Luděk Sehnal: I see the foreign experience as essential. In Australia, I found the scientific topic of a lifetime.

Scientist Luděk Sehnal, a successful applicant for several prestigious scholarships for which he and his family traveled the world, is finishing his work in Germany and plans to return to RECETOX. He wishes to pass on his experience and support the development of excellent science in the Czech Republic. What was Luděk's scientific journey like? Is foreign experience essential? How can we find antibiotics? Read the interview with Luděk and get inspired.

17 Apr 2024 Jitka Vaňáčková

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In 2021, you applied for the prestigious Marie Skłodowska-Curie Action - Postdoctoral Fellowships (MSCA-PF) to Prof. Ziemert's group in Tübingen, Germany, where you wanted to focus on "metagenome mining" of Antarctic microbes, i.e., using the genetic information of Antarctic organisms to discover new specialized metabolites, specifically new antibiotics. This is a very important topic, given the increasing resistance of microorganisms to antibiotics already in use. You have received the grant, and you are currently finalizing it. Can you please summarize how challenging it was for you to succeed and what was your primary motivation?

I was determined to go on a postdoctoral fellowship abroad. The Marie Curie grant is an excellent source of money that opens doors to places that are hard to get into. Anyone who succeeds will bring money to their chosen research group that will cover the cost of your salary and the research itself. So, you're much more attractive to the lab you've chosen than if you're a regular graduate student applying for a specific position. That's why I applied for this grant. The second reason was that I wanted to pursue research that was fulfilling and meaningful to me. My dissertation was very extensive and focused on several different areas. One was the pursuit of discovering new compounds of interest using a "metagenome mining" approach and synthetic biology methods. With these methods, I tried to look directly at environmental and genetic information for which genes and proteins might be responsible for producing new substances of interest and then create these substances in the lab. It turns out that this is precisely the direction I want to take. In this context, I was very interested in the polar regions. During the first year of my Ph.D., I went to the Arctic and Antarctica. I was also fortunate to be successful in the selection process for another project, which led me to go to Australia for a year. The fellowship to Australia opened the door and showed me the path to work towards my current research. Without overbetting, this is a "lifetime" topic for me.

You are a successful scientist who has found a topic that you enjoy, you also enjoy research, and you are "passionate" about it. What has helped you stay motivated in such a challenging field? Have the successes you have continuously achieved contributed to this?

What motivates me, and more importantly, encourages me to continue working hard, is that all these projects mentioned above have allowed me to do what I wanted. Simply put, I didn't have to work on a topic that my supervisor or someone else came up with. I worked on my own research project, and I could develop my thoughts and ideas. The projects allowed me to conduct my research 100% according to my ideas.

To what extent did you, as a student, actively seek out projects and opportunities that would allow you to work on your own research project? Did anyone advise you on the options or help you with administration or writing up your project?

I did the Arctic and Antarctic tents independently; nobody helped me with that, but my master's thesis supervisor, Prof. Barták, recommended them to me. The prestigious Australian Endeavour Research Fellowship was recommended to me by Dr. Ondřej Adamovský, the junior group leader still working at RECETOX. I filled out the application form entirely according to the available documentation. Prof. Luděk Bláha helped me a lot with the review of my application; he commented on the project, and it worked. The success rate for this scholarship is 1-2%, so it was a great success for me, even compared to Marie Curie, whose success rate is around 14%.

Do you think the individual scholarships have helped you succeed in other applications?

Definitely yes. It's all connected; each scholarship allows you to expand your scientific topic. Successful applications to the Arctic and Antarctic helped me get the Australian fellowship, which, in turn, helped me get the Marie Curie. Australia was a turning point for me in my scientific career; it showed me the direction where I wanted to go. I decided to focus on bioinformatics and molecular synthetic biology, which led to interesting natural products (secondary metabolites), first from cyanobacteria but now from prokaryotic organisms.

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Were you studying cyanobacteria in Australia?

I didn't deal with cyanobacteria there, but I've already focused on environmental samples, and that's my main direction. I'm trying to discover interesting genes that might be responsible for producing new interesting compounds directly from metagenomic information from environmental DNA. I started with this in Australia, where I was still working with cyanobacterial isolates and environmental samples.

Could you please explain as simply as possible what practical implications your research can lead to? Can it have an impact on the average person?

My current focus is discovering new antimicrobials, so I am trying to find new structurally different antibiotics. Today, despite global initiatives and awareness, antimicrobial resistance is a huge problem that needs to be improved.

Antarctica could be one of the exciting sources where new antibiotics could be discovered because the lifestyle of bacteria in Antarctica is very different. However, even there, the bacteria compete for resources, and this struggle occurs in an extreme environment. Recent studies show that many Antarctic organisms have evolved differently from bacteria elsewhere, and genetic information differs significantly. This finding presents great potential for finding new active compounds. So, as a part of my Marie Curie project, I am trying to discover new antimicrobial agents. The road from finding a substance with antimicrobial properties to becoming an antibiotic is very long, especially in Europe. However, we will not get new antibiotics anyway. The search for new antibiotics is one way to combat antimicrobial resistance. Specifically, we need to find structurally different molecules.

Are biotech or pharmaceutical companies interested in working with scientists? How challenging is it to arrange a collaboration that would lead to the production of antibiotics from an antimicrobial agent you have found?

I want to clarify that my primary interest is not the pharmaceutical or biotechnological potential of a given metabolite but its biological role in a given environment. So I am interested in why the substance is there, what it does, why the organism is producing it in the first place, what it is trying to gain, or what or who it is trying to suppress with the substance. Equally important is information about the molecular mechanism of action of the substance. However, at the same time, it is meaningful and essential that if such a substance with a potential use is discovered, we should apply this knowledge. It is challenging to cooperate with companies, and it is possible only when you have maximum information about the substance you have found. Clinical trials and the whole process are very costly, and the company must be convinced it is worthwhile. At the same time, it is the only way to make drugs from new substances.

You've had to sacrifice a lot to be a successful scientist. You've traveled the world to broaden your horizons as much as possible and to get the comprehensive package of information and approaches you need for your research. You have been searching for several years, every day, for a needle in a haystack; you have to secure your funding, and you don't have the opportunity to live in the Czech Republic. How many of your classmates have embarked on a similarly difficult journey?

I can't judge my classmates; during my studies, we were already profiling ourselves in our direction, looking for different paths, and many of my classmates didn't finish their studies. No one has taken the same path as me, or I don't know about them. But across the world, there is a large number of people who are strongly motivated to step out of their comfort zones and sacrifice a lot. For good science, this is quite common and necessary.

But from a personal point of view, it is not easy at all. My family travels with me, which can be challenging, especially for them. For me, it's a challenge to juggle everything. Without my family, I would be completely uprooted, and I appreciate that they provide me with a fundamental background. During the Marie Curie grant, I worked in Germany; I had the opportunity to go to America for one month to Prof. William Gerwick's lab. I have been very keen to go to this lab for many years, and I wish to collaborate with them. Because funding finally came up, I went there and was thrilled that my wife and son went with me. With them, everything goes much easier. When you have a stable environment at home, it's less of a worry. My son will soon be three years old, he is starting to pick up German and English words, and we speak Czech with him at home because we want to return to the Czech Republic. English is an absolute necessity nowadays, and I would be pleased if he could pick something up by living abroad and being surrounded by English and German. At the same time, we do not push him into anything artificially; he is small, and we wish him to enjoy the beauty of life.

So you are thinking about returning to the Czech Republic. That's probably not easy either.

It's indeed very complicated, but it's the only meaningful way for me.

I will aim a bit higher again, and under RECETOX, I will apply for an ERC Starting Grant. I studied at RECETOX, and I have a lot of great colleagues there. My research focus isn't there yet, but it overlaps with different groups, so it's very interesting for both me and my colleagues. I would be pleased to have the opportunity to return to the Czech Republic thanks to this grant and pass on the experience and knowledge I have gathered worldwide. At the same time, I would like to support the development of excellent science in the Czech Republic.

People who work in fields other than science usually don't understand why a scientist should have a "nomadic life" and should go on a "postdoc." You've been through this whole cycle. Do you think, in retrospect, that it was essential?

It’s undoubtedly the most efficient way to produce an excellent scientist. At the same time, it's the only way because nowadays, if you can't communicate internationally, you can't do science internationally. Many scientific topics are dealt with at the consortium level. This means that huge international projects are being set up, with many groups worldwide working on them, all with the same vision and a common goal. Everyone contributes their piece of expertise to achieve the goal. Another reason scientists have a nomadic life is that by working in different places and laboratories, they gain a lot of experience and become more independent and confident in communicating in a foreign language.

I have been lucky to experience how it works in five research groups - Australia, Germany, America, and the Czech Republic. It varied in all of them, but it worked brilliantly in all of them. This experience is very enriching; you see different styles of functioning, different perspectives on the issue, and different ways of thinking. I gained work experience in the Czech Republic at RECETOX and the Department of Experimental Biology.

Even within the Czech Republic, there are considerable differences in how research groups operate, and the differences worldwide are diametric. Foreign experience shapes people and broadens their horizons. If I ever grow to a position where I would supervise students, I would require them to go at least short-term abroad at all levels of study. Foreign experience is necessary, regardless of whether a person plans to stay in science. It is also enriching from a human point of view; it is an essential thing.

Based on your experience, you can be a great role model for your future students and even mentor them. Were you lucky to meet someone who mentored, advised, and directed you, or did you have the drive to manage everything independently?

I had the drive but would never have done it without mentors. There were a lot of important people around me. Everyone I had the privilege to work with was essential to me, pushed me, and gave me further direction. It started with Prof. Barták at the Institute of Experimental Biology and continued at RECETOX with doc. Hilscherova. In 2016, I had the privilege to work with Prof. Bláha, and I was very much helped by Ondra Adamovský, who introduced me to how to write projects. However, I must also mention my international supervisors. The absolute turning point for me was meeting Prof. Brett Neilen and the people in his group in Australia. There, I made the most significant intellectual progress in my scientific career. And, of course, my current postdoc with Prof. Nadine Ziemert in Germany, where every meeting with her and colleagues in her group is very enlightening and rewarding.

How important is choosing a study field and assessing your strengths and abilities for a successful career?

The choice of the field of study is crucial. Students have many options, so the chance factor plays a role. Moreover, students often come to a crossroads where they must choose a path without knowing which one is right. Luck also plays a significant role in career decisions. Only after some time can you determine if you made the right decision. It's essential to face challenges head-on, even if they don't go as expected. Not everything has turned out how I hoped, but I have mostly been rewarded for my efforts. If I could advise students, it would be never to give up.

At the end of January, you and your colleagues published a paper in the prestigious journal Nature Chemistry. Could you explain what you were working on in a simple way?

It is a very specific article because it is a "review" in which we explain a groundbreaking discovery in the field. Prof. Ziemert invited me to write it. This allowed me to comment on the unique combination of methods that led to discovering previously undetectable substances produced by cyanobacteria. Cyanobacteria produce a range of interesting substances encoded in their genetic information. In this review, we describe a study in which scientists have searched undetectable end products of a particular gene cluster (BGC = biosynthetic gene cluster). The groundbreaking research described here combined a wide range of bioinformatic, chemical, and synthetic biology methods that required exceptional expertise to be feasible. Indeed, the combination of these approaches ultimately led to the discovery of the final product.

How did the scientists find the final product?

In the end, the whole clue was quite simple, namely increasing and decreasing the chlorine content of the medium. The experiment worked because the scientists used a commonly used chlorine level in the medium and a reduced chlorine level in the medium. They looked at how this affected the spectrum of substances they could measure. Then, they folded the spectra of the substances over each other and found a group of substances in the medium with lower chlorine levels that were also reduced. So, they found that chlorine was affecting their production. However, in this group of substances (whose abundance had decreased with the lower chlorine level), they detected several substances that did not contain chlorine in their structure; these were the so-called cryptic halogenation products. In these unique reactions, the halogen (in this case, chlorine) is present only in the intermediate product, where it provides specific reactivity, but the final product no longer contains halogen. To simplify this, you can imagine that by translating the spectra, they discovered that there were, for example, 20 small molecules containing chlorine in the chlorine-reduced medium, but also two molecules that did not have chlorine, which was the final product. This approach showed the way to detect the products of cryptic halogenation reliably.

Is this approach unique because it is possible to produce previously undetectable substances?

This approach has discovered a method that is broadly applicable to different types of research because, in this case, chlorine was used. Still, in another, it may be a different substrate that is important for the production of a molecule. We can detect natural products we don't see through standard methods, but by combining these approaches and cell culture techniques, we can detect these substances.

Can this approach create a final product that would not be usually produced?

The final product was always there, but we've been looking for it for almost 20 years. In 2009, it was published that this particular cyanobacterium contained this cluster of genes, but despite all efforts to produce the final substance, we could not see it. By combining these methods, we were able to "measure" it and describe the mechanism how to detect these cryptic substances.

How can this finding advance your research?

I'm primarily interested in finding unique BGCs that might be responsible for making interesting compounds. This study described a mechanism that is applicable to any experiment with these clusters. Nowadays, you can already find with varying degrees of confidence from which organism taxonomically comes a given sequence. Then, you can try to insert those genes into some group of available bacteria and try to make the product in that strain by regulating the substrate level and combining it with downstream methods that have been published.

Can this combination of methods lead to the discovery of new antibiotics? If you find a cyanobacterium in Antarctica that you reduce the chlorine level, would it produce a substance from which an antibiotic could be prepared?

Theoretically, that's a way to discover a new antibiotic, but the critical substrate doesn't have to be chlorine. I'm now in my second year of a project where I've prioritized a spectrum of BGCs based on my data, and I'm trying to produce them slightly differently. I have chosen two routes; the first is an in-vitro experiment where I "manufacture" individually the proteins responsible for the final molecule and then mix the individual proteins in a test tube to produce the final molecule I want. The other route I use is to take the whole BGC and put it into some bacteria that might be able to deliver my target product. For this, I use actinomycetes, cyanobacteria, and E. Coli proteobacteria.

Is the scientific environment around you competitive or collaborative? You talked about the need for international collaborations. Can you share your data and consult them without having to "watch your back"?

I've been lucky that everywhere I've been, the environment has been completely open, and scientists shared their data and the approaches that they used with me. I do the same, so it is an open environment where we try to help each other out to make the target product.

To what extent do you find it worrying that recent publications have shown that some pesticides can travel very long distances, for example, to the Arctic, and have a much longer degradation time than expected? Could this affect, for example, cyanobacteria in these areas, which have the potential to produce substances with antimicrobial effects?

I think pesticides, including cyanobacteria, can affect microbial communities in the Arctic. In Antarctica, which is my research area, I would be skeptical of that. Nothing like that happens there because it's isolated by the Antarctic Convergence, which are wind and sea currents that isolate Antarctica from the rest of the world. So, they slow down the transport of pollutants to Antarctica. For the Arctic, I am not surprised by these results, as it is connected to the entire northern hemisphere by "hop" transport, and especially by currents. The general effect of all substances entering an environment where they have no business is a concern. Because, of course, all these substances can affect microbial communities differently.

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Which place did you enjoy living, exploring, and enjoying the most?

That's a tricky question. It's hard to say; everything has pros and cons, so I'll tell the Czech Republic because I have family there.

You come from Šošůvka, would you like to go back there?

Yes, I can imagine commuting from there to Brno. I always liked to go from Brno to nice Šošůvka, I would say: Šošůvka forever.

Finally, I will ask you a question from my children: Is it possible to pet a penguin in Antarctica?

Just when I was there, doc. Žákovská was involved in an international initiative to study penguins, so she took blood from them. I had the opportunity to assist her and see the penguins close up. Otherwise, the penguins sometimes stray somewhere on an iceberg, slide down on their bellies, down to the water, and are very funny. It was an exciting experience. If you're a Ph.D. student at Masaryk University and you're interested, there's usually a real chance to get on such an expedition. Of course, the prerequisite is a meaningful research project.

How did you catch the penguins?

Penguins are very shy, but when they come out on land, they can only “waddle”; they are very slow and vulnerable. In the water, of course, they're very fast. So, if a penguin is farther from shore, you'll typically run it down. It is like catching a chicken.

Thank you for a pleasant interview about your scientific journey. I hope you will return to Šošůvka soon, and I wish you all the best in your career.

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