[Narration] Adam Levy
Hello and welcome to the 2024 podcast for the Eppendorf Award for Young European Investigators. I’m your host for the year, Adam Levy. The awards ceremony took place as usual at the European Molecular Biology Laboratory in Heidelberg in Germany. So, I headed down to catch up with this year’s winner, Clemens Plaschka, who’s based at the Institute of Molecular Pathology in Vienna, Austria. Clemens’ award-winning research investigates messenger RNA (or mRNA). These molecules have received a lot of attention lately as many modern vaccines, including for COVID-19, make use of them. But mRNA is also a key component of all eukaryotic cells, that is cells that contain a nucleus, like human cells. So, I sat down with Clemens’ to ask him what mRNA is and his quest to find out how it operates in our cells.
Adam Levy
First and foremost, congratulations on winning the prize. Could you maybe recount your reaction when you heard that you’d won?
Clemens Plaschka
First, thank you so much. I got a phone call telling me that I’d won the prize and I was super excited and the first thing I did is I set up a quick, impromptu meeting with the entire lab for a surprise celebration, and they thought I was having another child, but it turned out to be something different and that was really great.
Adam Levy
Let’s actually talk about what you won the prize for which is mRNA, messenger RNA. Could you just give us a little bit of a breakdown on what mRNA is, what its function in our cells is?
Clemens Plaschka
Messenger RNA is the carrier of our genetic information. It transfers information from our genome that is stored in DNA to proteins that exert all sorts of activities in the cell. So in our lab we’re trying to understand how messenger RNA, as this key molecule for cellular life, is made.
Adam Levy
Why is it important then to actually understand mRNA and how these processes with mRNA work?
Clemens Plaschka
Messenger RNA is essential for cellular life. The processes that take place take place in every eukaryotic cell and in every cell in your body, at every moment, really. So, we think it is important to understand how a healthy cell functions. That has implications both for understanding the process but could also help in the events when defects of disease occur.
Adam Levy
At least when I learned about mRNA in school, I just learned about it as this go-between between DNA and these proteins and that was kind of it. But actually that “going-between” is a really complex orchestra of processes, right?
Clemens Plaschka
Absolutely, it’s really staggering to see how many individual steps there are when you go from the DNA to protein. One of the big reasons is to ensure the fidelity of gene expression such that only functional protein is made.
Adam Levy
The picture we maybe have of messenger RNA is actually probably quite simplistic and the real process is maybe quite a bit more complicated. How does your work try to unpick the complicated processes which take messenger RNA from the DNA and end up building proteins?
Clemens Plaschka
In the ideal scenario what we would like to see is a movie of how each of these steps occur, but in practice that is not possible. The way you can think about what we do is in thinking about a car. When you see a picture of a car you see the engine and the wheels, but seeing a single picture does not tell you what the wheel does or what the engine does. What is important to do is to get several snapshots of the moving car in order to understand how it works. In our research we try to do something very similar: we try to take three-dimensional snapshots of intermediates in that reaction to better understand how the car, or in this case this molecular machine, works.
Adam Levy
How hard is it, once you have these snapshots, to try and fill in the gaps in between them?
Clemens Plaschka
That depends a lot on which part of the path we’d be studying. For some, there has been sufficient work that it becomes easier to slot in the intermediates, but what I’ve been quite surprised by in the last years is that, whenever I felt that we understand these two steps because we had these two snapshots, a third comes around and it changes the picture or at least it adds something substantial to the picture. So how many pictures we will need is unclear. Every time we get a new one it’s of course great because it allows us to build new models and hypotheses that we can then test further down the line.
Adam Levy
Now, for people like me who aren’t from your field, it can sound kind of easy to just “take more snapshots.” Can you explain what is actually behind taking a snapshots of these processes?
Clemens Plaschka
Yes, it’s perhaps not as easy as I made it sound. What we need to do is we need to enrich this intermediate of the pathway, so imagine it as kind of a set of Lego blocks stitched together. We need to somehow purify this set of blocks from the cell. In a normal project, depending on what it is, it might take one to two to three years to prepare just that intermediate. Then you image it and then you analyse your data to try and build back up this three-dimensional picture. It is rather labour intensive but the reason we do it is because we hope and we know sometimes that we will get that picture.
Adam Levy
So far are there any key learnings about how mRNA acts within our cells that you can share with us?
Clemens Plaschka
There are multiple really exciting findings but I will highlight only two. The first one is that we have long known that that mRNA itself is not a string, like an unwrapped piece of yarn, but is rather a compacted molecule. In our lab we better elucidated how and which proteins act on the mRNA, to select it as mRNA and prepare it for the process of gene expression. And the second finding in the lab has been to then understand how once an mRNA has been identified as such, how it is further prepared for the so-called step of export, and that is the step where the mRNA is moved between two cellular compartments, one where DNA is stored and the other where protein is made.
Adam Levy
Now you’re someone who has been thinking about messenger RNA for a long time, long before you set up your own lab. With that in mind, how does it actually feel to be shedding these new insights on this really fundamental part of the working of our bodies, of ourselves?
Clemens Plaschka
It’s extremely exciting and satisfying, I think, when we make one of these discoveries. You can imagine that in the lab we spend years working towards a goal and when you finally get there it feels like you’ve climbed the peak of the mountain, and that is definitely super satisfying.
Adam Levy
Could you share a little bit what that actual process has been like of doing this, going from actually setting up your own lab to getting to this stage where your work is acknowledged with awards like this?
Clemens Plaschka
I would say that, overall, the experience has been really positive, but I do have to say that the first two years of setting up the lab were really stressful. You’re trying to set up something like a start-up company from scratch and the first two years most of what I could think was “this is not going fast enough,” for my tastes at least. But I’m very grateful for all the wonderful people who have worked with me in the lab, and so it’s definitely really, really cool to now see that we’re reaping some of those fruits of having invested a lot of energy to setting up what for me was a new system in this biological pathway.
Adam Levy
Actually, you’ve spoken before what lead to these successes in your work and you’ve really emphasised just how important picking the right people and setting up the right dynamics in the lab are. Could you share a little bit about what your approach to building a team is?
Clemens Plaschka
I’m not sure I’ve figured it out. What I do look for is people who seem to be passionate and excited about science, and who seem to be fun, which allows us to overcome these frustrations we very often meet in science. There are different ways that you could run a lab or a set of research projects. You could run them as every person does their own thing in principle, isolated of their neighbour. Then the alternative would be that people would work together towards a common goal and that has been our approach. One can argue that this is maybe perhaps not the most traditional approach, but I have found that to be extremely rewarding, which simply gets us to the goal faster and I think it makes our science also better.
Adam Levy
Apart from your approach to actually building your team and building your lab, what approach do you take for actually conducting the research within your lab?
Clemens Plaschka
I try to always ask myself when picking a project whether if we’ve got where we wanted to, would we pass the so-called deletion test. The test is, if we were to remove our contributions from the field, would it have made a difference. I would love for that answer to be Yes. In various stages of my career and also now, when we think about a project, we think about whether we can make with that project a unique contribution to the field and if it is then we feel that’s worth doing. More specific towards our approach, we feel that, based on what had been done in the field of this mRNA expression pathway, the information is also partially still really lacking and is to understand how these molecules, how they come together in three dimensions, and so that’s why we take this approach of trying to visualise these intermediates in three dimensions.
Adam Levy
So with those visualisations you now have these 3D snapshots, this kind of comic book of different moments along the process. Where is this research going, where do you see understanding of messenger RNA in the next five, ten years?
Clemens Plaschka
We are getting better and better at understanding how these individual steps work. I think the next big question for the field will be “how are these individual steps coupled functionally to each other?” How do we integrate all these individual steps which are, on their own, already quite complex into that big picture which is exactly what should be happening inside cells.
Adam Levy
What then does it mean for your research going forwards to have your work acknowledged with a prize like this?
Clemens Plaschka
I think there are two aspects to that. One is that it’s of course wonderful to be recognised for some of our contributions to the field. I think it’s extremely motivating for the team as well. The second aspect is that, I hope, in part, what this prize would bring is some extra visibility for the work that we do beyond our immediate field of research.
Adam Levy
For you, I assume you’re not purely motivated by prizes like this, so then what does motivate this kind of work? Is it more, I suppose, the fundamental understanding or the potential for medical implications down the line?
Clemens Plaschka
There are two aspects that motivate me in science. The first is very selfish: I like puzzles a lot, I like understanding problems. Trying to understand this very basic cellular pathway is a big puzzle that has bugged me for a few years and will continue to do so. That’s the very selfish motivation. The second aspect that I appreciate more and more, especially since having had a child, is that what we do is important, it contributes to our collective knowledge in society on basic processes that allow life. I think that is important in its own right. I of course hope that some of our work will be made use of in more medical contexts, but our primary motivation is really to understand the very fundamental steps.
Adam Levy
Have you spoken with any researchers who’ve shared any interest in using your kinds of findings to work on health implications?
Clemens Plaschka
I did actually speak recently to a clinician who was interested in one of the proteins that we work on. The future will tell where these kinds of conversations go, but I’m definitely excited to engage.
Adam Levy
Well congratulations again on the prize and I hope you enjoy the rest of the day including your presentation.
Clemens Plaschka
Thank you very much.
[Narration] Adam Levy
That was Clemens Plaschka, winner of the 2024 Eppendorf Young Investigator Award. While I was in Heidelberg, I had the chance to meet two of the judges of this year’s awards, Michael Sixt of the Institute of Science and Technology in Vienna, and Laura Machesky who’s based at the University of Cambridge in the UK. I started out by asking them just how special Clemens’ work is.
Michael Sixt
The impact is twofold. One is that, I think, it’s quite spectacular to solve the structure of a protein complex of this size. That, as such, is a technical achievement but I think it’s also a big question in the field, how the export actually of the mRNA from the nucleus works mechanistically, and the only way you can understand this is if you see the molecules at work.
Laura Machesky
This work has really changed the textbooks in the sense of we think of RNAs as these long strings that come out of the nucleus. Clemens’ works shows that that’s wrong and that they’re exported in packages rather than in this kind of long stringy sense.
Adam Levy
Given this impact that the work could have, and maybe already has had, how difficult was it to choose it as the winner of this prize?
Laura Machesky
I think this year it was fairly clear because, one thing I would say about Clemens’ work is that he’s made major discoveries at many stages during his career.
Michael Sixt
I think it’s also quite courageous of him to move from the transcription to the mRNA transport field which was basically completely empty when he started it. It takes courage to start something you don’t know anything about.
Adam Levy
Do you have a sense of where this avenue of research could go in the future?
Laura Machesky
Partly his work was enabled by the technological breakthroughs in cryo-EM and so as we are able to solve larger and larger complexes it may be that the future will be understanding an even larger assembly of mRNA and proteins that regulates these processes.
Adam Levy
Can you perhaps say a couple of words about the finalists this year because of course for this prize it’s not just about the winner?
Laura Machesky
The finalists, I would say, also have made really important, exciting discoveries over their career. Irma Querques for her amazing work on CRISPR transposons and really discovery of how this system works in prokaryotic systems of bacteria, and then how to apply that maybe to humans which is quite exciting and has new potential.
Michael Sixt
The other one is Phong Nguyen who is actually opposed to the other two, not really working on the molecular level. He’s rather started with an organismic approach. He looked at zebrafish and how the hearts of zebrafish regenerate which is possible in the fish, as opposed to the human, and very, very impressive and hard work.
Adam Levy
Just on a purely personal level, what’s it actually like to judge a prize like this, to read through this research and end up choosing the winners and the finalists?
Michael Sixt
It’s exciting as usual to see what the young generation is doing; it’s a privilege to be on this jury because you see simply the best science that is out there. It is very clear that there are many more excellent scientists at the Eppendorf Award so I think it’s just a pleasure to read through all that.
Laura Machesky
It’s always very exciting to open the packet and find out what the applications are and really get maybe a snapshot of the future of where science is going. It’s amazing to see what’s happening, what people are discovering and where we’re heading.
[Narration] Adam Levy
Laura Machesky and Michael Sixt there. That’s it for this year’s Eppendorf Award for Young European Investigators, which is the twenty-ninth of these awards. Congratulations again to this year’s winner, Clemens Plaschka, and until next time, I’m Adam Levy.
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