In 1993, Japanese researcher Shinya Yamanaka was a young doctor who dreamed of becoming a research scientist -- but no one was returning his phone calls.
The physician and recent Ph.D. graduate of Japan's Osaka City University sought to give up a promising career as an orthopedic surgeon to pursue his dream. He applied to 50 American labs. But he couldn't find a single team that wanted him.
Then his paperwork came across the desk of Tom Innerarity, at the time a senior investigator focused on cardiovascular research at the Gladstone Institutes in San Francisco. Innerarity accepted Yamanaka, due to his interest in heart disease.
"I applied to many, many research institutes in the United States, but I received no responses," recalled Yamanaka. "The one exception was Tom, who chose me to come to Gladstone and be a part of his research laboratory."
"They asked me if I would work hard and I said 'Yes, I would," he said, laughing, at a Monday morning post-Nobel news conference.
Thrilled, he came to San Francisco to train in biomedical research, working as a postdoctoral research fellow.
At the time, stem cells were far from his mind. It took a major research setback to redirect him to the work that on Monday won him the Nobel Prize.
His initial focus was on finding new ways to lower so-called "bad cholesterol," a major risk factor for heart disease.
His team's experiments on mice did show a successful reduction
This was a major blow to Yamanaka. But instead of getting discouraged, he became curious. He wanted to understand what went wrong.
"He undertook a risky project and it failed. Instead of therapy, it caused cancer," said Gladstone senior investigator Robert W. Mahley.
"That launched him to try to understand how cells proliferate and how they develop," he said. "He went into stem cell biology."
Soon he found the cause of the troubling tumor growth -- a dysfunctional protein called NAT1.
What were the molecular underpinnings of this runaway growth? He needed genetically modified mice to find out. So he started working with another UCSF lab to learn the steps, using mouse embryonic stem cells, to build creatures without NAT1.
"By accident, I had discovered that NAT1 was key to helping stem cells transform into individual cell types," according to Yamanaka. He credits Gladstone's philosophy -- allowing scientists the freedom to follow wherever their curiosity leads -- with his discovery.
This new direction took him back to Japan where, armed with the expertise learned at Gladstone, he identified which genetic factors among millions of possibilities instruct embryonic stem cells to become other types of cells.
This was a formidable task. The human body has 25,000 genes, and hundreds of cell types. He drew stiff criticism.
"Everybody around him was concerned about what he was doing -- that he was not doing something important in clinical medicine, was wasting his time and his career would be ruined if he didn't start doing something more important," said Mahley. "He persevered."
He sorted out the 20 to 30 genetic factors that seemed the strongest candidates to orchestrate cell growth, capable of turning an adult cell into a cell with embryonic-like traits.
He narrowed the list down to four, announcing the news at a 2006 stem cell symposium.
It seemed too simple -- and was met with skepticism. The scientific community was still reeling from a scientific fraud incident in which a prominent South Korean scientist claimed to have cloned a human. Stem cell biology had a black eye, and everyone was feeling cautious.
But Yamanaka freely and publicly distributed his easily reproducible technique.
"I said: 'It's time for you to come back to Gladstone,' " said Mahley.
Within a year, Yamanaka used the same four factors to produce human cells with embryonic traits.
He now splits his time between Japan and San Francisco, spending one week a month at Gladstone, where he supervises a lab of eight scientists. He also is a professor of anatomy at UCSF.
His current research focuses on how the regulatory genes are turned on and off. He's asking: What are the steps in the network that so profoundly changes the fate of these genes?
"There are still many unknowns," he said.