How do we know how big to grow? - Dr Nic Tapon

12 May 2012

Interview with

Dr Nic Tapon, Cancer Research UK London Research Institute

Nic - If you look around you, you look at animals in general, each species has a specific size and shape and there's not - I mean, there is some deviation from that specific size and shape, but by and large, they're all roughly the same size. It's a very interesting question how that's achieved time and time again as the animals undergo development and have to grow from a very small embryo to a very large adult, how they precisely know when they've reached the appropriate size and shape.

Kat - So we don't see fruit flies the size of birds, we don't see Basset hounds the size of mice.

Nic - Yes, that's exactly right. So, this question has very interesting evolutionary implications because related species vary quite considerably in size and shape. If you look at dogs for example, different species of dogs, and even with related species like wolves have very similar genetic material. So they're very similar at the level of their DNA and yet, their size and shape varies amazingly and so, that's a particular situation where very small changes in the genetic makeup of the species really has a huge influence.

Kat - Presumably, there are genes that are responsible for this. What do we know so far about the kind of genes that are controlling an organism's size?

Nic - Yeah, so there are many different genes that have been found to regulate size. The particular genes that we're interested in belong to a signalling pathway, so it's a pathway that tells the cell how much to grow and to proliferate, and that pathway is called the Hippo pathway. So it was discovered in flies and the reason it is called the Hippo pathway is not because the fly gets to be as big as a hippo, but the mutants are actually much larger and they become very wrinkly, a little bit like the skin of the hippo because there's so much tissue that the cells don't know where to go. And so, that particular Hippo pathway we think is influenced by many different factors really in the developing fly which allows it to sense tissue size.

Kat - What are some of the issues that influence how big an organism grows and how it controls its size?

Nic - One particular issue is nutrition. So, as you know, we are what we eat and during development, how much nutrition the organism receives has a very strong influence on overall size. And so, the Hippo pathway we think does respond to nutritional cues. In flies obviously, that's quite a big deal because as you can imagine, flies are very much exposed to their environment and very often, they don't get enough food or the larvae don't get enough food as they're developing. And so therefore they need very potent mechanisms to couple nutrition intake or availability with growth during development. The other type of mechanisms that regulate the Hippo pathway are to do with really the differentiation of the tissue itself essentially. So, they need to differentiate into that particular cell fate. This differentiation process is coupled to growth because when you become differentiated then you stop growing and dividing, and so, the Hippo pathway we think also is influenced by the differentiation status of the cells.

Kat - So, does this help to explain why a liver is always more or less the same size in relation to the rest of the body, your kidneys are always the same size compared to the rest of your body too?

Nic - Yes, that's right. So this is a process called 'allometry' which is that you need to coordinate the growth of all the organs in our bodies so that the proportions are respected, so you can't have somebody going around with huge liver and a tiny brain. That wouldn't work very well and so, that needs to be coordinated, and that's probably done by the organs communicating with each other. This is something that we still know relatively little about, but it's a very fascinating process both during development, but also in adults because remember that growth control is not just about reaching the right size which happens as you're developing from an embryo to an adult. But also, once you're an adult, you have to maintain, you have to keep sensing the maximum size and you have to maintain that, and that's a very interesting process as well because it relates to diseases such as cancer for example where those process' balance which is called homeostasis, goes wrong and you start to get tumours.

Kat - For you and your research, where are you headed next? What are the questions that are really bothering you?

Nic - We have many of the players that control growth. So the signalling pathways, we've identified them but we still don't really understand the precise cues that these pathways are responding to, so in particular, in the Hippo pathway, what we think or for the case of the Hippo pathway, what we think is that it responds to the physical environment that the cells are in. So, as you start growing, the kind of tension, the pulling and pushing forces that are sensed by your cells change. The force balance within your body changes as it gets bigger and we think that this is precisely what is being sensed by the Hippo signalling pathway and that once the force balance kind of changes in a particular way then the cells are told to stop proliferating because you've reached the right size. But that's a very vague concept as you can imagine and the tools for us to actually probe these forces - we're talking about really physical forces here, pulling, pushing, and the tools to probe these forces are still in their infancy and particularly, if you're looking at a system which is alive, which is a living system. And so, I hope in the future, we will develop better tools to visualise physical forces in developing tissues, and that will tell us really how growth regulation is happening.

Kat - Because it's very easy to think about nutrition, and chemicals, and glucose or whatever, affecting something but to get a handle on what must be tiny atomic scale forces, what sort of technologies are you starting to look at?

Nic - Well, for the moment, it's mostly to do with ablating little bits of tissues with lasers which we can do in cultured drosophila embryos and that's certainly works, but it's a very crude tool. It doesn't really give you kind of very good handle on the exact extent of the forces. It can give you relative measurements which is useful, but what the future is made of is really using biosensors. So you've probably heard of biosensors in every context as these are essentially reporters of particular physical processes - either physical or signalling processes inside the cells that are big business in the pharmaceutical industry as they're used to probe the function or the activity of drugs for example on our cells. We and others are developing biosensors of physical forces that should enable us to really in situ or in vivo examine these forces, but there are still - part of me wishes that I had a Star Trek tricorder, one of these lovely little devices that you just flash at someone and you get all of their physical parameters instantly downloaded onto your computer. But unfortunately, Mr. Spock hasn't given me one of these yet.

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