Bénédicte Sanson is a Reader in Developmental Morphogenesis and Wellcome Trust Investigator at the Department of Physiology, Development and Neuroscience at the University of Cambridge. Her lab works on axis extension and compartmental boundary formation in the Drosophila embryo, combining genetics with quantitative and computational approaches. In 2019 she was awarded the British Society for Developmental Biology's Cheryll Tickle medal, which recognises outstanding achievements in developmental biology of mid-career female researchers. We caught up with Bénédicte in a café close to her lab and discussed how she started research not with flies but with phages and how collaboration and interdisciplinarity have always been at the core of her science.
This year you were awarded the BSDB's Cheryll Tickle Medal: what does the award mean to you?
I knew about the award before – Jenny Nichols here in Cambridge was a previous winner – and I was very happy to hear the news. I guess there are pros and cons of awards specifically for females (one view is humorously represented in a recent episode of the BBC series Fleabag by a character played by Kristin Scott Thomas, but I won't elaborate on that!). For me, getting this award is an opportunity to step back and take a look at the science we've done over the years with all the people I've worked with – I've always worked in teams and I have been and am lucky to work with so many talented people. So this award is a way of celebrating these teams. I also find scientific journeys themselves interesting – in our department we have organised ‘Career Stories’ events and it is fascinating to discover the diversity of paths taken by people. So now I guess it is my turn to tell my story!
Let's go back to the beginning: when did you first get interested in science and biology in particular?
I think that as a teenager growing up in France, I was more interested in mathematics and French literature. I have one memory of looking after a vivarium of locusts at school for a few months and finding it great fun, but other than that I don't have a lot of memories about biology lessons at school. And I didn't really know what to do after I finished the French equivalent of A Levels, the baccalauréat: I was hesitating between science training and humanities training, and in the end thought science is hard to do in your spare time, whereas I can read whenever I want! And then within science, I went for genetics, which is very logical and appealed to someone like me who liked maths a lot. I liked the precision of genetics and its logic.
And then at the end of university I was again wondering what to do next, whether to carry on in science. I went to do a course in epistemology, which I found fascinating. I learned about the way that biology and physics evolved in the last century – physics went from small to big data, and now in biology we are doing the same, encountering the same challenges. I also had a very good lecturer who didn't work on Drosophila but gave some great lectures about it – imaginal discs, genetic experiments and so on. Listening to her lectures inspired me to work on flies.
But your first three papers are on bacteriophages – you didn't get to work on flies to start with?
No, but I tried! I went through the only course in France that did lab rotations before your PhD, and did one of the rotations in a fly lab. But it just happened that it wasn't possible, in Paris at that time, for me to get into a fly lab. So I thought if I can't do my PhD on a Drosophila project then I'll do one where I can learn a lot about biochemistry and molecular biology. So I picked this project on the bacteriophage T4. And I really enjoyed it – I did lots of quite hardcore molecular biology, and this was excellent training.
Did this training influence the way you do science in animals?
I think I like to understand how things work quite precisely, and that might be a consequence of it. The phage work was so mechanistic. And also, it was interdisciplinary science – I was in the Institut de Biologie Physico-Chimique in Paris, which has just celebrated its 80th birthday and was a precursor of the CNRS. The premise for the place was interdisciplinarity, even though I think I didn't really fully realise this at the time and probably took it for granted. Looking back I realise how important that environment was for me. There were molecular biologists, geneticists, structural biologists and biophysicists – all in the same building. And that's maybe why when I picked a Drosophila lab, I went to the LMB, which is also very interdisciplinary. And Jean-Paul Vincent, my postdoctoral advisor, was a physicist by training – I really clicked with the way he was thinking about the problems of development (it also helped that we could speak in French together, as my English was terrible when I arrived here!). It was clear that he thought differently compared to typical biologists.
When I moved from phages to flies, I realised that towards the end of my PhD I had been trying to do developmental biology on the phage! The thing I loved doing most was kinetics: I would always try to map what the genes were doing as a function of time. How things happen through time is the essence of developmental biology and in a way moving on to work on Drosophila developmental genetics was a natural transition for me.
Did Jean-Paul put you on a particular project when you joined the lab?
It was actually very fluid – we were making it up as we went along! For me it was really amazing – I came from a PhD where there were maybe two groups in the world working on the same topic. I was working on this enzyme called RegB, which cleaves the Shine–Dalgarno sequences (GGAG) present upstream of the AUG in bacterial RNAs to help the start of translation. The phage enzyme cuts GGAG RNA sequences in the middle very precisely, meaning the RNAs can't be translated. So I worked on this amazing killer enzyme, and there was just us in Paris and a group in Denver working on it. And then I arrived at the LMB and started to work on wingless, and suddenly there are dozens of other labs working on it. I had this feeling that I was driving a Formula One car without a license – things went so fast in the first 6 months. I had to learn very fast but it was super exciting, and I really enjoyed my 4 years at the LMB.
Was the early nineties a very exciting period for developmental biology in general?
It was, and a lot was driven by techniques. Drosophila labs had just started to use the UAS/Gal4 system – everyone was crossing everything with everything! It was an explosion. And then there were all these mutants from Eric Wieschaus and Christiane Nüsslein-Volhard's screen that were being cloned and sequenced. One of the genes I worked on was armadillo, which genetics had taught us was in the Wingless signalling pathway. Suddenly it turned out to be the fly β-catenin, and at the adherens junctions: how on earth did that work? So that was my first project. Jean-Paul had previously worked with Xenopus so he knew the vertebrate literature well, and gene sequencing was revealing how conserved a lot of genes were across animal development, so we decided to recapitulate those experiments in flies and ask if the functions of Armadillo at adherens junctions and in the Wingless pathways were separable.
How did you then find the transition to being a PI?
In the last of my 4 years, Jean-Paul moved to the NIMR at Mill Hill and I decided to stay in Cambridge. So I began to write applications for Career Development Awards. I had become really fascinated by the problem of cell sorting and what kind of physical mechanisms might underlie it. That was thanks to reading Peter Lawrence's book The Making of a Fly: he very carefully describes instances of sorting in the wing, and I just couldn't get this problem out of my head. So I wrote the grant to try to understand the basis for cell sorting in tissues, and got one from the Wellcome Trust for 4 years, settling in the Department of Genetics.
But then it took a very long time for us to make any progress on this question – this first part of being a PI was quite tough. It was a combination of things, really. One was short time scales – at the time the CDA grants were for 4 years, which is really quite short. I also had my first child. Once the time was up I had to find a job really quickly, so I took a temporary lectureship for 3 years. In the end, it was three short contracts as a young PI, two babies, and a very small group, which in turn made it hard to attract people: I felt like I was in survival mode. We did our best but it was a slow and arduous time. And at the end of it I was not sure I was going to be able to stay on in science.
So what changed so you could carry on in research?
I was applying for things, including outside Cambridge, but in the end I got a lectureship at the Department of Physiology, Development and Neuroscience (PDN). This was my first open-ended position, and it was much easier after that. Through this tricky period, I got very strong support from many colleagues, in particular Sarah Bray and Bill Harris in PDN, and my husband Daniel St Johnston.
Today, much of your recent work sits at the intersection between genetics and mechanics – what are the main questions your lab is trying to answer?
We're really thinking about how a genetic programme can pattern a tissue and the cell behaviours within it. Cells are physical objects and to move cells you need forces so we have to consider them as well. But I'm a biologist, not a physicist, so we have to collaborate. And because we have to analyse cell behaviours, first of all we had to collaborate with computational biologists. The other type of collaboration is with physicists and mathematicians to develop models of the process, to help us think about the mechanical responses of cell movements in the context of the tissue. We then ask what happens if you deform a tissue – how much of this is genetic programming and how much is forces, and how can forces fine-tune genetic programmes and vice versa.
And I imagine this kind of research requires a lot of high-content imaging and image analysis?
Soon after Richard Adams had joined the department of PDN, I got talking to him and also to Guy Blanchard, who had joined him as a postdoc around that time. They were building computational tools to analyse fish morphogenesis, but it turned out these tools were actually easier to apply to flies because the tissues are less complex. But even in flies, the cell behaviours are quite complex – during axis extension, which we work on, cells both rearrange and change shape for example. How these behaviours combine to deform a tissue is not intuitive, so we need to be able to describe this in a quantitative manner. We have become much more quantitative than we were in the beginning, with all the challenges that that brings.
So does modern developmental biology necessitate collaboration, or should young researchers be getting as broad a skillset as possible?
I see many young researchers today who have lots of different skills. I would say we and labs that work on similar problems to us need people who can navigate between different fields, people who are happy at the interface. And you can see more and more PhD programmes where they do exactly that, so I would encourage people thinking about these sorts of problems to consider interdisciplinary programmes.
What trends do you think will dominate developmental biology in the next decade?
Perhaps we have to define what strand of developmental biology we are talking about. I work on morphogenesis, and there is so much we can explore just on that topic. In morphogenesis, we need to understand the cell biology of morphogenetic cell behaviours, then understand how these cell behaviours cause tissue deformation. This requires a wide range of approaches, including interdisciplinary ones. Clearly, in flies, we have very strong quantitative labs looking at this problem, but these approaches are being used in other models, in plants and animals, and also beyond model organisms, which I find very interesting. There's quite a lot of interesting morphometrics being done in non-model species and supported by modelling, for instance. And together with techniques like CRISPR, it is becoming easier to investigate mechanistically their morphogenesis – this can then help us understand how morphogenetic programmes generate the seemingly endless diversity of shapes we see in the natural world. So evolution of morphogenesis is a very interesting trend within developmental biology, I think.
Given these advances, will model organisms like Drosophila be in less of a privileged position?
Drosophila will always have its hundred plus years of knowledge and enormous wealth of reagents, and these strengths are not going to go away. Also, thinking about quantitative biology, for instance, Drosophila embryogenesis is amazingly reproducible, which helps to make comparable measurements over many samples. In Drosophila, the questions are getting more and more precise and the answers more complex! So maybe there are still bigger questions we can ask in other organisms using some of the tools developed in flies, or using flies as a reference, a ‘toolbox of mechanisms’. I guess for me the emphasis would be on what the interesting and important questions are; once you identify one, then the next thing is to figure out is what model to use to answer them.
As the fourth winner of the Cheryll Tickle medal, what do you think about the position of women in developmental biology today?
Personally, I have witnessed a lot of change during my career. The problem with science is that with intense competition for grants and research funds, people might succeed thanks to advantages that are unrelated to science, such as money and time. Time, for women, is still an issue, and I struggled when my time was becoming limited as a young PI and mother. It's really important that people who are short on money or time or both are supported to carry on in science. And there are a lot of things that have been done to help this. For example, when I was doing my temporary lectureship, my contract was not extended by the duration of my maternity leave, but now this is more systematically done, which is very helpful. Having schemes for sharing parental leave I think is also very important – I just had my first male lab member taking parental leave and I thought it was fantastic. The University of Cambridge helps this, and also has this scheme for carers – so anyone with responsibility for caring for others can ask for funding to help them out. The great thing is that it is completely open – this could be help to attend a conference, for equipment or whatever. These things need to carry on and expand.
As someone from France who has lived and worked in the United Kingdom for the past 20 years, what do you think of the prospects for UK science given the current political situation?
If I had a crystal ball I would use it! No one knows what's going to happen, but I just hope that institutions carry on working together, whatever happens. I hope that UK-EU scientific collaboration – which fundamentally relies on the movement of people – won't be hindered by all of this. I guess I have trust in the scientific institutions to do their best to carry on, and trust in the scientists to keep on working together. This country has been extremely welcoming to the international community – of course the language helps – and it is punching way above its weight in terms of science. I hope that continues.
Do you have any advice you would give to someone considering a research career in developmental biology?
I think my advice would be to think about big questions and to investigate things that truly interest you. Motivation is very important in science because science can be so hard. Passion can help with this. So I guess I'd warn against trying to be too clever, in a way: your drive needs to come from a genuine strong interest in the scientific question or topic. Fashions in science can move quickly, and it is very hard to predict where it is going to be by the end of your PhD, let alone in a decade.
My advice would be to think about big questions and to investigate things that truly interest you
The other thing, as we talked about before, is interdisciplinarity – thinking of a problem in terms of different approaches. Try not to be too confined by a discipline or a field – this is something that I really benefitted from by moving from phage to fly, but it doesn't just have to be in the PhD-to-postdoc transition. If you love what you're doing in your PhD it's totally fine to carry on working on it as a postdoc – but you can think about bringing other methods to the problem, or maybe join a lab where they approach it differently. There are many ways to branch out.
I have had the chance to sit on the Wellcome Trust basic interview committee, and meet applicants for the Sir Henry Wellcome Fellowships for independent postdocs. The candidates were just amazing! The most impressive ones were those who, at the end of their PhD, knew what they wanted to work on, and knew which labs they wanted to bring together to help them do this. They could assemble a team to tackle a problem that interested them. Now, this is of course not for everyone – I was nowhere near that stage at the end of my PhD! – but it was really remarkable.
Of course the postdoc is such a crucial stage in your career. I've seen lots of positive changes since I was a postdoc: when I was at the LMB, there wasn't anything for socialisation or integration in the University of Cambridge for instance, but now there are lots of things in place to aid this, and also for career advice and professional development. The difficult stage is of course to get an open-ended position after the postdoc or a CDA. For postdocs applying for CDAs in the UK, I would advise them to look for sponsors that have mechanisms in place to access lectureship positions afterwards. Also, we have to increase fluidity between academia and other professional worlds, helping researchers who want to move out of academia, but also those who want to get back in. And with biology being more and more the work of teams, more thought needs to be given about team scientists. There are postdocs who are very advanced specialists, very strong scientists, who want to stay in science but not necessarily be a PI – we need to figure out how to keep them in, and have a proper career structure for them (see, for example, Anne Ridley's blog: https://blog.f1000.com/2019/04/05/now-is-the-time-for-a-team-based-approach-to-team-science/). I'm not sure about specific solutions but we need to be having this conversation because in the UK we have very few permanent, non-PI positions.
I guess the PI role also has its issues – for instance having to wear so many different hats. How do you manage that?
PIs do have to be well rounded – you have to do a lot of different things. But quite quickly you can lose touch with detailed work. There is a tension there for a scientist, and I definitely feel it. I don't spend any significant time at the lab bench any more (though I can still beat anyone in the lab at a cuticle preparation!). But I still like to be very involved in the project – my scientific identity needs to have this engagement with my students' and postdocs' projects. It's not necessarily something that you expect when you start – at least I didn't when I started.
But I do quite like other aspects of the job, for example the challenge of managing lots of different personalities that make up the lab. I'm interested in people and like people – and I think teams are very interesting. When you are trying to be a bit more interdisciplinary, it's even more challenging because we speak different scientific languages, come from different scientific cultures. It requires a lot of patience and respect as well, and I enjoy this challenge.
Finally, is there anything that Development readers might be surprised to find out about you?
I have very ordinary pursuits! Like many people, I love being outdoors, and try to get out with my family whenever I can. The past few summers, my husband and I have been taking our two teenagers to the French Alps, exploring the mountains by going from shelter to shelter with a rucksack. The first time we went, my daughter, who was 15 at the time, told me no one in their right mind did this, but now they love it! Once you get started it becomes very natural – you have everything you need on your back, start in one place and aim for the next; there's something both empowering and freeing about it.