FNR ATTRACT FELLOWS: Johannes Meiser THE PEOPLE BEHIND THE SCIENCE

You bounced around between a few scientific topics before you found your ‘scientific calling’. Can you give an overview of your journey in this respect?

“My PhD was in plant physiology. When I finished my PhD, I was not sure what my next step would be – and whether to stay in academia, go into industry, or become a teacher. I then came across Karsten Hiller, FNR ATTRACT Fellow at the LCSB at that time, who had just started a new lab working on mammalian metabolism using stable isotope tracing and mass spectrometry. It immediately caught my attention due to my keen interest in biochemistry. Consequently, I spent three years in Luxembourg as a Postdoc.”

During your initial time in Luxembourg as a Postdoc, you realised you wanted to keep studying metabolism. How did this realisation lead to your next destination, Scotland?

“As metabolism research was most advanced in the cancer field, I decided to go to a cancer research institute to learn more about cancer biology. I applied at the Beatson Institute in Glasgow where I wanted to work on folate mediated one-carbon metabolism. There, I joined the lab of Alexei Vazquez, a computational biologist by training, who just started his own wet-lab at that time. This seemed to be an exciting opportunity for me.”

The work you did in Glasgow also inspired the direction of your ATTRACT project. Can you elaborate on the connection?

“The research aims of my ATTRACT programme originate from my previous work in Glasgow, where we discovered and published research on the concept of serine catabolism and formate overflow.

"The major need why cells consume the amino acid serine is to make biomass for cell proliferation. Besides protein synthesis, you need this amino acid to make building blocks for DNA synthesis so that cells can proliferate.

"We discovered that a large fraction of this amino acid can be broken down into smaller products, which are then excreted from the cells. In the latter case, there is no biomass gain. Instead, energy is produced and this specifically takes place in the mitochondrion, an organelle also known as the “powerhouse” of the cells.

"We have shown that this metabolic pathway exists, but the million-dollar question is: Why are cells doing this? Why do cancer cells show increased rates of this pathway when it is not coupled to growth?“

When you arrived in Luxembourg, you worked on a project in collaboration with cancer researcher Prof Simone Niclou, related to your previous work in Glasgow. What did you find, and what does it mean?

“We found that one of the products of serine catabolism – formate - can promote the invasiveness of cancer cells. Thanks to the collaboration with Simone we were able to demonstrate this in context of glioblastoma cells.

"We applied an assay in which we can measure how many cancer cells invade into an artificial extracellular matrix and we observed more invasion of cells, when we increased the concentration of formate. This observation indicates that formate might play a role within the tumour microenvironment during the process when cells escape from the primary tumour and give rise to metastasis.

"One of my PhD students is now continuing this project trying to understand the mechanism behind how this formate molecule can lead to an increased invasiveness of cancer cells.

"That is one part of the story, but then we see this as one showcase, where we identified a metabolic process that can induce cancer cell invasion. Within the ATTRACT programme, we are starting to frame this into a bigger picture by asking which metabolic pathways are generally important for this process and why.”

Why is metabolism important in the context of cancer research?

“Metabolism is essential for any living organism to exist. It describes the utilisation and conversion of nutrients into energy to carry out work, like an old steam train where you throw coal in to get the engine going.

"Furthermore, metabolism provides building blocks for growth and development, essential requirements for proliferating cancer cells.

"In the context of cancer metabolism, we mostly narrow it down to the single cell level. We primarily try to understand how cellular metabolism is adapted to increased metabolic demands in challenging microenvironments. When a quiescent cell suddenly goes into proliferation, or when a cancer cell becomes metastatic at some point, metabolic adaptation is a requirement.

"Thus, metabolism can give clues as how cancer develops, and insights on how it might be targeted.”

What is the focus of your 5-year ATTRACT project at the Luxembourg Institute of Health (LIH)?

“In recent years, the research field of cancer metabolism expanded towards the direction of metastasis research. There have been great improvements on managing primary tumours.

"However, once it spreads, treatment efficiency is severely limited and the survival time decreases. This is where I am trying to establish our group’s research focus. Metastasis is a wide field, and the process itself involves several stages until cancer cells colonize other organs.

"At the moment, we focus on the first steps – how cancer cells can invade into the tissue and then start the process of metastasis: We want to understand this early process and how metabolism might adapt to allow the formation of metastasis in the first place.

"Primary tumour growth is dominated by growth requirements to build macromolecules, such as proteins and lipids, so that cells can divide. But when it comes to the metastatic cascade, there are different growth-independent steps that are important.”

How do you tackle this question technically?

“First, we profile the cell’s metabolism to identify cancer cell specific metabolic bottlenecks. In a second step, we try to figure out how we can perturb the system to stop cancer progression, or maybe even induce cancer cell death.”

From the start of your ATTRACT project, you established collaborations with fellow Principal Investigators (PIs), following your approach of teaming up with scientists from different backgrounds. Can you give examples?

“Apart from the work with Simone Niclou’s lab, my lab works in close collaboration with Dirk Brenner (also ATTRACT Fellow), who works on immunology and metabolism and who has a great variety of mouse models available.

"Here, for example, we were involved into a project looking at serine metabolism in regulatory T-cells. Dirk was one of the first researchers I met in Luxembourg and working with him was great from the first minute.

"I am also very happy that we are collaborating with Elisabeth Letellier from the Department of Life Science and Medicine at the University of Luxembourg, who is an expert in colorectal cancer.

"Furthermore, we work closely together with the Mass Spectrometry platform at the LCSB, where we analyse all our metabolite samples. The platform came about when Karsten Hiller was still there and I was a Postdoc in his lab. Therefore, I know most of the machines and methods quite well. In recent years, the platform extended its instrument and method portfolio, which is a great support for our group.

Finally, we also started to collaborate with Anne Grünewald, ATTRACT fellow at the LCSB, and with Rejko Krüger, PEARL chair for Neuroscience, working on astrocyte metabolism. Thanks to the FNR, this project has now been fuelled by a recently accepted CORE grant.”

With your ATTRACT grant, you were able to set up your own research group. How did you prepare for this new experience - and the lab and people management that comes with it?

“I try to learn as much as I can from past experiences. If myself, or people around me are not happy with their situation, I try to find out how it came about and then try to make it better.

"Only two years ago, I was a Postdoc working on my project and now, almost suddenly, I am a PI and need to lead a team of seven people. This is of course a completely different way of working.

"As one of the first things, I went to a leadership course when I started. There I was trained in conflict and project management, how to be efficient and how to delegate. All of these things become extremely important when you are the one leading the group.

"This is something I can highly recommend and I benefit from it on a daily basis. At the same time, it is also important for me to get feedback from my people. This is like a mirror and shows from an external perspective where you are doing well and where you can still improve.

"For example, this is how we got the idea to register the biochemistry sessions I initially only ran for my group at the Doctoral School. This way, my students can now collect ECTS credit and PhD students from other groups join our sessions as well.”

You generally take a collaborative approach if possible, always looking to bring different points of view and backgrounds together.

“Absolutely - it is impossible to do everything yourself. To work on complex questions takes an interdisciplinary approach.

"I think it is important to know where your strengths and weaknesses are and to then actively seek to work with people who are experts where you are not. We collaborate with nearly every PI in our department on different aspects.”

Is your interdisciplinary approach also reflected in the composition of your group?

“I hired people with different backgrounds - my core expertise is metabolism and analytical chemistry and it is easy for me to train everyone and they can learn quickly how this works.

"I think it is an advantage to pick people with different expertise. For example, one of my Postdocs has a strong background specifically on colorectal cancer and on DNA damage. The other Postdoc has profound experience in cellular biology.

"I try to stay actively involved in all of the projects within my group, always adding the metabolic point of view and training each and every person. I put a lot of effort into this."

"With the perspective of future growth, I currently consolidate my group at present size building up intermediate structures to support a sustainable and carefully paced expansion. If a group grows too fast, efficiency can easily be lost, because less time of the PI is dedicated to each team member and project.”

Many scientists find that once they reach the group leader level, their time for lab or fieldwork decreases significantly. In your case, you are quite happy to take a step back from lab work to look at the bigger picture.

“I stopped working in the lab as soon as I had trained my group members all relevant techniques. Now the lab manager knows all the standards and methods. I realised that it is rather inefficient to spread between the lab work and being a PI, as it needs a lot of focus in both cases. Thus, doing both in parallel may work for others; however, it is not my preferred style.

"I can contribute much more by not working in the lab. I enjoy reading papers, and discussing lab results with my group members. I like the fact that I do not have to focus on the execution of the experiments, but rather that I can now focus more on the big picture and develop ideas. It is great.”

The dynamic and interactions with your group members bring a lot of joy to your work, and you were able to avoid pitfalls you were warned about before launching your group.

“Yes - I have to say that I am extremely happy with every single person in the group. They are a great team, they help each other and it’s not like ‘single soldiers’ in the lab. They have a very collaborative approach and I thoroughly enjoy having them in my team and discussing science with them.

"When I started in the beginning, many people cautioned that hiring is tricky, that it can be hard to find good people. I cannot complain at all. Sometimes when I feel a bit depressed - for instance, when a grant was rejected - I come in to work and I feel motivated by seeing how motivated my team is."

"I think we are on a good track. Our group internal projects are running fine and we are involved in exciting collaborations that should turn into first publications soon.”

You have a flexible approach to working hours for your group and generally do not subscribe to the idea that success is tied to long hours – quality over quantity?

“Just working hard does not mean you will succeed. Often people stress themselves so much, working through the weekend, long hours, thinking when they do more and more experiments they will get their great paper in the end.

"If you do not have time to take a step back in between, to reflect and think about the bigger picture, you get lost. It is a tight balance – I like to say work smart, not hard. Quality over quantity.

"I was often limited in the hours I could spend in the lab, for family or other reasons. Just because people spend 10 or 12 hours in the lab does not mean they achieve more than someone else who is there for 8 hours productively.

"It’s about efficiency and not about the number of hours."

"When my group members started, I told them to come and go as they need, in line with the demands of their research and private life – the only thing I am interested in is the result."

"The best you can do is to create a good environment for your group members to flourish in. That is my job – to secure funding and all that comes with it, and to make sure we have great projects and collaborations to work on.”

Your research is basic research. Why is fundamental research important in your opinion?

“Fundamental research provides building blocks that shouldn’t be stored and stocked but continuously need to be followed up into application and vice versa.

"It is always hard to know which parts of research will end up in applied innovation. Take for example electric mobility. 20 years ago, when electric cars were shown at car exhibitions, people were more interested in the newest Ferrari. Then, suddenly over the last 5 years, electric cars have become a huge factor in modern mobility. This is a good example to illustrate the impact of long-term basic research on disruptive innovation.

I think that in the sector of life science, this should be anyway evident. In my view, it will always be important to understand mechanisms first and then to design tailored intervention strategies as a second step. Ideally, this goes hand in hand and I think that Luxembourg is on a good track.”

Do you have any advice for early-career researchers?

“It took me a while to realise, but I would say: the earlier you know where to go, the better! Find your niche. These processes do not happen overnight."

"I realised where I wanted to go with my research when I went to Glasgow. Then it took me 3 years to really reach that goal, which I think was still quite fast.

"What it takes to get there – to the stage where you can lead your own group – I learned a lot about in the last 3 years at the Beatson Institute in Glasgow. I was never exposed to such a competitive research environment before.

"Of course, there are things I wish I had known earlier. However, in retrospect, it is only important that you learn from your experience.

“Once you know where you want to go, you can start thinking how to get there and then go about ticking the right boxes.

"You also believe it is important to put yourself in the right places – and emphasise the importance of having a good mentor.

“It is important to select the right labs – and the right boss. There can be people who provide good mentoring and support you to get to the next level. Then there are other people who just see you as a resource and take a more exploitative approach."

"Both ways can lead to good publications, however, this is not sufficient to become a successful PI. For your own sake, it is better to look out for the mentoring type.”