Shinya Yamanaka (left) and Norio Nakatsuji at Kyoto University

In June, Shinya Yamanaka's name was splashed on the pages of the New York Times, USA Today,and other major news outlets. His claim to fame? Finding a technique that transforms cultured mouse skin cells into ones virtually identical to embryonic stem (ES) cells1. At the same time, two other research groups showed that the method also works in their laboratories2,3. If something similar works in humans, a straightforward skin biopsy could be used to create ES cell equivalents matched to a particular patient, without using embryos or even eggs. Labs are already racing each other to find a recipe that could produce similar human cells suitable for cell-therapy transplants or for screening drugs.

Yamanaka's discovery has also launched one of the world's longest commutes. Starting this August, he will make a 10-hour plane ride twice a month, splitting his time between the Gladstone Institute in San Francisco, California, and the Institute for Frontier Medical Sciences at Kyoto University in Japan.

The journey started, years ago, with a long, thin scar on the scientist's left wrist. A proclivity for judo and rugby landed the young Yamanaka in the hospital nearly a dozen times before and during medical school. Those experiences led him to become an orthopaedic surgeon, but neither setting bones nor removing casts was much to Yamanaka's liking. Surgery tends toward solitude, and he wanted more interaction with scientists. “I felt stuck,” he reminisced when I visited him in Kyoto in June, “I wanted to escape.”

The first escape was classical pharmacology, dosing dogs with drugs at Osaka City University. But then he read a paper that changed his career path yet again. The paper described how researchers could pick any gene and make a mouse that lacked it. “To knock out one gene,” Yamanaka said. “To me, it was just a miracle.” He decided he had to pursue it. Few scientists in Japan were making these knock-out mice, but Yamanaka had always wanted to go abroad anyway, so he sent off “50 or 60 resumes”. Eventually, he received a fax from Tom Innerarity of the Gladstone promising that, if he came to San Francisco, he could make knock-out mice.

He arrived at the Gladstone Institute in 1993 and soon began investigating a transgenic mouse prone to liver tumours. He happened on a gene, c-myc, that was a good marker for pluripotency—the ability of cells to develop into many different cell types. And so he shifted from studying whole mice to studying their cells. He also moved back to Japan, first to the Nara Institute of Science and Technology and eventually to Kyoto.

Yamanaka realized that if he had the right marker system, he could douse cells with antibiotics, and cells that weren't expressing pluripotency genes would die. Why not try to reprogramme differentiated cells and use the reporter system to see if it worked?

The original plan was to try to use a cDNA library to screen large swaths of the genome, but eventually Yamanaka settled on a more targeted approach. His co-author Kazutoshi Takahashi had a set of retroviral vectors packed with pluripotency genes and ready to go. They decided to “sprinkle” them all on to see whether anything that looked like an embryonic stem cell cropped up4.

When I spoke with Yamanaka, he made this research sound like serendipitous fooling around in the lab, but Deepak Srivastava, a director at the Gladstone, describes the work as bold, technically difficult experiments that required the systematic identification of combinations of multiple genes. “He made the leap,” says Srivastava, “that if a set of transcriptional factors was required to maintain pluripotency, one or some combination of these transcription factors would be sufficient to induce pluripotency.”

But there was no way to know how many proteins would be required. And while it's likely that cells would take in one or two different genes when exposed to a retrovirus, very, very few would take in three or four. For all the researchers knew, inducing pluripotency could require a dozen genes, assuming it was even possible. “Very few actually carry out such experiments,” says Norio Nakatsuji, director of the Frontier Institute. “I suspect that many scientists would give up.”

“We didn't think it would work, actually,” Yamanaka recalls. When it did, Yamanaka initially resisted the urge to go public. Korean scientist Woo-suk Hwang's claims to have cloned human embryonic stem cells had been denounced as fraudulent, and the entire community of stem-cell scientists, particularly in Asia, was on the defensive. Yamanaka decided to wait until he knew he could reproduce his results.

When Yamanaka announced his initial results in the middle of 2006, they were met with great excitement—and scepticism. It was then that Srivastava decided to find a way to bring Yamanaka back to the Gladstone. He set about convincing funders that a scientist like Yamanaka should have dedicated technicians, postdocs, and laboratory space, even if he's only going to be physically present for one week every month.

Despite such inducements, it was ultimately government regulations on both sides of the Pacific that pushed Yamanaka into his trans-oceanic commute. His wife, a physician in Japan, is not licensed to see patients in the United States, so it is better for her and his teenage daughters to stay in Japan. But regulations on human ES cell research in Japan stall Yamanaka's work there. At Gladstone, he'll engineer reporter systems in human ES cells, let them differentiate, then try to reprogramme them. At Kyoto University, he'll continue his work on cultured skin cells, trying to find reprogramming techniques that don't require retroviruses. One obvious technique, using viruses that don't integrate into the genome, hasn't worked yet, says Yamanaka.

Yamanaka and his once and future Gladstone colleagues clearly have fond memories of each other. Srivastava recalls that a group of research technicians from Yamanaka's postdoc days positioned themselves by the door Yamanaka would leave through when he finished the interviews for his new post. They waited for about 40 minutes, said Srivastava, “just to say hello to him and give him a hug.” One of the requirements of Gladstone investigators is working closely with colleagues. So Srivastava had to know Yamanaka could be a good Gladstone citizen even though frequently absent. Srivastava says he was convinced as he watched Yamanaka mingle with those he'd worked with years ago. For his part, Yamanaka says he longs for the kind of interactions he had during his postdoc years. “Here, I mainly order,” he says, referring to his Kyoto laboratory. “I just want to discuss.”

Several professors have set up laboratories outside Kyoto University, says Norio Nakatsuji, director of the Frontier Institute. He himself runs a separate government laboratory with 15 members, but that's nearby in southern Kyoto. There are very few cases of dual appointments abroad and the time spent traveling will be a burden. But then, Yamanaka is not one to stand still: Nakatsuji says he can often be found jogging around campus after hours.

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