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 Charles Janeway 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 Soviet Union 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, 430 dmm.biologists.org A MODEL FOR LIFE 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 NFB [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 NFB. 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 NFB. 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.