Current regulations
At the present time, no research on human embryos, including preimplantation blastocysts, can be supported with federal funds. Researchers must perform such studies with the aid of funding obtained from businesses, private foundations, or other philanthropic sources. This ban includes embryos stored frozen in IVF clinics and embryos created by SCNT.
The Code of Federal Regulations (CFR) is a collection of regulations issued by agencies of the federal government. Title 45 of the CFR covers the Department of Health and Human Services (DHHS). Part 46 — Protection of Human Subjects — of Title 45 covers research on human subjects and mandates the review of federally funded research involving human subjects by an institutional review board. The regulations originated in 1981 following revelations regarding the Tuskegee Syphilis Trial (1932–1972) in which a group of 400 indigent, black Americans, exploited and prevented from receiving penicillin during the 1940s, 1950s, and 1960s, were allowed to undergo the ravages of tertiary syphilis during the length of the trial. The study prompted the US Congress to establish the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Commission was asked to develop the basic ethical principles that should govern research using human subjects. The result was the Belmont Report, one of the most influential documents in the field of bioethics since it defined the basic ethical principles relevant to research involving human subjects: the principles of respect for persons (autonomy), beneficence, and justice. The protections of 45CFR46 became known as the Common Rule after adoption in 1991 by all federal agencies conducting research with human subjects. Subpart A deals with the basic policies for human subjects protection. Subpart B (now called Additional Protection for Pregnant Women, Human Fetuses, and Neonates Involved in Research) relates to research on viable fetuses, pregnant women, and human IVF. Subpart C pertains to studies involving prisoners, while Subpart D describes special requirements for experiments involving children.
In Subpart B, protections are extended to “the product of conception from implantation until delivery.” Recall that the ICM of the blastocyst is formed prior to implantation, which occurs on about day 14 after fertilization. Therefore, dissociation of the ICM is legal according to 45CFR46.
In 1996, Representatives Jay Dickey (R-AR) and Roger Wicker (R-MS) introduced an amendment to the DHHS Appropriations Bill (the source of NIH funds) that overrides Subpart B of 45CFR46 by extending protection to “any organism not protected as a human subject under 45CFR46 that is derived by fertilization, parthenogenesis, cloning, or any other means from one or more human gametes or diploid cells.” The Dickey Amendment includes “research in which a human embryo is destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero.” Thus, preimplantation blastulae are included in the Dickey Amendment. Dissociation of the ICM necessarily destroys the blastocyst and hence, places it above minimal risk. This amendment is attached to the Appropriations Bill each year. Both President Clinton and President George W. Bush have signed bills containing the language of the Dickey Amendment. This amendment blocks investigators in the United States from using federal funds to derive new stem cell lines from early embryos.
In early 2000, Harriet Raab, then General Council of the DHHS, adopted the view that stem cells are not organisms (embryos) and hence are not covered by 45CFR46 or by the Dickey Amendment. Research on hESCs could, therefore, be supported by government funds, provided that the cells were derived from embryos using private funds. This opinion was adopted by Harold Varmus, then-Director of the NIH, but it caused uproar in Congress as many members felt that the Raab opinion was a legalism that violated the spirit of the law. Nevertheless, the NIH formed a committee of scientists, lawyers, patient advocates, and clergy to consider guidelines for the use of hESCs. They labored for many months. The final document stated that an NIH grantee could use these hESCs provided several criteria were met, including the following: (a) the stem cells were derived from embryos produced in IVF clinics for reproductive purposes; (b) the stem cells were in excess of clinical need, meaning that the donors had achieved a successful pregnancy or had simply decided not to proceed with IVF; (c) the stem cells were derived from embryos that were frozen, allowing sufficient time between the emotional experience of creating the embryos and the decision regarding donation; (d) informed consent and institutional review board approval was obtained; and (e) no exchange of money was made, in order to avoid a financial influence.
These NIH guidelines were accepted by President Clinton but rejected by President George W. Bush soon thereafter. In his speech of August 9, 2001, President Bush recognized the value of research on hESCs and the promise of successful cell replacement therapies.
However, he said that he would not condone the destruction of additional embryos to create new hESC lines. At the time, he believed that 62 hESC lines were available in labs around the world, and he made it clear that all subsequent federally supported research would be confined to these existing lines.
Reaction in the scientific community was mixed. Some were relieved that the President recognized the importance of hESC research. Other investigators, skeptical about the existence of 62 cell lines, were disappointed. In the following months it became obvious that there were not 62 usable cell lines; there were fewer than 5. The number of available lines has since grown, and 21 lines are currently listed in the NIH registry. However, the tangle of intellectual property requirements and the fact that most of these hESC lines were cultured in contact with mouse cells and bovine serum limits their utility. Moreover, many of them still have not been well characterized in terms of viability and their ability to differentiate.
Elias Zerhouni, Director of the NIH, has made sure that the NIH has done its part to promote research using the approved cell lines. Special training grants for new hESC investigators have been created; supplements to existing research grants have been offered as lures; and many different calls for special grants (requests for applications and requests for proposals) have been issued. The formation of multidisciplinary teams has been encouraged, and research infrastructure grants in support of hESC-based studies have been proposed. hESC-related conferences have been supported, and an excellent hESC web site — the official NIH resource for stem cell research — has been created.
Whether it is 5, 21, or 62, the number of available hESC lines is simply not sufficient to provide for the genetic diversity among the recipient population. In developing a new medicine, one would not stop with the first chemical that produced an effect. Efficacy must be optimized and safety must be taken into account.
Creation of new cell lines from human embryos can proceed thanks to support from nongovernment sources. Recently 17 new hESC lines were derived with private funds, and more are sure to follow. However, in the long run, the talent represented by the community of scientists supported by the NIH and other federal agencies will be needed for this field to move forward.
Currently in the House of Representatives a bill introduced by D. Weldon (R–FL) and B. Stupak (D–MI) and in the Senate a bill introduced by S. Brownback (R–KS) and M. Landrieu (R–LA) would outlaw the formation of human embryos by SCNT in the private sector as well as by researchers receiving federal funds. This extraordinary legislation would criminalize scientific research, making it punishable by a $1 million fine and 10 years in prison. Effects of this chilling attack on the scientific process extend beyond hESC research. It casts a pall over all science. It indicates a widening gulf between those in public office and the scientific community — a reversal of the coming together of political and scientific minds over the stem cell debate that we are observing in other nations.
Current Stats
Opponents of President Bush's stem cell policy were buoyed by the election of Democratic Sen. Barack Obama as the 44th U.S. President. Obama had pledged to overturn the Bush policy and thus expand the number of human embryonic stem cell lines eligible for federally-funded research. On March 9, he did so through an executive order. The order did not lay out specific ethical guidelines but rather allowed 120 days for the development of such guidelines by the secretary of Health and Human Services through the director of the National Institutes of Health.
Members of Congress may still seek to codify the new stem cell policy by passing another Stem Cell Research Enhancement Act. Indeed, DeGette and Castle have reintroduced that bill (H.R. 873) in the House, as well as a bill called the Stem Cell Research Improvement Act (H.R. 872), which contains additional guidance and reporting requirements for NIH. Senators harkin and Specter have also reintroduced their bill (S. 487), the same one Bush vetoed in 2007.
World status
Countries colored in brown represent about 3.8 billion people, more than half the world's population. All have a permissive or flexible policy on human embryonic stem cell research and all except the U.S. have banned by law human reproductive cloning. (Black spots indicate Genome sequencing centres)
Ethical issues
When does life begin? The answer to this question has enormous consequences for the future study of hESCs. Defining life as the moment of conception is certainly a convenient starting point, but this relies on an assumption about the value of a potential life. In this argument, value is placed on function (potential for future development) rather than structure (current state of development). This starting point, conception, is also promoted by many of those who rely on revealed Scripture. For those holding such beliefs, research on stem cells and the destruction of human blastocysts are simply unacceptable.
To many, implantation of the blastocyst in the uterine wall is the best landmark for the definition of life. Indeed, this is the first stage at which the individual is defined (e.g., the blastula is past the stage in which it can split to form twins). This is the point described in Subpart B of 45CFR46 as the first stage covered by human protections regulations. This is also the last developmental stage accepted in the United Kingdom and in many other countries throughout the world. For research on human embryos, gastrulation is another strong candidate, as it is reasonable to consider the phase in which the nervous system is formed and the possibility of sensation first exists as the beginning of human life.
One of the most dangerous trends in this debate is that of offering religious opinions cloaked in the language and veneer of science (e.g., using systems theory to justify the belief that life begins at conception). We have emphasized differences between embryonic and adult stem cells because many in the public and in Congress have claimed, arbitrarily, that the two sources are identical. Richard Dorflinger, Deputy Director of the Secretariat of the pro-life activities of the US Conference of Catholic Bishops, has claimed that adult stem cells hold more promise than embryonic stem cells and that research on embryonic stem cells is therefore unnecessary. The passion behind Dorflinger’s statement is laudable, but it must be recognized that it is based on religious conviction, not on scientific induction or verified data.
Several commissions have explored the difficult ethical issues surrounding the definition of the beginning of life, including the National Bioethics Advisory Commission , the National Academy of Sciences Advisory Committee, and most recently, the President’s Council on Bioethics . Although each of these committees condemns research on reproductive cloning, research on SCNT has been upheld even by the President’s Council on Bioethics, widely considered to be the most conservative group of the three. While the leader of the President’s Council, Leon Kass, is opposed to the creation of embryos by SCNT for research purposes, the committee did not vote to ban SCNT research; rather they called for a four-year moratorium. At the time of the vote, the President’s Council on Bioethics contained 17 members; 6 were scientists but only 3 were involved in the fields of cell biology or molecular biology. There were dissenting opinions, but the moratorium carried the day. If one thinks of the time it takes to restart a program once it is dismantled, a four-year moratorium might well turn into a six-year hiatus. Careers would be difficult to maintain, and our best young scientists would probably enter different fields. A similar moratorium initiated at the Asilomar Conference in the 1970s threatened the development of recombinant DNA technology (see Remembering recombinant DNA). In retrospect, a prolonged moratorium would have changed the course of science and industry in this country.
Those opposed to research on embryos are concerned that we are on a slippery slope, facing a creeping moral degradation fostered by unbridled biotechnology . If we agree to destroy an organism that has the potential to develop into a human being, it may be easy to move on to other destructive acts. This zeal poses the danger of depriving millions who suffer from degenerative disorders of the hope and benefits that might derive from stem cell–based research.
There is no absolute right answer to the debate regarding the dissociation of blastocysts to produce more hESC lines. Here we present several considerations that convince us of the ethical validity of using embryos up until the 14th day after fertilization.
Up to embryonic day 14, the blastocyst has no central nervous system and, in our view, cannot be considered sensate. We now remove organs from patients who have been declared brain dead but who are still alive in some sense (e.g., they are warm, breathing, making urine). The use of these organs has saved many lives. We view these two hundred–cell embryos as cell donors certainly at the same moral status or less than these individuals.
The slippery slope argument that the use of blastocysts created by SCNT will lead to reproductive cloning is not compelling. With appropriate federal regulations and oversight, such as the Hatch-Feinstein Bill, introduced in the Senate by Orrin Hatch (R–UT) and Dianne Feinstein (D–CA), which seeks to prohibit human reproductive cloning while preserving the use of blastocysts to enhance stem cell research, the scientific community can proceed in an orderly fashion. The UK is now succeeding in this vein under the watchful eye of its Human Fertilisation and Embryology Authority, a nongovernmental body that regulates and inspects all UK clinics providing IVF, donor insemination, and embryo storage while also licensing and monitoring all human embryo research conducted in the UK. The guidepost — implantation into a uterus — is an unambiguous barrier.
The need for hESC research is extraordinary. We are on the doorstep of a new type of restorative therapy that goes beyond treating disease symptoms. Disorders in which the lesions are focal will be the first to undergo stem cell therapy. Replacing β cells in the pancreas, motor neurons in the spinal cord, and dopaminergic cells in the basal ganglia are the most obvious examples. We must weigh the obligations of the moral imperative to help suffering individuals against the inherent value of preimplantation blastocysts.
We have many examples in history where attempts to outlaw fields of study have led to terrible and terrifying consequences (from Galileo to Lysenko). Conversely, many technological breakthroughs now highly valued by both the scientific and lay communities, such as IVF or heart transplants, were once thought to be too dangerous or were seen as “playing God”.
Finally, this effort should go forward because we simply will not know the answers unless we do the research. The desire to know is absolutely intrinsic to humans and has a survival value as well as a moral one.
Conclusion
Arguments are often made that hESCs have not cured a single disease. Of course not. Research is hampered by current regulations, and it is difficult to succeed with one hand tied behind one’s back. As in all great scientific advances, it takes time and a great deal of money to translate fundamental discoveries into clinically useful treatments.
Scientific advances over the last decade have been extraordinary, but the process of discovery is a fragile one. Each advance raises new questions with new ramifications. It will take all of us — scientists, physicians, health care workers, and patient advocates — a certain amount of effort and courage in the face of contrary views to justify public trust and, thereby, enhance funding for basic research and for applied research.
We can be certain that without research, including federally funded research, we will remain in our current state of ignorance. The public must be kept informed about what the research community is doing. We hope that our great universities and research centers remain at the forefront of this effort.