TRANSCRIPT
[Narration] Adam Levy
Hello and welcome to the 2023 podcast for the Eppendorf Award for Young European Investigators. I’m your host for this year, Adam Levy. This year, once again, the awards took place in person at the European Molecular Biology Laboratory in Heidelberg, in Germany. I was able to travel down to Heidelberg to meet this year’s winner, Maurice Michel, of the Karolinska Institutet in Sweden. Maurice’s work involves an unexpected way of controlling enzymes, the biological catalysts that facilitate reactions within cells. Maurice and I started our conversation by discussing how enzymes do what they do.
Maurice Michel
Enzymes are molecules in our bodies, and they perform certain functions. And they perform this function in an active site, and this active site can be described a little bit like a mouth with which you’re chewing, so you need food to come in and be changed in its composition and then be swallowed or the product that’s being released.
Adam Levy
And this mouth of the enzyme, this is really the kind of crucial part of the enzyme where the action happens?
Maurice Michel
That is correct. The substrate the food in this picture. It needs to bind and go into the mouth, and then it needs to be changed in chemical composition and it needs to be swallowed. Of course, you can modulate, you can modulate it chemically with small molecules.
Adam Levy
Now, because enzymes are useful for well pretty much everything that goes on in the body and the cell, actually modulating their function is really incredibly useful. Can you explain first of all how we’re able to hold back an enzyme from performing its function, how we’re able to inhibit an enzyme?
Maurice Michel
Inhibition relates in this case to pharmacological inhibition, and that’s a small molecule that chemists optimise, that binds directly to the mouth. And that’s the most common inhibition mode of action. You take away the basic function by blocking the site.
Adam Levy
Now, it is also possible to do the opposite, to activate an enzyme in some way, to dial up its activity. Can you explain how this kind of activation has historically taken place when we’ve seen molecules able to activate enzymes?
Maurice Michel
Yeah, so enzyme activation is also performed in our bodies and this is happening outside of the active site because something that binds to the active site will inhibit, as I just outlined before. So, we are performing activation from outside of the mouth and we can use small molecules for that as well. And these then often change how fast the substrate gets in, or how fast the product goes out again, speeding up the rate of the binding step of the reaction.
Adam Levy
So that’s really the status-quo that, when you’ve got a molecule that tunes down the action of an enzyme that’s binding to the mouth of the active site, and when you’ve got a molecule that dials up the action of an enzyme, that’s pretty much always binding somewhere else. Now, we’re going to get to what’s a bit different about your work in just a second, but first let’s talk about the enzyme that your work actually involved, OGG1, can you tell me why this enzyme is of interest in the first place?
Maurice Michel
Yes, so OGG1 is a DNA repair enzyme, and it removes damaged DNA, nuclear bases, so those are part of the DNA of our genome. DNA is not an inert molecule; it gets damaged all the time and every day. So, we need repair enzymes that help us in maintaining DNA status, and OGG1 is taking care of one particular nuclear base that is guanine and OGG1, if it’s not removing it, we will have mutations, we will have a fast development of Alzheimer’s and other neurodegenerative diseases and such.
Adam Levy
Can you explain what you were initially setting out to look for, to discover, regarding OGG1?
Maurice Michel
When I joined the lab in 2017, we were all developing said inhibitors of the enzyme. Yes, so we are very successful in making said inhibitors and we are still researching those, but during my time as a postdoc I stumbled over a molecule in the literature that was claiming to be an activator, and there was no mode of action involved. So, out of scientific curiosity I started working with them, and the behaviour of these molecules was very weird, it did not fit any of the hypotheses or the established routes of small molecule activation.
Adam Levy
And when you actually looked a bit closer to see what the molecule was doing, where it was acting, what did you discover?
Maurice Michel
So, in high concentration it almost looked like it was acting like an inhibitor, and in normal concentration I indeed was observing an activating behaviour. That’s where science gets really interesting, you constantly need to shift your point of view and adapt to a new finding that you’re obtaining. And it took some months to actually come to some ideas, and then make changes to protocols, use other reagents and such. And it was a very stimulating and rewarding time. One thing that you need to know about OGG1 is that it can actually perform several enzymatic functions in its mouth, and one of them it’s very, very good at, and another one it’s not. So, you can imagine how some people can use them all for whistling as well, but some people are just really bad at it.
So we found the molecule one day to be sitting in the active site binding to the mouth of the enzyme, so we had hard proof, we could see it sitting there, and then we had to adapt again our hypothesis, and what we saw then is that OGG1 now, in addition to being able to chew and swallow food, can also whistle and we can use small molecules that we design as chemists basically to generate synthetic switches so we can use the enzyme to become so efficient that it doesn’t like chewing food at all, it’s only whistling all the time, which is kind of a nice place to be.
Adam Levy
So, you found this molecule now that can actually activate your enzymes so that it can whistle and strangely enough it is doing that by binding to the active site. We’ve already explained that that’s not the paradigm, but can you put in a little bit of context just how unusual it is to see an activating molecule binding to the active site to the mouth of an enzyme?
Maurice Michel
If you think about it for a moment, this completely reverses how we can use these small molecules. When we use inhibitors, we want to 100% stop the enzymes from working, so we’re using a thousandfold or even more axes. But if a small molecule helps an enzyme to do a new reaction, and it’s very efficient, it might be okay to just hit 2-5% of the enzyme and then induce this new function. So, we can use it in a different window, we can use less material to do new reactions in cells.
Adam Levy
Have molecules like this been found before in other contexts?
Maurice Michel
I wouldn’t say so, this is indeed the first molecule that’s used for the purpose of medicines where we can go into the cell. However, over the course of the last few decades, there have been numbers of scientific breakthroughs. This is typically used in biotech for example. So, yes this has been used, but for the feat of medicine rewriting an enzyme that’s already existent in the cell has never been done before.
Adam Levy
Well, how does it feel then for you personally to uncover this really crucial kind of behaviour that just hasn’t been seen in science before?
Maurice Michel
It’s very rewarding to have all these different discoveries, and it’s not like you do this by yourself, you have a great team and you’re bouncing back and forth with other postdocs. My background as a chemist helped me of course, approaching DNA repair from a different angle, but it was people who were proficient in DNA repair techniques that helped me in interpreting these results and moving forward. So, in that case I’m really thankful for the team that was behind that, and on the other hand of course this new technology now it can just lie there but people could also use it and act on it in the future and in a translational or even a clinical setting, so that’s very interesting.
Adam Levy
As you just mentioned, your background is actually as a more pure chemist. Can you give a sense of how important it was to be in really a very multidisciplinary team and also to have the kind of supervision, the kind of boss, that you had?
Maurice Michel
If we want to keep doing the same things that everybody does then we can just stick with our knowledge, but if we want to actually push human knowledge and the frontiers of science then we need to think outside the box and approach things with a different angle. And there I think it’s really important to work with people, have the expertise, and also have an open-door policy, you can walk in to anybody and you get helped. When it comes to the freedom I had for my research it was actually beneficial for my postdoctoral supervisor to leave the country for three years, so I was a little bit focusing on this little side project until it was so big that everybody had to get involved.
Adam Levy
You mentioned when we spoke on the phone before that at least a part of this research was what you call a Friday afternoon or Friday evening experiment. Can you explain what a Friday afternoon experiment is?
Maurice Michel
Often you read an article or go to a lecture or symposia, and you see a talk and you think “I wonder if this can be used for my research,” and then you think of an experiment that can be done very quickly. And it’s high risk, high reward, but if it fails, you’re kind of bummed out. So, I tend to do these kind of things and I now encourage my students to do so on a Friday afternoon, so then you have a really really good feeling if it really works out, and if it doesn’t work out it doesn’t matter, you can go to the park and play some football, for example.
Adam Levy
Can you give a sense of how relevant this kind of research is for applications, is it still at a stage where it’s just an academic curiosity or is this the kind of thing that hopefully relatively soon could make a difference to people’s lives?
Maurice Michel
Oh, I think we are definitely beyond just a basic discovery. Of course, the entire action with clinicians has been very stimulating over the last years since our publication, so we could use an OGG1 activator to enhance existing therapies and of course it’s a long way still to do but it’s very stimulating and fulfilling.
Adam Levy
As we’ve outlined this is really the first molecule of its kind that’s been uncovered. Are there research groups, are you, looking for other similar molecules for other kinds of enzymes?
Maurice Michel
Oh yeah definitely, that’s one of the basic expansions of my technology platform which I tried to build right now. So, we can use likely the same concept in an identical fashion for other enzymes or for transcription factors to render them an enzyme which would be even more fascinating. But in the future if you think about engineering enzymes themselves without the need of a small molecule, and it’s something we’re heavily pushing right now.
Adam Levy
For you, personally, what actually motivates your work, is it the fundamental scientific understanding or is it the hope for applications further down the line?
Maurice Michel
I think it is both. I have this big urge for understanding things and I constantly wonder whether something that I’ve picked up somewhere else that’s still whirling in my head can be applied here. So, I’m thinking, of course, basic science, but then if we are translating this and we can actually make something out of it and heal a disease or we can just help foster science in general that’s a big motivation.
Adam Levy
Now of course a huge part of the reward for research is the research itself, but that said what does it mean to you to win this Eppendorf Award and have your work honoured in this way today?
Maurice Michel
I think winning the Eppendorf Award has helped me in terms of visibility of my research as well. So, we entered a lot of exciting collaborations and that of course means a lot to leave this impact. At the same time, I also think it’s very nice how we focus and communicate science, I think it’s very important. I need to explain to friends, to families now, why my research is very fascinating and why I like to do it a lot. As part of this, also, training a new generation of students which is very close to my heart, and of course in the future I would like to expand on all of this, I would like to use the media attention around the prize to raise third party funding, expand on my activities, enter some more collaborations and so on.
Adam Levy
Do you remember how you felt when you actually heard the results and heard that you had won?
Maurice Michel
I remember it very vividly. I had my post-development dialogue just two hours earlier, and for that we always write down our goals and of course this had changed a little bit. With the prize Axel Jahns called me up and I was in the freezer room looking for an antibody and he told me that I had just won the Eppendorf prize, and then I thought “well, I really need to adapt my year plan now,” so what can I do this year? I was half-thinking maybe nobody else applied this year.
Adam Levy
I’m pretty sure from my conversations with the judges that others did apply and you weren’t the only one they could select from, so congratulations.
Maurice Michel
Thank you very much Adam.
[Narration] Adam Levy
That was Maurice Michel, winner of the 2023 Eppendorf Young Investigator Award. I wanted to find out a little more about how the winner was chosen and how Maurice was picked out from all the entrants, and so, before the ceremony at the European Molecular Biology Laboratory, I called up one of the judges Reinhard Jahn the retired director of the Max Planck Institute for Multidisciplinary Sciences.
Reinhard Jahn
First of all I would like to say that we had quite a strong field of applications this year, so it was not so easy to identify a winner among them, and this as usual takes quite a while of discussions and checking out and so on. And in the end, we chose the winner as Maurice Michel and to explain to you why we choose him, the work he has been doing is quite ground-breaking. And why is it ground-breaking? Well, he worked on an enzyme. Now normally you can, for instance in many cases it’s useful to inhibit an enzyme, for instance in cancer therapy there are enzymes which go out of control, we want to inhibit them, and usually inhibition is done by finding molecules which bind to the catalytic centre and basically prevent the enzyme from interacting with its natural substrate. In this case, the group was also searching for inhibitors where they found molecules that activated the enzyme. Now activation is also not uncommon, in this case however the unusual and very, I mean, mindboggling observation was that this activator also bound to the catalytic centre. Now in going on what the investigator found was not only did this small, organic molecule bind to the active centre, but it also enticed the enzyme to carry out a second reaction which it normally would not carry out. This is of fundamental importance, it is of fundamental importance not only for this particular enzyme which is involved in repairing nucleic acids but when our genetic material is damaged is capable of correcting that damage and enhancing these capabilities for quite a bit of importance to medicine, but it also is a new concept in biochemistry, that small molecules, small, organic molecules can operate as catalysts to change not only the activating enzyme but also to change it specificity.
Adam Levy
Do you remember your reaction when you first read about this molecule that could bind to an enzyme and actually enhance its reactions by binding to the active site?
Reinhard Jahn Yeah, I must admit that when I screened the applications, I didn’t immediately realise the importance. I mean I read this and thought “well, it sounds interesting, but since it’s far outside my field …” and then we started discussing, and when I fully understood and grasped the concepts, I was actually quite excited.
Adam Levy
Could you get a sense then of where this new, entire avenue of research could potentially lead in the future?
Reinhard Jahn
At this point is hard to predict but the concept that you can find small molecules that are capable of directly interacting, which is considered the Holy Grail of enzymes with a catalytic centre, and effective there is novel, and I think it has quite a bit of potential so this is very likely at least for enzymes of similar structure that this is a general principle which one can apply to other enzymes as well and people just have to start looking for it.
Adam Levy
And is this a principle that’s primarily academically interesting or are we actually talking about perhaps practical applications down the line?
Reinhard Jahn Enzymes are major drug targets in any case, and in many cases like in cancer for instance, DNA repair is very important, and in cancer you have mutations ongoing, and you have a system of enzymes repairing DNA being able to activate them or to steer them is obviously of very high interest and potential therapeutic potential in cancer biology.
Adam Levy
Now I understand that Maurice’s background is actually as more as a hard chemist, and he was in a lab which was quite mixed in terms of the scientific backgrounds of the other academics within the laboratory. How much does research like this rely on this kind of interdisciplinary approach?
Reinhard Jahn
I think he probably was at the best place, you can imagine, to do this type of work. When you’ve got the initial findings basically, I mean, was met with a lot of scepticism at the lab, but his supervisor gave him a lot of freedom to pursue his somewhat crazy line of research and then when he actually obtained more data for these very unusual concepts, and obviously people recognised the importance, and he got a lot of support.
Adam Levy
Can you give a sense of how this year’s selection compared to some of the other years’ that you’ve been judging?
Reinhard Jahn
I would say we have seen in recent years not necessarily an increase in the number of applications, but I think we have seen a very nice increase in quality, so it is always difficult to pick the winner, and this is why we decided about a year ago to have finalists. If you pick only one, let’s say you have several outstanding young scientists applying, this is the problem with awards, this is why I’m very glad that we actually made the decision to also have finalists.
Adam Levy
And this year you actually have two finalists besides the winner. You still then have to narrow it down to just three people, is that a challenge for the judges?
Reinhard Jahn
I meant it’s always a challenge, we have a quite diverse award committee, and so we discuss the pros and cons and usually we reach an agreement and that’s actually very nice, yeah.
Adam Levy
I think that’s everything that I wanted to ask you but is there anything you wanted to tell me that I’ve haven’t give you the chance to tell me?
Reinhard Jahn
I just would like to say that, really, this is my last year on the award committee, I will now be rotating off but this has been really a fantastic time and I really appreciate this award because it’s number one, it’s an award for young scientists, and also it’s an award where you can apply for it by yourself, you are not dependent on some kind of mentor or support or network to be proposed.
Adam Levy
And what has it meant to you personally to be a part of that award process?
Reinhard Jahn
For me it was obviously very rewarding to be able to honour young scientists with young, brilliant minds, of which quite a few are probably smarter than myself anyway, and it’s a pleasure to see young people again doing fantastic things in science and to recognise this, yes.
Adam Levy
Will you stay in the loop and see what’s happening with the award in future years even though it’s no longer your requirement?
Reinhard Jahn
Oh absolutely, I will be very much looking forward to the next years, yes.
[Narration] Adam Levy
Reinhard Jahn there. And that’s it for this year’s Eppendorf Award for Young European Investigators, which is the twenty eighth of these awards. Congratulations again to this year’s winner, Maurice Michel. Until next time, I’m Adam Levy.
