Web edition: October 8, 2012
Print edition: November 3, 2012; Vol.182 #9 (p. 13)
Two scientists who showed that a cell's fate is reversible have won the 2012 Nobel Prize in physiology or medicine. The Nobel committee announced October 8 that John Gurdon and Shinya Yamanaka are being honored for showing that cells once thought to be locked into a specific identity could remember and revert to the supremely flexible state they have in an early embryo.
Gurdon’s work, published in 1962, forever changed the view that adult cells are stuck in their fate. In a series of experiments, he transplanted the nucleus — the cellular compartment that contains DNA — from an intestinal cell of an adult frog into a frog egg cell from which the nucleus had been removed. The cell developed into a normal tadpole, demonstrating that DNA contains all the information necessary to make an embryo.
More than four decades later, Yamanaka, of Kyoto University in Japan, changed the debate over stem cells when he created induced pluripotent stem cells, which are capable of becoming nearly any cell in the body. He was trying to understand the factors that make stem cells isolated from embryos so malleable; many genes seemed to be involved. Yamanaka used viruses to insert combinations of candidate genes into skin cells, and found that only four genes are required to turn a mouse skin cell into a stem cell. The technique has since been used to convert adult human cells into embryonic-like cells and even to convert skin cells directly into heart or brain cells.
"This work I was involved in had no obvious therapeutic benefit at all. It was purely a scientific question: Do all our cells have the same genes? There was no prospect of that being useful to people,” said Gurdon, who heads the Gurdon Institute at the University of Cambridge in England. But, “you wait a while — sometimes a long while — and it then turns out that all discoveries of a basic scientific nature will turn out to have some kind of useful consequence.”
Gurdon's technique of transferring nuclei from adult cells into developing egg cells was used in the 1990s to create Dolly the sheep and many other cloned animals. But performing such techniques with human cells is generally considered out of the question.
At the time of Yamanaka’s discovery ethical debates were raging about the use of embryonic stem cells. “It looked like Yamanaka’s cells were going to simplify matters,” says Jonathan Moreno, a bioethicist at the University of Pennsylvania in Philadelphia. But reprogrammed cells have turned out to be far more complicated ethically than anyone first thought. Researchers have used techniques similar to Yamanaka’s to create mouse eggs and sperm in laboratory dishes. Such use of the technology “messes around with human reproduction and changes the way human beings relate to one another in terms of reproduction,” Moreno says.
Reprogrammed human cells have not yet been used clinically, but researchers hope such methods will one day be used to grow replacement cells and tissues for patients. The cells also show promise for studying how diseases develop and for testing drugs, says Larry Goldstein, a stem cell scientist and neuroscientist at the University of California, San Diego.
Some people are impatient with the progress reprogrammed cells have made toward clinical application, but Goldstein points out that many scientists believed the technology would take decades longer to develop than it has. He calls Yamanaka’s work “simply remarkable” and predicts that it will produce clinically important findings within a decade. Already Goldstein and others are reprogramming skin cells from patients with Alzheimer’s disease and other diseases and growing brain cells to study the disease process in the lab. And reprogrammed cells from patients may help rule out potential new drugs before they go through long and expensive clinical tests. It will probably be years before scientists will know if reprogrammed cells are safe enough to transplant into patients.
"It’s all about finding a balance between moving as aggressively as possible … and being cautious that we don’t hurt anybody,” he said.
Reprogrammed stem cells will be used in clinical trials for the first time next year, Yamanaka said. He started his career as a surgeon before turning to research. “But I still feel I am a doctor,” he said in an interview with the Nobel committee. “I really want to bring this technology to clinics. I really want to help as many patients as possible.”
Yamanaka got a call from the Nobel committee while he was at home doing housework, he said. His secretary had alerted him that someone from Sweden was asking for his phone number, but he was still surprised. “I just thought, ‘Wow! It’s really a phone call from Stockholm. I just couldn’t believe it.”
Gurdon, who arrives early at the lab, first got a 7:30 a.m. phone call from a reporter at an Italian newspaper. About an hour later, the Nobel committee called, but Gurdon was skeptical that someone was playing a prank on him. “Could it be that someone’s pulling your leg?” but he was soon convinced that he had won. “I’m immensely grateful,” he said.
Yamanaka and Gurdon will share prize money of 8 million Swedish kronor, about $1.2 million. Gurdon used money from previous awards to establish a fund for fourth-year graduate students and may apply the Nobel money to the same cause, he says. The amount is less than the 10 million kronor that has been awarded to winners since 2001.
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