Trio Wins Nobel Prize in Medicine for Discoveries on Immune System
One winner is off-the-grid on a backpacking trip, says his friend and colleague
Immunologists Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi were awarded the Nobel Prize in Physiology or Medicine for uncovering a process that prevents the immune system from attacking our own tissues, called peripheral immune tolerance. The work unlocked a new field of research and potential therapies.
The trio identified a core feature of how the immune system functions and keeps itself in-check: regulatory T-cells. They prevent other immune cells from harming our own bodies and developing autoimmune conditions including Type 1 diabetes and rheumatoid arthritis. Based on this fundamental knowledge, clinical trials are ongoing to test therapies for autoimmune diseases, cancer and post-organ transplantation.
“Their discoveries have been decisive for our understanding of how the immune system functions and why we do not all develop serious autoimmune diseases,” said Olle Kämpe, chair of the Nobel Committee on Monday.
Brunkow is now based at the Institute for Systems Biology in Seattle, Ramsdell at the San Francisco and Seattle-based Sonoma Biotherapeutics, while Sakaguchi is a distinguished professor at Japan’s Osaka University. The group will share the 11 million Swedish kronor, or roughly $1.1 million, prize.
Ramsdell, as far as anyone is aware, doesn’t know he has won the prize yet; he is backpacking somewhere in Idaho, says Jeff Bluestone, chief executive of Sonoma Biotherapeutics. They last talked when Ramsdell was heading out on the trip in September. Bluestone said he has tried text, email and phone calls that have gone to voicemail.
“He is literally off the grid,” Bluestone said, who has fielded calls and questions all morning. “I seem to have been the default if you couldn’t find Fred.”
The company is developing engineered regulatory T-cells for autoimmune and inflammatory diseases. They are planning on reporting their first set of clinical data on a drug for rheumatoid arthritis at the end of this month.
“The ability to manipulate these cells so that they can become powerful, specific therapeutics is really the promise of the field,” Bluestone said.
Humans are constantly exposed to microbes that could make us sick, and the immune system developed to protect us. As part of this complex system, T-cells have receptors that help the body detect viruses, bacteria or other threats, but some can also attach to and alert against our own tissues, causing damage.
Researchers understood in the 1980s that T-cells mature in the thymus and undergo a test to eliminate cells that would latch on to our own tissues. Yet some can still escape into the bloodstream and become dangerous. Regulatory T-cells can keep these stray, potentially harmful cells in check.
“I first became interested in this field because I wanted to know more about how the immune system works, how your own body attacks itself,” Sakaguchi said at a news conference on Monday. He called the win an honor and a happy surprise.
Sakaguchi made the first key finding while working at the Aichi Cancer Center Research Institute in Nagoya, Japan. His colleagues had discovered that removing the thymus in mice shortly after birth resulted in their immune systems going haywire and the development of autoimmune diseases.
Sakaguchi then isolated mature T-cells from genetically identical mice and injected them into the mice without a thymus, and that appeared to protect them. The results of this trial and others convinced him that the immune system must include some cells that calm it down, and after a decade of work presented the new class of previously unknown immune cells in 1995, called regulatory T-cells.
But many researchers were skeptical of the finding, the committee said.
American duo Brunkow and Ramsdell made a further key discovery in 2001, while working at a biotech company called Celltech Chiroscience in Bothell, Wash., that developed drugs for autoimmune conditions. They were looking at “scurfy” mice; males are unexpectedly born with flaky skin and enlarged spleens and only live for a few weeks, because their organs are attacked by their own immune cells.
Researchers suspected that the mutation causing the condition was somewhere on the X chromosome, because females, which have two X chromosomes, are less affected. The duo mapped a piece of chromosome from a scurfy mouse, a huge undertaking at the time, and planned to look at 20 genes in that area. They found the mutation on the final gene they checked, which they named the Foxp3 gene.
“It was really a molecular slog, to get to that exact mutation,” Brunkow said on Monday. “It was just a very small genetic alteration that results in quite a profound change in the immune system.”
Later, they also discovered that mutations in that human equivalent gene caused a rare autoimmune disease, IPEX, with help from pediatricians around the world who collected samples from affected boys. Two years after that, Sakaguchi and later other researchers were able to prove that the Foxp3 gene controls the development of regulatory T-cells. The T-cells also help the immune system calm down after fighting a foreign invader, so it doesn’t continue on overdrive.
The laureates’ discoveries have paved the way for research looking at forming more or modifying regulatory T-cells to fight autoimmune disease, as well as dismantling the co-opted T-cells that tumors use to hide from the immune system. Sakaguchi said that he wanted to continue researching how to enhance immune responses in cancer and to potentially prevent cancer cells from spreading and metastasizing.
“Suppressing immune responses and simultaneously boosting them when necessary,” he said. “I’d be thrilled if both approaches could be developed at the same time.”
Thomas Perlmann, secretary-general of the Nobel Assembly, said Monday at a news conference that he was able to reach Sakaguchi in his lab and relay the news, but he wasn’t able to get hold of Brunkow or Ramsdell at that point.
“We have their phone numbers, but they are probably on silent mode,” Perlmann said. “I asked them to, if they have a chance, to call me back.”
Brunkow later said that she assumed the call that came in the middle of the night was spam and ignored it. Then, she heard her husband talking with someone in the living room; an Associated Press photographer showed up on their front porch.
“I’m sure it hasn’t quite hit me yet,” she said on a 4:30 a.m. call with Nobelprize.org. “It’s an honor to have been a part of that initial work.”