Developmental genetics - from one cell to many

Nell - So the first one is looking at the genes behind autism and this is research in America and they've looked at about 600 families who've got people with autism in the family, and they actually found three new high risk genes. But it also looks like the whole disease is a lot more complicated in terms of which genes are contributing than we thought before.

Kat - Because I think it was thought there's about 200 genes involved in autism, but now, this new study puts the number at about a thousand. That seems very complicated.

Nell - Yeah, exactly and I mean, it's a behavioural disease so it's kind of what would be expected I suppose, that there's lots of different changes that can maybe cause the same types of symptoms in people, and they've actually looked at gene mutations that are not inherited from the parents, but are just arising spontaneously, so just little changes that happen by accident randomly.

Kat - So this is more likely to be relevant to autism and the whole population then rather than kind of specifically inherited syndromes, do you think?

Nell - Yeah, it sounds like that and I mean, I guess it's another one of those things where you can look at all these different changes, figure out how common they are as a background sort of thing, and then perhaps that will give you clues for ways to treat this and ways to tackle the problem.

Kat - Certainly, important because there's more and more people being diagnosed with autism. I think a lot of that is they've changed the criteria for diagnosis and more people are falling within that spectrum disorder. One of the interesting things and the challenging things I saw, I think in the press release, one of the researchers says the phrase, "The bad news is, there is heterogeneity out the yingyang..."

I think they've just found this huge number of genes and it's very complex. It's all sorts of different versions of them, so it's a really big challenge and how do you think they might straighten out?

Nell - Well I guess, I mean, one thing I thought was interesting is that could perhaps be part of the reason why you see this sort of spectrum of autism-like disorders I guess. You've got some people who are really badly affected, others who maybe just have some symptoms, and perhaps that could give us some clues as to what's going on there.

Kat - I think larger studies as well, just to try and figure out really what's going on a much larger basis.

Kat - Another story that we saw, also involving this large scale genome sequencing but not in humans, but in fishes. What's this one?

Nell - Yeah, I like this. This is about sticklebacks and how they've evolved and they were actually looking at how the different species evolved to adapt in the same sort of way, and it's a sort of convergent evolution thing. So they haven't all come from one common stickleback ancestor. They've all adapted similar genes in similar ways, but independently which is really cool.

Kat - So it's like 21 different species of sticklebacks that they sampled from different lakes around the world that obviously, they separate and they're separated by geography. But yeah, they found that the genes are changed in the same way to help the sticklebacks adapt so I thought that was a really nice example that tells you about how evolutionary processes might work. There was quite a sad thing I saw as well.

Nell - Yeah, at the end, they were saying that some of the sticklebacks they've been studying from a place called Bear Paw Lake were actually being threatened by some big pikes that are coming in which are invasive predators. I mean, you might think, "Oh, it'll be fine. They can re-evolve themselves" but we know that that's not true and every species is individual and unique, so yeah, they have a bit of a sad end to that.

Kat - They can't evolve. They've all been eaten.

Scientists from the University of Illinois have found more evidence to suggest that human headlice and body lice may be the same species - something that's hotly debated in the world of insect genetics. The researchers compared the activity of genes in both types of lice throughout their life cycle, and subjected them to a range of challenges, such as heat or bacterial infection. They found so few differences between the two that they could arguably be the same species. Interestingly, body lice can transmit diseases like typhus while head lice don't, so the next step is to try and understand how this difference exists when the two species are so similar.

An international team of researchers have made an important step forward in understanding how nature and nurture work together when it comes to birth defects linked to faulty genes, according to a new paper in the journal Cell. The scientists were studying a relatively rare disease called congenital scoliosis, which causes babies to be born with a poorly-formed spine.

Using mice with a gene fault that mimics the human disease, the team found that even short periods of low oxygen during pregnancy (known as hypoxia) increased the risk and severity of baby mice being born with spine problems. In humans, hypoxia can be caused by a range of things like maternal smoking, high altitude, drug use or medical conditions such as maternal diabetes or anaemia, so the researchers think that the same mechanisms may be at work in human babies, increasing the chances of birth defects where there's an underlying genetic defect.

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.

The short answer is "yes!" - although large doses of radiation from something like an atomic bomb or nuclear power station explosion are obviously very bad, any type of lower-level radiation doesn't cause specifically "good" or "bad" mutations, it just causes changes. As we heard in last month's podcast, these random changes happen all the time and may or may not be passed on to the next generation. But if there is a selective pressure, then we see beneficial mutations start to spread through populations. It doesn't matter what causes them, only that they have to be passed on, so they'd originally have to arise in the sperm or egg-producing cells for humans and other animals.