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The use of iPSCs and tetraploid complementation for human reproductive cloning would raise profound ethical objections. Professional standards and laws that ban human reproductive cloning by somatic cell nuclear transfer should be revised to also forbid it by other methods, such as iPSCs via tetraploid complementation.
Induced pluripotent stem cells (iPSCs), which are genetically matched to a somatic cell donor, are a powerful research tool that will probably lead to important discoveries into the mechanisms of disease, stem cell transplantation, and new methods of evaluating therapies. Because human iPSCs are created without destroying embryos, they avoid many of the moral controversies that surround human embryonic stem cell (ESC) research.
However, recent publications raise concerns about the potential use of iPSCs for human reproductive cloning. Three research teams have produced mice that are genetically identical to iPSC lines by tetraploid complementation (Boland et al., 2009; Kang et al., 2009; Zhao et al., 2009), one of several methods of deriving mice entirely from pluripotent stem cells (Dechiara et al., 2009; Poueymirou et al., 2007). In tetraploid complementation, two blastomeres are fused and cultured to produce a tetraploid morula or blastocyst. iPSCs are then combined with this tetraploid embryo, usually by injection into the blastocyst. When this entity is transferred and implanted into a uterus, the cells originating from the tetraploid blastocyst form the trophoblast and ultimately the placenta, whereas the developing fetus is derived from the iPSCs.
These studies provide definitive evidence that at least some iPSCs are pluripotent. They also raise the possibility that this technique of tetraploid complementation, or equivalent techniques, could be used with iPSCs for human reproductive cloning (Denker, 2009a; Denker, 2009b). In theory, injecting human iPSCs into a human tetraploid blastocyst could create a child who is a clone of the somatic cell donor and whose placenta comes from the donor(s) of the blastomeres.
In this article, we analyze the debates over human reproductive cloning and pertinent current legislation and professional guidelines. Because many current policies ban only human reproductive cloning by somatic cell nuclear transfer (SCNT), we propose policy changes to also ban other methods, such as iPSCs via tetraploid complementation, while not creating barriers to the research use of iPSCs.
After the birth of Dolly, the prospect of using SCNT for human reproductive cloning generated intense public debate. Several U.S. and international panels determined that safety concerns justified a ban (National Bioethics Advisory Commission, 1997; National Research Council and Institute of Medicine, 2002; The President's Council on Bioethics, 2002). Animal studies reported birth defects in offspring, fetal and neonatal deaths, errors in reprogramming and imprinting, and medical risks to the pregnant animal. Additionally, some people objected that having a child who has only one genetic parent and is the genetic twin of that parent violates cultural norms regarding reproduction and families and placed undue expectations on the children. Moreover, some critics opposed nonsexual reproduction, which they consider violations of divine or natural law (The President's Council on Bioethics, 2002). In contrast, others argued that if human reproductive cloning were shown to be safe, it should be allowed to respect the procreative liberty of individuals who could not otherwise have genetically related children. In their view, nonsafety arguments against reproductive cloning were weak and confused (Brock, 2002; Greely, 2002; Sunstein, 2002).
Currently, safety concerns regarding iPSCs and tetraploid complementation in animals justify a prohibition on human reproductive cloning using this technique. This ban could be supported now without resolving the speculative philosophical issue of whether a ban would be appropriate if the technique were safe. We believe this ban should be in place indefinitely, until there is persuasive evidence of safety and also societal agreement that human reproductive cloning is acceptable as public policy. Two previous U.S. reports recommended that reproductive cloning with SCNT be banned for a fixed period of time, leaving open the possibility that it might be shown safe and that social attitudes toward it might change (National Bioethics Advisory Commission, 1997; National Research Council and Institute of Medicine, 2002). However, there are problems with such a sunset clause. The choice of a “sunset” date would be arbitrary. Furthermore, because the issue is so sensitive, a policy decision to permit human reproductive cloning should result from extensive public and legislative debate and should not occur simply because a ban was not renewed. The recent increased acceptance of human ESC research illustrates that through vigorous public debate policy can be forged on contested issues.
Some critics objected to research uses of SCNT in humans, as well as for human reproduction. Several distinct arguments need to be analyzed for their possible relevance to research uses of tetraploid complementation with iPSCs. Such research could help elucidate early human development, particularly in the context of specific genetic defects, the nature of iPSCs, and how they differ from ESCs.
First, some objected to all human embryo research and hESC research because they believe that embryos have the moral status of persons. Logically, these critics would support iPSC research, which involves no embryos, but oppose creation of tetraploid comple mentation with human iPSCs, which require blastocysts.
A second objection to SCNT concerned the intentional production of embryos expressly for research purposes. A third objection to SCNT is the risk to women who would donate oocytes specifically for research (United Nations General Assembly, 2005). These objections pose no barriers to iPSC derivation and research because no embryos or oocytes are needed. Furthermore, tetraploid complementation with iPSCs for research purposes does not require fresh oocytes or embryos created specifically for research; it might be carried out only with blastocysts that were created for reproductive purposes but were no longer needed for that goal, that would not be donated to another couple, and that would otherwise be destroyed.
Fourth, some objected that SCNT in humans would be a dual-use technology that could be immediately applied for ethically inappropriate reproductive purposes. If an SCNT blastocyst could be produced and developed in the laboratory, it could be used either to derive an SCNT stem cell line or be implanted in utero for reproductive purposes. Implanting it in utero would not be difficult, requiring only techniques routinely used for in vitro fertilization and embryo transfer. Of note, this dual-use objection would not apply to iPSCs per se. The technical skills to develop an iPSC stem cell line would not be sufficient to permit human reproductive cloning. Additional and diffi-cult technical skills would be required for tetraploid complementation, although current techniques of embryo transfer could be used for transfer of an iPSC tetraploid blastocyst.
Finally, some raised “slippery slope” objections to research uses of SCNT. These objections are also relevant to research uses of tetraploid complementation with human iPSCs. This technique might produce a totipotent entity that could be directly implanted in utero by standard in vitro fertilization and embryo transfer procedures. Concerned that a rogue scientist might attempt to do so, some people might seek to ban even research uses of tetraploid complementation with human iPSCs. To address “slippery slope” concerns, rather than banning tetraploid complementation with iPSCs for research purposes, it would be preferable to draw a bright line and enact a strong ban on the undesired activity— human reproductive cloning.
In summary, many people who oppose human reproductive cloning with iPSCs and tetraploid complementation logically could support using this technique for research purposes.
Several U.S. and international panels have recommended a ban on human reproductive cloning through SCNT (see Table 1).
The President's Council on Bioethics used the broadest language, rejecting the production of a new human organism that is “genetically virtually identical to a currently existing or previously existing human being (The President's Council on Bioethics, 2002).” The National Bioethics Advisory Council and National Academy of Sciences reports explicitly support SCNT for research purposes, subject to safeguards and regulation. In contrast, ten of the seventeen members of the President's Council on Bioethics under President Bush supported a moratorium on cloning-for-biomedical research with SCNT.
Currently, 15 states prohibit human reproductive cloning (Table 1). Although most laws ban only the use of SCNT, some are framed in more general terms, for example to forbid “replication of a human being through the production of a precise genetic copy of nuclear human DNA” or “replication of a human individual.” Several states prohibit cloning for research purposes as well as for reproductive purposes.
International bodies have also opposed human reproductive cloning (Table 1). The U.N. has passed a resolution to prohibit all forms of human cloning “inasmuch as they are incompatible with human dignity and the protection of human life” (United Nations General Assembly, 2005). The Council of Europe prohibits the creation of a human being sharing the same nuclear gene set as another being, living or dead. The International Society for Stem Cell Research recommends prohibiting gestating or transferring human embryos that have been derived in vitro by nuclear transfer or nuclear reprogramming into a uterus.
Several countries with major stem cell research programs also prohibit reproductive cloning (see Table 1). Some countries, such as China and France prohibit cloning without defining it, whereas others are far more specific. Japan, for example, forbids creating an individual with the same genetic structure as a certain individual. The UK and Singapore forbid transferring in utero an embryo that has not been created through fertilization.
Current laws and policies, enacted before iPSCs were contemplated, have several shortcomings. For example, some laws ban only human reproductive cloning by SCNT but not by other methods, such as iPSC and tetraploid complementation, injection into eight-cell embryos, parthenogenesis, and embryo splitting. Prohibitions on “replicating a human being” are flawed. The root meaning of “replicate” is to fold back on itself, and a replica is an exact or faithful copy of something. However, there are epigenetic changes between human iPSCs and donor somatic cells. In addition, some methods of producing iPSCs may insert genetic material into the donor cells during the derivation of the iPSCs, so that the donor and iPSCs do not have exactly the same nuclear DNA. It would be preferable to ban creation of a human being that is virtually identical genetically to a currently or previously existing human being.
Even this broader language may not go far enough. In addition to prohibiting the creation of a human being through repro ductive cloning, it would be reasonable to ban attempts to do so. Thus we recommend prohibiting the implantation into a uterus of a totipotent entity that is nearly identical genetically to a currently existing or previously existing human being. This ban should cover transfer into both human and non-human uteri.
Existing U.S. state laws and guidelines forbid in vitro culture of human embryos beyond 14 days of development or after the appearance of the primitive streak. These bans prevent research on human embryos after the individuation and the development of structural precursors to the brain (National Bioethics Advisory Commission, 1999). These prohibitions should be interpreted to apply to new techniques whose products have the organization and structure for normal human development, such as tetraploid blastocysts with human iPSCs, injection into eight-cell embryos, parthenogenesis, and embryo splitting. Such restrictions should not impede scientifically important and ethically acceptable research, such as long-term culture of human embryoid bodies for deriving differentiated tissues or cell culture from disaggregated embryos and their clonal derivatives, such as ESCs. Although such research would be rejected by those who oppose all human embryo research, logically it would be acceptable to those who support stem cell research with embryos remaining after a patient has completed infertility treatment and would otherwise be destroyed.
Many states and foreign countries do not ban human reproductive cloning. Thus, a scientist who wanted to carry out human reproductive cloning could do so without legal sanctions in these jurisdictions. To deter this practice, in addition to legal prohibitions on human reproductive cloning, we recommend that professional societies, including the American College of Obstetricians and Gynecologists, the Society for Assisted Reproductive Technology, the American Society for Reproductive Medicine, and the International Society for Stem Cell Research, should revise their ethical standards to ban human reproductive cloning through any technology.
In summary, there continue to be compelling safety reasons to ban human reproductive cloning. Existing laws and professional guidelines should be carefully revised to cover tetraploid complementation with iPSCs and other technologies in addition to SCNT, thereby broadening the ban on attempts at reproductive cloning to existing and future technologies.
The authors wish to thank Gary Howard for his expert editing. This work was supported by National Institutes of Health (NIH) Grant Number 1 UL1 RR024131-04 from the National Center for Research Resources (NCRR) and NIH Roadmap for Medical Research and by the Greenwall Foundation. Those who provided funds had no input into the design of the project or the conclusions of the paper. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.
Supplemental Information includes references for policies cited in Table 1 and can be found with this article online at doi:10.1016/j.stem.2009.12.004.