the first time Federal 
funding from this line of research, which had never been funded 
before. At the same time, it does not preclude, preclude at 
all, the use of other funds for learning about cells derived 
after August 9, 2001.
    Senator Harkin. Well, I do not need to get into the weeds 
with you on that, Dr. Zerhouni. But I have often wondered why 
it is that it is moral and ethical to use these cell lines that 
were derived prior to 9 p.m.--I think that is the time--on 
August 9, 2001, but it is not moral and ethical to use it if 
they were derived at 9:01 p.m. on August 9.
    That has always eluded me, why that is so. I make this 
statement only myself. You do not even have to comment on it. 
It is arbitrary and in this case, where it holds so much 
promise for really developing new cures and interventions, that 
we have handcuffed our scientists in this country.
    Now, if the response is that other universities around the 
world can do it or that the private sector can do it and we do 
not have to worry about it, well, then I am wondering what we 
are doing with NIH and why we are putting so much money into 
NIH. Maybe we ought to give the money to the private sector.
    I am just--you know, I am expressing to you an extreme 
frustration. I will not speak for Senator Specter, but he and I 
have talked about this a lot and this is an area of research 
and development that commands us to move as aggressively as 
possible. Here we have NIH, we have doubled the funding for NIH 
in the last 5 years. You have got a lot of money, we have got a 
lot of good researchers in this country, and we could be moving 
rapidly.
    Every time I see someone with Parkinson's or I see someone 
with spinal cord injury or I see someone with Alzheimer's, I 
mean, you just keep asking the question: Why are we not moving 
more aggressively on this? The only answer I can give them is 
because of August 9, 2001, which is an arbitrary something 
plucked out of the air someplace and not a scientific basis, 
nor do I think it is moral and ethical. I mean, we can discuss 
the moral and ethics, but to put it on a timeframe like that, I 
just disagree with that.
    Well, anyway, I am not asking you to comment on that at 
all. But I have given you the sense of my frustration at least 
with this. Then when we find out that we have these in Sweden--
I guess my question to you is, I know they have got to peer 
review and they have got to publish and stuff, but I would 
assume, Dr. Battey, since you are the head of the group at NIH, 
that you have dispatched some of our researchers to go over and 
take a look at it.
    Dr. Battey. We are following the progress of this research 
very carefully, along with all the other breakthroughs that are 
taking place. If I could just reassure you a little bit about 
the progress that is being made in this field, I think 
availability of cell lines is a very important issue, and I 
think that this subcommittee is right to focus on the 
availability of cell lines. It is a key issue. It will continue 
to be a key issue as we move forward.
    But equally key is developing a cadre of investigators that 
is ready to write research grant applications. The success rate 
for a human embryonic stem cell research grant application is 
the same as any other grant application. The reason why, as 
Senator Specter pointed out, we have so much less funding in 
human embryonic stem cells is that we are getting fewer grant 
applications.
    We need to develop a pool of young and mid-career 
investigators that are able to write these grant applications 
and compete successfully for the funds. We are doing that with 
our hands-on training courses. I had the privilege of being at 
one just a couple of weeks ago at the University of Pittsburgh 
headed up by Dr. Gerald Schatten, who has testified before this 
subcommittee. There will be four others this year, each of whom 
will train 15 to 25 investigators in the hands-on techniques 
required to culture the cells.
    In my looking at where we are with human embryonic stem 
cell research, I think that is really the rate-limiting 
resource for moving things forward in this country. Let me 
assure you that we are addressing that as vigorously as we 
possibly can.
    Senator Harkin. Thank you very much, Dr. Battey.
    Dr. Zerhouni, do you have something?
    Dr. Zerhouni. Well, I would like to echo also some of the 
statements that Dr. Battey made, but also your concerns about 
whether or not we are doing everything we need to do in this 
field. Again, it is very important for us to be able to fund 
the teams, the training, the understanding of the very, very 
early milestones and steps that need to be overcome for any 
therapy to become real.
    I do not want to impart in any way that we at NIH are not 
as vigorously and as enthusiastically pursuing all areas of 
opportunity in this field of science, and we are in every way 
possible pushing the field. Now, the field is very young. It is 
only 18 months since funding has been allowed in this field. It 
is, as you well know, a long process to go from a new technique 
to the development of a therapy. Even regular drugs take 12, 13 
years to develop. Genetic therapy, gene therapy, is still a 
field that is evolving.
    I think we need to enlarge the base of knowledge as much as 
we can. I will tell you, I am committed to doing that without 
any politicization whatsoever. At least you have my commitment 
of that, Senator.
    Senator Harkin. Thank you, Dr. Zerhouni.
    Thank you, Senator Specter. I have no more questions.
    Senator Specter [presiding]. Dr. Zerhouni, there were 
reports from Singapore last year that described methods to grow 
stem cells without mouse feeders. Why didn't that issue become 
relevant at that time?
    Dr. Zerhouni. It is a very good question. I heard about 
those reports. The technique, however, was not shared openly. 
We could not understand exactly the source and the methods 
that, at least at my level----
    Senator Specter. Did you ask about the technique?
    Dr. Zerhouni. Yes, we did. But you know, again, these are 
private sources who are protecting intellectual property and 
not all private sources are forthcoming with the details of 
what they do.
    Senator Specter. Well, did you need to know the details of 
the technique in order to pursue the question about the 
availability of stem cell lines not grown on mouse feeder?
    Dr. Zerhouni. Well, again, if I have only one technique 
available, which was the only one we knew, and another supposed 
hearsay--I mean, technique where we do not have necessarily the 
ability to implement and use it, then the question becomes you 
cannot move until you have that in the public domain, that we 
can understand how they are doing it and why we would use it 
and expand it.
    It is the same question Senator Harkin was asking about 
hearsay of new methods and new approaches. As long as we do not 
have public access to them, it is very hard for us to exploit 
that advance.
    Senator Specter. Dr. Zerhouni, with respect to the reasons 
which I have articulated earlier and we discussed when we met 
informally 2 days ago, the reasons for additional lines, is it 
not important to have genetic diversity and is it not important 
to have a comparison of lines grown using mouse feeders and 
lines grown without mouse feeders as the second reason for 
additional lines; and the third reason the need for lines grown 
without mouse feeders for use in treatment? Are those not very 
strong reasons why there ought to be additional stem cell 
lines?
    Dr. Zerhouni. We just discussed the issue between human 
feeders and mouse feeders. The real scientific goal is to 
understand the molecular signals that the feeder cells are 
sending to the stem cells to make them grow effectively and 
appropriately. That is the goal of that research, and we are 
pushing that research. We are funding grants to find out what 
are those molecular signals so we can have better growth 
conditions.
    So that is very important, you are correct. The key thing 
there is to eventually make a breakthrough, which we will, in 
finding culture methods that do not rely on either mouse or 
human, although either one of those does not prevent 
therapeutic application. We can still proceed. But it would be 
in my mind better to not use animal feeders or human feeder 
layers.
    Senator Specter. Well, are not these reasons to have more 
stem cell lines available sound?
    Dr. Zerhouni. I think what is very important in the early 
stage of any research is to have very well characterized lines 
that all researchers can use and compare. Even in very 
developed fields of research, having too many lines early on 
where you do not understand all the mechanism is not 
necessarily the best strategy. And my colleagues across the 
stem cell task force and around the country will all tell you 
that when you want to make progress, for example, you do not 
want to have too much diversity early on. You want to 
understand the mechanisms and then go deeper into the 
understanding of the mechanism.
    Example: the human genome. We know that no more than six 
individuals contributed to the human genome and now that we 
have completed the genome we are looking at genetic variation. 
Mouse stem cells research is done on a handful of cell lines, 
and Dr. McKay here could give you the exact number. We have, 
for example, at NIH funded a large project on human cell 
signaling, how to find out how cells signal, that a Nobel 
laureate is directing, Dr. Al Gilman. All of that project is 
focused on two types of cells.
    In every early phase of science, you need to have first and 
foremost comparable, well-characterized material that a large 
number of scientists can use, and this is the strategy that I 
have been pushing since I became NIH director.
    Senator Specter. Well, reluctant as I am to disagree with a 
man of your background, I do. It seems to me that if there were 
more lines, more research, we would get there faster.
    Is it not fair to say, Dr. Zerhouni, that the vast majority 
of scientists disagree with your position and are in favor of--
--
    Dr. Zerhouni. Again, I have to----
    Senator Specter. You cannot even find one non-NIH scientist 
to come forward and back you up on this issue about whether 
there are other stem cell lines without mouse feeders? Isn't 
the official NIH position pretty much isolated?
    Dr. Zerhouni. Well, Senator, I have put a process in place 
which is open and transparent, which is the stem cell task 
force. I have on it scientists who have recently published in 
Science magazine, and Dr. Battey can comment, people who have 
been very outspoken about different views on the policy: Dr. 
Weissman, Dr. Brigid Hogan, others who are on--Dr. Curt Civin. 
And I am----
    Senator Specter. Are any of them saying that it is a 
disadvantage, that we should not pursue more stem cell lines?
    Dr. Zerhouni. My discussion with them is this: Bring facts 
to the table that will inform us what is it we need to do today 
to accelerate this field. They are coming to that table. They 
are telling me what we need to do, and I am trying to implement 
every part of it through that process.
    The issue of willing to testify, not willing to testify, is 
obviously more complex than just a scientific issue. I really 
have not focused on that particular aspect. But I have to say 
that all the scientists I talk to, all are welcoming of the 
openness of the process and their ability to come and state 
what is it that is needed. And I am welcoming any one of them 
to do so and do so transparently.
    Senator Specter. I commend you on the process, but that 
does not focus on the narrow question which I have asked you, 
whether the vast majority of scientists think it would be 
desirable, NIH scientists, to have more stem cell lines 
available for research.
    Dr. Zerhouni. Well, that is a question that I am willing to 
pose and ask. But I do not know that at this point one has 
enough knowledge. At the last hearing, for example, that you 
conducted, Senator, Dr. Roger Pederson stated that for the 
state of the science as we know it 10 to 12 cell lines might be 
sufficient, and then based on the knowledge that we accumulate 
from that we will know where to go.
    I can only deal with facts, not whether or not someone 
could or could not express an opinion. I can only deal with 
providing the medium for those discussions to occur. I am doing 
it and that is my commitment to this field. I am not in any 
way, shape, or form trying to slow down or, as implied, not 
respond to the scientific community. I am.
    Senator Specter. Okay, thank you very much, Dr. Zerhouni.
    Would you care to add anything, Dr. Battey?
    Dr. Battey. Only that the scientific community has 
articulated a number of needs to move the stem cell research 
area forward, including availability of cell lines, including 
enabling more investigators to become versed in the art of 
culturing cells, including providing standardized culture 
conditions under which all the cells could be grown. There are 
a whole list of things that the community has told us we need 
to do and we are vigorously going after all of those things.
    I just want the subcommittee to understand that we share 
your enthusiasm for this area of research. I think it is an 
extraordinary breakthrough.
    Senator Specter. But you are not vigorously going after the 
availability of more stem cell lines.
    Dr. Battey. We are funding infrastructure awards to expand 
to distribution level cell lines that are available on the NIH 
registry. That will increase the diversity of cell lines that 
are available for the community.
    Senator Specter. Well, perhaps I should not editorialize, 
but it is an occupational hazard of Senators. Senator Harkin 
told me he editorialized.
    We do not have to tout what enthusiasm we have brought to 
the appropriations process, from $12 billion to $27.5 billion. 
And not to have the full range of scientific freedom to use all 
that money is discouraging.
    Thank you very much, gentlemen.
    Dr. Zerhouni. Thank you, sir.
STATEMENT OF RONALD McKAY, Ph.D., SENIOR INVESTIGATOR, 
            NATIONAL INSTITUTE ON NEUROLOGICAL 
            DISORDERS AND STROKE, NATIONAL INSTITUTES 
            OF HEALTH, DEPARTMENT OF HEALTH AND HUMAN 
            SERVICES
    Senator Specter. We will now go to the second panel: Dr. 
Ronald McKay, Dr. John Kessler, Dr. Ron Ogle, Mr. James Cordy. 
Dr. Ronald McKay joined the National Institute on Neurological 
Disorders and Stroke as chief of the Laboratory for Molecular 
Biology in 1993, received his undergraduate and doctorate 
degrees from the University of Edinburgh.
    Dr. McKay, thank you for joining us and we look forward to 
your testimony.
    Dr. McKay. Mr. Chairman, Senator Harkin, it is an honor for 
me to have an opportunity to talk to you. I think, rather than 
just go through the document that I have provided, let me just 
summarize by just going to the last page the sort of major 
issues that I think are relevant. So in the statement that I 
provided I placed the specific issue of mouse feeder cells in a 
wider context of characterizing human ES cells, and I stated 
that there is new data coming from several groups, including 
our own, that confirms that human ES cells can differentiate to 
cells of great clinical interest.
    I comment in the statement that there are many potential 
sources of problems as we move forward with this technology, 
and I specifically discuss the idea that in the cells that are 
available to us that the exposure to mouse feeder cells and the 
concern that we have with it should be thought of as one of a 
general class of problems where the cells have a history which 
is irreversible which makes them sub-optimal.
    So if you are working with a restricted group of cells 
which has been generated at a particular point in time and 
these cells, for example, have been exposed to mouse feeder 
cells and the mouse feeder cells do something to these cells 
which you can no longer manipulate and that perturbation of the 
cells has serious consequences, then clearly this is an issue 
that we need to address if we are going to use this technology.
    But what I say is that that is one of several kinds of 
change that could happen as you grow cells and when you grow 
cells you need to be very concerned with these changes. Another 
change that is a great concern in our day-to-day work is not 
the introduction of a genome from a pathogenic organism coming 
from the mouse cells, but some manipulation of the genome in 
the human genome itself in the cell which would make the cell 
no longer normal.
    So I share your concern with the idea that these cells need 
to be--that their history, what happens to the cells, is of 
great interest and importance. But what I think is also 
important for me to say is that this is one of many issues that 
we will need to address as we move this technology forward. And 
I am not trying to diminish the importance of this issue at 
all. What I am trying to say is that as one develops these 
complex new technologies there are many occasions when it is 
important for the--let me put it this way, where we have to 
exercise leadership. And this is one, but there will be many 
others as we develop these techniques.
    I should say also that in my work on this issue the subject 
that you are raising today is of great personal concern to me 
and I think about it constantly, and I am confident that NIH is 
promoting work in this area which is at the edge of this field. 
And the idea that we will set up a unit at NIH to compare the 
human ES cells that are available under Federal funds, to study 
under Federal funds, at present is I believe a really important 
thing to do.
    I think I will close by saying that I am in the lucky 
position that I do not have to speak policy for NIH. I can just 
speak to you as a scientist, which is I understand something 
that you seek. Both in my role as director of the 
characterization unit and also just as an individual who is 
interested in this area, that I am quite relaxed in giving you 
a completely candid view of where the technology stands at 
present.
    If I thought that the mouse feeder cells posed a really 
serious inhibition of what I might do tomorrow in my research 
team, I would tell you so.

                           prepared statement

    Senator Harkin, you used the word ``handcuffed'' and I just 
want to say that I have thought about this very precisely in my 
own professional career, and if I felt handcuffed I would no 
longer be a Federal employee. And I am quite confident that if 
a situation arises where I feel that our efforts in this area 
are seriously impinged by our availability to cells, that I can 
convey that opinion strongly to Dr. Battey and Dr. Zerhouni. 
And I am also very impressed by your specific interest in this 
area.
    So I would be happy to expand on any of these points, and 
thank you for this opportunity.
    [The statement follows:]
                 Prepared Statement of Dr. Ronald McKay
    Mr. Chairman, Senator Harkin, and Members of the Subcommittee, I am 
pleased to appear before you today to testify about human embryonic 
stem cell research. Human Embryonic Stem (ES) cells have been proposed 
as a limitless source for the many specific cell types of the adult 
body. Cells obtained in this way will likely have many uses in the 
future, including the development of new cell therapies for 
degenerative diseases. There is wide agreement on the potential 
importance of knowledge about stem cells but much of this information 
comes from work on mouse ES cells. In the last few months, published 
reports have shown that mouse ES cells can generate cells of the skin, 
blood, brain and pancreas. Even in the mouse system there are technical 
questions we do not fully understand but there is no doubt that mouse 
ES cells can be used to generate many somatic cell types.There is clear 
evidence that human ES cells will form teratomas, complex mixtures of 
different cells, but much less is known about efficiently generating 
specific cell types. There are encouraging published reports of a 
preliminary nature but the research and biotech communities still needs 
to demonstrate that human ES cells can rapidly generate large numbers 
of a specific cell type of clinical interest. The recent wider access 
to human ES cells made possible by the President's decision of August 
9, 2001 will accelerate progress on this question and I am confident 
that procedures for making some of the human cells that most interest 
us will be reported in detail in the next few months.As this area is 
new and rapidly developing, the major technical barriers that may slow 
our progress are not understood. However, some of the potential 
difficulties can be anticipated. The human ES cells may be difficult to 
grow and differentiate. Their genome may be unstable. The different 
cells may show very different properties resulting from their genetic 
origin. There may be unexpected difficulties in taking the cells to a 
point where they are clinically relevant. And once we have obtained the 
differentiated cells, it may be difficult to integrate these cells with 
the other cells of the body. All of these possibilities may be 
influenced by the history of the cell line. There are several variables 
that differ when human ES cells were first placed in culture by 
different research teams around the world. But in the first wave of 
work most success was obtained by growing the human cells in the 
company of a supporting mouse cell. This procedure was derived from 
data showing that mouse ES cells grow well in the presence of another 
cell type, a fibroblast. We do not know the exact reason for the 
effects of this interaction. Workers in the field still actively 
discuss whether one or another type of mouse fibroblast is more 
effective. Recent work suggests that the beneficial effects of mouse 
cells can be replaced by human cells or by introducing specific 
chemicals into the environment that supports the human cells. There are 
many possible ways that differences in the growth conditions could 
influence the properties of the human ES cells. But there are two 
simple questions that must be asked: Can we accurately measure these 
effects of these different growth conditions and do they cause 
irreversible harm to the human ES cell lines? The answer to the first 
question is yes, but as we have discussed above, we are still 
developing the techniques to accurately measure all the interesting 
properties of human ES cells. So today, we cannot compare precisely the 
properties of cells grown under different conditions. A detailed answer 
to the second question depends on having access to these techniques. 
However, it is clear that any major irreversible change would 
immediately influence the use of an existing cell lines. The genome 
carries biological information through time so it is important to 
establish if the ES cells carry alterations in their own genes or 
harbor genes from other organisms that significantly affect their 
properties. Many cells carry pathogens that would have no practical 
consequences but we are explicitly concerned that the human ES cells 
have acquired significant genetic changes from any stage of their 
previous history.
    These problems have been clearly stated by the biomedical research 
community in discussions held by the NIH Stem Cell Task Force. The NIH 
response to these concerns is outlined in Dr. Zerhouni's statement but 
it might be useful for me to amplify on the resources and role of the 
Human ES Cell Characterization Unit that Dr. Zerhouni has asked me to 
direct. The ES Unit has been established to directly compare the cell 
lines that are available on the NIH stem cell registry. The groups 
holding intellectual property rights have agreed to allow the ES Cell 
Unit to compare the available cells and provide open access to this 
information. Space has been renovated, equipment is being purchased and 
we hope to have a core team of four scientists at work in 3 or 4 weeks. 
We are building strong contacts with scientists in this country and 
overseas to acquire additional eligible cells. This work is monitored 
by a committee that includes senior investigators at other medical 
research facilities. This project has been actively sponsored by Dr. 
Zerhouni, the Director of the Intramural Research Program, Dr. 
Gottesman and Dr. Battey. We will compare ES cells with adult stem 
cells that may be pluripotent and move quickly to analyze as many of 
the critical features of these cells as possible. The genetic 
composition of these cells will be one of several measures that we use 
to define the cells. Our immediate goal is to rapidly develop the Human 
ES Cell Unit as a source of high-quality information that will allow 
informed use of these cells.In this statement, I have placed the 
specific issue of mouse feeder in cells in the wider context of 
characterizing human ES cells. New data confirms that human ES cells 
can differentiate to cells of great clinical interest. We are all aware 
that there are many potential sources of problems as we move forward 
with this exciting technology. Should we find that the currently 
available cells carry irreversible changes that restrict their value, 
this information will be discussed openly without delay. But this 
specific issue is only one of many that we must address as we explore 
the potential of human ES cells. I am confident that the National 
Institutes of Health, here in Bethesda, will contribute both technical 
information and sound advice to the world-wide effort needed to harness 
the benefits of stem cells.

    Senator Specter. Thank you very much, Dr. McKay.
STATEMENT OF JOHN A. KESSLER, M.D., BOSHES PROFESSOR 
            AND CHAIRMAN, DAVEE DEPARTMENT OF 
            NEUROLOGY, NORTHWESTERN UNIVERSITY MEDICAL 
            SCHOOL
    Senator Specter. We now turn to Dr. John Kessler, Professor 
at Northwestern University Medical School. Thank you for 
joining us, Dr. Kessler, and the floor is yours.
    Dr. Kessler. Good morning, Chairman Specter and Senator 
Harkin. I am a researcher who has devoted his entire 
professional life to developing techniques for regenerating the 
damaged nervous system. I am also the father of a 17-year-old 
daughter, Allison, who 2 years ago suffered a spinal cord 
injury that confined her to a wheelchair. So I am speaking to 
you today both as a scientist and a representative of the many 
families who want to see stem cell therapies reach their 
potential.
    To avoid being redundant, since many of the issues I was 
going to discuss specifically were brought up already, I would 
like to not go through the prepared comments, but comment on 
some of the issues. The issue of the feeder layers has come up. 
That is very important. I think all scientists know that NIH-
funded scientists should have cells available to them that were 
developed without the mouse feeder layers to be able to compare 
to them.
    Dr. McKay has brought up an even more important issue, 
namely the history of the cells, the way they are derived, may 
change their behavior. That means that simply focusing on one 
way of deriving the cells, simply saying, gee, we have one way 
that works, now we are going to apply that to everything, will 
limit the field of science. We will perhaps be developing cells 
the one way that is not the optimal way. So we need to expand 
our ways of trying to develop the cells.
    The issue of genetic diversity is not one that I think has 
received enough attention this morning. One of the things that 
we have learned as stem cell biologists is that the genetic 
background absolutely alters the behavior of the cells, and the 
genetic background of a very, very limited number of cell lines 
that is available to us may critically alter the properties of 
the cells, and there may be other genetic backgrounds that 
would make them vastly more helpful for clinical uses.
    So I think it is very, very important to focus on that. You 
know, some individuals who oppose the derivation of new lines 
claim that all relevant experiments can be done with the 
existing lines and they overlook these two very critical facts, 
namely that the way they are derived and the genetic 
background, the history of the cells, will determine how they 
can be used.
    We are all of us very grateful for NIH funding, myself 
included. I am the recipient of four grants and a recent 
supplement for human ES cell work. However, without question, 
NIH-funded researchers are going to competitively find 
themselves at a disadvantage with foreign scientists and with 
scientists in the private sector, and I think that is damaging 
to our mission. We simply will not be able to compete if we 
cannot use the best techniques.
    One of the other things that the NIH really should be doing 
is developing a sponsored stem cell repository and registry, 
not just for those very specific 11 lines, but for all new 
lines and all appropriate lines. This is a policy which a 
recent article in Science, a large group of distinguished 
investigators, put forward as something that is really a 
necessity for the NIH, not just to deal with those lines, but 
be a repository and a registry.
    All the things we have discussed today I think are 
compelling scientific reasons for me as a physician and a 
researcher. As a father of someone--that has a daughter who is 
paralyzed with this kind of accident, I would really like to 
see all reasonable means pursued for finding a cure for her and 
for the millions of people suffering the diseases that Senator 
Harkin mentioned earlier.

                           prepared statement

    I hope my comments today have helped to clarify both the 
social and the scientific reasons for allowing federally funded 
researchers to derive and study new lines. I thank you for your 
bipartisan and consistent support for the NIH that you have 
mentioned in the past. We are very grateful for it.
    Thank you for allowing me to express my comments today.
    [The statement follows:]
               Prepared Statement of Dr. John A. Kessler
    Good morning Chairman Specter, Senator Harkin, and other members of 
the Subcommittee. I am Dr. John Kessler, Boshes Professor and Chairman 
of the Davee Department of Neurology at Northwestern University's 
Feinberg School of Medicine. I am a researcher and physician who has 
devoted his entire professional life to trying to develop techniques 
for regenerating the damaged nervous system. I am also the father of a 
17 year old daughter, Allison who two years ago suffered a spinal cord 
injury that confined her to a wheelchair. I therefore speak to you both 
as a scientist and as a representative of the many American families 
who wish to see stem cell therapies reach their full potential.
    Although the potential for using human embryonic stem cells for 
regeneration of damaged or diseased organs is truly remarkable, it is 
clear that there are still significant technical and biological issues 
to be addressed before embryonic stem cell therapies can be instituted. 
Obstacles that delay the development of stem cell therapies are 
counterproductive for all Americans. Federally funded research is 
currently restricted to the study of an extremely small number of human 
embryonic stem cell lines, and this research may not involve the 
derivation or study of new lines. This policy is hindering the work of 
stem cell researchers, and these restrictions will become progressively 
more damaging to the field with the passage of time.
    What is the specific basis for this statement? First, there are 
major issues regarding the techniques that were used to derive and 
maintain the cell lines that are currently approved under federal 
policy. All of these cell lines were developed using animal feeder 
layers of cells to support them. The possibility of contamination with 
mouse viruses or proteins poses unacceptable risks for use of these 
cells in patients, and it is unlikely that any of these cells could 
ever be used clinically. Recently it has become possible to grow 
embryonic stem cells without the need for animal feeder layers. Such 
cells should certainly be made available to federally funded 
researchers for their studies. More generally, the methods used to 
derive and maintain embryonic stem cell lines may alter their 
properties, and it is essential for American scientists to be able to 
utilize cell lines that were derived with the newest and best 
technologies. The importance of these seemingly technical issues should 
not be underestimated. To understand the point you need only look at 
how the supposed number of approved stem cell lines dwindled from the 
more than sixty announced initially to the mere dozen or so now 
reportedly available.
    Studies of mouse embryonic stem cells have made it clear that the 
genetic background of stem cells exerts a very large but poorly 
understood effect on their biology. Every stem cell line has a 
different complement of DNA, and new cell lines with different genetic 
backgrounds may have different and important properties which may be 
critical for their clinical use. This issue alone makes it vitally 
important to be able to develop new lines. For example, although a 
myriad of mouse stem cell lines have been derived, only a precious few 
have been useful for the experiments involving homologous recombination 
that revolutionized the whole field of mouse genetics. Genetic 
diversity is a wonderful thing, and limiting stem cell research to a 
narrow and random source of cells is an extraordinary handicap for the 
study of human embryonic stem cells. Such restrictions would have 
crippled the field of mouse stem cell biology and genetics if they had 
been imposed on it. Those who oppose the derivation or use of new lines 
sometimes state that all relevant experiments can be done with the few 
existing lines. This overlooks the crucial point that they may be 
biased by the way the cells were derived or by their genetic background 
and may therefore give unhelpful or even misleading results. Further 
they will all have to be repeated with appropriate new lines before any 
clinical use could be contemplated. The field of stem cell biology 
should be allowed to proceed in a parallel fashion on all fronts like 
every other field of biology. Past experience has made it abundantly 
clear that allowing broader access to breakthrough discoveries and new 
technologies greatly increases the likelihood of scientific innovation 
and of new breakthroughs.
    These issues highlight the biologic imperative for changing federal 
policy and broadening NIH support for stem cell biology. Interestingly, 
the policy towards embryonic stem cell research runs counter to NIH 
policies and general philosophy regarding research involving humans and 
human materials. Although individual investigators who use cell lines 
may be exempt from guidelines regarding human subjects, the NIH has 
recognized that medical studies should, whenever possible, include 
subjects with a diversity of ethnic and racial backgrounds, and both 
sexes, and that there may be subtle but important differences among 
groups that ultimately are important for health care. What can be said 
in this regard about the 11 stem cell lines currently available to 
federally funded investigators? Can investigators examine the role of 
such differences in the biology of stem cells? Will there be the 
statistical power to study how different genotypes influence the 
phenotypes of cells that differentiate from embryonic stem cells? Will 
stem cell therapies be designed only for the genetic backgrounds of the 
Americans in Wisconsin and elsewhere who donated the embryos for these 
11 lines? Thus, in addition to the scientific rationale for changing 
federal policy, there is also the social imperative to perform medical 
research that is applicable to all Americans.
    Fortunately non-federally funded researchers and researchers from 
other nations have been developing new cell lines and have been 
advancing the field with new skills and techniques. However this raises 
the issue that the limitations imposed on federally-funded researchers 
will inevitably result in the most advanced work being done by industry 
or by scientists in other nations. Market forces and foreign 
governments may then dictate the course of science and medicine without 
regard to the overall social benefit of Americans. Moreover American 
scientists will eventually find that they can no longer compete with 
foreign scientists. Some states may find that their Universities are 
depleted of the best researchers who have chosen to go either to states 
that have legislatively endorsed stem cell research or to other 
nations. Federal funding is the best way to guarantee that stem cell 
therapies are developed with the greatest concern for the public 
welfare. It is also the best way to assure that the highest ethical 
standards are maintained with federal oversight. For example, an NIH 
sponsored stem cell repository and registry that includes all new and 
appropriate cell lines would serve both to maintain the highest 
scientific standards and to facilitate providing material to 
scientists.
    Some individuals argue that multipotent stem cells that can be 
harvested from mature tissues (``adult'' stem cells) can be used in 
place of embryonic stem cells for therapeutic purposes, and this is 
used as a political argument to limit studies of human embryonic stem 
cells. However while it is clear that the embryonic stem cell can 
generate virtually every adult type of tissue, it is unproven and 
highly debatable whether adult stem cells can produce tissues other 
than the organ from which they are derived. My own laboratory has 
studied ``adult'' stem cells for more than a decade, and most 
scientists encourage continued study of such cells. However such 
research cannot substitute for the study of human embryonic stem cells.
    As a physician and a researcher these are compelling scientific 
reasons for allowing federally funded researchers to derive and work 
with new embryonic stem cell lines. As a father whose daughter suffered 
a devastating spinal cord injury, there are even more compelling 
reasons for pursuing every reasonable means of finding a cure for 
Allison, and for the millions of other Americans who suffer from 
incapacitating but potentially curable diseases. With regard to the 
ethical concerns about deriving stem cell lines from embryos slated for 
destruction, I question whether it is either moral or ethical to 
literally throw away a potential opportunity for treating human 
disease. Those of you whose families, like mine, have been touched by 
serious disease are best equipped to fully understand the issues. Those 
of you who have been more fortunate should carefully consider the 
overwhelming needs of Americans who have been devastated by diseases 
like the one afflicting my daughter.
    This discussion has focused principally on policies governing 
federal funding of research on human embryonic stem cells. However I 
feel compelled to comment on another major political issue confronting 
stem cell biology, the issue regarding somatic cell nuclear transfer, 
often called therapeutic cloning. At the outset I want to emphasize 
that no responsible scientist wants to clone a human being, and that 
this is not what this debate is about. The scientific and medical 
communities overwhelmingly support a ban on such reproductive cloning. 
However the fear of abuse of the technology should not lead to 
repudiation or criminalization of the benefits that can be achieved. 
Nuclear transfer potentially offers the possibility of generating 
embryonic stem cell lines that have the patient's own DNA. Development 
of successful techniques for accomplishing this would bypass all of the 
concerns about immune rejection of transplanted cells or other problems 
that may ensue from genetic mismatch between donor cells and host 
tissues. What about concerns about potential abuse of the technology? 
We learned on Sept. 11 that airplanes can be used to bring down 
buildings. This does not mean that airplanes should be banned, but only 
that inappropriate uses should be outlawed. The same is true of the 
technology involved in somatic cell nuclear transfer. Irrational fears 
of this technology have even led to proposed legislation that would 
impose criminal penalties on doctors or patients who seek access to 
treatments developed in other countries using nuclear transfer 
methodologies. I find it difficult to believe that the United States 
would enact legislation that would prevent my daughter Allison from 
accessing a treatment that might enable her to walk again. I cannot 
believe that Americans with juvenile diabetes, Parkinson's disease, 
Alzheimer's disease, heart attack, or other such debilitating diseases 
might be prevented from seeking effective treatments. I implore you to 
distinguish between reproductive cloning, which can and should be 
banned, and nuclear transfer techniques which may ultimately lead to 
treatments for many dreaded disease.
    I hope that my comments today have helped to clarify the scientific 
and social imperatives for allowing federally funded researchers to 
derive and study new human embryonic stem cell lines. I thank all of 
you for your bipartisan and consistent support for NIH funding, and for 
providing an opportunity for me to express my views.

    Senator Specter. Thank you. Thank you very much, Dr. 
Kessler.
STATEMENT OF ROY OGLE, Ph.D., ASSOCIATE PROFESSOR OF 
            NEUROSURGERY AND CELL BIOLOGY, UNIVERSITY 
            OF VIRGINIA MEDICAL SCHOOL
    Senator Specter. Our next witness is Dr. Roy Ogle, 
Associate Professor at the University of Virginia. He received 
both his undergraduate and Ph.D. from the University of 
Virginia. We look forward to your testimony, Dr. Ogle.
    Dr. Ogle. Thank you. It is an honor to be here.
    I will try to focus on a couple of issues and reasons that 
I think we need more stem cell lines that have not been 
mentioned, and I would echo several of Dr. Kessler's comments. 
First, I just want to try to convey the excitement that those 
of us in this field have right now and the enthusiasm we have 
for this. This is a fun time. I love going to the lab in the 
morning during these days. This is the most exciting thing that 
I have seen in my 31-year career.
    We will be able to repair and replace diseased and 
defective cells and tissues and deliver genes and drugs in ways 
that people could scarcely imagine. This is going to happen. I 
really believe that regenerative medicine therapies will 
happen. They will be standard practice within the lifetime of 
some of the people in this room today.
    I want to reiterate the comment on our competitive 
disadvantage with other countries where they have more cell 
lines. It is clear that we are constrained in ways that 
scientists in Europe and Asia are not. I know for a fact that 
China is making embryonic stem cell research the cornerstone of 
their biotech industry from people that I have been recruiting 
to come join my lab. So we need to keep up in this area. We 
need to be the leaders.
    As a scientific issue, clearly researchers need to be able 
to study many more embryonic cell lines than are currently 
available. The larger the number that we study, the better the 
statistical significance. We must study a large enough sample 
size to account for individual variation in genetic makeup or 
polymorphisms in genes that control the differentiation of the 
stem cells. We know this from birth defect studies, from 
population studies.
    The United States is so diverse genetically that our 
heterogeneous genetic background is a serious confounding 
factor in studying gene expression and the interaction of genes 
and environment. So the genes that make stem cells 
differentiate are often the targets for birth defects. Although 
we do not yet know what variability exists among the genes 
governing developmental processes in the cells isolated from 
different embryos, it is reasonable to assume that such is the 
case.
    It is gratifying that there has been excellent concordance 
in the results obtained so far at Wisconsin and at Johns 
Hopkins, but having so few cell lines is really of concern for 
other reasons. Each cell division carries some possibility of 
acquisition of genetic mutation. Cells in culture lack the 
protective mechanisms that those have in the body or in vivo. 
So culture of such rapidly growing, virtually immortal cells 
can rapidly amplify a genetic trait selected for by accident or 
that occurs.
    So we are really running the risk of characterizing cells 
that no longer reflect the properties common to most embryos. 
We cannot use the mouse cells for many reasons, and it is 
important to note that it appears that the human mitotic 
apparatus is much more fragile than that of other animals. So 
it is probably a barrier right now, until we surmount it, to 
nuclear transfer.
    There is a different complement of chromosomes. There are 
many differences in these cell lines. So this work has to be 
done with human lines.
    I would like to give just a couple of examples of what we 
are doing in my laboratory that I think emphasize the fact that 
those of us who work more with adult stem cells than embryonic 
still learn a lot. These cell lines probably interact or will 
interact in their applications.
    The most prudent approach to determining the optimal cells 
to use for anything is to cast a broad net. Therefore, we are 
comparing stem cells that we have isolated from human 
liposuction procedures, which are true adult stem cells. We are 
studying a cell line that my lab has discovered from the dura 
mater, the lining of the brain, that we will probably isolate 
in practice from fetuses, so these could be considered a fetal 
line. And we are looking at the human ES lines as well.
    We are delivering undifferentiated stem cells along with 
those that we have coaxed to become precursors of bone, 
neuronal cells, and Schwann cells, and right now we are 
injecting them to try to regenerate the sciatic nerve of rats.
    At every step of our work we have been helped tremendously 
by the advances that have been made in embryonic stem cell 
work. I do not think we would be anywhere near where we are 
without these.
    But the last reason that I would really like to look at is 
that these tissues actually--or these types of cells appear to 
act in concert. Many of us know of the recent studies at 
Hopkins where they have injected into paralyzed rats the 
differentiated cells from their ES cell line. It is not those 
cells that are doing the repair. It appears that those cells 
are stimulating the cells lining the spinal cord, perhaps my 
dura mater cells, to actually do the repair.
    So we have got to--no matter how great adult stem cells 
look, we are going to have to study the embryonic together with 
the adult to make sense of this whole thing.

                           prepared statement

    I would like to finish by just, by being bold. I think we 
always need to be bold in science, and I think we need to set a 
goal to assemble an immunotype library of human stem cell types 
that would cover every histocompatibility set among our 
population, and that we need to release for use those cells 
that are frozen, those embryos that are frozen, that have been 
donated for these purposes.
    Thank you very much.
    [The statement follows:]
                   Prepared Statement of Dr. Roy Ogle
    I am a developmental biologist and professor of Neurosurgery and 
Cell Biology at the University of Virginia Medical School, where I 
conduct basic and applied research into several types of stem cells 
including those from embryonic, fetal and adult sources. My major 
funding source is the National Institute of Dental and Craniofacial 
Research at NIH. The opinions expressed by me are those of a scientist 
and individual, and not official positions of the University of 
Virginia or the National Institutes of Health.
    The rapid advances in stem cell science in recent years are the 
most exciting I have witnessed in my 31-year career as a biologist. The 
new science of regenerative medicine has been born from a convergence 
of stem cell biology, gene therapy, tissue engineering, and materials 
science. We will be able to repair and replace diseased and defective 
cells and tissues, and deliver genes and drugs in ways we could 
scarcely imagine 10 years ago. I believe regenerative medical therapies 
will be standard within the lifetimes of some of those present today.
    The important studies that have fueled the progress were conducted 
with the support and review of the National Institutes of Health, with 
the exception of the pioneering human embryonic stem (ES) cell 
research. This work could not be done under federal support. Many 
scientists in this country, myself included, wanted to work with 
embryonic and fetal human tissues in the past, but simply could not 
find a way to do so without federal support. There is little doubt we 
would be much closer today to employing the technologies for repairing 
and replacing human tissues using stem cells had this not been the 
case. As we attempt to realize the great promise of regenerative 
medicine, we can accelerate the rate of discovery by making many more 
lines available and by increasing the funding available to study the 
new lines.
    This area of science is attractive to many of the best students 
training for careers in medicine, engineering and scientific research. 
My four brightest students of the past few years have all chosen to 
pursue careers in stem cell research. As educators, we can train 
outstanding young scientists anxious to devote their careers to 
regenerative medicine, but it is critical that they have the tools--
including adequate numbers of independently derived human ES lines--for 
their graduate and post-doctoral training as well as for establishing 
their own laboratories.
    While scientists in this country are constrained by limited numbers 
of cell lines, it is clear that many scientists in European and Asian 
countries are not. China, for one, is making ES cell research the 
cornerstone of their biotechnology industry. We must maintain our 
position of leadership in biomedical research for educational and 
economic reasons as well as the scientific ones.
    As a scientific issue, clearly researchers need to be able to study 
many more human embryonic stem cell lines than are currently available. 
The larger the number of individual lines studied, the greater the 
statistical significance of the results. We must study a large enough 
sample size to account for individual variation in genetic make-up or 
polymorphisms in genes that control differentiation of stem cells. The 
population of the United States is diverse genetically, and our 
heterogeneous genetic background is a serious confounding factor in 
studying gene expression and the interaction of genes and environment. 
We know from population studies of birth defects--many of which are 
caused by mutations in genes that are the same ones controlling 
differentiation in ES cells--these genes act differently in distinct 
genetic backgrounds. Although we do not yet know what variability 
exists among the genes governing developmental processes in the cells 
isolated from different embryos, it is reasonable to assume such is the 
case.
    While it is gratifying that to date, there has been excellent 
concordance in the results obtained with distinct human ES lines in the 
laboratories of Drs. Thomson at Wisconsin and Gearhart at Johns 
Hopkins, having so few lines under examination is of concern. Each cell 
division carries some possibility of acquisition of genetic mutation. 
Cells in culture lack some of the protective mechanisms afforded those 
in vivo. Culture of such rapidly growing, virtually immortal cells can 
rapidly amplify a genetic trait selected for by accident. Working with 
but a few lines carries the risk of characterizing cells that no longer 
reflect the properties common to most embryos.
    We cannot use the many mouse ES cells available to compensate for 
the limited number of human ES cells. Human cells differ from other 
animal cells in important ways, thus there really is no substitute. 
Human ES cells cannot be cultured in the presence of antibiotics while 
mouse ES cells can. The cellular structures that move chromosomes 
during cell division are different and more ``fragile'' than those of 
animals--a fact that has been suggested to be a major barrier to 
nuclear transfer technology. There is a different complement of 
chromosomes in human and mouse cells, and undoubtedly other significant 
differences in human and other ES cells that we have yet to discover.
    In my laboratory we seek methods to regenerate bone and nerve. I 
feel the most prudent approach to determine the optimal cells to use is 
casting a broad net, therefore, we are comparing stem cells isolated 
from human liposuction procedures--true adult stem cells; cells we have 
discovered in the dura mater, the lining of the brain and spine, which 
will probably be harvested from human fetal tissues; and human ES lines 
obtained from the University of Wisconsin. We are delivering 
undifferentiated stem cells along with those induced to become 
precursors of bone cells to rodent models to determine the optimal 
methodology to engineer new bone. In other studies we have succeeded in 
coaxing the fat-derived and dura mater stem cells to become true 
neurons and Schwann cells, critical cell types in the regeneration of 
nerve. We are currently testing the injection of both cell types to 
regenerate peripheral (sciatic) nerve, and hope to use a similar 
approach for regeneration of spinal nerve fibers in the future. Very 
preliminary studies suggest under some circumstances the cells may be 
able to ``home'' to the sites of tissue injury upon injection, which if 
true, will greatly facilitate this regenerative technology. We have 
drawn greatly on advances in culture and differentiation of ES cells in 
our study of the adult and fetal stem cells. Even though it appears 
likely that adult stem cells will find clinical applications before ES 
cells, progress in the ES research will clearly advance adult stem cell 
research. Advances in biology always come with surprises, so it would 
be foolish to not conduct rational experimentation, including 
comparisons of the stem cell types so there will be no doubt that the 
foundation of our new discipline is sound.
    There are other reasons we must study all stem cell types including 
ES cells. Different types of stem cells may work in concert to repair 
tissues. As discussed above, we hope injected Schwann cells will 
release factors that signal nerve cells to extend new axons, thereby 
repairing severed nerves. One recent study using the Johns-Hopkins cell 
line showed that injection of neural cell progenitors derived from ES 
cells into the spinal canals of paralyzed rats restored motion. The 
actual cells effecting the repair were probably endogenous, ``adult'' 
stem cells--perhaps the dura mater cells discovered in my laboratory, 
which were stimulated to act by factors released from the injected 
cells. There are also preliminary reports in the past week of a 
European study in which similar cells were injected into animals with 
demyelination similar to that of humans with multiple sclerosis. The 
differentiated stem cells were reported to stimulate replacement of 
missing myelin of the nerve sheaths. These studies underscore the fact 
that we cannot assume that support of research using only or primarily 
adult stem cells will suffice to meet our goals in advancing basic 
science and regenerative medicine.
    Looking to the near future, a reasonable goal might be to assemble 
an ``immunotype library'' of human ES cells. Such a cell library would 
contain at least one or more founder cell lines of each of the major 
human histocompatibility categories. Then the true advantages of the ES 
cells--unlimited potential to replicate and total developmental 
plasticity--might be realized. Perhaps advances in immunosuppression 
and transplantation will make this unnecessary. In any case, we stand 
to uncover many of the mysteries of early development by having a 
larger and more diverse set of cells, which are readily available to 
qualified researchers.
    In summary, I believe that providing both increased funding and 
many more cell lines for human ES cell research as soon as possible is 
critical to the future of healthcare, science, education and the 
biotechnology industry in the United States. It is hoped that the 
federal government will be involved in contracting and establishing 
standards for the process of isolating and distributing additional ES 
lines. There are reported to be many human embryos in the United 
States, which are frozen and would be donated for research purposes if 
allowed or otherwise destroyed. While ethical debates continue on 
creation of embryos for research, can we not make use of those no 
longer needed for reproduction?

    Senator Specter. Thank you very much, Dr. Ogle.
STATEMENT OF JAMES CORDY, FOUNDER, PARKINSON'S 
            ALLIANCE, ON BEHALF OF THE COALITION FOR 
            THE ADVANCEMENT OF MEDICAL RESEARCH
    Senator Specter. We now turn to Mr. James Cordy, founder of 
the Parkinson's Alliance, a national group comprised and 
administered by individuals with Parkinson's disease. He served 
as president of the Pittsburgh chapter and is a member of the 
board of directors. Mr. Cordy testified before this 
subcommittee back in 1999. He has a great hourglass which he 
uses so effectively.
    Mr. Cordy, in welcoming you here I listened very closely to 
the statement of Dr. Ogle on everything, but especially when he 
said there would be regenerative medicine within the lifetimes 
of people who are in this room today. And I just hope you are 
one of those people.
    Mr. Cordy. You and me both.
    Senator Specter. I am sure of that. We look forward to your 
testimony, sir.
    Mr. Cordy. Let me just add to the credentials a new one. I 
was present at the Pittsburgh course, a 3-week course of 
intensive stem cell work, and I would be glad to share my 
observations at the end of this presentation.
    Mr. Chairman, ranking member, Senator Harkin, members of 
the subcommittee, I thank you for the opportunity to testify 
today. I am here representing the many millions who will 
benefit from the human embryonic stem cell technology made 
possible by the dollars you appropriate. I view my testimony 
here this morning as my 5 minutes to change the world. If I 
choose the right words and paint the right picture, I hope to 
influence your decisions.
    I am here on behalf of the Coalition for the Advancement of 
Medical Research. My job today is to give you a view from the 
waiting room of biomedical science, what it is like for us 
waiting for the breakthroughs to happen. It is an awesome 
responsibility to represent over 100 million Americans who are 
likely to benefit--diseases such as Parkinson's and diabetes, 
heart disease, spinal cord injuries, liver disease, and many 
more.
    I hope to give you a glimpse not only of what it is like to 
have a neurodegenerative disease, but also the staggering sense 
of despair and frustration and even anger when you first 
receive that diagnosis.
    I use this hourglass I think fairly effectively to make two 
points: first, to help those who do not have Parkinson's 
appreciate the relentless and ruthless progression of this 
disease. Just as the grains of sand flow from this top chamber 
relentlessly, I lose dopamine-producing neurons relentlessly 
from my upper chamber, my brain. The result is a loss of 
functions, one after another after another. The worst case 
scenario, the one that everyone who has Parkinson's fears, is 
that which beset your colleague Mo Udall, who became trapped in 
a body, unable to speak or talk or move.
    Second, this hourglass also reminds everyone that we who 
have Parkinson's as well as many other diseases are in a race 
against time. How do I feel about the need for increased stem 
cell lines? You need only look at this hourglass. Time is not 
neutral. The promise is so great for so many that we must have 
the scientific equivalent of a full-court press.
    I think we have asked our gifted scientists to play this 
full-court press using only their left hand. As they are gifted 
scientists, they may do very well with that restriction. But 
could they do better if they did not have it?
    Due to my advancing Parkinson's and the increasingly 
erratic and ineffective performance of my medication, my 
physical abilities are eroding. My hands and legs sometimes 
shake and my body is sometimes stiff. I can no longer tie my 
tie or tuck my shirt in. I cannot shuffle papers or drive my 
car. I have lost facial expression, sense of smell, and I now 
have a monotone voice.
    But I consider myself fortunate for an individual who has 
had 15 years of Parkinson's. For the several hours a day of my 
on/off cycle when I get sufficient dopamine to my brain, I can 
function with some degree of normalcy, as you see me here 
today. Probably only my wife realizes the progression of my 
disease because I do not leave the house when I am off. I lie 
down and wait for the time to take the next pill and then wait 
some more for it to work.
    But I would not be here today if that was the extent of the 
problems. Unfortunately, those are just a preview of the 
horrors to come if we do not cure this sinister disease.
    By coincidence or perhaps serendipity, my invitation to 
testify came just as I spoke with senior scientists and 
beginning scientists from around the world at the 3-week 
symposium and course on stem cell technology in my home town, 
Pittsburgh. They are dedicated, brilliant, and enthralled with 
the potential of this new technology to dramatically improve 
the human condition.
    They are also quite concerned about the legislative 
initiatives restricting embryonic stem cell research. Publicly 
the scientists are cautious about their predictions, but 
privately you can see the gleam in their eyes as they marvel at 
the possibilities of this new technology. If only a portion of 
this potential is realized, it will revolutionize medicine.
    The development of the human embryonic stem cells 
technology may well be the most significant scientific 
initiative since we put a man on the moon. We need the same 
sense of urgency as when we did that. We are on the steep part 
of the learning curve of the technology. We know much, much 
more now than we knew when the President announced his policy, 
but we have much to learn.
    Just a few years ago when I employed this hourglass, the 
situation was once my brain was depleted of most of its neurons 
my future was desperate. Now this technology offers the 
possibility of replenishing the upper chamber, just as I have 
done by turning this hourglass over. I have hope, as do 
others--I speak not just for myself, but for many others--that 
this technology may help.
    But let me assure you, I am not going to sit back and wait 
for my body to stop working. I am determined to win this race 
against time. But I need your help and I appreciate your help. 
Please do not let time run out on me and the millions of 
Americans who could almost certainly benefit from this 
technology.

                           prepared statement

    I feel a tug on my heartstrings as I look at those in 
attendance today. Thank you all for coming. Missing are so many 
advocates that have been here at previous significant events 
with me. They are not here because of their advanced 
Parkinson's. Dale, Lupe, Peter, Jim Dandy, just to name a few, 
they are here in spirit even though they can no longer be by my 
side. We are going to beat this yet, and my message to them is: 
Hang in there.
    Thank you for this opportunity and I really appreciate your 
support.
    [The statement follows:]
                   Prepared Statement of James Cordy
    Good morning Chairman Specter, Ranking Member Harkin, and Members 
of the Subcommittee. Thank you for the opportunity to testify today on 
the limitations of the current federal policy regarding embryonic stem 
cell research.
    My name is Jim Cordy, and I am here on behalf of the Coalition for 
the Advancement of Medical Research.\1\ The Coalition is comprised of 
more than 75 patient organizations, universities, scientific societies, 
foundations, and other entities advocating for the advancement of 
breakthrough research and technologies in regenerative medicine in 
order to cure disease and alleviate suffering.
---------------------------------------------------------------------------
    \1\ 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.
---------------------------------------------------------------------------
    I'm here to give you a view from the waiting room of biomedical 
science and what it's like to be a patient waiting for a breakthrough 
in medical science. I have Parkinson's disease and the promise of 
regenerative medicine is a significant part of my hope for a cure and a 
better, longer life. At this early stage, we must not overstate the 
science, but given the findings to date, there is no denying the hope 
stem cell research offers.
    I am one of the many millions of Americans who will benefit from 
biomedical research, made possible by the dollars that you appropriate. 
I view this invitation to testify as my opportunity to change the 
world. If I choose the right words, paint the right picture, I hope to 
give you not only a glimpse of what it's like to have a 
neurodegenerative disease, but also a sense of the staggering utter 
despair, frustration, and anger that accompanies such a diagnosis. But 
the intensity of those emotions pale in comparison to my feelings as a 
potential cure is dangled in front of me only to see well-intentioned 
decision-makers limit our brilliant scientists and impede reaching that 
goal.
    Parkinson's disease means that the neurons, the cells in the brain 
which control movement, continue to die day after day after day. I 
found this hourglass to be an effective aide to help those that don't 
have Parkinson's appreciate the relentless and ruthless nature of this 
disease. Just as the grains of sand flow from the upper chamber into 
the lower chamber, the neurons in the upper chamber of my brain 
relentlessly die. The result is the loss of one function after another 
after another. The worst-case scenario- the one everyone who has 
Parkinson's fears- is that which beset your colleague Mo Udall, who 
became trapped his body unable to move or speak as a result of his 
advanced case of Parkinson's.
    You may ask how I feel about the need for increased stem cell 
lines. You need only look at my hourglass to know my answer. I'm in a 
race against time. Will the cure, which I hope for, come soon enough 
for me? We won't know until the scientists have the support of the 
federal government to fully explore this area. It's an unbelievable and 
horrible shock to hear the doctor say, ``you have Parkinson's 
disease.'' I'm sure it's the same for MS, cancer, cardiovascular 
disease, or Alzheimer's. But it is incredibly frustrating to see 
potential breakthroughs on the horizon and not be able to reach them as 
fast as humanly possible.
    Time is running out for the more than 100 million Americans with 
permanently disabling, and ultimately fatal, diseases and conditions 
such as Parkinson's, diabetes, and Huntington's. I am not a scientist, 
I am here today as the voice of all of us who may benefit from stem 
cell research. It is time to let the scientists work.
    Leading scientists inform us that embryonic stem cells have 
significant potential to treat conditions like Parkinson's, Rett 
Syndrome, and autoimmune diseases; federal funding is integral to 
finding the promise behind the potential--it is imperative not just for 
my sake, but for the sake of so many Americans.
    By coincidence, my invitation to testify here today came to me as I 
attended an intensive three-week course and international symposium on 
human embryonic stem cells. I've met and spoken with senior scientists 
and young scientists just beginning their careers. They are dedicated, 
brilliant, and enthralled with the potential of this new emerging 
technology to dramatically improve the human condition. I've seen and 
heard in detail the first steps taken to cure Parkinson's disease, 
Canavan disease, Kernicterus, liver disease, glaucoma, Tourette's 
Syndrome, urinary incontinence, and many more.
    I had lunch with one of the world's premiere researchers who left 
the United States because of its prohibitive laws regarding embryonic 
stem cell research. Although I believe this to be highly unusual, it 
could be the beginning of a terrible trend. Typically we see the best 
and brightest scientists from other countries coming to the United 
States because of the great strength and capacity of our biomedical 
research initiatives. I have spoken with a senior NIH scientist who is 
actually placing embryonic stem cells into the brain of a rat that had 
the symptoms of Parkinson's disease. The stem cells recognize the 
damaged neurons, produced new ones to replace the damaged neurons, and 
stopped producing neurons when a sufficient number was achieved. As a 
result the Parkinson's symptoms of the rat were greatly reduced.
    If we do not handcuff and shackle our scientists, the technology 
may be ready for clinical trials in the near future. Much of the 
embryonic stem cell debate has rightly focused on repair and 
replacement of damaged parts. But the unraveling of the secret of how 
these cells, which initially can produce any part of the human body, 
know to change into specific cells may be the Rosetta stone of human 
development and revolutionize medical science.
    While I applaud President Bush for keeping the door open for 
federal funding of embryonic stem cells research, I believe that the 
current policy needs to be revisited.
    It is my understanding that in 2001, when the President announced 
his embryonic stem cell research policy, there were thought to be at 
least 60 stem cell lines that qualified for federally-funded research. 
However, after first increasing that number to 78, the National 
Institutes of Health announced last month that there are just 11 lines. 
Furthermore, all 11 lines are contaminated by mouse ``feeder'' cells, 
which may disqualify them for human therapeutic use. Science has 
progressed, and now we have the technology to develop stem cell lines 
free of mouse cells.
    In light of this situation, the President should broaden his stem 
cell policy--it could be a matter of life or death!
    Debate on the current policy is not unwarranted, but please realize 
that every day that the debate continues and the current policy remains 
in place is one day less that patients spend with their families and 
friends as well as one day further from potential treatments--one day 
further from hope realized.
    We need to prime the pump so that if the science reaches the point 
where clinical trials are appropriate we're not waiting and playing 
catch-up with other countries which have access to ``clean'' stem cell 
lines. The United States needs a comprehensive stem cell policy based 
on science and saving lives and not on politics. The scientists tell us 
that Parkinson's disease could be close to a breakthrough, but the 
benefits derived from progress will not benefit Parkinson's alone--
since a rising tide raises all boats--cancer, juvenile diabetes, and 
others will benefit too.
    You have the power to provide the scientists with the necessary 
resources to explore the promise of regenerative medicine and make it 
real in terms of better treatments, advanced therapies, and ideally, 
cures. As an individual forced to wait for the day this research 
advances enough to begin clinical trials, I look to the federal 
government to fund new stem cell lines, uncontaminated by mouse cells, 
in parallel with the current policy. Why should we ask our researchers 
to do their work with one hand tied behind their backs?
    Due to my advancing Parkinson's, my physical abilities have 
eroded--my hands and legs shake and my body is stiff. I can no longer 
tie my tie, wash my hair, or tuck my shirt in. I can't shuffle papers 
or drive my car. I have lost my facial expression, sense of smell, and 
I now have a monotone voice. But I wouldn't be here today if that was 
the extent of my problems. Unfortunately those are just previews of the 
horrors to come if we don't cure this sinister disease.
    But I consider myself fortunate for an individual who has had 
Parkinson's for over 15 years. For the several hours of the on/off 
cycle when I get sufficient dopamine to my brain I can function with 
some degree of normalcy as you see me here today. Many of my fellow 
Parkinson's advocates are in wheelchairs. One dear friend is, at this 
moment, in intensive care having fallen down 18 steps because of the 
balance problems associated with Parkinson's. I rarely express anger 
about my disease, except when I see my dear friends get progressively 
worse. Peter, Dale, Lupe, Jim Dandy, to name a few, I know are with me 
in spirit even though they're no longer able to be here by my side.
    Probably only my wife realizes the progression of my disease 
because I don't leave the house when I'm off. I lie down and wait for 
the time to take my next pill and wait some more for it to work.
    I have hope, as do others. I speak not just for me and my disease, 
but for the others, their families, friends, and caregivers who have 
hope as well. Let me assure you that I'm not going to sit back and wait 
for my body to stop working. I am determined to win this race against 
time, but I need your help. Before concluding, I will turn this 
hourglass over. Notice that the top chamber is replenished--just as a 
scientific breakthrough which cures Parkinson's will replenish my brain 
cells.
    I believe we should leave the science to the scientists so the 
possibilities of the research can be uncovered. However, the potential 
reward is so great, it seems clear to me that we must pursue embryonic 
stem cell technology with all speed possible, which means developing 
new lines concurrently, and not sequentially.
    Please, please don't let time run out for me and the over 1.5 
million Americans with Parkinson's, and the over 100 million Americans 
with diseases and conditions who are almost certain to benefit from 
regenerative medicine, including embryonic stem cell research. It is 
unconscionable to let time run out--especially now that the scientists 
tell us the finish line might be within sight.
    On behalf of the Coalition for the Advancement of Medical Research 
I again thank the Committee for its deliberations and for the 
opportunity to speak to this issue.

    Senator Specter. Thank you very much for your very poignant 
testimony, Mr. Cordy, and for your hourglass. I quote you with 
frequency everywhere.
    Mr. Cordy. Thank you.
    Senator Specter. Dr. McKay, why is it that, notwithstanding 
repeated requests from the staff here for NIH to recommend one 
NIH scientist to testify in support of Dr. Zerhouni's position 
that additional stem cells are not required, that NIH could not 
make a single recommendation?
    Dr. McKay. You mean just any scientist, right? Why aren't 
scientists prepared to come and support the NIH position, is 
the question you have asked?
    Senator Specter. That is the question.
    Dr. McKay. Yes. Scientists usually do not have any trouble 
expressing their opinions, so I can only imagine that they have 
reservations about the position that NIH is holding here. But 
it seems to me that the question that Jim Cordy's testimony 
poses to me in a very direct way, sitting next to him and 
knowing him and having visited his workshop where this 
scientific device was constructed, is whether I believe that 
right now we are moving in my group as fast as we possibly can 
to work on Parkinson's disease.
    So I can say to you the answer is yes, I believe that is 
true. Now, if you ask me will there ever be a time when that is 
not the case, my answer is I can imagine that that would be 
true.
    Senator Specter. Beyond Parkinson's disease, how about all 
the other diseases?
    Dr. McKay. Well, sir, I suppose----
    Senator Specter. Are we moving as fast as we could if we 
had more stem cell lines available?
    Can I ask you that, Dr. Kessler. You have a 17-year-old 
daughter.
    Dr. Kessler. I would echo Dr. McKay's comments. I am moving 
as fast as I can. I am doing absolutely everything I can. Do I 
think the field as a whole could move faster? I know that the 
field as a whole could move faster. There is no question that 
when you get the very best scientists with the best tools the 
field moves faster than when you have scientists without the 
best tools, and I think there is a consensus among scientists 
that federally funded researchers are progressively not having 
access to the absolute best tools. That is why you are unable 
to get them to come and testify.
    Again, this is not a comment about the NIH. I really hasten 
to add, the NIH is very supportive to all of this. This is a 
policy, as you stated, that was enunciated 2 years ago, not by 
the director of the NIH. But it is a policy that most 
scientists disagree with.
    Senator Specter. It is the policy of the administration, 
but the administration does not have the last word under our 
Constitution. It is up to the Congress. Congress makes the laws 
for this country. The President can veto a law and the Congress 
has the option of overriding a veto. These decisions are up to 
the Congress, and they start right here. The buck starts right 
here.
    Dr. Zerhouni, I would appreciate it--first, I appreciate 
your staying, but I would appreciate if you would comment on 
one of the statements by Dr. Ogle, that the larger the line we 
study the better statistical significance we have. What do you 
think?
    Dr. Zerhouni. Well, statistical significance depends on the 
question you are asking at the time, the scientific question 
you are asking. I do not disagree with the notion that genetic 
diversity is an important issue that is an issue that needs to 
be considered in relationship to the specific strategies of 
therapy that anybody is proposing. At this point we do not have 
specific therapeutic strategies to consider that will be 
applied to the population at large, if that is the point that 
is being asked.
    The second is that before you can really assess that, as 
the doctor pointed out, we need to completely understand the 
genetic stability of the cell lines and the mechanisms that 
lead to that, because it is very important to first have an 
understanding of that. So I do not disagree with the issue of 
genetic diversity, but this is not an issue that I think can be 
addressed without progress being made on the milestones that we 
have identified.
    Now, the other statement I would like to make is that, you 
know, you are asking if the NIH Director has made a 
determination that the number of cell lines we have is 
sufficient. I do not recall having made that statement. I mean, 
my view is that we need to progress, we need to pass those 
milestones. And at this point I do not think anybody knows the 
answer to that question in terms of minimum or maximum for 
therapeutic applications, since at this point there is no 
therapeutic application that is being proposed in humans.
    But we want to accelerate the discoveries that will create 
the cells that will provide dopamine, insulin, and so on as 
fast as possible. To do that, I need more researchers that are 
involved in very characterized cell systems, that understand 
genetic stability, that create as fast as possible the models 
that will help Mr. Cordy here.
    So I want to be on the record to say that I agree with the 
questions that are posed. All of them are relevant at certain 
time points in the development of these therapies. But we 
cannot accelerate the therapy without understanding the basis 
of why the therapy will or will not work. That is my point, 
Senator.
    Senator Specter. Are you saying, Dr. Zerhouni--I thought I 
heard you say it, but I want to confirm it--that you are not 
contending that we have a sufficient number of stem cell lines?
    Dr. Zerhouni. If you ask me what is it we need to do today 
and again you are looking at is what we need to do today being 
done, the answer is yes.
    Senator Specter. Now answer my question.
    Dr. Zerhouni. With the number of cell lines that we have 
and the progress we are making in understanding all of the 
multiple aspects, that not only NIH scientists but also other 
scientists are providing us, we really, I believe, are doing 
what we need to do right now to advance the field. Whether or 
not in the future this will be sufficient is not known to me at 
this point and I am not making a statement that all the lines 
that we have today are sufficient forever in terms of being 
able to do the therapies that we need.
    Senator Specter. But do we have a sufficient number of stem 
cell lines available today for what we need to do today?
    Dr. Zerhouni. That is my statement.
    Senator Specter. Senator Harkin.
    Senator Harkin. Well, I guess it is just a different 
assumption here. Dr. Zerhouni, I do not need to have you back. 
Just this is my statement. I do not need to ask you a question. 
It is just that you assume these 78 derivations, and what do we 
need to do with them to develop treatments. My position is, why 
do we assume 78 derivations? That is the difference. That is 
sort of, that is what it comes down to, Dr. McKay.
    I can understand your points, that within that construct, 
within that construct, you are doing everything possible, and I 
have no doubt about that, that you are doing everything 
possible within that construct. We just keep getting back to 
the basic construct.
    Dr. McKay. Could I add something to this, because I think 
there is a point here which may be subtle, but I think Dr. 
Zerhouni and I share, which is it is possible that I think both 
of us would be here today and tell you that we were 
dissatisfied with the cells, that we could not do what we felt 
we needed to do.
    So the position we are holding, you might say, is 
constrained by the availability of cells and the policy, but we 
are not being--but I am in a position where I can quite easily 
tell you if I think that that is not true, that we cannot work 
with the cells that we have available. Do you see what I am 
saying?
    Dr. Zerhouni is also being quite explicit with you about 
this point, too. So we are not saying to you that there is a 
situation here where we are essentially making it up. The 
reason I want to be so explicit about this with you is I think 
it is very important that you understand it because it is 
possible that this situation could arise very rapidly. This 
technology is developing very rapidly.
    So what we are saying is quite explicit, because I get the 
impression that both of you think that in a way NIH is not 
being direct with you. But I think we are being very direct, 
but we are being kind of subtle.
    Senator Harkin. I do agree with that.
    But again, I make--Dr. McKay, I do not think I am wrong in 
this, in saying that, again if, if in fact there are four or 
five lines that have been derived, not only derived but 
actually taken down the path, I do not know how far--I do not 
think to the point of differentiation, but I do not even know 
that--in Sweden, and these have been done without any--I use 
the word ``contamination''; that is my lay term on it, with any 
kind of feeder cell layers--and since it takes a year from the 
derivation from the blastocyst to develop these lines, that if 
we do not utilize those now and we say, okay, we will let them 
go ahead, and then they find out that they can derive those, 
they can differentiate them, then we say, okay, now we are 
going to take what they did and go back to these 16 other cell 
lines that are still frozen, we are a year or more behind. That 
is my point.
    Dr. McKay. Yes, but I think what--I mean, we are not 
arguing, I do not think anybody at NIH is arguing, that we want 
to limit what people learn on cells all over the world and with 
non-Federal dollars.
    Senator Harkin. You cannot do that.
    Dr. McKay. But I think we are arguing very strongly, and I 
am personally arguing this to you and to Jim Cordy, that, the 
point that Dr. Zerhouni made, which is that there are going to 
be fundamental advances in our understanding of these cells, 
and so it is really in my view, the mouse feeder question is 
currently not the rate-limiting step in this area.
    If I thought there was a rate-limiting step in the cells 
that I can work on, I would tell you. That is what I was saying 
a minute ago. I would tell you quite directly. And if it comes 
up in our work, we will make it publicly available quite 
directly and immediately.
    Senator Harkin. Dr. Kessler, isn't it true that scientists 
have taken certain stem cells and used these in rats, 
laboratory rats, that have actually honed in on, if the stem 
cells were derived from--I think this is either a nervous 
system or a spinal cord injury in a rat, that these actually 
honed in and there was some indication that the rat had 
movement after that? Has this not been done?
    Dr. Kessler. Yes, there is evidence that in fact embryonic 
stem cells are able to help in animal models of spinal cord 
injury, and that is the focus now of a lot of work, including 
my own laboratory.
    With respect to what Dr. McKay said, it is very important 
to understand that the way the cells are derived and the 
constitution of the cells may make everything that is found on 
that specific cell line an artifact. And to put, as the 
expression goes, all your eggs in one basket or very few 
baskets is not really, I think, a valid scientific approach.
    In all other fields of biology, we proceed in a parallel 
fashion on all fronts. In this particular field we are being 
told we cannot do things in parallel, they have to be done 
serially, and we cannot do them on all fronts. I think that is 
the fundamental error that we are dealing with, and that is 
really what you are saying, precisely the same thing. We should 
not be doing them serially; we should be doing them in 
parallel.
    With respect to the spinal cord injury, as a scientist, of 
course, it is frustrating to see these handcuffs being put on, 
I think is the phrase someone used earlier.
    Senator Harkin. It may not have been a good phrase.
    Dr. Kessler. As a father, it is infuriating to see the 
handcuffs being put on. Like Mr. Cordy, I want to see every 
possible thing that can be done being done for the field, and I 
would like to see scientists free to pursue all the various 
avenues.
    Dr. McKay happens to be one of the most eminent stem cell 
researchers. Hopefully his research will lead to a cure for 
Parkinson's. But I think he would be the first to tell you that 
he does not know that his approach is going to be the right 
one. It may be somebody in another laboratory taking an 
entirely different approach. If we are constrained to have only 
one approach and not the whole diversity of approaches, it is 
going to slow the field.
    Senator Harkin. I think that is where I was headed, anyway.
    Dr. Kessler. I am sorry if I diverted it.
    Senator Harkin. Mr. Cordy, do you have something you wanted 
to add?
    Mr. Cordy. I spent 3 weeks with these scientists in 
Pittsburgh.
    Senator Harkin. Say again?
    Mr. Cordy. I spent 3 weeks with these scientists almost 
every day in Pittsburgh, and I do not believe I heard any of 
them say that their research was constrained right now because 
of the lack of additional stem cell lines. But I think the 
sentiment was that it will be at some point. I think the 
technology is so new, that there is so much to do, that they 
are busy doing the fundamental work.
    But as Dr. Battey said, this program by NIH to train new 
scientists--I was at the first one of these. But as we get more 
scientists and are able to do more work, it seems obvious to me 
that the constraints are going to hurt, and I do not think that 
is inconsistent.
    Senator Harkin. Okay. Thank you.
    Thank you, Mr. Chairman.
    Senator Specter. Thank you very much, Senator Harkin.
    Dr. Zerhouni, we would appreciate it if you would provide 
for the record: first, the total number of eligible stem cell 
line derivations; second, the total number of stem cell lines; 
and third, the total number of stem cell lines available to 
federally funded scientists.
    [The information follows:]
                  Questions Submitted to Dr. Zerhouni
    Question. What is the status of each embryonic stem cell 
derivation?
    Specifically, please give us the information requested below, and 
any additional information that you would feel would be significant for 
the Committee's understanding of the current implementation of the stem 
cell policy.
    Also, contrast this information submitted by the NIH to the 
Subcommittee on September 27, 2001 and in Secretary's testimony before 
the Senate Health, Education, Labor and Pensions Committee on September 
5, 2001. Explain all discrepancies.
    Answer. To respond to your questions, in the attached table, NIH 
has summarized the status of human embryonic stem cells (hESCs) from 
information we compiled in 2001, as well as updated information we 
received in June 2003 and again on September 23, 2003 from each of the 
14 providers listed on the NIH Human Embryonic Stem Cell Registry 
(http://escr.nih.gov) (Appendix A). In this response, we have also 
provided answers to additional questions from staff of the Senate 
Labor-HHS-Education Appropriations Subcommittee regarding differences 
between the information provided in 2001 and information gathered in 
June 2003 (Appendix B). In addition, NIH is submitting additional 
information from the providers that were received in June 2003 and 
again in September 23, 2003. These tables are included as Appendix C 
and D, respectively.
    It is important to note, those providers without NIH funding are 
not required to respond to NIH's questions. All providers on the 
Registry were sent an e-mail request outlining questions that your 
staff sent to the NIH Office of Legislative Policy and Analysis in June 
2003. NIH staff met with hESC line providers at the annual meeting of 
NIH stem cell infrastructure grantees in June 2003, where the providers 
presented data on their approved cells and discussed issues on 
characterization, development and distribution of their cells, which is 
outlined in the summary table. As part of the process to update the NIH 
Stem Cell web site (stemcells.nih.gov) with the most recent data, the 
NIH queried the providers again during the summer of 2003 and received 
their latest information on September 2003.
    Information provided to the Senate Labor-HHS-Education 
Appropriations Subcommittee in September 2001 was obtained in a similar 
manner, i.e., through e-mail, telephone contacts, and meetings with 
some of the providers in August 2001. The original 2001 report is 
attached as Appendix E, for your reference.
    In August 2001, the NIH identified 11 entities or organizations 
that derived and/or were capable of distributing hESCs that were 
derived from 64 unique embryos. In September 2001, the NIH reported 
that cells were in various stages of characterization; some were fully 
characterized and some were in the very earliest stages of 
characterization. In all cases, the providers agreed to work with the 
NIH to find ways to make cells available for research consonant with 
relevant national policies and depending upon their self-renewal 
capabilities, undifferentiated state, characterization, scalability, as 
well as the resolution of intellectual property issues. The process for 
characterizing and scaling up hESCs is lengthy and difficult, where 
success in generating a well-characterized hESC cell line ready for 
widespread distribution is by no means a certainty. Thus, some of the 
derivations identified in 2001 have not been able to be further 
developed; some are still in various stages of development, while still 
others are now available to researchers. Some of the derivations are 
still frozen, while providers explore more advanced culturing 
techniques. In still other cases, international policies have been 
developed which prohibit, hinder, or present barriers to the export of 
stem cell lines outside the country policies that were not in place in 
2001.
                        therapeutic applications
    Question. Do you think the 12 NIH approved human ES cell lines will 
prove sufficient for use of human ES cells in therapeutics in the 
future? Will more lines eventually be needed?
    Answer. Currently, cells from the NIH Human Embryonic Stem Cell 
Registry are being used to understand the basic principles of 
``stemness,'' e.g., factors involved in maintaining stem cells' 
undifferentiated and pluripotent states. In addition, these cells are 
being used by scientists to discover the molecular mechanisms that 
regulate differentiation into various adult cell types. NIH 
Infrastructure awards to the hESC providers listed on the Registry may 
result in additional hESC lines becoming available to researchers later 
this year. Until scientists fully understand the basics of hESCs, it is 
impossible to say with certainty whether or not more lines will 
eventually be needed. But any future experiments needed for 
therapeutics that require the derivation of new embryonic stem cell 
lines would not be eligible for Federal funds.
    Question. Do you believe that the mouse feeder component of the NIH 
approved human ES cell lines will affect clinical research in this 
area? If human ES cells were grown without mouse feeder material, would 
you think that they would be a better option for human clinical 
research? In your view, would it be ethical to use human ES cell lines 
made with mouse feeder cells if cell lines without mouse feeders were 
available?
    Answer. Representatives from the Food and Drug Administration (FDA) 
discussed with members of the NIH Stem Cell Task Force and with the 
hESC infrastructure awardees whether or not hESCs grown on human feeder 
layers could be used more readily and with greater safety than hESCs 
grown on mouse feeder layers. As with any proposed therapy, FDA safety 
requirements stipulate that risks must be balanced with the potential 
benefit achieved by the intervention. In the case of hESCs, the FDA 
would like to know certain facts before the cells can be used in 
clinical trials: the characteristics of the stem cells, how the stem 
cells were derived, the properties of any feeder layer used to 
propagate the cells, potential contaminants introduced through the 
media or serum used in culture, and the presence of infectious agents 
transmitted from feeder layer cells to cultured hESCs.
    One important point made by FDA representatives was that cell lines 
grown on human feeder layers are not necessarily safer for clinical 
trials than stem cells grown on mouse feeder layers. Both mouse and 
human feeder layers may harbor pathogens that could be transmitted to 
the hESCs grown on them. This said, there are presently therapies in 
clinical trials that have been developed using contact with animal 
cells. Thus, if the safety and effectiveness of hESC lines grown on 
mouse feeders can be demonstrated, these cells would be a viable option 
for therapy. Contact with feeder cells is one of many safety 
considerations that need to be assessed before clinical application of 
this technology.
    NIH appreciates the opportunity to respond to these questions and 
has made a good faith effort to present information obtained directly 
from human embryonic stem cell providers which outlines the progress 
made since 2001. In addition, NIH believes this information illustrates 
how quickly the science evolves in this exciting field of research.
                                 ______
                                 
               Questions Submitted to Dr. Von Eschenbach
    Question. This subcommittee has heard from many researchers over 
the past few years about the unique potential that stem cells could 
have for understanding the basic biology and treatment of cancer.
  --On September 14, 2000, Dr. Gerald Fischbach, now the Dean of 
        Columbia School of Medicine told the subcommittee that there is 
        evidence for stem cells becoming tumors to deliver toxins to 
        tumors cells.
  --On September 14, 2000, Dr. Lawrence Goldstein, professor of 
        Cellular & Molecular Medicine, an investigator with the Howard 
        Hughes Medical Institute at the University of California, San 
        Diego told the subcommittee that human ES cells could help 
        produce bone marrow to treat cancer.
  --On September 14, 2000, Dr. Richard Hynes, Director of the Center 
        for Cancer Research at MIT told the subcommittee that human ES 
        cells and adult stem cells are needed for cancer research.
  --On June 21, 2001, former NCI Director Richard Klausner told the 
        subcommittee that stem cell research could be helpful to 
        replace tissues in patients that were damaged by cancer.
  --On July 18, 2001, the hearing record includes a statement by former 
        NCI Director Richard Klausner noting that ``stem cell research 
        is critical to cancer research'' and expressed the need for 
        side by side comparisons of embryonic and adult stem cells.
  --On July 18, 2001, Dr. Mary Hendrix, FASEB President from University 
        of Iowa College of Medicine stated that human ES cells might 
        allow us to engineer cells and tissues that are resistant to 
        the most effective, but most toxic, cancer therapies.
  --On September 25, 2002, Dr. Curt Civin, Professor of Cancer 
        Research, Johns Hopkins University told the subcommittee that 
        studying Human ES cells will help discover the molecular 
        pathways by which they can proliferate without differentiating 
        and then figure out how this applies to adult stem cells. He 
        said this research would help develop new treatments for his 
        cancer patients.
    Do you agree with these views from leading cancer researchers that 
human ES cell research will be critical for cancer? Given these views, 
why did NCI spend only $48,000 of its nearly $5 billion budget on human 
ES cell research in fiscal year 2002 and why are you projecting no 
funding for fiscal year 2003? Isn't this woefully inadequate? How much 
do you think that NCI should spend on human ES research?
    Answer. The National Cancer Institute is fully supportive of 
cancer-related research on human embryonic stem cells within the 
current federal guidelines. We agree that stem cells will be an 
important tool in basic cancer research and, in the long term, offer 
potential new pathways to cancer treatment. This response to your 
questions will detail our current activities and our plans for near-
term initiatives, putting human embryonic stem cell research in the 
broader context of cancer-related stem cell research.
    Stem cells of several different types are relevant to cancer 
research. For many years we have funded a large share of the research 
on hematopoietic stem cells, because of the frequent use of bone marrow 
transplants in cancer patients. There is also growing support for the 
idea that tissue-specific adult stem cells are prominent targets of 
malignant transformation. If this is true, then prevention strategies 
should focus on protecting stem cells, and treatment strategies must be 
designed to eliminate not just the many more differentiated cells 
within a tumor, but the transformed stem cells that are responsible for 
continued cell growth. The immediate applicability of questions related 
to tissue-specific adult stem cells and cancer has given them high 
priority within the NCI, and we plan to organize a ``Think Tank'' on 
this subject in the coming year.
    Research on human embryonic stem cells will complement the research 
on adult stem cells, although direct application to cancer treatment is 
likely to take longer because so little is known about the biology of 
these cells. The research community has not submitted any new grant 
applications to NCI proposing work on human embryonic stem cells, so we 
have not had the opportunity to support new investigator-initiated 
research in this area. Last year was the final year for the grant that 
was reported for this area in fiscal year 2002. We are devoting 
resources to human embryonic stem cells through a contract mechanism as 
part of the NCI supported Cancer Genome Anatomy Project (CGAP). CGAP 
has been characterizing the genetic transcripts present in normal and 
transformed cells of many different types for several years, producing 
a great deal of information valuable to the research community. Because 
so little is know about human embryonic stem cells, NCI has recently 
added them to the set of cells characterized by CGAP. The expression 
profiles determined for these cells are unique, and this information is 
freely available to the research community through the NCI website.
    The fiscal year 2003 funding projections for human embryonic stem 
cell were based on the fiscal year 2002 research portfolio and 
confirmed fiscal year 2003 initiatives. This is an evolving area of 
research, and NCI continues to review the portfolio to identify other 
ways to learn more about human embryonic stem cells. The addition of 
human embryonic stem cells to the set of cells characterized by CGAP is 
one such initiative. As other initiatives are identified, they will of 
course become part of the research portfolio. In an effort to address 
the lack of investigator-initiated applications, the NCI has announced 
at a number of meetings its willingness to support investigator-
initiated applications proposing cancer-related studies of human 
embryonic stem cells, but this has been insufficient to attract 
applications. We are currently discussing the best strategy to attract 
new research grants in this area, and expect to begin work on one or 
more fiscal year 2004 initiatives shortly.




   Appendix B.--Explanation of Changes in Data Between 2001 and 2003
    Question. Why the differences between September 2001 and June 2003? 
What are the differences between June 2003 and the present (September 
2003)?
    Answer. NIH is pleased to respond to your questions about three 
specific differences between information from 2001 and June 2003 on the 
summary chart (Attachment A). We would like to underscore that all 
information provided in the charts was collected from the providers in 
2001, in June 2003, and then again in September 2003. Given the rapid 
pace of development in the area of human embryonic stem cell research, 
additional scientific information regarding the cell lines has emerged 
since 2001. In addition, the term ``characterization'' is applied 
differently over time as scientists discover new technologies to study 
the properties of these cells.
    As for your specific questions about three differences:
Cell Therapeutics, Skandanavia AB (CTS), Goteborg, Sweden
    9/2001: NIH reported the following: ``[19 or 18] stem cell lines in 
various stages of development. Of these, 3 are fully characterized cell 
lines, and 15 are under development. Of the lines under development, 
four are partially assessed, and 12 are in the early passages and 
beginning to undergo characterization.''
    6/2003: 19 derivations, 2 characterized, 1 derived characterization 
lost, 16 derivations not developed until new feeder techniques are 
perfected.
    9/2003: 19 derivations, 2 characterized, 1 derivation withdrawn by 
donor, 16 derivations not developed until new feeder techniques are 
perfected). Cell Therapeutics, Skandanavia (CTS), a biotechnology 
company founded out of University, requested that NIH report CTS and 
Goteborg University as separate entities, with SA-01 and SA-02 licensed 
from Goteborg and SA-04-SA-19 property of Goteborg University.
    Explanation.--In 2001, a representative of Gteborg University 
reported to NIH that it had ``fully characterized'' 3 derivations, 
``four are partially assessed, and 12 are in the early passages and 
beginning to undergo characterization.'' In June 2003, Goteborg 
University informed NIH that ``16 derivations were not developed until 
new xeno-free feeder techniques are perfected.'' In a licensing 
agreement between Goteborg University and CTS, three established cell 
lines have been transferred to CTS while Goteborg University retains 
the remaining derivations until cell lines are established. Also, in 
September 2003, CTS reports that 1 of the derived and characterized 
lines was withdrawn by the donor.
    In 2001, a representative of Goteborg University reported to NIH 
that four derivations were ``partially assessed and 12 are in the early 
passages and beginning to undergo characterization.'' On November 4, 
2003, a representative of Goteborg reported that this information is 
incorrect. Goteborg informed NIH that these same derivations remain 
frozen after minimal expansion and have not yet been developed further. 
Goteborg University told NIH that the cells had been through minimal 
expansion post-immunosurgery in order to have the critical mass of 
cells for cryopreservation, but there are no immediate plans to 
characterize these derivations. Goteborg also informed NIH that the 
derivations may have been exposed to fetal calf serum during the 
derivation process, but have not been exposed to mouse feeder cells.
The Karolinska Institute, Sweden
    9/2001: 5 derivations, 10 characterized
    6/2003: 5 derivations, (6 in cryopreservation, 2 of which were 
cultured on mouse feeders and are partially characterized, 4 of which 
were cultured on human feeders and have not been characterized, are 
viable but not proliferating . . .).
    9/2003: Same information as 6/2003, but the cells, ``. . . . are 
presumed to be viable, but are not currently being cultured.''
    Explanation.--Although the Karolinska Institute described these 
cells as characterized in 2001, since that time, given what they have 
learned about these cells, they no longer refer to them as 
characterized. The Karolinska Institute has been awarded an NIH 
Infrastructure grant which allows them to determine the viability and 
properties of their frozen cells.
WiCell Research Institute
    9/2001: 5 derivations, 5 characterized, available for distribution
    6/2003: 5 derivations, 3 characterized, 3 available for 
distribution
    9/2003: 5 derivations, 5 characterized, 3 available for 
distribution
    Explanation.--In June 2003, WiCell submitted a chart to NIH 
outlining characteristics of 3 cell lines, but omitted characterization 
information for two other lines that are undergoing further quality 
control testing and are not yet available for distribution. Based on 
that information, NIH reported 3 of 5 cell lines as characterized, 
which was different than what was reported in 2001. To verify this 
information, NIH contacted WiCell. WiCell confirmed that all 5 of their 
eligible human embryonic stem cell lines are fully characterized, but 
they did not include the specific characteristics for two lines in June 
2003 because these lines are not yet available for distribution. NIH 
updated this on the September 23, 2003 summary information on the 
attached table.
    Update on additional information since June 2003.
Maria Biotech, Korea
    9/2003: Provided additional information about cell characteristics.
Technion, Israel
    9/2003: NIH Notice of Grant Award made for Infrastructure grant.
Univ. of California at San Francisco
    9/2003: Provided additional information about cell characteristics.
 Appendix C.--Individual Provider Tables on Human Embryonic Stem Cell 
                              Derivations






                 response received from geron 6-12-2003
    All of the embryonic stem cell lines in Geron's possession that are 
on the NIH Stem Cell Registry were derived elsewhere. Five of them were 
derived at the University of Wisconsin-Madison; two are clones of one 
of the Wisconsin lines; and two others were derived at the University 
of California, San Francisco. Under Geron's agreement with Wisconsin 
Alumni Research Foundation, we are not permitted to transfer the 
undifferentiated Wisconsin cell lines to third parties, except for 
Geron collaborators for work on projects described and directed by 
Geron. WiCell Research Institute does distribute the Wisconsin lines to 
researchers, however, and UCSF distributes the UCSF lines.
    As to your specific questions: None of the lines is a frozen inner 
cell mass; they are all cell lines.
    They are all proliferating.
    The H1, H7 and H9 lines have been extensively characterized. We 
have recently submitted manuscripts on the detailed characterization of 
these three lines. We can provide you a copy of the manuscripts in 
confidence, or send them to you once they have been published. The 
lines have the expected markers to show undifferentiated status, and we 
have demonstrated differentiation in all three germ layers for all 3 of 
the lines.
    The H1, H7 and H9 lines have been passaged extensively. In most 
cases, over 70 passages have been achieved.
    The lines are all useful for research. Two of the lines, H1 and H7 
have been tested quite extensively for the presence of potential 
pathogens of human and animal original, based on the specified by FDA 
in its Points to Consider and other guidance.
    Please let me know if you need additional information, and if you 
would like to arrange to review the manuscripts confidentially.
    William D. Stempel, vice President and General Counsel, Geron 
corporation, 230 Constitution Drive, Menlo Park, CA Email: 
[email protected].





    Question. What is the status of each of your embryonic stem cell 
derivation listed on the NIH Embryonic Stem Cell Registry?
  --Is it a frozen inner cell mass?
    Answer. We established hES cells derived from ICMs of frozen-thawed 
blastocysts that were destined to be discarded 5 years after human IVF-
ET program.
    Question. Have these derivations been shipped to any NIH-funded 
researchers?
    Answer. Our cells are available to collabrators in our country.
    Question. If the derivation has not been shipped, are there any 
plans to develop this derivation to research quality?
    Answer. We have some plans to study for major chronic degenerative 
diseases (Parkinson's disease & Alzheimer's disease and Diabetes). 
Especially, as a preliminary study of PD animal model, our group 
submitted as Title of Genetically modified human embryonic stem cells 
relieve symptomatic motor behavior in a rat model of Parkinson's 
Disease in international journal.
    Question. When will they be readily available to NIH researchers?
    Answer. Our cells are all set available to collabrators in our 
country, no plans to ship cells abroad at present.
    Question. Have any restrictions been placed on the use of these 
derivation by your national laws?
    Anwer. There is no our governmental guideline to ship our cell 
lines abroad at present.
                additional e-mail received june 22, 2003
    (I) MB01 cell line;
    After immunosurgery, isolated ICM cell was cocultured with mouse 
STO cell and hES cell line was established.
    (II) MB02 and MB03 cell lines;
    After immunosurgery, isolated ICM cells were cocultured with mouse 
STO cell. To grow hES cells without a feeder layer, aged MB02 and MB03 
cells that had been passaged 10 times were cultured on Matrigel coated 
plates, respectively.
    Thank you for your consideration.
    Jinho Lim, MD, President/CEO, Maria Hospital/Maria Biotech, Co., 
[email protected].





       National Centre for Biological Science--Response to E-Mail
    Question. What is the status of each of your embryonic stem cell 
derivation listed on the NIH Embryonic Stem Cell Registry?
  --Is it a frozen inner cell mass?
    Answer. Yes
    Question. Is it proliferating?
    Answer. It was frozen after 7 days in culture. We have not 
characterised them. We are obtaining experience in generating new cell 
lines and will thaw these when we decide we have sufficient data and 
experience.
    Question. Has it undergone any characterization? If so, are there 
markers identified to show undifferentiated status? Is their evidence 
the cells can differentiate into any of the three germ layers 
(ectoderm, mesoderm, endoderm)?
    Answer. No evidence for that--see above.
    Question. If the lines are proliferating, how many passages have 
been achieved?
    Answer. See above.
    Question. Have these derivations been shipped to any NIH-funded 
researchers?
    Answer. No
    Question. If the derivation has not been shipped, are there any 
plans to develop this derivation to research quality?
    Answer. Yes, we hope to develop these and other lines.
    Question. When will they be readily available to NIH researchers?
    Answer. I hope that once they are derived and characterized they 
would be available to the academic community.
    Question. Have any restrictions been placed on the use of these 
derivation by your national laws?
    Answer. The guidelines that are being discussed at this point 
suggest that cells may not be shipped outside of India. My 
understanding is that this may be allowed in the future only on 
approval by a National Committee on a case by case basis for research 
purposes. The guidelines as available now place restrictions on their 
export.





 Appendix D.--Individual Provider Tables on Human Embryonic Stem Cell 
                              Derivations




    Appendix E.--The Development of Human Embryonic Stem Cell Lines

                          (September 26, 2001)

                             i. background
    The emergence of a policy for Federal funding of biomedical 
research using human embryonic stem cells has prompted many questions 
from scientists, Congress, volunteer health agencies, and the lay 
public regarding the establishment of cell lines. In this regard, NIH 
has provided the scientific evidence in the form of scientific reports, 
memoranda, and letters regarding existing human embryonic stem cells 
http://www.nih.gov/news/stemcell/082701list.htm. This paper provides 
additional information on the development of human embryonic stem cell 
lines.
    On August 9, 2001, President Bush opened the door for Federal 
funding of research using human embryonic stem cells by allowing such 
research to be conducted under certain criteria http://
www.whitehouse.gov/news/releases/2001/08/print/20010809-1.html. Prior 
to the President's announcement, Secretary of Health and Human Services 
Tommy G. Thompson, instructed the NIH to prepare a report on the broad 
area of stem cell research, including stem cells from adult tissues, 
fetal tissue, and human embryos. In developing the report, NIH was 
asked to obtain information from all sources of research--private and 
public sector, United States and abroad. In June 2001, the NIH 
transmitted the report, Stem Cells: Scientific Progress and Future 
Research Directions (NIH Stem Cell Report) http://www.nih.gov/news/
stemcell/scireport.htm to Secretary Thompson indicating that in 
developing its report, the NIH had identified approximately 30 cell 
lines which were either fully characterized or under development. Upon 
presenting the report to Secretary Thompson, NIH noted that there was 
some preliminary evidence that other laboratories had been conducting 
research with the intent of developing human embryonic stem cell lines, 
but that this evidence had not been confirmed.
    In early July, Secretary Thompson asked that the NIH pursue 
additional information on other human embryonic stem cell lines, 
including those that were under development. In late July, Secretary 
Thompson was informed that NIH had identified additional stem cell 
lines, some of which were in varying stages of development. On August 
27, 2001, NIH released a list of ten laboratories in the United States 
and around the world who reported that they had derived human embryonic 
stem cells from 64 individual, genetically diverse blastocysts. All of 
the existing cells lines, some of which in varying stages of 
development, reported to the NIH meet the President's criteria--that 
is, the derivation process (which begins with the destruction of the 
embryo) was initiated prior to 9:00 p.m. EDT on August 9, 2001; the 
stem cells were derived from an embryo that was created for 
reproductive purposes and was no longer needed for this purpose; 
informed consent had been obtained for the donation of the embryo and 
the donation did not involve financial inducements. NIH also 
acknowledged and continues to anticipate that other human embryonic 
stem cell lines are under development and will be disclosed in the 
future and that they may also be eligible for use in Federally funded 
research research under the President's criteria.
    This report addresses technical issues related to the laboratory 
processes involved in the development of human embryonic stem cell 
lines. The report does not provide information on the following issues: 
background or health status of the embryo donors, intellectual 
property, patenting or licensing or material transfer conditions, 
availability for distribution or research collaboration, informed 
consent, directed differentiation studies, distribution practices, 
research costs or financing of cell line developments, ethical, legal 
or social aspects of stem cell research, or development of public 
policies and oversight of such research. This report does not address 
scientific information about adult stem cells, embryonic germ cells, or 
stem cells of other species, unless designated. Finally, although the 
NIH reviewed information regarding human embryonic stem cells prepared 
using somatic cell nuclear transfer or from embryos that were created 
for research purposes through the use of gamete donation, these cells 
would not be eligible for Federally funded research according to the 
President's criteria and are, therefore, not discussed in this report.
    Data provided in this report are accurate as reported to the NIH 
and as of the state of the science on or about August 1, 2001. Given 
the rapid pace of development of this area of science, additional 
scientific evidence regarding the cell lines may have emerged since 
this data was first gathered. In developing this report, NIH did not 
review the data with the sources of the information, conduct further 
interviews, or obtain additional information that had not been 
previously reported to the Agency.
                          ii. key definitions
    As an aid in understanding the details of the descriptions of 
techniques and cells described in this report, a glossary of commonly 
used terms is provided. The definitions are taken from the NIH Stem 
Cell Report, Dorland's Medical Dictionary (25th edition), or other 
scientific resources.
    Blastocyst--a preimplantation embryo of 30-150 cells. The 
blastocyst consists of a sphere made up of an outer layer of cells (the 
trophectoderm), a fluid filled cavity (blastocoel), and a cluster of 
cells on the interior (the inner cell mass).
    Cell line--a group of cells derived from a primary culture at the 
time of first subculture, it is considered to be an established cell 
line when it demonstrates the potential for indefinite subculture in 
vitro.
    Characterization--the description of the biological properties of 
the undifferentiated human embryonic stem cell.
    Derivation--the process of removing the cellular contents of the 
inner cell mass from the blastocyst and the initial plating of the 
cells as a primary cell culture.
    Differentiation--the process whereby an unspecialized early 
embryonic cell acquires the features of a specialized cell such as a 
heart, liver, or muscle cell.
    Embryonic stem cell--undifferentiated cells from the embryo that 
have the potential to become a wide variety of specialized cells.
    Embryoid body--clumps of cellular structures that arise when 
embryonic stem cells are cultured. Embryoid bodies contain tissue from 
all three of the germ layers: endoderm, mesoderm, and ectoderm. 
Embryoid bodies are not part of normal development and occur only in in 
vitro culture conditions.
    Inner cell mass--the cluster of cells inside the blastocyst.
    Proliferation--the reproduction or multiplication of cells.
                      iii. sources of information
    The information used in the development of this report originates 
from multiple sources. Included are the NIH Stem Cell Report, 
scientific publications (including peer reviewed manuscripts and 
abstracts), presentations at meetings and conferences, and notes and 
personal communications with scientists who have conducted the research 
discussed in the report. The report does not include information from 
lay press publications. As of September 20, 2001, there are 11 known 
publications on research using human embryonic stem cells (1-11).
  iv. overview of the development of human embryonic stem cells lines
    In 1998, James Thomson et al. described for the first time the 
creation of embryonic stem cell lines from cells removed from the inner 
cell mass of human embryos (1). This paper and research preceding it on 
mouse embryonic stem cells has provided the research community with a 
framework for the description of human embryonic stem cells. However, 
other scientists have since developed their own techniques and 
augmented the studies of Thomson by providing alternative approaches to 
describing these cells. Therefore, while there is no question about the 
basic properties of these cells from the standpoint of the two 
essential features: the ability to proliferate and having the potential 
to develop into many different cell types, there are at this time no 
uniform standards or mutually agreed upon scientific criteria or 
parameters to describe the features of these cells. Thus, it is 
important to note that this report describes the procedures and 
features of stem cells from multiple perspectives, but does not make 
qualitative statements about the varying approaches to defining them.
    An overview of the procedures used in the creation of human 
embryonic stem cells is presented graphically in Figure 1, and details 
are provided in the following sections of the report. The concepts 
shown in this figure and the terms applied in the following sections 
were developed internally by NIH in 1999 to help distinguish the time 
point at which NIH funded investigators could use cells in their 
laboratory. Several broad steps are considered here. First, the 
derivation step is the use of a fresh or frozen human embryo (usually 
takes place around day 5 after fertilization) and the subsequent 
removal of the inner cell mass. It is the cells of the inner cell mass 
that will ultimately give rise to human embryonic stem cells. This 
process requires the destruction of the embryo. At the time of this 
report, there have been no human embryonic stem cell lines that have 
been established from a single cell from the inner cell mass. The 
reasons for this are not fully known, but are believed to be related to 
the requirement for cell-cell contact, which is thought to provide 
necessary nutrients or growth factors enabling cells to be maintained 
in the undifferentiated state.
    The cells are plated on a petri dish and cultured on so-called 
``feeder layers'' of cells. Feeder layers are live cells that have been 
treated with irradiation so they are alive but do not divide or grow in 
culture. These cells provide nutrients to the newly plated embryonic 
cells, hence the name ``feeder'' cells. These primary cultures take 
several days to grow into colonies of cells. Colonies that divide and 
grow in a characteristic pattern are selected for subsequent culturing. 
Each cycle of growing, selecting colonies, and culturing is referred to 
as a ``passage.'' With each cycle, the nutrient conditions may be 
adjusted and appropriate cell density is maintained so as to optimize 
cell growth and to help ensure they continue to divide in an 
undifferentiated state. This is sometimes referred to as the 
``proliferative'' phase in the development of a stem cell line, where 
the goal is to expand the number of undifferentiated cells in culture. 
At various time points in this process, researchers may examine a 
variety of factors that distinguish whether or not the cells retain 
their properties as unspecialized cells. This is often referred to as 
the ``characterization'' phase in the process. It is important to note 
that throughout each of these steps, there is a natural tendency for 
the cells to clump together and begin to specialize into defined cells 
and tissues.
    The typical process from derivation to the establishment of a cell 
line that retains the properties of embryonic stem cells is time 
consuming (6 to 8 months), labor intensive, requires special 
facilities, and is expensive. Some experts in tissue culture often 
refer to the culturing of these cells as more of an art than a science 
in that the techniques for maintaining and growing these cells are 
sometimes subtle and learned through trial and error. Generally 
speaking, many laboratories want to perform between 35 to 50 cell 
passages before beginning directed differentiation studies--that is, 
studies to direct these undifferentiated cells to become specialized. 
On the other hand, some laboratories employ strategies that attempt to 
partially differentiate cells early in the cell line development 
process as an intentional effort to direct the cell line development 
from a very early step. To date, there is no evidence that one approach 
has an advantage over another.
    Although much of the research performed on directed differentiation 
of embryonic stem cells is conducted only after the cell line is 
developed, many researchers consider cells in the earliest phases of 
the cell line development process to be a highly desirable for 
investigating many aspects of cellular regulation. As scientists begin 
their search for improved ways to control the specialization of cells 
for reparative or restorative functions, it is likely that much 
attention will be directed to these earlier phases of cell line 
development which occur long before the cells might be considered to be 
fully characterized.
    v. methods of derivation of human embryonic stem cells from the 
                               blastocyst
    In this report, the term ``derivation'' means the process of 
removing the cellular contents of the inner cell mass from the 
blastocyst and the initial plating of the cells as a primary cell 
culture. In this process the blastocyst (the early embryo) is 
destroyed. From the point of establishing the initial cultures, the 
cells are considered to have been derived and are eligible for Federal 
support.
    Thomson et al. (1) described the derivation of their cell lines in 
the following manner: ``Thirty-six fresh or frozen-thawed donated human 
embryos produced by IVF were cultured to the blastocyst stage in G1.2 
and G2.2 medium. Fourteen of the 20 blastocysts that developed were 
selected for ES cell isolation, as described for rhesus monkey ES 
cells. The inner cell masses were isolated by immunosurgery, with a 
rabbit antiserum to BeWO cells, and plated on irradiated (35 grays 
gamma irradiation) mouse embryonic fibroblasts. Culture medium 
consisted of 80 percent Dulbecco's modified Eagle's medium (no 
pyruvate, high glucose formulation; Gibrco-BRL) supplemented with 20 
percent fetal bovine serum (Hyclone), 1 mM glutamine, 0.1mM b-
mercaptoethanol (Sigma) and 1 percent nonessential amino acid stock 
(Gibco-BRL). After 9 to 15 days, inner cell mass-derived outgrowths 
were disassociated into clumps either by exposure to Ca 2+/
Mg 2+-free phosphate-buffered saline with 1 mM EDTA (cell 
line H1), by exposure to dispase (10 mg/ml; Sigma; cell line H7) or by 
mechanical dissociation with a micropipette (cell lines H9, H13, and 
H14) and replated on irradiated mouse embryonic fibroblasts in fresh 
medium.''
    The technical details are presented here for several reasons. 
First, to demonstrate that within one laboratory, multiple procedures 
were used in the first steps of establishing the early cultures of the 
cells. Second, to point out that the outer cell layers of the 
blastocyst were peeled away from the inner cell mass by using 
antibodies, so-called ``immunosurgery.'' This is important to consider 
as there are at least three other methods that other researchers have 
used in the removal of the inner cell mass cells from the blastocyst, 
including laser ablation, mechanical disruption, or digestion in 
culture medium.
    The cells growing on the culture plate are examined under a 
microscope and those that have the shape consistent with unspecialized 
cells are placed back into culture again. The unspecialized cells 
double in number (replicate themselves) about every two days, after 
which they are separated and cultured again to grow an even larger 
numbers of cells. This is called the ``proliferation'' process, where 
cells undergo new ``passages'' to be expanded into cultures with large 
numbers of cells. After 10-20 passages, researchers perform a series of 
tests to ensure that the cells are stable and retain stem cell 
properties. For example, the chromosomes are checked and tests are done 
for certain ``markers'' on the cells to make sure they haven't yet 
become specialized. This process is commonly referred to as the 
characterization of the cells. It is important to note that because 
research on human embryonic stem cells is in its earliest days and 
because so few investigators have had access to these cells, there are 
no agreed upon uniform scientific standards or protocol for the 
determination that a stem cell is ``fully characterized.'' If after six 
to eight months or between 30 to 50 passages the testing shows that the 
cells have been determined to (1) grow properly, i.e., continue to 
proliferate, and (2) have characteristics of stem cells, researchers 
determine them to be a stable cell line. Scientists can then begin 
their work at trying to make specialized cells (e.g., neurons, insulin-
secreting cells, etc.) from them. An important aspect that is often 
overlooked is that researchers can now conduct valuable research during 
the earlier stages of the cell development to better understand the 
molecular and cellular mechanisms that account for the unique 
properties of embryonic stem cells.
    Individual investigators have described variable success rates in 
establishing viable embryonic stem cells from the initial derivations. 
Success in achieving a stable culture of undifferentiated cells ranges 
from 20-50 percent.
vi. methods of assessing proliferative capacity of embryonic stem cells 
                               in culture
    One of the defining points about embryonic stem cells is their 
ability to replicate indefinitely. One aspect of their viability is 
determined by testing to ensure that after they are frozen and thawed, 
they retain their ability to divide in culture. Embryonic stem cells in 
culture have a characteristic doubling time of approximately 36 hours. 
Another important feature that many researchers examine is the length 
of telomeres and the enzyme that maintains their length. Telomeres are 
repeating sequences of DNA at the end of chromosomes (8-15 kilobases); 
as cells age, telomeres become shorter. Telomerase is a ribonuclease 
enzyme that adds the repeated sequences to the end of chromosomes 
maintaining their length and presumably extending the lifespan of the 
cell. Thus, telomerase expression is highly correlated with immortality 
of human cell lines and the restoration of it in some human diploid 
cells has been shown to extend the cell's lifespan. Therefore, 
researchers developing human embryonic stem cell lines expect to 
observe high levels of telomerase activity in these cells as an 
indication that they may propagate for a long time. However, not all 
embryonic stem cells show high levels of this enzyme.
   vii. methods of assessing properties of human embryonic stem cells
    Characterization of stem cells is typically refers to the 
biological properties that define cells as being undifferentiated (1). 
In the original publication by Thomson, the term ``characterization'' 
was used specifically to refer to the presence or absence of certain 
cell surface markers. Among the various investigators who have derived 
stem cells, there is no precise time in the developmental process when 
such marker studies are conducted. The characterization phase includes 
many steps, assays, and approaches and varies substantially from 
laboratory to laboratory. Described here are some of the approaches 
used.
A. Cell Surface Markers
    All cells have proteins on their surface membrane to which 
antibodies can be made to attach. Each type of cell has different types 
of proteins on their surface and the antibodies to them can be used to 
help identify particular cell types. From embryonic research in other 
species, it was recognized that embryonic stem cells have unique 
proteins called stage specific embryonic antigens (SSEA) of different 
types. Although they vary slightly from species to species, the 
detection of SSEA-3 and SSEA-4 on the surface of cells using antibodies 
to these proteins has been a cornerstone for detecting which cells 
retain an undifferentiated state. Cells that have become specialized do 
not express these proteins. While other species express SSEA-1, humans 
do not. Other proteins are also thought to be unique to embryonic cells 
that are unspecialized. These include tumor rejection antigens (TRA) 1-
60 and 1-81. Some laboratories use other cell surface markers to detect 
undifferentiated cells.
B. Alkaline Phosphatase Activity
    Alkaline phosphatase is an intracellular enzyme that is expressed 
in high levels in undifferentiated cells and its presence or activity 
is commonly used to describe embryonic stem cells.
C. Other Markers of the Undifferentiated State
    Researchers are making steady progress at developing other 
techniques to assess the state of the embryonic stem cell. The 
transcription factor Oct-4 is highly expressed in undifferentiated 
cells. Many studies have shown that the decline in the level of Oct-4 
signals processes that are under way in the cell for it to become 
specialized (e.g., begin expressing genes and other markers of 
differentiated cells). Some controversy exists about the degree of 
expression among various cell lines and its value of reflecting cells 
with undifferentiated characteristics.
D. Markers of the Differentiated State
    Another approach to assess embryonic stem cells in culture during 
the development of a stem cell line is to assess cellular markers that 
indicate that cells are becoming specialized. For instance, one 
approach is to measure the culture media for the presence of human 
chorionic gonadotrophin and alpha fetoprotein. More commonly scientists 
use antibody studies or gene expression methods to assess for the 
production of cell surface proteins or genes that are activated when 
cells begin to take on characteristics of specialized cells--such as 
neurons, muscle, bone, or epithelium.
    It should also be noted that embryonic stem cells when growing on 
feeder layers take on characteristic morphology, particularly at the 
interfaces of the two cells. Researchers continually inspect the cells 
for subtle features that may reflect that the cell is beginning to 
differentiate. During the course of the cell line development, 
researchers use any number of combinations of these methods to assess 
the characteristics of the cells. Many laboratories repeat these 
studies at various passages, but no standard protocol exists for when 
or which of these studies are conducted. Nor is there a standard 
frequency (passages) at which these tests are performed.
     viii. methods of demonstrating that embryonic stem cells are 
                              pluripotent
    The NIH Stem Cell Report and many scientific publications refer to 
human embryonic stem cells as being pluripotent--or capable of 
developing into nearly all cells of the human body. Historically, the 
major feature or evidence supporting the notion that these cells are 
pluripotent is the demonstration that embryonic stem cells can give 
rise to differentiated cells that are characteristic of cells that 
normally develop from all three germ layers--ectoderm, endoderm, and 
mesoderm. It is known that over 200 cell types exist in the human body, 
and obviously, given the brief history of the existence of human 
embryonic stem cell cultures, no one has yet demonstrated that human 
embryonic stem cells do develop into all of these various cell types 
(although there is no evidence to suggest that they cannot do this). In 
scientific reports, the term multipotent is sometimes used to describe 
that multiple cell types can be shown to develop from embryonic stem 
cells.
    There are three techniques that have been used to establish the 
multipotency or pluripotency of embryonic stem cells:
  --In mice, the undifferentiated cells are injected into the 
        blastocyst cavity and the resultant embryos implanted into 
        pseudopregnant mice. The embryonic stem cells contribute to all 
        cell types in a chimeric mouse, including the germ layer (12). 
        The mice of the subsequent generation contain the genotype of 
        the embryonic stem cells thereby providing evidence of their 
        pluripotency.
  --Subcutaneous injection of the embryonic stem cells into syngeneic 
        mice induces teratomas--a tumor that may include cells of 
        endodermal, ectodermal, or mesodermal origin (13). Laboratories 
        use different approaches to performing such studies, and they 
        require several million cells, therefore, they are usually 
        performed late in the development of the cell line when larger 
        amounts of cells are available.
  --In vitro assessment of embryoid bodies formed by the aggregation of 
        embryonic stem cells that develop into cells of distinct 
        endodermal, ectodermal, or mesodermal origin (5). In these 
        studies, researchers test for cellular markers of 
        differentiated cell lineages, such as noggin, nestin, gamma-
        globin, neurofilament-68 KD, albumin, neurotubulin, brachyury, 
        Pax-6, PDX-1, among others.
    Although the pluripotency of a mouse embryonic stem cell is usually 
determined using the first of the methods described above, research 
described in this report with regard to the pluripotency of human 
embryonic stem cells is limited to the latter two methods. The creation 
of chimeric mice by injecting human embryonic stem cells into mice 
embryos would not be deemed acceptable. Given this limitation, it is 
not yet possible to demonstrate the pluripotent capabilities of human 
embryonic stem cells to the same extent as pluripotency is established 
with mouse embryonic stem cells.
      ix. other methods used to assess human embryonic stem cells
    Researchers use other tests to demonstrate that embryonic stem 
cells retain properties that make them useful for research. These 
include:
  --karyotype analysis (determination of the number and structure of 
        the chromosomes) using either standard G banding or spectral 
        karyotyping (SKY);
  --other genetic analysis including fluorescent in situ hybridization 
        (FISH) for certain genes or proteins;
  --culturing and testing for growth of pathogens known to infect 
        laboratory cell cultures such as Mycoplasma species; and
  --development of subclonal lines from colonies grown in primary 
        cultures.
                x. descriptions of individual cell lines
    Provided here are descriptions of what has been reported to the NIH 
regarding the development of stem cell lines from the ten sources that 
are known to fulfill the President`s criteria. It is important to 
reiterate that there is no standard definition of what is a fully 
characterized line. Therefore, a designation of fully or partially 
characterized is at the discretion of the source and differs among the 
entities. It is also worth noting that a fully characterized line may 
or may not be ready for distribution. With regard to stem cells that 
are not fully characterized, entities may chose to collaborate with NIH 
funded investigators for the purposes of characterization research or 
developmental studies.
WiCell/University of Wisconsin
    There are five cell lines that were derived, and all are fully 
characterized according to the methods that were originally published 
in 1998 (1). Fresh and frozen blastocysts were used in the research 
leading to the establishment of the cell lines and the sources were 
from IVF clinics in Israel (as part of a collaboration with Dr. Joseph 
Itskovitz-Eldor) or Wisconsin. Of the blastocysts that yielded human 
embryonic cell lines, H1 originated from a blastocyst from Wisconsin 
and H7, H9, H13, and H14 from blastocysts that were from Israel.
    Cellular characterization of the undifferentiated state consisted 
of data on the presence of cell surface markers SSEA-3, SSEA-4, TRA-1-
60, TRA-1-81; the lack of expression of SSEA-1; and presence of the 
intracellular enzyme, alkaline phosphatase. This paper also provided 
data on a marker of the proliferative capacity of the cells by 
measuring levels of the cellular enzyme, telomerase. High levels of 
telomerase expression were shown in all five cell lines. Measurement of 
Oct-4 transcription factor levels was not reported in the original 
work, however, other investigators using these cells have confirmed the 
retention of Oct 4 expression.
    The tests for the capability to differentiate into specialized 
cells was conducted using the injection of cells from passages 14 to 16 
into rear leg muscles of four week old male SCID-beige mice. Seven to 
eight weeks after the injection, the resulting teratomas were examined 
histologically. The results of those tests included the demonstration 
of gut-like cells (H9), neural epithelium (H14), bone (H14), cartilage 
(H9), striated muscle (H13), tubular structures resembling fetal 
glomeruli (H13). Additional research showing multipotent 
characteristics of the H9 line has been shown using the approach of 
characterizing markers specific to cellular lineages in embryoid bodies 
(5). These cells showed the presence of markers for gamma globin, 
neurofilament 68Kd, alpha-cardiac actin, and alpha fetoprotein. Normal 
karyotyping has been reported at multiple passage levels and three cell 
lines are XY (H1, H13, and H14) and two are XX (H7 and H9).
    Several of the H lines have been used extensively in studies for 
directed differentiation in a variety of laboratories and a complete 
review of those studies is beyond the scope of this report. Subsequent 
studies with these cells have shown them to be stable in phenotype and 
karyotype for several years and over 400 population doublings.
    Researchers involved in the development of these initial cell lines 
have also developed approximately ten subclonal lines from the original 
five lines. A substantial amount of research is being conducted with 
several of the subclones, H9.1 and H9.2.
ESI/Monash University
    There are presently six human embryonic stem cell lines that have 
been reported to the NIH as being fully characterized and were 
developed in collaborations with researchers from the National 
University Hospital of Singapore and Monash University. These lines are 
designated as HES-1 through HES-6. The method used in the derivation 
used an immunosurgery technique but differs somewhat from the approach 
used by Thomson (1). The details of preparation of HES-1 and -2 lines 
have been described in detail (11). The steps involved in the initial 
culturing of the cells differs substantially from those described by 
Thomson (1). In initial cultures, cells were cultured in the presence 
of the growth factor LIF (leukemia inhibitory factor), but in 
subsequent cultures they were not.
    Marker expression studies in these cell lines have been done at 
multiple passage levels. All the cell lines test positive for alkaline 
phosphatase activity, have immunostaining present for SSEA-4, TRA 1-60 
epitopes, and are labeled with the antibody for GCTM-2 which detects 
keratan sulfate/chondroitin sulfate proteoglycans. They did not express 
SSEA-1. HES-1 and HES-2 have normal karyotype (HES-1 and HES-2 are XX). 
HES-1 through HES-4 have had xenograft differentiation studies done. In 
this model, cells from early and late passages were inoculated beneath 
the testis capsule of SCID mice. After five weeks, all mice developed 
teratomas that were resected and examined histologically. 
Differentiated tissues were observed to include cartilage, squamous 
epithelium, primitive neuroectoderm, ganglionic structures, muscle, 
bone, and glandular epithelium. One notable distinguishing feature is 
that these cell lines do not appear to develop embryoid bodies in 
culture and neural progenitor cells may be isolated from 
differentiating ES cell and lead to neuron formation (11). The 
proliferative capability of these cell lines has been demonstrated by 
their continued growth after multiple freeze/thaw cycles and the 
expression of Oct-4.
Technion University
    In addition to the cell lines developed as a part of the 
collaboration with Thomson et al., researchers led by Dr. Joseph 
Itskovitz at the Technion University and Rambam Medical Center in 
Haifa, Israel have established four additional cell lines, which have 
been reported to the NIH as fully characterized. These are 
characterized using several methods as described in the original paper 
(1). In addition, subclones of the primary embryonic stem cell cultures 
have been developed. At this time, the Itskovitz laboratory has 
approximately 19 cell lines that are being used for research (including 
subclones). The laboratory has collaborated in several studies 
demonstrating the first functional evidence of directed differentiation 
of human embryonic stem cells yielding muscle cells that contractions 
and have features of cardiac muscle and cells that secrete insulin (2, 
7).
BresaGen, Inc.
    Scientists at BresaGen in Athens, Georgia, have developed four 
human embryonic stem cell lines designated HES#4896, HES#7226, 
HES#6510c, and HES#7283a, which have been reported to the NIH as fully 
characterized. The derivations were conducted using fresh blastocyts 
from an IVF clinic in Georgia. The cell lines have been characterized 
by the immunostaining of the following markers: SSEA-3, SSEA-4, TRA 1-
60, TRA 1-81, and the lack of staining for SSEA-1. The cells have 
undergone multiple freeze/thaw cycles, demonstrate histologic 
characteristics of human embryonic stem cells, and have been shown to 
develop embryoid bodies when allowed to differentiate in culture. Each 
of the lines has undergone more than 30 passages. Expression levels of 
Oct-4 have been determined and alkaline phosphatase activity is 
present. Telomerase activity has also been assessed. Karyotype analysis 
has been conducted on each line and at multiple passages and shown to 
have normal number. Xenograft studies in mice are being completed for 
histologic analysis of tissue differentiation. Other studies are being 
conducted to evaluate markers of differentiation.
University of California, San Francisco
    Researchers at the University of California, San Francisco, have 
successfully established two lines of human embryonic stem cells, one 
of which has been reported to the NIH as fully characterized and the 
other as nearing completion. Drs. Roger Pedersen and Meri Firpo were 
developed them from fresh blastocysts donated at a California IVF 
facility and they are designated HSF-1 and HSF-6. The method of 
derivation is similar to that used by Thomson et al. (1). The stem 
cells have typical histologic morphology and possess the characteristic 
markers of human embryonic stem cells: SSEA-3, SSEA-4, Oct-4 
expression, and lack of SSEA-1. Karyotype analysis of HSF-6 has been 
completed multiple times and is XY and the analysis of HSF-1 was being 
completed. The capability to develop into specialized cells has been 
demonstrated using studies conducted on embryoid bodies in assessing 
the presence of specific markers for differentiated cells.
University of Goteborg
    Researchers at the University of Goteborg, Goteborg, Sweden, have 
reported to the NIH that they have [19 or 18] stem cell lines in 
various stages of development. Of these, three are fully characterized 
cell lines, and 15 linesare under development. Of the lines under 
development, four are partially assessed, and 12 are in the early 
passages and beginning to undergo characterization. successfully 
established cultures of embryonic stem cells cell lines These were 
derived from 19 individual blastocysts. The derivations were conducted 
using fresh blastocysts from IVF clinics in Uppsula and Goteborg. The 
derivation technique used in these is substantially different from that 
described by Thomson et al. (1) and uses a culture digestion method 
over the course of several days that allows for the dispersion of the 
cells of the inner cell mass. Regulations in Sweden allow for the 
blastocyst to be maintained in culture for up to 14 days. Researchers 
report that three of the cell lines have completed their 
characterization assessment, three are partially assessed, and 12 are 
in the early passages and under going characterization. Marker 
expression studies include presence of SSEA-3 and SSEA-4, alkaline 
phosphatase activity, and Oct-4 expression in those that have undergone 
characterization. Karyotype studies were normal on those that have 
completed characterization. The investigators are using multiple new 
approaches (proprietary) for developing conditioned medai for the 
expansion of their cultures. Although a major focus of their work at 
present is to develop a culture system that is free of mouse feeder 
layers, this has not yet been applied. The emphasis for this group is 
being directed to establishing cell lines for chondrocyte, neuron, 
insulin producing cell, and cardiomyocyte replacement strategies.
Reliance Life Sciences
    Scientists at Reliance Life Sciences in Mumbai, India, are in the 
process of establishing have reported to the NIH that they have seven 
human embryonic stem cell lines in various stages of under development. 
The project is headed by Dr. K.V. Subramaniam with his colleagues Drs. 
Firuza Parekh and Satish Totey. They conducted their derivations using 
frozen embryos donated from an IVF clinic in India. They used a 
modification of the method described by Thomson (1). Their scientists 
described the cells as having characteristic morphology of human 
embryonic stem cells and can form embryoid bodies in culture when 
allowed to differentiate. Characterization studies have been completed 
on one cell line and three additional cell lines are nearing 
completion. Three additional cell lines are in the early phases of 
proliferation, have undergone freeze/thaw testing, and retain 
characteristics of human embryonic stem cells. The laboratory assesses 
the cells as being undifferentiated by the positive immunohistochemical 
detection of SSEA-3, SSEA-4, the lack of detection of SSEA-1, and the 
measurement of alkaline phosphatase activity.
National Centre for Biological Sciences
    The National Centre for Biological Sciences at the University of 
Agricultural Sciences in Bangalore, India, collaboration headed by Dr. 
Mitradas Panicker with an IVF clinic in India, has have reported to the 
NIH that they have three lines under development, which conducted 
successful derivations of are in the earliest phases of expansion. As 
of mid-August, they were being retained in a frozen state and 
characterization studies had not yet been initiated. The derivation was 
conducted using frozen blastocysts with a laser ablation technique 
modified from that of Thomson et al. (1). Morphological characteristics 
of the cells are consistent with those of human embryonic stem cells.
Karolinska Institute
    The research on stem cells is being conducted between the research 
groups at the Huddinge University Hospital at the Karolinska Institute, 
Stockholm, Sweden. As of August, the researchers reported to the NIH 
that they have 10 stem cell lines in various stages of development. 
These lines developing ten separate cell lines that were established 
from the derivation from the inner cell mass of five individual 
blastocysts; these lines and are partially characterized. The 
blastocysts were obtained from a local IVF clinic using a method 
similar to Thomson et al. (1). The cell lines are noted to have 
positive detection of cell surface markers SSEA-3 and SSEA-4, and lack 
detection of SSEA-1. Karyotype results were completed in several cell 
lines and under way in others. Studies to demonstrate pluripotency 
using xenografts were reported as ongoing in multiple cell lines.
Cythera, Inc.
    Cythera, Inc. reported to the NIH that they have nine cells cell 
lines in various stages of development under development and that the 
ongoing characterization studies are being conducted with a focus on 
gene expression data. The derivations were conducted using fresh and 
frozen blastocysts that were donated at a California IVF facility. The 
derivation procedures and culture are custom designed. Laser surgery 
approaches are used for the removal of the inner cell mass, and 
proprietary methods are used to develop embryonic stem cells that 
proliferate, but express certain markers that are found with particular 
cell lineages. In this regard, the characterization of these cells will 
reflect the intent of directing them toward a particular germ line. 
Cells are noted to have undergone freeze/thaw testing, and expand with 
characteristics in culture similar to undifferentiated human embryonic 
stem cells. Characterization studies are being conducted with a focus 
on gene expression data.
                              xi. summary
    There are at least 64 individual human embryonic stem cell lines 
that are are either fully characterized or under developmentin various 
stages of development, all of which qualify for Federal funding under 
the criteria announced by the President on August 9, 2001. In addition 
to those listed above, NIH is aware of other such cell lines that are 
under development that may meet the eligibility criteria, but technical 
details have not been shared by those researchers. In nearly all cases, 
researchers in the various laboratories use techniques that are 
different from those which were originally described by Thomson et al. 
(1). The process of developing a human embryonic stem cell line is 
long, tedious, and successful development requires substantial skill 
and experience in cell culture techniques.
    It is worth noting that in all the derivations stem cell lines 
identified by the NIH, including those under development, the primary 
cultures were conducted on mouse feeder layers. At the present time, no 
investigators have been successful in deriving stem cells absent mouse 
feeder layers in the initial cell culture. It is also important to 
understand that, in most cases, animal proteins are also used in other 
stages in the development of an embryonic stem cell line. Some 
laboratories report, however, that they have been successful in 
removing animal proteins from these later phases in the development of 
a cell line.
    Nearly all scientists have reported that maintaining cell growth in 
the undifferentiated state is the major challenge in the development of 
the cell line. The cultivation of these stem cell lines continues to 
evolve as researchers test for improved methods and materials to work 
with these cells.
    Among the key features to assess during the cell line development 
process is the description of the key characteristics of the cells and 
their ability to proliferate. There are many approaches to this, and 
there does not exist any standard method or protocol to ascribe that a 
cell line has attained the status of a human embryonic stem cell line. 
To date, characterization of these cells usually consists of the 
demonstration of certain cell surface markers, alkaline phosphatase 
activity, and characteristic morphology. Proliferative capacity is also 
assessed by determining growth patterns, particularly after freeze/thaw 
cycles, and the measurement of telomeres and telomerase activity. There 
are several approaches to assess pluripotent capabilities of the stem 
cells, including the use of certain genetic markers and the formation 
of teratomas in animals.
    Of the 64 human embryonic stem cell lines in various stages of 
development that have been described to the NIH by the scientists who 
have prepared them, investigators have reported to the NIH that 24 have 
been fully characterized and are being prepared for use in laboratory 
experiments on directed differentiation or are having additional 
experiments conducted with them. Some of the other lines under 
development are partially characterized and are undergoing additional 
passages to expand their numbers and to reconfirm that their 
undifferentiated state has been retained. The remaining lines are in 
earlier stages of development. It is also noteworthy that in several 
laboratories, subclones of the original lines were developed in the 
primary culture stage and these are showing interesting laboratory 
findings in that they behave differently from each other and from the 
primary culture from which they were derived. This suggests that such 
subclones should be investigated as independent lines.
    In conclusion, there are heterogenous approaches to the development 
of a human embryonic stem cell line. Given the various techniques used 
in establishing these cells, and the lack of an embryonic stem cell 
line which has been derived from a single cell of the inner cell mass 
of the blastocyst, it is likely that research using existing stem cells 
will reveal many functional differences among them. Such differences 
must be fully explored to determine the optimal characteristics of 
embryonic stem cells for their differentiation into particular 
specialized cells for the purposes of tissue repair or replacement.
                            xii. references
    1. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel 
JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human 
blastocysts. Science 1998;282:1145-1147.
    2. Assady S, Maor G, Amit M, Itskovitz-Eldor J, Skorecki KL, 
Tzukderman M. Insulin production by human embryonic stem cells. 
Diabetes 2001;50:1696-1697.
    3. Lanzendorf SE, Boyd CA, Wright, Muasher S, Oehninger S, Hodgen 
GD. Use of human gametes obtained from anonymous donors for the 
production of human embryonic stem cell lines. Fertil Steril 
2001;76:132-137.
    4. Bongso A, Fong CY, Ng SC, Ratnam SS. Isolation and culture of 
inner cell mass cells from human blastocyts. Human Reprod 1994;9:2110-
2117.
    5. Itskovitz-Eldor J, Schuldiner M, Karsenti D, Eden A, Yanuka O, 
Amit M, Soreq H, Benvenisty N. Differentiation of human embryonic stem 
cells into embryoid bodies comprising the three embryonic germ layers. 
Mol Med 2000;6:88-95.
    6. Kaufman DS, Hanson ER, Lewis RL, Auerbach R, and Thomson JA. 
Hematopoietic colony-forming cells derived from human embryonic stem 
cells. PNAS 2001;98:10716-10721.
    7. Schuldner M, Yanuka O, Itskovitz-Eldor J, Melton DA, and 
Benvenisty A. Effects of eight growth factors on the differentiation of 
cells derived from human embryonic stem cells. PNAS 2000;97:11307-
11312.
    8. Kehat I, Kenyagin-Karsenti D, Snir M, Segev H, Amit M, Gepstein 
A, LivneE, Bina O, Itskovitz-Eldor J, and Gepstein L. Human embryonic 
stem cells can differentiate into myocytes with structural and 
functional properties of cardiomyocytes. J Clin Invest 2001;108:407-
414.
    9. Thomson JA and Odorico JS. Human embryonic stem cell and 
embryonic germ cell lines. TIBTECH 2000;18:53-57.
    10. Amit M, Carpenter MK, Inokuma MS, Chiu CP, Harris CP, Waknitz 
MA, Itskovitz-Eldor J, Thomson JA. Clonally derived human embryonic 
stem cell lines maintain pluripotency and proliferative potential for 
prolonged periods of culture. Dev Biol 2000;227:271-278.
    11. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A. Embryonic 
stem cell lines from human blastocysts: somatic differentiation in 
vitro. Nat Biotech 2001;18:399-404.
    12. Rossant J, Joyner AL. Towards a molecular-genetic analysis of 
mammalian development. Trends Genet 1989;5:277-283.
    13. Wobus AM, Holzhausen H, Jakel P, Schoneich J. Characterization 
of a pluripotent stem cell line derived from a mouse embryo. Exp Cell 
Res 1984;152:212-219.

    Senator Specter. This is an evolving issue. Mr. Cordy 
represents more than 100 million Americans. The figure has been 
put at 128 million Americans who have diseases like Parkinson's 
or Alzheimer's or heart disease or cancer or others. The 
subcommittee held its first hearing about 10 days after stem 
cells came on the scene in November 1998 and we are up to 16.
    We agree with the testimony that this could be the most 
remarkable breakthrough since man walked on the moon, and we 
intend to pursue it, to see to it if we can find a breakthrough 
with this remarkable method that is described of replacing 
defective cells.

                         CONCLUSION OF HEARING

    Thank you all very much for being here. That concludes our 
hearing.
    [Whereupon, at 11:26 a.m., Thursday, May 22, the hearing 
was concluded, and the subcommittee was recessed, to reconvene 
subject to the call of the Chair.]

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