Clotilde Cadart undertook her PhD thesis with Matthieu Piel at the Curie Institute in Paris, before moving on to a postdoc with Rebecca Heald at the University of California Berkeley. Her interests lie in understanding the links between cell ploidy, cell size, metabolism and developmental progress. Clotilde is one of Development's Pathway to Independence Programme Fellows, and we caught up with her over Zoom to find out why she left medical school to become a researcher, and what she hopes to achieve in her own lab.

When did you first become interested in science?

Actually, quite late: I was more interested in philosophy and literature as a high school student. And then I entered medical school because I wanted to do something where I would be useful. It was only during my second year of medical school that, out of curiosity, I joined an Inserm (L'Institut national de la santé et de la recherche médicale) programme designed to help medical students discover basic science. And I fell in love with it at this point: suddenly, science made a lot more sense to me, because it showed me that there was a process of research. In school science lessons, I had always had the impression that I didn't understand what was happening because the lesson raised so many vast questions I couldn't answer, and then during this programme I realised that this was normal, and that the goal was just to understand a little bit more!

Suddenly, science made a lot more sense to me, because it showed me that there was a process of research

For your PhD, you worked with Matthieu Piel at the Curie Institute in Paris, France. What attracted you to the Piel lab, and can you tell us a bit about what you worked on there?

I started in Matthieu's lab as a Master's student. At this point, I was still set on being a medical doctor, and I was just doing a Master's out of curiosity, planning to go back to medical school afterwards. Matthieu's lab is one of the most creative I know: he has an expertise in designing microfabricated tools to constrain the cell's environment. Visually, this is very fun to watch, because you get to see cells migrating in weird environments, and dividing under constraint, and so on. This playful aspect was super attractive to me. During my Master's, they gave me some microfabricated channels in which cells are forced to divide asymmetrically, and you end up with a very large sister cell and a very small sister cell. This fascinated me – I wanted to know if the cells were going to be able to correct these large abnormalities in size and I decided to stay on for a PhD. Obviously, it was very naïve to think that I might be able to answer such a big question in the course of a PhD, but I really thought – OK, I'll just do a PhD to answer this question and then I'll go back to medicine. In the end, I optimised a microfabricated device to measure single cell volume. This was new and allowed me to obtain the first dataset on animal cell volume growth, tracking single cells from birth to mitosis, which was key to investigating quantitatively how cell size control is achieved. With these new measurements, we found that, unlike unicellular organisms, animal cells need to regulate both the speed at which they divide (cell cycle progression) and the rate at which they grow. Most importantly, along the way, I also fell even more in love with the process of research.

How did you end up doing a postdoc instead of going back to medicine and why did you decide to go to Rebecca Heald's lab in Berkeley, USA?

The first conference I went to during my PhD was Workshop on mitosis organised by The Company of Biologists. This experience was instrumental because it was such a small meeting, and I got to meet and discuss with lots of PIs. It made me more comfortable to talk about my work and interact with leaders in the field. The questions I was asking in Matthieu's lab were a new direction for him, so I generally went to different meetings from the rest of the lab, but this experience at the Workshop gave me confidence to go to other conferences on my own. I got to meet lots of PIs, and one of them really encouraged me to do a postdoc. Meeting people who believed in me and thought I could do science really helped me to see myself in this job.

So then I started looking actively for a postdoc. I was really interested in bringing the question of size regulation, which I had been working on during my PhD, into a multicellular in vivo context. Frogs are a really great fit for this kind of question because they have a lot of interesting scaling properties. There were two things that attracted me to Rebecca Heald's lab. Firstly, she has unique expertise in comparing closely related frog species with different genome sizes, which is known to correlate with cell size. And secondly, while Rebecca had been focusing on subcellular scaling questions, she was very open to me bringing a new direction – going to a higher scale and looking at whole-organism physiology as a function of cell size. I had heard from a lot of people – and this proved to be true – that she's a really outstanding and generous mentor. As a postdoc starting on a risky new project, this was very important: it took a long time before I started to get results, but Rebecca believed in my intuition and kept giving me pep talks to get through that time.

It sounds like quite an ambitious project: looking at cell size, ploidy and metabolism in different species. How did you approach that question and what did you show during your postdoc?

My postdoc project started with two sets of observations in the literature. Firstly, it's very commonly known that – within an individual – there's a correlation between the amount of genome in a cell and cell size: polyploid cells like hepatocytes or muscle cells are much larger than, for example, diploid epithelial cells. This is also true across species, and this has been characterised a lot in frogs. Secondly, and this is less well understood, there are correlations between genome size and organismal variables like developmental rate. My intuition was that the link might be cell size-dependent changes in cellular physiology or metabolism, and this is what I set out to study. Briefly, the findings from my postdoc were that when ploidy increases, cell size increases and whole embryo metabolic rate decreases. I managed to develop a quantitative framework to assess where the energy goes in an embryo – how much goes towards growing and how much towards maintaining what already exists. What I found is that maintenance costs less energy when you are made of fewer larger cells, because the costs associated with plasma membrane maintenance are reduced in cells that are large and have a lower surface area to volume ratio. And what was then really fun was that I could compare across frog species to show that the correlation was between metabolic rate and cell size, rather than genome size.

All your work to date has been quite interdisciplinary. What are the challenges of bringing different fields together, and would you encourage other people to take an interdisciplinary view of science?

I really think that being interdisciplinary allows you to ask very different questions because you come as an outsider – in a way, you're more naïve. For example in my postdoc, I wasn't a developmental biologist, but coming from the cell biology field and having studied human physiology during my medical studies allowed me to ask an original question in the context of development: how does cell size affect embryo physiology? Both during my PhD and my postdoc, the quantitative aspect of my work was also very important: counting new things like cell volume or whole-embryo metabolic rate raised new questions. Though I have a real taste for very quantitative work, I'm not a physicist and one of the keys to a successful interdisciplinary study is also to find collaborators who push your work forward with their own expertise. During my PhD, the collaboration with theoreticians was very fun and instrumental for my work.

Being interdisciplinary is hard though, because you remain an outsider and your approach or the new question you propose is not often valued. Often you feel like you're not enough of a biologist or enough of a physicist to satisfy grant or paper reviewers – it's difficult being in between and having to convince two sets of people who are specialists in their fields. I hope that in the future this will become easier – there are, for example, more journals that focus on interdisciplinary science and try to find reviewers who really understand the goal of this approach.

You were also the President of the Postdoctoral Association while at Berkeley. How did that come about and what did it involve?

Initially, I just liked to party! At the beginning, I was on the social committee and I just wanted to organise a big party at the end of the year, and meet other postdocs from other fields. But then I became president of the organisation in the academic year of 2020-2021. Of course, this was the year of the pandemic, and also in the USA there was a lot of discussion around democracy and diversity, and it was really exciting to be president of the association at a time when there was so much going on. Specifically, I had the opportunity to co-organise, with another postdoc, a workshop on the value of research in society. The idea was to invite very different people with different backgrounds and to help postdocs think about the various ways that the skills we acquire as researchers can make us better citizens and help us serve society. I was very influenced by the work of Timothy Snyder, a history professor who speaks a lot about how to preserve democracy. He makes the point that each of us, regardless of what we do, can – by having a strong ethical sense – contribute to making society more robust to threats to democracy. I was very interested in this, and thought it would be valuable to get other postdocs thinking about how our training, especially in terms of critical thinking, can help us contribute to broader society.

As well as your work with the postdoc association, you've been involved in a few other initiatives around creating and nurturing communities. Can you tell us a bit more about these?

In general, I do think that building communities in science is very important and it's something that I really try to put energy into. For example, during my PhD, I initiated a program where I was hosting dinners with a mix of refugees and researchers from various different countries. I'm quite sociable and for me this was a small way of contributing to society.

Another thing I did, which was an amazing experience, was to organise one of the The Company of Biologists' Workshops. As I said earlier, I went to one as a PhD student and I had such a great time. And then, as a postdoc, I was getting quite frustrated because I'd had several funding applications rejected. So I thought that, if people didn't find my problem interesting, I needed to do something to make people more interested. I came across the opportunity to organise a Workshop and so, together with Matthew Swaffer, we put together a proposal on cell size and growth, and were fortunate to get selected. The Company of Biologists did an amazing job of facilitating all the logistics so that we could really focus on the science. The size and format of these events are really great for thinking creatively, and for generating a sense of community, which – as I say – is really important to me.

I do think that building communities in science is very important and it's something that I really try to put energy into

How did you hear about Development's Pathway to Independence Programme, why did you decide to apply and what do you hope to get out of it?

I heard about it on Twitter. And I knew The Company of Biologists, whose work I really admire, because I think they really fulfil a mission that's needed for the scientific community. I was in the middle of applying for positions in Europe, from the USA and I was finding this hard. My husband is also a scientist, and so we had geographic constraints in terms of where I could apply, which makes things even more complicated. So I felt I would benefit from some help in navigating the European system.

The mentor I was matched with, Thomas Lecuit, has been extremely generous of his time, and has helped me a lot by discussing strategy for my job applications and helping me with, for example, my chalk talk. Beyond this, I'm really excited to meet all the other fellows [all the PI Fellows will be getting together in Cambridge in late October for a meeting] because I'll get to talk with others who are going through the same difficulties, and at the same time – I hope this will be very helpful and interesting.

You've mentioned that you have the challenge of the two-body problem, and I also understand that you're on maternity leave at the moment. How are these factors influencing your job search, and where are you in the process at the moment?

I'm not going to lie – it's a real challenge to have all these constraints at once. In a way, though, it also simplifies the problem because it reduces the number of options you have, so you have to focus on the few openings that could work. In the USA, there is a strategy for dual hires, but in Europe it's very rare, and in France, it's zero. I really think there should be specific ways to help the trailing partner (who is often the woman) come back to their home country – for example, providing funds for someone to spend a year in a host lab while applying for positions. Otherwise, it's easy to end up in limbo. I'm hopeful that I will start my lab soon, but it's definitely been one of the most stressful periods of my life. I'm extremely grateful to the mentors I've met in France – including Thomas – who have helped me navigate the system here and encouraged me, and who have also had an understanding of how difficult it is to prepare for interviews just before or after having a baby. So, even though it's been extremely hard, I've felt very supported by the scientific community.

Who have been the key mentors during your career and how do you think they will influence your own mentorship style?

There's a lot of people to thank. I've definitely learned a lot from both my PhD and postdoc supervisors, who had very different styles, so have been very complementary in terms of what I learned. And I am grateful for the scientists I've met at conferences who've been interested in my work and have supported me or encouraged me. For example, I went to the Physical Biology of the Cell course at Woods Hole, and there I met teachers who are very invested in the students, even beyond the course, and who gave me a lot of advice when I was moving to the USA. As I've said already, Rebecca was, I think, a uniquely generous and supportive mentor. I really hope that I can foster some of those qualities in my mentoring style. But my experience, looking back at the students I've already mentored, is that people are so different and have very different needs. So I think one of the big challenges of starting a lab is to adapt to each individual, and to try and make the process of research – which can be very hard and sometimes lonely – happen in an environment where you feel secure, and where people will respect the pace at which you go and your anxieties facing a challenging project.

What excites you most about being an independent researcher?

Having the space to really develop my vision, which is to try to bring together my training in quantitative cell biology, my love of frog embryos and my initial training in physiology; and trying to understand better how energy is utilised and produced during development, and to integrate how this happens from the single cell scale all the way to the whole-embryo scale. I've been thinking about this question ever since I started my postdoc at Berkeley. And now I'm about to be able to really expand this vision and get other people to think about it and bring their own twist on my ideas. That's super, super exciting.

What specific research questions do you want to address?

Overall, the goal will be to look at development from an energetics perspective, which is, I think, quite new. I want to try to understand better how energy is allocated during development – how much does it cost to make an embryo and what are the constraints on growth, maintenance or morphogenesis? Where does the energy come from? And then the last aspect will be to understand at the single-cell scale, how cellular metabolism is affected by changes in ploidy and size, and to relate this to tissue or whole-embryo metabolism. The reason why I think this question is really interesting is that the consequences are new for development, because the energetics of development haven't been addressed. But findings could also shed light on evolutionary questions, for example, to understand the constraints on genome size evolution. Whole-genome duplication and abnormalities in cell size are also frequent in cancer, so understanding the metabolic consequences of this in a multicellular context is potentially very important from that perspective.

What do you think would be the biggest challenge in your transition to becoming a PI?

Being at Berkeley was super-fun because I had what felt like unlimited resources to address the problem in which I was interested. In my own lab, I'll have to make do with much more limited resources, so I'll have to be very strategic about which projects to pursue, so that we can get answers quickly enough to be able to attract more funding. I feel like this will be a big challenge. The other thing will be making sure that I manage to foster a nice atmosphere in the lab from the get-go. Despite the challenges regarding funding, I want to make sure that people are comfortable and secure enough to take risks and try things that may not work rapidly. But I was very happy in my postdoc lab so I hope this will give me some ideas about how to make the lab a fun environment in which to do research.

I want to make sure that people are comfortable and secure enough to take risks and try things that may not work rapidly

Finally, what do you like to do outside of the lab?

I'm very outdoorsy. So when I was in California, I took advantage of it, and I swam a lot in the ocean and I did a lot of hiking. Now, being back in Paris, I will have to lower my ambitions. But I hope that I can still do some of these things.

Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.

E-mail: [email protected]

Clotilde Cadart was interviewed by Alex Eve, Reviews Editor at Development. This piece has been edited and condensed by Katherine Brown, Executive Editor at Development, with approval from the interviewee.