1
Introduction

Stem cells are capable of self-renewal and also of differentiation into specialized cells. Some stem cells are more committed to a particular developmental fate than others; for example, they divide and mature into cells of a specific type or limited spectrum of types (such as heart, muscle, blood, or brain cells). Other stem cells are less committed and retain the potential to differentiate into many types of cells. It is believed that stem cells also form reservoirs of repair cells to replace cells and tissues that degenerate over the life span of the organism. The dual capacity of stem cells for self-renewal and for differentiation into particular types of cells and tissues offers great potential for regenerative medicine. The various types of stem cells differ substantially in these properties.

In 1998, scientists reported three separate sets of research findings related to the isolation and potential use of human embryonic stem cells. Two of the 1998 reports were published by independent teams of scientists that had accomplished the isolation and culture of human embryonic stem cells (hereafter referred to as hES cells) and human embryonic germ cells (hereafter referred to as hEG cells). One report described the work of James Thomson and his co-workers at the University of Wisconsin, who derived hES cells from a human blastocyst, comprising about 200 cells, donated by a couple that had received infertility treatments (Thomson et al., 1998). Their accomplishment was significant, because hES cells are considered by many to be the most fundamental and extraordinary of the stem cells; unlike the more differentiated adult stem cells or other cell types, they are pluripotent. (See the glossary for terminology used in this report.)

The second report described the successful isolation of hEG cells in the laboratory of John Gearhart and his colleagues at the Johns Hopkins University. That



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Guidelines for Human Embryonic Stem Cell Research 1 Introduction Stem cells are capable of self-renewal and also of differentiation into specialized cells. Some stem cells are more committed to a particular developmental fate than others; for example, they divide and mature into cells of a specific type or limited spectrum of types (such as heart, muscle, blood, or brain cells). Other stem cells are less committed and retain the potential to differentiate into many types of cells. It is believed that stem cells also form reservoirs of repair cells to replace cells and tissues that degenerate over the life span of the organism. The dual capacity of stem cells for self-renewal and for differentiation into particular types of cells and tissues offers great potential for regenerative medicine. The various types of stem cells differ substantially in these properties. In 1998, scientists reported three separate sets of research findings related to the isolation and potential use of human embryonic stem cells. Two of the 1998 reports were published by independent teams of scientists that had accomplished the isolation and culture of human embryonic stem cells (hereafter referred to as hES cells) and human embryonic germ cells (hereafter referred to as hEG cells). One report described the work of James Thomson and his co-workers at the University of Wisconsin, who derived hES cells from a human blastocyst, comprising about 200 cells, donated by a couple that had received infertility treatments (Thomson et al., 1998). Their accomplishment was significant, because hES cells are considered by many to be the most fundamental and extraordinary of the stem cells; unlike the more differentiated adult stem cells or other cell types, they are pluripotent. (See the glossary for terminology used in this report.) The second report described the successful isolation of hEG cells in the laboratory of John Gearhart and his colleagues at the Johns Hopkins University. That

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Guidelines for Human Embryonic Stem Cell Research team derived stem cells from primordial gonadal tissue obtained from cadaveric fetal tissue (Shamblott et al., 1998). hEG cells, which originate from the primordial reproductive cells of the developing fetus, have properties similar to those of hES cells, although there has been less research into their potential. The third report, an article in the November 12, 1998, edition of the New York Times, described work funded by Advanced Cell Technology of Worcester, Massachusetts. The report was not published in a scientific journal and therefore did not meet the higher standard of peer review, but the company claimed that its scientists had caused human somatic cells to revert to the primordial state by fusing them with cow eggs. From this fusion product, a small clump of cells resembling ES cells appears to have been isolated (Wade, 1998). In addition to those research accomplishments, the cloning of Dolly the sheep in 1997 using a technique called somatic cell nuclear transfer or, more simply, nuclear transfer (NT), illustrated another means by which to generate and isolate hES cells. hES cell preparations could potentially be produced by using NT to replace the nucleus of a human oocyte, triggering development, and then isolating hES cells at the blastocyst stage. Such a procedure was recently described by a group of Korean scientists (Hwang et al., 2004). The advantage of using NT to derive hES cells is that the nuclear genomes of the resulting hES cells would be identical with those of the donors of the somatic cells. One obvious benefit is that this would avoid the problem of rejection if cells generated from the hES cells were transplanted into the donor. Whether this approach will be technically or economically feasible is unclear. A more likely benefit of the technology is that it would further facilitate a wide range of experiments to explore the underpinnings of genetic disease and possible forms of amelioration and cure, many of which would not be possible using hES cells derived from blastocysts generated by in vitro fertilization (IVF), whose nuclear genomes are not defined. Although the promise of such research is as yet unrealized, most researchers believe that it will be a critical source of both important knowledge and clinical resources. It is important to note that stem cells made via NT result from an asexual process that does not involve the generation of a novel combination of genes from two “parents.” In this sense, it may be more acceptable to some than the creation of blastocysts for research purposes by IVF (National Institutes of Health, Human Embryo Research Panel, 1994). Use of NT for biomedical research, as distinct from its use to create a human being, has been considered by several advisory groups to be ethically acceptable under appropriate conditions involving the proper review and conduct of the research (NBAC, 1997, 1999a; NRC, 2002). However, there is near universal agreement that the use of NT to produce a child should not now be permitted. The medical risks are unacceptable, and many people have additional objections concerning the nature of this form of human procreation. In some countries there are statutory bans on the use of NT for reproductive purposes (see Chapter 4).

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Guidelines for Human Embryonic Stem Cell Research Finally, promising research has been conducted with adult stem cells (Lanza et al., 2004; Wagers and Weissman, 2004). Adult stem cells can be obtained from various tissues of adults or in some cases from neonatal tissues. A well-known example of the use of adult stem cells is bone marrow transplantation. Hematopoietic (blood-forming) adult stem cells from bone marrow or from umbilical cord blood give rise to all the cells of the blood. Skin cell transplants similarly rely on the transfer of skin stem cells. In both examples, the tissue involved naturally renews itself from its pool of stem cells—a property that can be exploited for medical use. It is possible that similar approaches can be developed for other tissues (such as muscle). However, in many other tissues, natural self-renewal appears to be a slow process, and stem cells for such tissues are correspondingly harder to characterize and isolate. There is also the possibility that some tissues may not contain a distinct subpopulation of undifferentiated stem cells at all. Furthermore, the anatomic source of the cells (such as brain or heart muscle) might preclude easy or safe access. There are important biological differences between embryonic and adult stem cells. Embryonic stem cells show a much greater capacity for self-renewal, can be cultured to generate large numbers of cells, and are pluripotent—they have the potential for differentiation into a very wide variety of cell types. In contrast, adult stem cells appear to be capable of much less proliferation and, in general, have a restricted range of developmental capacities; that is, they can differentiate into only a limited array of cells (Wagers and Weissman, 2004). Thus most experts consider “adult stem cell research” not to be an alternative to hES and hEG cell research, but rather a complementary and important line of investigation. hES cells currently can be derived from three sources: blastocysts remaining after infertility treatments and donated for research, blastocysts generated from donated gametes (oocytes and sperm), and the products of NT. Cadaveric fetal tissue is the only source of hEG cells. hES and hEG cells offer remarkable scientific and therapeutic possibilities, involving the potential for generating more specialized cells or tissue. This could allow the generation of new cells to be used to treat injuries or diseases involving cell death or impairment, such as Parkinson’s disease, diabetes, heart disease, spinal cord injury, and hematologic and many other disorders. In addition, understanding the biology of hES and hEG cells is critical for understanding the earliest stages of human development. Ethical concerns about the sources of hES and hEG cells, however, and fears that use of NT for research could lead to the use of NT to produce a child have fostered a great deal of public discussion and debate. Concern has also been expressed about whether and how to restrict the production of human/nonhuman chimeras when conducting research with hES cells. Such research could be tremendously useful in understanding the etiology and progression of human disease and in testing new drugs, and will be necessary in preclinical testing of both adult and embryonic stem cells and their derivatives. However, some are concerned that creating chimeras would violate social conventions built around the notion of species (Robert and Baylis, 2003).

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Guidelines for Human Embryonic Stem Cell Research THE NEED FOR GUIDELINES Since 1998, the volume of research being conducted with hES cells has expanded, primarily with private funds because of restrictions on the use of federal funds for such research. Those restrictions are both legislative and by executive order. Federal legislation forbids the use of federal funds for any research that destroys an embryo, that is, is “nontherapeutic” for the embryo. That effectively prevents any use of federal funds to derive hES cells from blastocysts. Research with established hES cell lines is further limited by presidential policy: the policy announced by President George W. Bush in 2001 restricts federal funding of research with hES cells to use of specific federally approved cell lines already in existence before August 9, 2001. The policy states further that funding is available only for research with hES cell lines that were derived before August 9, 2001 from frozen human blastocysts that remained at infertility clinics and that were (1) generated for reproductive purposes, (2) donated with informed consent, and (3) donated with no financial inducements.1 Laboratories or companies that provide cells that meet those conditions (originally thought to be roughly 60 cell lines, now thought to be about 22) could list the lines in the National Institutes of Health (NIH) Human Embryonic Stem Cell Registry. To do so they were required to submit a signed assurance that their hES cells met the criteria. Once the assurance was verified, the cell lines became available for use in federally funded hES cell research. The date of August 9, 2001, was set as the cutoff point to distance the federal government from any privately funded future use of embryos for hES cell research. Not all the original hES cell lines thought to be available for federally funded research have been viable, nor do they exhibit sufficient genetic diversity for all research endeavors and possible future clinical use. Furthermore, the roughly 22 lines now available were grown on mouse-feeder cell layers. That does not necessarily render them inadequate for research pursuing human applications, but it does raise concerns about contamination. The presence of animal feeder cells increases the risk of transfer of animal viruses and other infectious agents to humans that receive the hES cells and in turn to many others. There is also the risk that hES cells grown with nonhuman animal products will have incorporated antigenic glycolipids into their cell surface. If hES cell research and therapy are to be thoroughly investigated, cell lines that are more genetically diverse and free of animal contaminants must be available. A first step in that direction was taken in February 2005 with the publication of a paper documenting the first successful growth of hES cell lines without mouse feeder cells, although contact with a growth supplement derived 1   “Notice of Criteria for Federal Funding of Research on Existing Human Embryonic Stem Cells and Establishment of NIH Human Embryonic Stem Cell Registry (Nov. 7, 2001)”, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.

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Guidelines for Human Embryonic Stem Cell Research from mouse cells and bovine serum means that the lines are not yet completely free of contact with nonhuman materials (Xu et al., 2005). Despite the restricted use of federal funds for research, the derivation of new cell lines is proceeding legally in the private sector and in academic settings with private funds. Some states have banned some or all forms of this research (see Chapter 4), but other states are actively promoting hES cell research. Although general regulation of laboratory research exists, there are no established regulations that specifically address procedures for hES cell research. Several academic research centers are conducting hES cell research in this uncertain funding and regulatory climate and would benefit greatly from a set of uniform standards for conduct. Privately funded hES cell research is subject to some regulation or other constraints, primarily through human subjects protection regulations, the limits placed on licensees by the holders of NT and hES cell patents, state laws, and self-imposed institutional guidelines at companies and universities now doing or contemplating this research. Those aiming to produce biological therapies are also subject to Food and Drug Administration (FDA) regulation (see Chapter 4). Because of the absence of federal funding for most hES cell research being conducted today, some standard protections may be lacking, and the implementation of protections is almost certainly not uniform throughout the country. The techniques for deriving the cells have not been fully developed as standardized and readily available research tools and the development of any therapeutic applications remain some years away. Because there is substantial public support for this area of research (Nisbet, 2004), and because several states are moving toward supporting this research in the absence of federal funds, heightened oversight is essential to assure the public that such research can and will be conducted ethically. Because of the void left by restriction of federal funding and its attendant oversight of research and because of the importance that the scientific and biomedical community attaches to pursuing potential new therapies with hES cell lines, the National Academies initiated this project to develop guidelines for hES cell research to advance the science in a responsible manner. The project follows a series of reports issued by the Academies on this and related topics. The 2002 National Academies report Stem Cells and the Future of Regenerative Medicine (NRC, 2002a) called for human adult stem cell and hES cell research to move forward. It also concluded that so-called therapeutic cloning, or NT for research purposes, has a separate and important potential both for scientific research and for future medical therapies. The report argued for federal funding of research deriving and using hES cells from multiple sources, including NT, asserting that, without government funding of basic research concerning stem cells, progress toward medical therapies is likely to be hindered. It noted that public sponsorship of basic research would help to ensure that many more scientists could pursue a variety of research questions and that their results would be made widely accessible in scientific journals—two factors that speed progress substantially. Public funding also offers greater opportunities for regulatory oversight and scrutiny of research.

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Guidelines for Human Embryonic Stem Cell Research The committee recommended that, given the ethical dilemmas and scientific uncertainties raised by hES cell research, a national advisory body made up of leading scientists, ethicists, and other stakeholders should be established at NIH. It argued that the group could ensure that proposals for federal funding to work on hES cells were justified on scientific grounds and met federally mandated ethical guidelines. The committee noted that NIH had set up similar watchdog panels, such as the Recombinant DNA Advisory Committee (RAC), which oversees genetic engineering research on the basis of an extensive set of guidelines. In the report, Scientific and Medical Aspects of Human Reproductive Cloning (NRC, 2002b), the National Academies called for a “legally enforceable ban” on human reproductive cloning owing to scientific and medical concerns. The report recommended that such a ban be revisited in 5 years. Despite several legislative attempts to ban the use of NT for reproductive purposes, no such prohibition exists in federal statute, although FDA has stated that it has the authority to prohibit the use of NT for reproductive purposes on the basis of safety concerns.2 Moreover, although a voluntary moratorium has worked in the past to delay scientific research (such as recombinant DNA research), the committee judged that a voluntary moratorium was unlikely to work for human reproductive cloning, because reproductive technology is widely accessible in numerous private fertility clinics that are not subject to federal research regulations. In addition, when the RAC (a model of successful self-regulation leading to public policy) was established and its guidelines were put into place, the vast majority of research biologists in the United States were funded by NIH or the National Science Foundation, so the potential sanction—loss of federal grants—was a strong disincentive. That would not be the case for human reproductive cloning. Other national panels have expressed views about the regulation of reproductive cloning and the use of NT for research into new therapies. President William J. Clinton’s National Bioethics Advisory Commission (NBAC) also issued two reports on the issues. In its 1997 report Cloning Human Beings, issued before the isolation of hES cells, NBAC wrote that hES cells could provide critical strategies for cell-based therapies and that NT could be important in averting graft rejection in recipients of such therapy (NBAC, 1997). In its 1999 report Ethical Issues in Human Stem Cell Research (NBAC, 1999a), NBAC recommended that federal funds be available for the derivation and use of hES cells and that, for the moment, federal funding be restricted to research in which the cells were derived from blastocysts that remained after IVF or were derived from fetal tissue while research with cells derived in other ways remained legal and privately funded. The commission suggested that following this recommendation would make sufficient hES cells available for research. It also noted that the issue should be revisited if studies on those 2   See FDA letter to investigators/sponsors at http://www.fda.gov/cber/ltr/aaclone.pdf.

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Guidelines for Human Embryonic Stem Cell Research cell lines demonstrate the need for federal funding of research with NT-derived cell lines or cell lines from blastocysts generated for research purposes. In its 1999 report, NBAC outlined a system of national oversight to review protocols, monitor research, and ensure strict adherence to guidelines. Although intended for research with hES cells derived from IVF blastocysts, many of the recommendations could apply equally well to blastocysts derived using NT. NBAC’s regulatory paradigm was based in part on the regulatory system already in place governing fetal tissue transplantation research: strict oversight and separation of the decision to terminate a pregnancy from the decision to donate material. In its 2002 report, Human Cloning and Human Dignity: An Ethical Inquiry, 10 of 17 members of President Bush’s Council on Bioethics recommended a 4-year moratorium on “cloning-for-biomedical-research.” They also called for “a federal review of current and projected practices of human embryo research, pre-implantation genetic diagnosis, genetic modification of human embryos and gametes, and related matters, with a view to recommending and shaping ethically sound policies for the entire field.” The advocates of the moratorium argued that it “would provide the time and incentive required to develop a system of national regulation that might come into use if, at the end of the four-year period, the moratorium were not reinstated or made permanent.” Furthermore, they argued that “in the absence of a moratorium, few proponents of the research would have much incentive to institute an effective regulatory system.” Seven members of the 17-member council voted for “permitting cloning-for-biomedical-research now, while governing it through a prudent and sensible regulatory regime.” They argued that research should be allowed to go forward only when the necessary regulatory protections to avoid abuses and misuses of cloned embryos are in place. “These regulations might touch on the secure handling of embryos, licensing and prior review of research projects, the protection of egg donors, and the provision of equal access to benefits.” Finally, in September 2003, a worldwide movement of science academies led to a major meeting in Mexico City in which 66 academies—including the U.S. National Academy of Sciences—from all parts of the world and all cultural traditions and religions called for a global ban on the use of NT for human reproduction as a matter of urgency. The group of academies specified that no ban on NT for human reproduction should preclude hES cell research with NT blastocysts. A growing number of countries have far more permissive policies regarding such research than the United States has (Walters, 2004; see also Chapter 4). Because there is widespread agreement in the international scientific community about the potential value of hES cell research—including the use of NT to derive hES cell lines—and because there is, at present, general agreement that NT should not be used to produce a child, the best possible way to move forward with hES cell research in pursuit of new therapies is to have a set of guidelines to which the U.S. scientific community can adhere. A key reason for the remarkable success of science since its emergence in mod-

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Guidelines for Human Embryonic Stem Cell Research ern form—besides the application of the scientific method itself—is the communal nature of scientific activity. The tradition of sharing materials and results with colleagues speeds scientific progress and symbolizes to the nonscientific world that in the final analysis the goal of science is to expand knowledge and improve the human condition. Not all scientists want to or have the resources to derive new stem cell lines, so the ability to share cell lines will create greater access for qualified scientists to participate in human stem cell research. A uniform set of criteria for deriving hES cell lines and reviewing research will help to assure that research institutions that derive, store, and maintain hES cells meet a standard set of requirements for provenance and ethical review. Another positive aspect of a set of established and generally agreed upon guidelines would be greater public confidence in the conduct of hES cell research. The integrity of privately funded hES cell research would be enhanced in the public’s perception as well as in actuality by the existence of a standardized set of guidelines. Public confidence would also be increased by enhanced understanding of the research. Some of the concerns about hES cell research arise from lack of familiarity with the scientific issues. It is especially crucial that the public have access to accurate information and the scientific community needs to make greater efforts to explain what research is being proposed and why. Patient advocacy groups and those with a stake in the potential therapeutic benefits of such research have begun to provide some of the education that has been lacking. As part of the larger society, the scientific community and the lay public need to engage in constructive discussion about this and other promising new fields of biomedical research to ensure that public confidence is maintained. A BRIEF HISTORY OF U.S. DISCUSSIONS AND POLICIES REGARDING RESEARCH INVOLVING HUMAN EMBRYOS Public debates and deliberations about embryo research have extended over the last 30 years. In 1975, the Secretary of the Department of Health, Education, and Welfare (DHEW) announced that the department would fund no proposal for research on human embryos or on IVF unless it was reviewed and approved by a federal ethics advisory board. IVF was still an experimental technique: Louise Brown, the first IVF baby, was born in 1978 in the United Kingdom. The human subjects regulations that resulted from the work of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (National Commission) required review of such work by an Ethics Advisory Board (EAB) to be appointed by the DHEW Secretary (National Commission, 1975). In 1977, NIH received an application from an academic researcher for support of a study involving IVF. After the application had undergone scientific review by NIH, it was forwarded to the EAB. At its May 1978 meeting, the EAB agreed to review the research proposal and later approved it for initiation. With the increased public interest that followed the birth of Louise Brown that

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Guidelines for Human Embryonic Stem Cell Research summer, the Secretary of DHEW asked the EAB to study the broader social, legal, and ethical issues raised by human IVF. On May 4, 1979, in its report to the Secretary, the EAB concluded that federal support for IVF research was “acceptable from an ethical standpoint,” provided that some conditions were met, such as informed consent for the use of gametes, an important scientific goal that was “not reasonably attainable by other means” and not maintaining an embryo “in vitro beyond the stage normally associated with the completion of implantation (14 days after fertilization)” (DHEW EAB 1979, 106, 107). No action was ever taken by the Secretary with respect to the board’s report; for other reasons, the department dissolved the EAB in 1980. Considerable opposition to the moral acceptability of IVF was expressed by some and contributed to paralysis regarding reconstitution of the EAB (Congregation, 1987). Because it failed to appoint another EAB to consider additional research proposals, DHEW effectively forestalled any attempts to support IVF research with federal funds, and no experimentation involving human embryos was ever funded pursuant to the conditions set forth in the May 1979 report or through any further EAB review. A 1988 report by the congressional Office of Technology Assessment about infertility forced a re-examination of the EAB (U.S. Congress, OTA, 1988), and a later House hearing focused on its absence. The DHEW Assistant Secretary promised to re-establish an EAB, and a new charter was published, but it was never signed after the election of President George H. W. Bush (Windom, 1988). The George H. W. Bush administration did not support re-establishing an EAB. The absence of a federal mechanism for the review of controversial research protocols continued until 1993, when the NIH Revitalization Act effectively ended the de facto moratorium on support of IVF and other types of research involving human embryos by nullifying the regulatory provision that mandated EAB review. In response, NIH Director Harold Varmus convened a Human Embryo Research Panel (HERP) to develop standards for determining which projects could be funded ethically and which should be considered “unacceptable for federal funding.” The HERP submitted its report to the Advisory Committee to the Director in September 1994.3 In addition to describing areas of research that were acceptable and unacceptable for federal funding, the panel recommended that under certain conditions federal funding should be made available to make embryos specifically for research purposes. Acting on this submission, the Advisory Committee to the Director formally approved the HERP recommendations (including provision for the deliberate creation of research embryos) and transmitted them to the NIH Director on December 1, 1994. On December 2, pre-empting any NIH response, President Clinton intervened to clarify an earlier endorsement of embryo research, 3   Available at http://www.bioethicsprint.bioethics.gov/reports/past_commissions/index.html.

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Guidelines for Human Embryonic Stem Cell Research stating that “I do not believe that Federal funds should be used to support the creation of human embryos for research purposes, and I have directed that NIH not allocate any resources for such requests” (Office of the White House Press Secretary, 1994). The NIH Director proceeded to implement the HERP recommendations not proscribed by the President’s clarification, concluding that NIH could begin to fund research activities involving “surplus” blastocysts. But before any funding decisions could be made, Congress took the opportunity afforded by the Department of Health and Human Services (DHHS) appropriations process (then under way) to stipulate that any activity involving the creation, destruction, or exposure to risk of injury or death of human embryos for research purposes may not be supported by federal funds under any circumstances. The same legislative rider has been inserted into later annual DHHS appropriating statutes, enacting identically worded provisions into law (the so-called Dickey-Wicker amendment, named after its congressional authors). Thus, to date, no federal funds have been used for research that requires the destruction of additional human embryos, whether generated originally for reproductive purposes or for research, although the current federal policy permits research on specific cell lines derived from blastocysts prior to August 2001. When the reports of the successful isolation of hES cell lines were published in 1998, the question arose as to whether it was acceptable to provide federal funding for hES cell research that would use embryonic stem cells that were obtained from IVF blastocysts with private funding. The NIH Director sought the opinion of the DHHS General Counsel regarding the effect of the appropriations rider to the NIH Revitalization Act. The General Counsel reported that the legislation did not prevent NIH from supporting research that uses hES cells derived using private funding because the cells themselves do not meet the statutory, medical, or biological definition of a human embryo (NIH OD, 1999). Having concluded that NIH may fund both internal and external research that uses hES cells but does not create or actively destroy human embryos, NIH delayed funding until an ad hoc working group developed guidelines for the conduct of ethical research of this kind. These guidelines prescribed the documentation and assurances that had to accompany requests for NIH funding of research with human hES cells, and designated certain areas of hES cell research that were ineligible for NIH funding: the derivation of hES cells from human embryos, research in which hES cells are utilized to create or contribute to a human embryo, research utilizing hES cells that were derived from human embryos created for research purposes rather than for fertility treatment, research in which hES cells are derived using NT, that is, the transfer of a human somatic cell nucleus into a human or animal oocyte, research utilizing hES cells that were derived using NT,

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Guidelines for Human Embryonic Stem Cell Research research in which hES cells are combined with an animal embryo, and research in which NT is used for the reproductive cloning of a human. Before any grants could be funded, the 2000 election produced a new administration, and consequently the policies that exist today. As previously noted, on August 9, 2001, President Bush announced that NIH could fund research that uses hES cells but only if the cell lines had been derived prior to that date. The President maintained further that the guidelines for hES cell research developed during the Clinton presidency and the ethics advisory committee itself were no longer needed. Instead, an NIH Stem Cell Task Force composed entirely of NIH personnel was appointed to “focus solely on the science” of stem cell research. That might be explained by the fact that many of the remaining ethical guidelines that NIH had planned to put into effect were no longer needed, because they applied to issues surrounding federal funding of research on hES cell lines yet to be derived. Meanwhile, other countries have been active in developing laws and regulations governing research in this area (see Chapter 4). In addition, in the United States a patchwork of state laws and programs ranges from a complete ban on all hES cell research to a new program recently enacted in California that funds the development of new lines derived from both IVF blastocysts and using NT. STATEMENT OF TASK In light of the absence of federal guidelines, the Committee on Guidelines for Human Embryonic Stem Cell Research was asked to develop voluntary guidelines to encourage responsible practices in hES cell research—regardless of source of funding—including the use and derivation of new stem cell lines derived from surplus blastocysts, from blastocysts generated with donated gametes, and through the use of NT. The guidelines should take ethical and legal concerns into account and encompass the basic science and health sciences policy issues related to the development and use of hES cells for research and eventual therapeutic purposes, such as Recruitment of blastocyst, gamete, or somatic cell donors, including medical exclusion criteria, informed consent, the use of financial incentives, risks associated with egg retrieval, confidentiality, and the interpretation of genetic information developed from studies that use these materials and might have importance to the donor. The characterization of stem cells for purposes of standardization and for validation of results. The safe handling and storage of blastocysts and stem cell material and the conditions for transfer of such material among laboratories.

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Guidelines for Human Embryonic Stem Cell Research Prerequisites to hES cell research (such as examination of alternative approaches), appropriate uses of hES cells in research or therapy, and limitations on the use of hES cells. Safeguards against misuse. In accordance with the stated position of the National Academies that there should be a global ban on NT for human reproduction (NRC, 2002), the guidelines developed by this committee focus exclusively on research and therapeutic uses of hES cells and NT. To conduct its work, the committee surveyed the current state of science in this field and likely pending developments, reviewed the policy and ethical issues posed by the research, examined professional and international regulations and guidelines affecting hES cell research, and conducted a 2-day workshop with speakers who represented many scientific, ethical, and public policy perspectives. It did not revisit the debate about whether hES cell research should be pursued; rather it assumed that both hES cell and adult stem cell research would continue in parallel with federal and nonfederal funding. In addition, although the committee recognizes that successful resolution of intellectual property issues will be critically important in this evolving area of research, it was beyond its charge and beyond its capabilities to address adequately all of the legal issues that will arise. Chapter 4 briefly addresses ongoing efforts to ensure that intellectual property issues do not impede new developments in biomedical research. The guidelines presented in Chapter 6 focus on the procurement of embryos and gametes and the derivation, banking, and use of hES cell lines. They provide an oversight process that will help to ensure that research is conducted in a responsible and ethically sensitive manner and in compliance with all regulatory requirements pertaining to biomedical research in general. These guidelines are being issued for use by the scientific community, including researchers in university, industry, or other private sector research organizations, as well as practitioners of assisted reproduction, which will be one of the sources of donated embryos and gametes. PRECEDENTS FOR SCIENTIFIC SELF-REGULATION Perhaps the archetype of modern scientific self-regulation in the life sciences—although primarily focused initially on safety rather than ethical issues—was the moratorium on recombinant DNA research that emerged from a meeting of several hundred scientists at the Asilomar Conference Center in California. A controversy had erupted in 1971 about an experiment that involved inserting genes from a monkey virus, SV40, which can make rodent cells cancerous, into an E. coli bacterial cell. Prominent scientists called for a halt to recombinant DNA research until the matter could be resolved. The 1975 Asilomar conference concluded that safeguards should be introduced into recombinant DNA work, ultimately including the creation of the NIH RAC and guidelines for federally funded recombinant DNA

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Guidelines for Human Embryonic Stem Cell Research research. It is generally agreed that the Asilomar conference and the measures that followed helped to reassure Congress and the public that the scientific community took its responsibilities seriously and allowed the research to go forward. Although the recombinant DNA debate and its results have achieved a sort of iconic status in the annals of science’s self-regulation, less spectacular examples have also arisen in the absence of or as a complement to government regulation of science and medicine. The government often relies on the private sector to regulate itself and supports it with the threat of sanctions. An example is the Joint Commission for the Accreditation of Health Care Organizations; failure to meet its standards can result in the loss of Medicare reimbursement. In the field of assisted reproduction, the lack of government funding has resulted in professional efforts to generate standards, such as those promulgated by the American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technologies. Because there is no current federal support of hES cell research in which new cell lines are derived, the most applicable sets of guidelines in the United States for this purpose come from the Ethics Committee of the ASRM (ASRM, 2000, 2004b). Most international guidelines also call for some special oversight body for stem cell research to review documentation of compliance with the guidelines of various government agencies, both domestic and foreign. Such evaluation is in some cases folded into the evaluation of scientific merit; in others it is performed by stand-alone ethics review bodies. In the United States, review of scientific merit is typically conducted by the funding agency, which is often a federal agency. That will not be the case, for the time being, for most hES cell research conducted in this country. There are clear advantages to government action, especially with regard to the legal standing of industry standards. Outstanding examples relevant to this report and to cultural environments that are similar to the United States are the British Human Fertilisation and Embryology Authority and the more recent Canadian Assisted Human Reproduction Agency. But in the absence of such arrangements, our proposals for a system of local review combined with a national oversight panel would go far toward consolidating and monitoring the policies and practices of hES cell research. CONCLUSION In the absence of federal guidelines broadly governing the generation and research use of hES cells, the scientific community and its institutions should step forward to develop and implement its own, much in the spirit of Asilomar, which resulted in the RAC guidelines in use today. Such guidelines are needed by the scientific community as a framework for hES cell research and would reassure the public and Congress that the scientific community is attentive to ethical concerns and is capable of self-regulation while moving forward with this important research. The premise is not to advocate that the work be done—that has already been debated with some consensus reached in the scientific community and elsewhere—

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Guidelines for Human Embryonic Stem Cell Research but rather to start with the presumption that the work is important for human welfare, that it will be done, and that it should be conducted in a framework that addresses scientific, ethical, medical, and social concerns. The public increasingly supports this area of research and its potential to advance human health. The next chapter describes the current status of research involving hES cells. It also addresses possible novel sources of hES cell lines not yet developed and the use of human/nonhuman chimeras in research. Chapter 3 focuses on ethical and policy issues and how existing and proposed guidelines address them. In Chapter 3, the committee proposes a local review mechanism to oversee research involving hES cells. It also recommends establishing a national body to periodically update the guidelines recommended in this report and assess the status of the field. Chapter 4 describes the current legal and regulatory environment of hES cell research in the United States and around the world. Chapter 5 addresses recruitment of donors and the informed consent process and makes recommendations about review of the processes by which donated materials are obtained. Chapter 5 also discusses the need for some standards in the banking and maintenance of hES cell lines. The final chapter consolidates the recommendations made in previous chapters as formal guidelines.