Scientists Use Skin To Create Stem Cells
Discovery Could Recast Debate

By Rick Weiss
Washington Post Staff Writer
Thursday, June 7, 2007

Three teams of scientists said yesterday they had coaxed ordinary mouse skin cells to become what are effectively embryonic stem cells without creating or destroying embryos in the process -- an advance that, if it works with human cells, could revolutionize stem cell research and quench one of the hottest bioethical controversies of the decade.

In work being published today, the scientists describe a method for turning back the biological clocks of skin cells growing in laboratory dishes. Thus rejuvenated, the cells give rise to daughter cells that are able to become all the parts needed to make a new mouse.

If the process also works with human cells, as scientists suspect it will with some modifications, it would mean that a person's own skin cells could be converted directly into stem cells without having to collect healthy human eggs or destroy human embryos -- steps that until now have been required to obtain embryonic stem cells.

Those stem cells could then be used to make a wide variety of personalized replacement tissues.

The findings have generated tumult on Capitol Hill, where the House is set to vote today on a bill that would loosen President Bush's 2001 restrictions on the use of human embryos in stem cell research.

Acutely aware that their new work could undermine that key political goal, the scientists cautioned that their success with mouse cells does not guarantee quick success with human cells. They called for Congress to pass the bill, which would give federally funded researchers access to embryos slated for destruction at fertility clinics.

"A human is not a mouse, so a lot more work has to be done," said Marius Wernig, who led one team with Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Mass.

But opponents of human embryo research said the findings bolster their argument that stem cell science can progress apace without harming human embryos.

"Morally and practically, this new approach appears to be far superior," said Richard Doerflinger of the U.S. Conference of Catholic Bishops.

The new experiments reveal the remarkable degree of control that scientists have recently gained over the highly complex inner workings of living cells, and they generated intense excitement in the scientific community earlier this week as word leaked out.

"Clearly the work offers hope that similar methods can be applied [to develop] cell-based therapies," Robin Lovell-Badge, chief of developmental genetics at Britain's National Institute for Medical Research, said in a statement.

In nature, human embryonic stem cells are found nestled inside five-day-old embryos, which are about the size of the period at the end of this sentence. Since the cells can make every kind of human tissue, scientists want to use them to study development and to grow replacement parts for ailing patients.

Until now, however, retrieving them required destruction of an embryo. And creating the cells in the lab required collecting healthy human eggs from women donors, a process that poses medical risks.

Scientists knew that all adult cells, including easily retrieved skin cells, carry dormant genetic instructions for turning themselves back into embryonic cells. But they did not know how to activate that program, which is a matter of turning "on" or "off" certain of the cells' tens of thousands of genes.

Last year, Shinya Yamanaka of Kyoto University identified four genes in mouse cells that have the innate capacity to turn countless other genes on and off in the proper configuration to make a skin cell revert to an embryonic state.

Now Yamanaka and two American teams -- one led by Wernig and Jaenisch and the other by Konrad Hochedlinger of Massachusetts General Hospital and the Harvard Stem Cell Institute -- have gained good control over the process. They infected mouse skin cells with viruses genetically engineered to activate the four key genes.

About one in 10,000 of those infected cells became an "induced pluripotent stem" cell, or iPS cell, with all the characteristics of an embryonic stem cell, the teams report in three papers today in two journals -- Nature and Cell Stem Cell.

"It's pretty amazing. We can take a differentiated cell and basically make it back into an embryonic stem cell," said Kathrin Plath, a researcher with the Institute for Stem Cell Biology and Medicine at the University of California at Los Angeles, who was a co-leader on the Hochedlinger team.

The approach would have to be changed somewhat for use with human cells, Plath and others noted. The viruses used to turn on the four genes in mice are of a type that can cause cancer, so researchers are now studying alternatives -- using other engineered viruses, for example, or feeding the cells small molecules that can activate the key genes.

Moreover, scientists suspect that in human cells a different set of genes, as yet unidentified, is essential for reprogramming.

Some experts, noting that more than 20 years passed after the discovery of mouse embryonic stem cells before human embryonic stem cells were discovered, warned that it could take a long time to translate the new work to human cells. But others predicted that those hurdles would not prove too difficult now that the general approach has been proven in mice.

Separately, Kevin Eggan and colleagues at Harvard show in today's Nature another way of making embryonic stem cells. They removed the DNA from a fertilized mouse egg that had no potential to become a healthy embryo because it harbored chromosomal abnormalities, and replaced that DNA with the DNA from a mouse skin cell.

Until now, stem cell production by this method required healthy, unfertilized eggs. And those have been impossible to obtain, Eggan said, since various states passed legislation banning payments to women who donate eggs for stem cell research.

The newfound ability to make healthy mouse stem cells from eggs with severe genetic abnormalities suggests that human versions can be made using some of the tens of thousands of chromosomally abnormal fertilized eggs that are routinely discarded by fertility clinics.

Eggs with such severe defects "can never make a child," so there should be no ethical qualms about using them in research, said Eggan, who is now trying to replicate the work using human cells.

Sean Tipton, president of the Coalition for the Advancement of Medical Research, an advocacy group, said he was confident that the House would easily pass the stem cell bill, which has already passed the Senate.

"You cannot make good policy one scientific paper at a time, so I don't think anybody's vote is going to change because this or that paper is coming out," Tipton said.

Advocates have said that if Bush keeps his promise to veto the legislation again -- and if an override fails, as expected -- they will try to attach it to must-pass legislation.

"Supporters of this research are frustrated with this president who continues to thwart the will of the majority," Tipton said. "We will seize any opportunity that presents itself to change this policy."

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