Studies of human ES cells have demonstrated an enormous potential for generating tissues of therapeutic value, but we have also highlighted problems associated with inefficient differentiation, tumorigenicity, and immunogenicity in addition to the complexity of the ethical issues surrounding the isolation of cells from in vitro fertilized human embryos.
Five fundamental ethical principles are applicable to hES cell research: 1) the principle of respect for human dignity, 2) the principle of individual autonomy (informed consent, respect for privacy, and confidentiality of personal data), 3) the principle of justice and of beneficence (improvement and protection of health), 4) the principle of freedom of research (balanced against other fundamental principles), and 5) the principle of proportionality (no alternative more acceptable methods are available) (370).
Ethical judgements about the use of human ES cells in research and therapies rely on the status of the embryo. If one feels that an embryo is a human being or should be treated as one because it has the potential to become a person, then it would be considered unethical to do anything to an embryo that could not be done to a person. At the opposite end of the spectrum, one could express the view that the embryo is nothing more than a group of cells that can be treated in a manner similar to tissues used in transplantation. An intermediate position would be to ascribe a special status to the embryo, and depending on its stage of development, the embryo could be considered less than human life and deserving of respect. Such a special status would necessarily impose some limits or restrictions on its use.
On the basis of these fundamental issues and in conjunction with specific sociocultural and religious traditions, different opinions reflect the various positions of countries involved in stem cell research and stem cell biotechnology. Most countries have passed bioethical regulations or laws about principal requirements of human embryo and hES cell research (see Ref. 335). These regulations differ mainly because countries have different views regarding the status of the human embryo, which determine whether early embryonic stages are subject to manipulation. Because scientific success in stem cell research is developing so rapidly, such rules are under continuous change [for special regulations of hES cell research, see http://www.aaas.org/spp/sfrl/projects/stem/main.htm; www.nih.gov/news/stemcell/ (USA); www.nibsc.ac.uk/divisions/cbi/stemcell.html (UK); http://www.shef.ac.uk/eurethnet/news/index_news.htm (European countries including UK); http://www.aph.gov.au/house/committee/laca/humancloning/contents.htm; Australia].
Parallel to the extensive research activities using hES cells over the past 4–5 years, numerous reports of the presence of multipotential stem cell activity in adult tissues have raised hopes that these may offer an alternative and more acceptable source of regenerative tissue for transplantation purposes. However, as discussed in section IX, recent studies also highlight a number of uncertainties concerning the true extent and nature of the differentiation/transdifferentiation capacity of adult stem cells.
One of the major challenges for the emerging field of stem cell research will be the development of in vitro culture conditions that tease out and maximize the required regenerative potential from cultured stem cells. This is likely to require an understanding of the extrinsic signals, which recruit and direct stem cells in vivo, and of the intrinsic (endogenous) circuits, which both define and limit the ability of a stem cell to respond to a given set of conditions. A detailed understanding of these processes will require continued studies of the mechanisms of embryonic and adult stem cell biology and the identification of those factors and signaling components that are necessary to generate and to manipulate stem cell progeny for therapeutic applications. Although we cannot currently use ES cell-based therapeutic strategies in humans, the recent technical achievements of cell and molecular biology will positively influence stem cell research and, in the future, should result in the generation of functional tissue grafts for clinical applications.
We are grateful to Kathrin Seiffert, IPK Gatersleben, for expert help in the preparation of tables, figures, and the reference list; to our co-workers for providing experimental data (Fig. 6); and to Gary Lyons (B. Swanson, R. Baker, and G. Lyons) for furnishing us with unpublished data and figures.
We thank the IPK Gatersleben, the Deutsche Forschungsgemeinschaft (Grant WO 503/3–2), the Ministry of Education and Research and Fonds der Chemischen Industrie, Germany (to A. M. Wobus), and the National Institute on Aging (to K. R. Boheler) for funding our stem cell projects.
Address for reprint requests and other correspondence: A. M. Wobus, In Vitro Differentiation Group, Institute of Plant Genetics (IPK), Corrensstr. 3, D-06466 Gatersleben, Germany (E-mail: [email protected]
) and K. R. Boheler, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr., Baltimore, MD 21224 (E-mail: [email protected]