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Tuesday, December 11 2007 - 01:57am Alert posted by: dalmore
#2142 - Scientist at Work | Shinya Yamanaka

dalmore



December 11, 2007
Scientist at Work | Shinya Yamanaka
Risk Taking Is in His Genes
By MARTIN FACKLER
KYOTO, Japan — Inspiration can appear in unexpected places. Dr. Shinya Yamanaka found it while looking through a microscope at a friend’s fertility clinic.

Dr. Yamanaka was an assistant professor of pharmacology doing research involving embryonic stem cells when he made the social call to the clinic about eight years ago. At the friend’s invitation, he looked down the microscope at one of the human embryos stored at the clinic. The glimpse changed his scientific career.

“When I saw the embryo, I suddenly realized there was such a small difference between it and my daughters,” said Dr. Yamanaka, 45, a father of two and now a professor at the Institute for Integrated Cell-Material Sciences at Kyoto University. “I thought, we can’t keep destroying embryos for our research. There must be another way.”

After years of searching, and at times almost giving up in despair, Dr. Yamanaka may have found that alternative. Last month, his was one of two groups of researchers that independently announced they had successfully turned adult skin cells into the equivalent of human embryonic stem cells without using an actual embryo. The other group was led by James A. Thomson at the University of Wisconsin, one of the first scientists to isolate human embryonic stem cells.

Dr. Yamanaka had previously demonstrated this technique in mice, after which other scientists also began pursuing it in human cells. His mouse finding was hailed as a breakthrough because it offered a possible way around the thorny moral issues that have slowed the study of stem cells. Stem cells, sort of all-purpose cells that briefly appear in new embryos, hold the promise of aiding research into now incurable diseases and tantalizing new medical treatments, like growing replacement tissues for patients. But their use has provoked strong objections because, until now, the cells could be obtained only by destroying human embryos.

Dr. Yamanaka is widely credited with being the first to hit on the idea of reprogramming adult cells to behave as stem cells because of his mouse work. The crux of his idea was to add genes called master regulators to the skin cells’ chromosomes. These genes can change the cell’s behavior by turning other genes on and off.

The finding has been welcomed in the United States, where the federal government has refused to finance much stem cell research. But it is also being hailed in his native Japan for an additional reason: as a sign that the country may finally be coming of age as a center of scientific research. In recent decades, Japan has been trying to reverse its decades-old image as strong in making gadgets but weak in basic science.

“This is the first time that medical-related research of world importance has been done entirely in Japan,” said Dr. Hitoshi Niwa of the Riken Center for Developmental Biology in Kobe. “No one thought before of making stem cells this way. It is a totally new direction.”

Blazing his own path seems to come naturally to Dr. Yamanaka, who has a reputation at his university for being a bit of a creative eccentric. Tall and trim, Dr. Yamanaka has a boyish face and a penchant for casual attire that give him the air of a graduate student. He often sprinkles jokes into his talks, an American flourish that is less common in Japanese academia. Students also mention his fondness for sports, saying they frequently spot him doing laps at a campus pool or jogging along the river.

A self-admitted workaholic, Dr. Yamanaka routinely puts in 12- to 16-hour days. He is known on campus for refusing to join colleagues for lunch, choosing to eat by himself so he can keep working. He is also known for being demanding but personable to his research staff of 25, mostly university students and post-doctoral researchers.

Success has brought Dr. Yamanaka a taste of celebrity, which he seems to have not entirely welcomed. Since he announced his finding, a steady stream of domestic news media have marched through his office and two crammed laboratories at Kyoto University. In an interview in his office, he showed an edge of impatience in saying he was tired of all the attention because it pulled him away from his research.

When asked the source of his success, Dr. Yamanaka said it was his willingness to take risks. His career has in fact been unorthodox by Japanese standards. While many scientists here spend entire careers in the rigid academic world, Dr. Yamanaka began his professional life in medical school, where he trained to become an orthopedic surgeon.

He said his interest in orthopedics came from experiences growing up in the western city of Osaka, where he made frequent visits to the doctor for bones fractured by rugby and judo. But he chose research over medical practice because of the freedom it affords, both to take risks and follow whims — something he could not do treating patients.

“I like the freedom of research,” he said. “Plus, if I fail in science, I know I can always survive because I have an M.D. This has been my insurance policy.”

Dr. Niwa and others said one of Dr. Yamanaka’s biggest achievements was not only the idea to use reprogramming, but also the speed with which he used it to create stem cells, first in mice and then humans. One challenge was figuring out which genes would reprogram adult cells. With hundreds of candidate genes, the number of possible combinations was almost infinite.

Dr. Yamanaka said he narrowed the field with a very unscientific method: he made an educated guess.

He said he used his instincts, as well as published research of other scientists, to pick the 24 most promising genes. In the lab, he found that the 24 did indeed contain four genes that could reprogram adult cells into stem cells.

“Choosing those initial 24 genes was almost like buying a ticket at the lottery,” he recalled. “I was just lucky. I bought the right lottery ticket.”

Another challenge was adapting the reprogramming method, which he first developed with mouse cells, to human cells.

He failed for months, and at one point even went back to the pool of 24 genes to see if human cells required a different combination of master regulator genes than those of mice. He also began experimenting with seemingly minor changes, like switching the gel-like culture solution in which the cells are grown. It was the small changes that worked, finally allowing him to reprogram human skin cells with the same four genes.

“If you had asked me back in June,” he said, “I would have told you the same four genes wouldn’t work in humans.”

Despite the breakthrough, the procedure has shortcomings, including a tendency of the newly created stem cells to turn cancerous, a risk with stem cells in general but heightened because Dr. Yamanaka used a known tumor-causing gene. Cancer risk is one reason stem cell therapy still seems a distant possibility; stem cell research shows more immediate promise as a way to pursue basic science.

Since announcing the finding last month, Dr. Yamanaka has already taken a step toward reducing cancer risk. In the Nov. 30 issue of Nature Biotechnology, he announced that even without using the cancer gene, he was still able to reprogram cells, and with a much lower incidence of cancer.

He says the biggest remaining problem is the procedure’s use of retroviruses to insert the genes into the cell’s chromosomes. Retroviruses are a type of virus that can also cause mutations in the adult cells, making them cancerous. Dr. Yamanaka said his next research goal was to reprogram without retroviruses.

He said he also wanted to set up a commercial collaboration between his university and a private company to use stem cells right away in laboratory research for creating new and more powerful medicines. The current cancer risk is not a problem so long as the cells are used in the petri dish, and not transplanted into humans, he said.

“I want to find ways to put the stem cells to use quickly,” he said.

Dr. Yamanaka said it was in medical school that he discovered a love of laboratory work, as a student helping with autopsies and research into alcoholism. After graduation, he pursued a doctorate in pharmacology at Osaka City University instead of going into practice.

His interest in genetic work came when he stumbled upon a paper about genetically engineered mice, known as knockout mice. He recalls feeling fascinated with the notion of replacing genes, which seemed a far more precise way of treatment than the conventional medicines he was then studying.

The best place to learn about genetics and knockout mice was the United States, where Dr. Yamanaka had no friends or contacts. He said he sent some 30 letters to American universities and specialists whose names he culled from science magazines and journals. One of the few to respond was the University of California, San Francisco, which offered him a post-doctoral position in 1993.

In 1996, he returned to Osaka City University, bringing with him a batch of knockout mice. But as an assistant professor in the pharmacology department, he received little financing and just a single seat in a shared laboratory.

“I grew so depressed from the lack of support that I considered quitting,” he said. “No one understood me.”

In 1999, his career got a break when he was hired by other universities, including Kyoto University in 2004, that were willing to give him a laboratory and more money. At about the same time, he said, he visited his friend’s fertility clinic. That visit inspired him to find a way around the moral issues that had bogged down stem cell research, not just in the United States but also Japan, where the Education Ministry put tough restrictions on embryo use.

In fact, restrictions are so tight that he says he cannot use human embryos at his laboratories here. Instead, research using human embryos is done at U.C. San Francisco, where he maintains a small two-person laboratory. He said he had never handled actual embryonic cells himself, and the American lab uses them only to verify that the reprogrammed adult cells are behaving as true stem cells.

“There is no way now to get around some use of embryos,” he said. “But my goal is to avoid using them.”

                               
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