Interview transcript

[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!

[Both laugh]

[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.

[JH] Yes.

[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] Okay!

[JH] Okay!

[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.

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