Prof James Sharpe - Making fingers

25 August 2014

Interview with

Professor James Sharpe, Centre for Genomic Regulation Barcelona

Kat - Most of us are born with five fingers on each hand - but have you ever wondered how they get there? The answer was first put forward more than 60 years ago by mathematician and wartime code-breaker Alan Turing, who published a paper suggesting how molecules can interact to create stripy patterns - including the five stripes of bones that make up our fingers and toes. It's recently become clear that this kind of system is at work in developing limbs, but the exact identities of the biological players involved wasn't known. Now a team of researchers from the Centre for Genomic Regulation in Barcelona think they've found the answer. I asked James Sharpe, who led the work, about how he tracked down these mysterious molecules.

James -   So, the main approach was to distinguish between the cells that are going to form your fingers and the cells that are forming the tissue in between your fingers.  During early embryogenesis when your hand is forming, the hand is in fact a continuous plate of tissue.  And some cells will become fingers and the cells in between these regions will become the gaps between your fingers.  Although at these early stages, they're still cells.  So, it's a decision between two cell fates, making fingers or making the gaps.  The goal was simply to find which molecules show any sign of having an on/off, on/off pattern between these two cell fates as early as possible.

Kat -   So you're basically looking for things that are set up in stripes at this very, very early stage?

James -   Yes, exactly and they could be genes or proteins that are either expressed or active either in the cells that will become digits or ones that were only active in the cells that will become the gaps.  It could be one way or the other.  It doesn't really matter.

Kat -   So, you tracked down these molecules.  How do you know that they are the ones that are responsible for actually making this pattern and telling the fingers to grow there?

James -   That's a very good question.  The critical thing to do is to somehow make some predictions about what would happen if we manipulated these molecules to the pattern.  So, in addition to looking for the molecules, we also built a computer model, a computer simulation of the process based on as much evidence and data as we could get. 

With the computer model, we then made predictions about what would happen if you slightly repressed one pathway or the other, what would actually change in the pattern of the fingers.  And then finally, we were able to actually test that by taking little pieces of tissue, very small pieces of tissue at less than 1 mm from early mouse embryos and cultured them in a Petri dish and actually applied drugs to reduce one pathway or the other, or both pathways together.  And the very satisfying result was to see that when we did these experiments, they actually recapitulated the computer predictions very closely.

Kat -   And obviously, it's a really nice thing to know that this is probably what's going on to be able to understand the biological system like that, but is there any way we can take this forward?  How can this knowledge be used?  Is there any aspect of human health or tissue engineering that could be useful for this?

James -   In the long term, understanding how tissues build themselves.  It's the only way that we will be able to do proper tissue engineering.  What I mean by that is growing tissues in a dish, getting tissues to organise and build themselves so that they are functional tissues or pieces of organs or even hold organs.  To be able to do that, we have to understand how the body normally does that.  And that's essentially what this work contributes to.  Unless we understand all the parts of the story, all the basic principles by which tissues are organised, we will not achieve what must be naturally the long term goal of this work which is to rationally, consciously design tissues in a dish for various kinds regenerative medicine.  So, I believe that this is inevitably going in that direction, but it's also clear that it's going to be a long way in the future.

Kat -   One of the names that you've mentioned is Alan Turing.  Most people think of him as a computer scientist, a mathematician.  It's interesting to see that he's actually made such a contribution to understanding of biology even from so far in the past.

James -   He was really interested in how complicated and clever machines - let's say - arise in nature in general and this led to his interest in the brain and in artificial intelligence, and how you can calculate things, how you can work things out.  But also, to how these amazing machines such as the brain or such as a body in general comes into existence in nature.  So, I think that from his interests, these two things were not so different.

Kat - Professor James Sharpe from the Centre for Genomic Regulation in Barcelona. And you can read my feature on Turing patterns in biology for free in the online magazine Mosaic:

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