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Vol. LXII, No. 4
February 19, 2010

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‘Rules in Science’
Stem Cell Innovator Yamanaka Shares Secrets of Success

On the front page...

Not too long ago, a mild-mannered scientist from Japan was tending his own lab animal cages. He had no lab techs and no funds to hire any. Next thing he knew, he was becoming famous worldwide for a stem cell breakthrough so stunning the research community is still gasping. At least that’s the way Dr. Shinya Yamanaka, director of the Center for iPS Cell Research and Application, Kyoto University, told his story Jan. 14 to an SRO crowd in Masur Auditorium. Of course, he shared the groundbreaking technique for making all-purpose stem cells without using embryos. But more, he gave the audience a rare and humorous glimpse into the sometimes hard-knock life of a fledgling bench scientist. And he offered every hardworking but frequently frustrated postdoc a reason to stick with research as a career.


  Dr. Shinya Yamanaka spoke at NIH on Jan. 14.  
  Dr. Shinya Yamanaka spoke at NIH on Jan. 14.  

“It’s not very many times you remember where  you were when you read a particular scientific paper,” said NIH director Dr. Francis Collins, introducing Yamanaka, the guest speaker at a special Thursday edition of the Wednesday Afternoon Lecture Series. “I remember where I was [in August 2006] when I read [Kazutoshi] Takahashi and Yamanaka…I was at the beach. I was supposed to be getting away from the scientific hubbub, but I’d heard that there was this paper that really ought to be looked at. There had been stories flying around in the rumor mill that a Japanese group had come up with a truly dramatic way to reprogram cells...As I read that paper, I had the hairs stand up on the back of my neck because I could see that this was transformative…The era of the induced pluripotent stem cell was born.”

An Inkling Emerges

When Yamanaka took the podium next, he traveled even farther down Memory Lane, to his own postdoc days.

It was San Francisco circa 1995 and he was a former orthopedic surgeon pursuing a career in research in a Gladstone Institute lab. His PI, Dr. Tom Innerarity, had an idea involving mRNA editing that could lead to a way to lower bad cholesterol levels in mice, and eventually in people.

Yamanaka’s job was to generate a transgenic mouse line that overexpressed the APOBEC1 enzyme, which, their lab had found, seemed to lower plasma LDL cholesterol levels. In the course of the study, however, they also discovered the mice were developing huge liver tumors. APOBEC1, it turned out, is a cancer-causing gene. No way could an oncogene be used to fight heart disease.

Failure Feeds Fascination

“From this experiment I learned three important rules in science,” Yamanaka quipped, smiling. “First, science is surprising. It’s difficult to predict…That’s probably why I’m still doing science. The second rule is, we should never try new procedures, new medicines, new genes directly on patients—it’s too dangerous. We should do animal studies.”

Yamanaka’s third rule, “which may be the most important, is that you should not believe in your boss’s hypothesis,” he joked, drawing laughter from the audience.

Although his PI was disappointed with the result of the hypothesis, Yamanaka was only further intrigued. He spent the next 3 years studying how mRNA editing enzymes cause “these ugly tumors.” Eventually, Yamanaka came across another oncogene, which he named NAT1. He developed his own theory about how NAT1 influences APOBEC1 to generate tumor growth. His research was speeding along well.

Then family life intruded. His wife and young daughters relocated back to Japan, he noted with humor, leaving him hard at work in San Francisco. He soon learned another lesson: Don’t let the distance between yourself and your loved ones become too great. He missed his family.

Six months later Yamanaka returned to Japan, taking with him three elements that would play a huge role in his success story: several research mice, a hard work ethic and, perhaps most important, a now well-developed talent for genetic tinkering with NAT1.

Perseverance Pays Off

Guest lecturer Yamanaka (c) accepts a plaque of appreciation from NIH director Dr. Francis Collins (l) and NIH deputy director for intramural research Dr. Michael Gottesman.
Guest lecturer Yamanaka (c) accepts a plaque of appreciation from NIH director Dr. Francis Collins (l) and NIH deputy director for intramural research Dr. Michael Gottesman.

The researcher’s life in Japan was very different from what Yamanaka had grown to love in the States, however. Although he was discovering surprisingly similar biological properties in NAT1 and embryonic stem cells, Yamanaka was also suffering from a lack of scientific resources. It wasn’t long, he said jokingly, until he contracted a serious mental disorder called P.A.D.—“post-America depression.”

Gone were the glory days in the U.S. when lab techs helped him care for the hundreds of mice colonies. Non-existent were funds to hire. Yamanaka was virtually alone in the lab, cleaning cages. Friends advised him to give up on the rodents and pursue something more useful to human health.

Disheartened both in spirit and finances, Yamanaka was about to quit science altogether “when two things rescued me from P.A.D.”

Bold Goal as Bait

First was Dr. Jamie Thomson’s generation of human ES cells in 1998. Second was Yamanaka’s appointment to his own lab at Nara Institute of Science and Technology in 2000. The next challenge? Populate his lab with postdocs.

Competition for talented students was fierce, Yamanaka realized. As “the newest, youngest and proudest PI,” he needed an outstanding project to entice postdocs to join his lab. He announced an ambitious long-term goal: “Make ES-like stem cells not from human embryos but from somatic cells, like skin fibroblasts, by means of reprogramming.”

It could take 30 or 40 years to accomplish this, he guessed to himself. He didn’t share that thought with the prospective protégés. Three students, including Takahashi, signed on to Yamanaka’s quest. Long story short: By 2004 the group had made unimaginable headway in just a few years. They’d reached the bold goal in less than a quarter of the PI’s estimate.

During the rest of the lecture (and at a special meeting for NIH’s Intramural Research Program held the next day in Wilson Hall), Yamanaka discussed iPS strategies and research details. He readily acknowledged many substantial obstacles yet to overcome.

The energy in Masur Auditorium was palpable. Collins had noted that many in the research community believe Yamanaka “will no doubt enjoy a trip to Stockholm sometime in the not too distant future, given the way this observation has emerged as perhaps one of the most exciting developments in science in the last decade.”

Listening to the perhaps future Nobelist—humble, humorous, brimming with enthusiasm—describe various iPS concepts, one could easily learn about more than science.

Both events with Yamanaka are archived at NIHRecord Icon

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