[Senate Hearing 109-675]
[From the U.S. Government Publishing Office]
S. Hrg. 109-675
ALTERNATIVE METHODS FOR DERIVING STEM CELLS
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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
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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
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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
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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.
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\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.
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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.
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\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.
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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.
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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.
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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.
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\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.
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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?
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\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.''
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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\
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\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.
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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.]
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