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/N0T-0D-02-005.html.

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.

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

2See FDA letter to investigators/sponsors at http://www.fda.gov/cber/ltr/aaclone.pdf.

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

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.

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