[Senate Hearing 109-675]
[From the U.S. Government Publishing Office]



                                                        S. Hrg. 109-675

              ALTERNATIVE METHODS FOR DERIVING STEM CELLS

=======================================================================

                                HEARING

                                before a

                          SUBCOMMITTEE OF THE

            COMMITTEE ON APPROPRIATIONS UNITED STATES SENATE

                       ONE HUNDRED NINTH CONGRESS

                             FIRST SESSION

                               __________

                            SPECIAL HEARING

                     JULY 12, 2005--WASHINGTON, DC

                               __________

         Printed for the use of the Committee on Appropriations


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                      COMMITTEE ON APPROPRIATIONS

                  THAD COCHRAN, Mississippi, Chairman
TED STEVENS, Alaska                  ROBERT C. BYRD, West Virginia
ARLEN SPECTER, Pennsylvania          DANIEL K. INOUYE, Hawaii
PETE V. DOMENICI, New Mexico         PATRICK J. LEAHY, Vermont
CHRISTOPHER S. BOND, Missouri        TOM HARKIN, Iowa
MITCH McCONNELL, Kentucky            BARBARA A. MIKULSKI, Maryland
CONRAD BURNS, Montana                HARRY REID, Nevada
RICHARD C. SHELBY, Alabama           HERB KOHL, Wisconsin
JUDD GREGG, New Hampshire            PATTY MURRAY, Washington
ROBERT F. BENNETT, Utah              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
WAYNE ALLARD, Colorado
                    J. Keith Kennedy, 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            DANIEL K. INOUYE, Hawaii
LARRY CRAIG, Idaho                   HARRY REID, Nevada
KAY BAILEY HUTCHISON, Texas          HERB KOHL, Wisconsin
TED STEVENS, Alaska                  PATTY MURRAY, Washington
MIKE DeWINE, Ohio                    MARY L. LANDRIEU, Louisiana
RICHARD C. SHELBY, Alabama           RICHARD J. DURBIN, Illinois
                                     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
                              Rachel Jones


                            C O N T E N T S

                              ----------                              
                                                                   Page

Opening statement of Senator Arlen Specter.......................     1
Opening statement of Senator Ten Stevens.........................     3
Statement of James F. Battey, M.D., Ph.D., Director, National 
  Institute on Deafness and other Communication Disorders, and 
  Chair of NIH Stem Cell Task Force, National Institutes of 
  Health, Department of Health and Human Services................     4
    Prepared statement...........................................     6
Opening statement of Senator Tom Harkin..........................     9
Statement of Robert Lanza........................................    12
    Prepared statement...........................................    14
Statement of Ronald M. Green.....................................    15
    Prepared statement...........................................    17
Statement of George Q. Daley.....................................    18
    Prepared statement...........................................    22
Statement of William B. Hurlbut..................................    25

 
              ALTERNATIVE METHODS FOR DERIVING STEM CELLS

                              ----------                              


                         TUESDAY, JULY 12, 2005

                           U.S. Senate,    
    Subcommittee on Labor, Health and Human
         Services, Education, and Related Agencies,
                               Committee on Appropriations,
                                                    Washington, DC.
    The subcommittee met at 9:30 a.m., in room SD-124, Dirksen 
Senate Office Building, Hon. Arlen Specter (chairman) 
presiding.
    Present: Senators Specter, Stevens, Harkin, and Murray.


               opening statement of senator arlen specter


    Senator Specter. Good morning. This is the 16th hearing 
held by this subcommittee on this very important subject. When 
stem cells came upon the scene in November 1998, this 
subcommittee scheduled a hearing within 10 days thereafter, and 
has been pursuing this subject very, very diligently over the 
course of the intervening 7 years.
    The ban on Federal funding for stem cell research has 
impeded the National Institutes of Health from pursuing this 
very important subject. Through the leadership of this 
subcommittee, the funding for NIH has been increased from $12 
billion to $28 billion, providing very significant funding 
which could have been used for stem cell research but has not 
been because of the prohibition.
    Now, there is grave concern that we are not moving far 
enough or fast enough on scientific research on the issues 
where stem cells could save lives. There is a battle between 
those who say that it is the destruction of human life, which I 
believe it is not. These stem cells are created--or these 
embryos are created for in vitro fertilization and those not 
used are discarded. There are some 400,000 now frozen, which 
will be discarded unless they are used.
    This subcommittee again took the lead in appropriating some 
$1 million, which we are increasing this year to $2 million, to 
encourage adoption of embryos. If these embryos could be turned 
into life, none of us would advocate at all using them for 
scientific research. But when the option is to throw them away 
or use them, it seems at least to me, that it is a clear cut 
choice.
    We expect to have the Senate take up a number of bills 
coming to the floor in the course of the next several days. 
They are not yet all written and we are trying to get copies of 
them. The principal piece of legislation is the House-passed 
bill, which is identical to legislation which Senator Harkin 
and I have introduced in the Senate. That will remove the 
restrictions so that the Federal funds can be used for stem 
cell research.
    There is another promising approach, which we will be 
exploring in today's hearing, which is yet in the very, very 
early stages, which would be able preserve the embryo and still 
harvest the stem cells.
    Again, subject to what these hearings produce and what the 
floor debate produces, if we can pass the House bill, Specter-
Harkin, that is the most important bill to be enacted. If we 
can move ahead and enact other legislation which would hold the 
promise of preserving the embryos and still have stem cells 
harvesting, that is certainly worth exploring.
    There is the so-called Bartlett bill coming out of the 
House, which may be on the Senate floor. We have not seen the 
full contours of that, but I am advised preliminarily that--
that would maintain the ban which exists now to prohibit 
Federal funding. If that is so, I would be totally opposed to 
it.
    Just one final word on a personal note. President Nixon 
declared war on cancer in 1970. When we devoted the resources 
to that war, which we have devoted to other wars, I think we 
would have found a cure for cancer by this time.
    We all have very, very close personal experiences, some 
more personal than others, with members of our families or 
loved ones who have been stricken by the maladies where 
scientific research could have provided cures.
    Carey Lackman, a member of the Senate family, who many of 
you knew, my chief of staff for many years, worked for Senator 
Heinz more than a decade ago, worked for me as chief of staff, 
died last year of breast cancer; a beautiful young woman of 48. 
She is really symbolic of so many women who have lost their 
lives from breast cancer. That could be replicated on prostate 
cancer. It could be replicated on heart disease and many, many 
other ailments where there is the potential to save lives.
    As is well known from the terrible pictures which appear of 
me repeatedly in the press and on television, I have been a 
victim of identity theft. As I have said, from time to time, I 
look in the mirror every morning and cannot recognize who I am. 
But I cannot help thinking that had the Nixon war on cancer 
really been waged with intensity, that there would have been a 
cure, a preventative for Hodgkin's lymphoma cancer, with which 
I now am engaging in a fierce battle.
    So, there is a very strong personal note to my own view. As 
has been reported, some 50 Republicans voted for the 
legislation in the House, because in many ways personal 
experiences--I hope we do not have to come to a point where 535 
of us have personal experiences before we lead the battle for 
some 110 million Americans who suffer directly or indirectly 
from maladies which could be cured by the NIH research or 
perhaps by stem cells.
    Let me turn now to the distinguished former chairman of the 
full committee, who himself--well, he may want to speak for 
himself about his own leadership on the scientific research and 
his work to combat prostate cancer.
    Senator Stevens.


                opening statement of senator ted stevens


    Senator Stevens. Thank you, Mr. Chairman, for holding the 
hearing today. I am sorry I will not be able to stay through 
it, as I have my Commerce hearing at 10 o'clock. But this is a 
topic of critical importance.
    I do not think I know anyone who has not had some 
experience with cancer, personally or in the family. Mine was 
prostate cancer and I am pleased to say that so far I have 
survived that. I am very aware of your situation and admire 
your courage. So, I want to work with you in every way.
    I have been a long-time supporter of medical research and 
particularly stem cell research. It is a means of developing 
new ways to treat and cure diseases like diabetes, and 
Parkinsons, or spinal cord injuries. Being the son of a father 
who went blind just right after I was born, I hope that someday 
stem cell research may lead to ways to make the blind capable 
of seeing.
    I hope this hearing will explore new ways of tapping into 
potential stem cells, such as PGD, pre-implantation genetic 
diagnosis concept. These new means may not raise some of the 
ethical questions that haunted and hampered the progress of 
this research to date.
    I want to stress that these new technologies should not 
come at the expense of proceeding full speed ahead with current 
research efforts on stem cells, using methods that are already 
proven to work. My scientist and research friends tell me that 
lines of stem cells approved for use were from federally funded 
research in 2001 are simply not sufficient and that many may 
have been contaminated.
    I share your direct approach to stem cell research. I 
believe we should find some way to derive stem cell lines, and 
allow those lines to be developed, and used for federally 
funded research. We must do that now and not wait for new 
technology to develop. What is at stake is too important to put 
off.
    So, I commend the scientists who are pioneering new ways to 
treat this disease through stem cell research and I want to 
thank all of you for being here today.
    I will review the statements, Mr. Chairman. Thank you very 
much.
    Senator Specter. Thank you, Senator Stevens.
    I just want to officially note before turning to our first 
witness, I have a constituent in Pittsburgh whose name is Jim 
Cordy, and he suffers from Parkinson's. As we have heard 
testimony in this room, we are very close to a cure for 
Parkinson's.
    Jim Cordy introduced me to the hourglass, which I now carry 
with me from time to time. It is a great photo op.
    Every time I see Jim Cordy, he turns the hourglass upside-
down and he says to me, ``Arlen Specter, my life is drifting 
away, just as these sands are going through the hourglass. What 
are you doing about it?''
    This subcommittee, and Senator Stevens, and Senator Harkin, 
and I have done a lot about it but we have not done enough 
about it. We are not going to rest until we find a cure for 
Parkinson's, until we find a cure for cancer. In a country 
which has a gross national product of $11 trillion, it is not 
enough to put one-fifth of 1 percent on medical research.
    In a Federal budget of $2 trillion, $600 billion, it is not 
enough to put 1 percent into medical research. Health is number 
one. That is our major capital asset, and has languished for 7 
years with the opportunities for stem cell research, which are 
languishing, not being taken care of, is just as scandalous and 
intolerable. I am glad that the leaders are bringing the matter 
to the floor so that we can move ahead and to save lives.
STATEMENT OF JAMES F. BATTEY, M.D., Ph.D., DIRECTOR, 
            NATIONAL INSTITUTE ON DEAFNESS AND OTHER 
            COMMUNICATION DISORDERS, AND CHAIR OF NIH 
            STEM CELL TASK FORCE, NATIONAL INSTITUTES 
            OF HEALTH, DEPARTMENT OF HEALTH AND HUMAN 
            SERVICES
    Senator Specter. Dr. Battey, thank you for joining us 
today. Our first witness is Dr. James Battey, Director of the 
National Institute on Deafness and Other Communication 
Disorders of the NIH. He has his B.S. from California Institute 
of Technology, and M.D. and Ph.D. degrees from Stanford.
    Dr. Battey has testified before this subcommittee on many 
occasions, and at one time for a while we were afraid of losing 
you, Dr. Battey. Senator Bettilou Taylor tells me that some of 
us might have been helpful in keeping you at NIH, which is 
great for the country, great for the world. The floor is yours.
    Dr. Battey. Thank you very much, Senator. Also great for 
me, I might add. Thank you very much. It is a pleasure to be 
here again today to discuss with the subcommittee stem cell 
research.
    As the committee understands very well, human embryonic 
stem cells have already proven to be a very valuable tool for 
advancing our knowledge about cell specialization, and they 
offer enormous potential to be medically valued.
    However, using the established methods published by James 
Thomson in 1998, the only way to generate human embryonic stem 
cell lines is to remove the inner cell mass from a 5-day-old 
pre-implantation human blastocyst, which many feel is 
tantamount to destruction of human life.
    There have been recent announcements about alternative ways 
to establish human pluripotent stem cells, which may share some 
of the magical properties of the cell lines that were 
established using the technique of Dr. Thomson. These methods 
claim to avoid the contentious issue of creating, destroying, 
or harming human embryos.
    This past May, the President's Council on Bioethics 
published a white paper on ``Alternative Sources of Human 
Pluripotent Stem Cells'', and today I will focus my time with 
you on both describing these alternate methods and then giving 
a snapshot of the state of the science as we examine this issue 
today.
    Doctors Landry and Zucker observed that, during the in 
vitro fertilization process, a number of the embryos stop 
dividing and are, therefore, unsuitable for implantation and 
are referred to as ``dead'' embryos. They have raised the 
possibility that it might be possible to harvest cells from 
these dead embryos and use them to create pluripotent stem cell 
lines. In fact, they put forward the notion that this would be 
really no different than organ donation by a person who is 
judged to be brain dead.
    From a scientific perspective, though, there is no 
published study that shows it is possible to generate an 
embryonic stem cell line from a dead embryo in rodents, non-
human primates, or humans. Were such a cell line to be 
generated, one would have to look very carefully at the genetic 
content of those cells, because there was probably a reason why 
that embryo stopped dividing. That reason might compromise the 
value of a cell line derived from those cells, were there to be 
genetic abnormalities.
    Representative Bartlett has reminded us that, during the 
pre-implantation genetic diagnosis process, there is a process 
whereby, before implanting the embryo, a genetic diagnosis is 
made to eliminate genetic disease from being a problem, a 
difficulty for the soon-to-be-born child. At the eight-cell 
stage, roughly 3 days into development, one of these eight 
cells, called the blastomere, is removed from that embryo.
    Now the cells are still pluripotent at that point in time. 
What Representative Bartlett has proposed is that it might be 
possible to generate an embryonic stem cell line from this 
single blastomere that is removed from the embryo.
    There were some studies in mice that suggest that this can 
work. At the current situation now, though, is it has not been 
demonstrated to work for either non-human primates or for 
humans. So, we do not know that it is possible to establish a 
cell line from a single cell. In fact, the closest that anyone 
has come is to establish a cell line from the morula stage, 
which is the fourth day of development, where there are 
somewhere between 10 and 30 pluripotent cells. Dr. Yuri 
Verlinski, in Chicago, has been able to generate a cell line at 
that stage.
    Were we able to make cell lines, again, they would have to 
be checked very carefully for pluripotency, for the capacity to 
self-renew indefinitely, and all the other cardinal properties 
that make human embryonic stem cells the wonderful tool that 
they are for biomedical research and offer the promise for us 
to be able to someday generate populations of cells to replace 
cells that have been ravaged by diseases like Parkinson's 
disease or Type 1 diabetes.
    Now William Hurlbut, who is with us today actually, and 
will describe his proposal in greater detail, has a concept 
called altered nuclear transfer. I think rather than dwell on 
this idea myself, I will let Dr. Hurlbut describe this to the 
committee himself, since it is his idea.
    But what I will point out is that Dr. Hurlbut's method, 
although scientifically quite interesting, has yet to be proven 
in principle for the establishment of a human pluripotent stem 
cell line.
    Finally, there is the issue of reprogramming the nucleus of 
a somatic cell. The developmental biology community was 
absolutely stunned in 1997 when Ian Wilmut cloned a sheep, the 
sheep Dolly, because that showed that it was possible to 
reverse the differentiation process, to turn it backwards. Many 
of us thought, until that event, that differentiation was a 
one-way street and that once you were differentiated; there was 
no way to go back.
    Well, the cloning of Dolly proved that we were wrong. There 
is the capacity to turn the differentiation process in reverse. 
Were we able to understand biochemically, all of the molecular 
basis for doing this, we would be able to take a cultured cell, 
de-differentiate it back to pluripotent state, and then 
differentiate it to become whatever cell type we might need to 
treat disease or disorder.
    This is a wonderful possibility for the long-term future. 
But there are many, many basic science questions about the de-
differentiation process that will need to be understood before 
we can move forward and utilize this technology to generate 
cells that are interesting for medical research.
    So in closing, the NIH places a very high priority on 
support for research using all types of stem cells, and we are 
absolutely committed to supporting the development of a wide 
variety of methods to generate pluripotent cells that may be 
useful for basic translation and clinical studies.


                           prepared statement


    But let me point out that the NIH would be nowhere in our 
effort to fund research involving pluripotent cells or all the 
rest of our nearly 40,000 grants and contracts without the 
remarkable generosity of this subcommittee, and specifically, 
without the unflagging support of Senators Specter and Harkin.
    We remain extremely grateful to you for your continued 
support. I look forward to working with you for many years on 
this to advance all fields of biomedical research and would be 
happy to do my best to try to answer any questions the 
subcommittee might have at this time.
    [The statement follows:]
               Prepared Statement of Dr. James F. Battey
    Mr. Chairman, Senator Harkin, and Members of the Subcommittee, I am 
pleased to appear before you today to testify about stem cell research. 
Human embryonic stem cells (hESC) have proven to be an important tool 
for advancing our knowledge about cell specialization, and have great 
potential to be medically valuable. However, using established methods, 
these unique cells cannot be obtained without destroying human embryos. 
There have been recent announcements about alternative ways to 
establish human pluripotent stem cell lines that claim to avoid the 
contentious issues of creating, destroying or harming human embryos. 
This past May, the President's Council on Bioethics published a white 
paper on ``Alternative Sources of Human Pluripotent Stem Cells.'' I am 
focusing my testimony on analysis of the methods highlighted in this 
report.
                pluripotent stem cells from dead embryos
    Drs. Donald Landry and Howard Zucker at Columbia University College 
of Physicians and Surgeons noted that during the human in vitro 
fertilization (IVF) process, there are numerous embryos that fail to 
continue to divide, and are therefore judged to be unsuitable for 
implantation. These non-dividing entities are deemed to be ``dead,'' 
and they propose that harvesting cells from these embryos for the 
purpose of creating a hESC line is no different than organ donation by 
a person judged to be ``brain dead.'' They argue that this approach is 
morally acceptable.
    From a scientific perspective, there is no published study showing 
that it is possible to generate an embryonic stem cell line from a non-
dividing, ``dead'' embryo in rodents, non-human primates or humans. If 
stem cell lines could be derived from such embryos, the resulting cell 
line would have to be carefully checked for karyotypic (genetic) 
abnormalities or other defects, which may have been the underlying 
cause of the embryo's lack of development. This research will require 
that clear criteria be established to determine when a ``non-dividing 
embryo'' is dead.
    Finally, the Dickey Amendment to the Department of Health and Human 
Services (DHHS) appropriations act prohibits the use of funds 
appropriated to DHHS to support the creation of a human embryo for 
research purposes or research in which a human embryo is destroyed, 
discarded, or subjected to risk of injury or death greater than that 
allowed under Federal requirements for fetuses in utero. Applicability 
of this prohibition would have to be analyzed before NIH could fund 
research on this technique using human embryos.
            pluripotent stem cells from biopsied blastomeres
    This proposal, suggested by Representative Roscoe Bartlett (R-MD), 
involves creating an embryonic stem cell line by using a blastomere 
cell from an embryo. When performing pre-implantation genetic diagnosis 
(PGD), a single blastomere cell is removed from an 8-cell stage embryo 
(approximately Day 3 in embryo development where all cells are assumed 
to be totipotent) for genetic analysis, and the remaining seven cells 
constituting the embryo are used for reproductive purposes through the 
standard IVF procedure. The proponents of this proposal suggest that 
this is proof of principle that removal of a single cell does not 
frequently damage the remaining embryo. Using this premise, this 
proposal argues that a single cell, or several cells, might be removed 
from an embryo at the 8-cell stage at the same time the embryo is 
undergoing PGD and these additional cell(s) could be used for the 
purpose of creating a hESC line. The proposal further argues that if 
one limits this approach to embryos undergoing PGD, one is: (1) not 
compromising any embryos that are not already being compromised for 
PGD; and (2) assured the embryos being used were created only for 
reproductive purposes.
    From a scientific perspective, NIH is not aware of any published 
scientific data that confirms the establishment of hESC lines from a 
single cell removed from an 8-cell stage embryo. We are aware of the 
published research of Dr. Yury Verlinsky at the Reproductive Genetics 
Institute in Chicago that showed that a hESC line can be derived by 
culturing a human morula-staged embryo (Reproductive BioMedicine 
Online, 2004 Vol. 9, No. 6, 623-629, Verlinsky, Strelchenko, et al). It 
is also worth noting, however, that in these experiments, the entire 
morula was plated and used to derive the hESC lines. The human morula 
is generally composed of 10-30 cells and is the stage (Day 4) that 
immediately precedes the formation of the blastocyst (Day 5). It is not 
known whether a hESC line can be created from a single cell or a few 
cells because these cells appear to require close contact with 
surrounding cells for survival and for maintenance of the pluripotent 
state. Even with the hESCs derived from the inner cell mass of the 
human blastocyst, the odds of starting a hESC line from a single cell 
are poor, perhaps one in 20 tries. Thus, the odds of being able to 
start with a single cell from an 8-cell or morula stage embryo are 
likely to be challenging.
    NIH believes that such experiments might be pursued in animals, 
including non-human primates. Experiments in animal model systems could 
be conducted to determine whether it is possible to derive hESCs from a 
single cell of the 8-cell or morula stage embryo. To date, NIH is aware 
of only two published reports where scientists developed mouse stem 
cell lines from individual blastomeres. NIH also does not know whether 
these experiments have been tried and failed in other animals and/or 
humans and, therefore, have not been reported in the literature. NIH 
explored whether there have been any attempts to use single cells from 
the 8-cell or morula stage of an animal embryo to start embryonic stem 
cell lines by consulting with scientists that are currently conducting 
related embryo research. From these discussions, these scientists 
believe it is worth attempting experiments using a single cell from an 
early stage embryo or cells from a morula of a non-human primate to 
establish an embryonic stem cell line. If this approach is successful, 
the resulting stem cell lines would, of course, have to be validated 
for genetic stability, pluripotency, and unlimited self-renewal--all 
cardinal features of embryonic stem cell lines generated from 
blastocysts by culturing the inner cell mass.
    NIH concludes that the possibility of establishing a hESC line from 
an 8-cell or morula stage embryo can only be determined with additional 
research. NIH would welcome the receipt of investigator-initiated grant 
applications on this topic using animal embryos. As with all grant 
applications, such proposals would be judged for scientific merit by 
peer review and then will be awarded research funds if sufficient funds 
are available.
    Live births resulting from human embryos that undergo PGD and are 
subsequently implanted seem to suggest that this procedure does not 
harm the embryo; however, there are some reports that some embryos do 
not survive this procedure. In addition, long-term studies are needed 
to determine whether this procedure produces subtle injury to children 
born following PGD. This experiment in human embryos at either the 
morula or the blastocyst stage would require evaluations of not only 
normal birth but also unknown long-term risks to the person even into 
adulthood.
    Moreover, there are a number of questions to be resolved with 
regard to the nature of the cells removed from the 8-cell stage embryo. 
If the cells removed at this stage are totipotent (and most scientists 
would agree they are), then it might be argued that these cells are 
themselves embryos, i.e., having the potential to undertake all of the 
life functions of the adult. It is possible, however, that one could 
put these cells in an environment in which they will not continue to 
develop and, under these conditions, they would no longer be embryos.
    As with the Landry-Zucker proposal, applicability of the Dickey 
Amendment would have to be analyzed before NIH could fund research on 
human embryos.
            pluripotent stem cells from biological artifacts
    Dr. William Hurlbut at Stanford University asserts that it may be 
possible to do the following: (1) genetically modify a somatic cell in 
culture, either reversibly or irreversibly inactivating a gene 
essential for normal trophoblast function/development (which is 
required for embryo implantation and development of the placenta); (2) 
use this genetically modified somatic cell as the source of a nucleus 
and genome for somatic cell nuclear transfer (SCNT) into a human 
oocyte. Dr. Hurlbut refers to this method as Altered Nuclear Transfer 
(ANT); (3) allow this oocyte to proceed to develop into a blastocyst; 
and (4) attempt to generate a hESC line from the inner cell mass of the 
blastocyst. Dr. Hurlbut argues that since the entity generated by SCNT 
had no capacity to develop a trophectoderm (the embryonic cells which 
becomes the placenta and umbilical cord), it never had the capacity to 
develop into a fetus and ultimately a child; it is, therefore, not a 
human embryo. Dr. Hurlbut asserts that since this entity is not a human 
embryo, and its destruction at the blastocyst stage to generate a hESC 
line is morally acceptable. His opinion is currently under debate.
    From a scientific perspective, Dr. Janet Rossant at Mount Sinai 
Hospital in Toronto has identified a gene essential for normal 
trophoblast development/function in a mouse model system. However, no 
one has demonstrated that it is possible to execute the sequence of 
steps proposed by Dr. Hurlbut and obtain a pluripotent, genetically 
stable stem cell line. Embryonic stem cell derivations would need to 
undergo pilot experiments, first in rodents and then in non-human 
primates, to prove that this approach has merit and is technically 
feasible. If created, the stem cell lines would, of course, have to be 
validated as authentic, with all the properties associated with self-
renewing, pluripotent embryonic stem cell lines.
    Dr. Hurlbut's proposed approach to deriving hESCs is dependent upon 
the widespread acceptance of his assertion that the genetically 
modified entity created using his procedure is not, in fact, a human 
embryo.
    There are no limitations on any pilot studies performed in rodents 
or non-human primates. Limits of Federal funding of research for any 
extension of this approach to humans would require an analysis of the 
applicability of the Dickey Amendment.
         pluripotent stem cells by reprogramming somatic cells
    This proposal involves reprogramming human somatic cells, perhaps 
with the aid of special cytoplasmic factors obtained from oocytes (or 
from pluripotent embryonic stem cells), so as to ``dedifferentiate'' 
them back into pluripotent stem cells. Crucial to this approach is 
discovering a way to reverse cell differentiation all the way back to 
pluripotency, but not further back to totipotency.
    From a scientific perspective, it may be possible at some time in 
the future to culture populations of somatic cells in the laboratory 
and reverse their differentiating process, enabling them to become 
pluripotent. Scientists may also identify the molecules in cells such 
as embryonic stem cells that are responsible for maintaining cells in a 
pluripotent state and use these factors to dedifferentiate somatic 
cells. This proposal would raise ethical issues if the 
dedifferentiation process were to proceed too far and create a 
totipotent cell (a cloned human zygote). Research conducted with 
somatic cells can be conducted with appropriated funds since no human 
embryos are involved, unless the dedifferentiation process proceeds too 
far and results in the creation of a cell equivalent to a zygote.
                               conclusion
    Although some of these approaches may address interesting 
scientific questions and may even lead to new ways to derive stem 
cells, science works best when all available avenues can be pursued 
simultaneously.
    NIH places a high priority on support for research using embryonic 
and non-embryonic stem cells that will also be useful for basic, 
translational, and clinical studies. The NIH is very grateful for your 
continued support. I look forward to working with you to advance this 
and all fields of biomedical research. I will be happy to try to answer 
any questions that you and the Subcommittee might have.

    Senator Specter. Thank you very much, Dr. Battey.
    We have been joined by Senator Harkin.
    Senator Stevens, would you care to ask a question or two? I 
would be delighted to defer to you before you go to your other 
hearing.
    Senator Stevens. No. I defer to you. I agree with you 100 
percent.
    Senator Specter. Okay. Now that I have Senator Stevens's 
general power of attorney, we can proceed.
    I now turn to my partner for many years standing. We talk 
with pride about the seamless transfer of the gavel and working 
together on these important issues.
    Senator Harkin.

                OPENING STATEMENT OF SENATOR TOM HARKIN

    Senator Harkin. Thank you, Mr. Chairman. Again, I apologize 
for being late. I got stuck in some traffic downtown. But I 
just want to echo what I just heard Senator Stevens say. I 
agree with you 100 percent. So, that makes two of us who agree 
with you 100 percent.
    If you do not mind, Mr. Chairman, I would like to just make 
a short statement, if you do not mind.
    Senator Specter. By all means. We will reserve the time for 
your opening statement and then we will proceed with the 
questioning of Dr. Battey.
    Senator Harkin. I really appreciate that. First of all, I 
want to thank you, Senator Specter, for all of your years of 
leadership on this subcommittee and especially in this field of 
biomedical research. I think I can say without any fear of 
contradiction or being corrected that no Senator--no one here 
in the entire Congress--I include the House, too, has devoted 
more time, more energy, more intellectual pursuit of supporting 
biomedical research in this country than Senator Arlen Specter 
of Pennsylvania. No one. It has just been a real privilege to 
have worked alongside of you and with you through all these 
years in support of your leadership in this area.
    You and I held the first congressional hearing on stem cell 
research in December 1998. You were chairman. This is our 16th 
hearing on this topic; I suppose we will have some more. But 
today's hearing is focusing on alternative methods of deriving 
stem cells has suddenly become very popular around this town 
among other people who want to maintain current restrictions on 
stem cell research.
    Under this method, scientists take a 2-day-old embryo. It 
has eight cells. They extract one, a blastomere. Maybe you have 
gone into that, Dr. Battey. I do not know. I am sorry I missed 
your opening statement. But then they stimulate that blastomere 
to begin dividing. Then after a few days, scientists can use it 
to derive stem cells.
    The supposed advantage here is that the original embryo is 
not destroyed. First of all, I want to say I am intrigued by 
this method. I believe it is worth pursuing. But we need to be 
clear about one thing as we listen to today's testimony. There 
is only one reason why this method has suddenly become so 
popular and being debated around. I noticed the article that 
was in the paper this morning, an op-ed piece by Leon Kass. 
Because I believe that there are some who want to use this 
approach to defeat H.R. 810, or our bill, the Specter-Harkin 
bill, from being enacted and passed by the Senate, which I 
believe it has the votes to do, because it has strong 
bipartisan support.
    The strategy seems to be to convince senators that instead 
of supporting our bill, the Specter-Harkin bill, that we should 
pin all our hopes on this blastomere method or the so-called, 
quote, ``ethical'' alternatives. I think people figure some who 
want to stop this type of research, they figure if they can 
pull enough votes off of our bill, then they can stop us from 
getting the 60 votes that we need to stop a filibuster and pass 
it.
    I would point out that we had 58 signatures on the letter 
and we got more that want to support it. So, we have the votes. 
I can respect that position if blastomere extraction showed as 
much promise as our current method for deriving stem cells. But 
so far, it does not.
    The method we are discussing today has not been published 
in a single scientific journal. It has not been cleared through 
peer reviews. It has only been tried in mice. We are a long way 
from proving that it works in human embryos.
    So there are a lot of problems we have with it, and Dr. 
Kass, in his article, mentioned it this morning. He said it is 
too early to know which of these approaches, these alternative 
approaches, will prove most successful; or whether some 
alternative approach will be superior. As the council noted, 
these proposals raised some ethical questions of their own.
    Well, I am not going to read the whole article but he goes 
on to describe some of these other approaches. Then he says, at 
the end he says, ``We could be hopeful that a technological 
solution to our moral dilemma might soon be found and that this 
divisive piece of our recent political history will soon come 
to an end. The senators will be given a chance this week to 
enact legislation to increase funding for alternative sources. 
They should not miss this timely and promising thing.''
    But the point is that I am all for these alternative 
sources. I am all for these alternative methods. Let us go 
ahead and pursue them. But we already know how to derive stem 
cells. That was first done by Dr. Thomson at the University of 
Wisconsin about 8 years ago, I believe, now. So, we know how to 
do that.
    To the extent that these other alternative approaches might 
work, fine. Not as a substitute. Not as some way of stopping 
what we are about to do and stopping the derivation of stem 
cells from already existing embryos in in-vitro fertilization 
clinics.
    So, I think that is really the difference here. Somewhat, I 
think, to use this as a way of slowing this down and stopping 
it. When Dr. Kass talked about a moral dilemma, I would point 
out; the vast majority of the American people are speaking out 
on this. Did you see the front page--or the front cover of the 
Parade magazine this Sunday? A whole National Geographic issue.
    I would point this out. Parade magazine, stem cell 
research. If you would open it up, they had a poll that they 
took, American people, right here; 58 percent strongly favor 
this research on embryonic stem cells. Only 18 percent--well, 
29 percent oppose somewhat or strongly oppose it.
    So, I would just say to Dr. Kass one thing, I do not 
believe there is a moral dilemma here. Any kind of medical 
research of this nature is always going to have its detractors. 
We have been through this time and time and time again in the 
past.
    There are those who--let us face it. There are those today 
who believe that any form of artificial birth control is 
morally unacceptable. There are those who believe that oral 
contraceptives are morally unacceptable. There are those who 
believe using condoms today is morally unacceptable. But the 
vast majority of the American people do not believe that way.
    I give full license to those that have their own moral 
qualms about anything, but they should not impose their views 
on the vast majority of the American people who want us to 
pursue this course of action. That is what we are about. That 
is what Senator Specter has been the leader on all these years 
and what he is leading us on now.
    So, I just wanted to make that strong opening statement and 
I thank you for your indulgence, Mr. Chairman, because it is 
not about either/or. It is about pursuing all of these basic 
research things that you have let us on for all these years. If 
we are going to fund these alternative approaches, that is 
fine, but do not stop the process that we have right now of 
deriving embryonic stem cells that have so much promise for 
cures faster than going down the road of these alternative 
approaches. With that, Mr. Chairman, I thank you for this time.
    Senator Specter. Thank you very much, Senator Harkin. The 
proposition which you suggest on pursuing all the lines, I 
think is a very sensible one. You quote this morning's op-ed 
piece as saying we do not know--Dr. Kass does not know which 
would be the most fruitful, which suggests we ought to proceed 
on all lines.
    But we will have to examine the legislation very carefully 
to make sure there is not a provision, which I understand there 
may be in one or more of these bills, which would preclude the 
Castle-DeGette bill and the Specter-Harkin bill from moving 
forward.
    I was asked yesterday why I am having a hearing to explore 
alternatives which might produce some stopping of fundamental 
legislation which we have in mind. The object is to find out as 
much as we can, have a--see where we are and to see how much 
promise there is. If it is possible to preserve the embryo and 
harvest the cells, fine. But if it is very speculative and we 
have a bird in hand, let us not avoid going forward with what 
we know will work.
    Dr. Battey, you have already referenced the fact that there 
are others who are going to be--you have deferred to them on 
some of the alternatives. I think the hearing would be best 
accommodated if we call them to the witness table today, and we 
hear their opening statements, and then have an interchange 
among you high-powered scientists, if we may.
    So if Dr. Lanza, Dr. Green, Dr. Daley, and Dr. Hurlbut 
would step forward, we will proceed.
    Our next witness will be Dr. Robert Lanza, Vice President, 
Medical and Scientific Development of Advanced Cell Technology, 
and adjunct professor of surgical scientists at Wake Forest 
University School of Medicine, B.A. and M.D. degrees from the 
University of Pennsylvania. Thank you for joining us, Dr. 
Lanza, and we look forward to your testimony.
STATEMENT OF ROBERT LANZA, M.D., VICE PRESIDENT, 
            MEDICAL AND SCIENTIFIC DEVELOPMENT, 
            ADVANCED CELL TECHNOLOGY
    Dr. Lanza. Thank you. Good morning, Mr. Chairman and 
distinguished members of the committee. My name is Robert 
Lanza, and I am the medical director at Advanced Cell 
Technology, a stem cell company in the emerging field of 
regenerative medicine. I am also adjunct professor at the 
Institute of Regenerative Medicine at Wake Forest University.
    Regenerative medicine is accelerating its pace with many 
scientific groups worldwide, conducting research in preclinical 
tests of stem cells. International teams are beginning to pull 
away from researchers in the United States, given the current 
limitations of Federal funding of stem cell research.
    Access to funding for developing new ways of isolating stem 
cells will not only help address current ethical concerns but 
will help the United States maintain its leadership position in 
medical research.
    The most basic objection to stem cell research is rooted in 
the fact that embryos are deprived of their fundamental 
potential to develop to complete human beings. To date, there 
have been no reports of stem cells derived using an approach 
that does not destroy embryos.
    The President's Bio-Ethic Council, chaired by Leon Kass, 
has outlined four approaches for creating stem cells without 
destruction of embryos. The first approach is to generate stem 
cells using a biopsy similar to pre-implantation genetic 
diagnosis. PGD involves removal of one or two cells, called 
blastomeres, from an embryo to test for diseases such as cystic 
fibrosis.
    The procedure is relatively simple and is carried out 
routinely at IBF clinics worldwide. Using this approach, we 
have found that biopsied mouse embryos develop to term without 
a reduction in the developmental capacity. We have successfully 
isolated stem cells from single blastomeres, which demonstrated 
the ability to differentiate into derivatives of all three germ 
layers of the body, passing all of the tests associated with 
human embryonic stem cells.
    The Kass report raises two ethical concerns regarding this 
approach. The first objection is that the biopsy could 
adversely affect the embryo. We propose a simple solution. Use 
only blastomeres from embryos undergoing routine PGD. Experts 
estimate that 1,000 healthy infants are born every year from 
embryos that have undergone PGD, a number significant enough to 
generate numerous new stem cell lines.
    Another objection in the Kass report is that the biopsy 
cell could have the potential to develop into an embryo. In 
fact, human blastomeres have never been shown to have the 
capacity to generate viable embryos, and there is an increasing 
body of scientific knowledge suggesting that the cells in 
morula stage embryos, the 8 to 16 stage, have already committed 
to either becoming ICM cells or trophectoderm. That only 
totipotent cell is the fertilized egg in the first four or so 
cells produced by its cleavage.
    The blastomere approach does not involve the destruction of 
an embryo nor could the biopsy itself ever develop into an 
embryo. Eventually, we hope this method can be used to increase 
the number of lines that qualify for Federal funding and, at 
the same time, avoid some of the challenges associated with 
other methods in the Kass report.
    For instance, one approach favored by many uses cloning to 
sabotage the development of embryos. Supporters claim that the 
``bundle of cells'' that results is not an embryo. As a medical 
scientist, I think it is an abuse of science to use cloning and 
genetic manipulation to deliberately create crippled embryos, 
especially when these manipulations are not carried out for any 
scientific reason but rather to solve theological problems.
    Let us be honest. A human embryo is a human embryo whether 
or not this or that gene is knocked out. It is hard to believe 
that human ensoulment depends on the expression of CBX-2. The 
blastomere approach uses a technique that already exists and 
would not require taxpayer funding to develop human cloning 
techniques.
    The Kass report proposes two additional approaches. One is 
to deprive cells from embryos that are technically dead. 
However, we are talking about tiny clusters of cells, and you 
cannot take an EEG to determine if there is a loss of brain 
function. I have seen numerous human embryos stop dividing; 
fooling the embryologist into thinking they are dead. Then 
after a resting period, they go on to generate blastocysts. 
Unfortunately, the only way to know if an embryo is dead is if 
the cells are dead.
    The final approach, known as de-differentiation, does not 
require human eggs or embryos. This is an exciting concept and 
involves taking an adult cell and reprogramming it back to 
adult--to pluripotent stem cells. We and other groups have 
already generated some exciting data on this but it is still 
very preliminary and requires further research. This approach 
has few, if any, ethical objections.
    Given the data to date further investigations of the cell 
biopsy and de-differentiation approaches should be funded to 
determine if stem cells can be derived in humans. We believe 
that a commitment of $15 million to $20 million would 
significantly accelerate this research and its likely success 
in the future.
    The hope of these approaches described here today, we hope 
that this will result in the expansion of stem cell lines 
available for therapies. However, until these approaches are 
perfected in humans, it is important to emphasize the urgent 
need to continue access to surplus IBF embryos. It is for this 
research. Again, I cannot emphasize enough that the approaches 
that I am describing here are complementary to S. 471 and H.R. 
810.

                           PREPARED STATEMENT

    While you were listening to this testimony, another 10 
Americans have died of diseases that could potentially be 
treated using stem cells in the future. It would be tragic not 
to pursue all the options and methods available to us to get 
this technology to the bedside as soon as possible.
    [The statement follows:]
                 Prepared Testimony of Dr. Robert Lanza
    Good morning, Mr. Chairman and distinguished members of the 
committee. My name is Robert
    Lanza and I am the medical director at Advanced Cell Technology, a 
stem cell company in the emerging field of regenerative medicine. I am 
also Adjunct Professor at the Institute of Regenerative Medicine at 
Wake Forest University School of Medicine.
    The field of regenerative medicine is accelerating its pace of 
progress with many scientific groups worldwide conducting research and 
preclinical tests of human stem cell lines, and beginning to draw up 
timetables for clinical development. International teams are beginning 
to pull away from the researchers in the United States given the 
current limitations on Federal funding for stem cell research. Access 
to Federal funding for developing new ways of isolating pluripotent 
stem cells will not only help address current ethical concerns, but 
will help the United States maintain its leadership position in medical 
research.
    The most basic objection to embryonic stem cell research is rooted 
in the fact that ES-cell derivation deprives embryos of their potential 
to develop into complete human beings. To date, there have been no 
reports in the literature of stem cell lines derived using an approach 
that does not require destruction of embryos. The President's Bioethics 
Council chaired by Leon Kass has outlined four approaches for creating 
stem cells without the destruction of embryos.
    The first approach would be to generate stem cells using an embryo 
biopsy similar to preimplantation genetic diagnosis. ``PGD'' involves 
removal of one or two cells called ``blastomeres'' from an embryo to 
test for genetic diseases like cystic fibrosis. The procedure is 
relatively simple and is carried out routinely in IVF clinics 
worldwide. The ability to generate stem cells using this method could 
circumvent the ethical concerns voiced by many. Using this approach, we 
have found biopsied mouse embryos developed to term without a reduction 
in their developmental capacity. We successfully isolated stem cell 
lines from single blastomeres, which demonstrated the ability to 
readily differentiate into derivatives of all three germ layers of the 
body, passing all the tests generally associated with human ES cells 
(publication pending).
    The Kass report raises two ethical concerns regarding this 
approach. The first objection is that the biopsy could adversely affect 
the embryo. We propose a simple solution--use only blastomeres from 
embryos undergoing routine PGD. Experts estimate that a thousand 
healthy infants are born every year from embryos that have undergone 
PGD--a number sufficient to generate numerous new stem cell lines.
    Another objection in the Kass report is that the biopsied cell 
could have the potential to develop into an embryo. In fact, human 
blastomeres have never been shown to have the capacity to create viable 
embryos in the laboratory, and there is an increasing body of 
scientific evidence suggesting that the cells in morula-stage embryos 
(8-16 cells) have already committed to becoming either ICM cells or 
trophectoderm. At a minimum, it is clear that some degree of 
differentiation has occurred, and there is an increasing consensus that 
the only ``totipotent'' cells are the fertilized egg and the first 4-
or-so cells produced by its cleavage.
    The blastomere approach does not involve the destruction of an 
embryo, nor could the biopsied cell ever develop into an embryo. 
Eventually, we hope this method can be used to increase the number of 
stem cell lines that qualify for Federal funding, and at the same time, 
avoid the challenges associated with other methods outlined in the Kass 
report. For instance, an approach favored by many, and first proposed 
by ACT years ago, uses cloning to sabotage the development of embryos. 
Supporters claim the ``bundle of cells'' is not an embryo and could be 
used to ethically generate stem cells. As a medical scientist, I think 
it is an abuse of science to use cloning and genetic manipulation to 
deliberately create crippled human embryos, especially when these 
manipulations are not carried out for any medical or scientific reason, 
but rather to address theological problems. Let's be honest, a human 
embryo is a human embryo whether or not this or that gene is knocked 
out. It's hard to believe that human ensoulment depends on the 
expression of cdx2. The blastomere-approach uses a technique that 
already exists, and would not require taxpayer funding to further 
develop human cloning techniques.
    The Kass report also proposes two other approaches. One is to 
derive stem cells from ``technically dead'' embryos. However, we're 
talking about tiny clusters of cells; you can't take an EEG to 
determine if there's loss of brain function. I've seen numerous human 
embryos stop dividing, fooling the embryologist into thinking they're 
no longer viable; then, after a significant ``resting'' period, they go 
on to generate intact blastocysts. Unfortunately, the only sure way to 
know if an embryo is dead is if the cells are dead.
    The final approach, known as dedifferentiation, doesn't require 
human eggs or embryos. This is an exciting concept, and involves taking 
an adult cell and reprogramming it back into a stem cell in the 
laboratory. We and several other groups have already generated some 
exciting data on this, but it's still preliminary and requires further 
basic research. This approach holds great promise and there are few, if 
any ethical concerns.
    Given the our research to date and the data generated from animal 
models, further investigations of the single-cell biopsy and 
dedifferentiation approaches should be funded and encouraged to 
determine if stem cells can be derived in humans. We believe that a 
significant commitment of Federal funding of $15 to $20 million would 
significantly accelerate this research and its likely success within 
this decade.
    We hope the approaches described here today will successfully 
result in the future expansion of stem cell lines available for human 
therapies. However, until these approaches are perfected in humans, it 
is important to emphasize the urgent need for continued access to 
surplus IVF embryos that would otherwise be discarded. It is for this 
that I commend the sponsors of Senate
    Bill 471, and applaud you for your commitment to supporting ES cell 
research and the advancement of regenerative medicine.
    While you were listening to this testimony, another 10 Americans 
have died of diseases that could potentially be treated using stem 
cells in the future. It would be tragic not to pursue all the options 
and methods available to us to get this technology to the bedside as 
soon as possible.

    Senator Specter. Thank you very much, Dr. Lanza.
    We turn now to Dr. Ronald Green, Director of Dartmouth 
Institute of Study and Applied Professional Ethics. He 
currently heads the Ethics Advisory Board of Advanced Cell 
Technology. A graduate of Brown, a Ph.D. in religious ethics 
from Harvard. A member of the Human Embryo Research Panel, NIH, 
a Blue Ribbon Commission. Appointed to recommend policy for 
Federal funding on pre-implantation of human embryo. Thank you 
for coming to Washington today, Dr. Green, and we look forward 
to your testimony.
STATEMENT OF RONALD M. GREEN, DIRECTOR, ETHICS 
            INSTITUTE, DARTMOUTH COLLEGE
    Dr. Green. Thank you very much for having me here, Senator 
Specter. As we meet today and this morning, only 22 embryonic 
stem cell lines are available for federally funded research. 
This is far too small a number for effective research. 
Furthermore, as has been said, all of these lines are of 
limited clinical value because they are contaminated with mouse 
proteins or viruses that are likely to cause rejection or new 
human diseases.
    In the past year, four proposals have been put forward to 
find technical ways around this problem. One advocates the use 
of organismically dead embryos for stem cell derivation. A 
second argues for the use of altered nuclear transfer to 
produce developmentally incompetent embryos for the same 
purpose. Both of these proposals have been sharply criticized 
as involving the deliberate infliction of injury on early 
embryos. I substantially agree with these criticisms.
    A third approach involves the reprogramming of body cells 
so as to restore them to the pluripotency typical of embryonic 
stem cells. While this approach is ethically unobjectionable, 
it is well beyond current scientific capabilities; although, 
research in this direction should be supported.
    A fourth approach, and the one on which I want to dwell 
this morning, involves the use of single-cell blastomere 
biopsy. This procedure has already been well described by 
others this morning and I believe the technical detail is 
there. Because this approach does not involve the destruction 
of an embryo, if it could be applied to the creation of a human 
embryonic stem cell line, it could eliminate many of the 
ethical and legal objections to Federal support for embryonic 
stem cell research. So this is an approach with promise.
    Nevertheless, serious ethical and legal questions remain. 
It has not yet been scientifically established that blastomere 
extraction is harmless to the embryo and prospective child. As 
such, this research may subject a born child to unknown risks 
in order to develop a stem cell line of use to others.
    It might be argued that the child could benefit by having a 
line of stem cells made available for its future health care 
needs. But until research resolves the safety questions, this 
procedure cannot ethically be used on healthy embryos. I would 
add, I believe it cannot be used under current human subject's 
regulations as well.
    However, single-cell biopsy for stem cell derivation could 
possibly be conducted ethically and legally at present, in 
conjunction with a pre-implantation genetic diagnosis, PGD 
procedure. The risks here of removing a cell could be ethically 
justified by the benefits to the prospective child of avoiding 
a genetic disease.
    The use of any cells harvested in this procedure would be 
as ethically acceptable as the use of cells removed from an 
infant during a routine genetic diagnostic procedure. 
Nevertheless, although single-cell blastomere biopsy is an 
ethically promising way of deriving stem cell lines, it should 
not be regarded as an alternative to current methods that use 
embryos remaining from infertility procedures.
    There are at least two reasons why I say this. First, it 
has not been demonstrated that embryonic stem cell lines can 
successfully be derived in this way. Placing all our hopes for 
stem cell development on this technology is not prudent. Nor is 
it fair to the many people awaiting cures through stem cell 
research.
    Second, single-cell biopsy raises ethical questions of its 
own. As I have indicated, because of unknown risks it cannot 
ethically be used to derive stem cells from health embryos. 
Although this technology could be used in the course of legal 
analysis might conclude that Federal law prohibits funding for 
research on stem cell lines derived from PGD.

                           PREPARED STATEMENT

    The most responsible government action at this time would 
be to support further research on single-cell blastomere 
biopsy, to establish its safety and efficacy while moving ahead 
on proven methods of expanding the number of stem cell lines 
available to researchers. Thank you.
    Senator Specter. Thank you very much, Dr. Green, for 
tackling a very complex subject and making it, if not almost 
understandable, perhaps understandable.
    Dr. Green. Thank you.
    [The statement follows:]
                 Prepared Statement of Ronald M. Green
    Good morning, Mr. Chairman and distinguished members of the 
committee. My name is Ronald M. Green. I am a professor in the 
Department of Religion at Dartmouth College and Director of the 
Dartmouth's Ethics Institute. I also serve, in a pro bono capacity, as 
chairman of the Ethics Advisory Board for Advanced Cell Technology in 
Worcester, Massachusetts.
    U.S. law currently prohibits the use of federal funds for 
``research in which a human embryo or embryos are destroyed.'' \1\ On 
August 9, 2001, President Bush issued an executive order permitting 
funding for research on human embryonic stem lines established before 
that date. As of today, there are only 23 embryonic stem cell lines 
available for federally funded research. All of these lines are 
contaminated with mouse proteins and viruses that are likely to cause 
rejection or new human diseases.\2\ There are also too few approved 
cell lines to provide adequate genetic diversity for much stem cell 
research and clinical care.\3\
---------------------------------------------------------------------------
    \1\ Dickey-Wicker Amendment. Public Law 104-99, Section 128, 
January 26, 1996, 110 Stat 34.
    \2\ J. Ebert, Nature Online, 24 January 2005. http://
www.nature.com/news/2005/050124/pf/050124-1_pf.html
    \3\ Guidelines for Human Embryonic Stem Cell Research. National 
Academy of Sciences, Committee on Guidelines for Human Embryonic Stem 
Cell Research, National Research Council. Washington, D.C.: National 
Academies Press, 2005.
---------------------------------------------------------------------------
    In the past year, four proposals have been put forward to find 
technical ways around this impasse. All four proposals are presented 
and discussed in a White Paper issued by the President's Council on 
Bioethics.\4\ One proposal advocates the use of ``organismically dead'' 
embryos for stem cell derivation.\5\ A second proposes to use what is 
called ``altered nuclear transfer'' to produce developmentally 
incompetent embryos for the same purpose.\6\ Both of these approaches 
have been sharply criticized by commentators inside and outside the 
President's Bioethics Council as possibly involving the deliberate 
infliction of injury on early embryos.\7\ \8\ \9\
---------------------------------------------------------------------------
    \4\ President's Council on Bioethics. ``Alternative Sources of 
Pluripotent Stem Cells: A White Paper.'' Washington, D.C. May 2005.
    \5\ Landry, D. W. and H. A. Zucker, ``Embryonic death and the 
creation of human embryonic stem cells,'' The Journal of Clinical 
Investigation 114 (2004), 1184-1186.
    \6\ W. Hurlbut, President's Bioethics Council, Meeting Transcript, 
December 4, 2004. http://www.bioethics.gov/transcripts/dec04/
dec3full.html.
    \7\ J. Rowley, ``Personal Statement of Dr. Rowley.'' Pp. 89-90 in 
``President's Council on Bioethics. ``Alternative Sources of 
Pluripotent Stem Cells: A White Paper.''
    \8\ Comments by J. Hanson and R. Doerflinger, President's Bioethics 
Council, Meeting Transcript, December 4, 2004.
    \9\ D. A. Melton, G. Q. Daley, and C. G. Jennings, ``Altered 
nuclear transfer in stem-cell research--a flawed proposal.'' New 
England Journal of Medicine 351;27 (2004), 2791-2792.
---------------------------------------------------------------------------
    A third approach involves the reprogramming or de-differentiation 
of differentiated somatic cells so as to restore them to the 
pluripotency typical of embryonic stem cells. While ethically 
unobjectionable, this approach is well beyond current scientific 
capabilities.
    A fourth approach, and the one on which I want to dwell, involves 
the use of single-cell blastomere biopsy. This procedure is widely used 
in the process of preimplantation genetic diagnosis (PGD) as a way of 
testing for genetic disorders before the embryo is transferred to a 
womb. Hundred of PGD procedures have been performed in this country. 
The extraction of a single cell from the embryo at this stage does not 
appear to harm it or reduce its developmental potential. If this method 
could be applied to the extraction of a single cell for the creation of 
a human embryonic stem cell line, it could circumvent many of the 
ethical and legal objections to federal support for embryonic stem cell 
research.
    Nevertheless, ethical and legal questions remain. It has not yet 
been scientifically established beyond a reasonable doubt that 
blastomere extraction is harmless to the embryo and prospective child. 
As such, this research may subject a born child to unknown risks in 
order to develop a cell line of possible use to others. It could be 
argued that the child might benefit by having a line of stem cells 
produce for its future health care needs. But until future research 
resolves these safety questions and proves that this approach is 
innocuous, it is doubtful whether parents could responsibly exercise 
proxy consent in this case or that institutional review boards could 
accept their consent.
    The same problem arises when we ask whether such research could be 
permitted for federal support under current laws and regulations that 
prohibit research on an embryo or fetus that is not to its benefit and 
that involves greater than minimal risk.\10\ Although banking a line of 
stem cells is arguably to the embryo's benefit, it cannot be said with 
confidence at this time that removing a blastomere from an early embryo 
is to its net benefit or that it involves only minimal risk. It will 
take additional research, which might be supported by federal funding, 
to determine the level of risk to embryos associated with single-cell 
blastomere biopsy.
---------------------------------------------------------------------------
    \10\ 45 CFR  46.208(a)(2).
---------------------------------------------------------------------------
    However, if single-cell biopsy for stem cell derivation proves 
technically feasible, it could possibly be conducted ethically and 
legally at present within the context of PGD. The risks here could be 
ethically justified by the benefits to the prospective child of 
avoiding a genetic disease. Use of any blastomeres harvested in the 
procedure would be as ethically acceptable as the use of tissue removed 
from a child during an ordinary surgical procedure. Some of the 
blastomeres made available in this way would be from genetically 
unaffected embryos and could be cultured for testing and for stem cell 
derivation for transplant purposes. Blastomeres from affected embryos 
might be developed into stem cell lines that could be used in the study 
of the family's genetic disease condition.
    Would research on stem cell lines derived from blastomeres taken 
from embryos during PGD qualify for federal funding? This question will 
require further legal analysis, but there are reasons to believe that 
the research could qualify. Blastomere extraction does not destroy the 
embryo. PGD is a legitimate medical procedure widely used as a way of 
avoiding the birth of a child with a serious genetic disease. Even many 
of those who morally oppose PGD might agree that so long as the 
procedure is being conducted, it is morally permissible to use 
embryonic tissues remaining from it. In terms of the requirement 
prohibiting anything greater than minimal risk unless the research 
benefits the embryo, it could be argued that PGD ``benefits'' each 
embryo by affording it at least a chance of being born. In the absence 
of PGD, couples that carry disease-causing genes might entirely avoid 
trying to have biologically related children.
    If it could be successfully developed, therefore, single-cell 
blastomere biopsy offers a way of resolving our current ethical and 
legal debates about the moral acceptability of human embryonic stem 
cell research. It would permit many of those who believe that human 
life begins at fertilization to support the derivation of new stem cell 
lines without compromising their core ethical beliefs.
    Nevertheless, although single-cell blastomere biopsy is an 
ethically attractive way of deriving stem cell lines, it should not be 
regarded as an alternative to current methods that use embryos 
remaining from infertility procedures, an approach that many citizens 
regard as ethically acceptable. There are at least two reasons why this 
is so. First, it has not been demonstrated that embryonic stem cell 
lines can routinely and successfully be derived in this way. Placing 
all our hopes for stem cell development on this technology is not 
prudent, nor is it fair to the many people awaiting cures through stem 
cell research.
    Second, single-cell biopsy raises ethical questions of its own. As 
I have indicated, it currently cannot ethically be used to derive stem 
cells where healthy embryos are involved, since the absence of risks to 
the resulting children has not yet been sufficiently demonstrated. 
Although this technology can be used in the context of PGD without 
adding additional risks, some people object to PGD itself. In addition, 
further legal analysis might lead to the conclusion that the Dickey 
Amendment prohibits federal funding for research on stem cell lines 
derived from PGD.
    The most responsible governmental action at this time would be to 
support further research on single-cell blastomere biopsy to establish 
its efficacy and safety while moving ahead on proven methods of 
expanding the numbers of stem cell lines available to researchers.

    Senator Specter. We now turn to Dr. George Daley, Associate 
Director of the Stem Cell Program at Boston Children's 
Hospital, and a member of the Executive Committee of the 
Harvard Stem Cell Institute. Dr. Daley received his bachelor's 
degree and M.D. from Harvard and a Ph.D. in biology from MIT. 
We appreciate you being here, Dr. Daley, and the floor is 
yours.
STATEMENT OF GEORGE Q. DALEY, M.D., Ph.D., ASSOCIATE 
            DIRECTOR, STEM CELL PROGRAM, BOSTON 
            CHILDREN'S HOSPITAL
    Dr. Daley. Thank you, Senator Specter, members of the 
committee. Thank you for inviting me to testify. My name is 
George Daley. I am here today representing the American Society 
for Cell Biology, which is a professional society of nearly 
12,000 basic biomedical researchers here in the United States 
and throughout the world.
    I am an associate professor at Boston Children's Hospital 
Harvard Medical School, and president-elect of the 
International Society for Stem Cell Research. My research is 
focused on using embryonic stem cells and adult stem cells to 
develop new treatments for leukemia and genetic diseases of the 
blood, like sickle cell anemia.
    I am also clinically active at the Children's Hospital, 
where I see first hand the pain and suffering inflicted by 
these conditions on children and their families. My career is 
dedicated to making a difference in their lives through 
research and patient care.
    I am here today to state my strong support for Senate 
passage of the Specter-Harkin version of H.R. 810, which has 
already passed the House of Representatives with broad 
bipartisan support. H.R. 810 would ensure that scientists can 
use Federal grant funds to study the wide range of valuable 
human embryonic stem cells that have been created since August 
9, 2001, the date that President Bush announced his restrictive 
stem cell research policy.
    H.R. 810 would expand research opportunities and accelerate 
progress towards newer and better therapies for the many 
children that currently not treat successfully. I am also here 
to give scientific perspective on several proposed alternatives 
for deriving human pluripotent stem cells that have been 
considered recently by the President's Council on Bioethics, 
and which are the subject of this hearing today.
    I want to state at the outset that I support efforts to 
derive pluripotent cells by methods that would be ethically 
acceptable to all but I do not support delaying the pursuit of 
medical research on existing human ESL cell lines while these 
more speculative methods are tested. I believe that Senate 
passage of H.R. 810 is the surest means of supporting stem cell 
research at this juncture.
    First, let me illustrate how human embryonic stem cells 
offer unique opportunities for research and create an 
imperative that the Federal Government provides expanded 
support. Critics of embryonic stem cell research are fond of 
saying that adult stem cells have been used to cure dozens of 
diseases while embryonic stem cells have helped no one.
    I would like to challenge this claim. In essentially all 
cases of adult stem cell therapy, we are really talking about 
transplanting blood stem cells to treat leukemia, lymphoma, and 
genetic disease. Although bone marrow transplant has cured many 
lives, this form of adult stem cell therapy is not a certain 
cure. Even after many decades of clinical experience, bone 
marrow transplant remains an aggressive and toxic therapy that 
carries the highest mortality rate of any medical procedure 
that is routinely performed.
    Indeed, I have cared for many patients who have died during 
this treatment. All of us working in hematology today agree 
that additional research is required. My laboratory is studying 
human embryonic stem cells in hopes of making blood stem cell 
transplants safer and more widely applicable. A critical part 
of this strategy is using somatic cell nuclear transfer that 
generates stem cells that are customized to the specific 
patients I mentioned earlier, kids with leukemia, immune 
deficiency, and sickle cell anemia.
    We hope to correct the genetic defects in these patients, 
direct their differentiation of the cells into blood, and 
transplant kids with the genetically matched otology cells. 
This strategy is working in mice and we are eager to translate 
the work into humans but the current Federal funding policies 
have held us back.
    Although it is true that no one to date has been treated 
with cellular therapies based on human embryonic stem cells, I 
can assure you that mouse embryonic stem cells have had a major 
impact on medical research. Over the past 25 years, mouse 
embryonic stem cells have been used to create models for scores 
of human diseases including cancer, heart disease, obesity, and 
Alzheimer's.
    Research discoveries based on these models have lead to new 
drug development and, therefore, touched countless lives. As 
for the criticism that no one has been cured with embryonic 
stem cells, the field of human ESL research is a mere 7 years 
old, so it is premature to expect successful cell therapies to 
have already been delivered.
    I believe it is only a matter of time before human ESLs are 
used in drug development research and become the basis for 
important new drug therapies and cell therapies in a wide array 
of diseases.
    As further evidence of how human ESLs enable unique 
opportunities to study disease, consider research on Fanconi's 
anemia. Kids with Fanconi's anemia suffer bone marrow failure 
and often develop leukemia. Scientists have tried to model this 
disease in mice but the mice did not develop critical features 
of the human disease.
    Recently, a team from the Reproductive Genetics Institute 
of Chicago isolated a human ESL line that carries a Fanconi's 
mutation and would enable us to study the uniquely human 
aspects of this disease. However, because of the current 
presidential policy, we cannot study these cells. To date, we 
have been unable to generate a Fanconi's model using 
presidential cell lines, and by this direct example, the 
President's policy is hindering our research.
    Let me now turn to the several new proposals for making 
pluripotent ESLs that are designed to avoid the destruction of 
a human embryo. I want to point out that these so-called 
alternatives are not true alternatives, as they currently 
represent only speculative ideas for research that might or 
might not yield new stem cell lines and are fraught with their 
own ethical problems.
    In most of these cases, the experiments needed to establish 
feasibility of these proposals would require research on human 
embryos, which would currently be prohibited under the Federal 
law by the Dickey amendment. Far preferable to spending limited 
research dollars on these speculative proposals, in my opinion, 
is support for research on additional embryonic stem cell lines 
that are available today, lines that are similar to those 
already approved under the Bush policy.
    Senate passage of H.R. 810 would advance research that we 
know works, research where the ethical dilemmas have been 
understood and accepted by most.
    Now among the speculative methods under discussion, the 
first involves extracting stem cells from embryos that are 
considered dead, because they have stopped dividing and will 
not develop further. If individual cells remain alive, they 
might be used to initiate stem cell lines.
    The President's Council has found this strategy ethically 
sound and scientifically feasible, and so endorsed it. However, 
everything I know about deriving stem cells, tells me that to 
generate pluripotent cells from these defective embryos is 
likely to be far less efficient than IBF embryos. Even if cell 
lines can be generated, I imagine scientists will remain 
suspicious that they are abnormal and have questionable 
clinical utility.
    Senator Specter. Dr. Daley, do you have much more of your 
prepared statement?
    Dr. Daley. I just have about a minute more.
    Senator Specter. Proceed, then.
    Dr. Daley. The second method derives from pre-implantation 
genetic diagnosis, which we have already heard about. However, 
the biopsy procedure raises all sorts of ethical concerns and 
has, indeed, been dismissed as unacceptable during the initial 
inquiries of the council. Additionally, these first two methods 
did not produce genetically matched embryonic stem cells for 
patients.
    This third method we will hear about from Dr. Hurlbut 
involves altered nuclear transfer. Such a strategy is 
technically feasible but in a piece written for the New England 
Journal of Medicine, my colleagues and I have rejected the 
concept as flawed.
    Let me quickly summarize by saying that I do support the 
fourth speculative proposal, which is to derive pluripotent 
cells via direct de-differentiation of somatic cells to an 
embryonic stem cell life state, using chemical treatments or 
cell culture manipulation alone.
    The President's Council found merit in this proposal but 
also raised the technically thorny issue of how to rule out 
whether a totipotent and, therefore, morally significant cell 
might be created by this procedure. In my view, the last two 
proposals, altered nuclear transfer and de-differentiation, 
raise a curious and challenging question. Can we assign moral 
value to a human cell; say a reprogrammed skin cell, based 
solely on its particular pattern of gene expression? Can 
humanity really be diagnosed in a single cell?
    Finally, let me summarize that science cannot define when 
in the gradual course of human development we have deserved to 
be accorded individual and autonomous rights. I do not agree 
with the premise that the single cell zygote or any cell like 
it produced by nuclear transfer should be given the same 
considerations as living persons, and I do not view the embryo 
live in a practical world of choices, a world in which disease 
is a grim reality. Unless we want to turn back the clock and 
outlaw in vitro fertilization, then we as a society have 
already accepted that many more embryos are created than will 
ever become children.

                           PREPARED STATEMENT

    I feel it is morally justified for patients to derive 
benefit from these embryos through medical research instead of 
relegating them to medical waste. Unless we are willing to 
argue the biological absurdity that our humanity can be reduced 
to a particular signature of gene expression, that exists when 
we reprogram skin cells through nuclear transfer, then we must 
support embryonic stem cell research in all its forms, which 
are vitally important and available to medical researchers 
today.
    [The statement follows:]
                 Prepared Statement of George Q. Daley
    Senator Specter, members of the Committee, thank you for inviting 
me to testify before you. My name is George Daley. I am here today 
representing the American Society for Cell Biology, a professional 
society of nearly 12,000 basic biomedical researchers in the United 
States and 50 nations around the world. I am Associate Professor of 
Pediatrics and Biological Chemistry at Boston Children's Hospital and 
Harvard Medical School, the Associate Director of the Stem Cell Program 
at Children's Hospital, a member of the Executive Committee of the 
Harvard Stem Cell Institute, and Board Member and President-elect of 
the International Society for Stem Cell Research (term to begin June 
2007). My research is focused on using embryonic stem cells and adult 
stem cells to study blood development, and to develop new treatments 
for leukemia, and genetic diseases like immune deficiency, sickle cell 
anemia, thalassemia, and Fanconi's anemia. I am also clinically active 
as a hematologist at Children's Hospital, where I see first-hand the 
pain and suffering inflicted by these diseases on children and their 
families. My career is dedicated to making a difference in their lives 
through research and patient care.
    I am here today to state my strong support for Senate passage of 
H.R. 810, which has already passed the House of Representatives by an 
impressive and bipartisan margin. H.R. 810 would ensure that scientists 
can use Federal grant funds to study the wide range of valuable human 
embryonic stem cell lines that have been created since August 9, 2001, 
the date that President Bush announced his restrictive stem cell 
research policy. H.R. 810 would expand research opportunities and 
accelerate progress towards newer and better therapies for the many 
children I currently cannot treat successfully.
    I am also here to give scientific perspective on the several 
additional strategies proposed for deriving human pluripotent stem 
cells that have been considered recently by the President's Council on 
Bioethics, and which are the subject of this hearing today. I want to 
state at the outset that I support efforts to derive pluripotent stem 
cells by methods that would be ethically acceptable to all, but I do 
not support delaying the pursuit of medical research on existing human 
embryonic stem cell lines while these more speculative methods are 
tested. I believe that Senate passage of H.R. 810 is the surest means 
of supporting stem cell research at this juncture.
    First let me emphasize why research on human embryonic stem cells 
is so vitally important, and why alternative forms of adult stem cell 
research cannot substitute for the study of embryonic stem cells.
    Critics of embryonic stem cell research are fond of saying that 
adult stem cells have been used to cure dozens of diseases while 
embryonic stem cells have helped no one. I would like to examine that 
claim. In essentially all cases adult stem cell therapy really means 
transplantation of blood stem cells to treat leukemia, lymphoma, and 
various genetic diseases of the blood. Although bone marrow transplants 
have saved many lives, bone marrow transplant is never a certain cure. 
Even after many decades of clinical experience, bone marrow transplant 
remains an aggressive and toxic therapy that carries the highest 
mortality rate of any medical procedure that is routinely performed. 
For patients whose only bone marrow match is from unrelated donors 
outside the family, the treatment itself claims the lives of 30 
percent of patients in the first year. Indeed, I have cared for many 
patients who have died during treatment. All of us working in 
hematology today agree that additional research is needed.
    My laboratory is studying embryonic stem cells in hopes of making 
blood stem cell transplants safer and more widely applicable. A 
critical part of the strategy is using somatic cell nuclear transfer to 
generate stem cells that are customized to the specific patients I 
mentioned earlier, kids with leukemia, immune deficiency, and sickle 
cell anemia. We hope to correct the genetic defects in these patient-
specific cells, direct their differentiation into blood, and transplant 
kids with these genetically matched autologous cells. This strategy is 
already working in mice, and we are eager to translate this work into 
humans. The current Federal funding policies have held us back.
    Although it is true that no one has to date been treated with 
cellular therapies based on human embryonic stem cells, I can assure 
you that mouse embryonic stem cells have had a major impact on medical 
research. Over the past 25 years, mouse embryonic stem cells have been 
used to create models for scores of human diseases, including cancer, 
heart disease, obesity, and Alzheimer's. Research discoveries based on 
these models has led to new drug development and therefore touched 
countless lives. As for the criticism that no one has been cured with 
embryonic stem cells, the field of human embryonic stem cell research 
is a mere 7 years old, so it is premature to expect successful cell 
therapies to have already been delivered to patients. I believe it is 
only a matter of time before human embryonic stem cells are used in 
drug development research and become the basis for important new cell 
therapies.
    As further evidence of how human embryonic stem cells enable unique 
opportunities to study disease, consider research on Fanconi's anemia. 
Kids with Fanconi's anemia suffer bone marrow failure, and often 
develop leukemia. Scientists have tried to model this disease in mice, 
but the mice do not develop bone marrow failure, and the adult blood 
stem cells from Fanconi's patients cannot be maintained in culture. 
Recently, a team from the Reproductive Genetics Institute of Chicago 
isolated a human embryonic stem cell line that carries a Fanconi's gene 
mutation. This cell line could enable us to study the uniquely human 
aspects of Fanconi's anemia. However, because of the current 
Presidential policy, we cannot study these cells with our Federal grant 
dollars. Thus my lab has been left to attempt to generate a Fanconi's 
model in one of our Presidential stem cell lines, which has proven to 
be far more cumbersome than simply obtaining the cells from Chicago. To 
date, we have not succeeded. By this direct example, the President's 
policy is hindering our research on this terrible childhood disease. 
Senate passage of H.R. 810 would make available Federal funds to 
perform this important medical research. [I have written about the 
``missed opportunities'' for human embryonic stem cell research under 
the current Presidential policies, and wish to introduce this article 
into the record.\1\]
---------------------------------------------------------------------------
    \1\ Daley, G.Q. Missed opportunities in embryonic stem-cell 
research. N Engl J Med 351, 627-8 (2004).
---------------------------------------------------------------------------
    Let me now turn to the several proposed new methods for making 
pluripotent human stem cells that are designed to avoid the destruction 
of a human embryo. These so-called ``alternatives'' are not TRUE 
alternatives, as they currently represent only speculative proposals 
for research that might yield new stem cell lines, and are fraught with 
their own ethical problems. In most of these cases, the experiments 
needed to establish feasibility of these proposals would require 
research on human embryos, and thus would be prohibited under current 
Federal law by the Dickey amendment. Far preferable to spending limited 
research dollars on these speculative proposals, in my opinion, is 
support for research on additional embryonic stem cell lines that are 
available today--lines that are similar to those already approved under 
the Bush policy. Senate passage of H.R. 810 would advance research that 
we know works, research where the ethical dilemmas have been understood 
and accepted by most.
    Among the speculative methods under discussion, the first involves 
extracting stem cells from embryos that could be considered ``dead'', 
because they have stopped dividing and will not develop further. If 
individual cells remain alive (and hopefully normal), they might be 
used to initiate lines of stem cells. The President's Council found 
this strategy ethically sound and scientifically feasible and so 
endorsed it. However, I anticipate that attempts to generate 
pluripotent cells from these defective embryos will be far less 
efficient than from excess IVF embryos. Even if cell lines can be 
generated, I imagine scientists will remain suspicious that they are 
abnormal and might lead to erroneous conclusions in research.
    The second speculative method derives from pre-implantation genetic 
diagnosis, or PGD, in which one or two cells are removed from an early 
embryo and analyzed to diagnose serious inherited diseases like Sickle 
Cell Anemia. PGD insures that only embryos found free of gene defects 
are transferred to the woman so that she may have a healthy child. The 
suggestion has been made that biopsied cells might be used to produce 
pluripotent stem cell lines, and this would be ethically acceptable if 
the embryo remained unharmed. Dr. Lanza is here to represent his as yet 
unpublished success in using this strategy to produce pluripotent stem 
cell lines from mouse embryos. However, the biopsy procedure raises all 
sorts of ethical concerns and indeed has been dismissed as unacceptable 
during the initial inquiries of the President's Council. [Those who 
equate the zygote to a human being would reject the use of embryo 
biopsy because it removes cells at a stage when they might be 
considered developmentally equivalent to the zygote--that is, 
totipotent. Removing a totipotent blastomere is then the moral 
equivalent of producing a twin, which, in the view of opponents of 
embryonic stem cell research could not then be sacrificed for research. 
Embryo biopsy for stem cell research entails risks to embryos that are 
wanted for making a baby, rather than destined to be discarded as 
medical waste. If my wife and I carried a genetic disease we would 
accept the risk of the embryo biopsy procedure to insure we could have 
the healthiest child possible, but if we were simply infertile and 
using IVF to assist us in reproduction, we would not consent to having 
our healthy embryos biopsied; we would chose instead to donate our 
excess embryos to stem cell research. Dr. Lanza may suggest that lines 
be derived only from embryos already being biopsied for PGD, but the 
more cells one biopsies to accommodate both PGD and stem cell 
derivations, the greater the risk for embryo loss. As a practical and 
scientific matter, embryo biopsy for derivation of pluripotent cell 
lines is an unacceptable option.]
    The third speculative method involves deriving pluripotent stem 
cells from something the President's Council has termed ``biological 
artifacts''. The best described of this procedure is called ``Altered 
Nuclear Transfer'', which entails introducing a genetic defect into a 
somatic donor cell prior to nuclear transfer, so that a disordered 
embryo results that can be a source of pluripotent stem cells but 
cannot develop into a human. According to Dr. Hurlbut, the method's 
chief proponent, what is produced would ``lack the essential attributes 
and capacities of a human embryo'', a biological artifact whose 
destruction to produce pluripotent stem cells would be ethically 
justified. Such a strategy is technically feasible but in a piece 
written for the New England Journal of Medicine, my colleagues and I 
have rejected this concept as flawed.\2\ In reasoning echoed by the 
President's Council, we questioned whether the planned creation of what 
amounts to a defective embryo would silence ethical objections.
---------------------------------------------------------------------------
    \2\  Melton, D.A., Daley, G.Q. & Jennings, C.G. Altered nuclear 
transfer in stem-cell research--a flawed proposal. N Engl J Med 351, 
2791-2 (2004).
---------------------------------------------------------------------------
    A more recent proposal put forth by Markus Grompe is a variation on 
Altered Nuclear Transfer called Oocyte Assisted Reprogramming, (OAR). 
Grompe also suggests altering the input somatic cell so as to preclude 
formation of a viable human embryo. He proposes using a gene like 
nanog, which might promote reprogramming of the donor somatic cell 
directly to something that resembles an embryonic stem cell, which is 
pluripotent, and avoids generating a cell like a zygote, which is 
totipotent--that is, able to divide on its own and form a viable human 
blastocyst. Scientifically, this idea is a reasonable hypothesis that 
must be tested and might or might not work. But even if this strategy 
works in mice, there is no guarantee it will work in humans, and 
verification would then require the creation and destruction of many 
manipulated human embryos, which might or might not have the altered 
characteristics that would make this method ethically ``acceptable''. 
If it works, I am concerned that in order to use Federal dollars for 
research US Scientists will be relegated to less-efficient processes 
like Altered Nuclear Transfer, while Korean scientists employ superior 
techniques.
    The fourth speculative approach is to derive pluripotent cells via 
direct de-differentiation of somatic cells to an embryonic stem cell-
like state using chemical treatments or cell culture manipulation 
alone. The President's Council found merit in this fourth proposal, but 
also raised the technically thorny issue of how to rule out whether a 
totipotent and therefore morally significant cell might be created by 
this procedure. In my view, these last two proposals raise a curious 
and challenging question: can we distinguish the moral value of a human 
cell based on its particular gene expression pattern? Can humanity 
really be diagnosed at the level of a single cell?
    From my view, this last approach has scientific merit. We know 
cellular de-differentiation is possible; indeed, that is precisely what 
we do when we perform somatic cell nuclear transfer and reprogram a 
somatic cell back to a zygote. The Federal Government is already 
funding research into such cellular reprogramming. Indeed, last year I 
was one of nine recipients of the inaugural Pioneer Award from the 
Director of the National Institutes of Health to support highly 
innovative (that is, speculative) research of exactly this type. 
Although this strategy is worth pursuing, it is extremely high-risk, 
and may take years to perfect, and may never work as well as nuclear 
transfer, which we know we can practice today.
    Research on each of these proposed strategies is at present 
untested in human cells, but if judged to be meritorious by the peer 
review process, should be funded. However, the already proven routes to 
obtaining embryonic stem cells from excess IVF embryos or through the 
use of somatic cell nuclear transfer should not be put on hold pending 
the outcomes of the more speculative methods.
    Finally, let me emphasize that research on embryonic stem cells and 
embryo research in general is not solely about making tissues for 
transplantation to treat disease. Although the promise of new therapies 
is perhaps the most compelling reason to support expanded access to 
embryonic stem cells for research, I stress that it is equally 
important to pursue research that addresses fundamental questions about 
the earliest stages of human development. We know that a variety of 
birth defects can be traced to abnormal cell divisions during the first 
few days of life, and that infertility and miscarriage can also be 
traced to defects in the early embryo. We cannot learn everything there 
is to learn about these human disease conditions from studying animals. 
We must study the unique aspects of human embryo biology directly, and 
the Federal government should support this vitally important basic 
research.
    Science certainly cannot define when in the gradual course of human 
development we deserve individual and autonomous rights. I do not agree 
with the premise that the single celled zygote should be given the same 
considerations as living persons and I do not view the embryo as a 
human being, particularly when it is frozen in a freezer. As a 
physician and as a scientist and as a father I live in a practical 
world of choices, and a world in which disease is a grim reality. 
Unless we want to turn back the clock, and outlaw in vitro 
fertilization, then we as a society have already accepted that many 
more embryos are created than will ever become children. I feel it is 
morally justified to derive benefit from these embryos through medical 
research instead of relegating them to medical waste. And unless we are 
willing to argue the biological absurdity that our humanity can be 
defined by a particular signature of gene expression that exists in the 
totipotent cells of the early human embryo, then we must support the 
vitally important applications of embryonic stem cells to medical 
research.

    Senator Specter. Thank you very much, Dr. Daley.
    Our final witness on this panel is Dr. William Hurlbut, 
physician and consulting professor of the program in human 
biology at Stanford. After receiving his undergraduate and 
medical training at Stanford, he completed post-doctoral 
studies in theology and medical ethics. In addition to teaching 
at Stanford, he currently serves on the President's Council on 
Bioethics.
    Thank you for coming to Washington today, Dr. Hurlbut and 
the floor is yours.
STATEMENT OF WILLIAM B. HURLBUT, M.D., PROGRAM IN HUMAN 
            BIOLOGY, STANFORD UNIVERSITY
    Dr. Hurlbut. Thank you. It is an honor to be here. I want 
to say that I speak for myself, not for the President's Council 
as a whole. I want to say from the onset that I agree with 
Senator Specter on the moral imperative of biomedical research 
and the scandal of priorities in our consumer culture.
    It is clear to me that both sides of this difficult debate 
are defending important human goods, and both of these goods 
opening avenues for advance in biomedical science and 
preserving the fundamental moral principles on which our 
society is based are important to all of us.
    In 1999, President Clinton's National Bioethics Advisory 
Commission issued a report entitled, ``Ethical Issues in Human 
Stem Cell Research,'' acknowledging that a week-old human 
embryo is a form of human life that deserves respect. The 
Commission stated, ``In our judgment, the derivation of stem 
cells from embryos remaining following infertility treatments 
is justifiable only if no less morally problematic alternatives 
are available for advancing the research.''
    Two months ago, the President's Council on Bioethics issued 
a white paper, entitled, ``Alternative Sources of Pluripotent 
Stem Cells,'' which discusses such less morally problematic 
alternatives. After analyzing the scientific feasibility, 
practicality, and moral acceptability of a range of approaches, 
the Council endorsed for preliminary animal studies three 
proposals for the production of pluripotent stem cells, the 
functional equivalents of embryonic stem cells.
    One of these proposals, altered nuclear transfer, is a 
broad concept with a range of possible approaches worthy of 
exploration. Altered nuclear transfer would draw on the basic 
techniques of somatic cell nuclear transfer, popularly known as 
therapeutic cloning, but with an alteration, such that 
pluripotent cells are produced without the creation and 
destruction of human embryos.
    In standard nuclear transfer, the cell nucleus is removed 
from an adult body cell and then transferred into an egg cell 
that first has its own nucleus removed. The egg then has a full 
set of DNA, after the somatic cell nucleus is put into it, and 
then after electrical stimulation starts to divide like a 
naturally fertilized egg. This, of course, is how Dolly the 
sheep was produced. Altered nuclear transfer, used as the 
technology of nuclear transfer but with a preemptive alteration 
that assures that no embryo is created.
    The adult body cell nucleuses, or the cytoplasm of the egg, 
that is the egg contents, or both, are first altered before the 
adult body cell nucleus is transferred into the egg. The 
alterations caused the adult body cell DNA to function in such 
a way that no embryo is generated but pluripotent stem cells 
are produced.
    There may be many ways altered nuclear transfer can be used 
to accomplish this same end. One recent variation on this 
proposal, called oocyte assisted reprogramming, has been put 
forward by Markus Grompe, Director of the Stem Cell Center at 
Oregon Health Sciences University. In this variation of altered 
nuclear transfer, alterations of the nucleus of the adult body 
cell and the enucleated egg's contents before nuclear transfer 
would force early expression of genes characteristic of a later 
and more specialized cell type that is capable of producing 
pluripotent stem cells. Such a creation from its very beginning 
would never have the actual configuration or potential for 
development that characterizes a human embryo, and would, 
therefore, not have the moral standing of a human being.
    As described in a recent op-ed in the Wall Street Journal, 
and documented in a joint statement posted at the Ethics and 
Public Policy Center web site, this proposal has drawn 
encouragement from leading scientists and wide endorsement from 
moral philosophers and religious authorities.
    Altered nuclear transfer, in its many variations, could 
provide a uniquely flexible tool and has many positive 
advantages that would help advance embryonic stem cell 
research. Unlike the use of embryos from IDF clinics, altered 
nuclear transfer would produce an unlimited range of genetic 
types for the study of disease, drug testing, and possibly 
generation of therapeutically useful cells.
    By allowing controlled and reproducible experiments, 
altered nuclear transfer would provide a tool for a wide range 
of useful studies of gene expression, imprinting, and inter-
cellular communication. Furthermore, the basic research 
essential to establishing the technique would advance our 
understanding of developmental biology and might serve as a 
bridge to transcendent technologies, such as direct 
reprogramming of adult cells.
    Moreover, as a direct laboratory technique, altered nuclear 
transfer with unburdened embryonic stem cell research from the 
additional ethical concerns of the so-called leftover IBF 
embryos, including the attendant clinical and legal 
complexities in this realm of great personal and social 
sensitivity.
    I have discussed this proposal with leading molecular and 
cell biologists, and the general response is that altered 
nuclear transfer is technically feasible, might be rapidly 
developed. Most scientists agree that in 12 to 24 months we 
would have a very good idea and maybe get there. Furthermore, 
this technique would not burden stem cell research with 
excessive costs or inconvenience.
    The present conflict over the moral status of the human 
embryo reflects deep differences in our basic convictions and 
is unlikely to be resolved through deliberation or debate. Yet 
a purely political solution will leave our country bitterly 
divided, eroding the social support and sense of noble purpose 
that is essential for the public funding of biomedical science.
    In offering a third option, altered nuclear transfer, 
defines with clarity and precision the boundaries that our 
moral principles are seeking to preserve while opening fully 
the promising possibilities of embryonic stem cell research.
    Senator Specter. Dr. Hurlbut, are you about finished with 
your opening statement?
    Dr. Hurlbut. About 30 seconds.
    Senator Specter. Fine.
    Dr. Hurlbut. As described by my colleagues, altered nuclear 
transfer is just one of a range of hopeful proposals. Specific 
legislation to support exploration and development of these 
complementary ways of obtaining pluripotent stem cells would 
greatly encourage this research. I want to say, I would favor a 
stand-alone bill, unencumbered.
    As we enter the coming era of rapid advance in 
biotechnology, this kind of legislation would set a positive 
precedent for maintaining constructive ethical dialogue and 
encouraging creative use of our scientific knowledge. In 
recognizing the important values being defended by both sides 
of our difficult national debate over embryonic stem cell 
research, this approach could open positive prospects for 
scientific advance while honoring the diversity of opinions 
concerning our most fundamental moral principles. Such a 
solution is in keeping with the American spirit and would be a 
triumph for our Nation as a whole.
    [The articles follow:]

[Perspective in Biology and Medicine, volume 48, number 2 (spring 2005) 
                 by the Johns Hopkins University Press]

    Altered Nuclear Transfer as a Morally Acceptable Means for the 
               Procurement of Human Embryonic Stem Cells

                        (By William B. Hurlbut)

    With the sequencing of the human genome and our increasing 
knowledge of the molecular mechanisms of basic cell functions, we are 
entering an era of rapid advance in the field of developmental biology. 
Current scientific interest in embryonic stem cells is a logical step 
in the progress of these studies and holds the hope of providing 
important research tools as well as possible therapeutic applications.
    The ethical controversy surrounding cloning for biomedical research 
(CBR) \1\ and human embryonic stem cell (ES cell) research arises from 
the fact that to obtain these cells living human embryos must be 
disaggregated and destroyed. Many Americans oppose such embryo 
destruction, believing that there is an implicit dignity and 
inviolability in the individual continuity of a human life from 
fertilization to natural death. Many others, however, believe that the 
benefits of advances in biomedical science outweigh these moral 
concerns.
---------------------------------------------------------------------------
    \1\ Also termed therapeutic cloning, somatic cell nuclear transfer, 
or nuclear transfer for the procurement of ES cells. For the difficulty 
of terminology, see President's Council 2002, chap. 3.
---------------------------------------------------------------------------
    The present conflict over the moral status of the human embryo 
reflects deep differences in our basic convictions and is unlikely to 
be resolved through deliberation or debate. Likewise, a purely 
political solution will leave our country bitterly divided, eroding the 
social support and sense of noble purpose that is essential for the 
public funding of biomedical science. These concerns are already 
encoded in the Dickey Amendment, which prohibits the use of federal 
funds for embryo-destructive research and is the legislative foundation 
of the President's executive order restricting funding to ES cell lines 
created before August 9, 2001 (President's Council 2004, chap. 2). 
While there are currently no federally legislated constraints on the 
use of private funds for this research, there is a consensus in the 
scientific community that without NIH support for newly created ES cell 
lines, progress in this important realm of research will be severely 
constrained.
    In joining with fellow members of the President's Council on 
Bioethics in support of a moratorium on CBR in July 2002, I considered 
this recommendation not an admission of ambivalence on matters of 
policy, but a recognition of the difficulty of the moral issues 
involved and an affirmation of the need for further discussion and 
deliberation (President's Council 2002). Throughout our proceedings 
over the past three years, it has become increasingly apparent that 
without clear and distinct moral principles, grounded in scientific 
evidence and reasoned moral argument, no policy can be effectively 
formulated or enforced. Most specifically, the proposed limitation of 
14 days for research on human embryos and the prohibition against 
implantation appear to be arbitrarily set and therefore vulnerable to 
transgression through the persuasive promise of further scientific 
benefit. Clearly, a more thorough and thoughtful consideration of the 
moral status of the human embryo is warranted. It is in the spirit of 
this continuing discussion that I offer the personal perspectives that 
follow.
    As our science is changing, so is the nature of our moral dilemmas. 
Each advance forces us to think more deeply about what it means to be 
human. As the scientific focus on genomics moves on to proteomics and 
now to the early stages of the study of development, we are confronted 
with the challenge of understanding the moral meaning of human life in 
its dynamics of change, as both potential and process. Concerns about 
cloning are likely to be just the beginning of a series of difficult 
ethical issues related to embryo experimentation and medical 
intervention in developing life. In addition, advances in developmental 
biology will open more deeply the ethical dilemmas of human-animal 
hybridization, extra-corporeal gestation, and genetic and cellular 
enhancement. Driven by the vast range of research applications and 
opportunities for clinical interventions in disease and disability 
(especially the open-ended possibilities promised by regenerative 
medicine), this technology will be powerfully propelled into the 
forefront of medical science.
    Given the complex course of science and the drive to its 
development, any moral assessment of CBR or human ES cell research must 
describe the central human goods it seeks to preserve, the range and 
boundaries of these values, and the broad implications for science and 
society. Such an assessment should serve the dual purpose of helping to 
define the moral dangers while clearing the course for the fullest and 
most open future for scientific investigation and application.
                            moral principles
    Although there are already numerous promising approaches for 
research on human development even without cloning techniques, I 
believe this technology could provide valuable tools for scientific 
inquiry and medical advance. In my judgment, the moral imperative to 
foster an increase of knowledge and new modes of therapeutic 
intervention weighs heavily in the equation of consideration. 
Nonetheless, I believe that, as they stand, current proposals for CBR 
and human ES cell procurement will breach fundamental moral goods, 
erode social cohesion, and ultimately constrain the promise of advances 
in developmental biology and their medical applications. However, there 
may be morally acceptable ways to produce ES cells through nuclear 
transfer (the technique used for CBR) that could both preserve our 
commitment to our fundamental moral principles and strengthen our 
appreciation of the significance of developing life. Such a technique 
would sustain social consensus while opening positive prospects for 
scientific advance in ES cell research.
    The principle of valuing human life as the fundamental good serves 
as the cornerstone of law for our civilization. In no circumstance is 
the intentional destruction of the life of an innocent individual 
deemed morally acceptable. Even where a right to abortion is given, for 
example, it is based on a woman's right not to be encumbered--a right 
of privacy, not a right to directly kill the fetus--and if the fetus is 
delivered alive during an abortion, there is a legal obligation to 
resuscitate and sustain its life. This valuing of human life is indeed 
the moral starting point for both advocates and opponents of CBR. The 
principle of the inviolability of human life is the reciprocal respect 
that we naturally grant as we recognize in the other a being of moral 
equivalence to ourselves. Although different cultures and eras have 
affirmed this recognition in varied ways, I will argue that it is 
reasonable in light of our current scientific knowledge that we extend 
this principle to human life in its earliest developmental stages.
                            life as process
    When looked at through the lens of science, it is evident that an 
individual human life cannot be described atemporally, but must be 
recognized in the full procession of continuity and change that is 
essential for its development. From conception, our unique genetic 
endowment organizes and guides the expression of our particular nature 
in its species and individual character. Fertilization initiates the 
complex integration and functional unity of a self-directing, 
developing organism that may live for a hundred years or more. In both 
character and conduct, the zygote and subsequent embryonic stages 
differ from any other cells or tissues of the body; they contain within 
themselves the organizing principle of the full human organism.
    This is not an abstract or hypothetical potential in the sense of 
mere possibility, but rather a potency, an engaged and effective 
potential-in-process, an activated dynamic of development in the 
direction of human fullness of being. For this reason, a zygote (or a 
clonote) differs fundamentally from an unfertilized egg, a sperm cell, 
or later somatic cells: it possesses an inherent organismal unity and 
potency that such other cells lack. Unlike an assembly of parts in 
which a manufactured product is in no sense ``present'' until there is 
a completed construction, a living being has a continuous unfolding 
existence that is inseparable from its emerging form. The form is 
itself a dynamic process rather than a static structure. In biology, 
the whole (as the unified organismal principle of growth) precedes and 
produces the parts. It is this implicit whole, with its inherent 
potency, that endows the embryo with its human character and therefore 
its inviolable moral status. To interfere in its development is to 
transgress upon a life in process. The argument is sometimes made that 
potential should not be part of the moral equation, because of the low 
probability of successful development of the early embryo.\2\ This, 
however, is itself an argument based on potential, in this case the 
lack of potential to develop normally. The fact that life in its early 
stages is extremely fragile and often fails is not an argument to 
lessen the moral standing of the embryo. Vulnerability does not render 
a life less valuable.
---------------------------------------------------------------------------
    \2\ The argument based on probability fails because it does not 
acknowledge the continuity of essential nature that characterizes an 
organism across its various stages of development. Such an argument 
might hold some weight if one could argue that a given stage of 
development represents an emergent state in which a newly manifest 
property is in ontological discontinuity with the material from which 
it emerged. At first consideration, this seems true of all biological 
systems where the whole reveals properties unpredicted within the 
parts. The problem in this line of reasoning, however, is that these 
properties are exactly that to which the whole is ordered, and so are 
inherent powers, ``actual'' within the whole when seen across time. To 
know what a biological being is, we must observe it over time, 
understand it across its life span. It is the essence of life that it 
is ordered to employ these leaps to emergent states as an agency in 
development. New realities will emerge; this is established in the 
potency of the developing organism.
---------------------------------------------------------------------------
                          accrued moral status
    The major alternative to the view that an embryo has an inherent 
moral status is the assertion that moral status is an accrued or 
accumulated quality related to some dimension of form or function. 
Several arguments have been put forward for this position.
Gastrulation
    One such accrual argument is based on the idea that before 
gastrulation (designated as the 14th day), the embryo is an inchoate 
clump of cells with no actuated drive in the direction of distinct 
development.\3\ It is argued that the undifferentiated quality of the 
blastocyst justifies its disaggregation for the procurement of stem 
cells, while the evident organization at gastrulation reveals an 
organismal integrity that endows inviolable moral status to all 
subsequent stages of embryological development. Scientific evidence, 
however, supports the argument that from conception there is an 
unbroken continuity in the differentiation and organization of the 
emerging individual life. The anterior-posterior axis appears to be 
already specified within the zygote, and early cell divisions (at least 
after the eight-cell stage) exhibit differential gene expression and 
unequal cytoplasmic concentrations of cell constituents, suggesting 
distinct cellular fates (Gardner 2001; Grabel et al. 1998; Piotrowska 
and Zernicka-Goetz 2001).This implies that the changes at gastrulation 
do not represent a discontinuity of ontological significance, but 
merely the visibly evident culmination of more subtle developmental 
processes (at the cellular level) driving in the direction of 
organismal maturity.
---------------------------------------------------------------------------
    \3\ The differentiation of the trophoblast, which is evident by day 
four, is sometimes considered as distinct from the embryo itself. 
However, in light of current scientific evidence, it should be 
recognized as an inextricable component of the embryo, involved in a 
multitude of dynamic interactions essential for embryogenesis. The fact 
that it participates in the formation of the extra-embryonic membranes 
that are left behind at birth does not make it less central to the 
embryonic being and its development. Throughout the continuum of human 
life, cells, tissues, and organs are reabsorbed, transcended, and 
transformed: examples include the umbilical vein and arteries (which 
become supporting ligaments), neural cells (more than half of which are 
culled by apoptosis), and immune organs such as the thymus (which 
shrivels in an adult). We do not just develop and then age, but undergo 
a continuous transformation and fuller manifestation of our organismal 
nature present within the earliest embryo.
---------------------------------------------------------------------------
Twinning
    Another argument for accrued moral status is that as long as an 
embryo is capable of giving rise to a twin, it cannot be considered to 
have the moral standing of an individual. There is the obvious 
objection that as one locus of moral status becomes two, it does not 
diminish but increases the moral moment. But perhaps more 
substantially, this argument actually supports the notion that crucial 
dimensions of individuation (and their disruption that results in 
twinning) are already at work in the blastocyst, the stage at which 
most twinning occurs. Monozygotic twinning (a mere 0.4 percent of 
births) does not appear to be either an intrinsic drive or a random 
process within embryogenesis. Rather, it is a disruption of normal 
development by a mechanical or biochemical disturbance of fragile cell 
relationships that provokes a compensatory repair, but with the 
restitution of integrity within two distinct trajectories of 
embryological development (da Costa et al. 2001).\4\ In considering the 
implications of twinning for individuation, one might ask the question 
from the opposite perspective. What keeps each of these totipotent 
cells from becoming a full embryo? Clearly, crucial relational dynamics 
of position and intercellular communication are already at work 
establishing the unified pattern of the emerging individual (Wang et 
al. 2004). From this perspective, twinning is not evidence of the 
absence of an individual, but of an extraordinary power of compensatory 
repair that reflects more fully the potency of the individual drive to 
fullness of form.
---------------------------------------------------------------------------
    \4\ The fact that these early cells retain the ability to form a 
second embryo is testimony to the resiliency of self-regulation and 
compensation within early life, not the lack of individuation of the 
first embryo from which the second can be considered to have ``budded 
off.'' Evidence for this may be seen in the increased incidence of 
monozygotic twinning associated with IVF by blastocyst transfer. When 
IVF embryos are transferred to the uterus for implantation at the 
blastocyst stage, there is a two- to ten-fold increase in the rate of 
monozygotic twinning, apparently due to disruption of normal organismal 
integrity.
---------------------------------------------------------------------------
Implantation
    Some have argued that the implantation of the embryo within the 
uterine lining of the mother constitutes a moment of altered moral 
status. Implantation, however, is actually a process that extends from 
around the sixth or seventh day to about the 11th or 12th day, when the 
uteroplacental circulation is established. This complex circulatory 
exchange extends the earlier relationship between mother and embryo in 
which physiological conditions, including the diffusion of essential 
nutrients and growth factors, sustained the life and nourished the 
development of the pre-implantation embryo. Although these early 
conditions can be artificially simulated, as with in vitro 
fertilization (IVF), the delicate balance of essential factors and 
their effect on development is evidence of the crucial contribution of 
the mother even in the first week of embryogenesis (Fernandez-Gonzalez 
et al. 2004). Changes in the intricate interrelations between mother 
and infant cannot be viewed as an alteration of moral status, but as 
part of the ongoing epigenetic process all along the continuum of 
natural development that begins with conception and continues into 
infancy. This continuity implies no meaningful moral marker at 
implantation.
Function
    Arguments for a change in moral status based on function are at 
once the most difficult to refute and to defend. The first and most 
obvious problem is that the essential functions (even their minimal 
criteria and age of onset) are diverse and arbitrarily assigned. 
Generally they relate to the onset of sentience, awareness of pain, or 
some apparently unique human cognitive capability such as 
consciousness. But if human moral worth is based on actual manifest 
functions, then does more of a particular function give an individual 
life a higher moral value? And what are we to make of the parallel 
capacities in animals that we routinely sacrifice for food and medical 
research? Furthermore, what becomes of human moral status with the 
degeneration or disappearance of such a function? While we might argue 
that our relational obligations change along with changes in function, 
such as those that occur with senile dementia, we would not sanction a 
utilitarian calculus and the purely instrumental use of such persons no 
matter how promising the medical benefits might be. The diagnostic 
requirements of ``brain death'' for removing organs for 
transplantation, far from being a justification for interrupting a 
developing life before ``brain birth,'' actually point to the moral 
significance of potential and the stringency of the criteria for 
irreversible disintegration and death.
    From a scientific perspective, there is no meaningful moment when 
one can definitively designate the biological origins of a human 
characteristic such as consciousness. Even designations such as ``the 
nervous system'' are conceptual tools, reifications of the parts of 
what is actually an indivisible organismal unity. Zygote, morula, 
embryo, fetus, child, and adult: these are conceptual constructions for 
convenience of description, not distinct ontological categories. With 
respect to fundamental moral status, therefore, as distinguished from 
developing relational obligations, the human being is an embodied being 
whose intrinsic dignity is inseparable from its full procession of life 
and always present in its varied stages of emergence.
                      a bright line at conception
    If the embryo has an inherent moral status that is not an accrued 
or accumulated quality related to some dimension of form or function, 
then that moral status must begin with the zygote (or clonote). 
Anything short of affirming the inviolability of life across all of its 
stages from zygote to natural death leads to an instrumental view of 
human life. Such a revocation of our most fundamental moral principle 
would reverse a long and overarching trend of progress in moral 
awareness and practice in our civilization. From human sacrifice, to 
slavery, child labor, women's rights, and civil rights, we have 
progressively discerned and prohibited practices that subject the 
individual to the injustice of exploitation by others. The reversal of 
such a basic moral valuation will extend itself in a logic of 
justification that has ominous implications for our attitude and 
approach to human existence. This is not a mere ``slippery slope,'' 
where we are slowly led downward by the ever more desirable extension 
of exceptions to moral principle. It is, rather, a ``crumbly cliff,'' 
where the very utility of abrogating a basic moral prohibition carries 
such convenience of consequence that the subsequent descent is simply 
practice catching up with principle.
    The inviolability of human life is the essential foundation on 
which all other principles of justice are built, and erosion of this 
foundation destabilizes the social cooperation that makes possible the 
benefits of organized society. Medicine is especially vulnerable to 
such effects, since it operates at the intrinsically moral interface 
between scientific technique and the most tender and sensitive 
dimensions of personal reality in the vulnerable patient. As we descend 
into an instrumental use of human life, we destroy the very reason for 
which we were undertaking our new therapies; we degrade the humanity we 
are trying to heal.
    The promise of stem cells lies beyond simple cell cultures and cell 
replacement therapies. The 14-day marker will not hold up to logical 
argument.\5\ The technological goal is to produce more advanced 
tissues, organs, and possibly even limb primordia. Producing such 
tissues may require the complex cell interactions and microenvironments 
now available only through natural gestation. Embryonic development 
proceeds within the context of a highly refined spatial and temporal 
niche of organized complexity of positional cues, signal diffusion, and 
cell-cell contact between cellular lineages of diverse types (Nishimura 
et al. 2002).The benefits of implanting cloned embryos (either into the 
natural womb or possibly an artificial endometrium) so as to employ the 
developmental dynamics of natural embryogenesis seem self-evident. The 
implantation of cloned embryos for the production of patient-specific 
tissue types to bypass problems of immune rejection would further 
extend the logic of the instrumental use of developing life. The public 
pressure that has already been brought to bear on the politics of stem 
cells and cloning by patient advocacy groups has provoked such a sense 
of promise that it may propel the argument for allowing implantation of 
cloned embryos. Different people may have different limits to the 
duration of gestation they find morally acceptable, but in light of the 
current sanction of abortion up to and beyond the end of the second 
trimester, it is difficult to argue that creation, gestation, and 
sacrifice of a clone to save an existing life is a large leap in the 
logic of justification.
---------------------------------------------------------------------------
    \5\ The designation of 14 days as the moral boundary for embryo 
experimentation is in the category of a ``received tradition,'' almost 
a superstition in the sense that it is a belief in a change of state 
without a discernible cause.The validity of this designated moral 
marker has not been reexamined in the light of recent advances in our 
understanding of developmental biology. As a moral marker of 
ontological change, 14 days makes no sense. Even if one disagrees with 
the discussion above, the date should be set earlier: implantation is 
complete by the 12th day, the onset of gastrulation occurs as the 
primitive streak between the 12th and 14th days, and twinning is rare 
after the ninth day. Furthermore, it is worth noting that 14 days is 
not of current scientific relevance, since stem cells can be procured 
at the four- to five-day stage and, with present technology, human 
embryos can sustain viability in culture for only eight to nine days.
---------------------------------------------------------------------------
                        altered nuclear transfer
    While maintaining a bright line at conception safeguards our most 
fundamental moral principle, the challenge remains to find an 
acceptable method of drawing on the great medical promise of CBR and ES 
cells while precluding their use in ways that degrade the dignity of 
human existence. Some proponents of CBR maintain that the laboratory 
creation of the cloned embryo makes it a ``pseudoembryo'' or 
``artifact,'' a product of human technological production.They point to 
the unnatural means of its creation and the low probability of 
successful development to birth evident in most animal studies. 
Although we have no experience with the gestation of cloned human 
embryos (and only a single study involving gestation of nonhuman cloned 
primates), one significant difference from natural fertilization is 
that animal cloning consistently produces a high percentage of 
defective offspring (Jaenisch 2004). Indeed, most of the products of 
cloning never make it past early developmental stages, and among those 
that do, many die during gestation. Some argue that this high rate of 
early failure of development means that all products of nuclear 
transfer should be considered as lacking the moral standing of a 
natural embryo. The problem with this assertion is that, at least in 
some cases, the cloned embryo appears to share the developmental 
potential of the product of natural fertilization.
    Why some of the products of nuclear transfer proceed to develop 
while others do not is an important scientific question. The answer to 
this question is relevant to the search for a morally acceptable method 
for the procurement of ES cells and the proposal that follows. Evident 
abnormality during early development does not, of itself, preclude the 
formation of a whole and healthy offspring. IVF embryos often exhibit 
slower division rates and fewer cells at the equivalent stages of 
naturally conceived embryos (Barry Behr, Stanford University, personal 
communication). Likewise, at least in mice, intracytoplasmic sperm 
injection appears to disrupt the natural specification of cell fates 
and body axes normally associated with the point of sperm entry. In 
these cases, the capacity for regulation, for robust repair and 
restitution of the normal pattern of development, is evidence of the 
organizational integrity and unified principle of growth that 
characterizes a genuine organism. This capacity, together with the more 
fundamental powers of self-development and self-maintenance, is a 
crucial determinant in the moral status of any product of fertilization 
or nuclear transfer. To be rightly designated a human embryo with moral 
standing, an entity must have the organismal character of a living 
being.\6\ Clearly, many products of nuclear transfer lack these 
fundamental capacities of organisms, but since some are capable of 
integrated development, the fact of cloning alone does not establish a 
different moral status for the entity produced. Could we, however, use 
our advancing knowledge of developmental biology to create an entity 
that consistently lacks the qualities and capabilities essential to be 
designated a human embryonic organism? By intentional alteration of the 
somatic cell nuclear components or the cytoplasm of the oocyte into 
which the nucleus is transferred, could we truly create an artifact (a 
human creation for human ends) that is biologically and morally more 
akin to a tissue or cell culture?
---------------------------------------------------------------------------
    \6\ The word organism implies organization, an overarching 
principle of unity, a cooperative interaction of interdependent parts 
subordinated to the good of the whole. As a living being, an organism 
is an integrated, self-developing, and self-maintaining unity under the 
governance of an immanent plan. The philosopher Robert Joyce (1978) 
explains: ``Living beings come into existence all at once and then 
gradually unfold to themselves and to the world what they already but 
only incipiently are.'' To be a human organism is to be a whole living 
member of the species Homo sapiens, to have a human present and a human 
future evident in the intrinsic potential for the manifestation of the 
species typical form. Joyce continues: ``No living being can become 
anything other than what it already essentially is.''
---------------------------------------------------------------------------
    There are several possible approaches that might allow the 
production of ES cells without the creation and destruction of a human 
embryo. The ideal solution, one that many scientists believe will 
eventually be possible, would be the direct reprogramming of adult 
cells to become the functional equivalents of ES cells. In natural 
embryogenesis, ES cells are produced within a restricted area (the 
inner cell mass) of a blastocyst.\7\ Over the first few days of 
development, a series of cell signals induces the specific pattern of 
gene expression that characterizes ES cells and gives them their 
pluripotency, their capacity to subsequently produce all the cell types 
of the human body. With an understanding of the exact molecular nature 
of these signals, it may be possible to bypass embryogenesis and 
directly induce this transformation in adult cells. For example, as 
suggested by Alan Trounson of Monash University, Australia, we may be 
able to reprogram the nucleus of a somatic cell by transplanting it 
into the cytoplasm of an existing ES cell (personal communication). 
Unfortunately, it may be many years before our scientific knowledge and 
control of these factors will make this approach feasible.
---------------------------------------------------------------------------
    \7\ It is important to note that ES cells may be a product of 
laboratory isolation and culture and may exhibit properties quite 
different from their natural counterparts within the developing embryo.
---------------------------------------------------------------------------
    More immediately, there may be ways to obtain ES cells by 
harnessing partial organic trajectories apart from the full natural 
system of embryonic development. Using the techniques of nuclear 
transfer, but with the intentional alteration of the nucleus before 
transfer, we could construct a biological entity that, by design and 
from its very beginning, lacks the attributes and capacities of a human 
embryo. Studies with mice already provide evidence that such a project 
of altered nuclear transfer (ANT) may be able to generate functional ES 
cells from a cellular system that lacks the intrinsic potential of an 
actual organism, but possesses the limited organic powers of a tissue 
or cell culture. This proposal shifts the ethical debate from the 
question of when a normal embryo is a human being with moral worth, to 
the more fundamental question of what component parts and organized 
structure constitute the minimal criteria for considering an entity a 
human organism.\8\
---------------------------------------------------------------------------
    \8\ The mouse study by Chawengsaksophak and Rossant (2004) did not 
involve ANT, but it did demonstrate that ES cells may be procured where 
a gene essential at a fundamental level of embryogenesis is knocked 
out. As discussed below, whether an entity with such a dramatic 
disruption of development should be characterized as a ``disabled'' 
embryo or as a non-embryonic entity is an important consideration. 
Nonetheless, ANT could involve an intervention or complementary 
interventions at an even earlier and more fundamental level. Defining 
the moral boundary will be a crucial step in the implementation of this 
project.
---------------------------------------------------------------------------
    For practical implementation of ANT, a working definition of the 
term ``human embryonic organism'' might be any entity, regardless of 
its source or means of production, which, when provided the support and 
nurture of a natural gestational environment (or its technological 
equivalent), has the intrinsic potential to express the minimal 
manifestations of form and function that characterize a human organism. 
This still leaves open the discussion of the exact definition of such 
minimal developmental potentiality, but affirms that the moral status 
of such an entity is related to its intrinsic nature, not its mode of 
creation or present location. It is important to recognize, however, 
that such criteria of minimal developmental potentiality are only of 
secondary concern for ANT, where the most practical and (morally 
uncontroversial) technique may involve an alteration at a far more 
fundamental level. For a discussion of the defining criteria of a human 
organism, see Ashley 2001; Grisez 1989; Huarte and Suarez 2004.
           failures of fertilization and partial development
    The activation of an egg by the penetration of a sperm (or the 
equivalent events in nuclear transfer/cloning) triggers the transition 
to active organismal existence, with its potential for development 
toward the adult human form. But without all of the essential elements 
(the necessary complement of chromosomes, proper chromatin 
configuration, the cytoplasmic factors for gene expression, etc.), 
there can be no living whole, no organism, and no human embryo. Recent 
scientific evidence suggests that incomplete combinations of the 
necessary elements--``failures of fertilization''--are the fate of 
many, perhaps most, early natural initiations in reproduction. ANT 
proposes the artificial construction of a cellular system mimicking 
these natural examples, one that lacks the essential elements for 
embryological development but contains a partial developmental 
potential capable of generating ES cells.
    Many naturally occurring failures of fertilization may still 
proceed along partial trajectories of organic growth without being true 
organisms. For example, grossly abnormal karyotypes, such as trisomies 
of chromosome 1, will form a blastocyst but will not implant (Boue, 
Boue, and Gropp 1985). Even an enucleated oocyte, when artificially 
activated, has the developmental momentum to divide to the eight-cell 
stage, but clearly is not an organism. The mRNA for the protein 
synthesis that drives these early cell divisions is generated during 
the maturation of the egg and then activated after fertilization. Like 
a spinning top, the cells contain a certain biological momentum that 
propels a partial trajectory of development, but unlike a normal embryo 
they are unable to bootstrap themselves into becoming an integrated and 
self-regulating organismal entity.
    Some of these aberrant products of fertilization that lack the 
qualities and characteristics of an organism appear to be capable of 
generating ES cells or their functional equivalent (Byrne, Simonsson, 
and Gurdon 2002). Mature teratomas are neoplasms that generate all 
three primary embryonic germ cell types, as well as more advanced cells 
and tissues, including partial limb and organ primordia. Yet these 
chaotic, disorganized, and nonfunctional masses entirely lack the 
structural and dynamic character of organisms. Teratomas may occur as 
benign ovarian tumors that are, at least in some cases, derived by 
spontaneous and disorganized development of activated eggs. They 
generally have a complete karyotype (46XX), and they produce a 
diversity of cell and tissue types that suggests that they may proceed 
through a developmental process similar enough to natural embryogenesis 
to produce pluripotent stem cells. In fact, through intentional 
parthenogenetic activation of monkey eggs (which mimics teratoma 
formation), Vrana et al. (2003) were able to coax them to a blastocyst-
like stage and harvest ES cells. Serious scholars and scientists, 
including the geneticist and Dominican priest Nicanor Austriaco (2002), 
have made moral arguments supporting such a source of human ES cells. 
Furthermore, there are already patent applications for such a 
procedure.
    The disorganized character of teratomas appears to arise not from 
changes in the DNA sequence, but from genetic imprinting, an epigenetic 
modification that affects gene expression. In natural reproduction the 
sperm and egg have different, but complementary, patterns of 
imprinting, allowing a coordinated control of embryological 
development. When an egg is activated without a sperm, the 
trophectoderm and its lineages fail to develop properly. The 
differentiation of the trophectoderm and the inner cell mass (which 
forms the ES cells) is considered the first globally coordinated 
divergence into distinct cell lineages. The trophectoderm is necessary 
for the cross-inductions that are the foundation for all further 
coordinated and organized growth of the embryo. Later it contributes to 
the formation of the extra-embryonic membranes, but earlier in 
development it is crucial for both embryo structural integrity and the 
development of a normal inner cell mass. In the absence of the 
complementary genetic contribution of the male, the activated egg is 
simply inadequately constituted to direct the integrated development 
characteristic of human embryogenetic process.
    Interestingly, an inverse failure of formation characterizes 
development driven only by genetic elements from the male, where the 
complementary contribution of the female is missing. In complete 
hydatidiform moles an egg missing its nucleus is fertilized by one or 
more sperm. This time, lacking the maternal genetic contribution with 
its complementary imprinted genes, there is an overgrowth of 
trophectoderm with no apparent ES-like cells and little or nothing in 
the way of fetal parts.
    Recent evidence suggests that in their development both of these 
disorganized growths may proceed to the blastocyst stage. They may 
appear on visual inspection to be growing normally, but they carry an 
intrinsic insufficiency at the molecular level that renders them 
incapable of forming the body axes and essential infrastructure 
characteristic of human embryogenesis. (Clearly, the method and level 
of analysis we use will influence our interpretation of the identity 
and moral valuation of a thing. This highlights the importance of 
evaluating products of fertilization and nuclear transfer not simply by 
visual observation but also against the molecular signature that 
characterizes natural embryos.)
    The exact cause of the aberrant and disordered growth of these 
``failures of formation'' is not fully understood, but studies with 
parthenogenetic mice provide a remarkable window into the organizing 
(or disorganizing) role of a single genetic alteration. Using a 
technique similar to ANT, Japanese scientists produced a fully formed 
mouse by combining chromosomes from two oocytes, but with a single 
modification of an imprinted region to simulate the necessary male 
contribution (Kono et al. 2004). With this one change in genetic 
regulation directly affecting expression of just two genes, instead of 
disordered growth, normal offspring were produced. This simple 
restoration of the male/female complementarity of gene expression 
resulted in changes in the downstream gene expression of over a 
thousand other genes.
                     synthetic and systems biology
    This striking example of our increasing power to intervene and 
alter natural processes points to a coming era of challenging ethical 
dilemmas through advances in developmental biology. With new tools from 
cytology to synthetic biology, we are gaining control not just of 
component parts and their partial trajectories of growth, but of the 
principles and dynamics of organismal systems. Beyond highlighting our 
increasing powers over developmental biology, the parthenogenetic mouse 
points to another level of advance in our understanding: our new 
appreciation of systems biology, in which we see how even an alteration 
in a single gene can affect the entire balance of an enormous network 
of biochemical processes within the cell.
    Systems biology offers us a renewed appreciation of an organism as 
a living whole, a dynamic network of interdependent and integrated 
parts. There are essential subsystems of growth (cells, tissues, and 
organs), but a living being is more than the sum of its parts, and the 
parts are dependent on the integrated unity of the whole. Fully 
constituted, an organism is a self-sustaining, unified being with an 
inherent principle of organization that orders and guides its 
continuity of growth. In the human embryo, this principle of organismal 
unity is an activated dynamic of development in the direction of the 
mature human form. If severed from the whole, partial subsystems may 
temporarily proceed forward in development, but without the environment 
of their organismal system, they will ultimately become merely 
disorganized cellular growth. ANT proposes that small but precisely 
selected alterations will allow the harnessing of partial developmental 
trajectories apart from their full natural context in order to produce 
ES cells.
                                  cdx2
    There are numerous potential approaches to such a project, 
involving the alteration of genes necessary for early intercellular 
signaling, cell differentiation, or integrated patterning of 
development. Of course, there must first be a thorough discussion to 
decide what level of alteration would be consistent with both the 
scientific and moral goals of this project. For the sake of discussion, 
one possibility might be the alteration of Cdx2, a gene essential for 
the differentiation of the trophectoderm (which, together with the 
formation of the inner cell mass, reveals the first globally 
coordinated segregation of cell lineages). This may not be an 
acceptable final solution, but examining it as a specific example could 
allow us to consider the necessary criteria for scientific success and 
moral accept-ability.\9\ ANT must not be simply identified with Cdx2 
alteration, however, for the general proposal encompasses a wide range 
of alternative procedures.
---------------------------------------------------------------------------
    \9\ The ideal candidate would be a gene essential for the earliest 
expressions of organismal integrity, such that the ``partial trajectory 
of growth'' would lack the coordinated development of natural 
embryogenesis but be more akin to an ``inner cell mass culture.'' With 
the deficiency of a gene such as cdx2, which (by current evidence) is 
not expressed before the 16-cell stage, some might consider that the 
created entity is a ``disordered'' embryo. This is a serious concern 
and must be given careful consideration, but it is, of course, 
dependent on the definition of an embryo. It is possible, however, that 
this ``deficiency'' may be expressed earlier and at a more fundamental 
level of organization than that which produces a teratoma. While some 
might then argue that a teratoma is also a disordered embryo, a more 
convincing verdict would be that such an entity lacks the essential 
nature of a human embryonic organism and, as a pathological process, 
would be a proper target of therapeutic intervention at any stage in 
its development.
---------------------------------------------------------------------------
    Janet Rossant and her colleagues have shown Cdx2 to be an essential 
component of early embryogenesis (Tam and Rossant 2003). The gene is 
expressed immediately after compaction (around the 16- to 32-cell 
stage) and is necessary for the differentiation of the trophectoderm, 
the outer layer of cells that seals the embryo and controls the flow of 
water and ions to the inner cavity (Felix Block, University of 
Leicester, personal communication). Although the trophectoderm cell 
lineage is crucial in the formation of the extra-embryonic membranes, 
it is properly considered part of the embryo, as it plays a central 
role in the interactive cellular inductions that generate all 
subsequent embryonic development. Studies confirm that a functional 
trophectoderm is essential in embryogenesis. In mice, when Cdx2 is not 
expressed there is only a partial and disorganized developmental 
process resulting in a visibly abnormal blastocyst. Nonetheless, there 
is the formation of an inner cell mass from which functional ES cells 
have been harvested (Chawengsaksophak et al. 2004). For the purposes of 
ANT, Cdx2 might be deleted from the somatic cell nucleus prior to 
transfer. Once the ES cells have been procured, the gene could be re-
installed to restore a full genetic constitution. Alternatively, the 
same goal might be accomplished through temporary gene silencing using 
RNA interference. Indeed, some combination of alterations in gene 
expression could be affected by the complementary employment of several 
systems of genetic knock-out and/or knock-down.
    This technologically created, limited cellular system, from which 
the ES cells would be obtained, would fail to establish even the most 
basic features of human organismal infrastructure and would be 
incapable of implantation. A deficiency at the first complementary 
differentiation of cell types--the formation of the trophectoderm and 
the inner cell mass-means the absence of the most fundamental order. 
According to Dr. Maureen Condic, a developmental biologist at the 
University of Utah, ``When [the] trophoblast does not form, subsequent 
development follows a chaotic pattern, suggesting that organismal 
development has not been `disrupted' in the absence of [the] 
trophoblast, but rather that an organism never existed in the first 
place'' (Condic and Condic, in press).
    The resulting cells would have no inherent principle of unity, no 
coherent drive in the direction of the mature human form, and no claim 
on the moral status due to a developing human life. Rather, such a 
partial disorganized organic potential would more rightly be designated 
a ``biological artifact''--a human creation for human ends. The fact 
that some part of such a constructed entity will carry a certain 
momentum of development is morally analogous to the fact that we can 
grow skin in a tissue culture and may one day grow whole organs or 
limbs in isolation. Lacking crucial elements in its fundamental 
constitution, such an entity would never rise to the level of a living 
being. When the overarching integration of essential parts and 
functions is not present (or, as in the ``brain dead'' organ donor, no 
longer present), there is no living organism and therefore there is no 
being with human moral status.
                 advantages of altered nuclear transfer
    Unlike other proposals for ethical procurement, ANT would allow a 
uniquely flexible approach by providing a wide range of ES cell types 
that would have the full normal complement of human chromosomes, could 
be of specific genetic types for tissue compatible transplantation, and 
would not carry the danger of zoonotic contamination.
    In addition, this technique would offer a far wider range of 
scientific and medical possibilities than ES cell lines derived from 
``leftover'' IVF embryos, including generation of diverse and pre-
designed ES cell lineages for disease modeling and pharmaceutical 
development. Indeed, in allowing controlled and reproducible 
experiments, ANT might serve as a temporary bridge to transcendent 
technologies such as direct nuclear reprogramming. Furthermore, in 
establishing a morally acceptable means for the procurement of ES 
cells, this important realm of scientific investigation would be opened 
to federal funding and the advantages of both broad public support and 
cooperative research collaboration on a national level.
    ANT could also unburden ES cell research from the additional 
ethical concerns of the ``leftover'' IVF embryos, including the 
attendant clinical and legal complexities in a realm of great personal 
and social sensitivity. The one remaining link with IVF, the 
procurement of oocytes, is a subject of intense scientific research, 
and there appear to be several prospects for obtaining eggs without the 
morally dubious and expensive superovulation of female patients. These 
include the use of eggs left unfertilized from IVF procedures (nearly 
half of all eggs produced, some of which will fertilize with intra-
cytoplasmic sperm injection or nuclear transfer), xenotransplantation 
of human cadaveric ovaries or ovaries from oophorectomies transplanted 
into animals, in vitro maturation of ovarian tissue, and possible 
laboratory production of oocytes from ES cells.
         ethical harnessing of partial developmental potential
    All cloning procedures where living embryos are produced should 
rightly be recognized as acts of reproduction, even if these nascent 
human lives are intended for disaggregation early in their development 
for projects of scientific research. The intention in creating an 
intrinsically limited ``biological artifact'' through ANT would not be 
one of reproduction and disaggregation, but simply the desire to draw 
on natural organic potential through technological manipulation of 
biological materials. This intention is in keeping with the purposes of 
scientific research and medical therapy in which many ``unnatural'' 
manipulations are used for human benefit.
    The crucial principle of any approach employing ANT, however, must 
be the preemptive nature of the intervention. This process does not 
involve the creation of an embryo that is then altered to transform it 
into a non-embryonic entity. Rather, the proposed genetic alteration is 
accomplished ab initio: the entity is brought into existence with a 
genetic structure insufficient to generate a human embryo. From the 
beginning and at every point along its development, it cannot be 
designated a living being. No human embryo would be created, hence none 
would be violated, mutilated, or destroyed in the process of stem cell 
harvesting. If such a limited biological entity were accorded a certain 
cautionary respect (as with all human tissues), even though not the 
full protection of human life, this project would not compromise any 
fundamental moral principles. Moreover, such techniques could be 
developed using animal models and confidently extended to work with 
human cells without engaging in research that involves the destruction 
of human embryos.
    Over the course of the previous century, we have contended with 
ethical controversies over blood transfusion, tissue and organ 
transplantation, and the transfection of human genes into experimental 
animals. In this century we will be confronted by a series of even more 
challenging ethical questions related to the dynamic systems of 
developmental biology. Just as we have learned that neither genes, nor 
cells, nor even whole organs define the locus of human moral standing, 
in this era of developmental biology we will come to recognize that 
cells and tissues with ``partial generative potential'' may be used for 
medical benefit without a violation of human dignity.
                               conclusion
    The moral distinctions essential to discern and define the 
categories of organism, embryo, and human being will be vital as we go 
forward with scientific research involving human embryonic stem cells, 
chimeras, and laboratory studies of fertilization and early 
embryogenesis. Advances in developmental biology will depend on 
clarifying these categories and defining the moral boundaries in a way 
that at once defends human dignity while clearing the path for 
scientific progress.
    At this early stage in our technological control of developing 
life, we have an opportunity to break the impasse over stem cell 
research and provide moral guidance for the biotechnology of the 
future. This may require a constructive refinement of some aspects of 
moral philosophy, together with creative exploration of scientific 
possibilities, but any postponement of this process will only deepen 
the dilemma as we proceed into realms of technological advance unguided 
by forethought. We must initiate the cooperative dialogue that is 
essential to frame the moral principles that can at once defend human 
dignity and promote the fullest prospects for scientific progress and 
its medical applications.
                               references
Ashley, B. 2001. Cloning, Aquinas, and the embryonic person. Natl 
        Catholic Bioethics Q 1:189-202.
Austriaco, N.P. 2002. On static eggs and dynamic embryos: A systems 
        perspective. Natl Catholic Bioethics Q 2:659-83.
Boue, A., J. Boue, and A. Gropp. 1985. Cytogenetics of pregnancy 
        wastage. Adv Hum Genet 14:1-57.
Byrne, J.A., S. Simonsson, and J.B. Gurdon. 2002. From intestine to 
        muscle: Nuclear reprogramming through defective cloned embryos. 
        Proc Natl Acad Sci USA 99:6059-63.
Chawengsaksophak, K., et al. 2004. Cdx2 is essential for axial 
        elongation in mouse development. Proc Natl Acad Sci USA 
        101:7641-45.
Condic, M.L., and S.B. Condic. n.d. Defining organisms by organization. 
        Forthcoming. da Costa, A.L.E., et al. 2001. Monozygotic twins 
        and transfer at the blastocyst stage after ICSI. Human Reprod 
        16:333-36.
Fernandez-Gonzalez, R., et al. 2004. Long-term effect of in vitro 
        culture of mouse embryos with serum on mRNA expression of 
        imprinting genes, development, and behavior. Proc Natl Acad Sci 
        USA 101:5880-85.
Gardner, R.L. 2001. Specification of embryonic axes begins before 
        cleavage in normal mouse development. Development 128:839-47.
Grabel, L., et al. 1998. Using EC and ES cell culture to study early 
        development: Recent observations on Indian hedgehog and BMPs. 
        Int J Dev Biol 42:917-25.
Grisez, G. 1989. When do people begin? Proc Am Catholic Philosophical 
        Assn 63:27-47.
Huarte, J., and A. Suarez. 2004. On the status of parthenotes: Defining 
        the developmental potentiality of a human embryo. Natl Catholic 
        Bioethics Q 4:755-70.
Jaenisch, R. 2004. Human cloning: The science and ethics of nuclear 
        transplantation. N Engl J Med 351:2787-91.
Joyce, R.E. 1978. Personhood and the conception event. New 
        Scholasticism 52:97-109.
Kono, T., et al. 2004. Birth of parthenogenetic mice that can develop 
        into adulthood. Nature 428:860-64.
Nishimura, E.K., et al. 2002. Dominant role of the niche in melanocyte 
        stem-cell fate determination. Nature 416:854-60.
Piotrowska, K., and M. Zernicka-Goetz. 2001. Role of sperm in spatial 
        patterning of the early mouse embryo. Nature 409:517-21.
President's Council on Bioethics. 2002. Human cloning and human 
        dignity: An ethical inquiry. Washington, DC: President's 
        Council on Bioethics. Repr. New York: Public Affairs, 2002. 
        http://www.bioethics.gov/reports/cloningreport/index.html.
President's Council on Bioethics. 2004. Monitoring stem cell research. 
        Washington, DC: President's Council on Bioethics. http://
        www.bioethics.gov/reports/stemcell/index. html.
Tam, P.P., and J. Rossant. 2003. Mouse embryo chimeras: Tools for 
        studying mammalian development. Development 130:6155-63.
Vrana, K.E., et al. 2003. Nonhuman primate parthenogenetic stem cells. 
        Proc Natl Acad Sci USA 100 (suppl. 1):11911-16.
Wang, Q.T., et al. 2004. A genome-wide study of gene activity reveals 
        developmental signaling pathways in the preimplantation mouse 
        embryo. Dev Cell 6:133-44.
                                 ______
                                 

                 [The President's Council on Bioethics]

    Altered Nuclear Transfer as a Morally Acceptable Means for the 
               Procurement of Human Embryonic Stem Cells

   (By William B. Hurlbut, M.D., Program in Human Biology, Stanford 
                University, Presented December 3, 2004)

                              introduction
    I want to present some ideas that seem worthy of discussion and 
possibly preliminary scientific investigation. Those of us who have 
been working on these ideas have already explored some of the 
philosophical and technical dimensions, but there are important 
theoretical and practical issues that need further consideration.
    We offer these ideas not as an assertion of certitude, but as a 
promising avenue of inquiry, one that might move us beyond our current 
conflict over the procurement of ES cells by providing a ``third 
option,'' a technological solution to our moral impasse.
    In the broadest sense we propose a creative exploration of a full 
range of scientific approaches. More specifically, we raise the 
possibility that, using the technique of Nuclear Transfer, it may be 
possible to produce ES cells within a limited cellular system that is 
biologically and morally akin to a complex tissue culture, and thereby 
bypass moral concerns about the creation and destruction of human 
embryos.
    I want to make two points very clear from the beginning. What is 
proposed here is a concept, an approach to a problem; the specific 
examples, which may or may not be morally acceptable or scientifically 
feasible, are offered only to make clear the larger concept, and as a 
starting point for discussion.
    Second, we are at the stage of a constructive dialogue; if these 
ideas are deemed feasible, extensive studies with animal models must 
follow. We do not propose any projects involving human cells until we 
can be certain that embryos are not created by these methods.
                 political impasse and competing goods
    The present conflict over the moral status of the human embryo 
reflects deep differences in our basic convictions and is unlikely to 
be resolved through deliberation or debate. Many Americans oppose 
embryo destruction for the procurement of stem cells, believing that 
there is an implicit dignity and inviolability in the individual 
continuity of a human life from fertilization to natural death. Many 
others, however, believe that the benefits of advances in biomedical 
science outweigh these moral concerns.
    A purely political solution will leave our country bitterly 
divided, eroding the social support and sense of noble purpose that is 
essential for the public funding of biomedical science. While there are 
currently no federally legislated constraints on the use of private 
funds for this research, there is a consensus opinion in the scientific 
community that without NIH support for newly created ESC lines, 
progress in this important realm of research will be severely 
constrained.
    Notwithstanding this apparently irresolvable impasse, we believe 
there may be morally uncontroversial ways to obtain embryonic stem 
cells. Drawing on our increasing understanding and control of 
developmental biology, the technique of Altered Nuclear Transfer may 
allow us to generate ES cells even apart from the organismal system 
that is their natural origin.
                           life at conception
    In order to evaluate potential solutions and allow forward progress 
within moral consensus, we will have to understand the perspectives 
(and address the concerns) of those who believe that life begins at 
conception.
    By this view, the most fundamental principle, on which all other 
moral principles are built, is the intrinsic dignity and inviolability 
of human life across all of its stages. In both constitution and 
conduct the zygote and all subsequent embryonic stages differ from any 
other cells or tissues of the body; they contain within themselves the 
organizing principle for the self-development and self-maintenance of 
the full human organism.
    The activation of an egg by the penetration of a sperm, or the 
equivalent event in nuclear transfer/cloning, triggers the transition 
to active organismal existence, with the potential to develop into an 
adult human. But without all of the essential elements--the necessary 
complement of chromosomes, proper chromatin configuration, the 
cytoplasmic factors for gene expression, etc.--there can be no living 
whole, no organism, and no human embryo. Recent scientific evidence 
suggests incomplete combinations of the necessary elements--failures of 
fertilization--are the fate of many, perhaps most, early natural 
initiations in reproduction. Altered nuclear transfer proposes the 
artificial construction of a cellular system mimicking these natural 
examples, a system that lacks the essential elements for embryological 
development but contains a partial developmental potential capable of 
generating embryonic stem cells.
                       failures of fertilization
    It is important to realize that many of these naturally occurring 
failures of fertilization may still proceed along partial trajectories 
of organic growth without being actual organisms. For example, grossly 
abnormal karyotypes such as trisomies of chromosome number one (the 
largest chromosome, with the most genes) will form a blastocyst but 
will not implant.
    Even an egg without a nucleus, when artificially activated, has the 
developmental power to divide to the eight-cell stage, yet clearly is 
not an embryo--or even an organism. The mRNA for the protein synthesis 
that drives these early cell divisions is generated during the 
maturation of the egg and then activated after fertilization. Like a 
spinning top, the cells contain a certain biological momentum that 
propels a partial trajectory of development, but unlike a normal embryo 
they are unable to bootstrap themselves into becoming an integrated and 
self-regulating organismal entity.
    Some of these aberrant products of fertilization, which lack the 
qualities and characteristics of an organism, appear to be capable of 
generating ES cells or their functional equivalent. Mature teratomas 
are neoplasms that generate all three primary embryonic germ cell types 
as well as more advanced cells and tissues, including partial limb and 
organ primordial--and sometimes hair, fingernails and even fully formed 
teeth. Yet these chaotic, disorganized, and nonfunctional masses lack 
entirely the structural and dynamic character of organisms.
    These benign ovarian tumors, are, in some cases, derived by 
spontaneous and disorganized development of activated eggs. They 
generally have a complete karyotype (46XX) and they produce a diversity 
of cell and tissue types that suggests that they may proceed through a 
developmental process similar enough to natural embryogenesis to 
produce pluripotent stem cells. In fact, through intentional 
parthenogenetic activation of monkey eggs (which mimics teratoma 
formation), one private U.S. company was able to coax them to a 
blastocyst-like stage and harvest ES cells. Serious scholars and 
scientists, including the geneticist and Dominican Priest Nicanor 
Austriaco, have made moral arguments supporting such a source of human 
ES cells. Furthermore, there may soon be patent applications for such a 
procedure.
    The disorganized character of teratomas appears to arise not from 
changes in the DNA sequence, but from genetic imprinting, an epigenetic 
modification that affects gene expression (keeping some genes turned 
off and others on). In natural reproduction the sperm and egg have 
different, but complementary, patterns of imprinting, allowing a 
coordinated control of embryological development. When an egg is 
activated without a sperm, the trophectoderm and its lineages fail to 
develop properly. The differentiation of the trophectoderm and the 
inner cell mass (which forms the ES cells) is considered the first 
globally coordinated divergence into distinct cell lines. The 
trophectoderm is necessary for the cross inductions that are the 
foundation for all further coordinated and organized growth of the 
embryo. Later it contributes to the formation of the extra-embryonic 
membranes, but early in development it is crucial for both embryonic 
structural integrity and the development of a normal inner cell mass.
    In the absence of the complementary genetic contribution of the 
male, the activated egg is simply inadequately constituted to direct 
the integrated development characteristic of human embryogenetic 
process.
    Interestingly, an inverse failure of formation characterizes 
development driven only by genetic elements from the male, where the 
complementary contribution of the female is missing. In hydatidiform 
moles, an egg missing its nucleus is fertilized by one or more sperm. 
This time, lacking the maternal genetic contribution with its 
complementary imprinted genes, there is an overgrowth of trophectoderm 
with no apparent inner cell mass or ES-like cells, and little or 
nothing in the way of fetal parts.
    Recent evidence suggests that in their development both of these 
disorganized growths may proceed to the blastocyst stage: they may 
appear on visual inspection to be growing normally, but they carry an 
intrinsic insufficiency making them incapable of the essential 
formation of body axes and infrastructure characteristic of human 
embryogenesis.
    The cause of the aberrant and disordered growth of these ``failures 
of formation'' is not fully understood, but studies with 
parthenogenetic mice provide a remarkable window into the organizing 
(or disorganizing) role of a single genetic alteration. Employing a 
form of Altered Nuclear Transfer, Japanese scientists produced a fully 
formed mouse using only female chromosomes, but with a single 
modification of an imprinted region to simulate the necessary male 
contribution. With this one change in genetic regulation directly 
affecting expression of just two genes, instead of disordered growth, 
normal offspring were produced. To everyone's amazement, this simple 
restoration of the male/female complementarity of gene expression 
resulted in changes in the downstream gene expression of over a 
thousand other genes.
                     synthetic and systemic biology
    This striking example of our increasing power to intervene and 
alter natural processes points to a coming era of challenging ethical 
dilemmas through advances in developmental biology. With new tools from 
cytology to synthetic biology, we are gaining control of not just 
component parts and their partial trajectories of growth, but the very 
principles and dynamics of organismal systems.
    Beyond highlighting our strange and challenging new powers over 
developmental biology, the parthenogenetic mouse points to another 
level of advance in our understanding: our new appreciation of systems 
biology, in which we see how even a small change of one gene can affect 
the entire balance of an enormous network of biochemical processes 
within the cell.
    Systems biology offers us the view of an organism as a living 
whole, a dynamic network of interdependent and integrated parts. If 
severed from the whole, these partial subsystems may temporarily 
proceed forward in development, but without the larger environment of 
their organismal system, they will become merely disorganized cellular 
growth. ANT proposes that small (but precisely selected) genetic 
alterations will allow us to harness these subsystems of partial 
development, apart from their full natural organismal context, in order 
to produce ES cells.
                        altered nuclear transfer
    Eventually we may understand the biochemical factors that can 
transform a somatic cell to a pluripotent state. But while the ultimate 
goal for the generation of ES cells is the direct nuclear reprogramming 
of an adult nucleus, it may be many years before our scientific 
knowledge and control of cellular factors will make this approach 
feasible. More immediately, we may be able to use the techniques of 
Nuclear Transfer, but with the intentional alteration of the nucleus 
before transfer, to construct a biological entity that, by design and 
from its very beginning, lacks the attributes and capacities of a human 
embryo. Studies with mice already provide evidence this Altered Nuclear 
Transfer may be able to generate functional ES cells from a system that 
is not an embryo, but possesses the limited organic potential of a 
tissue or cell culture.
Cdx2
    For the sake of specifics in this discussion, let me propose one 
particular example of how this could be accomplished. This may not be 
an acceptable ultimate solution, but it will allow us to consider the 
necessary criteria for scientific success and moral acceptability.
    As well demonstrated in the work of Dr. Janet Rossant at Mt. Sinai 
Hospital in Canada, the gene Cdx2 is essential for embryogenesis. This 
gene is expressed immediately after compaction (around the 16-32 cell 
stage), and is crucial for the differentiation of the trophectoderm, 
the outer layer of cells that seals the embryo and controls the flow of 
water and ions to the inner cavity.
    Although the trophectoderm cell lineage is the source of the 
extraembryonic membranes, it is properly considered an integral part of 
the embryo, as it plays a central part in the interactive cellular 
inductions that generate all subsequent embryonic development. Studies 
confirm that a functional trophectoderm is absolutely essential in 
embryogenesis. In experiments with mouse models, when Cdx2 is not 
expressed there is only a partial and disorganized developmental 
process resulting in a visibly abnormal blastocyst. Nonetheless, there 
is the formation of an inner cell mass from which functional ES cells 
have been harvested, as reported in the May 2004 Proceedings of the 
National Academy of Sciences. For the purposes of ANT, Cdx2 might be 
deleted from the somatic cell nucleus prior to transfer. Once the 
partial ES cells have been generated, the gene could be re-installed to 
allow fully potent ES cells.
    This technologically-created limited cellular subsystem, from which 
the ES cells could be obtained, would fail to establish even the most 
basic features of human organismal infrastructure. A deficiency at the 
first differentiation of cell type--the formation of the 
trophectoderm--means the absence of the most fundamental order. 
According to Dr. Maureen Condic, a developmental biologist at the 
University of Utah, ``When [the] trophoblast does not form, subsequent 
development follows a chaotic pattern, suggesting that organismal 
development has not been `disrupted' in the absence of [the] 
trophoblast, but rather that an organism never existed in the first 
place.''
    The resulting cells would have no inherent principle of unity, no 
coherent drive in the direction of the mature human form, and no claim 
on the moral status due to a developing human life. Rather, such a 
partial, disorganized organic potential would more rightly be 
designated a biological ``artifact''--a human creation for human ends. 
The fact that some part of such a constructed entity will carry a 
certain momentum of development is morally analogous to the fact that 
we can grow skin in a tissue culture and may one day grow whole organs 
or limbs in isolation. Lacking crucial elements in its fundamental 
constitution, such an entity could never rise to the level of a living 
being.
    The scientific prospects for ANT remain largely unexplored, but as 
stated by Rudolph Jaenisch in testimony to the President's Council, 
they are within the reach of our current technology.
                         the advantages of ant
    Unlike other proposals, ANT would allow a uniquely flexible 
approach by providing a wide range of ES cell types that would have the 
full normal complement of human chromosomes, could be of specific 
genetic types for tissue compatible transplantation, and would not 
carry the danger of contamination from animal components.
    In addition, this technique would offer a far wider range of 
scientific and medical possibilities than ES cell lines derived from 
``left over'' IVF embryos, including generation of diverse and pre-
designed ES cell lineages for disease modeling and pharmaceutical 
development. Indeed, in allowing controlled and reproducible 
experiments, ANT might serve as a temporary bridge to transcendent 
technologies such as direct nuclear reprogramming. Furthermore, in 
establishing a morally acceptable means for the procurement of ES 
cells, this important realm of scientific investigation would be opened 
to federal funding and the advantages of both broad public support and 
cooperative research collaboration on a national level.
    ANT would also unburden ES cell research from the additional 
ethical concerns of the ``left over'' IVF embryos, including the 
attendant clinical and legal complexities in a realm of great personal 
and social sensitivity. The one remaining link with IVF, the 
procurement of oocytes, is a subject of intense scientific research and 
there appear to be several prospects for obtaining eggs without the 
morally dubious and expensive superovulation of female patients--the 
specifics of which we can discuss later.
                      the preemptive nature of ant
    The crucial principle of any technical variation of ANT, however, 
must be the preemptive nature of the intervention. This process does 
not involve the creation of an embryo that is then altered to transform 
it into a non-embryonic entity. Rather, the proposed genetic alteration 
is accomplished ab initio, the entity is brought into existence with a 
genetic structure insufficient to generate a human embryo. From the 
beginning and at every point along its development it cannot be 
designated a living being. If such a limited biological entity were 
accorded a certain cautionary respect--as with all human tissues--this 
project would not compromise any fundamental moral principles. 
Moreover, such techniques could be developed using animal models, then 
confidently extended to work with human cells without engaging in 
research that involves the destruction of human embryos.
                               conclusion
    The moral distinctions essential to discern and define the 
categories of organism, embryo and human being will be vital as we go 
forward with scientific research involving human embryonic stem cells, 
chimeras, and laboratory studies of fertilization and early 
embryogenesis. Advances in developmental biology will depend on 
clarifying these categories and defining the moral boundaries in a way 
that at once defends human dignity while clearing the path for 
scientific progress.
    At this early stage in our technological control of developing 
life, we have an opportunity to break the impasse over stem cell 
research and provide moral guidance for the biotechnology of the 
future. This may require a constructive refinement of some aspects of 
moral philosophy, together with creative exploration of scientific 
possibilities, but any postponement of this process will only deepen 
the dilemma as we proceed into realms of technological advance unguided 
by forethought. We must initiate the cooperative dialogue that is 
essential to frame moral principles that can at once defend human 
dignity and promote the fullest prospects for scientific progress and 
its medical applications.

    Senator Specter. Dr. Hurlbut, when you say if you would 
choose one stand-alone bill, would that be Specter-Harkin's?
    Dr. Hurlbut. I suggest that a range of alternative 
approaches be set aside. I agree with my colleagues that it 
should be a range of----
    Senator Specter. Well, but when you talk one stand-alone 
bill, what bill are you talking about?
    Dr. Hurlbut. I am speaking about a bill that would fund--
would provide funding for research to establish these 
alternative approaches.
    Senator Specter. Okay. I have not seen that stand-alone 
bill yet. Dr. Battey, let me commend Dr. Lanza and Dr. Hurlbut 
for what they are proposing here as an alternative. What the 
Congress is going to have to make an assessment on, if we can 
fund them all and move ahead with the wide range of 
alternatives, as Senator Harkin and I have both said earlier, 
we think that is a good idea.
    Dr. Battey, we know the potential if we remove the 
limitations now on Federal funding, which have been proposed by 
Castle-DeGette and Specter-Harkin. How speculative are the 
proposals by Dr. Lanza and Dr. Hurlbut?
    Dr. Battey. Mr. Specter, it is always dangerous to make 
predictions about the future, because science has so many times 
in the past surprised us. Both proposals, I believe, have lots 
of technical merit, and even some preliminary data to suggest 
that they may be possible. In fact, I think it is--the safest 
thing to say is that science moves forward the fastest when we 
pursue a whole variety of avenues and approaches towards the 
generation of pluripotent cells, because I hope my colleagues 
would agree with me that----
    Senator Specter. Dr. Battey, we do not have much time. If 
you had to make a choice among the three alternatives, which 
would you choose?
    Dr. Battey. That is a difficult choice to make. I would 
probably choose to pilot all three in pre-clinical studies and 
animal models, and go with whichever approach is the most 
promising.
    Senator Specter. Dr. Daley, you say that you have written 
in the----
    Senator Harkin. What three is he talking about?
    Senator Specter. Senator Harkin wants to know what three 
you are talking about. I am reluctant to answer his question to 
you.
    Dr. Battey. The three proposals in the President's Council 
on Bioethics, they were endorsed by them, which involved the 
attempts to create cell lines from embryos that are no longer 
dividing. Of course, with the Federal funds, all of these would 
be done initially in animal studies. We have been questioned 
whether or not we could use Federal funds to study any of 
these, using human embryos, because of the Dickey provision on 
the DHHS appropriation.
    But anyway, the idea about harvesting cells from embryos 
that are no longer dividing, altered nuclear transfer, and 
blastomere harvesting from the eight-cell stage embryo.
    Senator Specter. Dr. Daley, in your testimony you said that 
you have written in the scientific journals on Dr. Hurlbut's 
idea and have found it lacking. Could you amplify that, please?
    Dr. Daley. Yes. I think it is technically feasible. The 
question is whether it will satisfy all the ethical concerns. 
As Dr. Lanza said, engineering a gene defect so that you create 
something which is defective is engineering a defective embryo. 
There are many conservative thinkers who have argued against 
this policy.
    I wish it were so. I wish we could have an easy technical 
fix but I am afraid that this will not bring us to consensus. 
There will still be some who oppose altered nuclear transfer 
because it creates a defective embryo.
    Senator Specter. Dr. Lanza, if the Federal funding were 
limited to either being directed toward your proposal or to 
the--removing the current limitation, which would you have 
chosen?
    Dr. Lanza. Oh, that is a no-brainer. Removing the current 
limitations. We need to pass H.R. 810. It is that simple.
    Senator Specter. So, you would--if it came to an option of 
your proposal or Specter-Harkin, Castle-DeGette, you would 
choose to remove the current limitations?
    Dr. Lanza. Absolutely. Specter-Harkin. But we will take any 
additional money you would throw our way.
    Senator Specter. Dr. Hurlbut, are you going to be as 
generous with your conclusion as Dr. Lanza?
    Dr. Lanza. I will let you decide how generous I am. I 
believe we should find a way to go forward with our biomedical 
research that gathers in our whole Nation. The idea of people 
going to the hospital and having moral problems about the 
development of their treatment strikes me as a very unhappy 
prospect. I believe there are ways to go forward where we can 
go forward with consensus. I think we ought to explore those.
    Senator Specter. Dr. Hurlbut, we now have a situation, it 
was noted repeatedly even in this hearing, about 400,000 of 
these embryos frozen, they are going to be discarded. I, too, 
would like to find a consensus. But where you have the ideas 
which you and Dr. Lanza have articulated, as meritorious as 
they are, and my inclination would be to fund them all, 
providing there is not a limitation on Specter-Harkin. But how 
do we come to grips with the very basic objection, which has 
been raised by one side, that we are destroying a life, when 
these 400,000 embryos are going to be destroyed if they are not 
used?
    Dr. Hurlbut. Well, I guess that is your dilemma as a 
legislator. I put forward my proposal in the spirit of healing, 
to try to be inclusive. I want to say that I respectfully 
disagree with Senator Harkin. I do believe there is a moral 
dilemma here.
    A large percentage of our population does have moral 
concerns about the process of desegregating or destroying the 
human embryo in the procurement of embryotic stem cells. If 
there are ways to get these cells without the destruction of 
what many consider a human life in process; and I think 
biologically it is undeniably a human life; morally, you may 
make arguments differently.
    But if we can go forward without that action, which is 
apparently prohibited by the Dickey amendment, because even the 
Castle-DeGette bill does the actual destruction off-site, 
right? Am I right about that? It does not directly provide NIH 
funds for the actual active procurement of the cells. That 
seems to me a direct affirmation of the fact that there is a 
moral issue there.
    Senator Specter. Dr. Hurlbut, if Congress were to conclude 
that we support Dr. Hurlbut and Dr. Lanza, would you endorse 
Specter-Harkin?
    Dr. Hurlbut. I am among those who have moral concerns and 
believe that the best way for our country to go forward would 
be to take the time and energy, and I do not believe it would 
take that long, to explore these alternative methods. And then 
after that, I think we should revisit the kind of legislation 
that you are proposing.
    Senator Specter. So, that is a delayed yes?
    Dr. Hurlbut. It is a delayed answer.
    Senator Specter. All right. Well, then, what is the answer? 
We are not going to conclude the question without an answer.
    Dr. Hurlbut. Senator, are you asking----
    Senator Specter. I am now under Senator Harkin's time, by 
the way.
    Senator Harkin. That is okay. You are doing great.
    Dr. Hurlbut. Are you asking me if I have----
    Senator Specter. Well, I am asking essentially, recognizing 
your preference, and I can understand it, if we could solve all 
the concerns. But in the context where it is very speculative 
and uncertain as to whether your idea would work, Dr. Lanza's 
idea would work, but we do know if we removed the restriction 
on Federal funding, as Senator Harkin and I have proposed, and 
Congressman Castle and Congresswoman DeGette have proposed, you 
can move ahead with embryonic stem cell research.
    So, would you foreclose the prospects of scientific 
advantage by removing the current limitation on Federal 
funding, which Senator Harkin and I have proposed?
    Dr. Hurlbut. At this time, I would favor the pursuit of a 
way that can go forward without the institutional endorsement 
of the instrumental use of human embryos. I believe that we, as 
a society, would be stronger and more coherent, and I also 
believe it would lead to a better long-term result for the 
prosperity of our scientific enterprise.
    We have sequenced the human genome. We are learning about 
the proteins that the genes code for, and from here on out, it 
is developmental biology; living beings. We need to find 
principles to go forward. ESL research is just the beginning of 
a whole series of ethical dilemmas. If we can solve this in a 
positive way, we can set the frame for going forward.
    I think in the long run, instead of a series of battles, we 
will have a coherent moral platform to guide our science. That 
is why I put forward the kind of proposal I have done, because 
I think it would set the moral frame.
    Senator Specter. Well, you have articulated it accurately. 
It is going to be a matter of time. You have also articulated 
accurately it is a legislative judgment and we legislators are 
prepared to make it. Again, I only have one vote out of a 
hundred, but I have waited too long now. Eight years is too 
long to wait for stem cell research.
    Dr. Green, how do you evaluate the prospects of success of 
what Dr. Hurlbut and Dr. Lanza have proposed, contrasted with 
what we know can happen if we enact Specter-Harkin?
    Dr. Green. Well, I think there is no question that we could 
move ahead very quickly if Specter-Harkin is enacted to really 
moving stem cell research forward in this country. We are 
losing our ability to do that rapidly. I think there is no 
``if'' here. There is a question of moving ahead or not.
    I think these other proposals are speculative. I personally 
believe that single-cell blastomere biopsy is most acceptable, 
possibly in an ethical and legal direction, to support.
    I do want to say that I have rather grave reservations 
about altered nuclear transfer as a procedure. I believe that 
it can properly be characterized as deliberately creating and 
then destroying an impaired form of human life. I think that 
people who look more closely, ethically, will agree with that 
estimate of it.
    I think it also opens a slippery slope to the deliberate 
creation of impaired human beings for transplant purposes. I 
really do not see the difference between creating an impaired 
embryo and creating an impaired infant, an infant without a 
brain as a source of organs for harvest.
    So I think of all the proposals that have been put forward, 
this is the one that raises the most substantial and serious 
ethical--not simply technical--but ethical questions, whereas 
the other proposals, I think, are ethically worthwhile, 
praiseworthy, and should be supported and funded. But above 
all, I think we should use the methods we currently have to 
use--to take these cells from embryos that are being destroyed 
as we talk, by the thousands around the world. This is 
material--these embryos are being destroyed. They are not being 
destroyed by governmental officials. They are being destroyed 
by parents and clinicians. That material is going to waste.
    Why should they not be free to donate those cells for 
further research that saves human life? I think we should 
characterize it as allowing people to donate cells, from 
embryos that have been discarded, for lifesaving purposes.
    Senator Specter. Thank you, Dr. Green.
    Senator Harkin?
    Senator Harkin. Thank you. I do have a line of questioning 
but I see Dr. Hurlbut wanted to respond, so I want to----
    Dr. Hurlbut. Thank you. I want to say in response to that, 
that I put forward my proposal to solve this problem, not to 
create disabled embryos. I do not think that is a correct 
scientific analysis of what I am proposing.
    I am proposing to create something that has a natural 
analog. In nature, you have manifestation of certain types of 
biological developments that are clearly not embryos and yet 
are capable of producing embryonic stem cells. I think that to 
label what I am producing or what I am suggesting be produced 
as a development of a mentally incompetent embryo or inflicting 
injury on an embryo, is to presume the existence of an embryo 
in the construction that I make.
    That is not what I am going to do. I think that the nature 
of my proposal is such that one would analyze the science in 
such a way that you would not produce a unified, coherently 
operating entity that is the definition of an organism. The 
fact that, that is reasonable is evident in the statement that 
accompanies the proposal for oocyte assisted reprogramming, 
which has the affirmation of a broad range of moral 
philosophers and religious authorities who have examined it and 
thought carefully about it.
    This proposal really does provide a way forward. It does 
not create embryos. It creates entities that are non-embryonic. 
As they used to say about Oakland, there is no there, there. 
Well, it is the same here. There is no embryo there.
    Senator Harkin. Well, I would just respond that the white 
paper that the President's Council on Bioethics, page 59, ``The 
third proposal, cell is derived from specially engineered 
biological artifacts.'' That is what you are talking about. 
``Because this proposal raises many serious ethical concerns, 
we do not believe that it is, at this time, ethically 
acceptable for trials of human material. Although a few of us 
are not eager to endorse even animal and other laboratory work 
investigating potentially human applications, most of us 
believe the proposal offers enough promise to justify animal 
experimentation, both to offer proof of feasibility and utility 
and to get evidence bearing on some of the ethical issues.'' 
So, that is just from the President's Council regarding the 
altered nuclear transfer system.
    I guess, Dr. Hurlbut, since we are talking about this, you 
went to Stanford; they teach logic at Stanford, I am sure. If 
``A'' equals ``B,'' and ``B'' equals ``C,'' ``A'' must equal 
``C.'' So, let us start with that for logic.
    Are you morally opposed to in vitro fertilization? A simple 
question.
    Dr. Hurlbut. I think we are all troubled by the fact that 
in vitro fertilization creates more embryos than it implants, 
and we would all like to seek a way to not do that. Beyond that 
I feel like it is a therapeutic intervention against a 
disorder, and in that sense I think it should be a procedure 
that is within the spectrum of personal choice and reproductive 
options.
    Senator Harkin. So, you believe that if a couple wants to 
pursue in vitro fertilization they should be allowed to do so?
    Dr. Hurlbut. You know, when that issue----
    Senator Harkin. I do not mean to debate this. I am just 
asking you a simple question.
    Dr. Hurlbut. The simple question is: Should they be 
allowed----
    Senator Harkin. Yes.
    Dr. Hurlbut [continuing]. To do so?
    Senator Harkin. Should they be prohibited?
    Dr. Hurlbut. Given the fact that it is a private 
reproductive choice and is not the institutional endorsement 
with Federal funds, I think it is in a different category. If I 
were a legislator I would make it legal.
    Senator Harkin. I take from that, that you are not morally 
objecting to in vitro fertilization. If you are morally 
objecting, you would be objecting to whether it was private or 
public, right?
    Dr. Hurlbut. I am morally troubled by the creation of human 
embryos that are not implanted. That dimension of in vitro 
fertilization, I have moral concerns about.
    Senator Harkin. Well, I am still trying to figure out what 
that means. I am troubled by a lot of things in life. I mean a 
lot of things trouble me, but I do not find them totally 
objectionable, or that I want to impose some control, or 
something. I just happen to find them troubling.
    What I am trying to get to is if (A) you do not find in 
vitro fertilization morally objectionable, private or public, 
whatever, by the very fact that you have IBF, you are going to 
create surplus embryos. That is a fact on which we can all 
agree, therefore, that is (B). Therefore, (C), if you believe 
that in vitro fertilization is okay, and it is morally all 
right for couples to pursue, then you are (C) going to have 
excess embryos.
    Dr. Hurlbut. Senator Harkin----
    Senator Harkin. Am I wrong in that logic?
    Dr. Hurlbut. Yes, you are.
    Senator Harkin. Oh. Tell me where I am wrong in that logic.
    Dr. Hurlbut. There are at least two countries in the world, 
Italy and Germany that do not allow the creation of excess 
embryos but do allow IBF.
    Senator Harkin. What do they do with the excess embryos?
    Dr. Daley. That is true, but their success rates for 
assisted reproduction are dramatically less than in the United 
States.
    Dr. Hurlbut. Well, because they do not have all of the ones 
to draw from.
    Dr. Daley. Right.
    Senator Harkin. So, again, I do not understand why, if you 
create excess embryos, which we do, 400,000 we estimate here, 
and they are going to be destroyed--you agree with that, right, 
Dr. Hurlbut? They are going to be destroyed. They are being 
destroyed every day, right now, as we sit here; they are being 
destroyed every day.
    Dr. Hurlbut. There are an estimated 400,000 frozen embryos 
in the United States whose fate is currently uncertain. Only 
11,000 of those have specifically been designated for research. 
Of those, many of them would not qualify under the informed 
consent rules. The estimates are that we might get a couple 
hundred lines out of those.
    I do not disagree that we could fast forward to the science 
with new lines. I have never taken the position that embryonic 
stem cell research is not necessary in the positive sense of 
interesting exploration. We must acknowledge, of course, that 
it is speculative research; it is not absolutely proven. But I 
am with George Daley with this. I think we should try to find 
ways to go forward.
    I am concerned that we find a way to go forward that is 
encompassing, that includes the diversity of moral opinions in 
our society. That is----
    Senator Harkin. Well, now----
    Dr. Hurlbut. But I do not it is just simple logic. I think 
it is the art of governing a society.
    Senator Harkin. That is the position I think that Senator 
Specter and I have taken. That is these are all worthy of 
investigations. We have all said that. We have been saying that 
for a long time. But what is happening is that there are forces 
out there now that want to stop the Specter-Harkin bill and 
shift it only to these other things, which, as we know, have 
never been done in humans. There have been no trials; they are 
speculative. Even your own approach, as Dr. Kass said, it 
raises ethical concerns.
    I mean, if it is not an embryo, what is this sort of 
Frankenstein-thing that we are creating by taking the gene out? 
What is it called? What is it, if it is not an embryo? I do not 
know what it is.
    Dr. Hurlbut. We are going to have many questions like this 
as we----
    Senator Harkin. Sure.
    Dr. Hurlbut [continuing]. Go forward in the future. As I 
said, we are in the era of development biology. Someday we will 
probably be able to develop human organs in factories. That 
immediately seems gruesome to us, but on the other hand it 
could be very positive. The moral issues are going to be very 
challenging and we need to find a frame to go forward with 
them.
    Senator Harkin. Well, I----
    Senator Specter. Senator Harkin, may I interrupt you for 
just 1 minute?
    Senator Harkin. Yes.
    Senator Specter. Regrettably, I have some duties on the 
Judiciary Committee and I am going to have to excuse myself at 
this point. I am going to leave you with Senator Harkin all 
alone.
    Senator Harkin. I only have a couple more questions.
    Senator Specter. Before I go, I want to thank you for 
coming here today. I want to thank you for what you are doing. 
We have had--this is our 16 hearing. I think this has been our 
best, really, on the specifics as to what we are getting into.
    It may be that Senator Harkin and I understand more because 
we have been educated over a long period of time. And it takes 
a long period of time to educate us. But what you have done, 
Dr. Hurlbut, and what you have done, Dr. Lanza, we admire, in 
seeking another alternative.
    The dialogue that Dr. Hurlbut and Senator Harkin have had 
is very illuminating and shows the depth and intensity of the 
problem. We have taken the lead on putting up a lot of money; 
$28 billion is a lot of money for NIH. It is not enough, but it 
is a lot.
    We did not have a chance to get into what stem cells can 
do. We have done that at other hearings. We have had words from 
the directors of NIH as to the great potential, and so many, 
many lines. I think it is summed up in what Dr. Kass said when 
he--in his op-ed piece he said, ``It is too early to know which 
of these approaches will prove most successful.'' But we do 
know that if you have Specter-Harkin and the Castle bill, you 
can move ahead promptly in a very, very important line.
    I will be backing all the research and using this 
subcommittee as the leveraging factor to lead the Congress to 
more money for the scientific research. I do regret that I have 
to go, but we have a lot of conflicting demands on us here. The 
Judiciary Committee, as I know you see, is a very heavy one.
    I have turned the gavel over to Senator Harkin before, and 
it has worked out very well.
    Senator Specter. Thank you all very much.
    Tom, it is yours.
    Senator Harkin [presiding]. Thank you, Mr. Chairman. Dr. 
Lanza----
    Dr. Lanza. Yes?
    Senator Harkin [continuing]. Just to reiterate, your 
blastomere extraction technique has been successful only in 
mice, so far as I understand it?
    Dr. Lanza. That is correct.
    Senator Harkin. How long do you think it would take before 
you could achieve the same success in humans?
    Dr. Lanza. Well, obviously, that is an impossible question 
to answer. It could be a few years, it could take a decade. 
Until you do the research, you simply do not have that answer.
    Senator Harkin. We just do not know?
    Dr. Lanza. We do not know, no.
    Senator Harkin. Dr. Daley, again, for the record, some 
opponents of the Specter-Harkin bill, or H.R. 810 or S. 471, 
say that instead of lifting the current restrictions on stem 
cell research, we should focus entirely--well, either on three 
or four. I am a little confused. I thought there were four, and 
then I heard three. So it is either three or four unproven 
alternatives.
    Do you think this makes sense, from a scientific 
perspective?
    Dr. Daley. No. No. Absolutely not. No. I think that support 
for the speculative proposals that are being considered, 
instead of support for expanded access to embryonic stem cell 
lines, which we have available to us, and we already know are 
powerfully and vitally critical to medical research, is really 
a vote to delay important medical research. So, I do not think 
we should be keeping the scientific community or the patient 
community waiting.
    Senator Harkin. Address yourself to this question. If we 
had the approach--I want to phrase this correctly. If we had an 
approach that only focused on these alternative methods, but 
did not allow the current restriction on Federal funding of 
research on stem cell lines, H.R. 810 or S. 471, lifting that 
restriction, if we just focused on the alternative methods 
without lifting the present restrictions, would that delay our 
ability to find cures and treatments for diseases like juvenile 
diabetes, or Parkinson's, or ALS?
    Dr. Daley. Yes. I mean, it essentially puts us in the same 
unfortunate position we are in today, which is working with a 
small set of presidential cell lines, cell lines that do not 
provide us models for human diseases, do not allow us to do 
some of the most medically forms of research, do not allow us 
to take advantage of the hundreds of newer versions of cell 
lines. Cell lines that have been derived in the absence of 
mouse feeders, free of mouse contamination. Cell lines that 
model human disease. Customized patient-specific cell lines.
    Without Senate passage of H.R. 810 and without expanding 
access to these lines, we are in the same terrible position. 
So, I do not think that these alternatives solve the problem in 
any way. I think they are a quixotic attempt to divert us from 
the central task of expanded access to embryonic stem cells.
    Senator Harkin. Dr. Green, same question.
    Dr. Green. Yes. I very much agree with what Dr. Daley has 
just said. I would add to that the peculiarity that even if 
these approaches proved technically acceptable, there are 
profound ethical questions at the other side of them. People 
would look at altered nuclear transfer and raise some of the 
questions I did. They might ask questions about safety, about 
the biopsy technique. They would worry about the inducement to 
cloning in some of these technologies.
    So we could be going ahead on these technologies and find 
that many of the people who are currently opposed to the 
expansion of stem cell lines have as many objections, or more 
objections, actually, to these techniques than they do even to 
embryonic stem cell derivation now.
    Senator Harkin. I am going to work this around here. I am 
not--the question that I posed, and I am going to ask you is: 
By just focusing on the alternative methods, but keeping the 
present lid on the restrictions, keeping the present 
restrictions in place, would that delay the ability find cures 
and treatments for disease like juvenile diabetes, Parkinson's, 
and ALS? Both of you responded yes. Dr. Hurlbut, what say you?
    Dr. Hurlbut. Would it delay----
    Senator Harkin. Okay. I will reiterate my question.
    Dr. Hurlbut. Yes. I understand it. There is no question but 
that you can go forward faster with science if you do not 
take--do not have concerns about research subjects and a 
variety of moral issues. The point is that you can move ahead 
scientifically, but at the same time be moving backwards in 
terms of social consensus and social support of science, and 
you can be moving backwards in terms of the moral foundations 
of our civilization. We are at a hinge of history here. We need 
to take the time to get this right, to open the future of 
science in a positive way that does not have constant conflict.
    Let me say something and I do not raise this in the spirit 
of negativity or hysteria, and certainly not to encourage 
anything related to this. But a Stanford we have our animal 
research facility hidden under a parking lot, because there are 
the animal activists, animal rights activists.
    I just keep asking myself, where is the embryo facility 
going to have to be handled? Where is that going to be hidden? 
When so many Americans feel so strongly about this. Could we 
not, in the spirit of unity, engage in the constructive 
conversation and the positive creative use of our scientific 
tools to find an answer to this?
    I agree with Dr. Green. It is challenging. There are 
difficult ethical issues. But just as there are difficult 
scientific issues that we will have to solve, we can solve 
these difficult ethical issues, too, if we put our minds 
together and seek national unity to do so. I favor the science, 
but I also favor the moral frame for the science.
    Dr. Lanza. I think what we are hearing is that----
    Senator Harkin. Now, I want to stick on this question. So 
one, two, three of you have answered positively. Dr. Lanza.
    Dr. Lanza. I think there is a very real human tragedy out 
there and we need to move ahead with this ASAP. I think that 
the field of stem cell research has been crippled by the lack 
of accessibility to quality stem cell lines. So, again, I think 
there is no question.
    Senator Harkin. Dr. Battey. Do I need to repeat my 
question?
    Dr. Battey. No. Unlike my four colleagues, I am a member of 
the executive branch of the Government. As you know, Senator, I 
cannot comment directly on pending legislation. I am prohibited 
by law from doing that. But I can say that there is no 
scientist that I know that would argue that more cell lines 
would not accelerate the pace of research.
    Comments have been made about disease-specific cell lines, 
about, you know, designer cell lines, about cell lines that 
have been derived under different conditions than were extant 
at the time that Jamie Thomson wrote his first paper. All of 
these cell lines offer scientific opportunities that are right 
now beyond the reach of Federal funds. That I can say.
    Senator Harkin. Let me just say, try to bring this to a 
close. There are many people in our country who find in vitro 
fertilization morally unacceptable. But should that be the 
controlling factor, or should it be allowed for them to 
personally be opposed and not to engage in it themselves?
    I do not know where it becomes the tilt. At what percentage 
does it become all right, acceptable, to pursue a certain line 
of scientific inquiry based upon polling data? Is it 60 
percent? Is it 70? Is it 75? Is it 82? Is it 83.5? Where does 
it tilt? How do people know?
    I can only tell you from my own experience of traveling 
around Iowa and talking about this issue in front of audiences, 
that when I talked about it, people said, ``Wait a second. That 
is not what I thought. That is not what I was thinking about.''
    I will say this publicly, there has been a concerted effort 
by many, maybe because they find it morally objectionable, I do 
not know, maybe there are some politics, it could be all kinds 
of reasons out there, but some people have really tried to 
confuse this issue by equating an embryo to a fetus.
    There are many people who believe that what we are talking 
about is a fetus. When the debate was on the House floor, a 
certain Congressman talked about, and I heard the debate, 
talked about--and it was replayed again on CNN, talked about we 
cannot be engaging in dismembering human life to provide parts 
and stuff for others. That was played on CNN.
    CNN then put up a picture of a fetus on the screen. And so 
there are a lot of people out there that do not know. They 
think in their mind that when we are talking about embryotic 
stem cell research, they are thinking of fetuses. I know this 
for a fact.
    So that, every time I do my little thing and hold it up and 
say what I have here, I said that is what we are talking about. 
That is how big the embryo is. It is as big as a period at the 
end of a sentence. It has what, eight--how many cells does it 
have? Eight? Thirty? Less than a 100 cells. I do not know. I 
get confused how many cells.
    People do not realize--they do not get that. They finally 
say--and I have had people come up to me and say, ``I did not 
realize--I thought--I thought we were talking about a fetus.''
    So, I think that the more that knowledge gets out and the 
more information that gets out about exactly what we are 
talking about, how many cells we are talking about, and the 
fact that this is not a fetus, people then begin to say, 
``Well, then maybe I will change my thinking on this. Maybe I 
will think differently on this.''
    So, it has to do--I guess my point is, is knowledge, 
information that is scientifically pure as possible and not 
biased one way or the other that gets out there. I think that, 
what is it, around 60 percent that support it now, will 
probably go even higher.
    So, do we want 100 percent? Do we have to wait until every 
single person in this country agrees that something is not 
morally objectionable? We will never get there; that will never 
happen. So somehow, we have to find a way of encompassing as 
broad a consensus as possible. But to do it, I think, as best 
as we can, an intellectually honest approach, as to how we go 
about this.
    I think that the more information that gets out on 
embryonic stem cell research, whether it is National 
Geographic, with their issue, or Parade magazine, or Newsweek, 
or Time, or articles that are written about it, the more people 
that are reading about it, the more people who begin to 
understand it, the more support it gets for lifting these 
restrictions. Therefore, the moral objections fall away.
    Now there will always be some who are morally objectionable 
on religious grounds, ethical grounds, whatever. Basically, 
religious, more than anything. I understand that. There are 
religious objectives to, as I said earlier, artificial 
contraception. There are religious--strong religious objections 
in certain religions. Well, that is fine. But I do not know 
that--that ought to be the controlling factor in our society.
    So, again, we were talking about moving ahead in a way that 
gathers in the nation, one of you said that, I do not know who 
it was, gathers in the whole nation. Well, how long do we wait? 
Do we wait until it is 100 percent or not, or do we try to make 
science-based judgments that are at least morally acceptable to 
the vast majority of people in this country? It seems to me 
that is our system, and that is the way we ought to move ahead 
in this regard.
    There are people out there that suffer. People that have 
illnesses and diseases. I do not know whether this is going to 
work or not, but I think we ought to try it. We ought to move 
ahead in it. All these other approaches, even Dr. Hurlbut's, 
sure, I think we ought to pursue it. I think we ought to look 
at it. I have no problems with any of this stuff. I think there 
are certain ethical problems with all of these, as people may 
raise.
    But I am all for opening--I have always said basic 
research, Dr. Battey, to me, has always been like opening 
doors. You do not know what is behind them. That is basic 
research. That is why I have always said--people have said, 
well, you spend all this money on basic research and nothing 
comes of it. I said, ``Well, that is basic research.''
    If you have 10 doors, and you are only going to open 1 
door, the odds against finding your answer is pretty high. If 
you open five doors, it gets better. Seven doors, better. Eight 
doors, better. Once in a while you strike it lucky. Once in a 
while you open one door and you do strike it lucky.
    Dr. Battey. That is why we call it research and not 
engineering, Senator.
    Senator Harkin. That is research. So like I said, with all 
these things, I have no problems with that, and moving ahead on 
it.
    But I came back to where Senator Specter was, I do not mean 
to speak for him, but--and those of us who are supporting 
lifting the restrictions, do not stop this. Let us move ahead 
on it aggressively. Let us go ahead and investigate these other 
alternatives. Maybe one of them may even prove superior on down 
the road someplace. We do not know that.
    But we do know this one. Extracting embryonic stem cells 
from in vitro fertilization that are going to be destroyed 
under the ethical guidelines that we have constructed, informed 
consent, no money, and exchange hands, cannot be paid for, and 
third, can only be used for stem cell extraction, cannot be 
implanted. I think pretty good ethical guidelines and this is 
the way we ought to move ahead on this.
    Then if we want to bring up these other bills to find other 
alternative approaches, I will be first in line in voting and 
supporting for the funding for these alternative approaches. 
But to say to so many people who are suffering today, and 
children who are pinning their hopes on this, and that--and 
each one of you, every single one of you have said, in answer 
to my question, that it would delay our ability to find cures 
and treatments for disease like juvenile diabetes, Parkinson's, 
and ALS. You answered yes; it would delay it, if we do not lift 
the restrictions.
    So, to me, aside from the ethical or moral problems that 
some people have with it, and I understand that, the fact 
remains that the best approach that we know of right now, 
scientifically, to find the cures for these things, like 
juvenile diabetes, and Parkinson's, and ALS, and spinal cord 
injuries, is through embryonic stem cell derivation and 
research. That is why we have to move ahead.

                         ADDITIONAL STATEMENTS

    This material was receivd by the committee for the hearing 
record.
    [The statements follows:]
Prepared Statement of Joyce Frye, NCCAM Post-doctoral Research Fellow, 
           Center for Clinical Epidemiology and Biostatistics
    Senator Specter: Thirteen years ago, my 12 year old son was cured 
of Acute Renal Failure (Nephrotic Syndrome) with homeopathic medicine 
in what his pediatric nephrologist at Thomas Jefferson University 
Hospital described as a ``miracle''. He has had no further health 
issues and is now an Olympic aspirant in figure skating as an ice 
dancer. Since his amazing recovery, I have devoted my medical career to 
learning the art and science of homeopathy and attempting to do 
research in it. I am now blessed with the opportunity to further that 
aspiration as a post-doctoral fellow in the Center for Clinical 
Epidemiology and Biostatistics at UPenn, receiving a stipend for my 
research education from NCCAM. I have also served as the president of 
the National Center for Homeopathy and am currently the president of 
the American Institute of Homeopathy--the nation's oldest medical 
organization founded in 1844.
    However, NCCAM has yet to issue any funding specifically for 
homeopathy, and the CDC continues to ignore homeopathy as a potential 
response for emerging infections despite homeopathy's 200 year history 
of success in epidemics, especially the 1918 Spanish flu pandemic where 
mortality rates under homeopathic treatment were in the range of 1 
percent. Additionally, homeopathic practitioners on site in the Bali 
explosions and who have responded to Tsunami relief have hundreds of 
anecdotes of rapid and amazing responses to homeopathic care. It is 
troubling to watch events such as the London bombings knowing that it 
can happen in the United States again and that our trauma could could 
be substantially diminished if first responders were able to use a few 
simple and inexpensive homeopathic medicines.
    To that end, I hope that you will support a fiscal year 2006 NIH 
budget of $30.6 billion, an increase of 6 percent over the President's 
request, and insert or support language drafted by a committee of the 
National Center for Homeopathy in the Labor, HHS, and Education 
appropriations bill, which is attached.
    Thank you for all of your hard work for Pennsylvania and for the 
Nation, and wishing you a speedy recovery from your personal health 
challenges.
         funding request of the national center for homeopathy
    To explore the potential use of homeopathic medicine for protection 
against and treatment of agents of chemical and biological warfare, for 
underserved populations, and for emerging infections, $16.5 million for 
3 years to be used for:
  --Homeland security Homeopathic Emergency Response Training (HERT) by 
        the National Center for Homeopathy teaching homeopathic 
        protocols for response to trauma and bio-terror in 10 HERT 
        sessions located in strategically important regions of the 
        United States, each training session to be marketed to and open 
        to physicians and the general public.
  --Preparation and testing of Ultra High Dilution (UHD) forms of 
        agents of potential chemical and biological warfare for 
        prophylaxis against and treatment of injuries resulting from 
        exposure to said agents.
  --NIH Program announcement and directed funding for research specific 
        to homeopathy including funding for research in mechanism of 
        action and long-term longitudinal studies
  --Educational projects for self-care in underserved populations, for 
        utilization of urgent care facilities among users of homeopathy 
        for self-care, for use of telemedicine in rural populations, 
        for general health and absenteeism in occupational medicine and 
        worker's compensation clinics
  --Inclusion of experienced homeopathic practitioners in CDC 
        evaluation of emerging infections both in the United States and 
        abroad.
                                 ______
                                 
 Production of Pluripotent Stem Cells by Oocyte Assisted Reprogramming
                            joint statement
    As described in the President's Council on Bioethics' recent White 
Paper, altered nuclear transfer (ANT) is a broad conceptual proposal 
for producing pluripotent stem cells without creating and destroying 
embryos. In the description set forth below, we outline a research 
program for a form of ANT that should allow us to produce pluripotent 
stem cells without creating or destroying human embryos and without 
producing an entity that undergoes or mimics embryonic development. The 
method of alteration here proposed (oocyte assisted reprogramming) 
would immediately produce a cell with positive characteristics and a 
type of organization that from the beginning would be clearly and 
unambiguously distinct from, and incompatible with, those of an embryo. 
Incapable of being or becoming an embryo, the cell produced would 
itself be a pluripotent cell that could be cultured to establish a 
pluripotent stem cell line. Significantly, this cell would not be 
totipotent, as a zygote is.
    Our proposal is for initial research using only nonhuman animal 
cells. If, but only if, such research establishes beyond a reasonable 
doubt that oocyte assisted reprogramming can reliably be used to 
produce pluripotent stem cells without creating embryos, would we 
support research on human cells.
    With few exceptions all human cells contain a complete human 
genome, i.e. the complete DNA sequence characteristic of the human 
species. Specifically, one-celled human embryos, pluripotent human 
embryonic stem (or ES) cells, multipotent human adult stem cells, and 
differentiated (specialized) adult human cells such as neurons all 
contain a complete human genome. Thus, possession of a human genome is 
a necessary but not sufficient condition for defining a human embryo 
with its inherent dignity. Rather the nature of each cell depends on 
its epigenetic state, i.e. which subset of the approximately thirty 
thousand human genes is switched on or off and, if on, at what level. 
For example, the gene for albumin, a liver specific protein, is found 
both in human embryos and in adult human liver cells called 
hepatocytes. However, neither the messenger RNA (mRNA) for albumin nor 
the protein itself is found in single-celled embryos because in them 
the gene is silenced.
    This fundamental observation has given rise to the concepts of cell 
fate plasticity and epigenetic ``reprogramming.'' If successful, 
reprogramming converts a cell from one kind to another by changing its 
epigenetic state. The ability to clone animals, such as Dolly the 
sheep, by transfer of a specialized adult nucleus to an enucleated 
oocyte demonstrates the power of epigenetic reprogramming: the oocyte 
cytoplasm is sufficient to reprogram the somatic nucleus to a 
totipotent state. Human cloning has been proposed as a means of 
generating human embryos whose pluripotent stem cells would be used in 
scientific and medical research. Here, through a form of altered 
nuclear transfer, we propose to utilize the power of epigenetic 
reprogramming in combination with controlled alterations in gene 
expression to directly produce pluripotent cells using adult somatic 
nuclei, without generating and subsequently destroying embryos.
    How do pluripotent stem cells differ from totipotent single-celled 
embryos? Several key transcription factors essential for establishing 
and maintaining the pluripotent behavior of ES cells have been 
identified. Importantly, some of these are specifically expressed only 
in pluripotent cells, such as embryonic stem cells or the cells found 
in the inner-cell-mass (ICM) of the week-old embryo or blastocyst. They 
are not expressed in oocytes or single-celled embryos. Expression of 
these factors therefore positively defines and distinguishes mere 
pluripotent cells from embryos. These factors instruct a cell to have 
the identity of a pluripotent cell. Currently, the best studied example 
is the homeodomain transcription factor called nanog (Mitsui, Tokuzawa 
et al. 2003). Nanog is not present in oocytes or single celled embryos, 
but first becomes expressed weakly in the morula and then highly in the 
ICM (Mitsui, Tokuzawa et al. 2003; Hatano, Tada et al. 2005). Deletion 
of nanog does not prevent early cleavage stages of embryogenesis 
including formation of the ICM but does prevent the formation of an 
epiblast (Mitsui, Tokuzawa et al. 2003). ES cells in which nanog is 
blocked lose their pluripotency--which clearly shows that nanog is a 
positive factor instructing cells to be pluripotent, i.e. to behave 
like an ES cell. Furthermore, ES cells which constitutively express 
nanog can no longer be differentiated, i.e. are forced to remain in 
their undifferentiated state (Mitsui, Tokuzawa et al. 2003).
    We propose a procedure that combines epigenetic reprogramming of a 
somatic nucleus with forced expression of transcription factors 
characteristic of embryonic stem cells, to produce a pluripotent stem 
cell. As a result of this procedure, nanog and/or other, similar 
factors,\1\ would be expressed at high levels in somatic cells prior to 
nuclear transfer, to bias the somatic nucleus towards a pluripotent 
stem cell state. Such altered nuclei would then be epigenetically 
reprogrammed by transplantation into enucleated oocytes. Alternatively 
or concomitantly, the mRNA for these same factors could be introduced 
into the oocyte prior to nuclear transfer. This procedure could ensure 
that the epigenetic state of the resulting single cell would 
immediately be different from that of an embryo and like that of a 
pluripotent stem cell: the somatic-cell nucleus would be formed into a 
pluripotent stem-cell nucleus and never pass through an embryonic 
stage. Therefore, unlike some other proposed methods of ANT, this 
method would achieve its objective not by a gene deletion that 
precludes embryonic organization in the cell produced, but rather by a 
positive transformation that generates, ab initio, a cell with the 
distinctive molecular characteristics and developmental behavior of a 
pluripotent cell, not a totipotent embryo. This should allow us to 
produce a pluripotent stem cell line with controlled genetic 
characteristics.
---------------------------------------------------------------------------
    \1\ Nanog is only one example of a growing list of candidate 
factors, numbering probably at least 10. Oct3/4 is another well-studied 
example (3) and is noteworthy because it is also expressed at high 
levels in pluripotent adult stem cells.
---------------------------------------------------------------------------
                   references cited (with abstracts)
    Hatano, S. Y., M. Tada, et al. (2005). ``Pluripotential competence 
of cells associated with Nanog activity.'' Mech Dev 122(1): 67-79.

    Nanog is a novel pluripotential cell-specific gene that plays a 
        crucial role in maintaining the undifferentiated state of early 
        postimplantation embryos and embryonic stem (ES) cells. We have 
        explored the expression pattern and function of Nanog and a 
        Nanog-homologue, Nanog-ps1. Nanog-ps1 was mapped on Chromosome 
        7 and shown to be a pseudogene. Immunocytochemical analysis in 
        vivo showed that the NANOG protein was absent in unfertilized 
        oocytes, and was detected in cells of morula-stage embryos, the 
        inner cell mass of blastocysts and the epiblast of E6.5 and 
        E7.5 embryos, but not in primordial germ cells of early 
        postimplantation embryos. In monkey and human ES cells, NANOG 
        expression was restricted to undifferentiated cells. 
        Furthermore, reactivation of the somatic cell-derived Nanog was 
        tightly linked with nuclear reprogramming induced by cell 
        hybridization with ES cells and by nuclear transplantation into 
        enucleated oocytes. Notably, mouse Nanog (+/-) ES cells, which 
        produced approximately half the amount of NANOG produced by 
        wild-type ES cells, readily differentiated to multi-lineage 
        cells in culture medium including LIF. The labile 
        undifferentiated state was fully rescued by constitutive 
        expression of exogenous Nanog. Thus, the activity of Nanog is 
        tightly correlated with an undifferentiated state of cells even 
        in nuclear reprogrammed somatic cells. Nanog may function as a 
        key regulator for sustaining pluripotency in a dose-dependent 
        manner.

    Mitsui, K., Y. Tokuzawa, et al. (2003). ``The homeoprotein Nanog is 
required for maintenance of pluripotency in mouse epiblast and ES 
cells.'' Cell 113(5): 631-42.

    Embryonic stem (ES) cells derived from the inner cell mass (ICM) of 
        blastocysts grow infinitely while maintaining pluripotency. 
        Leukemia inhibitory factor (LIF) can maintain self-renewal of 
        mouse ES cells through activation of Stat3. However, LIF/Stat3 
        is dispensable for maintenance of ICM and human ES cells, 
        suggesting that the pathway is not fundamental for 
        pluripotency. In search of a critical factor(s) that underlies 
        pluripotency in both ICM and ES cells, we performed in silico 
        differential display and identified several genes specifically 
        expressed in mouse ES cells and preimplantation embryos. We 
        found that one of them, encoding the homeoprotein Nanog, was 
        capable of maintaining ES cell self-renewal independently of 
        LIF/Stat3. Nanog-deficient ICM failed to generate epiblast and 
        only produced parietal endoderm-like cells. Nanog-deficient ES 
        cells lost pluripotency and differentiated into extraembryonic 
        endoderm lineage. These data demonstrate that Nanog is a 
        critical factor underlying pluripotency in both ICM and ES 
        cells.
                               endorsers
    Institutional affiliations are provided for purposes of 
identification only and do not necessarily represent the views of 
organizations with which endorsers are affiliated. Endorsers who are 
not themselves specialists in biomedical science do not put themselves 
forward as experts in that field. Their endorsement of the proposal 
pertains to the ethics of ANT-OAR, assuming its technical feasibility.

Hadley Arkes, Ph.D.; Edward N. Ney Profesor of Jurisprudence and 
        American Institutions, Amherst College, Amherst, MA; Rev. 
        Nicanor Pier Giorgio Austriaco, O.P., Ph.D., Assistant 
        Professor of Biology, Providence College, Providence, RI; Rev. 
        Thomas Berg, L.C., Ph.D., Executive Director, The Westchester 
        Institute for Ethics and the Human Person, Thornwood, NY; E. 
        Christian Brugger, D. Phil., Assistant Professor of Theology, 
        Institute for Psychological Sciences, Arlington, VA; Nigel M. 
        de S. Cameron, Ph.D., President, Institute on Biotechnology and 
        the Human Future, Research Professor of Bioethics, Chicago-Kent 
        College of Law, Illinois Institute of Technology, Chicago, IL; 
        Joseph Capizzi, Ph.D., Catholic University of America, Fellow, 
        Culture of Life Foundation, Washington, D.C.; Maureen L. 
        Condic, Ph.D., Associate Professor of Neurobiology, University 
        of Utah, School of Medicine, Salt Lake City, Utah; Samuel B. 
        Condic, M.A., Department of Social Sciences, University of 
        Houston--Downtown, Houston, TX; Rev. Kevin T. FitzGerald, S.J., 
        Ph.D., Dr. David P. Lauler Chair in Catholic Health Care 
        Ethics, Center for Clinical Bioethics Research, Associate 
        Professor Department of Oncology, Georgetown University Medical 
        Center, Washington, D.C.; Rev. Kevin Flannery, S.J., D. Phil., 
        Dean of the Philosophy Faculty, Pontifical Gregorian 
        University, Rome, Italy; Edward J. Furton, Ph.D., Ethicist, The 
        National Catholic Bioethics Center, Philadelphia, PA; Robert P. 
        George, J.D., D. Phil., McCormick Professor of Jurisprudence, 
        Princeton University, Princeton, NJ; Timothy George, Th. D., 
        Dean, Beeson Divinity School, Samford University, Birmingham, 
        AL; Alfonso Gomez-Lobo, Dr. Phil., Ryan Professor of 
        Metaphysics and Moral Philosophy, Georgetown University, 
        Washington, D.C.; Germain Grisez, Ph.D., Flynn Professor of 
        Christian Ethics, Mount Saint Mary's University, Emmitsburg, 
        Maryland; Markus Grompe, M.D., Director, Oregon Stem Cell 
        Center, Portland, OR; John M. Haas, Ph.D., President, The 
        National Catholic Bioethics Center, Philadelphia, PA; Robert 
        Hamerton-Kelly, Th.D, Dean of the Chapel (Retired), Stanford 
        University, Palo Alto, CA; John Collins Harvey, M.D., Ph.D., 
        Senior Research Scholar and Professor Emeritus of Medicine, 
        Center for Clinical Bioethics, Georgetown University Medical 
        Center, Washington, DC; Paul J. Hoehner, M.D., M.A., FAHA, 
        Harvey Fellow in Theology, Ethics and Culture, The University 
        of Virginia Graduate School of Arts and Sciences, Associate 
        Professor of Anesthesiology, The University of Virginia Health 
        Sciences Center, Charlottesville, VA; William B. Hurlbut, M.D., 
        Consulting Professor in the Program in Human Biology, Stanford 
        University, Palo Alto, CA; John F. Kilner, Ph.D., President, 
        The Center for Bioethics and Human Dignity, 2065 Half Day Road, 
        Bannockburn, IL; Patrick Lee, Ph.D., Professor of Philosophy, 
        Franciscan University of Steubenville, Steubenville, OH; 
        William E. May, Ph.D., Michael J. McGivney Professor of Moral 
        Theology, John Paul II Institute for Studies on Marriage and 
        Family at The Catholic University of America, Washington, D.C.; 
        Rev. Gonzalo Miranda, L.C., Ph.L., S.T.D., Dean of Bioethics, 
        Regina Apostolorum Pontifical Athenaeum, Rome, Italy; C. Ben 
        Mitchell, Ph.D., Associate Professor of Bioethics & 
        Contemporary Culture, Trinity International University, 
        Bannockburn, IL; Most Reverend John J. Myers, J.C.D., D.D., 
        Roman Catholic Archbishop of Newark, NJ; Chris Oleson, Ph.D., 
        Associate Professor of Philosophy, Center for Higher Studies, 
        Thornwood, NY; Rev. Tad Pacholczyk, Ph.D., Director of 
        Education, The National Catholic Bioethics Center, 
        Philadelphia, PA; Rev. Peter F. Ryan, S.J., S.T.D., Associate 
        Professor of Moral Theology, Mount St. Mary's University, 
        Emmitsburg, MD; William L. Saunders, J.D., Senior Fellow and 
        Director, The Center for Human Life & Bioethics, The Family 
        Research Council, Washington, D.C.; David Stevens, M.D., M.A., 
        Executive Director, Christian Medical & Dental Associations, 
        Bristol, TN; Rev. Msgr. Stuart W. Swetland, S.T.D., Director, 
        The Newman Foundation, Adjunct Associate Professor, University 
        of Illinois at Urbana-Champaign, Urbana, IL; M. Edward Whelan 
        III, J.D., President, Ethics and Public Policy Center, 
        Washington, D.C.; and Rev. Thomas Williams, L.C., Ph.L., 
        S.T.D., Dean of Theology, Regina Apostolorum Pontifical 
        Athenaeum, Rome, Italy.

                         CONCLUSION OF HEARING

    Senator Harkin. With that, again, I will join with Senator 
Specter in saying that this was a very good panel and we thank 
you very much. I thank you for what you are all doing in your 
individual capacities to try to find our way through this maze, 
and thank you for being here today. Please keep up your good 
work.
    Thank you all very much for being here. That concludes the 
hearing.
    [Whereupon, at 11:08 a.m., Tuesday, July 12, the hearing 
was concluded, and the subcommittee was recessed, to reconvene 
subject to the call of the Chair.]

                                   - 
