The Ethical Controversies of Stem Cell Research
Introduction to Stem Cell Research
A stemcell is derived from the inner cell mass of an egg 4 days after fertilization. It is capable of indefinite reproduction, and is independently capable of generating every tissue that ultimately constitutes an adult organism. These powerful properties have launched stemcellsinto the forefront of a revolution that offers to change the way doctors treat degenerative diseases and scientists approach fundamental questions of development, birth, degeneration and death (Mayo Foundation for Medical Education and Research, 2004).
Recently, the term stemcell has also been applied, somewhat more loosely in the eyes of purists, to cells derived from adult animals and humans. The presence of these so-called adult stemcells has been known since 1998. They can be identified and harvested from adult animal and human organs such as heart, muscle, brain, blood or bone marrow and can actually be cultured in the laboratory. Not only that, these adult stemcells have the ability to propagate for long periods of time in the laboratory while retaining their ability to differentiate into the tissues from which they were initially harvested under certain conditions (Mayo Foundation for Medical Education and Research, 2004).
The earliest investigators demonstrated convincingly that the bone marrow of mice housed specialized cells known as "satellite cells" that migrated to the skeletal muscle when it was injured (and only when it was injured) and participated in a regenerative process that restored the injured muscle almost back to complete health. This finding has unleashed the hope of tremendous potential that such cells could be harvested and expanded in culture and therefore be applied to cure the damage inflicted by degenerative human conditions such as heart attacks, stroke, diabetes, Alzheimer's disease, wasting bone diseases such as osteogenesis imperfecta, and muscle conditions such as muscular dystrophy. In doing so, clinicians would be following the same paradigm established by colleagues that had developed strategies for repopulating the bone marrow that has been destroyed by high-dose chemotherapy (Shamblott, 1998).
Indeed, the successes that researchers have had in the isolation of human adult stemcells, and with resultant clinical application, have been astounding with the myriad scientific papers written on the subject. Investigators from all over the world have claimed that adult human stemcells can differentiate into structures as varied as liver, pancreas, intestine, brain tissue, heart, bone, cartilage and even fat. Not only that, the literature is filled with claims that these cells demonstrate remarkable plasticity, the ability to trans-differentiate from one structure into a completely unrelated structure. For example, fat cells have been shown to differentiate into blood vessels, muscle, cartilage and bone (Mayo Foundation for Medical Education and Research, 2004). Researchers would caution that the reproducibility of a lot of these claims is yet to be determined in rigorous peer-reviewed fashion.
The claims of dramatic tissue plasticity are probably inflated to some degree, and remain concerned that the true mechanisms of action by which these cells improve function are unknown. All the early clinical data emerging in the medical literature suggest that efficacy of adult stemcell implantation in human subjects, using current techniques and available small numbers of cells, is uncertain at best. Most of the parameters in which improvement is seen are subjective, raising the issue of powerful placebo effects, and true objective measures of improvement are lacking.
As long as absolute restrictions on the use of human embryonic stemcells for research exist, scientists cannot study these questions. Unfortunately, the embryonic stemcellquestion has been manipulated into a surrogate for America's argument over the ethics of elective abortion, although the strategies for embryonic cell extraction and elective abortion are distinct (Steinbock, 1992).
Procedures & Risks Involved in Stem Cell Research
There are three strategies for deriving a totipotent stemcell. The first is to extract the cell from very early human embryos. This is a strategy that was first explored by investigators at the University of Wisconsin in the 1990s. Human embryos created in IVF clinics were donated to investigators by couples that did not want to use them for purposes of "creating a child," and a series of human embryonic stemcell lines were successfully created and exist to this day (Shamblott, 1998).
Current United States law prohibits the use of federal funds for the creation of a human embryo for research purposes or for research in which human embryos are destroyed, discarded or knowingly subjected to risk, injury or death that is greater than that allowed for fetuses in utero. Accordingly, there is no role for clinical or basic scientific research as it applies to these embryos.
The numbers involved here are staggering. Only 10 percent of transferred embryos actually produce a baby, and over 120,000 of these procedures were performed in the USA in 2001, leaving us with an excess of 100,000 embryos each year that remain frozen in IVF facilities across America with no consideration for their moral position, role in society, or future use (Mayo Foundation for Medical Education and Research, 2004).
One pole of this debate views the creation and manipulation of living human embryos for the sole purpose of generating therapeutic tissue as incompatible with respect for vulnerable human life with opprobrium.
Researchers believe there is a distinct moral position between creating and destroying an embryo for research purposes to obtain stemcells exclusively versus using an embryo that was created for reproduction but will never be used for any purpose. In addition, well-developed fetuses and embryos can be argued to not share equal moral status, given the limited potential that pre-implantation embryos have to become fetuses and, therefore, adults. In fact, over 99 percent of such pre-implantation embryos are thought to be lost in a miscarriage even before the first menstrual period is missed (Warren, 1997).
The second technique is to extract human embryonic stemcells from 5-9-week-old aborted fetuses. This approach is charged with near-insurmountable ethical controversy in the current social and political climate in our country that it is not highly sought after. Such a strategy is unlikely to add significant benefit over the use of in vitro fertilization embryos.
The third technique, also known as "cloning," is to derive embryonic stemcells via somatic cell nuclear transfer. A complete set of genetic material that includes all 46 chromosomes that reside within the nucleus of a somatic cell is transferred into an enucleated female egg, which normally contains half the total complement of chromosomes.
Theoretically, once this egg "sees" a full set of chromosomes, as it would after fertilization by a male gamete, it would set into motion a series of events that allow maturation of that cell into an embryo. This is the technique whereby the sheep "Dolly" was cloned by Ian Wilmut and his colleagues at the Roslin Institute in Edinburgh, Scotland in the 1990s. The problem with this procedure is that it needs a large supply of eggs, is time consuming, labor intensive, and expensive. Because the supply of eggs is limited, and the demand is great, coercion and financial incentives to donate eggs are commonplace in our country, even though such incentives are banned in Europe. Nevertheless, this process has been performed on a human being in South Korea, and was approved for human use in the U.K. on August 11, 2004, under the auspices of the Human Fertilization and Embryology Authority (Pincock, 2004).
The scientific concerns behind such strategies are based on experiences with animal studies, in which the animals are abnormal and have unusual DNA methylation patterns and genomic imprinting. Moreover, these animals age rapidly and die chronologically premature (but physiologically normal) deaths, and for reasons not yet discovered. Sadly, even a promising technology such as this has been hijacked by fringe groups (such as Clonaid) for popular gain and has generated fear in the popular media of the cloning of genetically modified human beings, and the generation of embryos for spare parts--reducing human life to purely utilitarian values (Warren, 1997).
Arguments in Support of Stem Cell Research
Even though no clinical studies have been performed, from a purely scientific standpoint, embryonic stemcells offer scientists greater opportunities than adult stemcells do. These include the chance to study development of organisms and the processes that lie behind appropriate growth, maturation, and senescence. Scientists would be able to identify precursor cells--cellsthat are no longer stemcells but have the ability to differentiate into certain lineages--perhaps allowing scientists to one day circumvent having to harvest stemcells (Thomson, 1998).
Moreover, embryonic stemcells allow scientists to identify genes that are involved in the processes outlined above. Given the inextricable links between mistakes in development and disease, such approaches would give scientists the ability to identify genes involved in illness, identify potential therapeutic targets for gene and drug therapy, and allow scientists to test drugs for toxicity on certain cell types, thereby obviating the need for extensive animal testing that has little relevance to human application. In addition, embryonic stemcells allow scientists to develop a high-throughput functional testing strategy for drugs and gene therapy, which should accelerate delivery of more effective and less expensive medications for human use (Shamblott, 1998).
The idea of viability in obstetrics and in infertility is meaningful as a measure of whether a preordained goal, namely conception and birth, is possible under some particular circumstance. Researchers typically learn about the development of fetuses and embryos, and about the potential of germ cells and stemcells, only within the context of the goal of controlling reproductive activity. Researchers define success in pregnancy, and it means "delivery with the minimum amount of complication and the maximum amount of fetal flourishing." Viability is really a measure of the capacity of present technology to ensure the kind of successful ends held. When scientists note that approximately 8 percent of all conceptions in the womb result in miscarriage and thus were not viable pregnancies, scientists mean that in those cases there was no remedy within our grasp for whatever caused the miscarriage (Shamblott, 1998).
New technologies change the idea of viability by giving more and more embryos, tissues, cells, and fetuses the potential to turn out the way scientists want them to. When whole classes of tissues or cells can be reclassified in that way, the very idea of a viable pregnancy can change. If a somatic cell can now be transplanted into an enucleated egg and the resultant re-nucleated egg jarred into behaving like an embryo, one might say the resultant thing has the potential for reproductive viability, even though no conception was involved. If a large number of such re-nucleated eggs behave like embryos and when implanted do not spontaneously abort at a rate greater than that of "ordinary" embryos, one might well elect to say that they are viable--indeed that they are embryos. In every case, the meaning of viability is subject to the evolving nature of one’s technologies and the evolving set of purposes to which they can be put (Warren, 1997).
Arguments Against Stem Cell Research
Nevertheless, it would be shortsighted to claim that adult stemcells are a panacea. These cells are notoriously elusive and difficult to find. Their characterization has been challenging at best, and remains incomplete. They are harvested in small numbers and often need to be propagated in tissue culture for long periods of time, which is impractical from a clinical standpoint, and can lead to potentially damaging changes. The cells are difficult to harvest, and often require damage to the host organ, which is awkward if they are to be used clinically for regeneration of the same organ!
Even more critically, if these cells are being used in the clinical setting for autologous regeneration, they may actually carry the same genetic flaws that predisposed the host organism to the disease process in the first place (Thomson, 1998).
Embryonic stemcell use comes with its own set of unique limitations. Donor-recipient incompatibility is a major concern, but can be potentially circumvented by banking large numbers of human embryonic stemcells so at least one could work for you, or by genetically modifying them to resist immune challenges.
New discoveries in stem cell biology will soon bring revolutionary changes in the way physicians approach degenerative diseases, wound repair, autoimmune conditions, cancer, and reproductive medicine. Stem cells are self-renewing cells capable of producing many different cell types. Adult stem cells do well in repairing their organ of origin but have limited capabilities in self-renewal and distant organ repair under normal physiologic conditions. The degree plasticity potential of the adult stem cell has yet to be determined. Embryonic stem cells have tremendous therapeutic and research potential to produce any tissue of the body and to grow unperturbed in plastic culture dishes for many years (Thomson et al, 1998; Shamblott et al, 1998). Stem cells currently are used in transplantation regimens to repair wounded organs. They are also used experimentally in toxicity studies to test drug safety, cancer investigations to pinpoint methods of unregulated growth, and reproductive protocols to identify critical stems in fertility and pregnancy. However, along with these remarkable abilities, use of stem cells carries many ethical challenges.
Many religious perspectives consider the human fetus to constitute an individualized human entity. However, there is substantial debate regarding at which specific stage dignity is conferred in development (conception, primitive streak development, implantation, quickening, or birth) (Humane Vitae, 1968). Recently, a less specific developmental view of moral status surfaced, meriting moral rights to the individual as consciousness and relationships develop (Steinbock, 1992; Warren, 1997).
Taking into account the many perspectives on the moral status of the human embryo and the scientific promises of a healthier tomorrow through stem cell technology, our society has attempted to define the legal status of the human embryo. In the United States, the first pillar was constructed in 1973 when the US Supreme Court ruled that a fetus is not a person in terms of constitutional protection (Roe v. Wade, 410 US 113 ). For a better examination of the decision’s effect on research, the National Institutes of Health (NIH) imposed a moratorium on fetal research, and Congress founded the National Commission, charged to put together policy and guidelines on fetal research. Four months later, the commission published a report encouraging fetal research because of its potential, provided that the research risks to the fetus were minimal and were only those that would be accepted for a term fetus (US Dept of Health, Education, and Welfare; 1975). Thus despite Roe vs. Wade, the commission extended protection to a fetus (just as to adult patients) in research, including fetuses planned for elective abortion (Roe v. Wade, 2001; Steinbock, 1992).
The NIH moratorium was lifted in 1975. However, during President Ronald W. Reagan’s second term, Congress enacted legislation that further protected the fetus by ending federal support of fetal research involving any level of risk (US Dept of Health & Human Services, 2001). In 1996, Congress extended this restriction by banning federal funding for the creation of a human embryo for research purposes. This led the NIH to distinguish between deriving and using existing human embryos to support embryonic stem cell research. Under these guidelines, researchers using already established human embryonic stem cell lines derived from private sector support can receive public sector monies, provided that the fertilized embryos would otherwise have been discarded after IVF or were from already aborted fetuses, donors are aware of the research use, and no payment was made to the donors (The President’s Council on Bioethics, 2002).
The National Bioethics Advisory Commission (NBAC) was charged by former President William J. Clinton to thoroughly review moral and legal issues of stem cell research. This commission largely framed its moral position based on a utilitarianism argument – the good of many outweigh the status of one. In addition, it drew on medicine’s aims to heal and prevent disease, urging consideration of a long-term benefit-to-harm balance. In the end, the NBAC recommended allowing federal funding for human embryonic stem cell research on excess IVF embryos (National Bioethics Advisory Commission, 1999).
Analysis & Recommendation
By continuing the current limitation, the valuable opportunity to understand the mechanisms of regenerative medicine for repair of diseased or degenerated cells and tissue is lost. We fall behind other countries in leading the next generation of medical advances. We abdicate responsibility to supervise the private sector advances in the field. But more importantly from a societal standpoint, it deprives us of the intellectual openness upon which our great scientific and medical community was built.
Our citizens lose the benefit of rigorous competition for resources that is seen with federal (National Institutes of Health) funding. We lose the benefit of the openness that comes with a stringent peer review process. And we forfeit the demand for scientific accuracy and accountability that accompanies the sharing of scientific knowledge.
For example, if we are to ever use embryonic stemcells or adult stem cells for therapeutic purposes, we need to know if these cell lines are comparable, if large numbers of lineage-specific precursors can be purified, and if these cells are safe to use in clinical settings.
It is recommended that the current President allow federal funding for stem cell-related research and that he convene a dedicated federal panel (under the auspices of the Department of Health and Human Services and the National Institutes of Health) to oversee the activities of private and state-run enterprises.
Humane Vitae: Encyclical Letters of His Holiness Pope Paul VI on the Regulation of Birth (1968, July 25). Vatican City, Roman Catholic Church. Retrieved on November 19, 2004 from the World Wide Web at:
Mayo Foundation for Medical Education and Research (2004, May 3). Stem Cells: Medicine’s New Frontier. Retrieved on November 19, 2004 from the World Wide Web at: http://www.mayoclinic.com/invoke.cfm?id=GA00012
National Bioethics Advisory Commission (NBAC). (1999, September). Ethical Issues in Human Stem Cell Research. Bethesda, MD: Government Printing Office. Retrieved on November 19, 2004 from the World Wide Web at http://www.georgetown.edu/research/nrcbl/nbac/execsumm.pdf
Pincock, S. (2004, August 12). UK Grants Cloning License: Group Given Permission to Undertake Cell Nuclear Transfer. The Scientist. Retrieved on November 19, 2004 from the World Wide Web at: http://www.biomedcentral.com/news/20040812/04
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Steinbock B. (1992). Life Before Birth: The Moral And Legal Status Of Embryos And Fetuses. New York, NY: Oxford University Press.
The President’s Council on Bioethics (2002, July). Human Cloning and Human Dignity: An Ethical Inquiry. Retrieved on November 20, 2004 from the World Wide Web at: http://bioethics.gov/reports/cloningreport/fullreport.html
Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. (1998). Embryonic Stem Cell Lines Derived from Human Blastocysts. Science; 282: 1145-1147.
Warren MA. (1997). Moral Status: Obligations to Persons and Other Living Things. Oxford, England: Clarendon Press.
US Dept of Health, Education, and Welfare: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1975). Report and Recommendations: Research on the Fetus. Washington, DC.
US Dept of Health & Human Services (2001, November 13). Protection of Human Subjects. 46 CFR, 498 (a), Pub L 99-158. Retrieved on November 19, 2004 from the World Wide Web at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm
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