The embryonic stem cell debate

The new stem cell research policy of the United States runs into conflict with several of the ethical goals of medicine and related health disciplines.

ON August 9, President George Bush announced his decision to allow only limited research on embryonic stem (E.S.) cells with federal funding. Bound by a seven-year-old piece of domestic legislation that bans federally funded research involving embryos, he could not have done better on the highly emotive and controversial subject.

Of course, given the emerging potential of stem cell research in medical advance, Bush could have initiated measures to amend the law suitably, widening the scope of stem cell research with federal support. It is significant that he has refrained from doing so even after ordering a review early this year of the government's stem cell research policy, which was put in place by the Clinton administration. But it is equally significant that Bush did not go as far as to appease the pro-life groups and ban E.S. cell research altogether. Current scientific opinion is that research with E.S. cells, rather than other forms of stem cells, is important for an understanding of developmental biology and cellular processes, which is crucial for developing therapies for various functional disorders and debilitating diseases.

Stem cells are undifferentiated parent cells of all human cells. They are self-replicating and, with appropriate biochemical signals, have the capability to divide and grow into any of the 200-odd "specialised cells" in the body that make up the different tissues of the heart, the lung, the liver, muscles, limbs, bones, the brain and the nervous system. This property is termed "pluripotency" and the best source of human pluripotent stem cells is known to be the cell mass that gathers at the bottom of the hollow of a five-to-seven-day-old embryo, or the blastocyst.

Stem cells can be derived from sources other than embryos as well - from adult cells, discarded umbilical cords, human placenta and foetal tissue. Research on such stem cells is also promising. However, the versatility or pluripotency that E.S. cells are endowed with is not found in other kinds of stem cells. At least for the present, scientists believe that E.S. cells, and perhaps embryonic germ (E.G.) cells from primordial germ cells in the gonadal ridge of a five-to-10-week-old foetus, are the most promising source of pluripotent stem cells. Experiments have, however, suggested that adult stem (A.S.) cells are not as "specialised" or committed to forming a specific tissue as was thought earlier. But they are at best "multipotent" if not "unipotent"; that is, they can be directed to form more than one kind of tissue.

The breakthrough, made three years ago by scientists of the University of Wisconsin (UOW), Madison, and Johns Hopkins University (JHU), Baltimore, has demonstrated the possibility of isolating and maintaining E.S. and E.G. cells in culture. This has opened up the possibility of treating various disorders and diseases that lead to cellular and tissue degeneration, including cancer, by what has come to be called "cell therapy". This involves coaxing and directing cultured stem cells to divide and grow into specific tissues or organs and repair the damaged part. The remarkable feature of E.S. and E.G. cells is that they can regenerate themselves virtually forever in vitro and thus constitute an unlimited source of human pluripotent stem cells.

At the centre of the moral controversy about stem cell research is the status of the embryo and its "right to life". Deriving stem cells from embryos results in the destruction or "death" of the embryo, and critics of stem cell research argue that this denial of life to the embryo is immoral and unethical. In a society where abortion is a sensitive issue, even though abortion is permissible under the law, opposition to it is widespread - it is no surprise that there should be objection to embryo research in general and the emerging research with human-embryo-derived stem cells in particular. Indeed, this societal perception of morals and ethics with regard to embryos is what underpins the 1994 legislation that forbids federal funding of embryo research.

Critics of E.S. cell research have argued that given the recent evidence of increased 'plasticity' or 'multipotency' of A.S. cells, ethics demand that research be restricted to A.S. cells alone. However, according to stem cell researchers, this is a popular misconception. Haematopoietic (blood-forming) stem cells from bone marrow and foetal cord blood have been routinely used for long in therapy for the restoration of blood supply in patients affected by leukeamia or plastic anaemia after chemotherapy.

Source: National Institutes of Health

Until recently it was assumed that A.S. cells were programmed to produce specialised cells, but recent studies suggest that they may be able to show more malleability than previously believed. According to a fact sheet of the National Institutes of Health (NIH), there is, however, considerable evidence that A.S. cells may have limited potential compared to E.S. and E.G. cells. The NIH is an institutuion under the U.S. Department of Health and Human Service (DHHS). Human A.S. cells have not yet been isolated from all cell and tissue types of the body, and they have not been shown to be capable of developing into all of the different cell and tissue types of the body. Further, A.S. cells are difficult to obtain since they are present only in minute quantities, and multipotent A.S. cells are rarer still. A.S. cells are difficult to isolate and purify and their numbers appear to decrease with age. Moreover, A.S. cells have more DNA (deoxyribonucleic acid) damage and they appear to have a shorter life span than pluripotent E.S. and E.G. cells. For this reason, scientists believe that the study of both A.S. and E.S. cells is necessary to compare and understand the underlying cellular growth mechanisms.

It is this scientific perception of stem cell research and the restriction imposed by the 1994 legislation (P. L. 105-78, 513 (a)) that necessitated a presidential decision. The law prohibits the use of federal funds to support any research "in which a human embryo is destroyed, discarded or knowingly subjected to risk of injury greater than allowed for research on foetuses in utero." The term "human embryo" is defined in the statute as "any organism... that is derived by fertilisation, parthenogenesis, cloning, or any other means from one or more human gametes or human diploid cells." Accordingly, this ban is revised every year in the annual appropriations for the NIH. Clearly, since derivation of stem cells would destroy the embryo, stem cell research runs into conflict with the U.S. domestic law.

There are chiefly three sources of embryos. The process of in vitro fertilisation (IVF) generates many more embryos than are ultimately utilised for assisted reproduction in infertile couples. These "spare embryos" or "supernumerary embryos" are either cryopreserved or implanted in other infertile couples or destroyed. The other is the creation of embryos in vitro specifically for research purposes under consent from the egg- and sperm-donating couples. The third is the process known as Somatic Cell Nuclear Transfer (SCNT), popularly called cloning, which has in the recent past given rise to cloned primates like Dolly the sheep. For critics who do not hold extreme positions, while the first may be acceptable if patients' informed consent is specifically obtained for using the spare embryos for research, the other two are unethical.

The proponents of stem cell research argue that for up to 14 days the embryo cannot be treated on a par with a foetus in the matter of the right to life and stem cells derived therefrom, under no conditions, can grow into a full organism. In discussing the moral and ethical aspects of such research, they contend, the social good of possible treatment, for a host of disorders, that might result from the research should also be taken into consideration. This was the view of the National Bioethics Advisory Commission (NBAC) as well. In its report "Ethical Issues in Human Stem Cell Research" of September 1999, it said: "In our view, the (statutory) ban (on federal funding) conflicts with several of the ethical goals of medicine and related health disciplines, especially healing, prevention and research, (which) are rightly characterised by the principles of beneficence and non-maleficence."

However, in the wake of the pioneering experiments by James Thomson and colleagues at the UOW and John Gearhart and associates at the JHU - which were not federally supported - and the potential of such research for medical advance, the NIH sought specific clarification from the DHHS on the applicability of the 1994 law to E.S. cell research. After careful consideration, the DHHS declared on January 15, 1999 that since pluripotent stem cells cannot develop into an organism, they are not embryos and research utilising them was therefore eligible for federal funding. On the other hand, since E.G. cells are derived from gonadal tissues of aborted foetuses, research on these can be funded if the existing U.S. laws governing foetal tissue research are strictly adhered to.

In November 1999, the American Association for the Advancement of Science (AAAS), in association with the Institute for Civil Society (ICS), brought out a report, "Stem Cell Research and Applications: Monitoring the Frontiers of Biomedical Research". While the report said that federal funding for stem cell research was necessary in order to promote investment in this promising line of research, it recommended that public funding be not extended "at this time for activities involved in the isolation of embryonic stem cells". The report said that although the derivation of human stem cells could be done in an ethical manner, there was enough objection to the process of deriving stem cells to consider recommending against public funding. It also argued that for the foreseeable future there would be sufficient material isolated by researchers not using public funding and that this exclusion could not have a negative impact on research. The point to be noted here is the distinction that is being made between 'derivation' of E.S. cells (which results in the destruction of the embryo) and 'utilisation' of already isolated E.S. cells.

Recognising the ethical and legal issues involved in stem cell research and the need for stringent monitoring of such research, the NIH issued in January 1999 a moratorium on funding such research until appropriate guidelines were evolved and a monitoring mechanism was put in place. Subsequently, on August 25, 2000, the NIH issued the final "Guidelines for Research Using Human Pluripotent Stem Cells" and the conditions for NIH funding for the same when the moratorium was also lifted. The guidelines maintain this distinction between 'derivation' and 'utilisation' and state: "Studies utilising pluripotent stem cells derived from human embryos may be conducted using NIH funds only if the cells were derived (without federal funds) from human embryos that were created for the purpose of infertility treatment and were in excess of the clinical need."

However, the NBAC had recommended in its September 1999 report that federal funding be made available for both derivation and use of E.S. cells. Giving its arguments for recommending thus, the NBAC had said: "Although some may view the derivation and use of E.S. cells as ethically distinct activities, we do not believe that these differences are significant from the point of view of eligibility for federal funding... Relying on cell lines that might be derived exclusively by a subset of privately funded researchers... could severely limit scientific and clinical progress. Trying to separate research in which human E.S. cells are used from the process of deriving these cells presents an ethical problem, because doing so diminishes the scientific value of the activities receiving federal support. This separation... rests on the mistaken notion that the two areas of research are so distinct that participating in one need not mean participating in the other."

Stem cells in clusters, photographed at the Advanced Cell Technology in Worcester, Massachusetts, United States. FACED with pressure from groups opposed to stem cell research, Bush ordered the DHHS to undertake a review of the government policy on the matter. Following this review, Bush has permitted federally funded research only on E.S. cells from cell lines that have already been derived and maintained in different parts of the world. This is in accordance with the AAS/ICS recommendations, the NIH Guidelines and the 1994 law, but does not go as far as what the NBAC had recommended even though there are as many as 100,000-120,000 embryos in the various cryo banks, which are potential sources for E.S. cells. In his statement Bush asserted: "As a result of private research, more than 60 genetically diverse stem cell lines already exist. They were created from embryos that have already been destroyed... I have concluded that we should allow federal funds to be used for research on these existing stem cell lines, where the life and death decision has already been made... This allows us to explore the promise and potential of stem cell research without crossing a fundamental moral line... that will not sanction or encourage further destruction of human embryos." He has also earmarked $250 million for spending on research using these existing stem cell lines this year. In sum, Bush's new stem cell research policy says that (a) federal funds will be used only for research on existing stem cell lines that were derived with the informed consent of donors, from excess embryos created solely for reproductive purposes and without any financial inducement to the donors; and (b) no federal funds will be used for the derivation or use of stem cells from newly destroyed embryos, the creation of any human embryos for research purposes or the cloning of any human embryos (through SCNT) for any purpose. Although there is yet no U.S. legislation that forbids human reproductive cloning, there are six bills pending before Congress seeking to prohibit human cloning. While the bill H. R. 2608 seeks to prohibit the use of SCNT "to initiate a pregnancy or with the intent to initiate pregnancy" but recognises the importance of the technique for non-reproductive or "therapeutic cloning", including the creation of embryos for stem cell derivation, H. R. 2505 seeks a complete prohibition of SCNT as a research technique. Even though the present stem cell research policy forbids the use of SCNT for creating embryos for research, given the potential of SCNT as an important research tool (which the United Kingdom, for example, allows), the scientific community has voiced its concern over bills like H. R. 2505. On his part, Bush has expressed his opposition to human cloning but observed that "embryonic stem cell research is at the leading edge of a series of moral hazards... it is... important that we pay attention to the moral concerns raised by the new frontier of human embryo stem cell research." Clearly, this remark was prompted by the statement at the U.S. National Academy of Sciences meeting in Washington by two infertility specialists Panayioitis Zavos and Severino Antinori two days before the policy announcement by Bush that they can produce a human clone within 60 days. It remains to be seen what would be the nature of the Cloning Prohibition Act of 2001 that will be soon passed into law. There is apprehension, however, in sections of the scientific community about the workability of the new stem cell research policy in its present form. Reacting to the President's decision, the AAAS issued a statement on August 17, which said: "How the Administration's policy is implemented will be the real test of the approach the President has chosen" It pointed out that various issues need to be resolved before the new policy could be assessed. The statement said that the claimed number of 60 stem cell lines needed to be authenticated by making public immediately the sources of those stem lines because in its opinion the number was likely to be much smaller. Moreover, it was possible to determine whether the existing collection of cell lines was sufficient to foster productive research only after leading scientists in the field assessed the quality, genetic variability and access without restrictions (including those pertaining to intellectual property rights) of these cell lines, the AAAS statement said. According to the White House, the NIH had been entrusted with the responsibility of examining the derivation of all the cell lines and creating a registry of the same. Interestingly, a White House Fact Sheet released on August 9 following Bush's announcement said: "These existing lines are used in approximately one dozen laboratories around the world, in the U.S., Australia, India, Israel and Sweden." The mention of India as having E.S. cell lines was received with surprise by India's Department of Biotechnology (DBT). According to V .K. Vinayak, adviser in the department, while adult stem cell work is being done in some of the publicly funded laboratories of the country, no E.S. cell work is being done. However, he added, if any private IVF carried out such work, the department was not aware of it. The interesting thing, however, is that while the U.S. administration appears to have a record of E.S. cell lines in the country, the scientific administration has no information on it. This gives credence to AAAS's apprehension on the identity, quality, genetic characterisation and the manner of derivation of the 60-odd existing cell lines created out of privately funded research. This also is a sad reflection on the ethical and regulatory vacuum in which IVF clinics in India have been functioning for years. On the issue of access to the lines too the apprehension appears justified, judging from the tussle between the Wisconsin Alumni Research Foundation (WARF), which funded the research led by Thomson of the UOW that achieved the first ever isolation of human pluripotent embryonic stem cells and holds the intellectual property rights for E.S. cell technology, and Geron Corporation, U.S., to whom the WARF had licensed certain rights for human E.S. cells use since 1999. On August 13, the WARF filed a suit against Geron to ensure broad research access to the five stem lines developed by Thomson. The WARF has sought the court to declare that Geron has no right to additional cell lines under the earlier licence agreement. Geron had claimed that the WARF was obliged to transfer the rights of additional cell types on an exclusive basis under the agreement. The above points to the pitfalls of not allowing a wider scope for federally funded stem cell research that include the derivation of E.S. cells. Compared to this restrictive policy of the U.S., countries of Europe, the U.K. in particular, have adopted more forward-looking stem cell research policies. Ireland is the only E.U. country where embryo research is forbidden. Other members of the E.U. have evolved appropriate legislations to deal with the issue. This important policy difference may become the key to future directions in stem cell research in Europe and the U.S.