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TAKE ONE ADULT SKIN CELL:
Add four genes borne by viruses // watch as the cell reverts to infancy // steer it toward a different purpose.

The Other Stem Cells

By Rachael Moeller Gorman // Illustration by Mirko IliĆ // Spring 2009
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induced pluriopotent  stem cells

When a garter snake or the occasional bird attacks a newt, the predator often is able to snatch a limb or tail before the newt can slip away. A loss like that would be devastating to most creatures, but to this amphibian, it’s manageable. Within a day, the injury begins to heal; within a month, skin cells at the wound site actually start changing identity, moving backward in developmental time. The progenitor cells that those skin cells become are able to turn into all of the different cells the newt needs to create a leg. Just 10 weeks after the attack, five toes have pushed their way out of the growing mass of skin, cartilage and muscle, and, finally, the new limb emerges.

More complex species could never pull off the newt’s trick. “Development in mammals is a one-way road,” says Konrad Hochedlinger, a stem cell biologist at the Massachusetts General Hospital and Harvard University. “Once a cell becomes a skin cell, it remains a skin cell for the rest of your life. You can’t grow a liver, say, on your arm. It just doesn’t happen.”

Yet in 2006, Shinya Yamanaka at Kyoto University in Japan reported a “crazy” experiment (Hochedlinger’s word) to show that mouse skin cells in a petri dish, aided by four genes and viruses that inserted the genes into the cells’ DNA, could achieve something like the newt’s developmental reversal, becoming just about any cell in the mouse’s body. The new cells, which Yamanaka called induced pluripotent stem (iPS) cells, looked and behaved like embryonic stem cells, which are prized for their ability to transform themselves into almost any kind of tissue and, perhaps, someday cure disease—a more distinct possibility now that President Barack Obama has loosened restrictions on stem cell research.

Harvesting embryonic cells, however, is controversial because it results in the destruction of an embryo. The hope, in the wake of Yamanaka’s discovery, was that iPS cells could be a controversy-free alternative, conferring on humans a newtlike ability to regenerate lost or diseased tissue. Stem cells of either sort might be able to create healthy neurons for a patient with Parkinson’s disease, for example, or replace damaged or diseased cells of almost any type, promoting recovery from a wide range of maladies. IPS cells have already been used to treat sickle cell anemia in mice and Parkinson’s disease in rats. And iPS cells may have a particular advantage: Taking a person’s own skin cells, say, making them pluripotent, and then using those cells to grow whatever kind of tissue is needed could eliminate the use of debilitating immunosuppressive drugs, which are required when transplanting cells or tissue from a donor.

There were problems with Yamanaka’s initial technique for creating iPS cells, including an elevated risk of cancer and a very low efficiency rate, with only one in about 10,000 cells that received the four genes becoming an iPS cell. But a flurry of research findings published during the past few months indicates that several new approaches may get around those issues. One study even suggests it’s possible to reprogram cells inside an animal’s body, in this case changing exocrine cells in the pancreas into insulin-producing beta cells that might be used in diabetes treatments. “This is completely unexpected ground shift in the whole field of cell biology,” says Clive Svendsen, a stem cell biologist at the University of  Wisconsin, Madison. “Every time I wake up in the morning, I just cannot believe this has happened.”

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Six of One…

Induced pluripotent stem cells and embryonic stem cells are both important for research. Here’s how they compare.

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hed-dossier

1. “Nuclear Reprogramming in Cells,” by J.B. Gurdon and D.A. Melton, Science, Dec. 19, 2008. A comprehensive history of cell reprogramming and its potential, from frogs to Dolly to iPS cells.

2. “In Vivo Reprogramming of Adult Pancreatic Exocrine Cells to Beta-cells,” by Qiao Zhou et al., Nature, Oct. 2, 2008. In the latest stem cell breakthrough, Doug Melton and his co-authors describe turning one type of adult pancreatic cell into another, inside a living mouse.

3. “Induction of Pluripotent Stem Cells From Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors,” by Kazutoshi Takahashi and Shinya Yamanaka, Cell, Aug. 25, 2006. Revolutionizing stem cell research, Japanese scientists report creating the first iPS cell, turning a mouse skin cell backward in developmental time.

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