Cell scientist to watch – Samantha Lewis Free

Dr Samantha Lewis

What inspired you to become a scientist?

I was really into in Star Trek as a kid. I remember feeling that it would be wonderful to be part of a world where discovery is prioritised and where people were doing things that no one had done before. Also, because I'm a biracial black woman, seeing a society like the one in Star Trek, where people of all different phenotypes are welcomed and included, and their expertise is valued, made an impact on me. That was the world that I wanted to live in.

As an undergraduate, I entered Oregon State University as a chemical engineering major on chemistry scholarship, but at the end of my first year I took a developmental biology class that really connected with me. I didn't feel like I needed to study the material just for the exams – I wanted to learn more, engage with it and talk to my professors about it simply to satisfy my curiosity. I switched majors to biology, because it felt more natural to me. As a work study student, I worked as a dishwasher in my undergraduate advisor Dee Denver's lab. Pretty quickly, I got excited about the lab's research on molecular evolution of the nuclear and mitochondrial genomes in Caenorhabditis elegans. I asked for my own project, and everything came into alignment for me. I really enjoyed being able to complement what I was learning in my classes with my research in the lab.

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

I took a class taught by Dr Virginia Weis, a very well-known marine biologist, on the mechanisms of symbioses in both marine and terrestrial environments. My mind kept coming back to the question of how the mitochondrial ancestor became an endosymbiont in the first eukaryotic cells. Through this class and the research on nematode mitochondrial genomes I was doing in Dee's lab, I realised that I wanted a research career that would focus on mitochondria. I was only the second person in my family to get a bachelor's degree – my dad was the first, but he went to college later in life after he retired from the US military – so I didn't really know what a college campus would be like or what an academic science career would look like. But I knew that I really loved research and that I could get paid to do it! Dee encouraged me to apply to graduate school and even arranged for me to go to two conferences to present my senior research project. I ended up meeting my future PhD advisor, Dr Bradley Hyman, at one of those conferences.

What ultimately drew you to focus on the mitochondrial genome?

When I started my PhD in genetics, how multicopy mitochondrial genomes were maintained was not well understood. Mitochondrial biology felt like an area where there would always be something new and exciting to discover. In Dee's lab, I had worked on the molecular evolution of nematode mitochondrial genomes, and one of the things that I found was rampant mitochondrial genome rearrangement among different lineages. I was interested in understanding how some nematode lineages came to have the same complement of genes in their mitochondrial DNA (mtDNA) but different copy numbers and different gene order. I ended up going down a rabbit hole and became fascinated by recombination and DNA replication errors that remodel genome architecture. At the time, there wasn't a whole lot known about these processes in mtDNA, so that led me to study mitochondrial genome replication and recombination with Brad.

As a postdoc in Jodi Nunnari's lab, I expanded into cell biology because I fell in love with microscopy. I felt that imaging was a powerful tool to have in my arsenal because it allows the study of dynamic processes at the single organelle level. In Jodi's lab, I sought to visualise where and when mtDNA synthesis takes place in mitochondrial networks. I was relatively new to the world of fluorescence microscopy, and I learned a lot about confocal imaging from another postdoc in the lab, Dr Jonathan Friedman, who's now a PI at the University of Texas Southwestern. It took about a year for me to feel confident doing imaging, but watching mitochondrial network dynamics in front of my eyes got me hooked!

I knew that I wanted to continue working on mitochondria and anything to do with replication, maintenance and gene expression of mtDNA. Because I began studying this from a molecular evolution perspective and moved to genetics and then cell biology perspectives, my goal for my lab was to combine all these disciplines and to apply a genetic way of thinking to mitochondria and their cell biology. Now, I frame the questions we ask by thinking about the flow of genetic information through the constantly remodelling mitochondrial networks, then use cell and systems biology approaches to try to answer those questions.

What led you to UC Berkeley to start your lab, and what challenges did you face as a new PI that you didn't expect?

I came to Berkeley for the community. When I get interested in a new idea, there's an expert that I can go talk to, and I really enjoy interacting with my colleagues here. It was also important to me to come to a public institution. All my training is from public institutions, and I got an excellent education. I wanted to be able to give back the public through my career.

I started my lab just before the beginning of the COVID-19 pandemic. It was definitely a complicated time to start as PI. My son was two and a half years old at the time, so I was trying to figure out how to set up my lab under the pandemic restrictions while mostly being at home with a child, often working at night when my son was asleep. I recruited a PhD student in the fall of 2020, and he had a computational biology background, so that fall we were able to get started on what would become his first paper and I was able to deploy some of the bioinformatics skills I had gained in grad school. Even during lockdown, we found ways to be active and discover something interesting about mitochondrial gene expression.

What is the main theme of your lab's research?

Our big theme is understanding how the flow of genetic information shapes heterogeneity between mitochondria that coexist in the same cell. We use a variety of tools to profile individual mitochondria and understand how mitochondrial genome replication, transcription and translation of gene products occur at the organelle level. In humans, mtDNA is present in multiple copies per mitochondria and hundreds to thousands of copies per cell. My previous work and the work of many others has shown that these mitochondrial genomes are independently regulated, rather than regulated in coordination with the nuclear genome, the cell cycle or each other. This strongly indicates that there is some level of regulation occurring at the organelle level that I'm working to understand. My big picture goal is to define the pathways that control the replication and transcription of the mitochondrial genome, because if we know these pathways, we might be able to design therapies to treat diseases that arise from defects in mtDNA expression.

Are there any unique or interesting challenges associated with studying mtDNA?

A main challenge in my field has been development of tools to edit mtDNA or mtRNA. CRISPR/Cas9-based editing of mtDNA is challenging because designing exogenous RNA to guide Cas9 into mitochondria is not straightforward. Some newer methods like base editors and TALENs are now opening up possibilities, which is an exciting development that will partially overcome a long-standing challenge. Another major challenge that my lab has encountered is that in studying mitochondria at the organelle level, we generate a huge amount of imaging data. We typically employ confocal, super-resolution and Airyscan imaging. Figuring out how to both quantify our imaging data and manage the data itself is really challenging.

What do you enjoy most about studying mitochondrial biology?

I actually enjoy that mitochondria are so complicated because I feel confident that there will always be something new to learn about them! The ultrastructure of mitochondria was first described in the early 1950s, but it was only years later that it was first appreciated that mitochondria might have their own genetic material. Imagine working on mitochondria for 10 years or more before realising that they have their own genomes, and the questions and new lines of research that discovery opened up! I feel like we are again on the cusp of discoveries at that level of significance with regards to mitochondria. There is so much that isn't yet known and I want to dedicate myself to discovering new things about mitochondria. We are also on the cusp of being able to address primary mitochondrial diseases, which was considered almost impossible up until very recently, based on the basic knowledge about mitochondrial biology that the field is generating. The idea that we could cure the first primary mitochondrial disease in my lifetime is extremely compelling. I partner with the United Mitochondrial Disease Foundation, and I've been to their annual meeting a few times. Meeting patients at these events is extremely motivating and it shows us that our research is on the right track.

What elements, inside or outside the lab, have been key to your success so far?

I got into research early and I realised that I enjoyed it and that I could be good at it. I was fortunate to have very supportive mentors who encouraged me early in my career, and a very supportive family. I also think that one of the things that has contributed to my success is that I don't give up easily. If I decide I want something, I keep going for it! As a postdoc, I went through a bit of an introspective period, thinking about why I wanted a career in academia, what sacrifices I might choose to make to try to increase my odds of success and whether it would be worth it. I also wanted to be a parent, have a life outside the lab and pursue my hobbies. After a lot of this internal conversation, I decided that it would be worth it for the opportunity to make discoveries alone. Even if I never got a faculty job, or I ultimately wasn't able to continue in research after my postdoc, I felt like what I was doing was worthwhile, which gave me confidence to pursue the research I was excited about regardless of the outcome.

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

First, think deeply about what you can do that is unique. Don't be concerned about trying to fit in with trends or what other people are doing. What unique ideas or skills do you bring to your field? Second, don't be anxious if your work takes a long time. In my first two to three years, I worried that I didn't have enough articles coming out, but now I'm really glad that we took our time and did high quality work, because I can see that it was worth it. One of my mentors has told me many times that inconsequential findings will eventually be forgotten, so it's worth taking the time to do something that you think is important and do it right. Third, apply, apply, apply! I apply for pretty much everything that I'm eligible for. In my first three years as a PI, I made a contract with myself to apply for something every month. Those 36 applications yielded maybe ten awards. My ‘tough love’ advice is that you just have to get used to the rejections; do it over and over until it doesn't feel personal.

What is your philosophy on teaching and mentorship in science?

I recognise that good mentorship is really difficult. It takes a lot of time and consistency of effort and it's not always straightforward. I try to tailor my mentorship to each person, because people have different needs, and they show up to the lab with different backgrounds. The number one thing that I look for is passion for mitochondrial research, but the next thing I look for is commitment: does the person know why they're doing this? Surprisingly often, if I ask someone why they've come to grad school or to my lab specifically, they don't always have a clear answer. I'm looking for very clear, thoughtful answers about how working with my team is going to advance their goals, which requires they know exactly what their goals are. When people join the lab, we have a long conversation about their expectations, my expectations and the core values of the lab that we've set. Checking in about these things regularly is also very important.

You've co-authored a few articles that discuss societal issues affecting academic scientists. What do you think is the value of addressing these important issues in the research community?

I think that the current attacks on diversity, equity and inclusion in academia are a backlash to the fact that real changes have been happening and that the voices of people who have been systematically excluded from participation in academia have been heard or are starting to be heard. In my opinion, the thing to do in response is to keep doing what we have been doing, which is to take up space and show up to do our best work. Fundamentally, it's not possible to make big, important discoveries or progress without an inclusive scientific community. For me, it's not something that's up for debate.

We're having this discussion in spring of 2025, with mounting attacks on federal funding for science, the STEM training pipeline, freedom of expression and due process in the USA. These changes can be terrifying, and the uncertainty difficult to bear, at times. I draw on a well of resilience stoked by the support of my family and my experience in navigating this culture as a black woman. Very recently, a prominent scientist visiting my lab pointed out an award plaque I had received in recognition of a STEM outreach project, saying that it made me a target. If so, then I think it's more important than ever to keep doing the work.

If there were one thing you could change in academia, what would it be?

I'd love to see structural change to better support parents and caregivers in science. By structural change, I mean free or highly subsidised childcare for all, scheduling campus events and meetings to better align with public school hours, and better compensation. In the Bay Area, it's not unusual to pay 20–30 USD per hour for good quality childcare, for example. I worked with my dean to pilot a dependent care fund (https://ls.berkeley.edu/biological-science-faculty-child-care-fund) for junior faculty during the pandemic, a program which is still running due in part to our generous alumni.

In your opinion, is there enough support in academia for scientists who are raising children?

I think that academia is actually a great career to have as a parent because of the flexibility. It's up to me to make sure that I am both getting my work done and showing up as the parent that I want to be. I really appreciate that I can come into the lab for four or five hours in the morning, pick my son from school and spend the afternoon with him, and later do some writing in the evening. I find that I'm really enjoying being both a PI and a mom. But I do think that there are many ways academia could be better set up to support parents. Don't schedule seminar series at 4:00 pm – what if your kid's school day ends at 2:30? Trainees are also often required to move to new states or countries to advance their careers, away from family, and that can make it really difficult to simultaneously be a parent and do science at the highest level. I think that the more people – men, women, parents who are all different identities – speak up about these issues, the more inclusive the system will be.

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

Something most people don't know about me is that I was actually born abroad. When I was born, my dad was in the US Air Force and stationed at a base called Lakenheath in the UK, close to Cambridge, and I didn't move to the mainland US until I was older. Growing up, I enjoyed living in other countries and I still really love to travel and experience other cultures. My favourite place to live was Hawaii, when we were stationed at a base called Hickam, near Pearl Harbour.

Samantha Lewis 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.