Cell scientist to watch – Tom MacVicar Free

Tom MacVicar

What inspired you to become a scientist?

I didn't know what academic research really looked like until very late in my undergraduate studies, where I mostly had experience in massive teaching labs. When I started my undergraduate research project, I worked with a student who was really patient and enthusiastic, and I saw for the first time what teamwork was like in the lab. I think that's what inspired me to realise that doing a PhD could be really fun. The project focused on stress responses in Salmonella. Interestingly, these bacteria respond almost like mitochondria do to certain stresses – they fuse together and elongate into filaments. I wish I could say that even back then I was thinking about the ancient bacterial origins of mitochondria, but it was complete coincidence.

Tell us a bit about your scientific career path so far. How did you first get started working on mitochondria?

I started my PhD at the University of Bristol in the UK with Jon Lane, who worked on autophagy. I rotated around three different labs during my first year, and I really enjoyed working with Jon and again was fortunate to be supervised by a very kind postdoc, Virginie. During the short rotation project, a seminal paper in the Journal of Cell Biology from Richard Youle's group observed that recruitment of parkin, an E3 ubiquitin ligase, on the outer membrane of dysfunctional mitochondria led to their destruction by mitophagy. When I got access to some of the tools from this paper and looked at similar experiments using live-cell imaging, it was wild to watch how the mitochondrial network was completely degraded when we overexpressed parkin. That's what got me hooked on mitochondrial quality control, which, with great encouragement from Jon, ultimately led me to move to Thomas Langer's lab in Cologne for my postdoc.

By then, I had a better idea about what really fascinated me in mitochondrial biology – how metabolism impacts mitochondrial dynamics. We had just become interested in the role of proteases that sit in the mitochondrial inner membrane, and Thomas's lab was the world leader on this topic. Even though I moved to Cologne as a postdoc, because PhDs in the UK are so short, I felt vastly less experienced than many of the PhD students there, who were working on projects beyond 5 years. I dealt with some imposter syndrome at the beginning, but I had a great experience. My intention was only to go for a few years, but 8 years later I was still there! The environment in Cologne was excellent for mitochondrial research.

Towards the end of my time in Thomas's lab, I started to think about what kind of niche I could carve for myself. We were interested in how metabolism affects mitochondrial proteases and how this ultimately reprogrammes mitochondria in response to various environmental stresses. I was particularly interested in hypoxia and nutrient starvation, which are prominent stresses on tumours, and the idea that tumours can reprogramme their mitochondria to adapt to these conditions. Harnessing the amazing flexibility and plasticity of mitochondria and the mitochondrial network, and its significance for cancer, is something that I wanted to explore further, and that's why I ultimately came to a cancer research institute to start my own lab.

You started your lab at the CRUK Scotland Institute in 2021. What challenges did you face as a new PI that you didn't expect?

I started my lab in December 2021, which, looking back, was a bad idea, because winter in Scotland is very dark with not much happening. We were also just coming out of the COVID-19 pandemic, so there wasn't even a Christmas party! Starting as a group leader can be quite lonely at times because you're not jumping into a full lab environment as you do as a PhD student or a postdoc. However, supportive colleagues across the institute soon helped me relax and settle in. A lot of the advice I was given at the beginning was to take your time−don't rush. I took my time with recruitment and thought carefully about what the core values of the lab were going to be. We have five core values now−curiosity, inclusivity, respect, accuracy and fun. The next big challenge then came when the first two members joined the lab in July 2022, because they started the same week that my second child was born, while we were also moving house. They had also moved their lives, one from Brazil and one from Singapore, and I had really wanted to be there as much as possible to help them to settle in. Plus, I was super excited to finally have a team together! But these things happen in life and sometimes in retrospect you just acknowledge you could have planned a bit better.

What questions are your lab trying to answer currently?

Mitochondria are essential metabolic organelles required for compartmentalised metabolism, which is fundamental for life. We're interested in key regulators of this compartmentalisation – the metabolite transporters that sit in the impermeable inner mitochondrial membrane. These transporters are essential for coordinating the metabolic reactions of the mitochondrial matrix with the rest of the cell and are nodes of regulation by which the cell can adapt their mitochondria in response to signalling cues and environmental stresses. Currently, we're particularly focused on understanding how mitochondria take up nucleotides to regulate mitochondrial gene expression and whether there are any metabolic vulnerabilities related to this uptake in cancer cells, which are sometimes starved of the precursors for nucleotide synthesis. We're also interested in amino acid metabolism and transport into mitochondria. We are ultimately hoping to identify mitochondrial metabolic vulnerabilities that could be developed for therapeutic benefit in the future.

Your research on fundamental mitochondrial biology clearly has major disease relevance−are there any translational aspects to your work?

The translational aspect of this research was one of the main attractions for coming to the CRUK Scotland Institute. I passionately believe that advancements in understanding basic, mechanistic mitochondrial biology will ultimately provide strategies to metabolically target tumours in different scenarios. I've come to realise that it's never too early to be thinking about translatability. My mindset initially was that we will do our discovery work in cells, and then move to collaborating with people who work on pre-clinical models of cancer−which is what the Scotland Institute is world famous for−and continue to build from there, thinking about therapeutic strategies and drug design. I'm starting to appreciate that we can and should be designing some projects from the outset with translation in mind. I'm also really pleased that some of the students and postdocs in my group are involved in engagement with the public and patients. The ability to communicate the importance of what we're doing is very important, because doing the research that we're passionate about depends on hard-earned charity money donated by people who rightly expect the research to be ultimately translated for patient benefit.

Are there any new or challenging techniques that you've adapted for your research?

The opportunity to work with experts on pre-clinical cancer models was something that really drew me to Glasgow, which is a fantastic place for collaboration. We want to make the leap from observations in cells to elegant mouse models of cancer. We're also doing more work in 3D cell culture now−with liver and intestinal organoids−which is quite labour intensive and expensive for a group of our size but is invaluable for allowing us to ask our questions in more disease-relevant models. We also work with all the advanced research technologies available here, without which we wouldn't get anywhere. For instance, we collaborate very closely with the metabolomics facility. They've recently gotten a new mass spectrometry imaging platform, so that will be another exciting new way for us to address some of the questions we have, for example, about spatial control of metabolism in tumours and the heterogeneity of metabolism within tissues.

What would you say are some of the biggest open questions about the role of mitochondria in cancer?

If we do find metabolic vulnerabilities in mitochondria, how can we actually target them in cancer cells? There have been quite a few high-profile failures in trials of electron transport chain inhibitors in the clinic recently, which proved to be quite ineffective and intolerable for patients, so we need to better understand the nuances of how mitochondria are regulated in cancer and identify novel metabolic vulnerabilities that will hopefully allow us to not damage healthy tissues with high energy demands as well.

Really interesting work has also shown that the mitochondrial metabolism of the primary tumour is wired differently to that of metastases, which are the malignant growths that usually kill patients. Sometimes, mitochondrial activity and metabolism are polar opposites between the primary tumour and metastases. Does this switch occur along the journey of the metastasising cells, or is it at the site of metastasis – and can we block this metabolic re-wiring to effectively target the primary tumour and block metastasis?

Another area of massive interest is the role of mitochondria in cancer initiation. Mitochondrial DNA mutations have been identified in cancers, and understanding the contribution of the mitochondrial genome to the early stages of disease is a very pressing question right now. Many cancers accumulate mitochondrial mutations to various degrees of heteroplasmy in the mitochondrial network, and there are mutation hotspots in some respiratory chain enzyme subunits that can, for example, regulate redox metabolism by modulating the activity of the electron transport chain. There have also been very interesting links demonstrated between these mutations and tumour immune regulation.

What do you enjoy most about studying mitochondrial biology?

It's a super exciting time to be a mitochondrial biologist. There are many exciting new groups as well as established groups globally interested in mitochondria. The appreciation is now growing, among non-mitochondrial biologists as well, that mitochondria are more than just the ATP-producing ‘powerhouses of the cell’. People are starting to appreciate that they're multifaceted organelles involved in so many processes. For me, it's always fun to be able to communicate this with scientists from different fields. Researchers are identifying mitochondrial signatures in different omics experiments and considering the roles of these organelles in new contexts. For example, they are starting to care about mitochondrial gene expression in RNA sequencing data and what this tells us about the mitochondria in those cells. Many are also observing changes in mitochondrial morphology and appreciating how beautiful mitochondria are to image. The challenge is to explain what a change in mitochondrial morphology might mean in different physiological and disease contexts−unfortunately, I can rarely offer more than speculation!

What is the best science-related advice you ever received?

To do what interests you the most and to stay true to yourself in terms of your research, because you can be easily pulled in different directions. Ultimately, I think sticking to what really excites you in science is the way to survive, but on the flip side, keep your mind open as well. I was recently shown a painting that depicted the death of the Greek mathematician Archimedes. His city was under siege and a Roman soldier demanded that Archimedes come with him, but Archimedes appeared too busy trying to solve a mathematical problem, so the soldier murdered him in a rage. I personally take from this that, sometimes, it feels easier to focus on the problem in front of you and keep doing experiments, but you need to be aware of the big picture, pay attention to how fields are changing and avoid isolating yourself. It's also just good health and safety advice – if the lab is burning down around you, you should leave the building!

What advice would you give to researchers aiming to start their own lab?

When applying for positions, you want to find a supportive and collaborative environment in which to start. Never hesitate to reach out to people at institutes that you're interested in, particularly people who have just started a lab themselves. Having a good peer support network is important, and I've found that people are happy to talk about their experiences. Like I said before, it's important to find your niche when starting out, but that can also feel a bit restrictive. I think that always trying to do what interests you most should be the number one goal. Establish your research group around a question or topic that you're passionate about and then start to think about where you position yourself in the field. In the beginning, I was really worried about building a niche, establishing independence and proving myself. I eventually started to stop worrying whether I was doing things differently enough from my mentors and just focused on the questions that I want to ask.

It's also fine to take your time. It's completely normal at first for everything to move a bit slower than you're perhaps used to in the postdoc world, where you're flying through experiments. A good piece of advice I was given was not to retreat from the bench too quickly. I really enjoyed having time at the beginning to set up the lab and do experiments myself, which helped me train people when they joined and hit the floor running. It also gave me an opportunity to meet and interact with people in the building, including all the support staff. Nowadays I'm having to retreat a bit more. I'm fortunate to have a senior postdoc who's so good at organising the lab to the point that I'm a bit scared that I'm going to disrupt everything when I do go in! As you learn how to delegate and trust people, it becomes easier to leave the bench.

What is your approach to mentorship?

I don't have one single approach because it varies with each individual. I think that there is no right way – it's just about building an honest and trusting mentee–mentor relationship that will hopefully help empower and guide people. Everyone's different and everyone's got their own career ambitions. Helping each person work out their goals as soon as possible is very important for shaping a productive relationship. Upon reflection, I think I'm a better mentee now as a group leader than I was at any previous point in my career. As a PhD student or postdoc, I maybe wasn't active enough in searching for more than one mentor or in asking for more help at times. Now I realise the importance of having multiple mentors and people whom you trust to talk through any problem. I encourage my students to build their own mentorship networks, and I also mentor people who aren't in my group.

Finally, could you tell us an interesting fact about yourself that people wouldn't know by looking at your CV?

During my undergrad in biochemistry, while all my friends were taking relevant optional courses like pharmacology and immunology, I was doing medieval history instead. I even wrote a dissertation on the English invasion of Wales under Edward I. I'm very grateful that I had the chance to learn something completely different from my core science courses. Recently, I've gotten into science history. I just listened to a podcast about the Scottish polymath Mary Somerville. She was incredible; she studied so many areas of science back in the 19th century and was one of the first people to see the power of bringing together different research backgrounds – what we would call cross-disciplinary research today. Her publications really engaged the public with science, and the term ‘scientist’ was first used in a review of one of her journals. I thought she was an unsung hero of science, but then a friend pointed out that her portrait is on every Scottish £10 note! Still, I'd like to learn more about her fascinating life.

Tom MacVicar was interviewed by Amelia Glazier, Features & Reviews Editor for Journal of Cell Science. This piece has been edited and condensed with approval from the interviewee.