Embryo Stem Cells
It has been an extraordinary year for stem cell researchers and for the policymakers striving to keep up with them. In December 1999, the journal Science hailed embryo stem cell research as the most significant scientific breakthrough of that year. But formidable technical challenges must be overcome if we are to realize the enormous potential of embryonic stem cell technology. And the moral questions raised by using stem cells derived from preimplantation embryos or aborted fetuses are difficult, even polarizing.

Human embryonic stem cells are pluripotent stem cells that can generate all of the cell types in a fetus, and in adults have the potential to develop into all basic tissue types. Embryonic stem cells can be derived from 2 tissue sources: blastocysts (cells about 1 week old), and primordial germ cells. Grown in culture, embryo stem cells have unlimited potential for growth and differentiation.

Biologist Dr. James Thomson and his group at the University of Wisconsin, Madison, have isolated stem cells from human embryos and grown them into 5 immortal cell lines. Pluripotent stem cells have also been derived from fetal tissue obtained from terminated pregnancies. Dr. John Gearhart, a developmental geneticist, and his team at Johns Hopkins University in Baltimore, Maryland, isolated embryo germ cells from the primordial reproductive cells of the developing fetus. Following upon the work of Dr. Gearhart and Dr. Thomson, other researchers have begun to demonstrate the therapeutic potential of embryo stem cells.

In a promising step toward developing treatments for multiple sclerosis and other neurodegenerative disorders, Dr. Oliver Brüstle of the University of Bonn Medical Center in Bonn, Germany, and his colleagues in the United States have coaxed embryonic stem cells from mice to form myelin-producing glial cells. When injected into the spinal cords of rats unable to make myelin as a result of a genetic defect, the glia began coating the rats' neurons with myelin. Dr. J.W. McDonald and colleagues at Washington University School of Medicine in St. Louis, Missouri, injected immature nerve cells derived from mouse embryo stem cells into rats whose hind limbs had been paralyzed as a result of injury to their spinal cords. The rats regained some mobility, an extremely encouraging result given the fact that treatment occurred 9 days after the injury.

When Dr. Thomson testified before the Senate Subcommittee on Labor, Health, and Human Services, Education and Related Agencies: Regarding Human Embryonic Stem Cell Research in December 1998, he described his vision of a future made possible by embryo stem cell technology. When directed to specific lineages, embryo stem cells could enable the standardized production of large purified populations of normal human cells such as myocytes and neurons. These cells could provide a potentially limitless source of tissue for pharmacologic research and development and transplantation therapies. Future clinical targets for the repair of blood, bone, and other tissues include hematopoietic repopulation, osteoarthritis, Parkinson's disease, diabetes mellitus, spinal cord injury, stroke, burns, and myocardial infarction. Embryo stem cell lines could offer insights into abnormal embryogenesis and developmental events that cannot be directly studied in the intact embryo or other species, but which have important consequences in clinical areas including birth defects, infertility, and pregnancy loss.

Embryo stem cell lines could potentially be developed as an unlimited renewable source of cells for tissue transplantation. The implications for prevention of rejection of transplanted tissues are also promising. Embryo stem cells lines that represent the entire spectrum of major histocompatibility complex (MHC) alleles might be developed for specific donor cell line-recipient MHC matching. In addition, rejection might be avoided by development of universal donor lines with genetically altered MHC genes.

Going forward with embryo stem cell research, in particular with federally funded research, is a goal that is fraught with the ethical and policy problems long associated with research on embryos. In February 1994, a Human Embryo Research Panel was appointed by the Director of the National Institutes of Health (NIH). Later that year, the panel recommended that federal funding be allowed for certain types of research. Included in this category were research on surplus embryos from in vitro fertilization (up to the appearance of the primitive streak, day 14); and embryos purposely created for research, provided that there was a compelling reason for such research. When the report was released, the political uproar was immediate.

In December 1994, President Clinton banned the use of federal funds to create embryos for research purposes. Congress went even further, extending the ban to research on surplus embryos. This ban takes the form of a rider to the appropriations bill for the Department of Health and Human Services (DHHS), of which the NIH is a part. Public Law No. 105-78, 513(a) prohibits the use of federal funds for the initial development of an embryonic stem cell line.

In November 1998, the President asked the National Bioethics Advisory Commission (NBAC), comprised of 17 scientists, ethicists, and lawyers, to examine the issues. In their September 1999 report, the NBAC recommended that the federal government fund both the derivation and research of human embryo stem cells and the production of cell cultures.

But a more circumscribed role for government funding was already being discussed. In January 1999, the General Counsel of DHHS, Harriet Rabb, issued an opinion stating that the ban on federal funding for embryo research did not forbid embryo stem cell research, because embryo stem cells cannot develop into a person once they are removed from the embryo. On the basis of this opinion, the NIH developed draft guidelines for fetal and embryo stem cell research. The guidelines, which were published in the Federal Register on 2 December 1999, spelled out detailed criteria that cell lines would have to meet before NIH-funded researchers could use them. Private laboratories will continue to produce embryo stem cell lines from embryos, and the federal government will fund research using these cell lines as long as they are derived according to a strict set of requirements outlined by the NIH.

With respect to fetal tissue (as opposed to embryos), both the derivation of stem cells and their use in research may be funded by the government. Using stem cells to create a human embryo is prohibited, as is using such cells for reproductive cloning. Research that uses embryos that were derived specifically for research is prohibited as well. With respect to surplus embryos, signed donor consent is required. A Human Pluripotent Stem Cell Review Group will monitor the research.

There is another type of stem cell that is far less politically and morally problematic than the embryo stem cell - the multipotent or adult stem cell, produced when the pluripotent embryo stem cells specialize and become committed to a particular function. Several recent studies have shown that, in some cases, these commitments can be overridden. In a feat that the journal Science has likened to a music student becoming a successful professional baseball player, Italian and US scientists reported last January that stem cells from the brains of mice could situate themselves in the bloodstream and bone marrow and become mature blood cells.

While these cells do hold promise, there are significant limitations to their usefulness. Adult stem cells for all cell and tissue types have not yet been discovered. No cardiac stem cells have been identified, for example. Adult stem cells are only present in very small quantities, and would be difficult to isolate and purify. Growing them to order would take too long, especially if an illness were acute.

Thus, there seems no way to avoid an acrimonious debate. And the battle has been joined. The Patient's Coalition for Urgent Research, an umbrella group composed of dozens of patient organizations, has been lobbying the US Congress to allow federally funded embryo stem cell research to go forward. The American Association of Medical Colleges is one of many professional organizations arguing the merits of this research. On the other side of the debate are, among other groups, the National Conference of Catholic Bishops and its spokesman, Richard M. Doerflinger.

And where is the science 11 months after publication of the 2 landmark papers? When Dr. Thomson injected into mice freshly grown human stem cells more than 300 generations removed from the cells he had isolated from the human embryo, they differentiated into many kinds of tissues -- "some of them becoming hair, others teeth, and still others little masses of cardiac cells that beat in unison like a miniature heart." Clearly, a major hurdle looms in the distance -- directing these eternally youthful cells down designated and predictable paths so they can realize their extraordinary promise.