Lydia Finley studied biology at Yale University, USA, and then carried out her PhD work in the group of Marcia Haigis at Harvard Medical School on the post-translational regulation of mitochondrial function. During her postdoc in the lab of Craig Thompson at Memorial Sloan Kettering Cancer Center (MSKCC), she discovered that intracellular levels of the metabolite α-ketoglutarate, through regulating chromatin and gene expression, contribute to embryonic stem cell renewal. Lydia established her group at MSKCC in 2017, where they use genetic and metabolomic approaches to investigate the mechanisms that link metabolic pathways to cell fate decisions. Lydia is a Searle Scholar and the recipient of the Dale F. Frey Award for Breakthrough Scientists from the Damon Runyon Cancer Research Foundation.
What inspired you to become a scientist?
In my sophomore year in college, I took a physiology class and at the time I was also on the track & field team, so I was really interested in learning how my body worked. We had a lecture on muscle physiology, which sort of struck a chord because, in the course of the lecture, it became clear that there was no obvious reason why muscles got tired when you exercise – they don't run out of fuel, they just switch fuel sources. I realized there were a whole bunch of questions, and this led me, for the first time in my life, to go up to the professor after class and ask one; I wanted to know why after doing a really hard workout you are not sore immediately, but only after a day or two. He thought it was a great question and told me I should come and work in his group. So that's how I ended up in a muscle physiology lab studying mitochondrial metabolism during recovery from exercise. I was working nights and weekends in between track training and was trying to show phosphorylation of a protein during recovery from exercise, but I spent about a year getting blank western blots and achieved precisely nothing – I still really enjoyed the process though and having the hope every time I came in the lab. But what really got me to stay in science was my mentor Darrell Neufer, who treated me like a scientist and believed that I belonged there, which meant so much.
And you stayed in metabolism research ever since. What are the main questions your lab is currently trying to understand?
We are interested in the relationship between metabolism and cell identity. And there are two sides to this question. The first is, how do cells acquire their metabolic identity? Different cells in different stages of development, or different lineages, have different metabolic profiles, and so we want to know how those profiles are established and whether they are important for cell fate. This leads to the reciprocal question, which is how do metabolic changes affect the ability of cells to acquire their fate or carry out their functions? The idea here is that maybe shifts in nutrient availability or environmental perturbations can lead to changes in gene expression profiles that ultimately affect the identity of a cell.
Could you tell us how and why you started using embryonic stem cells as a main model for your questions?
Probably one of the most important serendipitous events in my scientific career was when I was starting my postdoc and Dave Allis introduced me to one of his new postdocs, Bryce Carey. We were both interested in the links between metabolism, gene expression regulation and cell fate, and Bryce had the idea to study metabolism in embryonic stem cells at different stages of their self-renewal, which ended up being just an incredible system. You can precisely control the variables that regulate embryonic stem cell state, and therefore really get at how metabolism is related to cell identity. For example, when working together we found that a major factor determining cell identity was what cells were doing with their glutamine – whether they burned it or preserved the glutamine-derived α-ketoglutarate.
What is your approach to generating ideas and interesting research questions, especially in the current age of ‘big data’?
I sometimes think of our lab as the little shrimp on the ocean floor – we don't generate a lot of big datasets, but we're very good at using the datasets other people produce to gain new insights. The other approach, which comes back to having a controlled embryonic stem cell system where you can toggle cell fate, is just letting the cells tell us what they're doing. It's amazing that now with technologies such as CRISPR you can delete a metabolic enzyme and then use isotope-tracing strategies to see how the cells unfurl themselves to you and show you exactly what they're doing with their nutrients. They'll take you through their metabolic networks, if you listen to them!
At a recent meeting, one of your slides featured a 1940 paper from Krebs. In your experience, what is the value of digging into the older scientific literature?
The old metabolism papers are amazing – although they're often not the easiest reads. But there's a huge amount of information that has been somewhat lost over time. The highlights make their way into textbooks and are passed down, but if you go back and read the original papers there is so much more to them than the punchline. I think going back to the fundamentals and asking ourselves how we know what we know is really important. So, when we were looking at the TCA cycle, we thought, if we were going to add anything new to the topic, we have to make sure we really know what Krebs has done and how he has done it – I actually have a whole binder of all the sequential works by him.
“I think going back to the fundamentals and asking ourselves how we know what we know is really important.”
On your Twitter bio you describe yourself as a ‘cell biologist with an interest in pretty much everything’. If you were not working on metabolism, which other research field would you study?
I think evolutionary biology or ecology; I loved these classes in college and to me, they're intellectually very similar to metabolism. They feature systems that are working together to reach some sort of fitness or steady-state equilibrium, which would be semi-predictable if we knew all the inputs – but of course we don't know all the inputs.
Let's go back to the time when you started your own lab. What did you experience as the main challenges of setting up a group?
The first few years are stressful because everything is a battle in the beginning, even just getting the first tissue culture up and running, and there's an incredible level of attention to detail that's required for everything to be in place and set up. A source of a lot of stress for new PIs is that after coming off of a successful postdoc where you've been extremely productive, and then having spent a long time on the job market coming up with project ideas, this all comes to a crashing halt as you get an empty room and a bunch of boxes, while the field of course is moving on. So oftentimes, the ideas that you thought were going to lead to the first stories from your lab are pretty quickly published by other labs. This certainly happened to me and almost all of my friends. So, it's important to let go of those first ideas and the sense that those were the projects you were going to start your lab on, and instead embrace the idea that your lab is a culture and if you get good people and build that culture right, new ideas and everything else will come. There are some things we are doing now that I never in a million years would have thought I'd be working on!
Speaking of lab culture, could you share your approach to mentoring and running your lab?
I think the idea of breaking everything down into achievements is so important in every aspect of what we do in science, because any progress we make is the product of little victories. And anything can be looked at in the context of a little victory, even if it's a mistake we made that we can learn from. We're not just showing up at the lab and churning out panels for papers – I don't know anyone who does science that way. Every figure panel is the tip of an iceberg of a million little battles that we've fought. So what I hope is that if the culture in the lab is to recognize that each small step is important, it will make the lab a more positive place where all science is celebrated, and even results that might be disappointing are recognized for important advances and accomplishments. This builds a culture of resilience and reproducibility, and I think the people in my lab are so amazing at propagating this culture.
“I think the idea of breaking everything down into achievements is so important in every aspect of what we do in science, because any progress we make is the product of little victories.”
What do you find the most rewarding part of being a group leader?
There are two things I really love: one of them is when my trainees get good news and I see it in my inbox and get to run into the lab and sort of shriek with them; the other thing I really like is looking at data together with people in the lab, and thinking about what the data are saying. I love that moment of insight of ‘oh, here's how we can look at it’, for example when we break down what the data can mean into different possibilities and think of experiments that can solve the puzzle. It's a huge source of satisfaction.
Is there any piece of scientific advice or words of wisdom that has stuck with you during your career?
My postdoc advisor Craig Thompson would always say “If you think you found something interesting or new, you better try to figure out why no one has found it before.” And I think that's been really important and is one of the reasons why I like to delve into the old literature a lot to see what's known or not known. The other thing I find myself often saying in lab meetings, which is another statement from him, is “how do you know you didn't just add hydrochloric acid?” – so basically how do you know that your negative or positive result is actually due to your intervention. I think that framework for thinking about experiments is really important.
Finally, if there is one thing you could change in academia, what would that be?
I'd like it if science was more broadly perceived as a team sport, and that there wasn't a perception that one person's success comes at the expense of another person's. I understand of course that with funding being tight it can feel that way. But I think science is most fun when everyone recognizes that one person doing well actually does raise the bar for the entire field!
Lydia Finley's contact details: Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Lydia Finley was interviewed by Máté Pálfy, Features & Reviews Editor at Journal of Cell Science. This piece has been edited and condensed with approval from the interviewee.