Ralph M. Steinman worked for decades to prove that cells he discovered in the immune system were integral to the way the body fended off disease, ultimately using his research to fight his own pancreatic cancer.
Yesterday, Steinman was awarded the Nobel Prize in medicine, three days after he died.
“Here’s a guy who single-handedly started a whole field and stuck with it after the rest of us would have given up to save our careers,” said Ira Mellman, vice president of research oncology at Roche Holding AG’s Genentech, and a former colleague of Steinman’s. “We all feel this is something that should have been done years ago, given the impact he had.”
Steinman, 68, a Canadian-born cell biologist at Rockefeller University in New York, was awarded the prize with Jules A. Hoffmann, born in Luxembourg, and American Bruce A. Beutler, for illuminating how the body’s immune system recognizes infection and marshals an attack against it.
Steinman’s discovery of what he named dendritic cells, which regulate and adapt the immune system’s defense mechanisms, “laid the foundation for an area of therapy development that’s just coming into its own, called immunotherapy,” said Louis DeGennaro of the Leukemia and Lymphoma Society, which helped fund Steinman’s early work.
The late laureate made his discovery in 1973, and it was more than a decade before the research gained credence in the scientific community, said Michel Nussenzweig, a collaborator and student of Steinman’s and a professor at Rockefeller.
“I remember a meeting in Paris, an international meeting where Ralph had me give the talk,” he said. The response from the audience “was abusive.”
The problem was that other scientists couldn’t immediately reproduce the research, Nussenzweig said.
“There was a terrific amount of skepticism in the early days that these dendritic cells were anything other than an artifactual variant of another cell type,” said Mellman, who described Steinman as his mentor in the late 1970s when they were at Rockefeller. “Because there was this skepticism, Ralph didn’t advance in a fashion that was anywhere near the rate of advancement had he simply gone with the flow.”
Steinman’s ability to purify the cells wasn’t replicated until a decade later, when researchers found ways to isolate them in larger numbers using newer techniques.
“It took a long time,” Nussenzweig said. “But he just always knew he was right.”
Four years ago, Steinman’s work took a personal turn. He was diagnosed with pancreatic cancer and started a clinical trial at the university in which he was the only patient, said Joseph Bonner, a Rockefeller spokesman.
“Ralph’s idea was that you could take a tumor, give it to dendritic cells, and then have the dendritic cells orchestrate a response against the tumor,” Nussenzweig said. “He used his own dendritic cells, which were loaded with tumor antigens, as part of his therapy.”
Whether it worked, “we’ll never know,” Nussenzweig said. “But one thing is for sure: he was able to make T-cells specific for his cancer. It obviously didn’t cure him, but it may have prolonged his life.”
Steinman “remained ever optimistic until just the last few weeks,” said Sarah Schlesinger, an immunologist at Rockefeller who directed Steinman’s clinical studies. “He had great faith in science to cure people and make people’s lives better.”
Rockefeller first heard about 5:30 a.m. yesterday that Steinman had won the prize. Half an hour later, they learned from his family that Steinman had died.
‘Dream’ of a Cure
“Ralph worked right up until last week,” Nussenzweig said. “His dream was to use his discovery to cure cancer and infectious diseases like HIV and tuberculosis. It’s a dream that’s pretty close.”
Steinman’s death on Sept. 30 created an unprecedented conundrum for the Nobel committee, which doesn’t award the 111-year-old prize posthumously. Hours after their official announcement of the prizes, the Foundation confirmed that Steinman’s prize will stand despite the timing of his passing.
Earlier this year, Steinman had given a lecture in Stockholm, where the Nobel Prizes are awarded, said Torsten Wiesel, president emeritus at Rockefeller and a Nobel laureate himself. The awards ceremony in December “will be another occasion like this one where people will celebrate him,” Wiesel said yesterday in a news conference.
Difficult to Reconcile
Steinman’s son, Adam, also spoke at the news conference, saying “It’s really impossible to describe what our family is feeling right now. We are devastated to have lost Ralph over the weekend” and, at the same time, “proud to be receiving this wonderful honor,” he said.
Mellman, of Genentech, described the timing as ironic, given the difficulty Steinman had initially in advancing his career.
“Everyone is thrilled, but at the same time, everyone has this great sense of irony,” Mellman said. “I think he was more than a bit vaguely embarrassed by even thinking about getting a Nobel Prize, but I think he wanted it as an affirmation for all his struggles, and I think he wanted it as an affirmation for the field.”
The other portion of the prize is split between Hoffman, 70, and Beutler, 53, for their discovery of proteins that stimulate the body’s first-line defense against attacking bacteria and other microorganisms.
Laying a Foundation
The work of this year’s winners has provided the basis for research into medicines for cancer, inflammatory diseases and infections, the Nobel committee said on its website.
“These are kind of the master cells in starting immune response,” James Allison, an immunologist at Memorial Sloan-Kettering Cancer Center, said of Steinman’s discovery in a telephone interview.
Steinman’s research is the basis for the prostate-cancer therapy Provenge, developed by Seattle-based Dendreon Corp., which last year received regulatory approval as the first medicine to train the body’s immune system to attack cancer cells like a virus.
“While he wasn’t directly involved in the founding of Dendreon Corporation, it was his science which our scientific founder, Ed Engleman, was working with as he was looking to find these type of cells,” said David Urdal, Dendreon’s chief scientific officer. “Ralph is really one of the giants in immunology.”
Other drugmakers are also developing cancer vaccines, including Bristol-Myers Squibb Co., which won approval for the melanoma treatment ipilimumab in March, Oncothyreon Inc., Merck KGaA and Oxford BioMedica Plc.
Steinman is survived by his wife, Claudia, and his three children, Adam, Alexis and Lesley. His mother, who lives in his native Canada, turns 95 this month.
Steinman was born in 1943 in Montreal, and studied chemistry and biology at McGill University in his hometown before receiving an MD from Harvard Medical School in Boston in 1968. He joined Rockefeller in 1970 as a postdoctoral fellow.
His research is now being applied toward the development of a vaccine based on dendritic cells to prevent HIV, which Steinman referred to “as our real work,” Schlesinger said. A vaccine is in testing at Rockefeller University Hospital and has already enrolled 44 patients, she said.
“We’re very sad that our dad won’t be here to see what dendritic cells do next,” Adam Steinman said. “We know he’ll live on through his scientific contributions.”