Cell rewind wins medicine Nobel

Posted: October 9, 2012 at 6:11 am

John Gurdon (left) and Shinya Yamanaka showed how to reprogram cells into their embryonic states.

J. Player/Rex Features; Aflo/Rex Features

The discovery that cells can be reprogrammed to an embryonic-like state has won this years Nobel Prize in Physiology or Medicine for two leading lights of stem-cell research: John Gurdon and Shinya Yamanaka.

Reprogrammed cells regain pluripotency, the potential to differentiate into many mature cell types. Many researchers hope that cells created in this way will eventually be used in regenerative medicine, providing replacement tissue for damaged or diseased organs. The field has become one of the hottest in biology, but the prizewinners discoveries were not without controversy when they were made.

Gurdon, who is based at the Gurdon Institute in Cambridge, UK, was the first person to demonstrate that cells could be reprogrammed, in work published 50years ago1. At the time, scientists believed that cellular specialization was a one-way process that could not be reversed. Gurdon overturned that dogma by removing the nucleus from a frog egg cell and replacing it with the nucleus from a tadpoles intestinal cell. Remarkably, the process was able to turn back the cellular clock of the substitute nucleus. Although it had already committed to specialization, inside the egg cell it acted like an eggs nucleus and directed the development of a normal tadpole.

Gurdon was a graduate student at the University of Oxford, UK, when he did the work. He received his doctorate in 1960 and went on to do a postdoc at the California Institute of Technology in Pasadena, leaving his frogs in Europe. He did not publish the research until two years after he got his PhD, once he was sure that the animals had matured healthily. I was a graduate student flying in the face of [established] knowledge, he says. There was a lot of scepticism.

Mammalian cells did not prove as amenable to this process, known as cloning by nuclear transfer, as frog cells. It was nearly 35years before the first cloned mammal Dolly the sheep was born, in 1996. Dolly was the only live birth from 277 attempts, and mammalian cloning remained a hit-and-miss affair.

Scientists were desperate to improve the efficiency of the system and to understand the exact molecular process involved. That is where Shinya Yamanaka of Kyoto University, Japan, made his mark. Yamanaka who was born the year that Gurdon published his formative paper used cultured mouse cells to identify the genes that kept embryonic cells immature, and then tested whether any of these genes could reprogram mature cells to make them pluripotent.

In the mid-2000s, the stem-cell community knew that Yamanaka was close. I remember when he presented the data at a 2006 Keystone symposium, says Cdric Blanpain, a stem-cell biologist at the Free University of Brussels. At that time he didnt name them and everyone was betting what these magic factors could be.

A few months later, attendees at the 2006 meeting of the International Society for Stem Cell Research in Toronto, Canada, packed out Yamanakas lecture. The audience waited in silence before he announced his surprisingly simple recipe: activating just four genes was enough to turn adult cells called fibroblasts back into pluripotent stem cells2. Such induced pluripotent stem (iPS) cells could then be coaxed into different types of mature cell types, including nerve and heart cells.

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Cell rewind wins medicine Nobel

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