Stem cells without embryos?

New methods of generating pluripotent cells may placate critics, but may not work, say scientists

By | March 25, 2005

Scientists are responding with a mix of encouragement and criticism to proposed sources of human pluripotent stem cells put forth at a meeting of the President's Council on Bioethics earlier this month that in principle could placate critics of embryonic stem cell research.

"Altered nuclear transfer," proposed by council member William Hurlbut, involves modifying conventional somatic cell nuclear transfer (SCNT) by silencing particular developmental genes in the somatic cell nucleus prior to transfer into the enucleated oocyte. For example, Hurlbut cited Cdx2, mutations in which have been shown in mice to cause death at the blastocyst stage because they fail to form a trophectoderm, which normally gives rise to the placenta. However, these embryos can still give rise to mouse embryonic stem cells.

Silencing of such genes, in principle, would allow cellular development such that embryonic stem cells could be obtained. But because the entity would have no "global, coordinated organization," it would not be considered an embryo, Hurlbut said.

The method would probably not work exactly as put forth, said Ira Black, of the University of Medicine and Dentistry of New Jersey. But "the point is that potentially there are alternative approaches to obtaining these cells," Black told The Scientist. "Hurlbut's hypothetical approach is one of them that I don't believe should be critiqued and dismissed out of hand."

Charles Jennings, one of several scientists at the Harvard Stem Cell Institute who harshly criticized Hurlbut's proposal in the New England Journal of Medicine, said the Cdx2 gene may not work in humans the same way it does in mice. To investigate, researchers would need to acquire human oocytes, a controversial task since the oocytes would be used not for a clinical experiment but for proof-of-principle research with an ethical rationale. "You need to destroy human embryos in order to test the idea," Jennings told The Scientist.

If the idea did work, the stem cells would be carrying a mutation that could make the cells unsuitable for any future clinical application. Jennings noted that altered nuclear transfer would also add multiple years of research as well as multiple steps to an already a tricky process. "If this were to gather momentum, it has great potential to delay the field and delay therapies," he said.

A related suggestion from the council, parthenogenesis—in which the egg is "tricked" into thinking it's fertilized—is much more established and has been shown to work in nonhuman primates. According to Ann Kiessling, a parthenogenesis investigator at the Harvard Institute of Medicine, the race is on among a few labs worldwide to successfully generate parthenogenic stem cells with human oocytes, although the United States does not permit federal funding for parthenogenesis research. Based on the nonhuman primate data, the process, said Kiessling, would be much more efficient than SCNT with far fewer eggs necessary per successful stem cell line. "You seem to be able to get an egg to activate with its own chromosomes far more easily than with foreign chromosomes," Kiessling told The Scientist.

Another proposal involved deriving human stem cells from early in vitro fertilization embryos that have died spontaneously. The issue would be determining specific criteria for declaring an embryo deceased. Identifying such criteria at the cellular level would be a difficult but not impossible task, said Black, a neurologist, who noted that the effort would be similar to that of defining now well established brain death criteria.

An additional proposal involved deriving pluripotent stem cells from blastomeres obtained via the biopsy of an early human embryo. Although obtaining the cells is scientifically feasible, according to Jennings—the process would be tantamount to preimplantation genetic diagnosis—ethical issues remain. "I personally would not want to take a blastocyst, remove the cells just for the sake of generating stem cells and then attempt to implant that blastocyst," said Larry Goldstein, of the University of California, San Diego. "What you've done has no benefits for that child and that pregnancy."

"The main problem is that each and every early blastomere has the potential to make a whole embryo and therefore the potential to make a whole animal," Douglas Melton, also at the Harvard Stem Cell Institute, told The Scientist via E-mail. For those opposed to destroying a cell with the potential to make a whole animal, then none of the above proposals are satisfactory, he said.

Because there's no rigorous definition of an embryo, "finding a technical end-run around moral objections to creating embryonic stem cells is likely to flop," said Thomas Murray, a bioethicist at the Hastings Center.

A final proposal from the council, reprogramming human somatic cells to force them to "dedifferentiate" them back into pluripotent stem cells, is already the focus of many investigators, including Black and Melton.

"All possible alternatives should certainly be explored," Goldstein told The Scientist. "But one should not halt legitimate research while looking for those alternatives."

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