The end of the politically explosive, decadelong ethical battle over human embryonic stem cells may finally be in sight. Two groups of researchers report today that washing human skin cells in similar cocktails of four genes enabled them to reprogram the cells to resemble those harvested from embryos. The finding potentially paves the way for scores of labs to generate new stem cell lines without cloned embryos, which had long been considered the only realistic way of making human stem cells in the short run.
"The long run's getting a lot closer," says stem cell biologist James Thomson of the University of Wisconsin School of Medicine and Public Health in Madison, a senior author of one of the studies. "I do believe this is the beginning of a great change."
He is not alone. British newspapers reported this weekend that Ian Wilmut, the University of Edinburgh biologist who led the team that in 1997 cloned Dolly the sheep, is getting out of the cloning business in light of the new findings, which seem to offer researchers a likely new source of stem cell lines for basic research that could one day lead to new treatments and perhaps cures for spinal injuries, diabetes and debilitating disorders such as multiple sclerosis and Parkinson's disease. In the nearer term, reprogrammed cells may improve the screening drug candidates for harmful side effects.
"That's the writing on the wall right now," says biologist Arnold Kriegstein, director of the Institute for Regeneration Medicine at the University of California, San Francisco, who was not involved in the research.
Although both groups' reprogrammed cells were able to differentiate into the three main tissue types when injected into mice, Thomson cautions that they may harbor subtle, yet to be found quirks, and will need considerable tweaking before they could be safely transplanted into humans. Importantly, researchers must still study existing embryonic stem cell lines—the gold standard—to rule out any hidden risks in the lab-made cells, he says. "People want to rush and say, 'we don't need embryonic stem cells anymore,' and over time that might be true, but right now that's premature."
The results help fill in the scientific puzzle kicked off by Dolly's cloning, which proved that mammalian egg cells were capable of dissolving the genetic roadblocks that limit the potential of most adult cells to give rise to only a single type of tissue—that of the organ from which they hail—whereas embryonic stem cells have the potential to become virtually any kind of body tissue.
So researchers began testing genes that were only active in embryonic stem cells to try to pin down those capable of triggering the change. One such group, led by biologist Shinya Yamanaka of Kyoto University in Japan, reported last year that four genes, delivered to mouse cells by a retrovirus, were sufficient to induce pluripotency (the ability to differentiate into a multitude of cell types). The genes—Oct 3/4, Sox2, c-Myc and Klf4—are molecular switches called transcription factors, which activate other genes in series like a power strip.
Yamanaka's group and two others followed up earlier this year with firmer evidence that these induced pluripotent stem (iPS) cells faithfully mimicked the patterns of gene activity and cellular differentiation observed in embryonic stem cells.
Now Yamanaka and his colleagues report in the journal Cell that the same combination of genes induced pluripotency in commercially available human fibroblasts (connective tissue cells that play a crucial role in healing) derived from the facial skin of a 36-year-old woman, the joint tissue of a man, aged 69, and a newborn, respectively.
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