Embryonic development and spina bifida
Richard - It's amazing logistical problem. So, how does that happen? In animal development, it's done by dividing and conquering the problem. We begin to make big decisions during development first and then you make more and more specialised decisions. So development begins by dividing that first fertilised cell into many, many cells. These cells, to the outside the observer, look very similar to each other. There's not necessarily any particular structure to the embryo.
Chris - Just a ball of cells.
Richard - Just a ball of cells, but of course we're clearly much more complicated than that, so the embryo must transform itself. That takes place in remarkable morphogenetic process - which means a change of shape of this ball of cells - and the process is called gastrulation. It literally means the formation of a stomach. What the embryo is doing is changing itself from a single population of cells into 3 concentric tubes of cells. The innermost tube is going to form the gut and associated organs. The intermediate layer of cells is going to form connective tissue and muscle, and the structural components of the body, and the outermost layer of the tissue is going to form our skin, and our central nervous system, our brain and our spinal cord.
Chris - How do those cells know who they are? So, if you go from this ball of cells where one cell just divides, makes two and then two become four and so on, how do they know, "I'm going to become the inner tube that's going to become a gut and I'm going to become the tube around that, that's my muscles and I'm going to become the outer layer that's going to be the skin." How do the cells get addressed?
Richard - Remarkably, very early in development where there's first divisions which might build an embryo that has maybe 10,000 cells. Many of those cells don't yet know what they're going to become, but they're going to be organised and influenced by a signalling centre, a small population of cells that are going to send out small diffusive signalling molecules that are going to induce the cells to take on the identities of endoderm or mesoderm.
Chris - And these are these different layers.
Richard - These are the different layers. Initially, these cells are sitting in concentric rings around the signalling centre and they must physically transform themselves into a structure that is physically a concentric series of rings. So, the whole embryo must transform itself physically from one shape into new shape which is now an endoderm surrounded by mesoderm, surrounded by ectoderm.
Chris - So, when the cells are making these decisions as to what to become under the influence of these signals coming out of other cells to say, "You Richard, you're going to become a gut or so on", does that irreversibly influence what genes are turned on, how the DNA is controlling those cells then?
Richard - At that point, yes. The first irreversible decisions are made, and now, the repertoire of decisions that that cells is able to take it is restricted. And then subsequent decisions would define which part of the gut for instance that cell would perform and which some subtype of cell of this progeny would be able to produce within the gut itself.
Chris - How do the cells move around in the embryo so that the ones that should be in the middle and making this gut tube are there and the ones that are on the outside to make the skin are in the right place as well?
Richard - The movements are very varied and interesting. Some are, just as Helen just described involving the cytoskeleton that change the shapes of cells, the cells are able to move on each other. But within the embryo, many cells are stuck together on structures of tissues. These populations of cells are able to transform themselves in much more sophisticated ways. So for instance, they can pull themselves in one direction which causes the tissue to elongate in another direction. This kind of transformation is the one that takes us from a ball of cells to an elongated embryo which is recognisable as a developing embryo.
Chris - When things work out, it's great because you have a perfectly proportioned, a perfectly developed baby, but we know it doesn't always work out like that. There are some neurodevelopmental abnormalities. Is that when one of these occurs, things like spina bifida and so on? Is that because the cells haven't migrated to the right place during development?
Richard - That's a problem that we're very interested in in our lab. We don't really know the details, but it's something to do with the communication within cells which enables them to collectively change shape. In the case of neurulation, it's a sheet of cells that is trying to just roll itself up into a cylinder and that cylinder is the precursor of the spinal cord. If this rolling process is incomplete then the two edges are unable to fuse and the spine remains unfused, and that is the lesion of spina bifida.
Chris - If we can understand through work like yours then why that goes wrong, that will potentially give us insights into how to prevent it going wrong or how to put it right when it does.
Richard - We would hope that what we can find are clues as to the underlying causes, what is physically wrong with the behaviours of cells, and that would give us clues as to how we might be able to intervene in the future.