2025 Nobel Medicine: Brunkow, Ramsdell, Sakaguchi Uncover Immune System's Security Guards
Виктория Тевс
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10-11Mia: This year's Nobel Prize in Physiology or Medicine honors Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their discoveries about peripheral immune tolerance. They uncovered how our incredibly powerful immune system is kept in check, preventing it from attacking our own organs, a crucial finding that has opened doors for new treatments for conditions like cancer and autoimmune diseases.
Mars: Exactly. It's fascinating to think that this complex defense system, which is essential for survival, could also be our own worst enemy if it goes unchecked. It's like having the world's best security team, but you need to make sure they have a clear list of who's a resident and who's an intruder. Their work essentially identified the immune system's internal peacekeepers.
Mia: So, the key takeaway here is that while the initial training of immune cells in the thymus, called central tolerance, is important, it's not the whole story. These laureates identified a second, critical layer of defense – peripheral tolerance – which acts as a crucial backup system to prevent self-attack.
Mars: Right, and what’s wild is that for years, the scientific community had actually rejected a similar idea. They had a hypothesis about something called suppressor T cells, but some bad data discredited the whole field. People just abandoned it. It took a lot of courage to go back and say, Wait a minute, I think there's something here.
Mia: Okay, so we have these incredible security guards for our immune system. But how did scientists even begin to suspect there was more to the story, and what were the initial clues that led to this discovery?
Mars: Well, that's where Shimon Sakaguchi's story begins. He was one of this year's laureates, and he was inspired by this really counter-intuitive experiment. You’d think that removing the thymus—the T cell school, basically—from newborn mice would give them a weaker immune system, right?
Mia: Yeah, that makes sense. Fewer T cells, less defense.
Mars: But that's not what happened. Instead, their immune systems went into absolute overdrive and attacked their own bodies, causing all sorts of autoimmune diseases. It was a total rebellion. This led Sakaguchi to theorize there must be some kind of security guard cell that matures in the thymus and whose job is to calm things down.
Mia: So he's looking for the opposite of a soldier T cell. He's looking for a diplomat T cell.
Mars: Exactly. And after more than a decade of work, in 1995 he finally found them. He identified a new class of T cells, now known as regulatory T cells, that were marked by specific proteins on their surface. But even then, the idea of a T cell that actively suppresses the immune response was so radical that many researchers were still skeptical.
Mia: So, Sakaguchi identified these regulatory T cells, but he needed more proof. What was the missing piece of the puzzle, and how did the work of the other two laureates, Mary Brunkow and Fred Ramsdell, finally solidify all of this?
Mars: This is where a very peculiar mouse comes into the story. Mary Brunkow and Fred Ramsdell were studying a mouse strain called scurfy, where the males had this terrible, fatal autoimmune disorder. Their own immune systems were just running rampant.
Mia: Let me guess, they suspected a genetic link?
Mars: Precisely. They decided they were going to find the single mutated gene responsible. And you have to remember, this was the 1990s. Mapping a gene wasn't a matter of days like it is now; it was like looking for a needle in a gigantic haystack. We're talking about a decade of painstaking work.
Mia: Wow. So what did they find after all that digging?
Mars: They found a brand new gene they named Foxp3. And here's the kicker: they realized that mutations in this exact gene were also the cause of a rare and devastating human disease called IPEX, which looked a lot like what the scurfy mice had.
Mia: Ah, I see. So the scurfy mouse and the IPEX syndrome in humans weren't just random diseases; they were essentially windows into a fundamental genetic control mechanism for our immune system.
Mars: You got it. The discovery of Foxp3 provided the genetic blueprint for the regulatory T cells that Sakaguchi had identified. It was the final, definitive proof. The gene was the master switch that created the security guards.
Mia: Absolutely. So, we've gone from understanding the need for immune regulation, to Sakaguchi identifying the cells, and then Brunkow and Ramsdell pinpointing the gene that controls them. This foundational knowledge must have had a profound impact. How is this understanding being used in medicine today?
Mars: The applications are huge and, frankly, mind-bending. For example, researchers found that some tumors are incredibly clever. They actually attract huge numbers of these regulatory T cells to create a protective shield around themselves, telling the immune system, Nothing to see here, move along.
Mia: Whoa, so the cancer hijacks the body's own peacekeepers to protect itself?
Mars: Yes! So now, a major strategy in cancer therapy is to find ways to temporarily disable or remove those regulatory T cells just around the tumor, letting the killer T cells go in and do their job. On the flip side, for autoimmune diseases or organ transplants, you want to do the opposite—you want to boost the number of regulatory T cells to calm the immune system down and prevent it from attacking healthy tissue or a new organ.
Mia: So you're either turning down the guards or beefing them up, depending on the problem. It’s like having a volume dial for your immune response.
Mars: That's a perfect way to put it. It has completely changed how we think about a huge range of diseases. To sum it all up, the key breakthroughs were really fourfold. First, the discovery of peripheral immune tolerance itself, this crucial backup system. Second, the identification of regulatory T cells by Shimon Sakaguchi, the security guards that maintain that tolerance. Third, Mary Brunkow and Fred Ramsdell’s discovery of the Foxp3 gene, which is the master controller for these cells. And finally, all of this fundamental knowledge has now spurred the development of completely new strategies for treating cancer, autoimmune diseases, and improving organ transplantation.