GENETIC TIME MACHINE: Put adult cells into an embryonic state with four genes. Such induced pluripotent stem cells (iPS cells) have attracted researchers hampered by restrictions on embryonic stem cells.
KEY CHALLENGES: Finding how to stop iPS cells from turning into tumors and how to create iPS cells without using retroviruses to deliver the rejuvenating genes. Image: Tim Hornyak
When historians chronicle the stem cell research wars, Shinya Yamanaka will likely go down as a peacemaker. The Japanese scientist has helped send the field on a surprising end run around the moral debate surrounding embryonic stem cells, the creation of which requires the destruction of embryos. Last year Yamanaka led one of two teams that showed that normal human skin cells can be genetically reprogrammed into the equivalent of stem cells. These so-called induced pluripotent stem cells (iPS cells) seem to be essentially identical to embryonic stem cells and possess the ability to become any cell.
The 46-year-old Yamanaka is a clean-cut, almost military figure. His small office in an aging wing of Kyoto University’s Institute for Frontier Medical Sciences is spotlessly tidy, with nothing to mark his achievement in producing iPS cells. A Nobel Prize may one day adorn his shelf space. As Yamanaka glances around, he remarks, “About 10 meters beneath us is a room that I have never entered. I’m not allowed to enter because I don’t have permission from the government. It contains the only stem cells derived from human embryos in the country.”
Though permissive in spirit, Japan in practice imposes strict rules on the production and (unlike in the U.S.) the use of stem cells derived from human embryos. Researchers can spend up to a year in paperwork submissions before gaining access to them.
It was Japan’s rule-bound, often stifling scientific culture that made Yamanaka an accidental pioneer. Originally an orthopedic surgeon in Osaka, he decided in the mid-1990s to do postdoctoral work on genetic reprogramming of cancer-related genes in mice at San Francisco’s Gladstone Institute of Cardiovascular Disease. There he found ready access to existing lines of embryonic stem cells, as well as an environment with solid funding and exchanges among leading researchers worldwide. At home, though, he went into a funk. “When I went back to Japan, I lost all those stimuli,” Yamanaka recalls. “I had only a little funding and a few good scientists around me, and I had to take care of almost 1,000 mice by myself.”
Fighting despair, he was about to quit and return to surgery. But two things galvanized him to continue: an invitation to head a small lab at the Nara Institute of Science and Technology and the creation of the first generation of human embryonic stem cells, which was made by the University of Wisconsin–Madison’s James A. Thomson (who last year led the other team that produced human iPS cells).
After Thomson’s achievement in isolating embryonic stem cells, many researchers began trying to control the differentiation of those cells into specific cell types that might replace diseased or damaged tissues, thereby revolutionizing clinical care. “That was too competitive for our small lab,” Yamanaka recounts, “so I thought I should do the opposite—instead of making embryonic stem cells into something, I would make embryonic stem cells from something else.” From Ian Wilmut’s success in cloning animals such as Dolly the sheep, he says, “we knew that even completely differentiated cells can go back to an embryoniclike status. But we also thought it would be a very, very long project,” one that might take 20 or 30 years.
It took fewer than 10. Yamanaka became highly motivated to solve two main problems surrounding embryonic stem cells. One was their source. He tells of visiting a friend’s fertility lab and observing early embryos under a microscope. The sight of fragile, nascent life moved him, although he emphasizes that he is not against using embryonic cells “to save patients.” The other problem is the threat of immune rejection if cells derived from an embryo are transplanted into a person. Differentiated cells created from a patient’s iPS cells would pose no such danger.