CHAPTER FOUR
Opportunities for and Barriers to Progress in Stem Cell Research for Regenerative Medicine

KEY SCIENTIFIC QUESTIONS

Both adult and embryonic stem cells can contribute to the development of regenerative medicine. Embryonic stem cells (ESCs) have the advantage of multipotency and have shown themselves to be readily culturable in the laboratory. Although the degree of plasticity of adult stem cells is still unknown and there are difficulties in purifying and culturing them, the only proven stem cell-based medical therapies that are currently available rely on adult-derived stem cells from bone marrow and skin, and adult stem cells from other tissues might someday provide therapies that stimulate the body’s own regenerative potential. Because of a misunderstanding of the state of knowledge, there may be an unwarranted impression that widespread clinical application of new therapies is certain and imminent. In fact, stem cell research is in its infancy, and there are substantial gaps in knowledge that pose obstacles to the realization of new therapies from either adult or embryoderived stem cells.

Bone marrow transplantation is a case in which clinical application proceeded without a thorough understanding of the underlying biology, but the success of the technique has improved dramatically as the understanding has grown (Thomas et al., 1999). We might not need a universal understand-



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Stem Cells and the Future of Regenerative Medicine CHAPTER FOUR Opportunities for and Barriers to Progress in Stem Cell Research for Regenerative Medicine KEY SCIENTIFIC QUESTIONS Both adult and embryonic stem cells can contribute to the development of regenerative medicine. Embryonic stem cells (ESCs) have the advantage of multipotency and have shown themselves to be readily culturable in the laboratory. Although the degree of plasticity of adult stem cells is still unknown and there are difficulties in purifying and culturing them, the only proven stem cell-based medical therapies that are currently available rely on adult-derived stem cells from bone marrow and skin, and adult stem cells from other tissues might someday provide therapies that stimulate the body’s own regenerative potential. Because of a misunderstanding of the state of knowledge, there may be an unwarranted impression that widespread clinical application of new therapies is certain and imminent. In fact, stem cell research is in its infancy, and there are substantial gaps in knowledge that pose obstacles to the realization of new therapies from either adult or embryoderived stem cells. Bone marrow transplantation is a case in which clinical application proceeded without a thorough understanding of the underlying biology, but the success of the technique has improved dramatically as the understanding has grown (Thomas et al., 1999). We might not need a universal understand-

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Stem Cells and the Future of Regenerative Medicine ing of the origins and embryonic development of stem cells, but we do need to know the answers to some fundamental questions: What causes stem cells to maintain themselves in an undifferentiated state? What cues do cells use to tell them when to start or stop dividing? What genetic and environmental signals affect differentiation? What physiological properties guide the functional integration of newly generated tissues into existing organs? The scientific investigations that will answer those questions need to be comprehensive and repeated before researchers can make strong claims about the capabilities of stem cells. Because stem cell research is relatively new, it is important to build a scientific foundation that can support the research community’s ability to evaluate and confirm new findings and demonstrations. The pillars of this foundation were identified at the workshop. They include markers that characterize specific types of stem cells; markers that distinguish stages of a stem cell’s commitment to differentiate into a particular cell lineage; profiles of gene expression in stem cells and their progeny; standard procedures for isolating stem cells from the body; techniques to propagate them reliably; and consensus on the physiological or other criteria that confirm restoration of tissue function following stem cell transplantation. As knowledge of stem cells grows, investigators will be able to ask meaningful questions about therapeutic approaches, including whether to implant cells in an undifferentiated state or a differentiated state, and which of the various sources of stem cells are best suited to address a specific clinical need. It may become apparent that combined therapies (transplanting multiple stem cell types, or using gene therapy in combination with stem cells transplants) will be needed, depending on such factors as the stage of a particular disease or the age of a patient. For now, all of these questions must wait for the establishment of a more firm scientific foundation. Because observing the behavior of tissue in vivo is difficult and the

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Stem Cells and the Future of Regenerative Medicine results can be confounded in many ways, sources of human stem cells that can be cultured in vitro are perhaps the most critical need of investigators. They will permit many more questions to be posed and answered. Many more experiments can be completed with cultured cells in the same amount of time and with the same degree of effort as in living organisms. Moreover, data from in vitro studies allow more insightful and better-defined experiments to be developed in living organisms. Access to ESCs is likely to ultimately determine the rate at which scientists make progress in this field. In fact, the successful cultivation of postnatal and adult sources of stem cells for regenerative medicine is likely to advance more rapidly if the study of ESCs proceeds and cells from different sources can be compared. ESCs exhibit many properties whose improved understanding could assist researchers in modifying adult stem cells to achieve better growth in culture and greater capacity for controlled differentiation. USE OF EMBRYOS FOR STEM CELL RESEARCH IS CONTROVERSIAL A second major obstacle to the development of new medical therapies based on stem cells is opposition to ESC research on ethical, moral, or religious grounds. No field of biological science has been more controversial than that involving human reproduction. Contraception, abortion, and in vitro fertilization have all provoked major debate and controversy in this country and abroad. Stem cell research also touches on some of the most fundamental issues with which society has grappled over the centuries, including the definition of human life and the moral and legal status of the human embryo. The workshop provided an opportunity for the committee to hear both from those who support ESC research and from those who oppose it on ethical grounds. The various speakers on the workshop panel articulated the main ethical arguments, which are summarized below. The committee acknowledges the importance and value of a dialogue that respects the many differing perspectives. Although it is not within

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Stem Cells and the Future of Regenerative Medicine our charge to judge the validity of the ethical arguments for and against this research, we believe it is appropriate to address aspects of the debate that touch upon scientific questions about the biology and derivation of stem cells. The most basic objection to ESC research is rooted in the fact that such research deprives a human embryo of any further potential to develop into a complete human being. For those who believe that the life of a human being begins at the moment of conception, ESC research violates tenets that prohibit the destruction of human life and the treatment of human life as a means to some other end, no matter how noble that end might be. There are widely divergent views on this subject. For example, in testimony to the National Bioethics Advisory Commission, Rabbis Elliot Dorff and Moshe Dovid Tendler explained that in Jewish law and tradition the embryo has no moral status until 40 days after implantation. Until it is born, the child is viewed as a part of its mother’s body, and its own life is believed to begin only when the child is born. Eggs and sperm mixed together in a petri dish have no legal status, because they are not even part of a human being unless implanted in a woman’s womb. In the same forum, Abdulaziz Sachedina discussed the Muslim tradition, which accords legal and moral status to the fetus only after ensoulment takes place, at the end of the fourth month of pregnancy. Because in both of those belief systems there is a mandate to save human life wherever possible, human ESC research can be deemed acceptable if it is conducted reasonably and ethically (National Bioethics Advisory Commission, 1999). In past Roman Catholic tradition, the Aristotelian view that life begins 40 days after conception was adopted by Augustine of Hippo and Thomas Aquinas and was maintained by the church for centuries. In 1869, however, a supplanting view that we cannot know with certainty when human life begins became established (Noonan, 1970). This view, which is currently held by the Catholic Church, requires that human life be protected at the earliest possible time, which is taken to be at conception. Protestant denominations hold diverse views: some conservative

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Stem Cells and the Future of Regenerative Medicine Protestants reject the use of embryos for research, but most accept ESC research. Moreover, not everyone who rejects embryonic stem cell research is either religious or conservative. Every federal commission (e.g., National Bioethics Advisory Commission, 1999) that has addressed research on human embryos and fetuses has, in light of the many differing perspectives, called for respect for these entities as forms of human life. For those who hold the views that human life begins at conception and that the moral obligation to preserve human life outweighs any potential health benefits of ESC research for regenerative medicine, the only morally acceptable position would be to adopt a complete prohibition on human ESC research without regard to the method of embryo production or whether the research is publicly or privately funded. Views that require less than a complete prohibition, however, permit consideration of trade-offs in defining what is acceptable. Many of the other positions rely on distinctions made about the source of the ESCs for research. Thus, one viewpoint would allow the use of embryonic cells already in laboratory culture but would prohibit the destruction of additional embryos to derive new cell lines. Another would permit the derivation and use of new cell lines as long as the cells originated in “excess” embryos that were produced by in vitro fertilization for reproductive purposes but are no longer needed for such purposes. Still another would permit the use of cells derived from embryos created specifically for the research from eggs and sperm donated by volunteers who are unrelated to each other and have no reproductive intent. The potential for creating embryos with the somatic cell nuclear transfer (SCNT) technique represents yet another approach that does not even involve fertilization of an egg by a sperm. Each of those constructs can pose its own ethical dilemmas. LeRoy Walters summarized many of the dilemmas and the diverse public-policy responses that have been adopted by various countries (see Box). As Kevin FitzGerald pointed out at the workshop, this issue is complex and confusing and poses challenges not only to science, but to society.

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Stem Cells and the Future of Regenerative Medicine International Perspective on Public Policy on Human ESC Research Germany: Prohibits the derivation and use of human ESCs from blastocysts. United States: As articulated by President Bush on August 9, 2001, permits federal funding only for research using cells from approximately 60 stem cell lines identified by the National Institutes of Health as having been derived from excess human embryos prior to the August 9 announcement. There is currently no federal law or policy prohibiting the private sector from creating stem cells by in vitro fertilization or by the SCNT technique for the purpose of research, but as this report went to print, legislative prohibitions were under consideration. The policies of most individual states also currently permit private funding of the use of human ESCs derived from excess in vitro fertilization embryos, embryos created by in vitro fertilization for the purpose of research, and embryos created with the SCNT technique, although a few states have banned some of these. France: Permits the use of human ESCs and their derivation from superfluous embryos not needed by the genetic parents for reproduction. (This approach has also been recommended by ethical advisory committees in Canada, Japan, and Germany.) United Kingdom: Permits the use of human ESCs and their derivation from leftover or superfluous embryos not needed by the genetic parents for reproduction, from embryos created for research purposes by in vitro fertilization, and embryos created with the SCNT technique. (The option of allowing human creation of ESCs for research purposes with the SCNT technique is also being considered in Italy, France, Australia, Israel, and Holland.) It is not for this committee to comment on the validity of the ethical or moral arguments for or against any of the alternatives. Indeed, it is highly likely that even the members of the committee would differ in what is acceptable to them personally. It is, however, appropriate for the committee to reiterate a few key points to increase the focus and clarity of the various ethical debates. First, arguments in favor of imposing constraints or even an outright prohibition on ESC research are frequently supported by the assertion that research on stem cells from adult tissues alone will lead to the development of the sought-after medical therapies. In his presentation

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Stem Cells and the Future of Regenerative Medicine at the workshop, for example, David Prentice cited many reports as supporting the argument that research on adult stem cells has all the necessary scientific potential and represents a morally less problematic alternative that obviates the need for research on ESCs. But Prentice also pointed out that much of this evidence is suggestive rather than definitive and that the hurdles so far encountered in research on adult stem cells suggest that predictions of success are highly speculative. As discussed in Chapter 2, the evidence indicates that there are substantial potential problems in realizing this goal. Stem cells in adult mammalian tissues are rare and difficult to isolate, and very few stem cell types have been confirmed to exist in adult human tissues. Most types of adult stem cells are difficult to grow in culture, and their potential plasticity has not been clearly established. Much of the work that is used to support the argument that adult stem cells can substitute for ESCs was done only in mice or other animal models, which might or might not prove applicable to humans (Chen et al., 2001; Clarke et al., 2000; Jackson et al., 2001; Kocher et al., 2001; Krause et al., 2001; Orlic et al., 2001; Ramiya et al., 2000; Torrente et al., 2001; Wang et al., 2000), or reported work performed with human hematopoietic stem cells (Bhardwaj et al., 2001; Cashman and Eaves, 2000; Colter et al., 2000; Gilmore et al., 2000; Laughlin et al., 2001), which is not generalizable to other cell types. It should also be noted that the study of human ESCs is likely to advance some applications of adult stem cells in the future. Second, the creation of stem cells with the SCNT technique is problematic to some because the technique is similar to that used for reproductive cloning. There is a scientific rationale for not foreclosing this avenue of research and for distinguishing clearly between SCNT to prevent transplant rejection and SCNT to create a fetus. Theoretically, the SCNT technique could produce genetically identical stem cells that could give rise to tissues that would not be rejected by a transplant recipient’s immune system. That is an attractive option because such a histocompatible transplant would not prompt the types of medically serious and potentially life-threatening immunological responses encountered by transplants of tissue from foreign donors.

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Stem Cells and the Future of Regenerative Medicine Third, the smaller the number of cell lines in use, the lower the genetic diversity that they represent. A prohibition on the derivation of new cell lines might result in research that focuses on cell lines that are not optimal and might preclude the replacement of inferior materials with more efficient cell lines. Experience with other kinds of cells in culture has shown that cell lines can be expected to accumulate mutations that reduce their suitability and safety for research (Kunkel and Bebenek, 2000). There is little evidence that ESC lines will behave any differently. Fourth, it has been suggested that it is biologically preferable to derive stem cells from embryos created specifically for research rather than from surplus embryos at in vitro fertilization clinics, although both employ similar techniques in the initial stages. Several ideas underlie that suggestion. Embryos from couples who have turned to in vitro fertilization because of infertility might have inherent, but as yet unrecognized, biological defects. From a broader genetic perspective, couples who seek treatment for infertility might not be representative of the genetic diversity of society as a whole. In addition, it might be preferable to obtain embryos that have not been frozen before stem cells are derived from them, inasmuch as freezing could have unexpected effects. Each of these concerns has only a theoretical basis, and there is currently little evidence with which to evaluate the relative merits of stem cells created specifically for research versus those derived from surplus embryos. PUBLIC FUNDING PROVIDES THE BEST OPPORTUNITIES FOR THERAPEUTIC ADVANCES Given the many unanswered questions about the biology of stem cells, the successful development of new medical therapies depends in large part on the performance of an enormous amount of basic research. Basic research is defined as systematic study directed toward greater knowledge or understanding of the fundamental aspects of phenomena and of observable facts without specific applications, processes, or products in mind. Since World War II, basic research has been the

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Stem Cells and the Future of Regenerative Medicine traditional domain of public funding, which optimizes opportunities for scientific advance in several ways: The differing roles of public and private investment in research. The increased likelihood of advancing knowledge through a broad spectrum of diverse research activities. The increased accessibility of research results as a consequence of public funding. The enhanced opportunities for oversight and regulation associated with public funding. The Roles of Public and Private Resources for Basic Research The National Institutes of Health (NIH) is the largest federal sponsor of health research, with a budget of more than $20 billion in FY2001. Even in 1997, pharmaceutical and biotechnology firms exceeded that total for overall biomedical research (Institute of Medicine, 1998), spending about $19 billion and $8 billion respectively in that year. In 2001, an estimated $50 billion will be spent on US biomedical research by public and private funding sources combined (Nathan et al., 2001). But within the larger system, NIH is the primary sponsor of the basic biomedical research that produces new fundamental knowledge. By its own accounting, NIH estimated that 62% of its budget was devoted to basic research in FY1996. By comparison, basic research represented an average of only about 14 percent of all private-sector pharmaceutical R&D in the 1990s, with pharmaceuticals representing the major area of concentration for private R&D according to a recently completed National Research Council report on trends in support of research (NRC, 2001). Although not-for-profit private entities, such as the Howard Hughes Medical Institute, also support basic research, private-sector efforts are dominated by for-profit companies that focus their research investments on product-related applications, such as new drugs, diagnostic tools, and medical devices that cure, detect, or prevent disease.

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Stem Cells and the Future of Regenerative Medicine Arti Rai, an expert in the legal aspects of biotechnology and health care whose work addresses the interactions between the public and private sectors in biomedical research, spoke at the workshop on this issue. She stated, “Because basic research is often far removed from commercial application, it is unlikely to be pursued at the levels at which it should be pursued by private companies that need to satisfy shareholders with short-term commercial results.” Absent public funding, she said, even fiscally conservative economists tend to agree that socially optimal levels of basic research will not be pursued. She noted, however, that Geron, which provided the funding for the stem cell discoveries of James Thomson and John Gearhart, had stepped into the breach when public funding for embryonic stem cell research was unavailable. Importance of Multiple Avenues of Research A prohibition on federal funding of ESC research would limit progress not only by limiting funds, but also by limiting the number of scientists who participate in the research. Dr. Thomas O’Karma, President and Chief Executive Officer of Geron Corporation, which funded and holds licenses to the stem cell discoveries of James Thomson and John Gearhart, commented at the workshop that it is frustrating not to be able to distribute these cells more widely to NIH-funded investigators for them to extend and validate the data Geron is generating. Although in principle academic scientists could accept private funding to pursue research that is subject to federal restrictions, this may not be a viable option for many. NIH can revoke a scientist’s funding for violating federally imposed restrictions. If a federally funded research institution were to support an individual scientist in such a violation, public funding of the institution as a whole could also be threatened. But drawing a sufficiently clear line between activities and infrastructure supported by the federal government and those supported only by the private sector in a single laboratory or university can be difficult. The establishment of separate privately supported laboratories that are free of federal funds, such as the University of Wisconsin’s WiCell Institute,

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Stem Cells and the Future of Regenerative Medicine entails substantial costs to duplicate infrastructure, equipment, and personnel (Gulbrandsen, 2001), and such measures may not be feasible for many academic institutions. Another issue is that confining the research effort to a small number of entities may diminish the rate of discovery and knowledge development. As discussed at the workshop by Arti Rai, the history of scientific innovation strongly indicates that basic research and its applications are best developed by multiple entities pursuing a variety of research questions. She gave examples from the automobile, aircraft, radio, and semiconductor industries, which went through a stage of development during which progress was slow in large part due to the fact that many of the key technologies were held exclusively by individual companies and not widely accessible. It was only when the companies agreed to share their interdependent technologies that progress accelerated. In general, during periods of dominance by a single entity with monopoly control over crucial patents, scientific and technological development can be impeded. In contrast, public funding of basic biomedical research has historically resulted in the results of the research being widely available to other scientists. Publicly funded researchers typically publish their research results in scientific journals, and this mechanism for information exchange can stimulate progress. (See also next section.) Even patenting of publicly funded research need not be a deterrent to progress if such patented research is licensed with terms that enable broad dissemination of the patented research. A notable example is the Cohen-Boyer patent on the recombinant-DNA technique, which emerged from public funding and was held by the University of California, San Francisco, and by Stanford University. Those institutions licensed the research widely at reasonable rates, and many analysts attribute the successful evolution of recombinant-DNA technology to those licensing arrangements. Arti Rai believes that the traditional academic focus on the importance of wide dissemination of fundamental knowledge has encouraged universities to shy away from exclusive licensing of the most fundamental research. Although never exercised, the Bayh-Dole Act contains a provi-

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Stem Cells and the Future of Regenerative Medicine sion that gives the federal government a limited legal right to compel licensing. Comparable authorities to compel licensing of privately funded basic research results are more limited and depend on specific legal authorities, such as a finding of an antitrust violation. Need for Accessibility A strong feature of publicly funded basic biomedical research in the United States is the widespread dissemination of experimental methods and findings through scientific publication as they emerge. Although the lines between industry and academe are increasingly blurred, the academic norm of free information exchange generally persists. Many benefits emerge from open access to data and methods. As scientists stay abreast of findings in a field, they are better able to refine their own research agendas, permitting an informed and broad base of research activities, which is important for innovation. Peer review strengthens the rigor of research, in that the design of experiments and reporting of data in grant proposals and publications must meet accepted scientific standards. Access to data also permits replication of a study, which is critical for authenticating scientific findings. It is important to note that many of the stem cell papers published to date, although heavily publicized by the mass media, have not yet passed the essential test of replication and scientific confirmation and must therefore be considered less than conclusive. Research Oversight The federal government in general and NIH in particular exert tremendous influence on the research that they fund through the mechanism by which they approve studies, the priorities they set, policy-making from informed-consent procedures to patent-seeking, and making the results of their research investments publicly available. When heightened public scrutiny is warranted, NIH can implement even more rigorous review and oversight mechanisms, as was the case for the

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Stem Cells and the Future of Regenerative Medicine controversial research involving recombinant DNA (see Box). Other means for regulating research exist, such as the passage of federal and state laws, but the public funding mechanism is the major means by which NIH influences the type of research performed and the way it is conducted. Public funding would guarantee regulatory oversight for stem cell research, allowing, for example, a careful informed consent procedure for obtaining ESCs that is subject to public scrutiny. Peer review, as noted above, helps to ensure the quality of research proposals. As part of peer review, the importance of the research questions addressed and the methods used to answer them are considered by leading scientists with appropriate expertise. In some fields, review committees also use the input of experts in ethics and representatives of the public who are stakeholders in the research, ensuring greater public The Recombinant DNA Advisory Committee The Recombinant DNA Advisory Committee, or RAC, was established by the director of NIH in 1975. Its creation was the result of concern among scientists and the public about the safety of laboratory studies aimed at introducing new DNA into organisms. The committee, after addressing laboratory safety and commercial development of recombinant DNA techniques and release of altered organisms into the environment, established benchmarks for review and approval of protocols for applying the techniques of gene transfer to humans. Both technical and ethical issues were considered. RAC advises the NIH director as to whether specific research proposals should be approved and gives guidance on recombinant-DNA research and relevant ethical issues. Scientists and physicians make up the majority of RAC’s membership with lawyers, social scientists, ethicists, and stakeholders from the public. Because it was a federal advisory committee, its meetings were announced in the Federal Register and were open to the public. When important new scientific projects came before the committee for review, mass-media attention would often be intense, giving the group’s recommendations extensive coverage. Although RAC officially was limited to providing advice to the NIH director on whether studies should be approved, its power extended beyond NIH-sponsored research. In a recent rechartering of RAC, nonvoting representatives from various other federal agencies were included. The Food and Drug Administration and Environmental Protection Agency indicated that any products developed using recombinant DNA must comply with RAC guidance. Source: Institute of Medicine, Society’s Choices: Social and Ethical Decision Making in Biomedicine. 1995.

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Stem Cells and the Future of Regenerative Medicine accountability. If specific rules govern a field of research, such as the need for informed consent of research volunteers or the requirements for research subjects of both sexes or various ethnic groups, the review process considers whether the requirements have been met or, if not, whether sufficient justification is provided for deviating from them. In short, public funding engenders considerable opportunity for shaping the types of research that are approved. In general, privately funded investigators are subject to less oversight and review, although activities such as the pursuit of patents or marketing approvals from the Food and Drug Administration represent other mechanisms for oversight that are less relevant to basic research.