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Scientists Re-Create Stem Cells

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By KAREN KAPLAN, Los Angeles Times

Published: November 21, 2007

Researchers from Japan and Wisconsin reported Tuesday they had reprogrammed mature human cells to behave almost exactly like embryonic stem cells, a biological breakthrough that recasts the field's ethical, scientific and economic landscape.

By activating a handful of dormant genes, researchers were able to coax the cells back to a point in embryonic development before they had committed to becoming a particular type of tissue.

The rejuvenated cells were able to grow into all the body's main tissue types, including muscle, gut, cartilage, neurons and heart cells.

The discovery provides a road map for creating genetically matched replacement cells that could be used to treat patients for a variety of diseases - the personalized biological repair kits that are the goal of regenerative medicine.

For scientists, the method offers an alternative to the tricky and still unsuccessful cloning process in which a patient's DNA is inserted into a human egg to create a cloned embryo whose stem cells theoretically could be harvested.

The technique also bypasses the debate over the morality of destroying embryos in the cause of alleviating human suffering.

"It's a win-win," said Richard Doerflinger, secretariat for anti-abortion activities at the U.S. Conference of Catholic Bishops in Washington. "The scientists can get all the benefits they think they might get from embryonic stem cells, and the rest of us can applaud and support it."

Several key hurdles remain before the technique is ready for clinical use. The viruses employed to turn on the genes cause mutations that can lead to cancer, and one of the genes has a tendency to cause tumors.

Scientists said solutions were in the works.

"This is a tremendous scientific milestone - the biological equivalent of the Wright brothers' first airplane," said Robert Lanza, a stem cell researcher at Advanced Cell Technology in Worcester, Mass., who wasn't involved in the research.

The White House praised the work as an example of cutting-edge research that was conducted "within ethical boundaries."

Discovery Anticipated For Months

The discovery had been eagerly anticipated since June, when three research groups achieved a similar feat in mice. Scientists had expected the experiments to be repeated in humans, but many said it would take years, not months.

Stem cells are coveted for their ability to grow into any kind of cell, such as the insulin-secreting islet cells that diabetics need.

Until now, the only source of such cells was the inner cell mass of an early-stage embryo, and harvesting them required the destruction of the embryo.

The key advance was made by Shinya Yamanaka and his colleagues at Kyoto University, who spearheaded the reprogramming technique in mice.

In their latest study, published in the journal Cell, they applied essentially the same recipe to human cells taken from the subsurface layer of facial skin belonging to a 36-year-old woman.

The idea was to turn on genes that are active during embryonic development to see if they would rewind mature adult cells. After testing combinations of 24 candidate genes, they hit upon a group of four.

Yamanaka's group used a retrovirus to turn on the genes. The proteins initiated a biochemical process that returned the cells to an embryonic state.

The researchers grew the cells in dishes and found they behaved almost exactly like embryonic stem cells. Under the right conditions, they became neural cells, or cardiac cells that beat in unison. When injected into mice, the iPS cells formed tumors containing a jumble of body parts.

"They are very, very close, if not functionally identical, to human embryonic stem cells," said Owen Witte, director of the Broad Center of Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles.

A second group of researchers, led by James Thomson at the University of Wisconsin in Madison, started with a group of 14 proteins they suspected would return mature human cells to an embryonic state. They winnowed that pool to four proteins.

Using their recipe, the Wisconsin scientists were able to reprogram fetal connective tissue cells called fibroblasts. It also worked on fibroblasts from the foreskin of newborn boys. Their results were published in the journal Science.

Thomson, who isolated the first human embryonic stem cells in 1998, said that the technique is being tested in older cells and that he is optimistic it would work.

Other scientists said it might be difficult to adapt the method to cells that are years removed from their embryonic origins.

Benefits Promised; Concerns Persist

The discoveries will bring a host of practical benefits.

President Bush made most embryonic stem cell research off-limits for federal funding, but this line of work is eligible because it doesn't destroy human embryos. Thomson's study was funded in part by the National Institutes of Health.

Although the new technique dodges some significant ethical problems, it also creates new ones, said Insoo Hyun, a bioethicist at Case Western Reserve University in Cleveland.

In previous experiments, mouse cells were transformed into sperm and egg cells. If the same could be done in people, he said, "it transforms what we think about human fertility."

Theoretically, the method would allow people to reproduce even after death if they banked a tissue sample.

"A person doesn't even have to be alive to create sperm or eggs," Hyun said. "It really is a new technology that brings with it a new set of issues."

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