In March’s blog post, we feature an interview with Dr. Adam MacLean, Assistant Professor of Quantitative and Computational Biology at the University of Southern California.

When did you first become interested in mathematics and biology?

I first became interested in the intersection of mathematics and biology during a biophysics class I took in my final (senior) undergraduate year of physics. It was actually in one lecture in particular that my curiosity was really piqued. I have E. coli to thank. More specifically: I have flagella to thank. This lecture, entitled “Why don’t bacteria swim like fish?” described how the Reynolds number affects the ability of organisms of different sizes (from big fish to small bacteria) to move around. The crucial point is: reversibility of motion becomes a big deal when you are small, because liquids get viscous. (There are some fun examples of such irreversibility on youtube). So bacteria must spin their flagella in only one direction (they go counterclockwise) to propel. If they were to flap their tails like a fish, they wouldn’t go anywhere. This lecture sparked an interest in me that hasn’t dimmed since: the search for simple theoretical methods that help us to make sense of complicated, messy biological phenomena.

Was the decision to do a Ph.D. an obvious and easy choice?

No, it wasn’t obvious to me. It was always an option in the back of my mind, but I always thought: I haven’t found any single topic that would capture my interest enough to study only that for years. (I now realize that the idea that “in a PhD you only study one thing” was a misconception - the reality is inevitably more topically varied.) For me, the decision to do a PhD was mostly whimsical. I am not a long-term planner. My general mode of being is to do my best to fall into those opportunities that present themselves. I chose a masters in bioinformatics and systems biology (thanks to E. coli) after graduating from physics, and really enjoyed the research there. Eventually, I applied for a PhD position in the same lab, and stayed! I certainly have no regrets about falling down this path.

How did you start your own lab?

I think it was the experience & timing of my postdoc positions in three different labs that prepared me, and helped me to land a PI job. In 2016, I left the UK for a postdoc at the University of California at Irvine (UCI). I had just finished two short postdocs at the University of Oxford, and in my PhD lab at Imperial College London. My work at Imperial/Oxford was topically a continuation of my PhD work: dynamical systems modeling in developmental and stem cell biology. When I joined UCI in 2016, I began to dive into the wealth of single-cell genomics data being newly generated, and started developing computational tools to help with their analysis. These methods opened up exciting new avenues to tackle questions in stem cell biology just as single-cell sequencing was becoming a mainstay of experimental biology labs everywhere. When it came round to looking for PI jobs, I think it was this combo of dynamical systems plus experience in the emerging field of methods for single-cell data analysis that gave a niche, and I’m grateful that the University of Southern California offered me an exciting environment for it. At USC, we have a brand new department for “Quantitative and Computational Biology” and our own undergraduate major in QBIO (quantitative biology) — these are great programs that I’m really fortunate to benefit from and contribute to as I grow a lab at USC.

What are your main research questions and why are they interesting?

I like to begin with the question: what makes a stem cell? I phrase this ambiguously on purpose, so it works as a prefix: what makes a stem cell BE? As in, what defines stem cell identity in different organs? This can be thought about in terms of internal gene regulation and external signaling factors. Next: what makes a stem cell PRODUCE? Stem cells differentiate into the specialized cells in our body that do useful things (blood, bone, etc). Again, the cell-internal and cell-external factors responsible are not very well described (if at all), we need new discoveries here. Finally: what makes a stem cell ACT? In addition to differentiation, stem cells must make other decisions, such whether to rest, proliferate, or migrate, or how to respond to a malignant invasion of their niche from cancer. We address these questions in a range of biological systems using tools we develop for mathematical modeling, statistical inference, and machine learning. Here, also, there are many exciting mathematical questions to address. How can we calculate the stability of states in stochastic or hybrid models? How can we perform parameter inference using single-cell genomics data as input? Can we make approximate Bayesian inference methods fast enough for use with agent-based/hybrid models? When do neural network-based approaches outperform the alternatives (PCA, UMAP) in dimensionality reduction of single-cell data for biological discovery?

Why are these questions interesting?? Oh boy! Take stem cells. Stem cells are wild. Blood stem cells, for example, are responsible for the continual precise production of dozens of cell types throughout our bodies. The most abundant of which - the red blood cells (erythrocytes) - are produced at a rate of two million cells every second. Every second, two million new red blood cells leave your bone marrow and enter circulation, and approximately the same number are recycled elsewhere (macrophages eat them, but that’s another story). This whole system must be exquisitely controlled under tumultuous levels of biological noise. Most of the time, stem cells accomplish this task perfectly. When the system breaks, cancer can result. We don’t know the rules of these stem cell-controlled systems yet, but if we can learn them, we will not only be cracking a fundamental code: what are the gene regulatory rules required to maintain cell types? We will also be in a position to tackle many medical challenges, from designing targeted therapies for cancer, to developing new therapeutics for conditions ranging from wounds & burns to sports injuries, by harnessing the regenerative capacity of stem cells.

What is a typical work day/week like?

Recently, more or less like this: Recently, more or less like this.

Do you have any advice for someone considering a career in mathematical biology?

I think one really important thing to remember is that there are many ways in. From mathematics, or biology, …or computer science, medicine, physics, or engineering. So I definitely advise against thinking “I don’t have a degree in X, therefore I can’t.” Look for research areas or research problems that excite you. Reach out to labs in these areas. One of the advantages of the move to virtual meetings over the last year has been the relative ease (and low cost) with which one can attend meetings worldwide. Come to SMB! Reach out to people whose work interests you. Maybe you have a specific question - on research, or advice, e.g. about graduate programs, or maybe you’d just like to introduce yourself. Either way, I think (hope) that SMB/math bio communities are welcoming places.

A note on this answer (also relevant to several other answers above related to my own career path). Personally, I have felt welcomed into scientific bodies (universities, societies, conferences) throughout my career. For others, this is unfortunately not always the case. People can feel less welcome based on their gender, identity, race, nationality, or many other factors. This is an unfair advantage that I have had in academia. Despite improvements taking place, we still have a very very long way to go towards leveling this playing field. I strive to help in ways I can, and hope slowly we will make science (and mathematical biology) a more welcoming and inclusive place regardless of background.

What do you like to do in your spare time outside of work?

Spare time these days is preciously sparse, mostly thanks to two kids at home. When I do steal a free hour or a day, I love to get outside. It’s one of the reasons I chose to live in California - beaches, mountains, and snow are all within a short drive. Skiing has always been my favorite sport, close by we have great local ski areas at Snow Valley and Big Bear. Slightly farther afield, Mammoth mountain is fantastic. I always planned to learn to surf properly when I moved here, but it hasn’t happened yet. My new plan is to tag along with my kids if they decide to pick it up, and perhaps we can learn together. If they’ll have me.

Sparking the kids' interest in surfing