Cell scientist to watch – Jörg Renkawitz

Jörg Renkawitz. Photo credit: Jan Greune.

What inspired you to become a scientist?

Even in early childhood, I remember trying to test and compare things. For example, I would fold paper airplanes. Every child loves trying to fold an airplane that flies the furthest. I remember building different versions and realising that the same airplane would sometimes travel further just by luck. I went up to the second floor of our house and tried throwing them into the garden, repeating it and getting kind of an average of several trials. I think that was one of the first ‘experiments’ I tried. I don't know if that was what inspired me to be a scientist, but at least I began to understand the importance of repeating and testing different things to see what works and what doesn't.

For your undergraduate and doctoral research, you worked on the biochemistry of DNA repair. What originally interested you in studying biochemistry?

In school, I was always very much interested in biology, chemistry and the intersection between both fields. My chemistry teacher was very good; he taught us about amino acids and how they fold into proteins, and how proteins ultimately create the function and shape of the cell. I became very interested in biochemistry when I realised that these simple chemicals can build such large, complex structures, and I decided to study it at university. Throughout my studies, I also had the privilege to have really fantastic mentors who were extremely creative and also great people. Prof. Dr Stefan Jentsch, my PhD supervisor, and Prof. Dr Michael Sixt, who was my supervisor during my Master's thesis and again during my postdoc, really inspired me to continue a career in science. After my Master's degree I applied to the PhD programme of the Max Planck Institute of Biochemistry in Martinsried, Germany, where Stefan Jentsch was Director, because I was fascinated with his research. This was very fundamental biochemistry research mostly on small protein modifiers, such as ubiquitin, and also DNA repair. I have always really appreciated this kind of fundamental research, and I very much enjoyed doing my PhD there.

For your postdoctoral work with Prof. Dr Michael Sixt at the Institute of Science and Technology in Vienna, Austria, and your current research, you now focus on the mechanobiology of cell migration. What inspired you to switch fields?

At the end of my Master's thesis at Ludwig-Maximilians-University Munich, Germany, I took a little ‘detour’. I had learned a lot about biochemistry and structural biology, but I was also interested in learning microscopy. I had the chance to work with Michael Sixt, who was then at the Max Planck Institute in Martinsried. In his lab, I was fascinated by seeing crawling cells live under the microscope. I enjoyed the molecular work of my PhD, but I was always still super curious about microscopy and migrating cells. So for my postdoc, I went again to Michael Sixt's lab, which had moved to the Institute of Science and Technology – so back to motile cells, microscopy and live cell imaging. ‘Seeing’ science really ended up being my true passion. Now, I combine molecular methods and biochemistry with the live imaging of motile immune cells.

What do you think are the career benefits and risks associated with changing fields?

There are some risks. Switching fields can give the impression of a gap in the CV; for me, there are several years between some of my publications on cell motility from when I was working on DNA repair during my PhD. But there are definitely benefits as well; I think that people appreciate it when you show that you can be successful in more than one field. For personal development, it's good to switch fields because you can learn techniques used in different disciplines and experience different ‘flavours’ of science. I think in the end I benefited from switching fields, because now I can combine my different areas of expertise. My PhD work involved unbiased genome-wide approaches, such as chromatin immunoprecipitation and ChIP-seq. I'm now implementing these types of approaches – including proteomics, RNA sequencing and CRISPR modification – in my own research on immune cell migration. Despite doing my PhD in a completely different field, that training was actually a very good molecular basis for the kind of research I am doing now.

In 2018, you started your own lab at Ludwig-Maximilians-University in Munich, Germany. What challenges did you face as a new PI that you didn't expect?

First of all, it's really fun to start your own lab! But of course, this comes with challenges. A really unexpected challenge was the COVID-19 pandemic. I started my lab very late in 2018 and my first PhD students started in mid-2019. Then the pandemic came at the beginning of 2020, so they were only there for roughly half a year before the lockdowns. It meant that a lot of the training phase that I really love, during which I can teach students different techniques and how to use the microscopes first-hand, just wasn't possible. It was also still too early for them to have enough findings to write up a manuscript. There were a few months that were just unproductive, but I think, in the end, we made the best out of it.

Another challenge that I didn't expect to be so difficult was definitely dealing with bureaucracy and securing grants. I wrote grants during my PhD and postdoc, but as a group leader, I now spend much more time on this. It was a surprise to see how reviewers can have such different opinions about the same proposal! The same project can be evaluated as high-risk but feasible by one person, whereas another says it's just not feasible at all. We all know that this happens in science, but it can be challenging to adapt to as a group leader. It's always helpful to have preliminary data that really support the concept of your proposal. This is easy if you have some previous data from your postdoc, but if you want to start different projects with new angles, it can be a bit more difficult to demonstrate the viability of a proposal.

What are the main questions your lab is currently trying to answer?

The overarching question of my lab is how the microenvironment influences cell functions. One of the major foci is how the microenvironment influences immune cell motility, and we are very much interested in the reciprocal relationship between the microenvironment and the cell. Cells utilize functions like macropinocytosis to sample their environment, but physical forces from the microenvironment itself also influence cell function. Immune cells in particular are very good at squeezing through extremely narrow spaces. How do immune cells maintain their stability when subjected to extreme mechanical stimuli, both from outside forces of the microenvironment, but also from inside forces generated by cytoskeletal dynamics during migration? How does the cell and its organelles remain intact and functional? For example, we know that the nucleus is a limiting factor in the sense that it's a very large cargo; it creates a bottleneck for cells migrating through very narrow pores. We have found that the nucleus itself acts as a guide to identify the path of least resistance via a process called nucleokinesis. When presented with possible paths with different opening pore sizes, the movement and mechanics of the nucleus are involved in helping the cell select permissive paths. But if a chemokine gradient is added to a path with a smaller pore size, the nucleus is also flexible enough to adapt the cell to a path of higher resistance when subjected to a strong environmental cue.

What new techniques have you adapted to better understand how motile cells navigate their environments?

To study cell motility, we use microchannels and microfluidic environments, which were pioneered in other labs, such as Matthieu Piel's and Ana-Maria Lennon-Dumeníl's groups. I started working with these systems during my postdoctoral research, using existing assets to construct certain features of the microenvironment. We continue to use these systems a lot in my own lab to rebuild different aspects of the microenvironment in a highly defined manner. It's very reductionistic, but a precise way to approach the questions we want to answer. We start with a general idea and typically directly design different variations of an environment – changing things like pore size and shape – and then test which one works best, leading us to an iteration that is more precisely suited to answering our question. For the study on nucleokinesis described earlier, we adapted a microchannel system to introduce a higher chemokine cue on one side and a mechanical cue of different pore sizes on the other side.

We've also optimised our imaging approaches to ensure we get robust and reproducible data. One way we achieve this is by imaging not only one sample at a time, but several. For microchannel experiments, we typically have an array of 100 to 200 channels. Next, we can image six of these microchannel devices next to each other and simultaneously test different six conditions. These experiments are very reproducible because we image the same cells, at the same time, in the same environment, with the same light exposure, etc. For example, we can test wild-type cells and two or three knockout cell lines at the same time under the same conditions. The ability to run these experiments in parallel really helps save time.

What would you say are the most important or interesting open questions about mechanisms of immune cell migration?

Overall, there are still many open questions about the interplay between the microenvironment and immune cell migration. How does the extracellular matrix influence immune cell migration, and how does migration affect the matrix? How do cells sense environmental cues and internally process them to make a functional decision? And then, of course, how do cells and their intracellular cargo maintain stability during the extreme forces generated during migration? We are currently working on understanding how the centrosome maintains its stability during migration, but we would like to expand to other organelles in the future.

We also have recently started an interesting project on how parasitic infection affects cell migration. Some parasites, such as Toxoplasma gondii – which infects ∼70% of the population, mostly asymptomatically – replicate intracellularly and seem to hide inside motile immune cells; a bit like being carried in a Trojan horse. Interestingly, the number of parasites inside motile immune cells can get quite large. They can form a parasitophorous vacuole inside the cell that is even larger than the host cell nucleus. It's relatively unknown how the parasite continues to spread when it introduces this challenge to its host cell. How did these parasites evolve to ensure that they don't get lost or damaged as the host cell squeezes through narrow pores? It looks like that even when the parasite cargo is very large, the host cell is still extremely good in migrating through narrow paths. This was surprising for us to see at the beginning of the project, and really exciting.

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

One aspect of my approach is having an open-door policy. It's really important for me to physically be there in my office when I'm not at a conference or a meeting, so that every team member can come by anytime to ask questions and really discuss things. In my group, we have a very flat hierarchy or even no hierarchy at all. It's important to me that everybody can feel equal in a discussion and share their good ideas, and that the discussion is not dominated by one person. We also make sure to take care of each other, even outside of the lab. This was quite difficult during the pandemic, but it's much better now. I'm very happy now that we can do regular lab retreats again to keep up the team spirit.

To make sure new lab members are a good fit for the team, I think it is important to see the applicant in person. What I typically do is discuss science and project ideas with the applicant and ask them to give a talk about their previous research, to get a good sense of their scientific thinking. Then, applicants usually spend a whole day in the lab and have individual discussions with every lab member. I collect opinions and see whether the applicant would be a good match for the group.

You and your lab members regularly attend and present at scientific conferences. What is your approach to conferences and what would you say is most valuable about attending them, for young PIs and for students?

The obvious value of attending conferences is having the chance to interact with others and discuss your work. Science benefits a lot from these discussions and from not hiding interesting data until publication. I think it's extremely important for PhD students to go to conferences that have a good thematic fit with their project in order to discuss their data and to also get new ideas. I try to have new lab members go to one or two conferences very early, in the first year if possible. I think this is great for students because if you're new in the field, you can get a direct sense about ongoing questions in the field, but also established topics and methods. I highly recommend doing this early on – even without having any data to present – to get a broad overview of the field.

What is the best science-related advice you ever received, and what advice would you pass on to young researchers?

No specific piece of advice comes to mind, but I learned a great deal from my PhD and postdoctoral mentors. Stefan Jentsch always really emphasised looking at fundamental principles and not getting too much into details, and Michael Sixt is super creative in the way he addresses scientific questions. What I took with me from my time in Michael's lab was his way of thinking outside of the box, because it's critical in science that you have fun while doing it! I would advise young scientists that it is important to ask fundamental questions about scientific principles, but also to follow the things that you are really interested in and motivated by. Sometimes, I feel that scientists are too focused on selling stories, almost as if we're marketing our findings. I really don't like that, because in the end, science should be about discovery. A good paper should be something new, and whether it's interesting or not can be judged by the scientific community.

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

I enjoy sports, and I like to go hiking and climbing. I have two sons aged ten and twelve and my youngest son is very much into soccer, so I've starting playing a little. My first son was actually born when I was still working on my PhD. I had kids earlier in comparison to my peers, but I never regretted starting a family because I had a degree of time flexibility during my PhD and postdoc. I would wake up very early in the morning with the baby and rock him in my arm while typing my thesis on an iPad. Being a parent let me exist in a completely different world for a while and gave me a bit of distance from science, which I think can be helpful for creative thinking.

Do you think there is enough support available for scientists with families?

Having children early in a scientific career can be difficult when advancing your career requires moving to new places. The older the kids get, the more challenging that is. I think it's also still a bit of a problem in science that eligibility for funding opportunities is often inflexible and time-limited. Many positive changes have been made, especially for women, but I think considerations should be given to any researcher who is a parent. As a father, having small babies at home still took up a lot of my time in addition to doing research full-time. Being a parent is just a different type of productivity, and I think it would be great if this was more acknowledged, especially for early-career researchers.

Jörg Renkawitz 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.