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“It feels great that metabolism is back to focus”

 

Heidelberg, 14 October 2020 – Markus Ralser, one of two recipients of the EMBO Gold Medal 2020, talked to EMBO about his work on the origins, evolution, and functionality of the metabolism, his fascination with biology, and the challenges he faced during his career. 

 

Q: When did you first become fascinated by biology?

A: I grew up on a farm in northern Italy, so I was surrounded by biology since my early childhood. Genetics, biology, chemistry have always been my favourite school subjects. After high school, I was supposed to take over my parents’ farm in the Alps, but then I said, ‘maybe I try something else,’ and I enrolled into an undergraduate programme in genetics. I never planned to be a scientist—perhaps I didn’t know at that age what being a scientist really means—but the closer I got to it, the more exiting it became, so I ended up doing a PhD.

 

Q: During your PhD, you focused on neurodegenerative disorders, then you transitioned to study metabolism. What motivated you to pursue metabolism as a research interest?

A: Neuroscience is exciting, but I always had the feeling that we are far away from understanding neurodegenerative diseases. When it came to metabolism, it was exciting to be able to use simple systems and have problems that are so precise that they were much easier to address.

 

Q: You have made some important discoveries about the origins and evolution of metabolism. What were the key findings of your studies?

A: We observed that metabolic pathways are much more flexible and dynamic than one would have anticipated from the textbook, and that the core structure of metabolic reactions doesn’t depend on the evolution of enzymes. We observed—more or less by accident—that a reaction sequence that looks very much like glycolysis, one of the most central metabolic pathways, spontaneously assembles in the presence of Fe(II), which is a very abundant metal ion in Archaean sediment. So, the basic structure of metabolism may not have originated over time by evolution, which was the dominating view, but it is the consequence of the reaction properties of the metabolites that constitute metabolism. For the first time, we had experimental evidence that the origin of metabolism is likely an environmental-chemical one.

 

Q: This discovery revived a long-discarded idea about how metabolism could have evolved in early life forms. How did the scientific community meet your findings?

A: Some colleagues really loved it, but other people called me an idiot. Now, getting the EMBO Gold Medal means that people start to trust our findings, but at the beginning not everyone would say, ‘well done,’ and pat me on the back—no way. That’s part of science: if you find something that everyone already knows intuitively, then everyone agrees from the start. But if you come up with something that is not obvious, or something that has been categorically excluded by some leaders in the field, then people get sceptical, and that's exactly how science needs to be.

 

Q: You have also contributed to our understanding of how metabolism functions. What insights did your work reveal?

A: We observed that if you stress cells—by exposing them to something toxic or to heat—metabolic pathways regulate themselves within seconds. This helps the cell to establish a protective metabolism. This system does not always require changes in gene expression or signalling—it’s a self-regulation of metabolism, and it can work really fast. More recently, we found that cells take up some metabolites not only for growth, but also to become more robust and stress-tolerant—we  call this ‘metabolic harvesting’. So, another key take from our work is the self-regulatory capacity of metabolism, and its role in stress protection.

 

Q: What is your lab focussing on now?

A: We're after the basic principles of metabolism. The more we understand the rules that govern metabolism, the closer we get to understand what defines a cell and the basic properties that make biological systems work. At the same time, our lab works a lot on technologies that help us to study metabolism. For instance, we developed a tool that can quantify a proteome in less than one minute, so we can now analyse thousands of proteomes in a short period of time and at low cost. Such a technology can be transformative in many medical applications, because you could use it to measure plasma samples from thousands of patients that suffer from a particular disease. For metabolism, using these large datasets, we were able to use machine-learning methods and predict a broad metabolome of a yeast cell quantitatively. There is amazing potential in this: if you can predict a complex phenotype, it means that you have captured its critical components, and hence you start to understand how these different components—enzymes and metabolites in our case—work together.

 

Q: You made some fundamental discoveries by building your own tools to address specific questions. How important is interdisciplinary research for you?

A: It is key. However, you cannot be at the same time a top-tier biologist, top-tier physicist, top-tier mathematician. If you do multidisciplinary science, you need to work with colleagues and learn from them—that's the only way to generate something new and make an impact. We need to break down the walls that exist between the different disciplines. This, of course, requires a lot of patience and tolerance from the ‘experts’, and also some self-confidence when someone calls you ‘naïve’.

 

Q: You started your own lab when you were only 27 years old. What did you learn and what’s your advice to young group leaders?

A: The challenge of becoming group leader at a young age is that you are less experienced than somebody who has done a lengthy postdoc. And the nice thing is that you are less experienced, and although you do some mistakes, there is some tolerance among senior scientists about that. I started my own lab before I had kids, which means I had to learn that when people have families, things are different. My advice to young group leaders is to appreciate that people are different from you: you can create a very nice atmosphere in the lab if you accept that everyone tries to work hard towards the goal in different ways.

 

Q: At the moment, you have one lab in London and one in Berlin. How do manage to coordinate research in two different countries?

A: It works because I have brilliant, smart, self-confident lab members, who make my life as a supervisor very easy.

 

Q: How did the COVID-19 pandemic influence your research?

A: When the pandemic hit Europe, we were working on a high-throughput proteomics pipeline, so we have been actively engaged in this research ever since: we have run thousands of samples on our mass spectrometers, and we can now predict COVID-19 disease progression. In a way, it was a very productive time—that’s important, because we are in the middle of a big crisis and there is a lot of work that needs to be done. My lab was always operational for projects that were considered of high importance such as the COVID-19 project. But we had to shut down the basic science projects. Many of my lab members had lots of datasets they needed to analyse, so they did this from home. Also, since my lab is split between London and Berlin, we were used to use video conferencing software: already before the pandemic, all of our meetings had a virtual component. So, for us it wasn’t a big shift to move to the cloud for organizing the lab. We had a little bit of a head-start in that sense when the catastrophe started to unfold.

 

Q: What does receiving the EMBO Gold Medal mean to you?

A: It’s just brilliant, I’m super happy. I was also so happy to hear that Sarah-Maria Fendt is the other recipient—I've known her for many years and she does fantastic work. It feels great that metabolism is back to focus.

 

This interview has been edited for length and clarity.

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Tilmann KießlingTilmann Kießling
Head, Communications
T. + 49 160 9019 3839