Two scientists who were awarded the Nobel Prize in Physiology or Medicine on Monday helped lay the foundation for regenerative medicine, the hotly pursued though still distant idea of rebuilding the body with tissues generated from its own cells. They are John B. Gurdon of the University of Cambridge in England and Shinya Yamanaka of Kyoto University in Japan.
Their discoveries concern the manipulation of living cells, and lie at the heart of the techniques for cloning animals and generating stem cells, the primitive cells from which the mature tissues of the body develop. Gurdon was the first to clone an animal, a frog, and Yamanaka discovered the proteins with which an adult cell can be converted to an egg-like state. The prize was announced in Stockholm.
Both men had to overcome false starts in life. Gurdon was told as a boy that he was wholly unsuited for biology, and Yamanaka trained as a surgeon only to find he was not so good at it.
The techniques they developed reach to the beginnings of life, and have generated objections from people who fear, on ethical or religious grounds, that scientists are pressing too far into nature’s mysteries and the ability to create life artificially.
Gurdon’s discovery came in 1962, when he produced living tadpoles from the adult cells of a frog. His work was at first greeted with skepticism, because it contradicted the textbook dogma that adult cells are irrevocably assigned to their specific functions and cannot assume new ones. (His prize was the first Nobel to be awarded to a cloner.)
Gurdon’s technique was to extract the cell nucleus, containing the frog’s DNA, from a mature intestinal cell and inject the nucleus into a frog egg whose own nucleus had been removed. The egg was evidently able to reprogram the introduced nucleus and direct its genes to switch from the duties of an intestinal cell to those appropriate to a developing egg.
But how did the egg cell body accomplish this reprogramming feat? The answer had to wait 44 years, while molecular biologists gained a more intimate understanding of genes and the agents that control them.
Working with mice, Yamanaka discovered in 2006 that the reprogramming can be accomplished by just four specific gene control agents in the egg. The agents, known to biologists as transcription factors, are proteins made by master genes to regulate other genes. By injecting the four agents into an adult cell, Yamanaka showed that he could walk the cell back to its primitive, or stem cell, form.
Stem cells generated by this method, known as induced pluripotent cells, or iPS cells, could then be made to mature into any type of adult cell in the body, a finding with obvious potential for medical benefits.
Biologists hope the technique will enable replacement tissues to be generated from a patient’s own cells for use against a wide variety of degenerative diseases. For the moment, that remains a distant prospect. But the cells have already proved useful in studying the genesis of disease. Cells generated from a patient are driven to form the tissue that is diseased, enabling biologists in some cases to track the steps by which the disease is developed.
Gurdon’s early academic career did not hint at what the future might hold.
“I believe Gurdon has ideas about becoming a scientist; on his present showing this is quite ridiculous,” his high school biology teacher wrote. “If he can’t learn simple biological facts he would have no chance of doing the work of a specialist, and it would be a sheer waste of time, both on his part and of those who would have to teach him.”
At Oxford University, a more positive mentor encouraged him to try transplanting the nucleus of adult cells into frog eggs. The idea was to see if the genome — the hereditary information — stayed unchanged during development or underwent irreversible changes. In producing living tadpoles from the nucleus of adult frog cells, Gurdon showed that the genome of both egg and adult cells remained essentially unchanged.
But the possibility that animals, including humans, could be cloned did not seriously impinge on the public imagination until his work was reproduced in mammals with the generation of Dolly, the cloned sheep, in 1997. The following year saw generation of the first human embryonic stem cells, which are derived from the early human embryo. Such cells are called pluripotent because they can develop into any of the mature tissues of the body.
The two developments led to the concept of therapeutic cloning — take a patient’s skin cell, say, insert it into an unfertilized human egg so as to reprogram it back to pluripotent state, and then develop embryonic stem cells for conversion into the tissue or organ that the patient needed to have replaced. Since the new tissue would carry the patient’s own genome, there should be no problem of immune rejection.
But human eggs are not so easily obtained. Of course, the reprogramming might be accomplished without human eggs if only the relevant factor in the egg could be isolated. But that seemed a distant prospect until Yamanaka’s discovery that 24 transcription factors, later whittled down to four, could reprogram a nucleus when introduced into cells on the back of a virus.
Dr. George Daley, a stem cell researcher at Children’s Hospital Boston, praised the creativity of Yamanaka’s experiment. At the time, he and others were trying to reprogram cells by adding one gene at a time. The idea of inserting 24 genes all at once “is the kind of experiment that would have been laughed out of the room” in a grant committee meeting, he said.
Rudolf Jaenisch, a biologist at the Whitehead Institute in Cambridge, was another who considered that Yamanaka’s surprising experiment was correct, despite widespread doubts. “I believed it immediately because I knew him to be very careful and there was a logic to it,” he said.
Gurdon and Yamanaka will receive a handsome cash prize, but one reduced by 20 percent from previous years. The Nobel Foundation announced in June that its investments had not kept pace with expenses over the past decade, and that the prize money would be reduced from 10 million to 8 million Swedish krona. Still, at today’s exchange rate even this is worth $1.2 million.
In a brief interview today, Yamanaka, who was born in 1962 in Higashiosaka, Japan, said that he had trained as surgeon but “gave it up because I learned I was not talented.”
Having seen how little the best surgeons could do to help some patients, he decided to go into basic research and did postdoctoral training at the Gladstone Institutes in California.
In an interview, Gurdon said he had recovered from the setback of his biology teacher’s report with the help of his family and an uncle who studied snails. Asked how he felt about having to wait 50 years for his prize, he said that “I am lucky to be still alive.”