Prof Lazar: – I put my mind to thinking

Biotechnology – what has it changed in our thinking about life sciences?

Life sciences used to be sciences that described nature. It wasn't until the discovery of antibiotics or vaccines that gave a push to the dynamic development of the discipline we now call biotechnology. Biotechnology not only allows us to produce the aforementioned antibiotics on a larger scale, but also allows us to create something that was previously impossible. Using our knowledge of how metabolic pathways work, we can design them ourselves. The development of metabolic engineering and synthetic biology has definitely given us powerful tools to work with in modern biotechnology.

If you give up, you won't achieve what you have set out to achieve, but that doesn't mean that you should falsify the results in the pursuit of your goal. If something doesn't work out, it's important to persistently examine why that is.

What triggered the development of biotechnology? The aforementioned discovery of enzyme pathways, research in the field of microbiology, chemistry, the discovery of DNA?

It all depends on how one understands biotechnology, because it is a very broad discipline. From my point of view, that impetus was the development of molecular biology and understanding how life functions at a molecular level. We learned about the structure of DNA. We found out what enzymes are involved in the processes of replication, transcription and translation, or protein production. And when we were able to create tools to modify genomes, especially of microorganisms, modern molecular biotechnology took off. It was then that we could really start modifying the genome in the direction that the cell we were modifying was going to act.

Cardiac surgeons stereotypically are said to have a god complex. Interfering with the genome of a cell raises similar risks for the researcher, who may feel like a demiurge in the laboratory?

Unfortunately, it can. I myself believe that nothing is impossible until someone invents it. Because everything used to be impossible until someone figured out how to do it. That is why someone can indeed feel that they are such a god, because they are modifying the genome. There was once a famous story of a Chinese researcher who modified the genome of a pair of twins to produce a specific immunological effect, in this case resistance to HIV infection. But we are concerned with yeast, the famous Yarrowia lipolytica. We are modifying them towards the overproduction of organic acids. So the possibility of increasing the biosynthesis of erythritol, which successfully replaces sucrose in food products and is safe for diabetics. Research in this direction is conducted for the good of humanity, so I am an advocate of genetic engineering. It would be strange if I cut myself off from it. I tell my students that I leave the ethical aspect of research to them to judge for themselves. As a Western society, we have a lot of ethical norms that seem insurmountable. After all, these include the fact that we test new drugs on animals first  and only later on humans. So one might ask, who gives us the right to test them on animals? But on the other hand – should we test new drugs on humans straight away without knowing how they work?

We would be returning to the grim practices of concentration camps.

And we cannot allow this to happen. Of course, science should move towards minimising the use of animals in this type of research, but as yet we have no other tools.

Why did you choose biotechnology?

It was a coincidence. I was finishing my degree in food technology and just before my thesis defence I got a job at an American corporation. I went to work for Cargill, but quickly resigned. Probably my career would have accelerated after a while, but at the time I was doing things that didn't suit me completely. That's why I went back to university. At that time, Professor Małgorzata Robak had a place for a PhD student, and I always thought I would like to go into molecular biology. The problem was that after food technology I had little idea about molecular biology, so it was a challenge. Professor Robak opened the door to a new world for me but it required a lot of effort from me. I had to catch up on biotechnology for my PhD. It was a good start, though. That’s why I believe that it is never too late to change. Because it was due to this change, among other things, that I went to the ETH in Zurich for an internship. During my time there I dealt with glycobiology and genetic engineering, neither of which I had any idea about.

What is glycobiology?

The biology of sugars. In Zurich, I worked on N-glycosylation, the attachment of sugar residues to proteins, a process that is one of the challenges in biotechnology if you want to produce proteins with therapeutic purposes in microorganisms.

What therapies are we talking about?

Erythopoietin, for example, is produced in the kidneys and, to a lesser extent, the liver, and the stimulus for this process is tissue hypoxia. The development of a method to obtain EPO has made it possible for patients with chronic kidney disease to improve their red cell parameters without the need for blood transfusions. EPO, of course, became 'famous' when it was discovered to be used as doping by cyclists, but primarily it has medicinal uses. Its abuse is a matter for the relevant services that investigate it.

What did you have to learn during your internship in Switzerland?

Genetic engineering and glycobiology. Understanding the process of protein glycosylation allowed me to modify this process with the help of genetic engineering tools. And because I was working on cap fungi (Coprinopsis cinerea), this required a lot of patience from me.

Why?

To make modifications, I first had to learn how to make them. Then I had to wait for the mushroom to grow. And only then could I harvest it and see if it was successful or not. I was in Switzerland for a year. At that time, we managed to make transformants right off the bat, although we didn’t have any spectacular success in terms of changing the mushroom's morphology. We did, however, manage to characterise the enzyme, a glycosyltransferase, which was responsible for the attachment of one additional N-acetylglucosamine to the sugar component.

Does your personal experience of jumping in at the deep end influences your work with students and PhD students? You could always say 'if I could do it, anyone can'. And not everyone can, not everyone knows how to, and not everyone has the courage.

I don't impose anything, but I very much encourage it. My PhD students travel the world. My first PhD student, who is now doing a post-doctoral fellowship at Imperial College in London, has been on four placements, in France, Austria and Sweden. Each gave him something different, because each lab he went to dealt with something different. One was typically technical, so there he could learn how to operate chromatographs. In the second he learned how to modify yeast, and in the third he learned techniques such as analysing RNAseq data. The second PhD student I didn't have to encourage at all. She was in London. Now she is in Australia. These are fantastic experiences. I myself have been on three placements - at the ETH in Zurich, Switzerland, at INRA in Thiverval-Grignon, France, and at MIT in Cambridge, USA. In total, I spent five years abroad. Each time, it was hard at the beginning. You wanted to go back after a month, but if I went back, it would be a failure to myself. And I’d be unsatisfied. So I gritted my teeth and did my job.

Was it worth it?

Very much so. Every place functions differently, every boss manages their team differently and, above all, you meet people from different cultures. This was particularly evident in the United States, where there were people from all over the world fascinated by science, staying in the lab until late evening hours. Which you shouldn’t do by the way. I tell my students and PhD students that private life comes before anything else, because if they are unhappy or  frustrated, they won’t be of any use in the lab.

I had to catch up on biotechnology for my PhD. It was a good start, though. That’s why I believe that it is never too late to change.

Are you more stubborn or ambitious?

Both. Ambition pushes you to do something new, but without stubbornness I wouldn't be successful - if something doesn't work out, I just keep going until it does. In science, 90% of experiments don't work out, you have to repeat them and wait patiently for the result.

Is humility necessary to accept these failures and not 'turn up the results' to the rush to success?

If you give up, you won't achieve what you have set out to achieve, but that does not mean that you should falsify the results in the pursuit of your goal. If something doesn't work out, it's important to persistently examine why that is. That's all there is to it. Especially since it is very often by chance that you discover something. With one of my doctoral students, we waited two years for a single transformant, which allowed him to move forward with his research. And we discovered it by accident, because the plate had been left in the hothouse too long. It turned out that one colony had grown and it was the one we had waited so long for.

After five years of working abroad, could you say what the strengths and weaknesses of Polish science are?

We have to spend a lot of time on administration and teaching. I like teaching, it was one of the things I stayed at the university for – one day I woke up and the first thought that popped into my head was "I want to be a teacher". But you also need time for your own research. They are, after all, central to my work.

Teaching others is creative too, it opens minds.

Of course. I really like it when students come to the lab. There's a lot of things they don't know, but they learn and start to see the point of what they're doing. It's great to work with a smaller group of people who are developing by working on some chosen topic. In lectures, on the other hand, I ask a lot of questions. I don't know if the students like it, but I go on the assumption that there are no stupid answers. I ask and wait. If the answer doesn't satisfy me, I point them in a direction and wait to see if they can correct themselves.

That is to say, you rely on thinking.

I have heard this many times from students. For me, it is an amazing feeling when I see a smile on their faces because they have understood something, they have reached the essence of an issue. That is fantastic. And, of course, I try to catch the balance between teaching, administration and my own research work. Although there's no denying that post-doctoral placements were the best for me.

Because?

I didn't have to teach at all. I had one student doing research with me. I was able to put him through his paces. To teach what he didn't know, so that he did what he was supposed to do.

A bad scientist will not pass on the newest knowledge in a given field.

It's true, a scientist should share knowledge, so the teaching process is inextricably linked to us. I just want it to balance with the research part, which develops the scientist, although sometimes it brings unexpected challenges.

What kind of challenges?

In France, I was given a student to supervise – she spoke almost no English, I spoke very little French. France forced me to learn French. If you want to live there, you have to speak the language. But Julie spoke English even worse than I spoke French, and somehow we had to get along. And that gave me a lot of confidence, because I realised that even if I’m bad at grammar, but I speak communicatively, I am able to get along with another person.

You have overcome a barrier that stops many Polish people – we're afraid to speak foreign languages because we want to be perfect and we're afraid of mistakes.

This is a completely unnecessary fear. When foreigners come to Poland and learn Polish, even if they speak incorrectly, we are able to understand them. And that's what understanding is all about.

Becoming the leader of a Leading Research Group – was it another career step or more of a challenge?

Challenge. On the one hand, our job is to work on practical applications, i.e. the implementation of biotechnological solutions developed by our team. On the other hand, each of us is an experienced scientist, each of us knows what we want to do. The challenge is to create a common pathway, because we are dealing with issues ranging from bacteriophages, yeast and plants to lipid nanotechnologies. At the same time, we each have these competences that complement each other, and it's an incredible driving force that we all can bring something to this team that the other doesn't have. And I think that contributes to this success.

It was at the Wrocław University of Environmental and Life Sciences that the first biotechnology faculty in Poland was established. It was created, not without resistance in Warsaw, by Prof Leszczynski. Do you have a sense of continuity and tradition?

Tradition is important. After all, our biotechnology faculty is one of the best in the country, so I think everyone is aware of that and wants it to be even better. I myself tell students to look at the history of discovering new drugs or technologies. If we don't look at the past, if we don't learn from the mistakes or successes of our predecessors, we won't move forward. Why knock down an open door?

It used to seem that progress in science was about individual illumination. Today, I get the impression that it is overwhelmingly about reading the literature and catching gaps that can be filled. Such development seems to be a closed loop.

Indeed, when one reads the literature, one sees that the author of a publication has missed something interesting almost under his nose, because he was so focused on something else, and accidentally came up with something he did not appreciate or notice. But it gives you a great deal to discuss with scholars around the world – that's what conferences are for. Reading the literature is one thing, but we only publish successful outcomes, and yet 90% are not. And it's interesting to answer the question, why is that? The joint discussion of different points of view is wildly inspiring and a driving force for work. And besides, such contacts breed cooperation. Coming back to literature, you have to keep up to date with it, not only as a researcher. You have to look at where people are going, what's happening at the moment, what's coming out and what can be improved. This is important not only in science, but also in business. After all, our graduates go to work in the industry and are expected to be specialists in their field. In order to keep up with what's going on in the world, they have to read the latest news in their field, otherwise, in 10 or 20 years' time, their knowledge will almost be prehistoric.

Science seems to have accelerated, as has the world. Today, you can become a professor at the age of 35. And one with a lot of scientific achievements too.

These are fascinating personalities, because you can see the passion in these people that has allowed them to get to this point in such a short time. So passion helps, but with us, colloquially speaking, you have to wait for something to grow, and then you see that it hasn't grown the way you wanted it to. And you have to go back to the beginning and start all over again. And that takes time. But if we're talking about pace in science, I'll admit that I don't like the race. We publish at breakneck speed because we are judged for these publications. This rush, in turn, very often results in the fact that we do not look at these results for a sufficient amount of time. And we could often come to conclusions that would push us in a different, new direction.

Why yeast? What is so special about it apart from the fact that it is the flagship of the Faculty of Biotechnology and Food Science at Wrocław University of Environmental and Life Sciences, with which you are associated?

Again, a coincidence. It was Professor Małgorzata Robak who got me interested in the Yarrowia lipolytica yeast and the subject of protein glycosylation. Hence Switzerland and Zurich later on. When I started to lean into the subject and read more literature, it turned out that our yeast is suitable for many different processes. It’s a micro-organism that likes oil-based compounds, hence it is very suitable for bioremediation processes in soil that is contaminated with such compounds. One of the projects I worked on was the treatment of soil in a railway sleeper saturation plant, which was actually successful. Another of the characteristics of Y. lipolytica yeast is that it secretes a large amount of enzymes into the culture medium, so its protein secretion pathway functions very well, making it an ideal candidate for use in the production of proteins of therapeutic importance. Thanks to this yeast, we also have erythritol, a safe sweetener for diabetics. We know a lot about the pathway for its production, but there are still areas to explore. This multidirectional applicability of this yeast in many different industries is insanely inspiring. I myself have been involved for a very long time and am still involved in the production of lipids with it. In France, I worked on the 'ProBio3' project to produce lipids with micro-organisms, including the yeast Y. lipolytica, for the production of aviation fuels. One of the partners in this project was Airbus. Today, we know that the production of yeast oils for biofuels will never be profitable enough to beat the production of fuels from plant or fossil raw materials. At the same time, we are constantly looking for alternatives to fossil fuels in the form of biodiesel or ethanol. The 'ProBio3' project has shown that fuel from yeast is not viable, but the yeast Y. lipolytica itself has become a model organism in the study of lipid biosynthesis. Today, thanks to the availability of synthetic biology tools, we can freely modify this pathway and produce lipid derivatives useful in medicine, pharmacy or cosmetology. For me, Y. lipolytica is fascinating and so versatile that there is still much to learn about it, and I think I will continue to work with it until retirement.

When you walk into the lab, do you talk to 'your' yeast?

I speak to it as I would to a pet at home. So first they hear "come on, do what I've been asking you to do for a year", and when I see that it hasn't worked out again, I get frustrated and then I reproach them with "why wont you work with me?".

kbk

• 

  Tutoring at the UPWr Doctoral School – It works!

  PhD students Sepideh Fallahi, Joanna Bubak and Hassanali Mollashahi talk about their experience with the UPWr Doctoral School's tutoring programme one year on.

• 

  Bekker scholarship for three UPWr scientists

  Prof. Aleksandra Mirończuk, Estera Trzcina and Dr. Luca Demarchi are this year's recipients of the Bekker scholarship from the National Academic Exchange Agency. They received more than half a million PLN for their projects.