“There weren’t the tools for understanding how the innate immune system detects infection, and I think that’s where we contributed”
Transcript of the telephone interview with Bruce A. Beutler following the announcement of the 2011 Nobel Prize in Physiology or Medicine, 3 October 2011. The interviewer is Adam Smith, Editorial Director of Nobel Media.
[Bruce Beutler] This is Bruce Beutler.
[Adam Smith] Oh, hello. Professor Beutler, this is Adam Smith calling from Nobelprize.org, the official website of the Nobel Prize, in Stockholm.
[BB] Oh, hello. How are you?
[AS] Hello, I’m delighted to hear your voice. First of all, congratulations on the award of the Nobel Prize.
[BB] Thank you very much.
[AS] We have a tradition here at Nobelprize.org of recording very brief telephone interviews with new Laureates. Would you be able to speak for just a few minutes?
[BB] Yes, I can. You probably hear beeping in the background because someone else is trying to call me. That might be a problem. I’m all alone with my cell phone. But go ahead.
[AS] I’m sorry, you’re probably being bombarded by press from every side. I gather I’m catching you in California, although you’ve actually moved your affiliation to Texas now.
[BB] That’s right. I’m in the middle of moving to UT Southwestern, which is where I did the work, that I’m being feted for right now, back in the nineties.
[AS] Oh, well, I’m sorry to catch you on the hop. What were you actually doing when you received the news, and how did you receive the news?
[BB] I was in bed. I happened to wake up in the middle of the night. I looked over at my cell phone and I noticed that I had a new email message. And, I squinted at it and I saw that the title line was ‘Nobel Prize’, so I thought I should give close attention to that. And, I opened it and it was from Göran Hansson, and it said that I had won the Nobel Prize, and so I was thrilled. And, I was a little disbelieving and I went downstairs and looked at my laptop, and I couldn’t get into the Nobel site for quite a while because it was all packed. So, I went to google news and in a few minutes I saw my name there and so I knew it was real.
[AS] You’ve been the recipient of quite a few prizes in the recent past. You must be getting used to it. And you must have had, I guess, some suspicion that this was on the way?
[BB] Well, one always hopes. But, one never knows. And, that’s kind of a special attribute of the Nobel Prize, that it’s done with such secrecy and, of course, I was absolutely delighted.
[AS] I can well imagine. You’ve been awarded half the prize, together with Jules Hoffmann, for your discovery that in his case Toll, and your case the Toll-like receptors were the eyes of the immune system – the sensors of innate immunity. Was it a great surprise to you that the immune system in flies and in mammals is so similar?
[BB] At the time, yes. Of course, we know that some things go very far back and are preserved even to the Cambrian times. And, nonetheless, it still was a surprise to me at the time that everything was so similar in the fly as in the mammal. When we made our discovery, which was a couple years after Jules made his, I had only a very dim awareness of the situation in flies. I didn’t really know him at that time. And, my first contact with him, on reading the bit about the namesake of the family, was to telephone him and ask for the picture that he and his colleagues had used on the cover of Cell, when they showed a fly was overwhelmed with fungal infection if it had mutation in Toll. Because it made perfect sense that in the mouse the same sort of situation applied and there was overwhelming gram-negative sepsis if you had a mutation in Toll-like receptor 4 (TLR4). So, I saw right away the parallelism. But, yes, it was a surprise.
[AS] And, the press release cites just your 1998 paper in Science, in which you revealed that Toll-like receptors were behaving in this way. But that was really the culmination of research that had begun long before – perhaps back in 1985, when you had first identified tumour necrosis factor as an inflammatory protein.
[BB] Yes, that’s correct. Yes, certainly that started me on a pathway toward finding the Toll-like receptor and I realized quite early on, as you’ve alluded, that TNF was one of the major executors of endotoxic shock. And, it was strongly induced by LPS, and therefore we always took it as a marker of the LPS response. It was the endpoint that we followed, just as Professor Hoffmann followed the production of antimicrobial peptides. It took a very long time to find the Toll-like receptor for a molecule because we didn’t use a genetic approach for quite a while. We used conventional approaches: cross-immunizing mutant mice with wild type mice and looking proteomically as it stood in those days to try to find a difference between the two strains. And all of that was fruitless. It took a very long time before we were able to start positionally cloning.
[AS] Sometimes the fruits of one’s labours look as if it’s just been a straightforward and rather rapid discovery. But, actually, there’s a lot of work that lies before it.
[BB] Certainly true in this case.
[AS] And, this was basic research, increasing our understanding of how the immune system works. But, of course, there are now applications, hoped for at least, from the understanding that we gained of innate immunity. What do you think are the most hopeful?
[BB] I think that the most hopeful lie in the realm of inflammatory and auto-immune disease because I believe now, as I believed long ago, that inflammation is something that evolved to cope with infection. And when we speak of sterile inflammatory diseases, like rheumatoid arthritis, and autoimmune diseases like lupus, probably some of the same pathways are utilized. And, it may very well be that by blocking TLR signalling we’ll have very specific therapies for those kinds of diseases.
[AS] In some ways your discoveries and those of Jules Hoffmann reignited interest in the innate immune system. Is that true, that it had sort of lain a little bit dormant before you reinvigorated the field with these discoveries?
[BB] Yes. I’d be careful to say that we only reinvigorated it. It’s not as though we discovered it or initiated the field! Because, of course, clinicians had known for a very long time that if patients are neutropenic – if they don’t have neutrophils – they’re at grave risk for infection of all kinds. And that’s nothing but innate immunity, of course. So, it shouldn’t have come as a surprise to anyone that innate immunity was important. But there weren’t the tools for understanding how the innate immune system detects infection, and I think that’s where we contributed.
[AS] Thank you. When you come to Stockholm in December to receive your Nobel Prize we will happily have the chance to speak at greater length about all this. But, I just wanted to ask in closing whether you’ve had time to think about how you might celebrate this in the midst of your move?
[BB] I’ve hardly had time to think about it, but I’ve had so many letters from friends and from people in my past, some of whom really are in the distant past, that it’s given me a warm glow. And, that’s kind of celebration in itself. And, I think there will be much more of that.
[AS] I’m sure there will. And I’m sure you’ll be claimed by both institutes: the one you’re leaving and the one you’re going to.
[BB] Well, perhaps so. That will be nice too, I suppose.
[AS] Anyway, again congratulations! Thank you for talking to us and I wish you …
[BB] Thank you, Adam.
[AS] I wish you all the best. Thank you.
[BB] I’ll look forward to seeing you. Bye bye.
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