MRC National Institute for Medical Research, Mill Hill, London, UK
What is the current focus of your research?My group seeks to understand the transcriptional basis for lineage choice in embryos and embryonic stem cells (ESC). As differentiation and ESC self-renewal are different sides of the same coin, we can be seen as working on both understanding differentiation and the factors that maintain ESC as pluripotent. For example, our recent work on signaling regulators in ESC and their interaction with networks of transcription factors, suggests these cells are maintained by inhibiting differentiation towards specific lineages. Our work has largely focused on the endoderm lineage, both the early extra-embryonic endoderm and the later definitive endoderm which will give rise to the liver, pancreas, lung and thyroid. We explore the networks downstream of transcription factors in early endoderm with an assortment of model systems ESCs and ESC differentiation, mouse models and Xenopus embryos.
Our vision of physiological cell culture models (i.e. non transformed) is that they trap transition states in lineage specification. So how do we know what a transition state looks like? In enzyme kinetics these states only exist very fleetingly. However, they can be described by doing the crystal structure of enzyme bound to a non-catalyzable inhibitor. As that enzyme blocks catalysis, so does the culture system block progressions in lineage specification, giving us a window in the process of cell fate choice that may occur extremely rapidly in actual development or differentiation. Somehow cells get frozen in stasis and expand at the point where they are making decisions. Thus we showed that naïve ESCs resemble the blastocyst and contain a heterogeneous mix of functionally primed and interconverting cell types for the epiblast and endoderm lineages. Through manipulating signaling we can also establish stable transcriptional states in ESC that reflect different stages of pre-implantation development. We hope that by understanding the nature of these states we can understand the basis for cell fate choice in vivo.
We have also characterized the interface between signaling and transcription in differentiation. This work has increasingly been focused on how forces outside the cell, either the extra-cellular matrix or cell-cell contact influence the gene expression programs produced during differentiation. However, we have been able to use the same principles we have used with ESCs to develop cell culture systems to expand multi-potent progenitor cells from later in embryonic development in the developing endoderm.
One theme to arise from our approach of using cell culture systems as models for lineage choice is that these systems have made available to us the capacity to do more quantitative biology and as such we have recently started a new center in Copenhagen for the interface between physics and stem cell biology - http://stemphys.nbi.ku.dk
What led you to become a scientist and to stem cell research?I think I had fantasies about being a scientist from my time in junior high school, but the real turning point came as a result of my high school biology teacher, Mrs Simon. She taught us about biology as an exciting, continually changing field populated by brilliant, charismatic and living scientist. I remember very vividly that she made the early molecular biologists into sports heroes for us. From this point on I was determined to become a scientist, although ironically it was nothing like a linear trajectory. I went to University and started with biology, then switch to chemistry, moved increasing towards physics, did a minor in philosophy, almost started a second minor in archeology. For all that motivation, I was a little lost. However, after a three year break, I ended up in a PhD program.
I did my PhD with Mark Ptashne, one of those molecular biologists I had read about in high school. I worked on basic mechanisms of transcription in yeast and mammals. Although this was a great time when we were trying to figure out how the black boxes of transcriptional activation (and repression) worked, I felt a need to explore these questions in a more biological context. So I went to Rosa Beddington’s laboratory. Rosa was a pioneer in early mouse development and she had just discovered a potential clue to how all mammals know how to distinguish between where to make their heads and tails. Work in her lab had uncovered a new anterior signaling centre in a little studied extra-embryonic endoderm lineage (visceral endoderm), previously thought to only play a support function in development. In Rosa’s lab in 1996, I needed an in vitro model that could be used for molecular biology that approximated the early embryo and extra-embryonic endoderm, and so I started working with ESCs. I honestly had no idea that stem cells would become a field in itself at the time, as this was before Dolly etc., it just seemed the right model to work with.
While I was in the laboratory, Rosa became very ill (and was to die tragically of complications relating to cancer, in 2001 at the age of 45). As one of the last things she did, she worked to sort out the futures of the people in her lab. For me she pushed me to what was to become the Institute for Stem Cell Research (at the time it was the Centre for Genome Research), at the University of Edinburgh. I established my own lab there in 2001, and in the next few years the field of stem cell research grew around us.
How do you spend your free time?Mostly with my 11 year old daughter and my wife. We enjoy Copenhagen. We have been here for three years and love the city. We moved here and no longer have a car. It is liberating and we live in the centre of the city. We bike everywhere and have really enjoyed sampling all the culture this beautiful city has to offer.
What is one thing your peers would be surprised to learn about you?At the same time as I became interested in biology, I also became obsessed with becoming a DJ on college radio. I started DJing from my first year at college, became music director and then when faced with indecision at my future, I decided to take a few years off and work for the CMJ New Music Report, where I eventually became an associate editor and worked on our annual convention and MTV awards show. I then went on to briefly work for an indie record label, What Goes On, where I worked to promote band like the Celibate Riffles, Eastern Dark, Soul Asylum, and got a band called Bitch Magnet signed to our label. I eventually got bored with the music industry and realized it was time to go back and spent a year doing GREs, etc. I had a naïve idea that I could run a small indie record company while doing my PhD, something I rapidly realized was impossible, although I continued to DJ on WHRB through out most of my PhD.
What do you like most about living and working where you do?In 2011 most of my laboratory moved from Edinburgh to Copenhagen. It has been a fantastic experience. The Danish Stem Cell Centre (DanStem) was established by two grants, one from the Novo Nordisk foundation for basic stem cell biology and other from the Danish government for translational of these findings. As scientist who continues to be fascinated by these amazing cells (stem cells), how they act out their programs, chaotically and autonomously in a dish, and how these programs can be precisely orchestrated during embryonic development, DanStem is a fantastic place to be. We have managed to assemble Europe’s (and maybe the world’s) most concentrated grouping of people working on different aspects of endoderm.
In general the scientific environment in Copenhagen is in a very exciting growth phase. DanStem is located right next door to one of the world’s leading centre’s for Physics, the Niels Bohr Institute, and this has given fantastic opportunities to cultivate new and exciting interdisciplinary directions. The faculty of health sciences at Copenhagen has also embarked on the formation of a set of new centres, cultivating fantastic new international recruitments in the areas proteomics, cell cycle and DNA replication, metabolism and chromatin. It is great to be in at the beginning of a great experiment in creating a new European center of excellence across so many fields in modern biology.