What is the current focus of your research, and what do you find most rewarding about your work?
Like many stem cell biologists, I am fascinated by a very basic problem: how do cells decide on their fate? In my research, I like to break this problem down by scales in space and time: how do cells generate stable states? How do cells in tissues coordinate decisions? And how does evolution make new cell types? Right now, my lab is mostly focused on the second of these problems. We primarily use vertebrate embryos and mammalian hematopoiesis as our principle model systems, but over the past few years I have also studied epithelial tissue stem cells, such as those residing in the skin and intestine.
It is hard for me to choose just a single most-rewarding aspect to our work. Probably it is the privilege of working with a brilliant, diverse, and compassionate group of lab members. I have learnt so much from them over the last few years. On the science side, there are some close contenders for “most rewarding". Seeing a new technology come to life is incredibly rewarding — such as our development of droplet microfluidics for single cell RNA sequencing. Developing computational methods offers its own “wow” moments — such as discovering simple structure in what looked like a messy data set just days before. But such methodological developments are just means to an end. The long-term reward is in discovery — such as clarifying proliferative hierarchy, identifying and then validating the presence of a novel cell type, or investigating how signaling modulates tens of fate decisions.
What led you to become a scientist and to stem cell research?
I studied Physics as an undergraduate in Cambridge University, and I wasn’t at all sure that I wanted to become a scientist. I even got a job as a management consultant. But a few months before graduating, I had an electrifying experience (no, not literally) that changed my mind. This happened when I was working on my final-year undergraduate research project. This project was a theoretical problem relating to how light is altered as it passes through a certain type of tunable liquid crystal. The details aren’t important. For the first time, I found that I had solved a problem that was not in the textbooks. This was new knowledge. It was not a solution previously understood by my professors or by the postdoc working on the project. What’s more, the solution felt “elegant". It built on knowledge I had spent the last few years learning. Suddenly science just clicked in me. The sense of adding to human knowledge was one of the most exhilarating experiences I had ever felt. After a few months as a management consultant, I quit and went back to start graduate school.
In my PhD, getting involved in stem cell research was a happy accident. I thought I was going to study quantum matter in my PhD (how cool is that?). During my first week at graduate school, my PhD supervisor, Ben Simons, suggested that I consider a small side-project in biology looking at some lineage-tracing data that Phil Jones’ lab had generated. Phil was interested in how stem cells in the epidermis maintain tissues over adult life. He had genetically labeled a small fraction of cells in the epidermis, allowing their progeny to be tracked. After one year of life, the resulting labeled clones looked incredibly heterogeneous, both in size and in shape. It looked like there was no hope at all of finding a principle of stem cell turnover from such seemingly noisy data. But bringing ideas from statistical physics, we showed that the data contained a simple pattern that results from the dynamics of progenitor cells in the epidermis (Clayton et al., Nature 2007; Klein et al., Phys Rev E 2007). Eventually, what was planned as a side-project ended up defining my PhD and introduced me to biology and to stem cell biology in particular. We later showed that stem cells have a similar behavior in many tissues: they undergo rapid and stochastic competition. This early work convinced me that biology was an incredibly exciting place, and that it needed more quantitative approaches. But I also felt that I would never understand fate choice using theory alone. I needed to learn to do experiments myself. I entered the lab, wore that white coat, and picked up a pipette.
What guidance would you share in talking with trainees interested in pursuing your area of research?
Let’s assume "my area" encompasses single cell genomics and the study of mechanisms of fate choice.
First, these are very exciting areas with a lot to do. Good choice!
Second, I strongly advise daring to cross the computational/experimental divide. Don’t outsource your analyses. If you are an experimental biologist, learn some quantitative analysis and try to define your own questions. You can run published code - but try to understand it well enough to state the assumptions you are buying into by using it. If you are a computational biologist, try spending at least a short amount of time seeing where your data comes from. Get into the lab, even for a bit. If you want to become an independent scientist, you’ll benefit greatly from this exposure.
Third, try to think whether you already have the assays you need to answer your question available. If not, you might be working on the wrong question. OR... you may have the best question to pursue! Building new assays is an excellent training, and it will make you a better scientist in the long term.
Do you have any mentors or individuals who have inspired you in your stem cell work?
Many! It is very hard not to list dozens of people here who have inspired me and continue to do so. I will list a few here. The first group are not stem cell biologists in any conventional sense. My PhD supervisor Ben Simons shaped my desire to find quantitative principles in biology. He showed me the impact that quantitative, predictive laws can have on our understanding of cell biology. Marc Kirschner and Tim Mitchison are not stem cell biologists, but their creativity and fearlessness in developing new assays and in drawing deeply from chemistry and biochemistry continues to inspire me. Uri Alon, Eric Siggia, amd Naama Barkai are systems biologists and biophysicists whose theories have been deeply influential on my thinking about fate decisions.
I must also mention my colleague Angela DePace. Her brilliant work, which challenges our understanding of transcriptional control, has also influenced me deeply. It is humbling (and at times troubling) to look for principles of cell fate choice when our understanding of transcriptional regulation is so tenuous. I should disclose that Angela, Tim, and Marc are all members of my department. I feel extraordinarily lucky to go to work every day with people who inspire me.
How do you spend your free time?
I love reading to my two girls - mostly about pirates these days. And going hiking, reading (trashy) fantasy novels and (less trashy) books on the history of science. I also love board games, but hardly get to play these days. So, I have been watching (wait for it…) board game reviews on YouTube. Yes, reviews. Of board games. It’s a thing. Well, you did ask.
What is something your peers would be surprised to learn about you?
Did I mention I like watching board game reviews? Geeks unite!
What do you most value about your membership with the ISSCR?
I am incredibly impressed by the sense of community that ISSCR has created, and the training opportunities that ISSCR offers spanning from basic research to translational applications. ISSCR and the stem cell community has really got the balance right on this.