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Photo: © Science VARIOUS STAGES: Human embryonic stem cell colonies, shown here in different states of development, sometimes include a core of undifferentiated cells surrounded by a margin of differentiated cells, such as the small colony at right in figure B. Gene therapy researchers call them the "ultimate target." Tissue transplant specialists refer to them as the "Holy Grail." Stem cells, perhaps because they play such a fundamental role in the developmental chain, tend to draw hyperbole. But hyperbole resulting from two recently published reports on successful cultures of different lines of immortalized, pluripotent human stem cells in vitro, has made some of the researchers involved cringe. Unwelcome responses to the findings include media reports that would have scientists soon growing organs in petri dishes. James A. Thomson, an associate research veterinarian at the University of Wisconsin's Regional Primate Research Center in Madison, led a group that derived stem cells from human embryonic tissue that can divide indefinitely and form a variety of cell types (J. A. Thomson et al., Science, 282:1145-7, Nov. 6, 1998). John Gearhart, a professor of gynecology and obstetrics at Johns Hopkins University School of Medicine in Baltimore, and colleagues published similar results in human embryonic germ cells--cells slightly farther along in the developmental continuum, but still capable of producing a number of different cell types (M.J. Shamblott et al., Proceedings of the National Academy of Sciences, 95:3726-31, Nov. 10, 1998). Gearhart had reported preliminary results last year (R. Lewis, The Scientist, 11[9]:1, Sept. 29, 1997). Biologists still have years of work--perhaps a decade or longer--before patients will receive either stem-cell-derived tissue transplants or stem-cell-based gene therapy, both scientists agree. Before the two laboratory experiments can turn into clinical applications, biologists must learn how to control and direct differentiation of the dividing cells into specific cell types, and bioethicists, scientists, and public policy makers must resolve a host of ethical issues. Federal policy now prohibits public funding of research based on human embryonic cells, on which both groups based their research. Continued prohibitions could place constraints on future work. Both groups received funding from Geron Corp. of Menlo Park, Calif., which wants to turn the research into therapeutics. But that will take time and effort, reiterates Thomson in a telephone interview. "Because these are such basic stem cells--we've just isolated them--there's more work to be done before we get to something that's actually a therapeutic." However, he predicts that the purified cell lines may be used for in vitro drug screens within five years. "There's a great deal of interest in these cells in the short term for drug development because it'll be fairly easy to purify a population of, say, heart muscle cells." Thomson's group will now focus on controlling neural differentiation. "We have expertise in our lab in that particular area and it's a fairly easy one compared to other lineages," he explains. "There's a lot of work that has already been done on it in mouse stem cells." Still, mouse models will only help to a limited extent (R. Lewis, The Scientist, 12[21]:10, Oct. 26, 1998). A number of laboratory hurdles also must be cleared prior to controlling differentiation. For starters, Thomson would like to produce cells without the accompanying fibroblasts, or find an easy way to remove them. "It would be very nice to get rid of them some day, because it's kind of labor-intensive." Gearhart, too, notes a number of technical issues that must be resolved before their techniques result in, say, lab-grown tissue patches for organ repair. For instance, the cells now clump together. Finding a simple way to make them desegregate would aid the process. Also, catching the cells at different stages of development may be of use. And scientists must also find easy ways to scale up if they want to produce the billions of cells necessary to form tissue. Still, other scientists find it difficult to quell their enthusiasm for the future therapeutic possibilities both papers suggest. Gail K. Naughton, a practicing cell biologist, and president and chief executive officer of Advanced Tissue Sciences Inc., of La Jolla, Calif., thinks technical issues will be resolved. She notes that cell biologists have already identified many cellular matrix proteins and growth factors in mice and will likely find human homologues. "I think that with the [number] of markers they have right now for various matrices, and with various growth factors and various RNA expressions, they're going to be able to go and look at normal embryological development and find some keys to what happens during the differentiation process; then they are going to apply that to the cells themselves." The ethical obstacles will also be cleared, predicts Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania. But a solution may require much discussion, followed by layers of bureaucracy. Pioneers of new technologies often must face the most regulation, at least initially, notes Caplan. For example, W. French Anderson's recent early protocol for in utero gene therapy went through 26 reviewers--including theologians, bioethicists, and doctors (see Notebook). The first clinical stem cell work will likely receive similar treatment. However, Caplan predicts that moral reservations based on the embryonic origins of the stem cells will be overshadowed by the utility of a technology that could be applied widely--from creating virus-free blood sources to repairing spinal cord damage. Caplan also predicts that multiple disease groups will converge upon Congress if members remain recalcitrant about changing the rules on embryonic research. "That lobby, I think, will overwhelm moral reservations."

Stem Cell Scientists Caution: Clinical Applications Remain Years Away

Nov 22, 1998

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