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See Inside February 2008

Potent Alternative

Reverse-engineered human stem cells may leapfrog the embryonic kind

Ten years after introducing the world to Dolly the sheep, the first cloned animal, University of Edinburgh biologist Ian Wilmut announced last November that he was quitting the cloning game. He was not going out on a high note—neither Wilmut nor any of his colleagues had succeeded in cloning an adult human cell by implanting its nucleus into a properly prepared egg, yielding precious embryonic stem cells. Rather his announcement heralded the publication a few days later of a method for directly transforming human skin cells into a form that was essentially equivalent to the embryonic kind. Cloning, Wilmut told reporters, had become obsolete.

In principle, if the products of this transformation—called induced pluripotent stem (iPS) cells—are sufficiently versatile and defect-free, they could relatively quickly become the go-to source of stem cells for modeling disease more realistically, testing drugs and designing future therapies derived from cell lines matched to a patient’s immune system. “All this now becomes much more tractable, and the prospect of not having to use human oocytes for this work is extremely attractive,” says biologist Arnold Kriegstein, director of the Institute for Regeneration Medicine at the University of California, San Francisco.

The existence of Dolly demonstrated that reprogramming is possible; the question was how. An adult cell fused with an embryonic stem cell will adopt the embryonic state, according to a 2005 Science study, implying that some cocktail of gene products initiates the change. The very next year a group led by stem cell biologist Shinya Yamanaka of Kyoto University in Japan published a recipe for reprogramming mouse fibroblasts, cells found in connective tissue. The method called for inserting four powerful regulatory genes—Oct4, Sox2, c-myc and Klf4—into the cells’ DNA, each delivered by its own retrovirus. Called transcription factors, these genes act like power strips, activating many other genes at once. The transformed cells passed a major test for embryonic “stemness,” or pluripotency: when injected into a mouse embryo, they continued to develop into all three of the embryo’s fundamental tissue layers.

Corroborating reports came earlier last year from the labs of Rudolf Jaenisch of the Massachusetts Institute of Technology’s Whitehead Institute for Biomedical Research and Konrad Hochedlinger of the Harvard Stem Cell Institute. Then, in November, Yamanaka’s group and an independent team at the University of Wisconsin–Madison, led by James Thomson, published reports in Science extending the technique to human fibroblasts. “I really thought this would be a 20-year problem, and it seems like it’s going a lot faster than that,” says Thomson, who in 1998 became the first to extract stem cells from a human embryo.

Notably, Thomson and his team created iPS cells without using c-myc, a gene that promotes cancer, although they reprogrammed neonatal and fetal cells only, not adult cells. Just a week later Yamanaka and his co-workers reported their own success transforming adult human and mouse fibroblasts without c-myc in Nature Biotechnology. Of 26 mice in Yamanaka’s study derived from iPS cells, none died of cancer after 100 days, compared with six of 37 generated with c-myc.

In further refining the technique, investigators will have to replace the retroviruses used to deliver the genes. Retroviruses insert their DNA cargo into the genome at random, potentially interfering with key genes. Indeed it is conceivable—if unlikely—that the retroviruses could have activated c-myc in Yamanaka’s latest iPS cells, says Jacob Hanna, a postdoctoral researcher in Jaenisch’s group. One immediate goal of iPS research is to identify small molecules that could induce reprogramming in place of virus-delivered genes.

Whatever the source of pluripotent cells, applying them to cure disease is still largely uncharted territory. In a proof of principle for reprogramming, Hanna and others from the Whitehead lab reported in early December that they used iPS cells (with c-myc genetically excised) to partly restore to normal the blood of transgenic mice engineered to bear the human gene variant responsible for sickle-cell anemia.

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