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Medical Institute, Juvenile Diabetes Research Foundation, and Harvard University together funded ES cell research conducted by Harvard-affiliated investigators that led to the derivation of seventeen ES cell lines that were made available to researchers for noncommercial studies (Cowan et al. 2004; Gearhart 2004). The study was approved by Harvard’s IRB, and the investigators’ method for deriving the lines was applauded as setting ‘a standard for the characterization of embryonic stem-cell lines’ and recommended for inclusion in the NIH registry (Phimister and Drazen 2004: 1352).

These and other well-publicized subnational and private funding programs provide a context in which policy and ethical issues can be identified and debated, especially when universities are the recipients. For example, planners of a privately financed stem cell institute at Harvard University announced that they would consider ethical issues with the help of the ‘schools of government, law, business, and divinity’ at the university (Lawler 2004). Other universities are also using or planning to use private funds for stem cell research, such as the University of California – San Francisco and Johns Hopkins University. These funded studies will, when they reach the clinical stage, presumably bring with them protections for human research participants, including IRB review, and can, with proper leadership, solicit broad deliberation and produce guiding principles and practices.

State Governments

Another avenue for innovative policy and public deliberation arises at the state level. Two states — California and New Jersey — have passed laws authorizing ES cell research, including studies using embryos created through SCNT (Cohen 2004: 113). Although a number of states bar therapeutic SCNT by law, others have introduced bills to allow ES cell research. California, which was the first state to ban reproductive SCNT, was also the first state to endorse therapeutic SCNT. Its law, which went into effect in early 2004, is designed to lessen suffering from diseases in view of the ‘immense promise’ of stem cell research and to protect against economic losses if research does not proceed. In relevant part, it permits ‘research involving the derivation and use of human embryonic stem cells, human embryonic germ cells, and human adult stem cells from any source, including somatic cell nuclear transplantation’ (California Health and Safety Code 2003; emphasis added). The bill’s preface points out that the United States and California ‘have historically been a haven for open scientific inquiry and technological innovation’.

New Jersey’s governor signed a Stem Cell Research Bill (S1909) into law in 2004. The law is designed to assure researchers that the state will not interfere with ES cell, embryonic germ cell, and adult stem cell research, including cells developed from SCNT (Mansnerus 2004). It regards ‘open scientific inquiry and publicly funded research’ as the most efficient and responsible way to produce benefits

from stem cell research. New Jersey’s governor set aside $6.5 million in the state budget to establish a Stem Cell Institute to be administered by Rutgers University and the University of Medicine and Dentistry of New Jersey, funded by state and private money (Kocieniewski 2004; Mansnerus 2004). The governor noted at the bill-signing ceremony that the law would make New Jersey ‘a leader in medical research and medical care’ (State of New Jersey 2004).

The effort to proceed with ES cell research in states with permissive legislation will be undercut by public misunderstanding of therapeutic SCNT. In addition, political divisions even within supportive states may interfere with well-intentioned policy. This is especially true for issues relating to human embryos, about which the lack of ‘societal accord about the moral and legal status of the embryo’ makes lawmaking difficult (Andrews 2004: 220). At the least, however, the efforts can, in the presence of committed leadership, encourage discussion of goals and priorities and public participation in the development of science policy (Holman and Dutton 1978: 1524). The California and New Jersey laws have a greater potential for deliberative decision making than exists at the federal level. New Jersey’s law, for example, establishes a nine-member IRB to advise the governor and legislature on stem cell issues (State of New Jersey 2004). This body sets up the basis for participatory deliberations about the goals and practice of ES cell research in the state. Or, with attention, commitment, and a sense of mission, it could be a location for thoughtful deliberations. It is, at the least, a point of access for pluralist interests to prompt problem solving to protect research participants, acknowledge the interplay of conflicting values, and weigh the merits of future research and development.

California’s law recommends ‘full consideration’ of the ‘ethical and medical implications’ of the research and notes that ES cell research raises ethical and policy issues that must be ‘carefully considered’ even though they are ‘not unique’ (California Health and Safety Code 2003). The research must be reviewed by an IRB, although this does not appear to be a new state-wide body. Another effort at making stem cell policy democratic was undertaken by citizens in California, who gathered more than the requisite number of needed signatures to place a Stem Cell Research and Cures Initiative on the November 2004 ballot. The measure passed (Knight 2004a). Among other things, this initiative provided for the raising of $3 billion from state-backed funds ($295 million per year for ten years) to fund stem cell research and set up the California Institute of Regenerative Medicine at universities and medical research facilities. These facilities were to be built separately to avoid overlap with research facilities using federal funds (Holden 2004b). The initiative was designed to encourage stem cell research, and specifically ES cell research, which is unlikely to receive federal funds. It permitted funding for therapeutic but not reproductive SCNT. The new law sets up an Independent Citizen’s Oversight Committee to issue, among other things, annual reports and to hold at least two public meetings a year. Funded researchers were to follow NIH protections for human research participants. Payments for cells were to be limited

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and research on embryos could not proceed for more than twelve days after the first cell divisions. Much of the oversight is to be conducted by working groups. The initiative has been criticized on both moral and financial grounds (Knight 2004b).

International Policy

An important international element underlines ES cell research as investigators and/or governments in Australia, Singapore, the United Kingdom, and other nations set up centers and cell banks for storing cells and providing products derived from ES cells for further research (National Institute for Biological Standards and Controls 2004; Nelson 2004). Nations operate under a variety of laws ( Jones and Cohen 2004), which provides an opportunity to witness deliberations and innovative policies. In the United Kingdom therapeutic SCNT is supported by the government, and this policy brings with it guidelines and a supportive rationale. It is also witnessing plans for a large stem cell institute at the University of Cambridge. Therapeutic SCNT research would be allowed inasmuch as it is permissible under national law. In Canada the government passed in 2004 an Assisted Human Reproduction Law that, in relevant part, allows the derivation of ES cells from donated embryos (but not therapeutic SCNT). The law establishes a body to license the research (Canada/Government 2004). In the Netherlands it is permissible to create embryos for ES cell research (Gruss 2003). Each nation with emerging policy has held meetings and produced advisory group opinions that become part of the advocacy community.

While a review of the policies in these nations is beyond the scope of this chapter, the point is that policy making becomes enriched when perspectives go beyond national borders to examine policy developed through an open and pluralistic process in nations where ES cell research is welcomed. Policy governing therapeutic SCNT in the United Kingdom, for example, is not ethically less persuasive or authoritative than policy in California or New Jersey simply because it lies outside US borders. Taking an international perspective greatly broadens the resources for modeling ethical and policy analysis.

Corporations

The extent to which biotechnology companies conduct research into ES cells is hard to gauge. Corporations follow FDA regulations if they are developing biological products for eventual marketing, but this process is protected by secrecy. Companies may voluntarily follow federal guidelines for protecting research participants even if conducting privately funded research, and some follow or modify guidelines produced by an NIH ad hoc working group that made recommendations for

obtaining donated embryos for stem cell research in 1999 (Cohen 2004: 110; National Institutes of Health 1999). Although one would not expect corporations to play a critical role in ES cell policy development, they are part of the community of advocates. In at least two instances corporations have set up ethics advisory boards (EABs) to propose guidelines for ES cell research and they have made public the process.

One, Geron Corporation, the company that funded the 1998 study by Thomson et al. in which the researchers first derived human ES cells, set up an EAB in mid-1998 to advise the company on ethical issues raised by ES cell research. After publication of the study, Geron contacted editors of the Hastings Center Report, and in spring 1999 the journal published a symposium with a report by Geron’s EAB and essays by commentators. The company’s EAB reached conclusions similar to those reached in the NIH’s 1994 Human Research Policy report ( Tauer 1999). Among other things, it advised that researchers should not engage in reproductive SCNT or mix the ES cells of different humans or of humans with a different species to make a chimera. The EAB also spoke of the importance of securing informed consent from egg donors. It advised that all research on human ES cells be approved by the EAB as well as an IRB (Geron Ethics Advisory Board 1999).

A second company, ACT, initiated an EAB in 1999 with a bioethicist as chair, to ‘weigh the moral implications of therapeutic cloning research’ (Green 2001). The EAB published the guidelines on the magazine’s website, which included the restriction that research on embryos created through SCNT could continue for no more than fourteen days after fertilization. In regard to egg donation, the EAB advised that donors be limited to women aged 24 – 32 who had at least one child. Donors were required to undergo psychological and physical tests and could be compensated no more than $4,000 (Green 2001). Investigators aimed to secure approximately ten eggs from each donor. The researchers used anonymous somatic cell donors for fibroblasts. Some were healthy and others had conditions potentially helped by SCNT research (Cibelli et al. 2002). Somatic cell donors were warned about media attention and were told that their identity would be kept secret. Embryos were kept in a secure location, and measures were initiated to ensure that the embryos were not used for procreation (Saletan 2001).

In an example of clinic-based ethics review, the Jones Institute for Reproductive Medicine published guidelines for obtaining eggs from women to create embryos (through fertilization) for ES cell research. Clinic personnel did not actively recruit women for donation. Instead, they queried women who had applied to give eggs to help others conceive but were turned down because of problems with their medical background or because no recipients were available. They also used as donors women who had heard of the research and contacted the program (Lanzendorf et al. 2001).

Corporate EABs have obvious limits as conduits of ethics deliberations and as sources of policy. Open discussion is difficult in the context of corporate secrecy.

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Corporations are also geared more to product development than to basic research, where ethical questions about whether one should proceed are appropriately raised. As entities set up by companies, corporate EABs may be insufficiently independent or critical and they may be set up after research has commenced rather than before (Hall 2000). Given their scarcity, they have minimal impact. As one analyst noted, ‘the work of a small advisory board convened by one private company in no way measures up to the task of exercising oversight of human stem cell research or other types of research that the company invests in and investigators may choose to pursue’ (White 1999: 41; emphasis omitted). In addition, there is ‘no real motive to share guidelines across companies’ (White 1999: 41). Even if corporations mutually sponsor an EAB, they will lack an incentive to enforce guidelines.

Corporate EABs are also criticized for their narrow focus on procedures rather than broader ethical issues (Fischer 2001; Saletan 2001). Questions about payment for EAB members and conflict of interest also dog these committees (Saletan 2001). One bioethicist notes that as of 2004 ‘no common ethical standards for conducting embryonic stem cell research have been developed in the private sector’ (Cohen 2004: 111). In addition, the guidelines do not cover embryos created by SCNT or studies on parthenogenesis or other studies involving embryos created outside of fertilization (Cohen 2004: 111). Furthermore, the private sector has not produced ‘commonly accepted ethical guidelines’ for the range of issues arising from ES cell research that might, for example, involve the derivation of gametes from stem cells (Cohen 2004: 112). The paucity of national ethical standards evokes concerns that privately funded researchers will ‘wing it’ ethically (Cohen 2004: 111).

While such criticisms identify flaws in corporate ethics oversight, they need not foreclose an interest in corporate policy. The corporate EAB makes an interesting case study. Corporations are under no obligation to develop guidelines beyond IRB or equivalent review or FDA standards, much less to publish them. Thus, an examination of the motivating forces for doing so might encourage others to follow suit. Moreover, the content of the guidelines and deliberations is noteworthy and may be added to a meta-analysis of guidelines. The corporate world, in a nation with limited federal funding, is an early place for indicating issues and directions in research and development. Certainly an expectation that they will consider issues in the public interest and pledge not to undertake some forms of research is preferable to no pledge. Geron’s EAB arranged to publish its guidelines, according to its members, to ‘contribute to and invite . . . public discourse’ stemming from the ‘complex ethical issues emerging from ES cell research’ (Geron Ethics Advisory Board 1999: 32). Also, it contributed specific recommendations, such as warnings to include explicit provisions about financial disclosure when securing consent from couples donating embryos. One commentator has observed that Geron’s EAB ‘provides an example of private – public ethical collaboration through the board’s acknowledgement and application of previously developed federal guidelines’ ( Tauer 1999: 45).

Professional Associations

Professional associations, made up of professionals in science and medicine, have issued statements related to both reproductive and therapeutic SCNT. After Dolly’s birth, the three main associations with members who could theoretically be involved in reproductive SCNT research — American Society for Reproductive Medicine (ASRM), the Biotechnology Industry Organization, and the Federation of American Societies for Experimental Biology (FASEB) — all called on their members to observe a moratorium on reproductive SCNT. After scenarios of therapeutic SCNT emerged, numerous groups recommended that it proceed, including the Institute of Medicine, the American Medical Association, FASEB, the American Association for the Advancement of Science, and the ASRM in the United States. Internationally, supportive groups include the European Society of Human Reproduction and Embryology and the Australian Academy of Science (ESHRE Task Force 2002; Australian Academy of Science 1999).

These and other organizations can be expected to take part in developing guidelines for therapeutic SCNT as questions arise in research and later practice. They provide a forum, through journals, conventions, ethics committee statements, and press releases, for mobilizing discussion. For example, professional associations proposed a somewhat more stringent process for securing consent from couples to donate spare embryos for ES cell than for other types of research using embryos. It is reasoned that ES cell research is different because the cell lines can exist indefinitely, potentially be traced to donors, and may hold considerable commercial value (ESHRE Task Force 2002). Among other things, groups recommend giving detailed information to potential donors about the specific research protocol and erecting a ‘solid wall’ in the consent process between the person seeking to help the patient become pregnant and the person seeking ES cells for research (American Association for the Advancement of Science 1999). The Ethics Committee of the ASRM in 1997 issued a statement for donating embryos for research and in 2002 issued a second statement directed to donating embryos for ES cell research (Ethics Committee, ASRM 1997, 2002). The latter was more explicit in what should be conveyed to potential donors in the consent process inasmuch as ES cell lines may have ‘considerable commercial value’ and can potentially be traceable.

Concern has been expressed about egg donors in therapeutic SCNT research and practice (European Group on Ethics in Science and New Technologies 2000). The need to secure human eggs is a limiting factor in this research because eggs are scarce and are secured at some risk to the donor. Investigators in South Korea used 2,061 eggs from 129 women in research to derive ES cells from embryos created through SCNT (Steinbrook 2006). Ethical questions were raised early on about the way the volunteers were recruited, however, and critics were later vindicated when it turned out that junior members of the research team were, indeed, among those who gave eggs. This development suggests the possibility of subtle if not explicit

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pressure placed upon the women to participate (Normile et al. 2006). Although it is not unusual for researchers to involve themselves in their investigations, the alleged lack of transparency in this case led the government to place a hold on further studies until a licensing system for using human eggs could go into effect (Cyranoski 2004). Irregularities in the recruitment of donors had taken place before the policy changes.

On the matter of recruiting egg donors, the ASRM Ethics Committee said that paying women who donate eggs for reproduction over $5,000 would ‘require justification’ and payments above $10,000 ‘go beyond what is appropriate’ (Ethics Committee, ASRM 2000: 219). According to the committee, sums above this might cause donors to minimize physical and psychological risks and convey the message that eggs are commercial products. In addition, high sums might make donation too costly for all but wealthy recipients and, if given to donors with particularly desirable traits, might have eugenic overtones (Ethics Committee, ASRM 2000: 217).

With therapeutic SCNT, medical therapy, not reproduction, is the end. Some might argue that higher payment is justified here because the taint of ‘buying’ gametes for reproduction does not apply and because the potential benefit reaches more people. On the other hand, the same arguments that urge caution for reproductive donation arguably apply for research donation. Donors may, if offered high sums for their time and effort, be more likely to discount risks. In addition, high payments for medical therapy might again make treatments too costly for all but the wealthiest patients.

Another issue relates to women who donate repeatedly. The number of donations for reproduction that lead to births can justifiably be limited by concerns of inadvertent consanguinity of offspring. In donation for research, however, this restriction does not inhere. Should women willing to accept the risks of donation be limited in the number of times they donate for research as well as for reproduction, albeit for different reasons? In addition, if donors are scarce, what is the impact on fertility programs if women donate instead to research programs? The impact could be significant if the price is higher for regenerative medicine than for fertility purposes. It is not unreasonable to assume that wealthier citizens will have access to cell therapies made possible from therapeutic SCNT, especially if insurance companies are reluctant to reimburse for procedures using cells derived from human embryos.

In another aspect of egg donation, if therapeutic SCNT were to proceed and eggs were still needed, would it be ethical for patients to recruit their own egg donors? Would special protections be needed in this situation to ensure donors are not pressured to donate? Presumably donors would also be given a background check for mitochondrial disease and would need to be apprised of that. In a related scenario, what guidance would be needed if female patients wanted to use their own eggs for tailor-made ES cell lines? All donors would have to be told of commercial potential resulting from research and development and whether they would share

in the profits. As developed by those in the field, consent by egg donors must enable them to ‘understand how exactly the gametes, embryos, and cell lines will be used in the future and the possible financial benefits the institution may receive as a result of any ESC lines the donor’s gametes produce’ (Lanzendorf et al. 2001: 136).

Somatic cell donors provide another topic that invites voices from the field. For example, ACT used ‘several . . . anonymous individuals’ to donate fibroblasts. Some were healthy and some had disorders that therapeutic SCNT might one day address (Cibelli 2002). Somatic cell donation would not be physically risky, as it would pose only a ‘remote possibility of an infection at the site of the skin biopsy’ (Green 2001). In might, however, draw negative publicity, so the EAB of the ACT recommended confidentiality (Green 2001). In addition, if the SCNT process worked, the embryo potentially could be transferred for a pregnancy. Thus the investigators would be obligated to undertake restrictions to ensure that this did not happen. This might involve not freezing embryos created through SCNT, for example. Investigators would also need to make clear to somatic cell donors that the embryos would not be used for procreation even if the donors wanted to use them for procreation. In case donors had moral reservations about embryo research, they must be told in the consent process ‘that ES cell research typically involves deriving cells from the inner cell mass of an embryo at the blastocyst stage, which leads to the embryo’s destruction’ (Ethics Committee, ASRM 2002).

Professional associations are not neutral but neither are they one-dimensional. They are pluralistic and they represent differing perspectives. Not all members should be regarded as supporting therapeutic SCNT even if the official position is supportive. Yet they are part of the community of advocates who can be expected to play a role in developing guidelines and who provide a forum, albeit one with borders, for ethics deliberation and guidance.

Policy Advisory Groups

Policy advisory groups refer to groups that are governmental or nongovernmental and permanent (e.g. the Institute of Medicine) or temporary (e.g. the National Bioethics Advisory Commission). An example of a nongovernmental group is the eighteen-member interdisciplinary body initiated by the Program in Cell Engineering, Ethics, and Public Policy at Johns Hopkins University and funded by the Greenwall Foundation to ‘discuss novel ethical and policy challenges in stem cell research’ (the JHU group) (Dawson et al. 2003: 1077). The JHU group started with the assumption that ES cell research will proceed and it asked what should be done to prepare. Its members identified ethical and policy issues arising from basic research, clinical trials, and human therapies. It did not review issues relating to SCNT, although it provided a model for how therapeutic SCNT could be studied. The group published one report exploring the preconditions for ethically

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proceeding with clinical trials (Dawson et al. 2003) and a second report raising questions about the ethical allocation of benefits after therapies are available (Faden et al. 2003).

In its first report, the group warned that several preconditions were necessary for clinical trials. First, new cell lines must be developed; clinical trials should not commence using ES cells derived prior to 9 August 2001 because these lines were cultured on animal feeder cells that risk the spread of infectious disease. Developing new lines means more human embryos will be destroyed, but this is justified by the need to protect human subjects by producing stem cell lines not exposed to mouse cells. In a second precondition, ES cell lines require quality control and standards and assays for making sure the lines are stable. If the lines do not meet the standards, investigators must not use the cells in clinical studies even if it means a delay in research. Third, investigators must consider the genetic risks posed by using cells derived from donated embryos. Existing cell lines are problematic because investigators do not know what genetic mutations to screen for in the lines. Therapeutic SCNT would mitigate this concern; for political and ethical reasons, however, this option may not be available. Fourth, investigators must be able to monitor cells so they will not go to the wrong target or de-differentiate, ensure that the cells will not form tumors, and develop methods to prevent immune rejection. Sponsors, researchers, and regulators must interact and develop criteria for testing.

The group also urged not proceeding without advance thinking about how to select participants for clinical trials and adequately protect participants. Federal funding is essential for protecting the safety of research participants, but funding restrictions mean the science is attracting insufficient federal oversight of ethics. It is important regularly to ‘engage in serious discussions about the next generation of ethical and policy issues’ for stem cell research before rather than after scientific developments (Dawson et al. 2003: 1077). In preparation for clinical trials, health care professionals should set up patient advisory boards, specify people to monitor the consent process, appoint patient advocates, and enact procedures to protect earliest human subjects. The group was not persuaded that a body such as the Recombinant DNA Advisory Committee would be helpful for protecting human subjects, owing in part to the lack of federal funding.

In a second report, the JHU group asked how ‘equitable biological access’ to cell lines can be secured for research and therapy (Faden et al. 2003). The group posited that some people will have greater biological access to banks of stem cell lines than others. The members were concerned that the banks will not adequately reflect the country’s ethnic and racial biological diversity. The group advised preemptive planning and envisioned a stem cell bank in the United States that ‘would be composed of the fewest number of cell lines that would reflect the ancestral backgrounds of all of the major ethnic groups in the United States’ (Cohen 2004: 109). Among other things, this would draw attention to diseases that are not limited

to occurrences primarily among Caucasians. Therapeutic SCNT would address the access problem because it would allow transplantation using a patient’s own cells. But this technique is ‘not practical at present’ because of the costs of developing individualized therapies and the political barriers wrought by the ‘political and moral controversy’ of therapeutic SCNT (Faden et al. 2003: 15).

The difficulty in securing eggs, especially from minority populations, further burdens the creation of stem cell banks, at least with current technologies. So too do moral controversies about using embryos, although these could be lessened by waiting until there is ‘solid evidence’ that ES cell therapies will work before building stem cell banks. Still, to get to that stage, more embryos will need to be used. For this reason, private funds presumably will be needed to develop the bank. In short, the group confronted some of the decisions that must be made for ES cell benefits to be realized. This will involve calculations about whether ensuring equitable benefit from ES cell research or protecting embryos is more valuable. It will also involve revisiting federal funding policy, financial incentives, and patent protections to address justice concerns.

CONCLUSION

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One observer has said that ‘the prospect of a patchwork approach to human stem cell research is not encouraging’ (White 1999: 42). If a policy patchwork holds for ES cell research in general, it does even more so for research into therapeutic SCNT as a subtype of ES cell research. Whereas ES cell research is burdened by conflicts over the status of the embryo, therapeutic SCNT shares a technique with reproductive SCNT, which makes it doubly contentious. Yet research is proceeding, however slowly, and few signs of national oversight are in view.

In an effort to seek alternative policy sources and suggest new directions for academic commentary, this chapter directs attention to what might be called a policy community of advocates — the advisory groups, experts, interest group members, and others who share an interest in ES cell research, including therapeutic SCNT. This community, loosely defined, took form in debates in the US Congress. Because it is not neutral, it must not be the only voice in deliberations. Still, its biased voice can play a role in policy making in that its members presumably have a sense of mission that can be marshaled to promote research and development under guiding principles. This community exists in the public sector (states and other nations) as well as the private sector (corporations and professional associations). It is a source of oversight generated by those eager for research and clinical application to succeed and to be practiced ethically. The community is a case study in policy development where federal oversight is minimal, and it opens the door to policy leadership.