Announcing: The Nobel Prize in Physiology or Medicine 2011
Announcing: The Nobel Prize in Physiology or Medicine 2011
The Nobel Prize in Physiology or Medicine 2011 was divided, one half jointly to Bruce A. Beutler and Jules A. Hoffmann “for their discoveries concerning the activation of innate immunity” and the other half to Ralph M. Steinman “for his discovery of the dendritic cell and its role in adaptive immunity”.
Bruce A. Beutler Jules A. Hoffmann Ralph M. Steinman
Bruce A. Beutler
Born: 1957, Chicago, IL, USA
Affiliation at the time of the award: The Scripps Research Institute, La Jolla, CA, USA, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
Prize motivation: “for their discoveries concerning the activation of innate immunity”
Listen to the Interview 12 min. Play
“There weren’t the tools for understanding how the innate immune system detects infection, and I think that’s where we contributed.”
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 Goran 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.
Jules A. Hoffmann
Born: 1941, Echternach, Luxembourg
Prize motivation: “for their discoveries concerning the activation of innate immunity”
Listen to the Interview 12 min. Play
“That’s one of the positive aspects of the Nobel Prize … people start wondering”
Telephone interview with Jules A. Hoffmann, recorded on 5 October 2011 following the announcement of the 2011 Nobel Prize in Physiology or Medicine on 3 October 2011. The interviewer is Adam Smith, Editorial Director of Nobel Media.
[Jules Hoffmann] Hello?
[Adam Smith] Hello, this is Adam Smith, from Stockholm.
[JH] Hello, Adam.
[AS] Hello. So, again, welcome back to France. And, you must have stepped from one media storm in China to another media storm here?
[JH] Sort of, yes!
[AS] You were in Shanghai on the day of the announcement. And, I gather the Committee failed to reach you, so how did you actually hear the news that you had been awarded the Nobel Prize?
[JH] Well, I heard it with a few hours of delay. Frankly, I did not expect it – I was not waiting for something like that to happen. So, I was I was in Shanghai proper; we were at the museum and then we had dinner with a Chinese friend. And then, when we wanted to go back to the hotel, there was enormous fireworks. They were celebrating – it was the holiday, the Chinese national holiday – they were celebrating, and then we were in the crowd and my friend got phone calls from the hotel saying that we should come back, but we were not clear about what it was! And they said journalists were there and wanted to see me. So, finally, we took the metro to get back because, with our car, the driver could not advance. And, so, we came to the hotel and there were journalists there from Reuters and others, and then they said, “Well, you’ve got the Nobel Prize.” And, I was still uncertain about with whom because I wanted to know what field it was given for.
[AS] Yes, of course.
[JH] And then when they said Bruce Beutler and Ralph M. Steinman, of course I knew that it was for innate immunity and then I started believing it!
[AS] Well how wonderful! So the fireworks were in part for you!
[JH] I don’t think so! But the Chinese were very nice. They were really … they were organizing a party and they did all they could. They were very happy about it!
[AS] How lovely, yes. What a nice place to be to hear the news. It’s been quite a year of prizes. Because you were in fact in China to receive the Shaw Prize, were you not?
[JH] Yes. The Shaw, that was the week before, yes. We were actually with Bruce Beutler. We shared it with Bruce Beutler and Ruslan Medzhitov
[AS] So, you must be getting quite used to all this media attention?
[JH] Well, I hope it’s going to calm down soon! But, yes, okay, I mean I have to stand up to it!
[AS] Are you somebody who enjoys the attention?
[JH] I mean, I wouldn’t downplay it now. I wouldn’t say that I hate people saying, “Well, it’s interesting what you did,” and so on. But, I don’t like it to be overplayed. And I don’t think – because we did, with my colleagues, some nice work on immunity – that I’m a competent person now to speak about everything in science and society. So, I try to avoid getting involved in that aspect.
[AS] Well, let’s turn to immunity then. You were awarded the Nobel Prize for your discovery that Toll was the sensor of innate immunity in the fly. What started you studying immunity in flies anyway?
[JH] Well, actually we started – it’s a long story – we started looking at antimicrobial defences in insects, initially in grasshoppers, in the sixties. And, the reason we did that was that I did my PhD in the laboratory which was working on grasshoppers, and grasshoppers were, at that time, still a very big plague in countries which were administered by the British and the French. And, so, our laboratory was doing endocrine studies, that is to say transplant endocrine tissues or organs from one insect to the next. And, they noted that it was never infection coming up – never opportunistic infection coming up – without any special care being taken to avoid microbes in the environment; there was no aseptic conditions.
So, actually, in the lab my thesis supervisor suggested that I take up the question of what helps the insects fight infections. And so that’s what, then, I did. And initially it was experimental biology with X-ray treatments and so on. And then we got from there, we got into the biochemistry of the effector molecules and then we discovered the antimicrobial peptides and so on. Then, finally, at a given moment in ninety or so, we decided with my colleagues – particularly Jean-Marc Reichhart and Charles Hetru here – we decided that we would go over to Drosophila. Also, no peptides had been identified yet. No effector molecules had been identified yet in flies. But we thought that we might be able to find something – we hoped we would be able to find something because we had, by that time, found in larger flies induction of antimicrobial peptides. And, so, we went ahead and then we went over to Drosophila, we hired in a Drosophila geneticist, Bruno Lemaitre and later Dominique Ferrandon, and the team then became both biochemistry, cell biology, molecular biology and molecular genetics and so on. Finally, at a given moment … Well, the way we came to Toll was through the work of Nüsslein-Volhard …
[AS] Of course, because she had identified it as a gene important in embryonic development, yes.
[JH] … Yes. And what she had seen is that this activates Dorsal – and Dorsal is an NF-kappaB family member. And, we found that there were sites … we found that there were, in the promoter sequences of the antimicrobial peptide genes, there were NF-kappaB binding sites, and then we could, through transgenesis experiments, we could demonstrate that those sites were mandatory, conducibility, and so, step by step, we worked up to … But initially it was not something obvious that Toll – Nüsslein-Volhard had described Toll as being a maternally expressed gene – and now here we’re working on adult flies, we were working on males, which there was no material effect involved. And so we first had to show that, really, the system was inducible in adult flies – adult males – and so on. And then this is what got us to find that this was an immune function for this cell receptor.
[AS] It very nicely illustrates the tremendous amount of background that lies behind a seemingly sort of singular discovery such as Toll’s role in innate immunity.
[AS] When Bruce Beutler, two years later, showed that Toll-like receptors performed a very similar job in mammals, was it a great surprise to you that the systems were so similar?
[JH] Actually, Bruce got at it in a different way. Bruce had been working on TNF, you know, this..,
[AS] Yes. Tumor necrosis factor.
[JH] … inflammatory cytokine. And, TNF is induced in an NF-kappaB dependent manner by lipopolysaccharide (LPS). That was known. But, the receptor for lipopolysaccharide was not known. And so he started out in the nineties to identify – to clone the LPS receptor. And eventually he had narrowed it down to some relatively short interval. At that time 60 genes was still a tremendous long stretch of DNA. And, in that stretch there was a Toll homologue. And so eventually what he found was that the LPS receptor, yeah, the receptor for lipopolysaccharide – lipopolysaccharide is responsible for the endotoxic shock, which is in a large part due to hypersecretion of TNF – so, Bruce Beutler found that this receptor was a Toll-like receptor, and then this made everything coherent.
Now, there still was a problem: which cells do react in the first line to LPS and those cells are in particular dendritic cells, which were found by were found by Ralph Steinman.
[AS] Yes, indeed, indeed. They act as the bridge between the innate and adaptive systems.
[JH] Yes, exactly.
[AS] But was it a surprise to you that the systems were so similar in flies and in mammals?
[JH] Yes. That really was one of the big surprises, yes. I mean, we might have – in hindsight – we might have anticipated that. But, we were maybe not Darwinistic enough, or evolutionary-minded enough. But, now in hindsight we know, through the work of other laboratories, we know that the system exists already in sea anemones and in sponges. So it’s a very ancient system which probably appeared at the moment when multicellularity appeared, that is to say about one billion years ago.
[AS] Right, right. But …
[JH] The essence of the – I mean the molecular circuitry and the building blocks have been conserved.
[AS] And although, as you’ve pointed out, you weren’t actually studying flies as models of human disease but for their own sake – in fact I suppose this illustrates how important flies are as models of human disease.
[JH] Absolutely, yes, in many respects.
[AS] Do you think that there’s enough recognition of that? Is that …
[JH] Well, certainly, well that’s one of the positive aspects of the Nobel Prize because it … people start wondering, as you just did, and many journalists whom I’ve met those days say, ‘Why would you work on the fly? What is particular in flies?” and so on. And then you end up illustrating examples and then you try to convince them.
[AS] And, this was all done to answer basic research questions, but of course there is application of the knowledge. What do you think will be the most immediate effect of understanding the sensors of innate immunity?
[JH] Well, I mean, in human systems it certainly will have an influence – and it has already – on working out adjuvants. Because some of the adjuvants which are used regularly now work though Toll-like receptors. That is one respect. The other respect is that autoimmunity also involves Toll-like receptors. And then inflammation often, if not always, involves Toll-like receptors. So you have a whole sequence of events where you can imagine therapy.
[AS] But this is for humans. In the case of the fly, is there a direct application as well?
[JH] No, certainly not for the time being. But, in the fly we are extending now, with co-workers here, with some of my associates – we are extending work to antiviral defences, which is a really new frontier, a nice frontier. And also in mosquitoes – again with other colleagues – the mosquitoes against … the defence against plasmodium/malaria parasites.
[AS] Okay, thank you. So, just to close: you’ve described the Chinese celebration, but you arrived back in France today. So, what is the French celebration that’s planned?
[JH] Oh! [Laughs] That will come. We just … well, we had, my colleagues, when I was in China, had champagne, and now there will be quite some celebrations going on here but it’s not yet settled.
[AS] Good luck with your plans and we look forward to meeting you in Stockholm in December, thank you so much.
[JH] Yeah, it was nice talking to you. Bye bye, sir.
[AS] Bye bye.
Ralph M. Steinman
Born: 1943, Montreal, Canada
Died: 30 September 2011
Affiliation at the time of the award: Rockefeller University, New York, NY, USA
Prize motivation: “for his discovery of the dendritic cell and its role in adaptive immunity”
Dendritic cells as the conductors of the immune system
The Royal Netherlands Academy of Arts and Sciences has awarded the 2010
Dr A.H. Heineken Prize for Medicine (USD150,000) to Professor Ralph M. Steinman of The Rockefeller University in New York, USA, for his discovery of the drendritic cell and its role in the immune response.