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Advance May End Stem Cell Debate
Labs Create a Stand-In Without Eggs, Embryos

By Rick Weiss
Washington Post Staff Writer
Wednesday, November 21, 2007

Researchers in Wisconsin and Japan said yesterday that they have turned ordinary human skin cells into what are effectively embryonic stem cells without using embryos or women's eggs -- the previously essential ingredients that have embroiled the medically promising field in a nearly decade-long political and ethical debate.

The ability to turn adult cells into embryo-like ones capable of morphing into virtually every kind of cell or tissue, described in two scientific journal articles yesterday, has been a major goal of researchers for years. In theory, it would allow people to grow personalized replacement parts for their bodies from their skin cells and give researchers a powerful means of understanding and treating diseases.

Until now, only human egg cells and embryos, both difficult to obtain and laden with legal and ethical issues, had the mysterious power to turn ordinary cells into stem cells. And until this summer, the challenge of mimicking that process in the lab seemed almost insurmountable, leading many to wonder whether stem cell research would ever unload its political baggage.

As news of the success spread in recent days, stem cell scientists seemed almost giddy that their field could suddenly become like other areas of biomedical science: appreciated, eligible for federal funding and wide open for new waves of discovery.

"These are enormously important papers," said George Q. Daley, a stem cell researcher at Children's Hospital Boston who was not involved in the work. Like others, he spoke with stunned elation reminiscent of scientists' reactions in 1997 to the cloning of Dolly the sheep from a skin cell, the first proof that adult mammal cells could have their genetic clocks turned back.

Their enthusiasm notwithstanding, scientists warned that medical treatments are not immediately available. The new method uses genetically engineered viruses to transform adult cells into embryo-like ones, and those viruses can cause tumors. But the cells will be instantly useful for research -- "to move a patient's disease into a petri dish," as Daley put it. And some scientists predicted that, with the basic secret now in hand, it may be only months before virus-free methods for making the versatile cells are found.

"This is a tremendous scientific milestone, the biological equivalent to the Wright brothers' first airplane," said Robert Lanza, chief scientific officer of Advanced Cell Technology in Worcester, Mass., a developer of stem cell therapies.

Especially gratifying to stem cell researchers was that some of their biggest critics seemed mollified.

Richard Doerflinger of the U.S. Conference of Catholic Bishops said he was at a Vatican-sponsored meeting recently where the technique was described. "All the Catholic scientists and ethicists at the conference . . . had no moral problem with it at all," he said. "This seems to be a way to get all the same uses that embryonic stem cells and cloning might be put to, without the moral problem."

Another crucial vote of confidence came from James Battey, vice chairman of the National Institutes of Health's stem cell task force, which oversees decisions about funding stem cell research.

"I see no reason on Earth why this would not be eligible for federal funding," Battey said. "I think it's a wonderful new development."

Many teams had been racing to be first to create human embryonic stem cell equivalents without embryos after researchers in June succeeded with mice. Yet scientists around the world agreed that nobody deserved to win that race more than the two competing scientists who did: James Thomson of the University of Wisconsin at Madison, who first isolated stem cells from 5-day-old human embryos, and Shinya Yamanaka of Kyoto University, who led the recent effort to obtain mouse stem cells without embryos.

Thomson, a shy and laconic laboratory researcher whose 1998 discovery made him the focus of religious opprobrium and repeated congressional hearings, expressed relief that he may now be able to work without being at the center of what had become America's other abortion debate.

"What a great bookend," Thomson said in an interview. "Ten years of turmoil and now this nice ending. I can relax now."

Yamanaka also expressed relief -- and surprise, upon learning that others were so close on his heels.

"Many people in other labs were kind enough to tell me they were working on it," he said. "But I did not know they had actually generated" the cells.

Thomson's and Yamanaka's reports were released online yesterday by the journals Science and Cell, respectively.

Human embryonic stem cells, from days-old embryos, can multiply without limit and also develop into all of the 200 or so types of cells that make up the body. But because extracting them typically destroys the embryo, experiments with them have been attacked by those who believe that even the earliest stages of human life have moral standing.

An alternative way of making the cells, in which scientists fuse a skin cell to an egg cell whose own DNA has been removed, proved that egg cells harbor chemicals that can turn adult cells into embryonic ones, apparently by turning key genes on or off. But this method, too, raised concerns because large-scale harvesting of eggs from women can be medically risky and exploitative.

The dream of doing in a lab dish what an egg cell does naturally began to come true in June, when Yamanaka's team identified four genes in mouse skin cells that, when operating at high levels together, can turn countless other genes on and off in just the right pattern to make skin cells almost indistinguishable from embryonic stem cells. Yamanaka put copies of those four genes into retroviruses, Trojan-horse-like viruses that insert their genetic payloads into the DNA of cells they infect. Once infected, the skin cells took on virtually all the characteristics of embryonic ones.

Because the rejuvenated cells did not come from embryos and behave slightly differently from embryonic stem cells, Yamanaka named them "induced pluripotent stem cells," or "ips" cells (pluripotent means "able to become virtually every kind of").

He immediately tried the same technique on human skin cells but failed repeatedly. What he did not realize, he said, was that the process takes weeks in human cells, compared with just days in mouse cells. After waiting several days for signs of colonies, he had been throwing out his cultures in frustration.

"We were not patient enough," he said.

Ultimately, he found he could get about 10 ips cell colonies from every 50,000 skin cells, an acceptable ratio given how easy it is to grow thousands of skin cells from a tiny sample. He coaxed the ips cells to become nerve cells, heart cells that beat in the dish, and other major cell types. And he showed that they were exact genetic matches to the skin cells they came from, suggesting that tissues or organs grown from them could be transplanted into the donor of the skin cells and not be rejected.

At the same time, Thomson, Junying Yu and colleagues were racing ahead. Working from an initial list of 14 genes that seemed to make human cells embryonic, they gradually narrowed their recipe to just four genes, too.

"It took us forever to get to the finish line," Thomson said. A lot of that time was spent checking for the emergence of slow-growing, embryo-cell-like colonies in dishes, so "there was no eureka moment. It was a drawn-out thing."

His cells passed the same tests as Yamanaka's, though in his final recipe, two of the genes he used were different.

"Apparently there are various ways to get to Rome," said Rudolf Jaenisch, a stem cell researcher at the Whitehead Institute for Biomedical Research in Cambridge, Mass. "We don't have to do it like the egg. We can do it differently."

Some of the hurdles to medical applications have already begun to be overcome. One of the genes that Yamanaka used, called c-myc, can initiate cancers, for example. But Thomson's recipe does not include c-myc, and in recent studies Yamanaka has succeeded with a three-gene cocktail that excludes c-myc.

More generally, retroviruses are a problem because they disrupt a cell's DNA in random locations, which can trigger tumor growth.

Both Thomson and Yamanaka said they are now testing methods that don't involve retroviruses. Among them are adenoviruses and fatty bubbles called liposomes, which deliver genes to cells without harming DNA, or even direct-injecting the biochemicals that the added genes produce inside cells.

Scientists differed on how big a challenge it would be to transcend retroviruses, but several said they were not concerned. "I don't think it is a big hurdle," Jaenisch said.

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