Shinya Yamanaka

Shinya Yamanaka (Osaka, Japan; 1962) studied medicine at Kobe University, before completing his residency in orthopedic surgery at Osaka National Hospital in 1993. That same year he took up a postdoctoral fellowship at the Gladstone Institute of Cardiovascular Disease in San Francisco, where he became a staff research investigator in 1995. The following year he returned to Japan where, in 2008, he became Director of the Center for iPS Cell Research and Application at Kyoto University. He has also been associated since 2004 with Kyoto’s Institute for Frontier Medical Sciences, and is a Senior Investigator in the Gladstone Institute of Cardiovascular Disease at the University of California, San Francisco (United States).

He has held posts as assistant professor at Osaka City University Medical School in Japan (1996-1999), and as associate then full professor at the Nara Institute of Science and Technology (1999-2003). Since receiving the BBVA Foundation Frontiers of Knowledge Award (2010), he has gone on to win the Nobel Prize in Medicine jointly with Sir John Gurdon (2012). His other major honors include the Albert Lasker Basic Medical Research Award (2009), the Wolf Prize (2011) and the Breakthrough Prize in Life Sciences (2013).

The dizzying pace of new discoveries in biology in these past few years is proof that the advance of knowledge is not a gradual process. Scientists are becoming skilled at reading the genetic instructions that govern the body’s construction, and, in some cases, are beginning to manipulate them at will. But even in a field accustomed to surprises, there are discoveries that stand out. Shinya Yamanaka, 2010 BBVA Foundation Frontiers of Knowledge laureate in Biomedicine, is the author of one. With a mix of curiosity, intuition, hard work and the willingness to take risks, this orthopedic surgeon born in Osaka (Japan) in 1962 has delivered a genuine paradigm shift in biology.

In 2006, Yamanaka succeeded in generating “induced pluripotent stem cells” or iPS cells with the ability to differentiate into virtually any kind of specialist cell. Until he proved differently, scientists believed that this could only be achieved with embryonic stem cells. iPS cells, however, are obtained from already specialized adult cells that have been reprogrammed to pluripotency. With Yamanaka’s technique, a skin cell, for instance, can be made to generate any other tissue with no need – and here lies the breakthrough – to first obtain an embryo. The fate of each cell is rewritten; the arrow of cellular time is turned the other way. A phenomenon until recently considered, if not impossible, then improbable in the extreme. The paper presenting the finding in human cells, achieved moreover in record time, is one of the most cited in the history of biological science (“Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors,” Takahashi K., et al., Cell 131[5]: 861-72, 2007).

The personal story leading up to that moment begins with a young man crazy about judo and rugby who was drawn to the study of medicine by the example of his team doctor. After graduating from Kobe University (Japan), Yamanaka completed his residency in orthopedic surgery at Osaka National Hospital, but finally chose research over clinical medicine after discovering “the freedom of research,” as he puts it, in autopsy practice and in a group studying alcoholism. He switched to pharmacology and received his PhD from Osaka City University in 1993.

A project on transgenic mice was his introduction to the “fascinating” world of genetic research, then in its infancy. Manipulating genes, Yamanaka explains, seemed a far more precise form of treatment than anything in conventional medicine. Determined to seek training in this field in the United States, where he had not a single contact, Yamanaka dashed off some thirty letters in his doctorate year to the specialists whose work he was following in scientific journals.

The University of California in San Francisco accepted him as a postdoctoral fellow at the Gladstone Institute of Cardiovascular Disease, where he would come into contact with embryonic stem cells. What did it for him, though, was his discovery of a gene implicated in their differentiation. “I became fascinated by embryonic stem cell research thanks to this experience,” he relates, “and decided to make it my future laboratory’s main research theme.”

But his resolve would be sorely tested on his return to Japan, in 1996. As an assistant professor in the Pharmacology Department at Osaka City University he found himself with barely any funding and only a minimum of space. The lack of support was so disheartening that he considered resigning his position. Finally, however, after a stint at the Nara Institute of Science and Technology, Kyoto University assigned him funds and a laboratory. This was 2004.

And then occurred a trivial but decisive event. Yamanaka relates that when visiting a friend in a fertility clinic, he had the chance to observe an embryo through a microscope. And he thought of his teenage daughters. It was then he decided to find a way to avoid use of embryos in research. “I understand there are many people who are against the use of human embryos, but I also understand how important embryonic stem cells are for medicine. That is why I started my project to convert somatic cells into stem cells without using embryos.”

He got his initial inspiration studying the experiments that produced the first cloned frogs, back in the 1970s, and Dolly the sheep in 1996. “From their work I learned that we should be able to convert somatic cells back into their embryonic state. That is what convinced me to start my project.” This was an ambitious and uncertain enterprise given the state of knowledge at that time. So it was doubly surprising just how quickly the results came: “At first I thought it would be very difficult, it would take twenty or thirty years, but it took us less than a decade. We were pleased but at the same time surprised by our own progress,” Yamanaka admits.

The first reprogrammed adult cells were obtained from mice. The scientific community was both enthused and astonished by the news, and rushed to explore the new and unexpected vistas opened up by the Japanese team. The following year, in 2007, Yamanaka and another group at the University of Wisconsin (United States) succeeded independently in reprogramming specialized human cells.

Shinya Yamanaka is currently Director of the Center for iPS Cell Research and Application at Kyoto University (Japan), and a professor in the Institute for Frontier Medical Sciences at the same center. He is also a senior investigator in the Gladstone Institute of Cardiovascular Disease at the University of California-San Francisco. His daily agenda takes in twelve to sixteen hours’ work plus several lengths of the swimming pool or perhaps some jogging. He declares himself enamoured of San Francisco’s Golden Gate Bridge.

His work has shaken the foundations of developmental biology and will likely have a far-reaching impact in medicine. The jury of the 2010 BBVA Foundation Frontiers of Knowledge Award in Biomedicine emphasized the new avenues that iPS cells open up for both basic and clinical research, with personalized therapies and more precisely targeted drugs. The possibility of working with iPS cells derived from patients themselves would avoid “treating patients as guinea pigs,” in the words of its citation. It will allow new cell-based screening methods to be used to search for small molecule drugs, and, ultimately, may also facilitate patient-specific cell-based treatments, in particular for neurodegenerative diseases.

Yamanaka knows that much still needs doing. “Finding the best way to generate safe and healthy iPS cells” is the next challenge along the way. “Because we have to be sure that they don’t produce cancer.” He is confident, however, that iPS cells will eventually become “a therapeutic reality.”