WHITE PAPER: Alternative Sources of Pluripotent Stem CellS
The President's Council on Bioethics
Washington, D.C.
May 2005
www.bioethics.gov
Personal Statements
The preceding text constitutes the official body of this White
Paper; it stands as the work of the entire Council. In the interest
of contributing further to public discussion of the issues, and
of enabling individual members of the Council to speak in their
own voice on one or another aspect of this White Paper, we offer
in this Appendix personal statements from those members who have
elected to submit them:
Statement of Michael S. Gazzaniga, Ph.D.
Statement of Robert P. George, D.Phil., J.D.,(joined
by Mary Ann Glendon, J.D., M. Comp. L., and Alfonso Gómez-Lobo,
Dr. phil.)
Statement of William B. Hurlbut, M.D.
Statement of Janet D. Rowley, M.D., D.Sc.
Statement of Michael J. Sandel, D.Phil.
***
Personal Statement of Dr. Gazzaniga
I do not support publishing this report with the implied endorsement
that special efforts be made in the scientific areas described.
While some of the suggestions could be explored in a scientific
setting, most are high-risk options that only have an outside chance
of success and raise their own complex set of ethical questions.
Of primary concern: this effort is a diversion from the simple task
at hand which is to move forward with the established laboratory
techniques, that are already grounded on a clear ethical basis,
for studying embryonic stem cell research and biomedical cloning.
The simple proposals that are now widely accepted by the majority
of ethicists and scientists alike are as follows:
Allow the use of spare IVF embryos to develop more human stem
cell lines. These are entities that do not possess a single
neuron and are ready to go and can create tens of thousands of cell
lines. Put another way, a piece of DNA is not a human being. A human
being is an entity with a functioning brain consisting of billions
of neurons with trillions of synapses that develops over time and
with crucial interactions with the environment.
Allow biomedical cloning (SCNT) to go forward.This laboratory
procedure has been tested and it works. SCNT can only be carried
out in a laboratory and the 14-day-old entity that results from
the procedure also has not a single neuron. After the specific stem
cells are harvested by 14 days, the remaining tissue is disposed
of.
From a purely scientific point of view I offer the following remarks
on the alternative suggestions made by the Council, based on consultation
with stem cell experts:
Proposal 1, the Landry-Zucker proposal, is absolutely dependent
on defining a battery of "death markers." The criteria they offer
lack the specificity and selectivity required. To what degree, for
example is "embryo-dead" analogous to "brain dead?" What are the
long-term consequences (through adulthood) of using blastomeres
from "dead" morulae? These are answerable, but formidable problems.
Blastomere removal must be validated in vitro and in vivo, with
respect to mitosis, survival, differentiation, etc., none of which
are inaccessible. No assumption whatsoever can be made that these
are "normal cells." At the same time, these questions are scientifically
accessible.
Proposal 2, relies on biopsy, and this represents a new
field, which must be explored experimentally. For example, and most
obviously, what is the relationship of cellular to organ removal
and transplantation? Are the biological rules homologous? We need
the data.
Proposal 3, Bill Hurlbut's proposal, is also scientifically
tractable, though fraught with ethical conundrums. Defective nuclear
transfer could certainly be accomplished in theory, though issues
of viability, etc., would be paramount. And replacing genes at the
"wrong" time could be devastating either acutely or chronically.
Although a myriad of additional potential problems could be cited,
they are again empirical, not theoretical. Why delay what we know
works with this sideshow? As pointed out in the paper, one of the
leading stem cell research scientists in the world, Dr. Doug Melton
at Harvard, has written an article in the New England Journal
of Medicine dismissing this idea both scientifically and practically.
Proposal 4, dedifferentiation, is similarly approachable
scientifically, though it is a high-risk strategy. Questions, however,
raised with this idea can be answered with a huge and costly scientific
program in place.
At the same time and from an ethical perspective, I must add that
I find this proposal strained at best. Winding the clock back on
a developed somatic cell and to stop it at a critical point is supposed
to be void of ethical issues while letting a cell grow forward to
just before the same point as with SCNT is not ethical?
This is the potentiality argument in reverse. In one version the
film of life is running forward and in the other it is running in
reverse. In both scenarios humans are making decisions about life
and its origins. It reveals how the so-called ethical concerns are
being laid over molecular events moving either forward or backward
in time.
In summary, these proposals, in spite of being experimentally
approachable, are, ultimately, high-risk gambles. Each presents
formidable, but not impossible, technical problems. The scientific
challenges must not be confounded with the complex moral issues.
Most troubling, this effort dilutes the essential question: Is the
United States of America going to allow embryonic stem cell research
and biomedical cloning to go forward using the now widely accepted
techniques used by the private sector, by the State of California,
and by dozens of other countries, or is it going to remain hostage
to the arbitrary views of those with certain beliefs about the nature
of life and its origins?
Michael S. Gazzaniga
***
Personal Statement of Professor George (joined
by Professor Glendon and Dr. Gómez-Lobo)
I support the Council's efforts to identify means of obtaining
human pluripotent stem cells for biomedical research that do not
involve killing or harming human embryos and do not invite the exploitation
of women to obtain ova. If such means can be identified, research
involving embryonic or embryonic-type stem cells could go forward,
and be funded by the federal government, without ethical qualms
and controversy. Assuming that supporters of embryonic stem cell
research and its public funding are sincere in saying that they
have no intention or desire to derive tissue or organs from post-implantation
human embryos or from human fetuses, this would bring to a close-honorably
and without rancor-a divisive chapter in our recent history. Frankly,
I do not see how any person of goodwill could be opposed to such
a resolution of the matter.
I commend everyone who has stepped forward to propose possible
methods of obtaining human pluripotent stem cells while fully respecting
human life at every stage of development. I thank our Council's
staff and consultants who have helped to provide in this White Paper
a thorough, if necessarily in some ways still preliminary, analysis
of each of the four proposals we sketch and analyze. Although I
do not hold out hope of obtaining pluripotent stem cells harmlessly
via blastomere extraction from living human embryos (proposal II),
I believe that each of the other three proposals merits further
exploration (including, where indicated, experimental research involving
non-human animal cells) and analysis.
The best long-term solution is likely to be somatic cell dedifferentiation
(proposal IV). But while scientists work towards the goal of dedifferentiating
somatic cells back to their corresponding progenitor cells, it may
be possible ethically to employ one or both of the other two
methods, namely deriving cells from embryos that have died (proposal
I) or from nonembryonic entities produced by altered nuclear transfer
(proposal III). I say, with emphasis, may be because serious
moral and practical concerns have been raised about both proposals.
Research and further analysis will be required to determine whether
the proposed methods are technologically possible and ethically
sound. That research and analysis should, in my opinion, go forward.
Of the four possible methods explored in our White Paper, the
one that has attracted the most intense interest outside the Council
is altered nuclear transfer. There are two major concerns: (1) the
question whether the entity produced would be truly non-embryonic,
and not a disabled embryo or an embryo genetically programmed for
a premature death; and (2) the question whether ova could be supplied
without subjecting women to the painful and possibly dangerous process
of superovulation. Neither of these questions is, strictly speaking,
ethical, though both have what I consider to be decisive ethical
implications. Like Dr. Hurlbut, who has taken the lead in formulating
this proposal, I will not support altered nuclear transfer as a
method of obtaining human pluripotent stem cells unless it can be
shown that (1) the procedure truly and reliably produces nonembryonic
entities, rather than damaged embryos, and (2) it is possible to
carry out altered nuclear transfer on the scale required without
subjecting women to harmful and exploitative practices.
I recognize that some people have objections to altered nuclear
transfer even if these conditions are met. Dr. Krauthammer, for
example, objects even if the sources of stem cells created can be
shown truly to be nonembryonic. Because Dr. Krauthammer also objects
(as I do) to the creation for destruction of true embryos (by cloning
or any other method), I take his concerns very seriously and welcome
his criticisms of my own more permissive view. I would not finally
endorse altered nuclear transfer using human cells prior to engaging
the argument with him more fully and considering with the utmost
care the considerations he adduces against it.
It is more difficult to credit the ethical objections to altered
nuclear transfer of those who support the creation of true embryos to
be destroyed in biomedical research. How can it be right deliberately
to create and destroy true human embryos-beings that no one can deny
are human individuals in the embryonic stage of development-yet somehow
wrong to produce disorganized growths that are the moral equivalent of
gamete tumors rather than embryos?
One final point: the effort in which I am happy to join to find
morally legitimate means of obtaining embryonic or embryonic-type
stem cells should not be interpreted as indicating any acceptance
of the hyping of the therapeutic promise of embryonic stem cell
research that has marred the debate over the past four years. This
promotion of exaggerated expectations dishonors science and shames
those responsible for it by cruelly elevating the hopes of suffering
people and members of their families. It should be condemned.
Robert P. George
(joined by Mary Ann Glendon and Alfonso Gómez-Lobo)
***
Personal Statement of Dr. Hurlbut
Since I find myself in the unusual position of being both a member
of the Council and, at the same time, the principal advocate of
one of the four proposals here under consideration, I am mindful
that a delicate balancing of roles is required in the way I frame
the following remarks. I shall take care that my comments not cross
the line separating impartial analysis of the four proposals from
partisan advocacy of one of them.
While I believe that, by and large, the White Paper, like a good
preliminary hearing at law, does an admirable job of presenting the
four proposals and beginning their ethical, scientific, and practical
analysis, it seems to me deficient in two main respects. First, I think
there is much more to be said about the importance, for the future, of
finding a scientific and ethical solution to the problem of deriving
human stem cell lines. Second, I think that some of the ethical
concerns raised about the ANT proposal could have been answered more
effectively. In the brief remarks that follow, I will try to supply
these two deficiencies.
1. General comments about the importance of the project
In our report Human Cloning and Human Dignity: An Ethical Inquiry
(July 2002), I joined colleagues who called for a moratorium on
cloning-for-biomedical-research. I believed that our nation needed
time to consider more thoroughly the moral status of ex vivo human
embryos and to seek scientific methods for procuring embryonic stem
cells that could sustain social consensus for a unified federal
policy. This White Paper both deepens the dialogue and encourages
progress toward these goals, but it does not make it sufficiently
clear why it is urgent that we succeed.
The past three years have been characterized by controversy about
the scientific prospects for embryonic (versus adult) stem cells
and a widening political divide over the ethics of ESC research.
Advances have been made in the study of ES cells, yet predictions
of imminent cures have been moderated by a recognition of the technical
difficulties in emulating in vitro the intercellular signals and
microenvironments that promote cell differentiation within natural
embryogenesis. Nonetheless, scientists generally believe that ESC
research is both essential to the broader study of both natural
development and pathogenesis and promising for medical interventions
against a range of serious diseases. They also believe that, without
NIH support for newly created ES cell lines, progress in this important
realm of research will be severely constrained.
Yet even as these scientific prospects have become clearer, advances
in our understanding of developmental biology have strengthened
the case of those with ethical objections to embryo destruction.
New scientific evidence supports the idea that there is an integrated
unity and unbroken continuity of development from fertilization
onward-and undercuts claims that the early embryo is an "inchoate
clump of cells," available for instrumental use with little or no
moral concern.
These findings have solidified the convictions of many people
that any instrumental use of human embryos must be acknowledged
as a choice for destruction of human life (albeit at a very early
stage of development), justified not by scientific evidence or moral
reason but by a purely utilitarian calculus based on the promise
of cures and even commercial considerations. This approach, grounded
not on principle but on a balance of benefits, would seem vulnerable
to being easily persuaded toward additional exceptions and extensions
as further promising projects become evident.
Beyond their destruction for the procurement of ES cells, some
fear the industrial scale production of living human embryos for
a wide range of research in natural development, toxicology, and
drug testing. These concerns have already been aggravated by proposals
to use ES cells in the creation of human-animal chimeras, including
projects involving their gestation to various stages of development
in the wombs of animals. Furthermore, some see ominous implication
in the evidence that later stage human embryos (beyond 14 days)
can provide the critical conditioning environment for the transformation
of adult stem cells into useful cell types, tissues, and possibly
organs.
Our current 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. Furthermore, the emerging
patchwork of state policies threatens to create a situation in which
many patients will enter the hospital with qualms about the moral
foundations on which their treatments have been developed. The traditional
sanctuary of compassionate care at the most vulnerable and sensitive
moments of human life is becoming an arena of controversy and conflict.
As we enter the era of developmental biology, we will face many
more moral dilemmas; the current conflict over ES cells is just
the first of a series of difficult controversies over the experimental
use of emerging life that will require us to define with clarity
and precision exactly which boundaries we seek to defend. Chimeras, parthenotes, and projects involving
the reaggregation of ES cell products will continue to challenge
our definitions of human life. How we act now in the stem cell
dilemma will set a precedent for all future efforts to exploit nascent
human life for scientific ends. There is thus much more at stake
than the proposals herein discussed.
The proposals presented in this White Paper open a realm of intellectual
inquiry and creative scientific investigation in the search for
a solution to our current impasse over the procurement of embryonic
stem cells. Such a solution must be grounded in deep ethical reflection
and in careful preliminary studies with animal cells. The incommensurate
good of human life, and the corresponding danger of its instrumental
use (thereby violating the principle we are trying to protect),
mean that the highest levels of caution must prevail as we proceed
forward with this project. 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.
2. Answers to ethical concerns raised about
ANT
Throughout this report we draw a distinction between pluripotency,
the capacity to give rise to many if not all the different cell
types of the human body, and totipotency, the capacity to
give rise to the whole organism as an integrated living being. Employing
these concepts in the search for a technological solution to our
ethical impasse, we must consider any entity that has the intrinsic
potential to develop as a human organism (totipotency) as bearing
the inviolability of a human life. This status applies regardless of its means of
production or present location.
Proposals 1 (Landry-Zucker) and 3 (Altered Nuclear Transfer) may
hold the best near-term promise for practical application, yet they
also raise the most difficult conceptual considerations. Landry-Zucker
would extract ES cells from embryos that are no longer totipotent,
and Altered Nuclear Transfer (ANT) would create and extract ES cells
from "biological artifacts" that never rise to the level of totipotency.
Both proposals shift 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 living
human organism.
Each of these proposals draws on the idea that a living organism
is a self-subsisting being, a coordinated and coherent whole with
the capacity for self-directed development, maintenance, and repair.
The very word organism implies organization, an overarching
principle of unity, a cooperative interaction of interdependent
parts subordinated to the good of the whole. For an embryonic organism,
this implies an inherent potency, a drive in the direction of the
mature form. By its very nature, an embryo is a developing being,
its wholeness defined by both its manifest expression and its latent
potential; it is the phase of human life in which the organismal
whole produces its organic parts.
For Landry-Zucker, the conceptual and moral challenge is to define
the meaning of "embryo death," the cessation of integrated form
and the totipotent capability that characterizes a living human
embryo. A secondary, scientific challenge is to identify a physical
marker of this state. For Altered Nuclear Transfer, the conceptual
and moral challenge is the more difficult task of defining the boundary
between mere cellular growth lacking integrated form and a living
organism. The scientific challenge of ANT is to find the right genetic
or epigenetic alteration to ensure that pluripotent cells can be
produced while not creating an embryonic human being. It is here
that the White Paper, in my view, does not make sufficiently clear
how the proposal in fact meets that challenge.
That an ANT product might during its earliest stages visually
resemble an embryo does not make it an embryo, for an entity's fundamental
nature must ultimately be based on its internal biochemical structure
and organization. Likewise, cell division and growth are not sufficient
evidence that the entity is a human embryo. 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. Moreover, the possibility that the alteration
could be reversed does not affect the fact that the targeted alteration
has preempted the ANT entity from having the nature (the ontological
status) of an embryo.
The product of ANT would, by intention, lack the active potential
and inviolable moral nature of a living human being. Without this
moral standing, there is no obligation of repair because there is
no living being to be repaired. Nonetheless, even such a limited
biological entity should be accorded a certain cautionary respect
as with all human tissues, though not the full protection of human
life.
Some fear that the precedent of intentional genetic intervention
(essential to ANT), and its justifying argument based on the intrinsic
insufficiency of the entity produced, could become the basis for
further projects in the bioengineering of ever more human-like "intermediate
biological forms." This is a serious consideration, but one that
would be better addressed to those who maintain an "intermediate
moral status" (worthy of dignity but not inviolability) for the
human embryo and already accept the destruction of fully normal
human beings at an early stage of their development.
The very foundation of the moral argument for ANT should work
to mitigate the concerns about the "slippery slope" potential for
ES cell research. Since ANT seeks to defend human dignity from conception,
it is less likely to lead to such indiscriminate and instrumental
use of human life than the practices it seeks to preempt. By establishing
a principled concern for the protection of human life from fertilization
to natural death, ANT sets a firm foundation for the later distinctions
necessary for further moral discrimination. Other proposals for
the procurement of ES cells (SCNT and "leftover" IVF embryos) give
little or no guidance to override the persuasive power of further
promise from extending exceptions to moral principles. By establishing
the primacy of ethical principle as the foundation of all scientific
progress, ANT could help set the foundation and frame for the additional
ethical dilemmas that will inevitably arise with advances in developmental
biology. The difficult definitions and distinctions established
in the moral deliberations associated with the ANT proposal could
help chart the course and protect the path of future projects in
this emerging arena of biology. If slippery slope arguments express
prudential concerns, it seems reasonable to weigh ANT against the
much more slippery scenario that will likely follow in its absence.
Finally, there is the less easily argued but wider wisdom of our intuitive
aesthetic response, and the concern that somehow we may violate
or distort the principles of natural order that sustain the coherence
and sense of significance of human life. I consider this the most
compelling objection to both ANT and the whole of the modern project
of biological intervention in the natural world. Clearly, no project
that enters into such proximity with the most central and sacred
realms of human life should be undertaken without a sense of cautionary
concern and serious purpose. Employing these powers of our most
basic biology demands a sensitive awareness of the radiance of respect
that must attend any technological use of body parts or processes
apart from their proper place in the larger purposes of life. Nonetheless,
where great good is possible, human tissues and organs have been
used in the service of healing, and in this coming era of control
over the primary forces of developmental biology, we will learn
to use partial trajectories of organic growth even apart from their
context within the living whole of the human body. The moral concerns
and sensitivities that animate the proposal for ANT can, in fact,
enable us to do so without losing our humanity.
William B. Hurlbut
See Yokoo, T., et al., "Human mesenchymal stem cells in rodent
whole-embryo culture are reprogrammed to contribute to kidney
tissue," Proceedings of the National Academy of Sciences USA
102(9), 3296-3300 (March 1, 2005).
These
studies will not be limited to ES cells and the first few days
of embryogenesis, since there are compelling scientific and medical
reasons to seek an understanding of the entire trajectory of human
biology from fertilization to natural death. Beyond the obvious
benefit of understanding the fundamental biological factors behind
the estimated 200,000 birth defects per year, it is becoming increasingly
evident that pathologies that manifest themselves in adult life
(such as hypertension, diabetes, etc.) are influenced by, or have
their origins in, early development.
A
practical measure of this intrinsic potential would be the ability
to develop when provided the support and nurture of a natural
gestational environment or its technological equivalent.
***
Personal Statement of Dr. Rowley
Proposal 1
Landry and Zucker propose to thaw out embryos to follow the natural
history of "dead" embryos. Because they do not know in advance which
embryos will not divide and which will, some portion of embryos (about
half) will continue to divide and will be healthy embryos. What happens
to these healthy embryos? The proposal says healthy embryos in excess
of those to be implanted will be allowed to die while scientists
struggle to recoup a few living cells from the dead embryos! This seems
to me to be the height of folly. As noted on page 21 in a footnote, I
raised this concern during the public discussion.
Proposal II
I think this is risky research, although I recognize it is currently
done as part of prenatal genetic diagnosis. In the latter case, it is
done to prevent implantation of an embryo with a serious disease
present in the parents; in the former, in the present proposal, it is
done to circumvent a problem that causes ethical concerns to some
people. There are at least two critical questions: can you get a cell
line from one cell or two, and does it harm the embryo that will
subsequently be implanted? Just because experiments in mice seem to
indicate that it is feasible in mice (but with increased inter-uterine
mortality), does not mean it will work for human embryos. In support of
this proposal, it is absurd to say that this cell line, if it grows,
will be a source of cells for the child later in life. A much more
effective procedure would be to harvest stem cells from the cord blood
and preserve them.
Proposal III
This proposal is scientifically unsound, and for individuals concerned
about manipulating human oocytes for experiments, it should be
ethically unacceptable! It has proven very inefficient to remove the
nucleus from a human oocyte and to replace it with a normal,
unmanipulated nucleus from a donor. In the proposed experiments, the
donated nucleus will be made defective by some uncertain genetic
strategy. The defective nucleus will be inserted into the enucleated
oocytes, the oocytes will be stimulated to grow, and then the genetic
defect will be corrected so that the cells are "normal." In my view,
this research asks women to donate oocytes for research that is highly
unlikely to result in cell lines that would be useful for treating sick
patients, which is the purpose of trying to perfect the development of
human embryonic stem cell lines.
Proposal IV
This proposal does not involve embryos, but rather differentiated cells. The
purpose aims to dedifferentiate these cells. At least some of the
purported successes with this strategy have had flaws when examined
carefully. This proposal should be submitted to the National Institutes
of Health and if it passes peer review with a sufficiently high
score to be funded, then the research will go forward.
My concerns with many of these proposals is that they will use
financial resources that would be better devoted to proposals that
are likely to be more productive. I find the notion that it is ethically
sound to let healthy embryos die rather than use them to try to
develop cell lines that could benefit sick and dying patients totally
baffling. We talk about protecting human dignity. We should strive
to help patients with serious illnesses that could potentially be
treated with embryonic stem cells to live as fulfilling and dignified
lives as is humanly possible. The research proposed in this White
Paper largely fails to achieve this good, and thus I cannot support
proposals I, II and III.
Janet D. Rowley
***
Personal Statement of Professor Sandel
I share the goal of seeking ethically uncontroversial ways of
pursuing embryonic stem cell research. In my view, the first proposal
(deriving cells from dead embryos) and the fourth (somatic cell
dedifferentiation) are ethically acceptable and worthy of further
exploration. I find the third proposal (deriving cells from specially
engineered biological artifacts) to be morally objectionable.
As one who supports embryonic stem cell research, I do not regard
the early embryo as inviolable. But neither do I regard it as disposable,
open to any use we may desire or devise. For this reason, embryo
research carries a special moral burden; it is justified only for
the sake of saving human lives or curing devastating diseases. The
proposal to genetically engineer a nonviable, embryo-like being
would remove the moral burden by creating something that, lacking
the capacity to develop into a human person, would be wholly disposable,
presumably for any purpose, weighty or trivial. The very project
of creating such a being is morally troubling, for reasons that
are well-stated in the ethical analysis (pp. 38-45 above). I therefore
do not believe that this proposal should be encouraged or endorsed.
Michael J. Sandel
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