Developmental genetics - Dr David Ish-Horowicz

12 May 2012

Interview with

Dr David Ish-Horowicz, Cancer Research UK London Research Institute

David - In the case of the mammalian embryo, probably the first decision that's taken is when there are enough cells that some of the cells are on the inside, and other cells are on the outside, those two types of cells become different. And the outside cells become kind of accessory cells that aid the inside cells to form the actual mature animal. In the case of other animals, we work a lot on fruit flies. You actually start off by making an embryo which has a few thousand cells and at that point, actually, the embryo then knows its front from its back, and its top from its bottom. And it also knows that it's going to make a segmented, a repeated animal, and so, from then on, it refines these initial asymmetries into what ultimately becomes a very complicated animal. You might think a fly is simple, but in fact, when you look at it in detail, it's pretty complicated, and it's just as difficult for us to envisage how you make a fruit fly as how you'd make a human being. It's just a matter of scale and indeed, what's been exciting over the last 30 years or so is the discovery that the genes that are important in making a fruit fly are actually the same genes that are important in making a human being.

Kat - And that's quite crazy because they are such different processes. I remember if I cast my mind back that the fruit fly egg has a front and a back, and it's very organised whereas a mammalian egg looks a bit different and a bit less well-organised, but you were saying that it's actually the same genes that are controlling the subsequent process after that.

David - The same genes are always used, but not always in the same way because there's only a limited repertoire of genes. So, you use them again and again, and they do different things in different contexts. I think the fruit fly is unusual because quite a lot of its patterning is done in the mother as an unfertilised egg whereas in the case of a human embryo, most of that patterning happens after fertilisation. I think what it comes down to is that because you only have a limited number of genes,  and a limited number of ways in which they interact - you've got a limited number of building blocks, but you can use the building blocks in many different ways. Just as when you build a house, you may have a fixed set of components, but you can build radically different houses. The same is true of animals and quite subtle differences in timing can make apparently big differences in the final appearance of the animal, but actually, underneath it all, it's really not as different as you might think. I mean, at the end of the day for example, if you have a muscle cell, what a muscle cell does is it takes chemical energy and converts it into movement and once evolution had worked out a way of doing that, it stuck with it because that's what you do. You use what works. So obviously, there are differences between muscles in flies and in humans, but there are massive similarities in the way they work as well.

Kat - Tell me a bit about what you've got going on in your lab at the moment. What questions are you really trying to get to the bottom of?

David - I suppose the thing we're most interested in are the asymmetries. The flies are a particularly strong example whereby the asymmetry of a final animal, the complicated architecture is anticipated by asymmetries very early in development and in fact, by asymmetries within a single cell. So, we're interested in how a single cell can have a front and a back, and a top and a bottom. What are the cues that set up these spatial differences? And that turns out to be the putting of particular chemicals in particular places when you're building the cell. And so, you can put one particular chemical at the front of the cell and a different chemical at the back of the cell, and now, you've got the difference between the front and the back, and so on and so forth. We're interested in the different kinds of mechanisms whereby that can happen. One of those mechanisms in the fly is actually to use little molecular motors that take energy and move molecular cargoes to particular places in the cell where they are needed. Now that's a particular use of molecular motors. In fact, they're used very widely throughout development to put things in the right place.

Kat - So, it's an incredible mental image of a tiny, tiny cell, and all these motors scuttling around, delivering things to one end, to the other end, and then as it begins to divide to make an embryo, you're separating off these different types of cargo from different ends.

David - It is indeed very exciting and one of the breakthroughs in the last 10 to 15 years is that microscopy has allowed us to actually see these movements. I mean, the advances in microscopy means we can image where things are and watch them move.I mean, it's aesthetically very beautiful to see some of the time-lapse movies that people can make, things moving around cells, just to be placed in the right position to work.

Kat - And these are in living, developing organisms?

David - Indeed, you can now do it -  you used to just have to study things in animals or the tissues when things were dead but increasingly, we can look at things actually happening because the sensitivity of the microscopes and the resolution of the microscopes, and the techniques of labelling molecules so that you can see them have improved beyond recognition.

Kat - Where next for this field? What do you think are the big questions that we still need to figure out?

David - We know a lot of the components that are involved. I mean, we know the gene sequences and we know a lot of the words involved in building the book that's an animal because we know the genes, and we know what proteins they make, but we don't necessarily know what the proteins do and we don't necessarily know how they work together. And so, I think a lot of the logic behind it is still to be discovered. Exciting things for the future I suppose are to take what we know already and extend them amongst other things into how the nervous system works, the real logic behind the very, very complicated circuitry in even a fruit fly brain. That I think is going to happen gradually over the next years. We know so much more than we thought we would know 20 years ago, but we're still scratching the surface about many other things.

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