Ahead of the Curve

Everything about Shinya Yamanaka’s discovery was right—except for the timing. The 44-year-old Kyoto University stem-cell researcher had found a way to genetically reprogram an ordinary mouse skin cell to revert to the virtual equivalent of its embryonic state, in which it has the potential to grow into any kind of tissue. The finding was a promising first step toward the creation of stem-cell lines for near-miraculous medical treatments—and because Yamanaka did not use human embryos, his technique offered researchers everywhere a way to sidestep the ethical controversies that have dogged the field since its birth. But it was March 2006, just months after the South Korean stem-cell scientist Hwang Woo Suk—who had become an international sensation after claiming to have cloned a human embryo, a first—had been exposed as a fraud. As another Asian stem-cell scientist announcing a surprise advance, Yamanaka knew his peers would put him under the microscope. “I was very nervous,” he recalls. A few weeks later at a scientific conference in Whistler, Canada, where he delivered his findings to an audience of international colleagues, “I could tell from their tone that many people did not believe me,” he says.

Vindication came on June 7, when the rest of the scientific world caught up with Yamanaka. Two separate teams of stem-cell researchers affiliated with the Massachusetts Institute of Technology, Harvard University and the University of California, Los Angeles published papers essentially confirming and refining Yamanaka’s findings, while his own team released a new study that improved on his original research. The collective work—which one cloning pioneer compared to turning lead into gold—raises the possibility that scientists might one day be able to reprogram a patient’s own adult cells to transform into human embryonic stem cells and then into heart, nerve or any other kind of tissue. That could give doctors the ability to repair or replace cells destroyed by disease or injury, without fear of immune-system rejection. Experts were quick to warn that significant hurdles remained before the technique might ever be used in people, but the sheer simplicity of Yamanaka’s discovery—he found just four genes were required to reprogram the mouse skin cells—was cause for elation. “This is great science,” says Alan Trounson, professor for stem-cell sciences at Monash University in Melbourne, Australia. “It takes us a big step closer to reprogramming adult cells.”

For years, many stem-cell researchers sought to accomplish that through nuclear transfer—transplanting an adult cell’s nucleus into an egg that had been emptied of its own genetic material. This process is expensive and difficult, and so far no one has been able to pull it off in humans. Yamanaka never tried. Starting with a tiny team in 1999 at the Nara Institute of Science and Technology—he moved to Kyoto in 2004—Yamanaka focused on finding the genes that could persuade an adult cell to regress on its own to an embryonic state, without the messy mechanics of nuclear transfer. “I thought that since so many people in this field were concentrating on [nuclear transfer], I should concentrate on the opposite,” Yamanaka says.

That maverick streak comes naturally to the driven Yamanaka. Many Japanese scientists, even the best ones, can seem detached and dreamy. Though he has only worked in academia, Yamanaka by contrast has the no-nonsense air of the hybrid researcher/entrepreneur, a type that plays a big role in American stem-cell science. “He used to be an orthopedic surgeon, so he has a good sense in connecting his research to a practical application,” says Yoshiki Sasai, a stem-cell scientist at the RIKEN Center for Developmental Biology in Kobe. “He’s like a venture [capitalist]. He couldn’t do big-scale research, so he narrowed his focus and gave everything to it.”

Fluent in English—a rarity in Japanese science—Yamanaka worked in the U.S. in the early 1990s. He’ll be spending more time in America later this year—he has accepted a post as a visiting scientist at the J. David Gladstone Institute in San Francisco. But his overseas travels will be limited. Yamanaka says he’ll remain based in Japan because he doesn’t want to pull his children out of high school. He has also been a father figure to younger colleagues—one that isn’t afraid to share the credit. “He’s a guiding teacher,” says Kazutoshi Takahashi, an assistant professor at Kyoto and Yamanaka’s first student. “Everyone in the lab gets the opportunity to have their names in big papers.”

No one expected those opportunities to come so soon. Trying to discover the right combination of genes that would reprogram adult cells was a scientific fishing expedition in a deep ocean. In early 2004 Yamanaka had worked up a list of 24 possible genes he thought were instrumental in cell programming, and was ready to begin testing them. There was no guarantee any of the 24 suspects were the right ones, and when Yamanaka offered the experiment to one of his students, the researcher turned him down. “We knew the chance that the correct answer was in those 24 factors was very small,” says Yamanaka during an interview in his cramped office on the second floor of Kyoto University Hospital. “It was a risky project, and you had to be very brave.”

Fortunately, Yamanaka had one student who was brave—or at least, knew when to say yes to his boss. Takahashi spent endless hours screening the candidate genes. “Perhaps this is not something Kyoto University should know, but I worked 365 days a year,” Takahashi laughs. Using retroviruses to deliver the genes into mouse skin cells, Yamanaka and Takahashi eventually narrowed the number down to four active genes that triggered the transformation.

That the process proved so straightforward shocked Yamanaka. Scientists had assumed that reprogramming would likely require a complex arrangement of far more genes. “We were very surprised,” he says—and with the Hwang debacle on their minds, “we were very worried.” Yamanaka had another researcher repeat Takahashi’s work, and when they published in the journal Cell in August 2006, he took the unusual step of including every last bit of lab data in the supplementary section of his paper. Still, Yamanaka’s results weren’t fully accepted until his work was replicated by others—the gold standard of scientific proof.

Now that Yamanaka has helped show science the path, the race is on to discover the researcher’s holy grail: a way to reprogram adult cells in human beings. The Japanese pioneer finds himself at a disadvantage. Scientists in the U.S. and Europe can draw on deeper reserves of money and talent. U.S. states such as California and Massachusetts are spending billions of dollars on stem-cell research, hoping to lay the groundwork for development of new medical industries. In contrast, Yamanaka’s lab at Kyoto is relatively basic, and the Japanese government has only recently begun channeling real funding into the field. “There is a lack of understanding about how important this research is among government people, and Japanese in general,” he says.

For Yamanaka, the temptation exists to flee to greener pastures. But he says that he intends to stay in Kyoto for now, where his discoveries can directly benefit Japan. Besides, his small lab jumped to an early lead, and Yamanaka hints that they may have more breakthroughs in store. “I think that this year or next year we could see [reprogramming] in human cells,” he says. “I really believe it could come from our lab.” If it does, Yamanaka won’t have to worry so much about the skepticism of his fellow scientists.