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Nobel winner dies before receiving prize

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Dr. Ralph M. Steinman was a creative and dogged researcher who spent years convincing a doubting scientific community that he had found cells that were key to the working of the immune system.

Diagnosed in 2007 with pancreatic cancer, which usually kills within months, he decided to try to fight back with a therapy based on his own discoveries decades earlier.

On Friday, he succumbed to the disease at age 68.

On Monday, the Nobel committee awarded him the Nobel Prize in Physiology or Medicine, unaware that he had died.

The Canadian-born Steinman will posthumously receive half of the $1.5-million award — an unprecedented move by the committee, which does not normally grant awards to people who have died.

The board of the Nobel Foundation had to pore over its own rules and regulations before posting a statement that Steinman's award would stand because it was made "in good faith."

The other half of the prize will be split between two other immune system researchers, Jules A. Hoffmann of the University of Strasbourg in France and Dr. Bruce A. Beutler of the Scripps Research Institute in La Jolla. The pair, working independently, discovered sensors on the surface of immune cells that help the body detect invaders such as bacteria and viruses.

Taken together, the three scientists' work revolutionized understanding of the immune system and how it leaps into action, the Nobel committee said.

The cells Steinman discovered, which he dubbed dendritic cells, are born in the bone marrow but appear all over the body — in skin, kidneys, liver, gut and elsewhere.

He found them in 1973 and was convinced that they were the "missing link" that direct white blood cells to attack infection and disease with precision.

"Nobody believed it for a long time," said Michel Nussenzweig, who was Steinman's first student and is now a professor at Rockefeller University in New York City, where Steinman also worked. The pair slogged for years to try to win over their colleagues.

Today Steinman's work is well accepted and has begun to influence novel drug development. Last year, the Food and Drug Administration approved Provenge, a vaccine that harnesses dendritic cells to fight advanced prostate cancer, and trials are underway testing the approach for other illnesses.

When the researcher learned that he had pancreatic cancer, he wanted to try dendritic therapy himself, Nussenzweig said.

Developing a treatment wasn't easy. First, Nussenzweig took cells removed from Steinman's tumor and cultured them in mice. Next, he said, "labs all over the world" scrambled to identify the antigens — small pieces of protein that the immune system recognizes as "foreign" — that Steinman's tumor contained.

The scientists introduced those antigens into dendritic cells taken from Steinman's body to create revved-up cells that would spur his immune system to attack the cancer. Then they put the cells back into his body.

Steinman received traditional chemotherapy as well, and it's impossible to know for sure whether the effort bought him extra time, Nussenzweig said.

"We don't know if it worked. Certainly it didn't work well enough to save his life."

Steinman's daughter Alexis, 34, said in a phone interview that her father "definitely did think it helped." She said that for most of the years after his diagnosis he was healthy, "traveling and running around."

Nussenzweig said the two discussed work just last week; Steinman was trying to develop ways to create cheaper, universal dendritic therapies, he said.

Hoffmann's and Beutler's work during the 1990s helped describe the so-called innate immune system, which acts as a first line of defense against invaders like bacteria and viruses.

Working with fruit flies and mice, respectively, they identified the chemical receptors in immune cells that bind to these invaders and trigger an immediate response that halts infection. Then the adaptive immune system, of which dendritic cells are a part, clears it away.

"They helped write the book on a whole branch of the immune system we hadn't known anything about before," said Stanford immunologist Mark Davis.

The pair's research also changed the way immunologists think about vaccines, Davis said. Scientists now believe that adjuvants — substances added to vaccines that are known to improve their effectiveness — work by triggering the innate immune system.

Beutler, who is relocating from Scripps to the University of Texas Southwestern Medical Center in Dallas, where he conducted his award-winning research, said in a phone interview that he felt "terrific" about winning the Nobel Prize.

He only regretted that his father, also a scientist at Scripps, did not live long enough to witness it. Ernest Beutler died in 2008.

Beutler received word via email in the middle of the night and, disbelieving, resorted to looking at Google News to confirm it was real.

Steinman's family got word of his prize early Monday, when his wife, Claudia, a real estate agent who lives in Westport, Conn., heard the researcher's cellphone buzz at 5:30 Eastern time and woke the whole family.

"We were jumping up and down," said daughter Alexis. "We haven't really grasped the fact that he's gone. It was like, 'We have to tell Dad he won.'

"It was really bittersweet. It vacillates between sorrow and joy."

eryn.brown@latimes.com

shari.roan@latimes.com

Times staff writer Tony Perry contributed to this report.

Copyright © 2014, Los Angeles Times
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