Preface
In the face of extraordinary advances in the prevention, diagnosis, and treatment of human diseases, devastating illnesses such as heart disease, diabetes, cancer, and diseases of the nervous system, such as Parkinson’s Disease and Alzheimer’s Disease, continue to deprive people of health, independence, and well-being. Research in human developmental biology has led to the discovery of human stem cells (precursor cells that can give rise to multiple tissue types), including embryonic stem (ES) cells, embryonic germ (EG) cells, and adult stem cells. Recently, techniques have been developed for the in vitro culture of stem cells, providing unprecedented opportunities for studying and understanding human embryology. As a result, scientists can now carry out experiments aimed at determining the mechanisms underlying the conversion of a single, undifferentiated cell, the fertilized egg, into the different cells comprising the organs and tissues of the human body. Although it is impossible to predict the outcomes, scientists and the public will gain immense new knowledge in the biology of human development that will likely hold remarkable potential for therapies and cures. Derivation of ES cells from early human embryos, and EG and fetal stem cells from aborted, fetal tissues raise ethical, legal, religious, and policy questions. Further, the
potential uses of stem cells for generating human tissues and, perhaps, organs, is a subject of ongoing public debate. Taking all the above matters into account, the American Association for the Advancement of Science (AAAS) and the Institute for Civil Society (ICS) decided to undertake a study in order to propose recommendations for conducting stem cell research. To do so, we assembled a working group with broad expertise and diverse views to advise us and to assist with preparing a report. This study and the recommendations flowing from it were
informed by the values of the members of this advisory group, the discussions that took place during a public meeting hosted by AAAS and ICS on August 25, 1999, as well as reports and recommendations of other groups in the United States and elsewhere that have reflected on the issues involved. These values include belief in the promotion of patient welfare and the social good, scientific freedom and responsibility, selfdetermination, encouragement of civic discourse, public accountability of scientists and research institutions, and respect for diverse religious, philosophical, and secular belief systems. AAAS and ICS recognize that there are varied social, political, ethical, and religious viewpoints to be considered in discussions about the scientific use of tissue from human embryos and fetuses. Scientists do not presume to know all the answers and ramifications of basic research in human stem cells. Therefore, it is important to promote continued dialogue among all segments of society concerning the implications of stem cell research, and AAAS and ICS are committed to fostering an ongoing educational process that informs such public dialogue.
Findings and Recommendations
• Human stem cell research holds enormous potential for contributing to our understanding of fundamental human biology. Although it is not possible to predict the outcomes from basic research, such studies will offer the real
possibility for treatments and ultimately for cures for many diseases for which adequate therapies do not exist. The benefits to individuals and to society gained by the introduction of new drugs or medical technologies are difficult to estimate. The introductions of antibiotics and vaccines, for example, have dramatically increased life spans and improved the health of people all over the world. Despite these and other advances in the prevention and treatment of human diseases, devastating illnesses such as heart disease, diabetes, cancer, and diseases of the nervous system such as Alzheimer’s disease present continuing challenges to the health and well-being of people everywhere. The science leading to the development of techniques for culturing human stem cells could lead to unprecedented treatments and even cures for these and other diseases. As with all research, our ability even to contemplate the possibilities offered by stem cellderived therapies is a result of many years of research. The science of stem cells dates to the mid-1960s, and many papers have been published on the isolation and laboratory
manipulation of stem cells from animal models. While these models are imperfect, they are accepted in the scientific community as good initial predictors of what occurs in human beings. There already exists evidence from animal studies that stem cells can be made to differentiate into cells of choice, and that these cells will act properly in their transplanted environment. In human beings, transplants of hematopoietic stem cells (the cells which eventually produce blood) following treatments for cancer, for example, have been done for years now. Further, somewhat cruder experiments (e.g., the transplantation of fetal tissue into the brains of Parkinson’s patients) indicate that the expectation that stem cell therapies could provide robust treatments for many human diseases is a reasonable one. It is only through controlled scientific research that the true promise will be understood.
• This research raises ethical and policy concerns, but these are not unique to stem cell research. Innovative research and new technologies derived from such research almost always raise ethical and policy concerns. In biomedical research, these issues include the ethical conduct of basic and clinical research as well as the equitable distribution of new therapies. These issues are relevant to discussions about stem cell research and its eventual applications; however, they are part of a constellation of ethical and policy concerns associated with all advances in biomedical research. Guidelines or policies for the use of human biological materials have been issued at many levels, from internal review boards to the National Bioethics Advisory Commission, which recently released a
detailed report on the use of such materials. Existing policies cover all aspects of research, from the use of cell lines in laboratories, to human subjects protections, that will surface in the consideration of stem cell research.
• It is essential that there be a public that is educated and informed about the ethical and policy issues raised by stem cell research and its applications. Informed public discussion of these issues should be based on an understanding of the science associated with stem cell research, and it should involve a broad
cross-section of society. It is essential for citizens to participate in a full and informed manner in public policy
deliberations about the development and application of new technologies that are likely to have significant social impact. The understanding of the science is particularly important for discussing ethical and policy issues. Ideally, scientists should communicate the results of their research in ways that will be readily understandable to a diverse audience, and participate in public discussions related to stem cell research. The ethical and policy issues raised by stem cell research are not unique, but this research has received a significant amount of public attention and there is much to gain by open reflection on the implications of this sensitive area of research. Congressional hearings,
public meetings by government agencies, and media coverage have pushed stem cell research issues into a spotlight. There should be continued support for the open manner that has allowed all those interested to observe or participate in these processes and for a sustained dialogue among scientists, policy makers, ethicists, theologians, and the public to consider issues that emerge with the advancement of stem cell research.
• Existing federal regulatory and professional control mechanisms, combined with informed public dialogue, provide a sufficient framework for oversight of human stem cell research. The appearance of new technology can evoke apprehension and engender uncertainty among segments of the population about its uses. Where these concerns are related to issues having important ethical and social implications, certain levels of oversight are appropriate. But it is important to create new oversight mechanisms or regulatory burdens only when there are compelling reasons for doing so. Federal funding would automatically trigger a set of oversight mechanisms now in place to ensure that the conduct of biomedical research is consistent with broad social values and legal requirements. While basic laboratory research with personally non-identifiable stem cells does not pose special ethical or oversight challenges, an elaborate system of review is in place for research involving human subjects, ranging from procurement issues to the conduct of clinical trials. The Federal Common Rule governing human
subjects research provides for local and federal agency review of research proposals in such circumstances, weighing risks against benefits and requiring involved and voluntary consent. The Food and Drug Administration (FDA) has the authority to regulate the development and use of human stem cells that will be used as biological products, drugs, or medical devices to diagnose, treat or cure a disease or underlying condition. Further,
states should adopt the Federal Government’s Model Program for the Certification of Embryo Laboratories.
Complementing these regulatory mechanisms are the National Bioethics Advisory Commission (NBAC), which has demonstrated its legitimate claim to respect for its efforts as a national body to promote public input into social policy related to advances in biomedical research, and the Recombinant DNA Advisory Committee (RAC), which
currently has a mandate to review the ethical and policy issues associated with gene therapy and could be authorized to change its mission to broaden its purview. These federal bodies should work with interested stakeholders in the conduct of stem cell research—professional organizations, patient disease groups, religious communities, the Congress, funding agencies and private foundations, industry, and others—so that the
public can be assured that appropriate safeguards are in place as this research evolves. Thus, at the present time, no new regulatory mechanisms are needed to ensure responsible social and professional control of stem cell research in the United States.
• Federal funding for stem cell research is necessary in order to promote investment in this promising line of research, to encourage sound public policy, and to foster public confidence in the conduct of such research.
Realizing the potential health benefits of stem cell technology will require a large and sustained investment in research. The federal government is the only realistic source for such an infusion of funds. For those who are challenged daily by serious diseases that could in the future be relieved by therapies gained through stem cell research, public funding holds the greatest promise for sooner rather than later research results that can be
transferred from the bench to the bedside. Without the stimulus of public funding, new treatments could be substantially delayed. The commitment of federal funds also offers a basis for public review, approval, and
monitoring through well established oversight mechanisms that will promote the public’s interest in ensuring that stem cell research is conducted in a way that is both scientifically rigorous and ethically proper. Additionally, public funding contributes to sound social policy by increasing the probability that the results of stem cell research will reflect broad social priorities that are unlikely to be considered if the research is carried out in the
private sector alone. There are segments of American society that disagree on moral grounds with using public
monies to support certain types of stem cell research. However, public policy in a pluralistic society cannot resolve all the differences that arise in national debates on sensitive social issues. In the context of stem cell research, this leads to three practical conclusions. One is a willingness to permit individuals, whether they are researchers or
embryo or fetal tissue donors, to act in conformity with their own moral views on these matters. A second is the commitment to public involvement in research support when this research is related to the promotion and protection of public health, including the acquisition of new molecular and cellular insights into basic human developmental biology. A third is respect for opposing views, especially those based on religious grounds, to the extent that this is consistent with the protection and promotion of public health and safety.
• Public and private research on human stem cells derived from all sources (embryonic, fetal, and adult) should be conducted in order to contribute to the rapidly advancing and changing scientific understanding of the potential of
human stem cells from these various sources. There are three primary sources of stem cells, each with different characteristics as to how many different developmental paths they can follow and how much they can
contribute to our understanding of a functioning organism. Embryonic stem cells (ES cells), derived from a very early embryo, and embryonic germ cells (EG cells), collected from fetal tissue at a somewhat later stage of development, have particular promise for a wide range of therapeutic applications because, according to our present knowledge, they are capable of giving rise to virtually any cell type. Research on these primordial cells
will also provide a unique opportunity to study human cell biology. Adult stem cells, obtained from mature tissues, differentiate into a narrower range of cell types. As a result, many cells of medical interest cannot currently be obtained from adult-derived stem cells. It is also less feasible to develop large-scale cultures from adult
stem cells. However, it is important to note that, at this time, it is only adult human stem cells that are well-enough understood that they can be reliably differentiated into specific tissue types, and that have proceeded to clinical trials. Because the study of human stem cells is at an early stage of development, it is difficult to predict outcomes and findings at this point in time. As more research takes place, the full developmental potential of different kinds of stem cells will become better understood.
In view of the moral concerns surrounding the uses of embryonic and fetal tissue voiced by a segment of the American population, strengthening federally and privately funded research into alternative sources and/or methods for the derivation of stem cells, including further initiatives on adult stem cells, should be encouraged. Human stem cell research can be conducted in a fully ethical manner, but it is true that the extraction of embryonic stem cells from the inner mass of blastocysts raises ethical questions for those who consider the intentional loss of embryonic life by intentional means to be morally wrong. Likewise, the derivation of embryonic germ cells from the gonadal tissue of aborted fetuses is problematic for those who oppose abortion. In contrast, adult stem cell research is more broadly acceptable to the American population. Public funding should be provided for embryonic stem cell and embryonic germ cell research, but not at this time for activities involved in the isolation of embryonic stem cells, about which there remains continuing debate. This approach will allow publicly-funded researchers to move more quickly toward discoveries that will lead to alleviating the suffering caused by human disease. Although the derivation of human stem cells can be done in an ethical manner, there is enough objection to the process of deriving stem cells to consider recommending against its public funding. Further, for the foreseeable future there will be sufficient material isolated by researchers not using public funding that this exclusion will not have a
negative impact on research. There are many individuals who believe that any use of human embryos other than for
achieving a pregnancy is unethical, believing that the embryo is a full human being from the earliest moments in the conception process. However, many religious traditions take a “developmental” view of personhood, believing that the early embryo or fetus only gradually becomes a full human being and thus may not be entitled to the same moral
protections as it will later; others hold that while the embryo represents human life, that life may be taken for the sake of saving and preserving other lives in the future. The dialogue about these issues is ongoing in the United States, but these concerns need not exclude publicly-funded research activities on cell lines that have already been
established.
• Embryonic stem cells should be obtained from embryos remaining from infertility procedures after the embryo’s progenitors have made a decision that they do not wish to preserve them. This decision should be explicitly renewed prior to securing the progenitors’ consent to use the embryos in ES cell research. The most ethical source of human primordial stem cells is embryos produced for the process of in vitro fertilization whose progenitors have decided not to implant them and have given full and informed consent for the use of these embryos for research purposes. Two appropriate potential sources of donation are embryos with poor quality that makes them inappropriate for transfer and embryos remaining when couples have definitely completed their family and do not wish to donate the excess embryos to others. Informed consent requires that the woman or couple, with substantial understanding and without controlling influences, authorize the use of their spare embryos for research
purposes. Because assisted reproduction can be a stressful process, informed consent should be secured in two stages. The two-stage process would also maintain a separation between personnel working with the woman or couple who hope to get pregnant and personnel requesting embryos for stem cell research. At the beginning of the process, personnel working with the woman or couple whohope to become pregnant should ascertain their preferences as to the future of embryos remaining after the assisted reproduction process. These options should include consent for embryo donation to another couple, consent for donation for research, and consent for
destruction of the spare embryos. Once a couple has definitely decided that it has completed its family, then the couple should be approached a second time to secure an explicit consent to use the embryos in ES cell research.
• Persons considering donating their excess embryos for research purposes should be afforded the highest standards of protection for the informed consent and voluntariness of their decision. Securing embryos for the purpose of harvesting stem cells must proceed in a careful fashion for several reasons. These are to protect the interests of the gamete donors, to reassure the public that important boundaries are not being overstepped, to enable those who are ethically uncomfortable with elements of this research to participate to the greatest extent possible, and to ensure the highest quality of research and outcomes possible. Consonant with good research practice, policies on the procurement of embryos should include at least the following points: (1) Women should not undergo extra cycles of ovulation and retrieval in order to produce more “spare” embryos in the hope that some
of them might eventually be donated for research; (2) Analogous with our current practice for organ donation, there should be a solid “wall” between personnel working with the woman or couple who hope to get pregnant, and personnel requesting embryos for stem cell purposes; (3) Women and men, as individuals or as couples, should not be paid to produce embryos, nor should they receive reduced fees for their infertility procedures for doing so; and (4) Consent of both gamete donors should be obtained.
• Where appropriate, guidelines that can attract professional and public support for conducting stem cell research should be developed. At present, stem cell research raises no unique ethical or policy issues. As research advances issues may emerge that challenge acceptable ethical practices and public policy. Hence, there should be opportunities for public reconsideration of the need for guidelines specifically targeted to human stem cell research. Such efforts should be informed by the most current scientific evidence and should occur through a process that
encourages broad involvement by all sectors of society. Almost two decades of experience with the Recombinant DNA Advisory Committee’s (RAC) oversight of recombinant DNA research suggest that the RAC could be an
effective institutional focal point within the federal government to facilitate the type of public dialogue on stem cell research proposed here, and to coordinate efforts to develop new guidelines, where needed. The RAC has a proven track record of providing an open forum for sorting out complex ethical issues and of defusing conflict. Furthermore, it has acquired a degree of legitimacy among scientists in both the public and private sectors,
with its widely accepted Points to Consider in the design and conduct of gene therapy.
• In order to allow persons who hold diverse moral positions on the status of the early embryo to participate in stem cell research to the greatest degree possible without compromising their principles, and also to foster sound science, stem cells (and stem cell lines) should be identified with respect to their original source. Patients and researchers should be able to avoid participating in stem cell use if the cells were derived in a way that they would consider to be unethical. As a matter of good scientific practice, records are routinely maintained on the sources of biological materials. It is of utmost importance that documentation of the original source of the stem cells can be made readily available to researchers and to potential recipients of stem cell therapies.
• Special efforts should be made to promote equitable access to the benefits of stem cell research.
The therapeutic potential for treating and possibly curing many serious diseases constitutes a major rationale for large-scale investments of public and private resources in human stem cell research. To justify funding stem cell research on the basis of its potential benefits, particularly the use of public resources, however, requires some
assurance that people in need will have access to the therapies as they become available. Several factors make it unlikely that there will be equitable access to the benefits of this research. Unlike other western democracies, the United States does not have a commitment to universal health care. More than 44 million people lack health insurance and therefore do not have reliable access even to basic health care. Others are underinsured.
Moreover, if stem cell research were to result in highly technological and expensive therapies, health insurers might be reluctant to fund such treatments. Overcoming these hurdles and assuring equitable access to the benefits of stem cell research in this country will be a politically and financially challenging task. It is
therefore appropriate to begin considering how to do so now in advance of the development of applications. The federal government should consider ways to achieve equitable access to the benefits derived from stem cell research.
• Intellectual property regimes for stem cell research should set conditions that do not restrict basic research or encumber future product development. The U.S. Patent and Trademark Office (PTO) has already stated that purified and isolated stem cell products and research tools meet the criteria for patentable subject matter. When research is funded by the private sector, as is currently the case with stem cell research, and is patented, it is a private matter whether and under what terms new intellectual property is obtainable for research purposes or development. This is of particular concern because the private sector will not invest resources in potential applications that they consider to lack commercial value, but that may have considerable therapeutic promise. Given the promise of stem cell research, it is important to encourage the development of broadly beneficial therapeutic products with widespread access. This objective could be achieved in a variety of ways. Government investment in promising areas of research would enable federal agencies and laboratories to hold patents and to exercise them in ways that enhance development and contribute to the dissemination of this stem cell technology. Congress or the PTO should define a strong research exemption that would give third parties access to stem cell products and research tools for research purposes without having to obtain permission from the patent holder. Another possibility is to require compulsory licensing under limited and clearly defined circumstances.
• The formation of company-based, independent ethics advisory boards should be encouraged in the private sector.
Private sector research has played a crucial part in the advancement of research on stem cells. The leadership exhibited by the company that has sponsored all of the published human embryonic and germ cell research to date in establishing an external Ethics Advisory Board to develop guidelines for the ethical conduct of such research is laudable. While these private sector boards are not a substitute for public oversight and guidance, they can be a positive influence on the way that industry-funded stem cell research proceeds. The credibility and impact of such ethics advisory boards will be enhanced if they review ethical issues at the start-up phase of the research, have multidisciplinary membership, including representatives from the local community, give minimum, if any, financial
compensation for service, and share their own findings and recommendations with other companies. The latter provision could be especially helpful in developing a “case law” in the private sphere that would inform public efforts to develop national guidelines.
The Science of Stem Cell Research and Potential Therapies
The benefits to society gained by the introduction of new drugs or medical technologies are considerable. The introductions of antibiotics and vaccines, for example, have dramatically increased life spans and improved the health of people all over the world. The science of stem cell therapies, potentially as important as these other advances, is about to enter a phase of research and development that could lead to unprecedented cures and palliative treatments. The current excitement over potential stem cell therapies emanates from new understandings of genetics and developmental biology. Although there is no way to predict the outcomes from basic research, there is enough data to indicate that much of the enthusiasm is warranted.
Current Status of Human Stem Cell Research
Overview
“Stem cells” is a term to describe precursor cells that can give rise to multiple tissue types. There are important distinctions, however, regarding how developmentally plastic these cells are; that is, how many different paths they can follow and to what portion of a functioning organism they can contribute. Totipotent stem cells are cells that can give rise to a fully functional organism as well as to every cell type of the body. Pluripotent stem cells are capable of giving rise to virtually any tissue type, but not to a functioning organism. Multipotent stem cells are more differentiated cells (that is, their possible lineages are less plastic/more determined) and thus can give rise only to a limited number of tissues. For example, a specific type of multipotent stem cell called a mesenchymal stem cell has been shown to produce bone, muscle, cartilage, fat, and other connective tissues. There are many potential sources for stem cells. Embryonic stem cells are derived from the inner cell mass of a blastocyst (a very early embryo). Embryonic germ cells are collected from fetal tissue at a somewhat later stage of development (from a region called
the gonadal ridge), and the cell types that they can develop into may be slightly limited. Adult stem cells are derived from mature tissue. Even after complete maturation of an organism, cells need to be replaced (a good example is blood, but this is true for muscle and other connective tissue as well, and may be true for at least some nervous system cells). Because these give rise to a limited number of cell types, they are perhaps more accurately referred to as multipotent stem cells, as discussed above. Knowledge about stem cell science and potential applications has been accumulating for more than 30 years. In the 1960s, it was recognized that certain mouse cells had the capacity to form multiple tissue types, and the discovery of bona fide stem cells from mice occurred in 1971. Limited types of stem cell therapies are already in use. The most well-known therapy is the stem cell transplant (a form of a bone marrow transplant) for cancer patients. In this therapy, stem cells that can give rise to blood cells (red and white cells, and platelets) are given to patients to restore tissue destroyed by high dose chemotherapy or radiation therapy. But it has been only recently that scientists have understood stem cells well enough to consider the possibilities of growing them outside the body for long periods of time. With that advance, rigorous experiments can be conducted, and the possibility of manipulating these cells in such a way that specific tissues can be grown is
real. It is impossible to project when actual treatments or cures might emerge from such research, but the paths this research might take and potential applications have been much discussed. To understand the potential clinical applications, it is critical to understand the research that is taking place now.
Sources and Characteristics of Human Stem Cells
Human Embryonic Stem Cells. The study of human stem cells has barely begun and what is known is summarized in this section. The vast majority of experimental data discussed here are the results of experiments in mice. ES cells from the mouse have been intensely investigated since their discovery 18 years ago. Therefore, what is said about human ES cells assumes in part that their fundamental properties will resemble those of mouse ES cells. While on the surface this assumption appears to be reasonable it will have to be proven through intensive further investigation. There is an abundance of stem cell lines from mammals including some from human beings. ES cells are valuable scientifically because they combine three properties not found together in other cell lines. First, they appear to replicate indefinitely without undergoing senescence (aging and death) or mutation of the genetic material. They are thus a large-scale and valuable source of cells. Second, ES cells appear genetically normal, both by a series of genetic tests and functionally as shown by the creation of mice with genomes derived entirely from ES cells. In mice these cells are developmentally totipotent; when inserted into an early embryo, they join the host cells to create a normal mouse, differentiating into every cell type of the body (it is this property that earns them the name “stem cell of the body”). ES cells can also differentiate into many cell types in tissue culture, including neurons, blood cells and cardiac and skeletal muscle. The normal embryo has about 100 cells with the properties of ES cells that exist for about one day and then develop into more advanced cell types. The isolation and subsequent growth of ES cells in culture allow scientists to obtain millions of these cells in a single tissue culture flask, making something once rare and precious now readily available to researchers. It is worth noting here the striking parallel to recombinant DNA and monoclonal antibody technologies, both of which have amplified rare and precious
biological entities. Like those technologies, ES cell technology may well be transformative in opening scientific arenas that to date have been closed. The isolation, culture, and partial characterization of stem cells isolated from human embryos was reported in November of 1998.
1 The ability of the cells to maintain their pluripotent character even after 4 to 5 months of culturing was demonstrated.
2 There is concern that this feature of these cells could also lead to cancerous growth. Thus far there are no data indicating the induction of malignant tumors, although there is some evidence for benign hyperproliferation (overgrowth of cells).
3 Human Embryonic Germ Cells. Embryonic germ cells are derived from primordial germline cells in early fetal tissue during a narrow window of development. Unlike embryonic stem cells, animal experiments on embryonic germ cells have been limited. In November of 1998, the isolation, culture, and partial characterization of germ cells derived from the gonadal ridge of human tissue obtained from abortuses was reported.
4 These experiments showed that these EG cells are capable of forming the three germ layers that make all the specific organs of the body. There are fewer data from animal EG cell experiments than from ES cell experiments, but it is generally assumed that the range of potential fates will be relatively limited compared to ES cells, because the EG cells are much further along in development (5-9 weeks as opposed to 5 days in the published experiments). Fetal tissue may provide committed neural progenitors, but the feasibility of large scale sourcing and manufacturing of products utilizing such cells is questionable. Furthermore, the behavior of these cells in vivo is not well understood; significant research will be required to avoid unwanted outcomes, including ectopic tissue formation (additional, unwanted tissue), tumor induction, or other abnormal development .
5 Human adult stem cells. From post-embryonic development through the normal life of any organism, certain tissues of the body require stem cells for normal turnover and repair. Stem cells that are found in developed tissue, regardless of the age of the organism at the time, are referred to as adult stem cells. The most well-known example of this are the hematopoietic stem cells of blood.
6 More recently, mesenchymal stem cells (MSC) required for the maintenance of bone, muscle, and other tissues have been discovered.
7 Adult stem cells are multipotent; the number of tissues that they can regenerate compares poorly with the pluripotency of embryonic stem cells and embryonic germ cells. However, the MSC is in fact an excellent example of the potential for use of stem cells in human therapeutic procedures. MSCs are capable of differentiating into
bone, cartilage, muscle, fat, and a few other tissue types. Their use for bone and cartilage replacement is undergoing FDA-approved clinical trials at the present time. Adult-derived stem cell therapies will complement, but cannot replace, therapies that may be eventually obtained from ES cells. They do have some advantages. For example, adult stem cells offer the opportunity to utilize small samples of adult tissues to obtain an initial culture of a patient’s own cells for expansion and subsequent implantation (this is called an autologous transplant). This process avoids any ethical or legal issues concerning sourcing, and also protects the patient from viral, bacterial, or other contamination from another individual. With proper manufacturing quality controls and testing, allogeneic adult stem cells (cells from a donor) may be practical as well. Already in clinical use are autologous and allogeneic transplants of hematopoietic stem cells that are isolated from mobilized peripheral blood or from bone marrow by positive selection with antibodies in commercial devices. In general, there is less ethical concern over their
initial source. Additionally, since they normally differentiate into a narrower set of cell types, directing them to a desired fate is more straightforward. However, many cells of medical interest cannot, as of yet, be obtained from adult-derived cell types. Production of large numbers of these cells is much more difficult than is the case for ES cells. Based upon our present knowledge base, it appears unlikely that human adult stem cells alone will provide all of the necessary cell types required for the most clinically important areas of research.
The Clinical Potentials for Stem Cell Products
The economic and psychological tolls of chronic, degenerative, and acute diseases in the United States are enormous. It has been estimated that up to 128 million people suffer from such diseases; thus, virtually every citizen is effected directly or indirectly.
8 The total costs of treating diabetes, for example is approaching $100 billion in the United States alone.
9 As more research takes place, the developmental potential of different kinds of stem cells will become better understood. As the science is understood now, adult stem cells are limited in their potential to differentiate. Embryonic germ cells have a great differentiation capacity, and embryonic stem cells are thought to be able to
differentiate into almost any tissue. Thus, different types of stem cells could have different applications. Below is a discussion of potential stem cell applications.
Some Examples of Treatments for Major Diseases
Type 1 Diabetes in Children. Type 1 diabetes is an autoimmune disease characterized by destruction of insulin producing cells in the pancreas. Current efforts to treat these patients with human islet transplantation in an effort to restore insulin secretory function (obtained from human pancreas) are limited severely by the small numbers of donated pancreas available each year combined with the toxicity of immunosuppressive drug treatments required to prevent graft rejection.10 Pluripotent stem cells, instructed to differentiate into a particular pancreatic cell called a beta cell, could overcome the shortage of therapeutically effective material to transplant. They also afford the opportunity to engineer such cells to effectively resist immune attack as well as graft rejection. Nervous System Diseases. Many nervous system diseases result from loss of nerve cells. Mature nerve cells cannot divide to replace those that are lost. Thus, without a “new” source of functioning nerve tissue, no therapeutic possibilities exist. In Parkinson’s disease, nerve cells that make the chemical dopamine die. In Alzheimer’s disease, cells that are responsible for the production of certain neurotransmitters die. In amyotrophic lateral sclerosis, the motor nerve cells that activate muscles die. In spinal cord injury, brain trauma, and even stroke, many different types of cells are lost or die. In multiple sclerosis, glia, the cells that protect nerve fibers are lost.11 Perhaps the only hope for
treating such individuals comes from the potential to create new nerve tissue restoring function from pluripotent stem cells. Remarkably, human clinical experiments have demonstrated the potential effectiveness of
this approach to treatment. Parkinson’s patients have been treated by surgical implantation of fetal cells into their brain with some benefit. Although not completely effective, perhaps owing to lack of sufficient numbers of dopamine secreting cells, similar experiments using appropriately differentiated stem cells should overcome those obstacles.12 More complex experiments have already been successfully conducted in rodent models
of Parkinson’s.13 Similar approaches could be developed to replace the dead or dysfunctional cells in cortical and hippocampal brain regions that are affected in patients with Alzheimer’s. Primary Immunodeficiency Diseases. Pluripotent stem cells could be used in treatment of virtually all primary immunodeficiency diseases. Presently, there are more than 70 different forms of congenital and inherited deficiencies of the immune system that have been recognized. These are among the most complicated diseases to treat with the worst prognoses. Included here are diseases such as severe combined immunodeficiency disease (the “bubble boy” disease), Wiskott-Aldrich Syndrome, and the autoimmune disease lupus. The immune deficiencies suffered as a result of acquired immune
deficiency syndrome (AIDS) following infection with the human immunodeficiency virus are also relevant here.14 These diseases are characterized by an unusual susceptibility to infection and often associated with anemia, arthritis, diarrhea, and selected malignancies. However, the transplantation of stem cells reconstituted with the normal gene could result in restoration of immune function and effective normalization of life
span and quality of life for these people. Diseases of Bone and Cartilage. Stem cells, once appropriately differentiated, could correct many diseases and degenerative conditions in which bone or cartilage cells are
deficient in numbers or defective in function. This holds promise for treatment of genetic disorders such as osteogenesis imperfecta and chondrodysplasias. Similarly, cells could be cultivated and introduced into damaged areas of joint cartilage in cases of osteoarthritis or into large gaps in bone from fractures or surgery.
Cancer. At the present time, bone marrow stem cells, representing a more committed stem cell, are used to rescue patients following high dose chemotherapy. Unfortunately, these recovered cells are limited in their capacity to restore immune function completely in this setting. It is hoped that injections of properly-differentiated stem cells would return the complete repertoire of immune response to patients undergoing bone marrow transplantation. Complete and functional restoration will be required if, for example, immune/vaccine anticancer therapy is to work. More importantly, success would permit use of very toxic (and effective) chemotherapeutic regimens that could not currently be utilized for lack of an ability to restore marrow and immune function.
Uses in Research
Much is left to be discovered and understood in all aspects of human biology. What has been frequently lacking are the tools necessary to make the initial discoveries, or to apply the knowledge of discoveries to the understanding of complex systems. These are some of the larger problems in basic and clinical biology where the use of stem cells might be the key to understanding. A new window on human developmental biology. The study of human developmental biology is particularly constrained by practical and ethical limitations. Human ES cells may allow scientists to investigate how early human cells become committed to the major lineages of the body; how these lineages lay down the rudiments of the body’s tissues and organs; and how cells within these rudiments differentiate to form the myriad functional cell types which underlie normal function in the adult. The knowledge gained will impact many fields. For example, cancer biology will reap an especially large reward because it is now understood that many cancers arise by perturbations of normal developmental processes. The availability of human ES cells will also greatly accelerate the understanding of the causes of birth defects and thus lead directly to their possible prevention. Models of human disease that are constrained by current animal and cell culture models. Investigation of a number of human diseases is severely constrained by a lack of in vitro models. A number of pathogenic viruses including human immunodeficiency virus and hepatitis C virus grow only in human or chimpanzee cells. ES cells might provide cell and tissue types that will greatly accelerate investigation into these and other viral
diseases. Current animal models of neurodegenerative diseases such as Alzheimer’s disease give only a very partial representation of the disease’s process. Transplantation. Pluripotent stem cells could be used to create an unlimited supply of cells, tissues, or even organs that could be used to restore function without the requirement for toxic immunosuppression and without regard to tissue matching compatibility. Such cells, when used in transplantation therapies, would in effect be suitable for “universal” donation. Bone marrow transplantation, a difficult and expensive procedure associated with significant hazards, could become safe, cost effective, and be available
for treating a wide range of clinical disorders, including aplastic anemia and certain inherited blood disorders. This would be especially important in persons who lost marrow function from toxic exposure, for example to radiation or toxic agents. Growth and transplant of other tissues lost to disease or accident, for example, skin, heart, nervous
system components, and other major organs, are foreseeable. Gene Therapy. In gene therapy, genetic material that provides a missing or necessary protein, or causes a clinically-relevant biochemical process, is introduced into an organ for a therapeutic effect. For gene-based therapies (specifically, those using DNA sequences), it is critical that the desired gene be introduced into organ stem cells in order to achieve long-term expression and therapeutic effect. Although techniques for delivering the therapeutic DNA have been greatly improved since the first gene therapy protocol almost 10 years ago, there are as yet no bona fide successes. Besides delivery problems,
loss of expression or insufficient expression is an important limiting factor in successful application of gene therapy and could be overcome by transferring genes into stem cells (which presumably will then differentiate and target correctly).
The Moral Status of Human Stem Cells
Human embryonic germ (EG) cells are derived from the gonadal ridge tissue of an aborted fetus within five to eight weeks after conception. The procedure is analogous to the harvesting of organs from a cadaver. Here the ethical issue is not so much the status of the aborted fetus, but whether those who consider abortion an illicit act, despite its legality, can participate in the research on tissues so derived. The ethical status of human embryonic stem cells partly hinges on the question of whether they should be characterized as embryos or specialized bodily tissue. Although the answer to this question will be less important to those who believe that the early
embryo has little or no moral status, it will shape the views of those who regard the embryo as significantly protectable. One way of approaching this question is by looking first at ways in which the embryo has
been understood. In the context of the abortion and human embryo research debates, a series of criteria has been proposed to determine the moral status of the pre-implanation human embryo. Among these are an entity’s possession of a full human genome; its potential for development into a human being; sentience; and the presence of welldeveloped cognitive abilities such as consciousness, reasoning ability, or the possession of self-concept. Those taking the position that the early embryo has full moral status (equal to that of any child or adult human being) usually stress the first two of these criteria: possession of a unique human genome and the potential for development into a human being are regarded as sufficient for ascribing full moral status to it.
Since most cells in the human body possess a unique diploid genome and are not regarded as morally protectable, the question of whether ES cells are morally equivalent to somatic cells or whether they are more like human embryos largely hinges on an understanding of stem cells’ potentiality. Here the matter calls for further refinement since, as developments in mammalian cloning technology suggest, any human cell (or tissue) may have the potential to become a person. To avoid this problem, potentiality arguments typically appeal to some consideration of normal or natural processes: embryos have a natural potentiality to become a person in that the natural development of an embryo, unlike tissue, is to become a human being. Of course, the interpretation and significance of the word “natural” is controversial. Can we conclude that stem cells have equivalent moral status because of their potential to become a human being? Since potentiality is being understood here as “natural potentiality,” determining the moral status of a stem cell rests in part on whether its potential to become a person is natural, as it is with embryos, or contrived, as it would be with cells that are cloned. Being natural or contrived does not refer to the ease or facility of the process or the need for technological intervention. Regardless of how cloning technology may develop, for example, it will not be seen as a natural process by those who hold that embryos have a natural potential to become a full human being. To fail to distinguish between the natural and contrived development of the embryo would otherwise, among other things, unreasonably commit us to the full moral protection of every human cell. The potential of a stem cell to become a human being seems to be much more like that of a somatic cell that could be cloned than like an embryo. The natural development of the individual cells of the embryonic disk (from which stem cells are derived) is to become parts of a human being. Isolated from the total structure of the embryo or blastocyst, these cells, even under favorable growth conditions, will not develop the trophoblast (the outer layer of cells of the embryo) or other structures needed for continued development.
Another way of putting this is to say that stem cells are pluripotent rather than totipotent. It is true that advanced technology might be able to render these cells effectively (if not actually) totipotent. Research undertaken in Canada in 1993 involving the aggregation of mouse stem cells with a genetically manipulated embryo led to the cells’ subsequent growth and population of the entire organism.20 However, such manipulations are
arguably even less “natural” than is current cloning technology. Insofar as potentiality considerations alone are concerned, therefore, stem cells would not seem to have the same moral status as embryos. For those following this line of reasoning, including those who accord significant moral status to the embryo, stem cells may thus be regarded and treated as any other form of human bodily tissue. Potentiality is a complex idea, drawing on even more complex and undeveloped notions of “nature” and “the natural.” Rather than entirely clarifying these matters, biology complicates them by indicating the developmental continuum always present in human
growth and maturation. Continuing discussion will be needed involving the many viewpoints around the question about how we can best protect the multiple values evoked by research at life’s beginnings. These include values such as our commitment to the protection of human life generally, the promotion of human health, and respect for the views of others in a civil, democratic society. Moral Issues Surrounding the Sources of Stem Cells
At present, there are three possible sources of stem cells: adult stem cells derived from pediatric or adult donors; embryo germ cell stem cells (EG cells) derived from aborted fetuses; and embryonic stem cells (ES cells) derived from disaggregated preimplantation embryos. The first of these sources poses no special ethical problems for the majority of people. Adults and children can donate tissue so long as the appropriate conditions of
consent are respected. Individuals who do not object to induced abortion will be less concerned about the use of EG cells than those opposed to abortion. The least ethically problematic case would be to harvest stem cells from spontaneously aborted fetuses. There are, however, several obstacles to obtaining useful EG cells from spontaneously aborted tissue. Foremost is the problem of the harvesting healthy cells from fetuses. For the foreseeable future, extracting and culturing stem cells will be more of an art than an established technology. The amount of material that can be derived this way is limited even under the best circumstances.21 Results from several studies indicate that about 60% of all spontaneous abortions arise as a result of specific fetal anomalies;
specific chromosomal abnormalities were identified in about 20% of those.22 While stem cells with damaged genetic complements may be useful for a limited number of experiments, they are unlikely to be the basis of experiments leading to useful “normal” tissue. Finally, there is the matter of timing. EG cells can only be obtained during a narrow developmental phase, within the first eight weeks after conception. Most spontaneous
abortions that occur during this period do not take place in a hospital or clinic where the
tissue can be readily obtained. Those who do not accord significant moral weight to the pre-implantation embryo will probably not object to its being destroyed to be used as a source of ES cells. Some people
holding this view may also accept the deliberate creation of embryos for this purpose, while others would only permit the use of so-called “spare embryos” remaining from infertility procedures. The second and third source noted above (i.e., embryonic stem cells or embryonic germ cells obtained from elective abortions), however, raise special moral questions for those who regard either abortion or the destruction of early embryonic life as morally wrong. Can such people support or become involved in research using EG or ES cells when these cells are derived from what they regard as the morally unacceptable killing of a fetus or embryo? This raises the question of “complicity” or “cooperation” with evil. In the past, this issue has sometimes been discussed by Roman Catholic thinkers in connection with the issue of fetal tissue research.23 What constitutes morally wrongful cooperation with evil deeds? It is clear that not all use of goods produced by wrongful acts is immoral. For example, medical researchers routinely employ tissues of people who are victims of murder or other wrongful acts. At what point does use become “cooperation” or “complicity”? In answer to this, philosophers have focused on four different ways that could make one guilty of cooperation with evil. First, there is actual, direct involvement in the wrongful deed, as
when a researcher administers the lethal dose to an innocent victim in order to secure tissue samples.
Sources of Stem Cells and Guidelines for Use
Securing stem cells for research, whether from children, adults, aborted fetuses, or embryos, must be done under conditions of the most rigorous integrity for several reasons. These are to protect the interests of the donors, to reassure the public that important boundaries are not being overstepped, to enable those who are ethically uncomfortable with elements of this research to participate to the greatest extent possible, and to assure
the highest quality of research and outcomes. As already noted, there are three different types of stem cells, derived from three different sources. Obtaining the first type, adult stem cells, presents no new ethical problems.
Whether from adults or from children, protection of donors comes under the heading of research with human subjects, where adequate protection and regulation exist. The second source is cells derived from aborted fetuses. Research with fetal tissue of all types is already ongoing in both the private and public sectors. Current federal regulations that clearly separate the woman’s decision to have an abortion from her decision to donate tissue27 from the aborted fetus appear adequate to cover the situation of fetal stem cells as well, because the issues are the same. The third source, pre-implantation embryos, requires the greatest care. Human embryonic stem cells should be derived from two sources. The first are so-called “spare” embryos, those remaining after a couple has completed their family or for some other reason decided that they have no further use for their stored embryos. The second are embryos that are not of sufficient quality to be candidates for transfer to the uterus. There are tremendous emotional, social, marital and financial strains associated with infertility. A couple grappling with infertility has very difficult decisions to make. Therefore it is necessary to adhere to the highest standards of protection for persons who are considering donation of their excess embryos for research purposes, with special
concern for the informed consent and voluntariness of their decision. Persons create embryos through in vitro fertilization with the intent of transferring one or more of them to the uterus, the hoped for outcome being a successful pregnancy and a healthy baby. Because the process of procuring eggs for IVF presents some risks to a
woman’s health, many women attempt to produce as many eggs from one cycle as possible. Because eggs cannot be frozen but embryos can, persons using IVF usually aim to produce a group of stored, frozen embryos to support as many attempts at pregnancy as necessary to achieve their goals. Often, they end up with more embryos than they need to use. Persons with excess embryos have the option of donating them to other infertile couples, destroying them, or donating them for research purposes.Informed consent requires that the woman or couple, with substantial understanding and without inappropriate influences, authorize the use of their spare embryos for research. Because assisted reproduction is such a stressful and usually drawn-out process, informed consent should be secured in two stages. Like the model of organ procurement protocols, the consent process should also maintain a separation between personnel working with the woman or couple desiring to get pregnant and personnel requesting embryos for stem cell research. At the beginning of the process, personnel working with the persons who hope to become pregnant should find out their preferences about what they want done with any possible spare embryos left over from the assisted reproduction process. Once a couple has definitely decided that it has completed its family, or for some other reason has no more use for the remaining embryos, then they should be approached a second time to secure an explicit consent to use the embryos in stem cell research. Consonant with existing norms of good research practice, policies for securing embryos should include at least the following points: (1) Women should not undergo extra cycles of ovulation and retrieval in order to produce more “spare” embryos in the hope that some of them might eventually be donated for research; (2) Analogous with our current practice for organ donation, there should be a solid “wall” between personnel working with the woman or couple who hope to become pregnant, and personnel requesting embryos for stem cell purpose; (3) Women and men, as individuals or as couples, should not be paid to produce embryos, nor should they receive reduced fees for their infertility procedures for doing so; (4) All reasonable efforts should be made to obtain the consent of both gamete donors. If these norms are adhered to, the procurement of embryos for the derivation of stem cells does not raise ethical problems which constitute a bar to research. In addition, in order to allow persons who hold diverse moral positions on the status of the early embryo to participate in stem cell research to the greatest degree possible, stem cells (and stem cell “lines”) should be identified with respect to their provenance. Patients and researchers should be able to avoid participating in stem cell use if the cells were derived in a way that they would consider to be unethical. As a matter of good scientific practice, records are routinely maintained on the sources of biological materials. It is of utmost importance that documentation of the original source of the stem cells can be made readily available to researchers and to potential recipients of stem cell therapies.
Conclusion
The pursuit and production of knowledge through scientific research is an undertaking that offers enormous intellectual rewards for researchers while also performing an important social function. The advancement of science has transformed our lives in ways that would have been unpredictable just a half-century ago. Whether stem cell
research will have a similar effect remains to be determined, but the promise is so great that it seems wise to consider seriously how best to further such research in a manner that is sensitive to public sensibilities. Public conversations about research and use of human stem cells are well underway. This report is intended to contribute to and inform this ongoing dialogue. We recognize that science does not exist in isolation from the larger community that feels its effects, whether perceived as good or bad. The work of scientists is, and should be, conditioned and directed by consideration of broader human values. This means that the development of public policy, especially where highly controversial matters are involved, must take all interested sectors of the public into account. It is only through broad-based participation that the values of all stakeholders in the research enterprise can be carefully considered and weighed. We hope that this report has offered an approach that balances the promise of human stem cell research with the public’s genuine concerns about such research in a manner that will lead to a consensus on how best to proceed.
- Audrey R. Chapman, Ph.D. Mark S. Frankel, Ph.D. Michele S. Garfinkel, Ph.D
- https://drive.google.com/drive/folders/1ODt7UAKVsSEQ_8pWPf-216kaesdPKyKF?usp=sharing
- https://www.aaas.org/sites/default/files/content_files/StemCellResearchandApplicationsReport.pdf
- The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
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