An interview with Lydia Finley Free

How did you first become interested in science and then, more specifically, cellular metabolism?

I realised that science was something that I was really motivated to study because of a physiology class I took in college. I was struck by the beauty of biology – it's astonishing to see how the whole body comes together. I was not somebody who would ever ask questions in class; I would sit in the back, I'd be quiet, and at the end of the class I'd pick up my bags and go home. But we had one class where we learned about how muscles work. The Professor was teaching us how muscles could continually switch to using new fuels, and I remember that this fact knocked my socks off. I thought this was amazing, but it was also annoying because I was on the track team and I got really tired during workouts, and it frustrated me to know that it wasn't because my muscles were running out of fuel. I remember thinking that there has got to be more to understand, and that was how I eventually ended up in Darrell Neufer's lab at Yale studying metabolism during recovery from exercise, and I've been in metabolism labs ever since.

At what point did you decide to pursue an academic career?

This is a question I really like to answer because it was never obvious to me (based on my interests) what my long-term career might be, and I never had an agenda to be an academic scientist. I knew I loved science and I knew I didn't want to go to medical school, and so for a long time I thought I would be a teacher because I really liked learning. I actually was a teacher after college for a while, but I wanted even more science and so ended up in graduate school. Even during graduate school, I wasn't sure what I wanted to do next. Towards the end of my PhD, when I was trying to decide whether I should do a postdoc, I had a conversation with my thesis mentor, Marcia Haigis, and I remember the take-home advice she gave me was essentially: just keep going up the ladder; keep going up until you don't want to go up anymore, and then go somewhere else. I found it so reassuring that I didn't have to know where I wanted to go. I think a lot of trainees struggle with this question of ‘should I stay in academia or not?’, or they think ‘I want to, but I hear it's hard’. I think that sometimes we put too much pressure on ourselves to know what it is that we want to do 5,10, 20 years down the line. I try to approach it one step at a time. So, I probably decided I was going to be an academic scientist when I signed my job as an Assistant Professor.

You completed your PhD in Marcia Haigis’ lab at Harvard University, USA. What did your research focus on there?

I studied mitochondrial sirtuins, which are a family of NAD-dependent enzymes. It had just been discovered that mitochondrial proteins are heavily acetylated, which was really surprising because, at the time, acetylation was thought to be largely restricted to cytoplasmic and nuclear proteins. The discovery that roughly 60% of the mitochondrial proteome was acetylated led to all sorts of questions, like ‘what is it doing?’ and ‘how might it be important for metabolism?’. SIRT3 is the major mitochondrial deacetylase, so I studied what SIRT3 deacetylated and whether or not it was important for metabolism. This developed a story on SIRT3 regulating reactive oxygen species (ROS) production that ultimately controlled hypoxia inducible factor (HIF) stability, which was emerging as a regulator of aerobic glycolysis. This was during the early days of cancer metabolism when everyone was excited about the concept of aerobic glycolysis, and our work ended up taking us right into that direction.

You then moved to the Memorial Sloan Kettering Cancer Institute, NY, USA, for a postdoc in Craig Thompson's lab, before subsequently starting your own lab there in 2017. What did you work on during your postdoc?

I worked on several things, many of which did not pan out. What ultimately led to publications was our work in embryonic stem cells (ESCs). This work was in collaboration with Bryce Carey, then a postdoc in David Allis’ lab. This collaboration came about because when I was thinking about the transition to postdoc, I was really interested in this very new concept that intracellular metabolites were not only substrates for biochemical processes involved in metabolism, but also for processes that could control cell fate, like histone or DNA modifications. Craig Thompson had published a paper demonstrating that the metabolite succinate controlled HIF stability, which was very influential to me during my PhD, and Dave Allis was a pioneer in chemical modifications of histones, so I thought one of those two labs would be a really good fit to study the links between metabolites and chromatin. I ended up joining Craig's lab, where I started working on a completely different project studying propionate metabolism. Unfortunately, despite a lot of hard work, it was clear the question I was asking wasn't well matched to the system I was studying. When I said to Craig, ‘I think my project is dead’, he said, ‘oh, one year in, you're right on schedule’.

Conveniently, right around that time, we had just done our first isotope tracing in ESCs with the Allis lab, and the data was astonishing; it showed this black and white difference between the cells in different stages of pluripotency. This then became the focus of my postdoc, and we showed that different states of pluripotency have different levels of metabolites that control chromatin and cell fate. This was the dream hypothesis all along, but we got there accidentally. I often wonder what would have happened if those data had landed in our laps at a different time. What if my other project had been going really well? It all worked out in the end, though, and we realised that ESCs are a phenomenal system to study cell metabolism.

Why did you decide to stay at Sloan Kettering as a group leader?

A lot of different factors go into the decision of where you open your lab; many of them are scientific, as you need to think about where you're going to have the resources and support you need to do the science you want. But there are also many personal considerations, for example, where you are going to be able to live the life that you want to live. In many ways, becoming a group leader is the first potentially permanent position of our lives, so this is a big decision. I am absolutely thrilled to be at Sloan Kettering for both personal (I'm from New York!) and scientific reasons. The Sloan Kettering Institute is committed to fundamental, basic science and is full of extraordinary researchers studying cell, developmental and molecular biology. We also have more disease-oriented programmes and, of course, we are surrounded by one of the best cancer hospitals in the world, which provides incredible opportunities to study metabolism in clinical contexts. I'm very happy to be in an environment that values basic research and gives us the freedom to go wherever we think there are important questions.

What are the main questions your lab is trying to answer?

During my postdoc with Craig Thompson, we showed that the metabolite α-ketoglutarate controlled cell fate in ESCs. So, the founding goal of my lab was to figure out how α-ketoglutarate can control cell fate; some of the first papers from my lab helped to extend this regulatory role to cancer and adult stem cells as well. Working with Elaine Fuchs, we showed that α-ketoglutarate controls epidermal differentiation. We also teamed up with Scott Lowe's lab and showed that α-ketoglutarate controls cell fate in pancreatic cancer. There are lots of hypotheses as to how this metabolite influences cell fate; the obvious hypothesis is that it is regulatory because it is a co-substrate for a large family of enzymes that control histone and DNA demethylation, among other processes. I think that is still the most viable hypothesis, but we have work to do to test it. More generally, we want to understand more about this interface between metabolism and the regulation of cell fate, particularly regarding specificity; how can a metabolite ever induce a coherent fate change when it doesn't have any inherent sequence-specific information? What are the mechanisms that allow for specificity to arise? And then of course, is this a physiological process that is happening during development?

You recently published a paper describing a non-canonical TCA cycle that is required for the exit of ESCs from pluripotency. What are your thoughts on the shift in the field, recognising that metabolism is a driver of differentiation, rather than a product of it?

When we think about factors that control differentiation, most of the work to date focuses on transcription factors or signalling networks. But I think it is becoming more evident that metabolism is a really integral third pillar of development and that in order to transition to a given cell state, cells have to acquire the appropriate metabolic resources. I'm so happy that people are now recognising this, because I think that this opens up huge new avenues for understanding environmental influences on development and the links between metabolism and cell biology. How is metabolism rewired when cells change their state? What are the many different configurations that metabolism can adopt? Understanding links between metabolism and development, especially in early life, will also provide key insights into how environmental factors control health outcomes, which I think is a really important avenue with a lot of public health relevance.

One of the things that has struck me is that most of our knowledge of cell metabolism comes from studies in adult tissue. All of the pioneering scientists who mapped out metabolic networks were using differentiated tissues from mice, pigeons, frogs, etc. because that is what was available. There was no model system for studying metabolism during development. I think this is a field that really only could have arisen at this point in time, because now we have the tools to perturb metabolism and look at developmental phenotypes. I think this is a really exciting moment where we now can take the fundamental principles of metabolism that we've worked out in adult systems, along with newer tools to study metabolism in vivo or in rare cell populations and organoids in vitro, and put them together and ask, ‘how is metabolism rewired during development and how does it control developmental processes?’.

Reflecting this shift, this Development Special Issue focuses on metabolic and nutrient control of development and regeneration. Why did you decide to get involved as a Guest Editor?

There are two main reasons. The first is to learn. I think handling papers is one of the best educations in science because it ‘parachutes’ you into a different country in your scientific globe and allows you to see up close what questions people are asking in different areas of your field: what are the techniques they're using? What are the challenges they are facing? Especially when you then start to read the back and forth with reviewers, you begin to appreciate any technical sticking points and conceptual controversies. This process provides an interesting way to get a good glimpse of what is going on in other related areas of the field, and thus allows you to be a better scientist.

The second reason is that I think that being an Editor is a really important opportunity to help shape a field. This field of developmental metabolism is a relatively new one and so, as an Editor, you have an ability to help set the tone for how you want the discourse to go. I don't necessarily mean what questions we think are important, but what is the standard of evidence that we as a field would need to publish? How are we going to respond to specific concerns and encourage the collegiality that you would want in a field? So, I think it's an amazing opportunity to try to help ensure that this field is growing in a positive and constructive direction, and there is no better venue than Development, which has set the tone and standard in developmental biology for decades.

What does your role as a Guest Editor entail and what impact would you like to make?

My main role as Guest Editor is to read papers as they come in and decide if they should be sent out to review. And, of course, if they go out to review, I try to help shepherd that paper through the process and make sure that the minimal amount of work is requested of the authors to address any crucial points raised, which is something I take quite seriously. My aim is that the authors who have their work sent to Development and handled by me (and others) feel that they've been read and understood. Even if they don't love the decision, I want them to feel that they were heard and that their work is appreciated, because it always is.

What type of papers do you most enjoy handling?

For me, it's not a particular topic or technique that really gets me excited, it's how the paper is put together; papers that are clearly crafted and constructed with obvious love and care are the ones that I adore handling. If you imagine the authors are a waiter at a fine-dining establishment, you want them to set the table, lead you to your chair and tell you what is on the menu. It becomes this beautiful dining experience where you know what to expect and you know what to look for.

In recognition of your excellent research, you have received a number of awards since starting your lab, including the Damon Runyon-Dale F. Frey Award for Breakthrough Scientists (2017), Searle Scholars Program (2018) and Pershing Square Sohn Cancer Research Prize (2020). What do these awards mean to you and how have they impacted your career?

These awards have all transformed my research or career – they bring validation, support and freedom to pursue our research. I think the most meaningful award I ever received was probably the Damon Runyon cancer research fellowship I got as a postdoc. This one was meaningful to me for a lot of reasons, one of which is that I didn't get it the first time I applied, I got it the second time. But I was the same scientist and it was pretty much the same proposal; one time I didn't get it, and one time I did. I've always remembered this as a sign that sometimes things go your way, and sometimes they don't. This is something I've tried to keep with me all the time and remind myself to be really grateful when they come along, as these awards are transformative to our science; they allow us to move forward with more freedom and be a little bolder. Another reason the Damon Runyon award was so meaningful is that it came along at the right time, just as the project I was working on fell apart. That's really what all of these awards do – they hold out a hand, saying, ‘you can do this, we support you’. I can point to the research trajectories that each of these awards enabled; I'm sure we wouldn't be doing what we're doing now if it wasn't for the support of these foundations.

In 2022, you attended The Company of Biologists Workshop on ‘Development Metabolism and the Origins of Health and Disease’. What were the highlights of the Workshop and what did you gain from it?

That was the best meeting I've ever been to. There are two things that made it really special for me. First, it was the first meeting about developmental metabolism that I'd ever attended in person. It was really exciting to have a chance, for the first time, to talk with other scientists about a topic that I'd thought a lot about on my own. Usually, I go to cancer meetings, where I'm one of few thinking about development, or if I'm at a stem cell meeting, I'm the only person talking about metabolism. And so I hadn't had a chance to see all these people interested in the same question, but from different perspectives, come together with their view of how these fields intersect. Second, it was an amazing education; I had been aware of the impact of early life environment on development, but I hadn't really focused on the literature, or the numbers, or the possible mechanisms. What this meeting did was give real relevance to the field; it tackled questions that are not only interesting biological questions, but ones that are relevant for human health, because changes in metabolism and early development have lifelong impacts on people in the world.

Finally, how do you think the field will develop in the next 5-10 years?

I think there's some basic work that needs to be done, for example, cataloguing the metabolism of different cell types during development. I think there are also lots of mechanisms yet to be determined. How are these networks regulated? How are the metabolites affecting development, especially for the metabolites that are proposed to be regulatory for cell fate? I think there is also going to be a lot of interesting research from people working on inborn errors of metabolism. Why are certain mutations affecting specific lineages? But I'm sure there are going to be a lot of surprises, seeing how it all comes together, whether or not metabolism is working cell autonomously, or if there are interactions between different tissue types.

I think a current ‘black box’ of the field is the placenta, which is clearly mediating a lot of the metabolic interface between a mother and the fetus, and I think there is so much more to know about how that works. It's clear that maternal health can affect fetal development, but we know very little. There are of course experimental hurdles to drawing those arrows and making those links, but I think that's a really exciting time for the field, figuring out strategies and workflows to go from an environmental insult in a parent to a developmental phenotype in an offspring, and ask ‘what are the mechanisms at play?’.

Lydia Finley was interviewed by Daniel Routledge, Cross-title Reviews Editor at The Company of Biologists. This piece has been edited and condensed with approval from the interviewee.