How cells decide their fate

20 April 2020

Interview with 

Afnan Azizi, KCL and The Francis Crick Institute




In order to be here today deciding to listen to this podcast and incredibly complex decision making cascade occurred in your mother's womb before you were even born. And it can be rather difficult to pinpoint exactly when during development in the uterus, the brain is actually formed.

Afnan - I would say a brain is not really a brain until probably the beginning to middle of the third trimester because all the neurons and all the connections of the neurons haven't actually formed until that time.

Katie - That's developmental biologist Afnan Azizi who works at KCL and The Francis Crick Institute trying to understand what's going on in very early mammalian brain development. So what is involved in getting us from a fertilized egg cell to a human being? Well a lot obviously, but what Afnan is particularly interested in is the cellular decisions being made during this very early brain development process. And we're talking from just a few weeks when a woman might not even realise she's pregnant yet.

Afnan - The way I think about it is a series of decision-making from cells of what kind of cells they're going to become, what kind of connections they're going to make with their neighbouring cells and you know, farther off cells, and how these connections are going to be strengthened or weakened. So when you start off from a single cell, this cell divides - at some point, you end up with these three layers. Each of them are going to give rise to different body organs. The outside layer, which we call the ectoderm, that gives rise to the skin and the nervous systems, the middle layer, the mesoderm, that gives rise to the bones and the muscles and cartilage and things like that. And the inside layer, the endoderm, which has the gut and the respiratory system and those things covered.

Katie - Right so if we all start off as these incredible balls of stem cell potential, how do some cells know to turn into a brain cell whereas others will be a lung cell or a heart cell? Afnan explained.

Afnan - You have a large number of molecules, proteins that are made from the genes, and a lot of these are the same across various species and these molecules, at different time points and at different parts of the body, are expressed in a way that they form a location system. Imagine if you had multiple coloured paints and you drew a massive red circle on one side of the street and a very small circle on another side. Then on the second side you drew a really big green circle. Then you actually have now a system that tells you what part of the street you're on and you can point to different addresses based on how much green or red you have. It's a very similar system. The way it works is you go from creating a very generalized area. So like I just said, the three layers, one of them is like skin and neuron cells, which is obviously very different things, but you're slowly restricting the type of cells that they will become. So at the beginning you have a ball of cells that have no identities associated with them, and then you send a signal, say, okay, well the one that's on top is going to become this ectoderm for example, and it's going to become the skin or a neuron cell.

Katie - This amazing system conjures, in my brain at least, a super complex version of those decision tree quizzes I remember from teenage magazines like "what animal's the perfect pet for you!" Remember? You answer yes or no and eventually you funnel down into either dog, cat or hamster... But Afnan imagines it like a family tree with the original ancestor being that fertilized egg cell.

Afnan - It's the one that can make anything. We call those cells totipotent. So they're 'totally potent' to make all kinds of cells within the body and the placenta, in fact.

Katie - So all sorts of things can influence which cells these stem cells and their intermediate go onto become: what signals they're exposed to, when they're exposed to them, and where the cells are in relation to the signal. But back to the brain. How do the neurons and glial cells and everything else needed for a brain - how do they get made? Well Afnan said it's important here to consider brain axes: top to bottom, left to right and back to front.

Afnan - Very early on at least the left-right symmetry is mostly maintained - so you don't get much difference between what's happening on the left side and on the right side, it kind of comes out a bit later. But the bottom-top, and the front-back symmetry breaks quite quickly. So you get this top-bottom asymmetry broken very, very early on. And that allows the different parts of the central nervous system to be defined. So your brain and your spinal cord are different from each other. So one very important aspect of the brain and the way it works is that you need these different regions. You need these different areas to do different computations, to connect various parts of your nervous system together. And these all come from this breaking of symmetry. And then the other symmetry breaking is the front and back. And that also happens really early on and that's a lot more like complicated, but it is really important because that's what forms the difference between your cortex and like other parts like the hippocampus and the hypothalamus. So a lot of these happen from a lot of these different regions that are important for this work. We talk about neurons of different identities. They don't all come from the same stem cells. Like I said earlier, it's kind of a slow breakdown and slow specialization. It's not that you go from like, 'Oh well I have all these stem cells that all are the same and then one of them is going to become cortex, one of them is going to become cerebellum'. You actually start making more specialized stem cells and those end up in their areas, and then those more specialized stem cells make even more specialized stem cells and more intermediate stem cells. And then finally you make a neuron, for example. Even then you end up specializing those neurons even more by like, okay, well out of these 10 neurons that this one very specialist stem cell made, maybe two of them are gonna like have a different neurotransmitter and then one of them is going to die. So there's a lot of dynamics going on all the way up to like the third trimester and after birth.

Katie - Afnan's particularly interested in the signaling molecules which influence what differentiated cells will eventually come from the starter stem cells. And these molecules are very similar across species like humans and mice, but it's how they used that seems to differ. It's our genes that determine when these signals come on, where they come on, and what subsequent genes these signals can then turn on. Studying very early human development is so important in order to understand more about, for instance, disorders of development. But it's very difficult to study these things directly in humans for ethical reasons. So scientists like Afnan work to compare how early brain development happens across species to ultimately better understand how we are made.


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