Interview with the 2024 Hooke Medal winner Emmanuel Derivery

Emmanuel Derivery. Image Credit MRC Laboratory of Molecular Biology.

Congratulations on winning the BSCB Hooke Medal. What does this award mean to you?

I'm deeply honoured on different levels. For our team, this award highlights that our excitement for the way we do science, combining fundamental research with technology development, is shared by the community, which is a great feeling. In my lab, sometimes our work takes us in many different directions at the same time, but I think that this is a very good tribute to us having overall the right approach. Also, as a microscopist myself, it is a very big honour to be recognized for a microscopy-related award like the Robert Hooke medal. The cherry on top of the cake is that the medal was designed by Brad Amos, who is not only a microscopy legend but also from the LMB. Obviously, that was before my time, but it means a lot. The last bit is that, because I'm French and the UK is my country of adoption, it's amazing to feel recognized by the British Society for Cell Biology. I think it's really a tribute to the internationality of science.

What first inspired you to become a scientist?

My family. My dad was an engineer, and he taught me that when you see something, you should always try to understand how it works, whether it's a machine, an electrical circuit or an organism. My mum was an academic in the humanities and she gave me a love of in-depth study, research and dedication to a certain topic. I eventually discovered that my passion was not to understand how machines work, but how cells work. I think the reason I went into biology is that I was always interested in doing a little bit of everything – cell biology is a multidisciplinary field where you can use math, physics, chemistry and biology to understand a problem. That was the place where I felt I would have the most fun!

During your PhD and postdoc, you worked on regulators of actin polymerisation. What drew you to studying fundamental cell processes?

My studies were in cellular and molecular biology. I wanted to study basic molecular mechanics in cells, and I've always loved the cytoskeleton. It's been studied for so long that we have a really good understanding of its structures, biochemistry and kinetics. There was so much already known about the cytoskeleton that I thought it was the perfect thing to build on in terms of complexity. I wanted to use all the knowledge we had about the cytoskeleton in vitro to understand how it is regulated in cells. In my third year of university, I did my first ever summer internship at the Institut Curie in Paris in the lab of Alexis Gautreau, who also ended up being my PhD advisor later on. He was working on actin, and he hooked me on it. I've been working on actin ever since!

How did you then become interested in cell polarity and asymmetric cell division?

There are two reasons behind my move into asymmetric cell division and polarity: one is the phenomenon and the other is a person. At the end of my PhD, I was considering either going into single-molecule imaging and understanding single molecules and structures, or more towards tissue-level complexity beyond the cell and understanding how cells talk to each other. I interviewed in labs that were doing either full-blown in vitro reconstitution or tissue work. Then I met Marcos González-Gaitán. He was working at the tissue scale in Drosophila, but I told him that I was interested in single-molecule methods as well. Amazingly, he told me that if I came to his lab, I could do both. At that time, they had discovered this fascinating unequal segregation of endosomes during asymmetric cell division. How this happened was a big mystery and I thought that would be a very cool subject to work on. I think asymmetric cell division is super interesting because it's fundamentally a symmetry breaking process that happens very quickly, over about half an hour. Polarity exists in all kinds of cells, like epithelial cells or neurons, but it takes much more time – days – to break the symmetry of those cells. However, a lot of the molecular modules in asymmetric cell division and polarized epithelia are likely the same. The cells are always reusing the same molecules, so asymmetric cell division is a perfect system for studying and imaging cell polarity in a reasonable time frame.

When you started your own lab in 2016, what questions did you set out to answer?

While I was studying the asymmetric motility of endosomes during my postdoc, I discovered that the anaphase spindle becomes asymmetric. This was causal to the polarised endosome phenomenon, but from a cytoskeleton point of view, it didn't make any sense how there could be more microtubules on one side of the cell than the other. I decided to try to understand this when I started my lab, and I was lucky enough that my postdoc advisor let me leave with the project. We initially worked on it from two angles. We continued to use the bottom-up approach using genetic screens in flies to identify all the machineries that are involved, but I also knew right from the beginning that I also wanted to do the reverse – impose polarity on an unpolarized cell to figure out the minimum machinery required to do the job. This is what led me to synthetic biology.

While I was writing my proposal for a faculty position, I had the idea of using a transmembrane protein segment that could act on the inside of the cells by transmitting polarity signals from the outside, but the problem was how to polarize this tool. The strategy I put in my original proposal obviously didn't work. Then, I had a fearless PhD student, Joe Watson, join the lab. He tried many, many crazy ideas until we ended up with de novo designed protein polymers through our collaboration with David Baker's lab. Subsequently, a postdoc who later joined the lab, Lara Kruger, pushed the power and applications of this system forward. This is definitely not the way I thought we would solve this problem, but it was a fun ride.

Your research incorporates a great deal of in vitro reconstitution and protein design. In your opinion, what insights can these methods offer to cell biologists?

I'm a firm believer that more biologists should adopt in vitro reconstitution. There's a classic quote from Richard Feynman: “What I cannot create, I do not understand.” I would paraphrase it into, “What I cannot reconstitute, I don't understand.” I think the beauty of in vitro reconstitution is that it can tell you the minimum number of proteins that can reconstitute a cellular phenomenon. It doesn't necessarily tell you how the cell does it, but it tells you what is sufficient for the system to work and gives you a theoretical framework for how to think about the process you are interested in. I view a lot of the in vitro reconstitution approaches in the same way as synthetic biology approaches – it's really all about sufficiency. What are the proteins that are sufficient to induce a phenotype or phenomenon? If you have identified a sufficient cause, it will pretty much guarantee the effect. For example, from our work on reconstitution of PAR complex polarity, I now know that a cell that has an asymmetric cortical enrichment of the PAR complex must also have an asymmetric spindle. If it doesn't, something is missing. This in-depth understanding that these approaches bring is a real strength. Even though you can't use in vitro reconstitution for everything – it requires a field that is really advanced, with decades of existing work to have identified all the players – I think that every time in the history of biology when people have managed to reconstitute a phenomenon in vitro, this has led to a giant leap in our understanding.

How complex are the biological phenomena that you have worked on reconstituting?

A simple system might look at the effect of one protein on tubulin dynamics using only two proteins in solution, and it's relatively easy to understand who is doing what. Looking at multi-protein complexes, a lot of complexity is added, but it's still a one-to-one stoichiometry. These systems are kind of the bread and butter of the lab. Our very ambitious projects involve dozens of proteins. Keeping all those proteins happy is a conundrum, because they don't like to be out of the cell, but you have to take them out to understand what they do; yet when in solution, they don't do what they are supposed to do! It's very difficult. One of the major achievements of the in vitro reconstitution field came from the lab of Marie-France Carlier, who reconstituted actin motility with six purified proteins in 1999. This required a lot of work because the activity of each of those proteins was basically a bell curve that was a function of the five other proteins' activities. These dimensions create an immense space to explore to find the point where everything will work properly.

How many proteins is too many? We often discuss this problem in the lab, and I think there are two solutions. First, if you have many proteins in your reconstitution assay, you should image them all together to collect a lot of information from the same experiment. This is why we are developing technologies to image many proteins at the same time – to enable us to do fewer experiments but get more information per experiment. Second, I think it's important to go back to the complex solution of the cell or cell extract to see whether it says the same thing as your in vitro reconstitution. If we want to understand cell behaviour, we will have to understand, for example, all the cytoskeletal proteins and how they are regulated, which means adding back in the regulators and unentangling that complexity. Hopefully at some point the data meet, and this is when you have understood the phenomenon. However, it takes many, many years to do all those individual reconstitutions. I think that at some point we are going to need high-throughput in vitro reconstitution approaches, the same way we have high-throughput cell biology and imaging, to explore the full range of concentrations and variables. That's why a place like the LMB is great, because they are interested in these kinds of long-term projects.

You've led a lab for 8 years now. How are the challenges you face now different from when you first became a PI?

When I started the lab, we were only two or three people in total. I was still at the bench, so I could follow what everyone was doing. Also, everyone was mostly using techniques that I knew how to do, and I was teaching them, little by little. Mentoring was very smooth. Now, 8 years later, the lab is much bigger. We do a lot more things, and so I feel that I can't follow everything as much as I would like to. But this is by design as well – to keep our creativity very high, I've hired people that know how to do things I don't. That means that I always have do some to catching up to understand what they are doing. I would say that's the biggest difference, and it's very challenging, but my lab members are incredibly fearless, and they keep me sharp.

On the infrastructure side, when I started the lab, we had to install our instruments, make sure that they worked, establish standard operating procedures for everything and create databases and storage servers. Now, I can see everything that we did wrong, like the things we kept track of that were ultimately useless and the things that we did not keep track of that actually would have been very useful. I'm obsessed with traceability, but keeping track of absolutely everything sometimes creates a burden for the people working in the lab. For example, setting up a system to track the number of aliquots of every reagent just ends up increasing entropy whenever someone forgets to update the list. I've learned to rely on people to organise themselves in addition to streamlining processes and promoting efficiency.

What is your approach to mentoring and establishing a good lab culture?

I try to listen as much as I can. A tough part of this job is understanding how to have a good working relationship with different lab members and help them integrate with the team. We are very multidisciplinary lab, and I try to make sure everyone talks to each other. We have pure biochemists, cell biologists that also do some work in flies, and now a microscope builder and a physicist have joined the lab. We have a lot of synergy because everyone has different skills, and they can all help each other. I expect the people I hire to be curious about what the rest of the lab is doing even if they don't know certain techniques. When I hire an engineer or a physicist, they just need to be interested in biology; they don't have to know all the details of the biology we are working on. Vice versa, I also expect the biologists in my lab to want to learn enough about microscopy to do imaging correctly. However, as a PI, I also have to be very careful that people don't think that a project is not theirs anymore. I try to always make it clear that there is no competition in the lab. So far, I think it's been working well. Basically, everyone in the lab contributes to all our projects in some way or another, which to me is a great source of pride.

What is the most exciting project or discovery that you've been part of?

It's hard to say! I'm excited by everything! Usually what excites me most is our latest results, and then 1 week later it's something new. Beyond my own lab, we've seen a revolution in what protein design can do for cell biology. Protein design is a major breakthrough of the past decade, hand-in-hand with AlphaFold and structural modelling. We now apply it to basically every project in the lab. Through our collaboration with the Baker lab, it's amazing to see that now we can modulate cell biology in ways that we couldn't until very recently. You can actually design a protein that will do what you want. This gives us an extra set of tools to interrogate cell biology, and I think it's just remarkable. Protein design and synthetic biology are going to impact big questions in cell biology in the future. For instance, if you are studying interactions between two proteins that are involved in multiple specific phenomena, it's challenging to isolate the function of one interaction and not another. With protein design, you just make a protein that blocks one key interaction, without changing the expression of any of the proteins, so you can really pinpoint its molecular function.

What is the best science-related advice that you've ever received?

A piece of advice that has shown up a few times for me is that sometimes you have to stop talking and listen. No matter the level you are at, at conferences or in interviews or in rebuttal letters, it's easy to feel attacked when somebody is questioning your data. Scientists have a tendency to want to promote their own ideas, but sometimes we don't necessarily easily convey what we mean or why we see a problem with an experiment. Science is also international, and we often have a language barrier as well. I think it's very important to just sit down, relax and try to really understand what the other person is saying, because usually they have a point. It's very important to listen to others' science, because science is an exchange, and you can learn just as much by listening.

What advice would you give to early career researchers looking to start their own labs?

First: location, location, location! Be sure the place you're applying to is the right one for you, your family and your science, not the right place for somebody else. The environment and your colleagues where you start your lab are so important−I wouldn't be where I am now if I had not chosen to come to the LMB. I'm a purely curiosity-driven scientist. At the LMB, my colleagues John O'Neill and Rachel Edgar were working on circadian rhythms and osmolarity regulation. I have a historic interest in measuring biophysical properties of the cytoplasm, like viscosity, and we started a discussion that led us to study how water, temperature and the biophysical properties of the cytoplasm are regulated. That collaboration produced a completely new research area in the lab, working on how cells cope with changes in temperature. None of us set out to study that question; it just popped up out of nowhere.

The second piece of advice I would give is not to grow your lab too fast. In my lab, I think it was definitely very useful that we took things slowly. This allows you to keep close account of things at the beginning to make sure the lab is on the right track. In an interdisciplinary lab, if you expand really quickly you might not have the right dialogue among members with different research backgrounds. This is a very personal choice, and some people naturally have the mentality to lead armies in their labs. For my personality, I really like to teach and closely mentor the people in the lab, so a small lab was the best option.

Finally, could you tell us an interesting fact about yourself that people wouldn't know by looking at your CV?

I like to read about engineering, especially spy planes and spacecrafts from the 1960s.

Emmanuel Derivery was interviewed by Amelia Glazier, Features & Reviews Editor for Journal of Cell Science. This piece has been edited and condensed with approval from the interviewee.