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So humble an entity, so hot a potato: a blastocyst-stage human embryo, from which specialists glean embryonic stem cells.

The Stem-Cell Debate
by Ronald M. Green

Editor's note: The author was a member of the National Institutes of Health's Human Embryo Research Panel in the mid-1990s. The panel recommended ethical guidelines for all future federally funded research on human embryos. These guidelines helped influence President George W. Bush's decision in August 2001 to permit federal financing for research on human embryonic stem (ES) cells using established ES cell lines.

Stem-cell research has enormous potential value in both medical and commercial terms. Stem cells are the progenitors of all specialized cells in the body. Blood stem cells (hematopoietic cells) reside in bone marrow and continuously produce a variety of blood and immune system cells. Mesenchymal stem cells are the source of new bone, cartilage, and connective tissue cells. Neuronal stem cells produce a variety of nervous system tissue, mostly during early embryonic development but, as we are beginning to learn, later in life as well. During early development the precursors to all these more specialized stem cells, sometimes called "pluripotential stem cells" (PSCs), are found in the inner cell mass of the preimplantation embryo and in certain cell populations of the early fetus.

Stem-cell research took a great leap forward in 1998, when two independent research groups, led by Dr. James Thomson of the University of Wisconsin, Madison, and Dr. John Gearhart of Johns Hopkins University, reported success in growing human stem cells in culture. Thomson and Gearhart, using different approaches, had isolated these very early precursor cells and spread them out on a feeder layer of mouse cells to produce an immortalized pluripotent human stem cell culture. Research showed that the resulting cell lines produce the enzyme telomerase, which resets the cells' chromosomal clocks and prevents the timed death suffered by most differentiated cells. This resetting allows the cells to be cultured indefinitely during repeated cell divisions (or passages).

One day, doctors treating a cancer patient with chemotherapy may be able to replace his or her damaged blood or marrow cells with new ones grown from ES cells.

In the future, when better understanding has been gained of the growth factors that induce specific forms of cell differentiation, immortalized PSC lines like these may be induced to produce specific tissue types. It would then be possible to generate in the laboratory insulin-producing islet cells to cure diabetes or dopamine-producing cells, the absence of which causes Parkinson's disease. Also on the distant horizon lies the possibility of new cardiac tissue for heart attack victims, replacement blood and marrow cells for those who have undergone chemotherapy or radiation therapy for cancer, new skin tissue for burn victims, bone for those suffering from severe fractures or osteoporosis, and so on. Closely studied, stem cell lines might give scientists new clues about the growth factors that drive tissue differentiation from the earliest embryonic stage forward. This would permit new understanding of cellular abnormalities, including cancer, and new ways of steering cell differentiation in desired paths.

Thomas Okarma, president of the Menlo Park, California-based Geron Corporation, which funded Thomson's and Gearhart's work in return for exclusive licensing of the technologies the two teams developed, articulated Geron's corporate hope and a likely reality when he predicted that in the 21^st century, cell-replacement therapies based on pluripotent stem cell lines will render obsolete many current drug and medical interventions. At the end of 1999, the journal Science, in a special cover article and editorial, declared pluripotent stem cell research to be the scientific "breakthrough" of the year.

In 1999, the journal Science declared pluripotent stem cell research the scientific "breakthrough" of the year.

A funding issue

Major legal, ethical, and political hurdles stand in the way of these advances. In large part, these obstacles result from the fact that, of the three sources of stem cells, human embryos are the most promising. One source is the "adult," or mature, stem cells that reside in the body from infancy onward. These cells are "multipotent," meaning they are able to produce a range of related tissues, such as the differing types of blood system cells. A second source is embryonic germ cells that are derived from the primordial reproductive tissues of aborted early fetuses. These are the cells that John Gearhart used in his research. They are pluripotent, able to give rise to all tissue types, although recent research suggests that their usefulness in cell-replacement therapies might be limited because they have already begun to take on some specific characteristics of their reproductive function.

Finally, there are ES cells, derived from the inner cell mass of blastocyst-stage embryos. These pluripotent cells are the most ubiquitous of all. Once removed from the blastocyst they lack the outer trophoblast structures for continued embryonic development, but they can theoretically be "nudged" into becoming any cell type found in the human body. These are the cells that Thomson used in his research.

In a trice, the groundbreaking work of James Thomson (left) and John Gearhart brought the issue of government funding of stem-cell research to the fore.

Publication of Thomson's and Gearhart's studies made the issue of federal support for human embryo research unavoidable. Gearhart's use of tissue from aborted fetuses could be federally funded because research using cadaveric fetal tissue is currently not prohibited by federal law. However, Thomson's use of spare human embryos provided by the University of Wisconsin's infertility clinic would be a direct violation of the existing ban on federally funded human embryo research. In order not to imperil the university's massive budget of government-supported research, Thomson set up a separate lab in a building across campus from where he did his NIH-funded research.

Three issues spurred the debate over whether or not the government should fund stem-cell research. One concerned the moral status of PSCs themselves. Are they morally protectable entities, or are they more like other disposable tissues gleaned from the human body? A second issue concerned the derivation of PSCs. Assuming that at least during the earliest phases of research, human embryos produced via in vitro fertilization (IVF) would be the best source for producing immortalized stem cell lines, could research go forward that depended on the dissection of living human embryos?

Someday researchers may create new ES cells lines using a technique similar to that brought to bear in the birth of Dolly, the famous cloned sheep.

Finally, there was the question, still somewhat remote but now looming: whether to permit the creation of research embryos. For cell-replacement therapies to fulfill their promise, cell lines must be produced that can overcome rejection by the recipient's immune system. The hope is that we will develop enough knowledge to do this by manipulating the immune system factors of standardized pluripotent stem cell lines. If this is not possible, each therapeutic intervention will require the preparation of tissues that are immunologically suitable (histocompatible) for the patient.

One way to do this might be to combine Thomson's stem cell work with the cloning technology developed by Ian Wilmut and his colleagues at the Roslin Institute. (In 1997, Wilmut and his team announced the birth of the cloned sheep Dolly, the first mammal cloned from the cell of an adult animal.) A somatic cell could be taken from the recipient individual, its nucleus inserted into an enucleated egg cell that is stimulated to begin dividing, and the resulting blastocyst-stage embryo then disaggregated to produce a histocompatible pluripotent stem cell line.

Continue: Moral Seasoning

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