Disease Models & Mechanisms 3, 11-14 (2010) doi:10.1242/dmm.004952 Published by The Company of Biologists 2010 A MODEL FOR LIFE

The accidental biologist: an interview with Jim Smith

Jim Smith has made fundamental contributions to our understanding of early embryonic development. Here, in conversation with DMM Consulting Editor Kathy Weston, he discusses his stutter, how he became interested in developmental biology, and his role in helping establish what will be the UK’s biggest multidisciplinary research laboratory, the UK Centre for Medical Research and Innovation (UKCMRI).

he determination of cell fate in exams and liked both arts and science sub- the early embryo is driven by in- jects. However, at my secondary school, I tercellular signals, which in turn realised that anything to do with the spoken induce the transcriptional activa- word was going to be hard for me to tion of regulatory genes that succeed in, as I had a rather bad stutter at directT morphogenesis and cell differentia- that time. So, I suppose I lurched towards tion. Work from Jim Smith’s lab helped science because I felt that having a speech show that transforming growth factor impediment was less restrictive in science (TGF)- family members are involved in than it was in the arts. But I don’t want you

DMM mesoderm induction, the first inductive in- to think that that’s the only reason I went teraction in early vertebrate development into science. By the age of 11, I had a chem- (the mesoderm eventually gives rise to istry set, and I enjoyed making things out of tissues such as muscle, bone and blood). wood and doing things with my hands, so More recently, he has shown that the tran- I’ve always had an interest in how things scription factor Brachyury is a target of work, which I suppose is what still drives TGF- signalling that is only activated at in- me. termediate levels of ligand. Brachyury is both necessary and sufficient for normal So you chose to specialise in science at Photograph courtesy of Samantha Morris. mesoderm formation, and its targets about the age of 15 and got a place at include genes that are involved in the reg- Cambridge to read natural sciences. Why ulation of gastrulation and in many aspects Cambridge? Why the natural sciences ditional biology, which seemed to over- of posterior mesoderm formation. option? emphasise the importance of naming Smith is now using frog, fish and mouse All of the universities that I applied to had things. Richard Feynman wrote about the embryos to understand the genetic regula- courses that allowed one to do all three of difference between knowing the name of tory network that is initiated by Brachyury, maths and physics and chemistry because something and actually knowing what it is. Disease Models & Mechanisms and is finding that the signals that direct cell I couldn’t decide which of these subjects I It’s not enough just to be able to name differentiation have been conserved was most interested in. I liked the things. You have to know what they do, how throughout the animal kingdom. His work Cambridge course because students could they work, and how they interact with their may inform attempts to drive stem cells combine maths, physics and chemistry with environments. But then I also realised that along particular developmental pathways. one other subject. I decided initially to do we didn’t know the answers to many of the X-ray crystallography for my fourth subject, simplest questions in biology, and that’s the Your motivation for choosing a life in but then I met my director of studies, great thing about it. Again, Feynman sums science is a bit different from that of Douglas Barker. Douglas persuaded me to this up well: you have to know an awful lot many people. Can we talk a little about do cell biology and this decision changed of physics and chemistry before you can that? my life. I fell in love with cell biology and find a problem that hasn’t been solved. In I was very catholic in what I was interested discovered that I had a passion to under- biology, you just have to lift up a leaf. in at school, and I was reasonably good at stand how cells functioned and how life worked. It was a life-changing event. It was such an exciting time for cell and molecular biology when you were at Jim Smith is the Director of the MRC National Institute for Medical Research (NIMR) in London. He Was cell biology a completely new area Cambridge. Knowledge was expanding was Director of the /Cancer Research for you? so quickly in those areas. What was it like UK Gurdon Institute in Cambridge from 2001 to 2008 Yes. I didn’t do biology at school. Biology at to be part of it? and, before that, was a senior scientist at NIMR. Until my school was for people who didn’t do At the beginning of my time at Cambridge, recently he was Editor-in-Chief of DMM’s sister journal, Development very well at maths, physics and chemistry. I didn’t know enough about cell and mol- ([email protected]) And I always struggled with the idea of tra- ecular biology to realize how much was

Disease Models & Mechanisms 11 A MODEL FOR LIFE Jim Smith

unknown. But in my final year there, in the had just done some experiments, which you’re always thinking ahead to figure out second epiphany of my life, I did discover they had sent to Nature, where they had whether there are words coming up that how much I loved developmental biology. taken the equivalent region from a mouse you can’t say. So, while you’re speaking, you There was a series of lectures given by embryo and grafted that into a chicken and have to try to simultaneously think of a John Gurdon, the pioneer of nuclear trans- found exactly the same thing. So this word that will replace the difficult word. fer, and another given by Peter Lawrence, demonstrated the universality of the idea That’s actually quite tricky as you have to who was studying compartments and cell and it also demonstrated to me that you think of an alternative word that has the lineage during development. John’s lec- could get a paper into Nature if you had a same meaning but begins with a different tures were very good and interesting but good idea and did the right experiment; in letter! It also helped me express myself con- Peter’s, about pattern formation in other words, you didn’t have to sweat and cisely; even now, I always use the fewest Drosophila, really grabbed my imagina- you didn’t have to work really hard and for number of words I can when I’m saying tion. He spoke about Antonio Garcia- a long time. Luckily, Lewis accepted me. something. And it’s still true that I try to Bellido, the compartment hypothesis, and My interview was painful because I really make sure I know what I’m going to say the engrailed gene, work that was bril- stuttered a lot, but Lewis was kind enough before I say it. I don’t know if that’s a good liantly summarised in a paper that Peter to take me and I haven’t looked back. thing or a bad thing – probably good. wrote with [Science (1975) 189, 340-347]. As my friend Phil Ingham How did you get rid of your stutter? So you still feel good when you give talks knows, I was never very good at under- Well, I had received speech therapy inter- and they’re stutter free? standing insects, but even I could see this mittently from when I was about 7, but it Well there’s a sort of buzz about it and was fantastically excit- didn’t really work terri- somehow it feels like a success that I’ve ing. There is a lovely I like the idea of bly well, or maybe I given the talk, no matter what the content! logic to development didn’t make it work. I coordinating groups of DMM – there are elegant and even had some therapy Where did you go after your PhD? universal rules – and people, helping people to when I was a PhD Well, I had an understanding of the princi- this really drew me to do their best science, being student: Lewis recom- ples of developmental biology from Lewis, the subject. Peter in- mended somebody to but I knew that to make progress I had to troduced me to the around when that good me, but that didn’t work learn some cell biology, so I went to work work of Lewis Wolpert science is being done, and either. Then, when I with Chuck Stiles at Harvard Medical who explained pattern having a say in what became a tolerably suc- School and learned how platelet-derived formation, and what cessful scientist as a growth factor (PDGF) makes cells divide. he called the French happens. Those are quite postdoc and then as an Then I went and did a postdoctoral position flag problem, in terms appealing things independent investiga- with Jonathan Slack, because I wanted to of positional informa- tor, I realised, you might work with embryos again. And that’s when tion. The idea is that, by knowing where say belatedly, that having a stutter would be the frog connection started. they are in the embryo, cells will know how a major handicap in my desire to be a suc- to differentiate appropriately and will cessful scientist. So off my own bat, as What has been your best moment as a form, for example, the French flag with opposed to having someone do it for me, I scientist? blue, white and red stripes. I just got com- arranged to have speech therapy and I went Well, near the end of my time in Jonathan’s Disease Models & Mechanisms pletely turned on by this – I loved it. I to see someone called Frances Cook. She lab, he drew my attention to work by Heinz decided immediately that I wanted to do a took a completely different approach that Tiedemann, who had been working on a sub- PhD with Lewis because his writing on the looked at the whole person rather than just stance called vegetalising factor that mimic- subject was so enticing and so exciting. the stutter, and she understood me well ked the effect of vegetal pole cells and could enough after a while to know that what cause animal pole cells to become meso- Is that how you first got interested in would work for me was a dissection of the derm. Tiedemann performed his experi- frogs? way you speak. She took my speech to ments by grinding up chicken embryos, No, for my PhD I worked on chick limb de- pieces and helped me put it back together making insoluble pellets, and using the velopment. When I went for my interview again. I did a lot of reading about how you pellets as the filling of a sandwich in which with Lewis, his lab was working on a make letters, how you make words, and that the pieces of bread were bits of Xenopus ec- region in the chick limb bud called the was what did the trick – I took a sort of aca- toderm. I thought this was really interesting zone of polarizing activity, which when demic approach to the problem. The stutter because Tiedemann’s pellets clearly con- grafted to the anterior region of the limb still comes back occasionally but it’s fine tained a factor that could change the fate of causes it to develop with mirror image now and I don’t have any problems. I don’t cells but, from my time with Chuck Stiles, I symmetry. They had recently published a mind having had it, actually. knew that in order to identify the factor we paper in Nature where Dennis had to make something soluble. I started Summerbell and Cheryll Tickle showed Do you think there have been any posi- working on this. I got hold of two Xenopus that it looked as though this was a dose- tive things about it? cell lines from my colleagues Michael dependent response, just like Lewis’s Well, I think I can claim to have a remark- Sargent at NIMR and Liz Jones in Warwick, French flag. On the day I went there they ably large vocabulary! If you have a stutter, England, and I asked whether these Xenopus

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cells would produce an inducing factor. I ini- cycle through a series of superficial experi- of the science recognised both within and tially pelleted the cells and used them for ments without getting stuck into anything. without. The second thing I’m trying to do is sandwich experiments like Tiedemann’s, but However, thinking about it, some of the sci- to remedy a lack of investment in some then I tried conditioned medium. My most entists that I admire most have not stuck at aspects of science at NIMR, for example, exciting moment in science was undoubtedly one thing. One of my scientific heroes, bioinformatics, genome biology, that sort of the day that I cultured pieces of ectoderm in Sydney Brenner, has made fundamental con- stuff. I’m trying to address this, and I hope this conditioned medium and I found that tributions to many different fields, but he’s that the new people coming in will comple- they changed shape after a couple of hours; brilliant – he’s a genius. I haven’t done that: ment all sides of the Institute and benefit us they began to elongate as if they were gas- I’ve stuck with the one thing. Maybe, to be a enormously. I also think it’s important for me trulating. Tears welled in my eyes, literally! better, rounded scientist, I should abandon to be as visible as possible, and as accessible I knew this was important – I can remember mesoderm induction and tell myself to do as possible to everybody. The senior scien- walking along the street hugging this something else. tists need to be supported, but so do the amazing secret to myself. And then I’m postdocs, the students, and the technical and proud of dropping everything and following So what would the something else be? administrative staff. And, importantly, I am it up. It took a really long time to purify the Well if I knew, I’d be doing it! Actually, now very keen on celebrating the successes of the stuff because I still didn’t really know any bio- I’m involved in doing all these other things institute – Dimitris Kioussis was elected a chemistry. I had to teach myself, and I’m still it would be foolish to attempt to do some- Fellow of the Royal Society this year and we so ashamed of the mistakes I made at the thing different. had a very nice party for him. time that I won’t tell you what they were! Anyhow, I made a lot of mistakes but I suc- Let’s move on to the other things then. You’ve mentioned this entity UKCMRI. ceeded in the end. What is it that has led you to become Could you explain briefly what exactly Director of the National Institute of UKCMRI is?

DMM Do you think it is possible to get as much Medical Research (NIMR) and before UKCMRI stands for United Kingdom pleasure out of the work your lab does as that Director of the Gurdon Institute? Centre for Medical Research and Innovation from the work you did yourself? Are you just completely power crazed or and the idea is that there will be a big lab built Good question. I still get a visceral plea- is there some other motivation? in central London where NIMR will move to, sure when people in my lab do something Well, I asked this question in a together with the Cancer Research UK good, but it’s not the almighty rush that previous DMM interview, and I think I London Research Institute and some people you get from doing it yourself. For agree with him in that we’re essentially from University College London. It is jointly example, shortly after the experiments I doing it to cover our arses. What we both funded by the Medical Research Council, just described, I had a terrific postdoc mean by that is you feel that you have to Cancer Research UK, the Wellcome Trust, called Jeremy Green and he, with just a justify your existence in the scientific com- and University College London. We want to little help from me, looked at the concen- munity to some extent and you worry that create a big multidisciplinary research insti- tration-dependent effects of the activin you’re ability to do good independent tute that brings together the strengths of all that I had purified. I got great pleasure science might decline as you get older. So, of the constituent institutes and labs. It’s a from him doing those experiments. to continue to show that you’re making a fantastic opportunity to make something contribution, you can start running stuff to really new. I think that critical mass is really Clearly one of the qualities that have use your experience to help people in dif- important in creating a multidisciplinary in- Disease Models & Mechanisms made you a successful scientist, apart ferent ways. To be honest, I also feel truth- stitute. When I was in Cambridge, we were from being thoughtful and very smart, is fully that I do a decent job of it. I like the so close to everything else that the city itself that you are extremely tenacious, and you idea of coordinating groups of people, was effectively a big multidisciplinary insti- can follow a good hunch. What else has helping people to do their best science, tute. If you wanted to do something, then the helped? being around when that good science is place was small enough to get on your bike To make me a good scientist? You have to be being done, and having a say in what and go and find anybody you really wanted good with your hands and I was good with happens. Those are quite appealing things. to interact with. That’s harder to do in my hands. Actually, I’m completely anal London, so you do need a big institute. when it comes to doing experiments. I set You’ve been Director of the NIMR since everything up perfectly in advance; I’m a very the beginning of this year. What have you Does this mean that NIMR will lose its organised sort of person. I set it up, and been up to? identity at some point? everything works pretty much first time NIMR has been through a torrid time since Well, we will all be merged physically into because I’m so careful doing it. Also, I know before the previous Director John Skehel the same building, and the challenge un- what’s important and I stick at it. And, I don’t retired, because it hasn’t been clear for a very doubtedly is to maintain a sense of identity spend too much time reading the literature. long time what was going to happen to it, in a building of that size. NIMR is a fan- Nowadays there is just so much of it and, as whether it was going to close, or move, or tastically friendly and interactive place. It a scientist, it’s very easy to get distracted by stay the same. One of my first tasks, which I was like that when I was there from 1984 something else that sounds interesting, drop hope I’m achieving, is consolidating the in- to 2000, and it is still like that. I think that what you are doing and start working on stitute, calming things down, making NIMR one of the worries is that, by creating an that. Then the next thing comes along so you people feel valued, and having the excellence institute that is twice the size, we have to

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work very hard to maintain that ethos and Gurdon Institute I ran five days a week. The it’s not always the case that success comes atmosphere. But I’m optimistic at the truth is that, nowadays, I’m finding it diffi- from the numbers of hours worked. I think moment. The science planning committee, cult to find the time to go running and this that if you are passionate about science, chaired by Paul Nurse, is trying to make a is irritating the hell out of me! have good ideas and plan your time effi- building and infrastructure that will en- ciently, then you will succeed. One advan- courage those interactions, and help to So, is the only way that one can succeed tage of science as a career is that we do have build new ones. in science, and have a life outside of a much more flexible working day than science, to work as you do? Or, do you see many other people, so it is possible to fit I’d like to ask you now about that hack- that ever changing? For example, there work in and still see your kids. You just don’t neyed phrase ‘work-life balance’. You’ve wouldn’t be any question in your mind of have time for anything else! got three children, you still live in people being given a bit of a break Cambridge so you’re commuting to because they have small children and Finally, what would you still like to do? Is London, and your wife Fiona Watt is also cannot function at one hundred percent there anything left that you haven’t done? a prominent scientist, so you have solo while their children are little. Is that just I want to succeed in what I’m doing now. Is child care to do when she’s away at meet- too bad? there anything left that I haven’t done? We’ll ings. How on earth do you fit all this into I know what you’re saying of course, but the see what I do next. your life? truth is that in any career if you want to DMM greatly appreciates Jim Smith’s I work almost all the time! succeed in it, you have to work hard. The time and willingness to share his personal difficulty in science is that success is mea- story. We are grateful for the opportunity to Do you resent that? sured by publications, and although com- present his story here as A Model for Life. Mostly I don’t, because I like it, but there are mittees take account of maternity and pa- Jim Smith was interviewed by Kathy times when I think a bit less to do would be ternity leave, it is difficult to quantitate this Weston, Consulting Editor for DMM. This

DMM nice. Actually, I should tell you that my properly. However, I’ll come back to what I piece has been edited and condensed with hobby is running and when I was at the was saying at the beginning, which is that approval from the interviewee. Disease Models & Mechanisms

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