An interview with Jean-Paul Vincent Free

Congratulations on being awarded the BSDB Waddington medal! What does this award mean to you?

The BSDB has been my scientific home for the past 30 years. It's amazing to get this recognition from my peers and the people I've been exchanging ideas with over so many years.

Let's go back to the beginning, what got you into science in the first place?

I'm not one of those people who can say that I was into science ever since I was a kid. I was just interested in learning about a lot of things. I wasn't planning to go into science. I went initially for a master's degree at Berkeley to study photosynthesis, with the naïve thought that it could guide the design of solar cells. But then I saw developmental biology in action, and I fell in love with basic science. I have to say that, sometimes, especially with global warming, I've been wondering if I should have done research in something more directly relevant. But I am comfortable being a cog in the large basic science enterprise, since one cannot predict where meaningful applications will come from.

Your first degree was in engineering and applied physics in Belgium. How do you think your physics background influenced your subsequent scientific interests?

It's very scary how fast you forget. I can barely solve a differential equation anymore. But what my physics background has given me is an ability to talk to mathematicians and physicists, and to understand what they're talking about. My school offered either physics, maths or chemistry, but no biology. I was terrible at chemistry, so I ended up on a maths/physics track for my undergraduate degree. I wish I could have done an integrated degree to learn about all kinds of sciences. I subsequently always felt that I needed to catch up in biology, but it has been fun at every step.

How did you come to do a PhD at the University of California, Berkeley, and what did you work on?

I always had this background frustration of not being able to do biology when I was an undergraduate. In Europe, at least at the time, it wasn't easy to change fields. That was why I decided to go to the USA. I approached George Oster, who was a mechanical engineer studying biology, to do a PhD with him on fluid dynamics in the Xenopus egg. I spent 2 months in George's lab, and we published a paper on cortical waves. He then put me in contact with John Gerhart. My thesis with George and John showed that the dorso-ventral axis of frog embryos is specified by the so-called subcortical rotation in the egg.

I enjoyed my life at Berkeley. I worked hard, but never in the evenings. I lived in a communal house, with people studying literature and economics, and every night we had dinner together. We had a big blackboard in the kitchen, and we spent the evenings talking about what we were doing.

Although your PhD was in Xenopus, for most of your career, you have worked with Drosophila. What makes Drosophila an attractive model organism for you?

In the 1980s, Drosophila was a powerhouse of gene discovery (just think of all the gene names). I believe that it is still one of the best systems for clean rigorous experiments. In what other model organism would it be possible, within the time frame of a PhD student, to make quintuple Wnt mutant tissue specifically in one organ? However, the time when one could go through life as a fly person without giving much thought to other systems is over. And I am grateful to my colleague James Briscoe for regularly asking me why such-and-such experiment needs to be done in flies. It is no longer enough to be just a fly person. Drosophila research needs to be combined with other approaches and systems.

You joined Patrick O'Farrell's lab at University of California, San Francisco (UCSF), as a postdoc. Can you summarise the work you did there?

That was not the plan at all. Scott Fraser at the time was working on retino-tectal mapping – how the retina finds its connection to the brain. I found that to be a really exciting problem to work on. Scott is a physicist, and I liked his way of approaching things. We went to UC Irvine and started looking for housing. Then my wife got into grad school at Berkeley, and I thought it was fair that I adjust my plans for her to fulfil her dream of becoming a journalist. I ended up scrambling to find a place in the bay area. I went to chat to Bruce Alberts (who famously wrote the Alberts ‘Molecular Biology of the Cell’ textbook) at his office, and he introduced me to Pat. That was how I ended up working in Pat's lab. The intellectual atmosphere of his lab was very stimulating and the other postdocs there were amazing. The atmosphere was competitive but in a good way. I'm still friends with people I met in Pat's lab. But it was also a very destabilizing time because I felt I didn't know enough molecular biology. Credit to Pat, he saw that I was unhappy and suggested a project (triggered by the arrival of Tim Mitchison at UCSF) that would fit better with my tinkering style. I knew no chemistry, but Tim basically gave me instructions on how to build the first cell lineage tracer based on caged dye technology. The paper that came out of this project got me a PI job, 6 years after I started my postdoc, which was considered quite long at the time.

Why did you decide to move to the UK to start your own group at the MRC Laboratory of Molecular Biology (LMB) in Cambridge?

In those days you would go through the back pages of Nature to find a job. I applied for jobs in various places, mostly outside the USA because my PhD fellowship had a 2-year home residency requirement. In the end, the UK seemed like a good middle ground between Europe and the USA. I applied for a job at the MRC LMB in Cambridge, which I realised later was for a tenured position! I obviously received the ‘thank you but no thank you’ official letter from MRC. On the same day, however, I got a phone call from Peter Lawrence, who was the head of cell biology, inviting me to give a seminar at the LMB. I was subsequently offered a position and a minimal amount of lab space, enough for me and a PhD student, who had to sit somewhere else in the building. It took a year or two before I was given enough space for four people. I never got to really build a proper team there, although I had all the resources I needed.

What did your group work on initially? How did you find your own research niche?

I had this plan of tracking repatterning after injury because I was intrigued by the fact that engrailed expression was not fixed through cell division. My project required being able to track gene expression in live tissues, but GFP had not been discovered back then. The only thing available at the time were fluorogenic β-galactosidase substrates (devised by Jon Minden when he was a postdoc at UCSF). The substrate had to be injected so it was very messy. This never took off. But things in the lab somehow worked out organically. Bénédicte Sanson, my first postdoc, was interested in the link between morphogenesis and pattern formation, and this led us to to investigate how the signaling and adhesion functions of Armadillo (β-catenin) affect each other. I also spent a lot of time talking to different people at the LMB canteen over lunch, especially with Peter Lawrence. We got along really well. I had made transgenic flies expressing β-galactosidase uniformly, and we realised that it could be used as a genetic marker in mosaics. Peter knew how to do nuclear transplants, so we spent a lot of time in the lab together transplanting nuclei. I would line up embryos; he would do the transplants. That's how I got interested in the range of Wingless, which ended up becoming a kind of obsession.

Your group then moved to the MRC National Institute for Medical Research (NIMR; now part of the Francis Crick Institute) in London. What was your experience moving labs and institutes?

I enjoyed my first few years at the LMB. It was incredibly productive, but I felt that the atmosphere in Cambridge did not suit me. Some people thrive in an environment where self-confidence is essential. That was not for me. When I was looking for a tenured position elsewhere, I heard of an opening at the NIMR, and they welcomed me with open arms. It was probably my hardest decision because our family had to move again. But it was also the best decision I made. I was hired alongside Alex Gould to join the newly formed division of mammalian development (yes!) headed by Rosa Beddington. Rosa fostered an atmosphere that was intellectually stimulating and cooperative. Since we headed the only two fly groups at NIMR, Alex and I formed a very effective (and enjoyable) support system, which I'd like to call peer-ship, or peer mentorship. There's mentorship where the mentee learns from a more senior person, but I think there is also amazing value in mentorship among peers. You are facing the same problems and trying to solve them together. I think it's very important to find supportive colleagues who are at the same level as you, especially when starting your own lab.

Apart from finding supportive peers, what would be your advice to people starting their own labs?

Maybe it's easy for me to say this now, but I see that many junior PIs are very stressed from the beginning. Stress has this effect of making you go into panic mode. When you panic you don't make good decisions. I always use tennis as an analogy: if you're overstressed, you're stiff and you never hit a good ball; if you're not stressed enough, you're not focused. You have to find your right level of stress, stimulating but not stifling. That is advice I give to almost anybody at any stage of their career. If you're overstressed and not enjoying what you're doing, then it's not worth doing.

My other advice is don't work too hard but think hard. Always think about why you're doing specific experiments, and keep in mind the question you're addressing. And before embarking on a project, always ask yourself what are the best- and worst-case scenarios? Are you happy to land in between?

In your award lecture, you reluctantly said that understanding the range of Wnts has become your obsession. What makes this topic so interesting to you? If you hadn't followed this path, what might you have studied instead?

How a lipidated protein can act as a long-range signalling molecule is a simple and yet fundamental conundrum. It is a challenging question and yet it is easy to define. It can only be approached by bringing various disciplines together (physical biochemistry, structural biology, genetics, cell biology and physics). At the beginning of my research career, I considered a path into mechano-biology, a result of George Oster's influence and the comfort of my training in engineering. But at the time there was no way to estimate stresses and strain in tissues. And it is still hard to rigorously perturb mechanics within an embryo. I am happy to stick with signalling, which can be rigorously investigated in vivo, especially with the advent of genome engineering. Here is a good place to thank Cyrille Alexandre for putting my group at the forefront of these techniques, and for being such an amazing colleague over the years.

Can you summarize what your current group is working on?

Over the years, I have benefited enormously from letting junior colleagues decide what they work on. But, of course, this needs to be balanced by the need for synergy, technical or conceptual. So, my job has been a bit like herding cats, making sure that all the projects in the lab feed into each other. This is especially true around the time of my quinquennial review, when I need to present a coherent research project. The upcoming quinquennial review will be my last, and I have allowed projects to diverge quite a bit. We have projects on growth control by morphogens, developmental tempo, the effect of hypoxia in growth dynamics, the response to tissue stress and even the evolution of insect wings. We also have technical projects, including developing means of tracking protein glycosylation and a diagnostic assay for colorectal cancer. Of course, we are also pursuing my core interest (obsession?) in the range of Wnts, and I am hoping that, at curtain time, we will have a rigorous model of Wnt release and transport in epithelia.

Over the years you have collaborated with chemists, theoretical physicists and structural biologists. How do you approach forming collaborations and finding synergies with other fields?

Collaborations are like relationships in life, they are rewarding but take time and effort to develop and maintain. I tend readily to seek out help or advice when I hit a barrier. I favour direct interactions, e.g. at meetings, but sometimes, I literally pick up the phone to reach out to a specialist. Of course, only a small subset of such interactions leads to a collaboration, but every collaboration needs to start somewhere. Sometimes collaborations can help solve a specific question or bring complementary data together into a strong publication. Other times, collaborations develop into a long-term relationship that become integral to a research program. Learning from outside your field is always enriching. And explaining your question to outsiders is equally rewarding. Feynman's famous and overquoted phrase ‘What I cannot create, I do not understand’ could equally be ‘What I cannot explain, I do not understand’.

What are you most excited about in developmental biology at the moment?

The new generation of developmental biologists is probably more qualified to answer this question than I am but what I see emerging is exciting both in terms of approaches and questions. Multidisciplinary is now the norm. Sequencing, genome engineering and in vitro technologies are opening so many avenues that could not be dreamed of previously. For example, a variety of organisms are becoming accessible to genetic analysis, rejuvenating the field of evo-devo. And synthetic biology is bringing to life Feynman's original quote. A lot of fundamental questions are still up for grabs. I can think of scaling, growth termination, developmental time, robustness and evolvability, the concept of cell fate, and the molecular nature of mechanical feedback.

What are your hobbies outside the lab?

I have found organised sport and the outdoors a great complement to life in the lab. I was briefly in Belgium's over-60 field hockey national team. But a ruined ankle has put an end to all this, at least for now. There is still a lot to enjoy outside science (the arts, nature, cooking and, most importantly, my family).

Jean-Paul Vincent was interviewed by Joyce Yu, Online Editor at Development. This piece has been edited and condensed with approval from the interviewee.