Winter, 2005
This is an edited and updated transcript of a forum presented by the Harvard Medical School Division of Medical Ethics in November 2004. it was moderated by Dan W. Brock, PhD, Director of the Division of Medical
Ethics.
Few medical ethics issues have attained the public prominence of stem cell research. There are a number of reasons for this that we will explore today. One of course is the great scientific and medical promise that stem cell research holds both for understanding many diseases and then, further down the line, treating them. There's also great ethical concern because producing embryonic stem cell lines requires the destruction of human embryos. At least some persons view human embryos as full human persons. Many more view them as at least deserving of significant respect. There are also policy concerns about how to regulate stem cell research. Other countries such as Great Britain have a regulatory body to license research in this area, but at this point, the United States does not.
George Q. Daley, MD, PhD,
is Associate professor of Pediatrics in the Division of Hematology/Oncology at Children's hospital and Associate Professor of Biological Chemistry and Molecular pharmacology at Harvard Medical School.
I will start by defining the stem cell as a single cell that can both self-renew and generate progeny that continue to differentiate or specialize. In contrast to the rather restricted developmental possibilities for stem cells in the adult, the stem cells of the early embryo are fated to become all of the tissues of the body. One can isolate these embryonic stem cells from the five-day old human blastocyst, grow them extensively in culture and coax them to form specific cells and tissues that scientists hope will one day enable the treatment of a range of diseases by cell replacement therapy.
What are the diseases that might be treated by cell therapies? I offer three simple criteria: 1) diseases that represent the loss of a single cell type, 2) diseases for which evidence already exists that transplantation of whole organs or cells will ameliorate the condition and 3) diseases for which the current supply of organs or tissues are limited. By these criteria, insulin dependent diabetes type 1, which results from autoimmune destruction of the insulin-producing beta cells of the pancreas, is an excellent target. Diabetes can be treated effectively by whole pancreas or islet cell transplant, but organ supply is severely limited. A second disease is Parkinson's, a movement disorder caused by loss of mid-brain dopaminergic neurons. Patients who receive transplants of midbrain tissue from aborted fetuses have shown motor improvement in some cases. Clearly, embryonic stem cells represent a preferred source for dopaminergic neurons. Finally, work in
my own laboratory is aimed at treatment of a variety of genetic and malignant blood disorders. Bone marrow transplantation harnesses the regenerative power of hemopoietic stem cells to cure leukemia, but unfortunately most patients don't have suitable tissue-matched bone marrow donors. My laboratory has succeeded in generating a supply of adult hemopoietic stem cells from embryonic stem cells.
There are two significant challenges to using embryonic stem cells in therapy. First, undifferentiated embryonic stem cells have tumor-forming potential, and therefore we must go to great lengths to purify the specialized cell of interest away from the undifferentiated embryonic stem cells in order to minimize the risk of tumor formation in treated patients.
Second, the tissue products of embryonic stem cells will face the same immune barrier that complicates organ transplantation. Until we can overcome this threat of rejection of transplanted cells, we must poison the recipient patient's immune system with Stem Cell Research: Science, Ethics and Policy immunosuppressive drugs, leaving the patient susceptible to life-threatening infection. One of the most theoretically appealing strategies for overcoming the immune barrier to cell transplantation is to combine somatic cell nuclear transfer (SCNT) with embryonic stem cell biology to create tissues that are genetically identical to the patient.
Let me take you through how SCNT might be applied to a patient with sickle cell anemia. This procedure would involve microsurgical extraction of the nucleus from one of this patient's cells, say a skin cell, and transfer of the nucleus into a human egg (from which the DNA has first been removed by a micro-needle). This reconstructed cell is then activated chemically or by an electric shock. With this process, the genes that are active in the skin cell nucleus are silenced, and the genes that are normally active during early embryonic development are reawakened. The skin cell begins to cleave, and the cluster of cells that develops begins to adopt the structure of a blastocyst, an early stage embryo. That embryo harbors pluripotent stem cells that can be extracted and placed in the petri dish, and grown as a continuous line of embryonic stem cells. Because these embryonic stem cells derive from the nucleus of our patient, they are a perfect genetic match and carry the genetic lesion typical of sickle cell anemia. The genetic lesion can be repaired directly in this line of cells. The repaired cells can then be differentiated into blood stem cells and transplanted into the patient without the need of immune suppression, because the blood cells are genetically identical to the patient. If successful, normal blood cells would grow in the patient, effectively reversing the sickle cell anemia.
While much of the promise of embryonic stem cells derives from our hopes for treating patients, I want to make a very important point. Even if embryonic stem cells are never successful as therapies, they remain enormously valuable tools for scientists in basic research. These cells can teach us about aspects of human developmental biology and gene control. They're becoming increasingly employed in the pharmaceutical industry as a way of validating drug targets, for providing assays for drug development and as surrogates for certain forms of drug toxicity testing, thereby limiting the use of animals.
The science is progressing very, very quickly and is proceeding under the cloud of a vigorous ethical debate. The debate hinges on the source of embryonic stem cells, which are human blastocysts - the earliest stage of human embryonic development. Couples that undergo in vitro fertilization are often left with excess blastocysts and are, thereafter, faced
with the decision to discard them as medical waste, or to donate them to medical research. Many in the general public don't appreciate that the human blastocyst is a miniscule speck of cells, a cluster smaller than the period at the end of this sentence. The blastocyst harbors no specialized tissues, no neurons and no bodily form. The fact that it is a primitive, unspecialized clump of cells doesn't negate the fact that the moral status of this entity is what is at issue. At conception, a new genome is formed, a fact that is frequently offered as a biological definition of the beginning of life. But from a biologist's perspective, the beginning of meaningful individual life is a bit fuzzier. Of course, one can quibble with the definition of individual, but twinning can occur up to 14 days after conception, and some normal individuals are actually the products of two distinct conception events and represent the coalescence of four gametes, a condition called tetragametic chimerism, which can be compatible with normal human development.
President Bush supports research on a small set of embryonic stem cell lines that were derived prior to August 9, 2001. The NIH Registry lists 22 such lines, a small minority of the cell lines that were promised when bush announced his policy three years ago. Today, the numbers and variety of human embryonic stem cells is increasing daily. Many of these lines have advantageous features that make them valuable to scientists interested in studying particular diseases, including lines that carry disease-specific mutations, essentially modeling human disease in the petri dish. Unfortunately,
none of these new, medically relevant lines can be studied with federal dollars. There is also no funding for the use of SCNT to treat disease.
Let me finish by reiterating that embryonic stem cells are important research tools. Scientists are already making important discoveries that advance understanding of human development and disease. One hopes that
eventually our capacity to direct the differentiation of human embryonic stem cells will usher in a critical new modality of medicine: cellular therapy. My advocacy of human embryonic stem cell research is in no way meant to trivialize the value of somatic or adult stem cells. I support research on both. I also believe that research into the process of somatic cell nuclear transfer is critical to realizing the ultimate and full potential of stem cells.
Michael J. Sandel, DPhil,
is Anne T. and Robert M. Bass Professor of Government at harvard University and also a member of The President's Council on Bioethics.
There are two main objections to embryonic stem cell research. One might be called the embryo objection. This has to do with the fact that extracting the stem cells kills the embryo. It destroys what some regard as a human life and what most people would agree is at least potential human life. The second objection is the slippery slope objection. It holds that, even if embryonic stem cell research isn't wrong in itself, it is likely to lead to morally objectionable practices. According to this objection, stem cell research today on embryos left over from fertility clinics will lead tomorrow to the desire to go further: to create embryos for stem cell research through cloning or somatic cell nuclear transfer. And if therapeutic cloning becomes a widespread practice, the argument continues, sooner or later it will
lead to human reproductive cloning. Let's first say something about the slippery slope objection.
Perhaps the most familiar and serious version of the slippery slope objection is the worry that it will lead to human reproductive cloning. Reproductive cloning is currently unsafe; I would argue that, even if it were safe, it would be morally objectionable. The desire to create a child through cloning is objectionable because it springs from the desire to create a child of a certain kind. This is the designer baby worry, which seems to me a reason to oppose human reproductive cloning even if the safety objections were overcome. But is the slippery slope worry decisive as an argument against
embryonic stem cell research? I don't think so; there are ways to avert or at least to minimize that danger through sensible public policy and legislation, including a ban on human reproductive cloning as most European countries have adopted and limits on how long stem cells can be allowed to develop in vitro.
A second version of the slippery slope objection fears that permitting embryonic stem cell research on spare embryos from fertility clinics will lead to the desire to do therapeutic cloning or to create embryos for the sake of research. This argument goes as follows: It is one thing to carry out research on existing, spare embryos languishing in IVF clinics. According to one estimate, 400,000 embryos are in freezers in IVF clinics, most of which will ultimately be discarded. Some argue that it is morally permissible to use such embryos for life-saving research, but morally impermissible to create
embryos for the sake of research. According to this argument, to create human embryos for the sake of experimentation and research is to cross a moral line.
What about this distinction? It seems sensible at first glance, but on reflection, it doesn't hold up. Imagine a clinic that accepted egg and sperm donations for two purposes, reproduction and stem cell research. Such a clinic would have two groups of embryos - one from gametes donated for the purpose of IVF and another from gametes donated by people who care about advancing the cause of stem cells research. Now which of these embryos may an ethical scientist use for stem cell research? If you believe that there is a morally important distinction between the two, you would have to say that researchers may only use the embryos created for the sake of reproduction, not the ones that were created for the sake of research. But why draw the line there? If it is immoral to create and sacrifice embryos for the sake of curing or treating devastating diseases, why isn't it also objectionable to create and discard spare IVF embryos in the course of treating infertility? Or to look at the argument the other way around, if the creation and sacrifice of embryos in iVF is morally permissible, why isn't the creation and sacrifice of embryos for stem cell research also morally permissible? Both practices serve worthy ends. in fact, curing diseases such as Parkinson's and diabetes is at least as important as enabling infertile couples to have genetically related children.
If this argument is right, what it shows is that stem cell research on IVF "spares" and on embryos created for research, whether natural or cloned, are morally on a par. This argument only shows that all of these practices stand or fall together, morally speaking. It remains to ask whether they all stand or all fall. To answer that question, we have to return to the embryo objection.
It is important to recognize that, if the blastocyst is morally equivalent to a person, then embryonic stem cell research is wrong and should be rejected. So it is impossible to resolve the ethical status of embryonic stem cell research without resolving the question of the moral status of the embryo. Many of you may be tempted to think that the moral status of the
embryo is a religious question, impossible to resolve. But the mere fact that a certain view about when personhood begins may be informed by certain religious convictions doesn't mean that it's not possible to assess and evaluate competing answers to that question. That is what I will try to do now.
What is the argument of those who regard the six-day blastocyst as morally equivalent to a person? It goes like this: Human beings are inviolable; they can't be treated as things or used as mere means. Human beings are worthy of respect. But when does this inviolability kick in? When does human life become worthy of respect? The answer can't depend on the age or the developmental stage of a particular human life. Even infants are inviolable, and few people would advocate yanking organs for transplant even from a fetus. Human development is a continuous process. There is no clear biological line that can tell us definitively when human life becomes worthy of respect. Therefore, the argument continues, while it's true that only some embryos develop into mature human beings, it's also true that every human being began life as an embryo. If we believe that our lives are inviolable and worthy of respect simply by virtue of our humanity, then it would be morally arbitrary to say that at some younger age or earlier stage in our development we weren't worthy of respect.
That's the argument. Is it persuasive? I think it is flawed for the following reasons. The fact that every person began life as an embryo doesn't prove that embryos are persons. Consider an analogy: every oak tree was once an acorn, but it doesn't follow that acorns are oak trees. Those who view embryos as persons often assume that they must be persons, because the only alternative is to treat them with moral indifference, as mere things. But that assumption is mistaken. You don't have to regard the embryo as a full human being in order to accord it a certain respect. To regard an embryo as a
mere thing, open to any use we desire or devise, seems to me to miss its significance as potential human life. Few people would favor the wanton destruction of embryos or the use of embryos for trivial purposes, like developing a new line of cosmetics, for example. What this suggests is that personhood is not the only warrant for respect. The moral test that embryo research has to pass is that it should be for a weighty purpose related to life or the sustenance of life. Given the diseases at which it aims, and given the prospects of success in developing cures, it seems to me to pass the test.
There are other ways of challenging the idea that an embryo in a petri dish has the same moral status as a person. One way is to play out the full implications of that idea. If harvesting stem cells from a blastocyst were truly on par with harvesting organs from a baby, then the morally responsible policy would be to ban it, not merely to deny it federal
funding. If some doctors made a practice of killing children to get organs for transplantation, no one would say that the infanticide should be ineligible for federal funding but allowed to continue in the private sector. Current federal policy - which restricts federal funding but does not ban embryonic stem cell research - therefore, cannot rest on the premise that embryos are persons, but must presuppose some version of the slippery slope objection. But the best way to deal with the slippery slope objection is not to deprive promising biomedical research of federal funding, but to enact sensible regulations to prevent abuse, beginning with a simple ban on human reproductive cloning.
Jonathan D. Moreno,
PhD, is Emily Davie and Joseph S. Kornfeld Professor of biomedical Ethics and Director of the Center for Biomedical Ethics at the University of Virginia. He is also Co-Chair of the National Academy of Sciences committee on Guidelines for Human Embryonic Stem Cell Research.
I'm going to talk about human embryo research policies both here and around the world. The first policy option, of course, is to ban all human embryo research. Some jurisdictions have done that. The second is to permit research only on existing lines. This is essentially the Bush administration policy, which permits research on lines existing as of August 9,
2001. The third option is to permit research only on so called "spare embryos" left over from patients' reproductive purposes in IVF clinics. This is probably the consensus favorite for those who would like to see embryo research go forward but don't want to see some of the other possible sources utilized. The fourth option is to permit research on spare embryos and embryos created for research via in vitro fertilization. The fifth option is to permit the use of embryos created by cloning or somatic cell nuclear transfer (SCNT). There is dispute about whether the cloned embryos really are properly called embryos. Number six is to permit research on spare embryos and on embryos created for research via SCNT using non-human animal eggs. This is the way that the options have been characterized. I'm going to go around the world, region by region, indicating where various countries stand.
The UK and Belgium, and perhaps Sweden, permit embryonic stem cell research on IVF embryos and on embryos created by somatic cell nuclear transfer. A number of countries in the European Union (EU) are rather conservative and for internal political reasons have prohibited all embryo research. There is a very interesting problem for the EU now in trying to develop consensus guidelines within their system when member countries vary so much in their views. Germany permits research only on existing lines. They also import stem cell lines from Israel. Most European countries seem to be moving in the direction of at least permitting research on spare embryos. The Middle East is a very interesting situation, because both the Jewish and Islamic traditions agree that the embryo does not have the same status as the fetus has
later on in gestation, and not the same status as an infant. So in Israel there's a lot of work being done on artificial reproduction, including human embryo stem cell work. Embryonic stem cell research is also permitted under islamic law. In Asia and the Pacific Rim there's a very aggressive move toward creating a whole biotech platform around artificial reproduction. Closer to home the Canadians allow research only on spare embryos.
Here at home, of course, we have a lot of policies. In august 2001, President Bush established a policy that only human embryonic stem cell lines that had been created by August 9, 2001 were eligible for federal research support. About 68 or so lines were listed as available, but in reality, there are so far 22 lines. The state responses are quite varied. All human embryo research is banned in 11 states. Two states explicitly endorse research cloning - New Jersey and California. In the remaining 35 states, nothing is prohibited by law.
Right now we are in a very interesting period. The results of Proposition 71 in California, the Stem Cell Research and Cures Initiative, will provide $3 billion over 10 years. We are also hearing that Massachusetts,
Wisconsin, New Jersey and other states are now concerned. They want to keep up. the marketplace seems to be moving in a very interesting way and very rapidly.
So this is where we are now in the United States. Since august 9, 2001, about $28 million in grants have been awarded by NIH for human embryonic stem cell research on the 22 available lines. It is estimated that 128 cell lines are available around the world. It's growing fast.
If you look at all the policies, if you look at the laws, if you look at the regulations in various countries, you see a number of themes that repeat themselves. Prohibited research includes reproductive cloning of a human. You also see that the standard tends to be that research on the embryo is permitted for a 14-day period, before the primitive streak appears. The
guiding principles tend to be that the project must serve an important research aim, that there is no other way to do this work and that whatever review mechanism is imposed must recognize the special moral status of the human
embryo. There is general agreement that there is something about the human embryo that must be respected and the process for approval of this work has to somehow incorporate that. You also tend to see pretty specific rules concerning the nature of embryo and egg donation to avoid exploitation of women. There is also agreement that there has to be separation between the pregnancy termination process - and embryo donation for research. Finally there are various statements around the world, in the UK and Canada especially, concerning what has to be in a consent form required for people who are interested in donating eggs. A very important point is that the egg donor or the couple donating the fertilized embryo must realize that they will receive no financial reward if others make a lot of money out of this activity.
Clearly there needs to be some kind of oversight process. although the institutional review board (IRB) seems to be the obvious place to send these protocols, it is not clear that the IRB, which is set up to review human subjects research, is appropriate in the case of a human embryo. Would that be bringing the human embryo under an ambit that some people will feel is inappropriate? It is also the case that very few IRBs have the expertise to review embryo research.
Let me conclude by saying a little bit about what the
National Academy of Sciences is doing. The National Academy of Sciences has already taken the position that both human embryonic stem cell research and adult stem cell research should go forward. Our committee is not revisiting that foundational question. Rather, the question is, given that human embryonic stem cell research should go forward, what should the conditions be?
To show you what the topics at our public workshop were, just to get a sense of what some of the issues are that we are exploring, the first day was mostly devoted to getting up to speed on the science and where it is now as well as the legal and regulatory requirements here and abroad. The second day was mostly concerned with the ethical issues and oversight problems. For example, in a very interesting talk the vice president of BIO, the biotechnology Industry Organization, said, "Please regulate us. Industry needs regulation so we know what we can do and what we can't do." This is a little different than the response from the sciences. I've never yet heard a scientist say, "Please regulate me," but capitalists like regulation, because it tells them what is feasible and what isn't. So The National Academy of Sciences committee will file a report, probably by March that will then go through the usual external review process and modification prior to release. The Committee is very much in the middle of its work. Its conclusions, we hope, will be of
some help to the scientific community in this country in developing a set of standards that are consistent and respect the special moral status of the human embryo.
in collaboration with
Dartmouth-Hitchcock Medical Center
The opinions expressed in the journal, Lahey Clinic Medical Ethics,
belong to the individual contributors and do not represent the institutional position
of Lahey Clinic on any subject matters discussed.
