Q&A: What can physics teach biology?

Ben Simons

Dr Ben Simons, of the Gurdon Institute, comes from a different world. He’s applying analytical methods developed for physics to work out how stem cells regulate themselves, including self-renewal. I asked him what it’s like to be a physicist in a biologist’s world.

So, you’re a physicist….

In the jargon, I’m a condensed matter theorist. What that means is I’m a theoretical physicist who works on low-energy physics (as opposed to high-energy physics, like the stuff at CERN, which is what most people will have heard of). I’m interested in things like superfluidity and superconductivity and most of my research is about a problem associated with ultracold atom physics. I’ve been doing that for about 20 years, but in the last five years I’ve gotten involved in biologically-inspired research.

How did that come about?

It was purely by chance. Long before I got involved, there was an investigation done by a group at the Hutchison/MRC Cancer Cell Unit in Cambridge. One of the researchers, Phil Jones, was investigating the maintenance of interfollicular epidermis, (the renewal of the cells that make up the tissue surrounding hair follicles).  He made use of a genetic labelling system in which cells in mouse epidermis could be induced to express a yellow fluorescent protein. Using this, Phil gathered a lot of lineage data over a long time course. Following a suggestion from my wife, who works at the Hutchison Centre, I was asked to analyze the complex dataset to assess the pattern of cell fate. Instead, we ended up finding something very surprising and dramatic: that the pattern of tissue turnover was very different from the accepted paradigm in the field.

Since then I’ve been involved in large number of collaborations doing similar kinds of things in different tissues and actually uncovering a kind of conserved pattern of stem cell fate across different tissues. What’s anecdotally interesting is that the patterns that emerge are very different from the ones that are held as the prevailing view of how these tissues are maintained.

What have you found and how is it different from previous thinking?

Most tissue stem cell biologists assume that it’s the microenvironment surrounding the stem cell that is largely responsible for their regulation, and that the default pattern of stem cell fate is fate asymmetry, in which cells divide in an invariant manner producing one more differentiated progeny and conserving the stem cell. But what we’ve found is a neutral competition where stem cells are lost and replaced by their neighbours and asymmetry was achieved on a population basis.

This appears to be the pattern of fate followed by practically every system we’ve looked at. It’s a rather different picture of how to think about the microscopic mechanisms of stem cell regulation. We’re not providing the answers as such, but we’re beginning to change the questions that people are asking. People have been thinking in terms of the external factors regulating the microenvironment. We’re saying this might be the wrong place to look. The real question is about stem cell cell–to-cell signalling or intrinsic mechanisms of achieving stochastic fate. If you’re looking for molecular mechanisms of stem cell regulation, you’re better off knowing what it is that’s being regulated!

And these findings came about because you were applying a physicist’s viewpoint and methods to biological problems?

Exactly. The way that we analyse these data sets leant on what are the commonplace methodologies in the realm of non-equilibrium statistical mechanics. The toolkits that have been developed over many years are precisely the ones you can apply well to these systems. It was a big shock to me how well they worked. There was a lot of luck involved, of course, but a key element was that the techniques that drew out the correlations in the data were established in a very different context.

Physicists have often remarked that biology can seem quite chaotic.

Physicists are trying to identify basic rules or common behaviours across very different systems; it’s a philosophy of reductionism and unification. Biologists are fond of saying that, while those principles are all very well and good, they don’t belong in biology. Biology is much more complex and evolution leads to processes of increasingly high complexity, so the idea of looking for commonality or common behaviours just doesn’t belong.

I have some sympathy with that view, but my experience so far is that that isn’t really true. One can find very simple and conserved patterns of behaviour in situations where the underlying regulatory mechanisms are very complex; the output can be something that is very ordered and simple. The problem of tissue stem cell fate in homeostatic tissues appears to fall precisely into this category. If you go and look at lineage tracing studies across a variety of different tissues, you find that the behaviours that you’d predict are manifest. And, as I mentioned, it’s interesting that what you find is very different to the paradigms that people have hitherto thought about.

Is there anything that you’ve learnt from biology?

Well, low energy physics is facing a bit of a crisis in that it’s becoming increasingly difficult to find areas that are genuinely exciting and at the same time tractable. What biology is bringing to physics is a whole plethora of brand new and important problems. I’m not so arrogant as to think that we’ll spark some great revolution and everyone will be grateful, but I think there is a huge opportunity for physicists. Biology, particularly cell biology, presents an exciting new arena to apply a lot of the concepts and ideas that have been developed very successfully in physics over the last 100 years.

There’s a good pedigree for it though.  Francis Crick, for example, had a physics background and his great discovery came at a time when many physicists were approaching biological problems.

That’s true, but I slightly hesitate at that. There was a revolution then, but I’m not yet convinced that there will be another. I think physicists have to learn to ask very different kinds of questions. They can bring new technologies, for example high-resolution imaging, and this is clearly leading to exciting developments. But I think the most exciting things they can bring are new ways of thinking and new concepts. I don’t think that’s been very much exploited in the past.

What I’m excited about is this reductionist way of looking at things, stripping out complexity and identifying a backbone of what really matters, which I personally think cell biology is in desperate need of. One sees these enormous gene regulatory networks and I can’t help but think that there must be a better way to understand the basic developmental biology or cell biology processes. Physicists are very good at stripping out complexity and identifying what really matters and I’m optimistic enough to think that this can be recapitulated in different ways in different areas of cell biology.

Can you tell me a bit about your research collaborations?

I’ve had some very exciting collaborations, one with Shosei Yoshida in Japan on spermatogenesis, another with Hans Clevers at the Hubrecht Institute in the Netherlands on intestinal stem cells. In Cambridge, I still have the collaboration with Phil Jones and another with Doug Winton at the Cancer Research UK Cambridge Research Institute. And I’m working on the development of retina with Bill Harris, who’s supported by the Wellcome Trust.

I am also part of the Cambridge Stem Cell Initiative, which is substantially supported by the Trust. I’m spending a year on sabbatical at the Gurdon Institute, particularly with the idea of developing new ideas of research and new collaborations. Here, I’ve starting working on cell turnover in trachea and lung with Emma Rawlins, and I’m trying to set up new collaborations with other people at the Gurdon as well.

I’m incredibly grateful to the Institute because it’s providing a really great environment where I can immerse myself in all these different activities. It’s a really nice environment to work in; compared to a physics environment it’s better resourced and you feel that. We’d also have a much more substantial teaching load in a physics department. All in all, the Gurdon is a model for how all researchers would like to be housed and looked after. It’s very well run and the facilities are very good. The result is you get very good science.

References:

• Snippert H J, van der Flier L G, Sato T, van Es J H, van den Born M, Kroon-Veenboer C, Barker N, Klein A M, van Rheenen J, Simons B D and Clevers H (2010) Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134-144

• Lopez-Garcia C, Klein A M, Simons B D, and Winton D J (2010) Intestinal stem cell replacement follows a pattern of neutral drift. Science published online Sep. 23 2010, DOI: 10.1126/science.1196236

• Klein A M, Nakagawa T, Ichikawa R, Yoshida S, and Simons B D (2010) Mouse germ line stem cells undergo rapid and stochastic turnover. Cell Stem Cell 7, 214-224

• Klein A M, Brash D E, Jones P H, and Simons B D (2010) Stochastic fate of p53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia. Proceedings of the National Academy of Sciences 107, 270-275

• Clayton E, Doupe D P, Klein A M, Winton D, Simons B D, and Jones P H (2007) A single type of progenitor cell maintains the epidermis. Nature 446, 185-189

Image credit: Ben Simons