Long live our genes

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:
http://mosaicscience.com/story/how-zebra-got-its-stripes-alan-turing

The day when we can grow fully-functioning organs in a dish have come a step closer, as researchers at the University of Edinburgh have managed to create a mouse thymus in the lab - this is the organ responsible for making T-cells in the immune system - and transplant it back into an animal.

Publishing their findings in the journal Nature Cell Biology, the researchers took mouse embryonic cells called fibroblasts, and used a gene called FOXN1 to turn them into thymus cells. When these were mixed with other types of thymus cells and transplanted back into a mouse, the cells organised themselves into a replacement organ that functioned the same as a regular adult thymus. It's the first time that scientists have made an entire living organ from cells that were created outside of the body by reprogramming.

Although the work's currently still at an early stage, the scientists hope that their lab-grown cells could one day form the basis of thymus replacement therapies, or even lead to personalised T-cells grown in the lab to help people with faulty immune responses.

Rosalie - A lot has happened since I started being involved in the late 1980s. They found the gene at that time, so they know where the gene is and they found a bit about the function of the gene. The gene product is really this tumour suppressor. So, simply stated, it keeps cells controlled. So, it stops them growing too much and dividing too much. The research has gone into a number of areas. It's gone into learning problems which is one of the commonest manifestations of the condition. It's usually mild learning problems. Research has gone into tumours - both benign and malignant - and it's gone into bone. I think these are sort of the big areas. The two things that are being done, they're looking at underlying molecular mechanisms so that they can target treatment to the particular problem, and they're also looking quite carefully at something that is not quite so buzzy, but very important, which is outcome measures. So, it's no good having a treatment if you don't know how to measure whether it's been beneficial or not. When you look at outcome measures, you want to look at things that are objective have you shrunk the size of something, have you improved intelligence. But importantly, you want the patient's point of view because that doesn't always coincide with what you see as an improvement.

Kat - Have there been significant advances in treatments for these types of tumours and diseases?

Rosalie - Yes, they're starting to come through. I think one always needs to be cautious. So, if you take for instance the benign neurofibromas, the lumps, they cause a lot of problems because they're cosmetically difficult. They can cause neurological problems. They can cause pain and bleeding. They've used mouse models which are very good models for the disease to screen potential drugs that may block these rather complex tumour formation pathways. There have been a few drugs that have been tried with limited success. There was a new drug called a MEK inhibitor. MEK is just one of those signals on the pathway that activates tumour formation. Very early results suggest that they shrink neurofibromas a little. I wouldn't say massively, but a little bit promising. So, the hope is to increase the clinical trials for that. From the point of view of learning, they've tried statins - statins are buzzy for lots of reasons - but it was thought again from the mouse models that statins might help with improving learning. They've done a couple of trials on children and so far, there haven't been huge beneficial results. What this is saying is that it's a huge step forward to understand a bit more of the molecular mechanisms underlying complications. These are early stages in treatment where people are trying to have certain blocking different bits of this very complex pathway. There are treatments available. Are they effective? At this stage, it's quite early to say.

Kat - Thanks to listener Ann Hawke and Professor Rosalie Ferner. If you've got any questions about genes, DNA and genetics, just email them to me at genetics@thenakedscientists.com.