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Yamanaka, Gurdon Share 2012 Nobel for Cell Reprogramming

By Anette Breindl
Science Editor

Freshly minted Nobelist Shinya Yamanaka has a pretty humble explanation for his success: He wasn't any good as a surgeon.

"I started my career as a surgeon," he said. "But it turns out I am not talented as a surgeon. So I decided to change my career from the clinic to the laboratory. But I still feel I am a doctor. . . . I really want to help patients. So my goal all my life has been to bring . . . stem cell technologies into the clinic."

On Monday, his contributions toward that goal were honored by the Nobel Assembly, which awarded Yamanaka and John Gurdon the 2012 Prize in Physiology or Medicine "for the discovery that mature cells can be reprogrammed to become pluripotent." The two had previously shared the 2009 Lasker Award. (See BioWorld Today, Sept. 15, 2009.)

IPS cells have been hailed as embryonic stem cells minus the ethical headache, though followup work identified some differences between the two cell types. (See BioWorld Today, Feb. 7, 2011, and May 16, 2011.)

Multiple groups have worked to optimize the transcription factors necessary for their creation; to create them from the elderly patients with genetic diseases who are most likely to ultimately benefit from them clinically; and to create disease-specific cell lines for research purposes. (See BioWorld Today, Aug. 11, 2008, and Aug. 28, 2008.)

Yamanaka's team, as well as another team around the University of Wisconsin's James Thomson, first published papers describing how to create human induced pluripotent stem (iPS) cells about five years ago, a year after they were able to create mouse iPS cells. (See BioWorld Today, Nov. 21, 2007.)

But the work has its roots in much older research published in 1962, the year that Yamanaka was born.

That research, by co-Nobelist John Gurdon, demonstrated in frogs that it was possible to reprogram, or clone, the nucleus of a mature intestinal cell by transplanting it into an egg cell. Current thinking at the time was that as cells develop from a stem cell into mature cells, their DNA changes in a way that makes such development a one-way street. Gurdon's experiments showed that cell fates are not irreversible, and his method, somatic cell nuclear transfer, was ultimately used to clone mammals, first Dolly the sheep and by now, multiple species.

Yamanaka's contribution to reprogramming was the discovery that cells can be returned to a pluripotent state without a transplant. His team treated mature fibroblasts with a cocktail of four transcription factors – Oct3/4, Sox2, KLF4 and c-Myc – to return them to en embryonic-like state in which they could once again head down multiple developmental paths.

Yamanaka's team's reports were, in fact, initially greeted with some skepticism in the scientific community, for two reasons. Given that there are thousands of genes whose expressions differ in embryonic vs. adult cells, turning one into the other by manipulating only four factors seemed quite literally too good to be true.

Plus, Yamanaka's team published his results not too long after another set of findings had indeed turned out too good to be true: those of Korean stem cell scientist Woo-Suk Hwang, whose claims of creating patient-specific stem cells with very high efficiency were fraudulent. (See BioWorld Today, May 20, 2005, and Jan. 11 , 2006.)

But unlike Hwang's work, that of Yamanaka's team soon met the key test of any scientific advance: reproducibility. A year after his team published their methods, many labs across the world had been able to use them to make iPS cells themselves.

In a press conference Monday, Gladstone Institutes president Sandy Williams said that the Nobel Prize "is not the end, but it's really the beginning. The work that Shinya has done is transformative" in several ways. Yamanaka holds a joint appointment with the Gladstone Institutes and Kyoto University, while Gurdon is at an Institute he founded himself, the Gurdon Institute.

Regenerative medicine – using stem cells as a fountain of youth to replace broken-down body parts or cell types – is the aspect of stem cells that has most captured the public's imagination, but also the one that is furthest off. Few people would argue that the time is ripe for clinical use of iPS cells, though one of the speakers at the press conference said that "it's not too early" to begin the dialogue about how such cells would be tested and regulated.

But the cells can also be used in preclinical research, essentially creating a new type of study that uses disease-specific human cells in culture to look at the effects of experimental therapeutics. They are being used for such purposes by companies including Cellectis SA, Fate Therapeutics Inc. and iPierian Inc.

"A better batting average" for predicting drugs, as well as "more personalized medicine and reversing what is today irreversible, Williams said, "Shinya's work opens the door to all of that."