A MODEL FOR LIFE Disease Models & Mechanisms 4, 430-432 (2011) doi:10.1242/dmm.008151

Innovating immunology: an interview with Ruslan Medzhitov

Ruslan Medzhitov was inspired to become a researcher in immunology on reading a 1989 paper written by that outlined a new theory for immune system activation. Just a few years later, having achieved a postdoc position in Janeway’s lab, he carried out the experiments that confirmed the theory, re-igniting interest in the field of innate immunity and launching his own career. Here, he discusses this early discovery and explains what he considers the three most important questions facing immunologists today.

wo decades ago, the mechanisms Ruslan Medzhitov grew up in the former that led to the activation of the in a large city called Tashkent, adaptive immune system were where he enrolled in college at the age of 18. largely unknown. Adaptive Owing to unusual demographics at that time, immune cells – such as T and B the government extended its compulsory

DMM cellsT – and the cytokines that they produce army service to college students for a short had been characterised in some detail, yet period, meaning that he had to spend two how an invading pathogen could induce their years serving in the Russian army before actions was a mystery. In 1989, Charles returning to complete his college education. Janeway proposed in a landmark paper (Janeway, 1989) how this might take place: How did your time in the army influence invariant molecular structures expressed by your academic training? invading pathogens would activate pattern Two years in the Russian army can be very recognition receptors on innate immune damaging – they were probably the most cells, which in turn would trigger the miserable two years of my life. The Russian expression of co-stimulatory molecules and army is very different than in other countries: important signalling pathways to instruct it’s extremely anti-intellectual, and it’s just the activation of adaptive immune cells. horrible. On coming back to college, students However, the experimental evidence to were essentially completely unable to prove this theory was lacking until Ruslan continue their studies, or found it extremely Anyway, when I got back from serving in Medzhitov joined Janeway’s lab as a postdoc difficult. In fact, by the time I returned to the army, I could not simply continue in my Disease Models & Mechanisms a few years later, and they published a seminal college, university professors had started second year of college – it was like everything paper describing the capacity of a human protesting the fact that students were being had been erased. I had to go back to 7th grade Toll-like receptor (TLR) to activate both recruited, because returning students were chemistry and physics textbooks to start innate and adaptive immune responses all failing in their studies. They protested that remembering things. Overall, it was very (Medzhitov et al., 1997). This discovery, recruiting students was a huge mistake, and unfortunate – the time when you’re supposed together with others in the then-quiet corner that continuing the practice would mean to be most productive in terms of learning, of the field, led to an explosive interest in that the country would become depleted of and it was completely wasted for me. innate immune signalling. Since then, scientists, which would have implications investigators including Ruslan Medzhitov for national defence and so on. (This was still What led you to pursue a research career have mapped out a myriad of different at the time of the Cold War.) They eventually in the United States? receptors and pathways that are involved in convinced the government to stop the After I graduated from college I went to the mechanisms of pattern recognition. practice. Moscow University to do my PhD in 1990. That was unfortunately when the Soviet Union broke up into different countries, and Professor Ruslan Medzhitov, PhD, is the David W. Wallace Professor of Immunobiology at Yale School of a time of economic crisis. It was not a good Medicine, and a Howard Hughes Medical Institute Investigator. e-mail: [email protected] time to do experimental science as there was © 2011. Published by The Company of Biologists Ltd no funding. At that time I was interested in This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share various theoretical conceptual questions, Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions mostly related to the evolution of molecular of the work or adaptation are subject to the same Creative Commons License terms. recognition. But I couldn’t do experiments,

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because there was no funding, so I would just and induce the expression of co-stimulatory proper context to induce an immune go and sit in the library and think. Towards molecules and inflammatory cytokines – response. However, what we don’t know is the end of my PhD, I became interested in that helped us to look for the right type of how to induce a protective immune response immunology because it has a lot to do with receptors. Of course, there are always prior – one that will provide protection from a molecular recognition. I’d never taken a discoveries that guide you in your work, and given pathogen. And, because we don’t know formal immunology course, and much of the what helped us tremendously was the fact that, the majority of vaccine candidates don’t literature I was reading was very confusing that there was already some information work. In cases where vaccines do work, I or outdated – it was prior to molecular available about inflammatory signalling: the think it’s just a lucky coincidence, because in biology and molecular definition of various signalling pathways of NFB [nuclear factor- reality we don’t know how to design them. cytokines and so on. But, by chance, I read B] and the IL1R [interleukin-1 receptor] The exception to that is protective immunity Charlie Janeway’s famous article where he were known, and the TNF [tumor necrosis mediated by neutralising antibodies, which proposed the pattern recognition theory of factor] pathway was being characterised at work well for flu vaccines and some other innate immunity in the proceedings of Cold the time. The similarity between IL1R and antiviral vaccines. But when it comes to Spring Harbor Symposia (Janeway, 1989). Drosophila Toll had also already been protective immunity mediated by other arms Reading that paper changed the course of my recognised, as had the fact that both of those of the adaptive immune system, we don’t career: it was at that point I decided that I receptors could activate NFB. From there, know the rules. Protective immunity may would like to study that particular area, at least in retrospect, it was natural to think involve its own set of signals, cytokines, because I believed that understanding the that the receptors that we were looking for processes and mechanisms, or there might concept that Charlie had proposed would would be something that would be similar to be something different about how the system sort a lot of things out. It was one of those IL1R and Toll and would activate NFB. So, is engaged initially. It may have a set of transformative moments. Email had just that all happened during the period when I characteristics that currently we simply just become available, and I initially contacted was a postdoc, and it was very exciting. do not understand. A protective immune

DMM Charlie that way, and we exchanged a few response is induced during most natural emails. At that time, you set out to address a key infections, which means that the During the last year of my PhD I went to question about the mechanisms linking mechanisms controlling protective immunity UCSD [University of California, San Diego] innate and adaptive immunity. What do can be naturally engaged. But, when we on a fellowship to study bioinformatics you consider to be three key questions in immunise, we probably only mimic (which at that time was called protein immunology today? immunogenicity and not those protective evolution) in Russell Doolittle’s lab. He We now know a lot about pattern mechanisms, which is why we often don’t connected me with local immunologists, recognition: in addition to TLRs, there are induce protective immunity with a vaccine. including Dick Dutton, who at the time was several other families of receptors – both the President of the American Association of transmembrane and intracellular receptors – “We now know a lot about Immunologists. Dick Dutton helped to that function by recognising conserved convince Charlie to take me on as a postdoc, microbial structures. But there is a growing immunogenicity…However, despite the fact that I had no experience in suspicion that there are additional types of what we don’t know is how to immunology, or even in experimental innate immune sensing mechanisms that are induce a protective immune biology. not based on pattern recognition but rather on other principles. It’s likely that the kind response – one that will Disease Models & Mechanisms While working in Charlie’s lab, you of principles involved are similar to the ‘guard provide protection from a given generated evidence to confirm his pattern theory’ described in the plant immunity field pathogen” recognition hypothesis. That must have by Dangl and Jones (Dangl and Jones, 2001; felt like a wonderful achievement. Van der Biezen and Jones, 1998), whereby the Third, questions related to allergy are on I think I was just in the right place at the right immune system senses the consequences of the list – in fact, probably even before the time – anyone else in the same position some stereotypic function of a pathogen or other two questions, because we don’t even would probably have done exactly the same virulence factor. That is, instead of directly understand first principles when it comes to thing. I was just interested in that particular sensing the microbial structure, these sensors allergy. When I said before that we question: identifying the hypothetical detect unusual suspicious activities understand immunogenicity, I should qualify receptors that might detect microbial associated with the microbial virulence that: we actually understand it in the case products and then activate antigen- apparatus, such as disruption of the when pattern recognition receptors are presenting cells and induce immunity and cytoskeleton or of endocytic trafficking. This involved in triggering the immune response. inflammation. And Charlie’s lab was exactly kind of sensing would complement pattern When it comes to allergens and parasitic the right environment for that project: it was recognition mechanisms. worms [helminths – the types of parasites not driven by quick publications, and we The second area where I think there are a that induce type 2 immunity, which were not restricted by resources, for the lot of important unanswered questions contributes to allergic responses], we don’t most part. The fact that we had certain relates to how protective immune responses really understand immunogenicity. This issue expectations on theoretical grounds about are induced. We now know a lot about is complicated by the fact that there is more what these kinds of receptors might do – that immunogenicity: you need ligands for innate than one distinct pathway that can activate they would activate antigen-presenting cells receptors, you need antigen and you need the type 2 immunity. In my opinion, there are at

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least four distinct pathways, and these on one area. For example, we work on flu, scooped myself a couple of times, and very correspond to different purposes of type 2 but we’re not a flu lab; we work on quickly I developed the attitude of not immunity. And, accordingly, there are at least transcription, but we’re not a transcription wanting to be involved in anything four different classes of allergens that activate lab. Projects in the lab are determined by the competitive. So, I just try to ask questions these four different pathways. A conceptual type of question one can ask. We don’t ask that are not obvious. problem in understanding allergens is that the same questions as labs that are experts they belong to all sorts of biochemical classes: on flu or transcription: rather, we ask If you could switch gears and go back to some are enzymes, such as proteases, some questions that are as simple as possible, and the bench and start a completely different are lipid-binding proteins, some are synthetic that are different from the questions that are project, what would you do? molecules, some are xenobiotic, and some being actively pursued in the field. The idea The question that I am very interested in is don’t seem to fit into any of these categories. is to find a question that is not obvious in the innate stereotypic behaviours. I’m referring I think these classes correspond to the field and that addresses a conceptually novel to behaviours that are genome-encoded, that different pathways that I’m referring to. But question – and ideally something that is are hard-wired. There are many types of there has been very little progress recently simple. The answer may not be simple, of behaviour like this: aggression, mating in understanding the mechanisms of how course, but ideally the project begins with a behaviour, territorial behaviour and so on. allergens work. For every example of an simple question. These are my favourite types You can study this in flies and C. elegans, but allergen, you can find examples of at least of questions. There are actually many simple some of this work can also be done in three classes of allergens that do something questions that are unaddressed. Obvious mammals. different. I don’t think there will be one questions are being addressed to saturation. discovery that explains allergy: there would Obvious questions are fashionable, and those When it comes to model organisms, what need to be characterisation of the many fields tend to be very crowded. Simple do you think is one that is understudied, different pathways that lead to allergy. And questions are not always obvious (although and that could teach us a lot about biology?

DMM at this time we do not even understand one some are) – and those are the ones we like. The one that I would definitely study is of them. We can afford to have one student or one amoeba – a single-celled soil amoeba like One pathway that we are close to postdoc working on that question. Amoeba Proteus, which is an incredibly understanding the rationale of is that involving beautiful organism. I’ve tried to study it – I’m allergens that mimic the activity of helminth- “The idea is to find a question still trying to convince someone in the lab to derived products, particularly helminth- that is not obvious in the field work on it! I could stare at it through the derived proteases. The idea is that the host microscope for hours, it’s so beautiful. These senses helminths not by pattern recognition and that addresses a single-celled organisms eat bacteria, and but through a mechanism that is described by conceptually novel question – they’re a little bit like macrophages, which is guard theory, which I mentioned earlier, and ideally something that is my favourite cell type. I think there are a lot whereby the immune system senses abnormal of interesting questions about cell biology, activities associated with worm infection. One simple” signalling, gene expression, behaviour and so of these is secretion of highly active cysteine on that could be studied in those animals. proteases that all worms secrete as part of their One consequence of this approach, and And I’m interested in Amoeba Proteus infectious cycle. It appears that the host has one of my goals, is that we actively avoid because this is a truly beautiful animal – it’s protease sensors that detect this protease competition. I like almost everything about

Disease Models & Mechanisms just spectacular! activity by virtue of being cleaved, and that science, but one thing I don’t like is cleavage then activates these sensors. The competition. It’s counterproductive. Excerpts from this interview can be heard in the podcast identity of these sensors is not known; this is Competition can be healthy and can provide associated with DMM Vol. 4, Issue 4 at something we’ve been working on for several a self-correcting mechanism. If you’re the http://www.biologists.com/DMM/podcasts/index.html. years now. So, this hypothetical sensor that the only one working on something, you’ll never DMM greatly appreciates Ruslan Medzhitov’s host uses to sense parasite infection might be be sure if you’re right or wrong. People are willingness to share his unique thoughts and experiences. He was interviewed by Sarah Allan, only sure about something when multiple triggered inadvertently by protease allergens Scientific Editor for DMM. This piece has been edited and perhaps environmental allergens, such as labs reproduce it. But what I mean is that I and condensed with approval from the interviewee. pollen. This idea is probably correct because don’t like to be involved in competition in there is a lot of experimental evidence addressing an obvious question. I try to avoid REFERENCES supporting it, but it certainly doesn’t explain competition for two main reasons: first, Dangl, J. L. and Jones, J. D. (2001). Plant pathogens and integrated defence responses to infection. Nature all allergies. There are other types of allergens because if you’re involved in competition in 411, 826-833. that don’t fit that model. addressing questions that ten other labs are Janeway, C. A. Jr (1989). Approaching the asymptote? working on, what you’re doing is redundant. Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1-13. Your lab has many interests. How do you And, second, I hate the fact that the people Medzhitov, R., Preston-Hurlburt, P. and Janeway, C. choose what to focus on? that do the work can end up being scooped, A. Jr (1997). A human homologue of the Drosophila It’s true that I’m interested in many different which can be devastating if that project Toll protein signals activation of adaptive immunity. questions. My lab generally works as one involved years of hard work and dedication. Nature 388, 394-397. Van der Biezen E. A. and Jones J. D. (1998). Plant person per project, so we cannot be doing In the end if they get scooped, that can have disease-resistance proteins and the gene-for-gene the same things as a lab that specialises only a very negative effect on everyone. I’ve been concept. Trends Biochem. Sci. 23, 454-456.

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