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Aiming high!

Skitouring, scrambling crests towards the summit, climbing steep rock faces. Maria Hondele is aiming high. As a newly appointed professor, she is also climbing to academic heights. The recently awarded ERC Starting Grant comes just in time for a successful start at the Biozentrum.

You have just started here as a professor of biochemistry. Was this a lifelong dream?
In my school days, I always wanted to become a physician, a helicopter doctor in Norway and later a pediatrician. That is why I initially studied medicine for two years

But then things turned out differently?
While studying Medicine in Regensburg, I soon realized that I wanted to fully understand how things work and that I wanted to be a researcher, not a physician. I was very lucky that my department supported me in my rather unusual ambition to study biochemistry and medicine in parallel, but it worked out really well. Later, they even continued this model and a “Molecular Medicine” degree, combining both disciplines, was officially launched.

What came after your studies?
I started my PhD in chromatin biology at the European Molecular Biology Laboratory (EMBL) in Heidelberg and completed it at the Ludwig Maximilian University of Munich (LMU). So I already have some experience with moving a lab (she laughs).

And why did you do your PhD at two institutions?
It wasn’t planned that way. I had been at EMBL for three years and just started writing my thesis when my supervisor moved to the LMU as a full professor, so the plan was that I finish in Heidelberg. But while writing I had an idea about how to crystallize a protein complex. That weekend I went back to the lab to try, and it worked! It was clear that this could be a big story, so I stopped writing and went back to my beloved pipettes. During that time, we moved to the LMU.

And then you were drawn to the ETH Zurich…
Yes, for the past six years I was a postdoc in the lab of Prof. Karsten Weis. After my PhD, I wanted to change research direction and methods a bit, so – and this I would encourage any PhD to do – I asked friends and colleagues which labs they would recommend. This resulted in quite a list of really good suggestions, from which I visited three and finally chose Karsten’s lab. The combination of cell biology, biochemistry and structural biology was exactly what I had been looking for.

Did you already touch on your current research field there?
I wanted to work on RNA and was thinking about study- ing its turnover. Karsten tried to convince me to work on Pbodies, membraneless organelles that play a role in RNA turnover. At first, I was not sure – these P-bodies had a somewhat shady reputation among some of my structural biology friends – but I pretty soon became fired up, and the story also developed far beyond P-bodies. The more I learn about these membraneless organelles, the more fascinating they become!

What are they?
They were first described as such about ten years ago, as liquid-like cellular structures that concentrate certain molecules, but unlike classical organelles are not membrane bound. Hence their name membraneless organelles. When I started my postdoc, this was relatively new and I had to first convince some of my colleagues that those droplets which I started to “build” were real structures. At first, some thought this was condensation on the microscope’s objective and that I should clean it properly.

If these droplets can be seen so clearly, why weren’t they discovered earlier?
From the literature, we know that these structures had actually already been observed much earlier. But back then, people probably did not recognize the special biophysical properties of these droplets and that they could have a special function. Now researchers worldwide are studying this phenomenon but there are still so many unanswered questions: What are the droplets good for? Why are they important for the cell? Why do the components accumulate at a certain location in the cell? What can their components achieve together that each of them cannot individually?

Is it known how membraneless organelles develop?
They are formed by a process called liquid-liquid phase separation. It is kind of similar to making vinaigrette, where the oil droplets do not mix with the vinegar. In principle, the same occurs for some proteins in the cell. Droplet formation, which also depends on the state of the cell, is extremely dynamic and reversible. It was fascinating to discover that an entire family of enzymes, the so-called DEAD-box ATPases, regulate the formation of some of these membraneless organelles. This makes phase separation an actively regulated process, so the cell gains influence on the flow of substrates and information.

What is the function of these droplets?
There is much discussion about this. They could be storage depots, but also serve as biochemical mini-factories, where enzymes and substrates are concentrated to enhance reactions. I have specialized in RNA containing droplets. I am interested in how these membraneless organelles influence the fate of RNAs, and how this is controlled by the cell. It could even be a novel layer of gene expression regulation.

These membraneless organelles seem to be quite important for the cell. What happens if they don’t function properly?
They have been linked to neurodegenerative diseases, such as Alzheimer’s or amyotrophic lateral sclerosis (ALS). Defective membraneless organelles might be a precursor of harmful protein aggregates. On the other hand, it has been speculated that such phase-separated structures might have formed at the origin of life, as tiny reaction chambers in the primordial soup.

Science thrives on good ideas. How do you get your ideas?
When I am out in nature. In the morning when I run or for example also once on a ski tour. I got up before 5 am and drove to the mountains with a friend, before going to lab. The day was perfect, the sun just about to rise after a clear but freezing cold night, perfect powder and nobody but us in this winter wonderland. When you walk up you can hardly talk, you just follow the trail, it is very quiet. And that’s when I had the idea for an experiment that had troubled me for quite some time – and it really worked. Switching off and recharging my batteries in the mountains works very well for me. In winter it is ski tours, in summer alpine hiking, biking and climbing.

Yes. Climbing is often like a mini holiday. Sometimes you have to start early, so you often sleep outside in the mountains, if you are lucky you even see the Milky Way. I like climbing as a sport. It requires technique, precision, concentration and “mind power”. Of course, dangerous situations can also happen, though very seldom. So you have to develop a certain routine and ability to stay calm, and choose a climbing partner that you can trust completely. But above all, when you climb you get to know yourself.

Curriculum vitae
Since September 1st, Maria Hondele has been an Assistant Professor of Biochemistry at the Biozentrum. Prior to this, she worked for six years as a post- doctoral researcher at the ETH Zurich. Maria Hondele studied preclinical medicine and biochemistry at the University of Regensburg. She carried out her PhD at both the European Molecular Biology Laboratory (EMBL) in Heidelberg and the Ludwig Maximilian University of Munich (LMU).