Getting Inside your Genes
This week, we're introducing the new Naked Genetics podcast - This time, Kat Arney takes a look at the world of top models - not the kind that won't get out of bed for less than ten grand, but the model organisms used by researchers all over the world to answer some of the most challenging questions in biology. We'll also be hearing about the origins of polar bears, the extinction of Tasmanian tigers, fitter frogs with faster-changing genomes and promiscuous bees. And move over Beyonce, because our gene of the month is the curvaceous Callipyge - Greek for beautiful buttocks.
In this episode
01:42 - Model worms - Professor Jonathan Hodgkin
Model worms - Professor Jonathan Hodgkin
with Professor Jonathan Hodgkin, University of Oxford
When you think of super-models, you may think of skinny, pouting beauties strutting up and down the catwalk. But one of the more recent stars on the modelling scene in the world of genetics research is just over a millimetre long, completely transparent, and you can pop it in the fridge over the weekend. To find out more about these curious creatures, I spoke to Jonathan Hodgkin, Professor of Genetics at the University of Oxford...
Jonathan - I and hundreds of other labs around the world, we work on a tiny worm called C. elegans - Caenorhabditis elegans - which lives in the soil all over the world, but it turns out to be a wonderful organism for studying in a lab for all sorts of problems because it's just incredibly easy to work with, and geneticists love it because it goes through two generations a week, so it grows incredibly fast. Work on this started about 40 years ago and it just kept on expanding. So back then, which is actually when I started working, there was just one lab and now, there are about 800 around the world.
Kat - So, who first thought this was a good idea to look at these tiny worms? Where were they first found?
Jonathan - Well, these particular tiny worms, the one we work on, they all come from one worm that was isolated on a mushroom farm near Bristol in the early 1950s. One of the reasons it's a handy creature to work on is that it can reproduce by self-fertilization. So, you can trace everything back to one worm.
Kat - I understand they're quite handy as well. You can pop them in the fridge, you can put them in the freezer.
Jonathan - Absolutely. That's a big, big advantage. You can slow them down or you can speed them up. Very importantly, you can just freeze them completely and keep them in liquid nitrogen or minus 80, and they will leave forever like that and then you just thaw them up and it's actually wonderful to watch them waking up after having been frozen for what, for them, is the equivalent to 40,000 years and they just go, "Oh! Ahh..."
Kat - "Here we are again."
Jonathan - "Here we are again," Yeah.
Kat - So, tell me a bit about how studies into these worms have told us about human biology because you might not think that there's an awful lot of similarity between a tiny worm and humans, but they have had a really big impact on our understanding of some processes.
Jonathan - They certainly have. One of the things that was originally intended in this process was to understand how you put together a nervous system. That's led to an enormous amount of basic understanding of how that happens. Both how you make a nervous system, how you wire it up, and how it functions. But then there've been all sorts of completely unexpected things that came out of this and two of those ended up as Nobel Prize-winning discoveries, and one was understanding cell death - apoptosis, which is absolutely crucial to health and to just everything that happens in your development, and all the time in yourself, cells are dying all the time. They haven't really been appreciated and how important that was that there's actually a special programme that allows cells to commit suicide gracefully, and that was really all worked up because of the C. elegans worm. And the other thing is this novel process called RNA interference which is a new way of turning genes on and off. And again, we didn't expect that to be discovered. It wasn't predicted. It came as a complete surprise, but we were able to use the power of the experimental system to get to that point.
Kat - And now, RNA interference is being used in all sorts of studies in human diseases and across the biological world.
Jonathan - It certainly is. Like every discovery, the initial dreams that people had didn't quite pan out but some of them did pan out, and there's still a huge amount of potential for using this RNAi process to control disease, to control viruses.
Kat - One of the other things that you're interested is testing drugs on worms and presumably, these are not drugs that will have an impact on the worms, but these are drugs that may be useful or beneficial for humans.
Jonathan - Well, worms are a good system for this, partly because they're so small. I mean, a fully grown worm is only a millimetre long, you can barely see it, but that means you can grow it and keep it just in a tiny, tiny drop of liquid and that means that therefore, if you want to screen a million different compounds for their effectiveness as a drug, you only need a tiny amount of the drug in order to do the test. And also, it's very easy to see what's going on because the worm is completely transparent and you can see what's happening inside it all the time. So, if a drug has an effect, it's immediately dramatic. As far as a lot of human diseases, what we can do is basically humanize the worm. We can put human genes into the worm and then they can be given these human diseases and we can try and cure them in the worm. So Alzheimer's disease is an example of this, where worms don't normally get Alzheimer's disease, but you can make them have it by putting the relevant human genes in there and then you can test for drugs that will be ameliorative for Alzheimer's.
Kat - And as well as their benefit for humans, worms are also an agricultural problem. They're an agricultural pest.
Jonathan - They sure are.
Kat - So, there are some ways that we can try and develop new ways of tackling them as a pest, as well as beneficial species.
Jonathan - Yup, that's the other side of what we do and what I'm increasingly interested in my own work is that C. elegans is completely harmless. I said we've found it in the mushroom. It was found in a mushroom farm originally, but if anything, it's beneficial to growing mushrooms, but it's totally harmless but there are lots of other related nematodes which are very bad crop parasites and it's estimated that something like 10, 20% of all primary crop production is severely at risk with nematodes. There are places where you simply can't grow tomatoes because of the nematode risk. So finding new ways of attacking nematodes and particularly plant parasitic nematodes is very important and it's even more important because the main compound that was used for many years - methyl bromide - to control plant parasitic nematodes - is quite rightly no longer allowed to be used because it's a very dangerous compound. So there's a big gap and need for new drugs to control plant parasite nematodes.
Kat - So maybe from these tiny worms, we could get new drugs for human diseases and new drugs to combat this agricultural side.
Jonathan - Exactly! Absolutely and we can also - as well as the plant parasitic nematodes, there are human parasitic nematodes which are a significant health burden in particularly the developing world. Things like river blindness, things like elephantiasis, and then in more insidious things like hookworm. There are hundreds of millions of people who have got hookworm. Hookworm doesn't kill you, but it makes you pretty unhealthy and finding new ways of controlling that would make an enormous difference in many countries.
Kat - That was Professor Jonathan Hodgkin, who was awarded this year's Genetics Society Medal for his work with tiny C. elegans worms.
09:11 - Polar bear evolution
Polar bear evolution
with Nell Barrie
Nell - So the first one is about a polar bear evolution. Now, everybody likes polar bears. They're cute, they're fluffy. What we're looking at here is how did polar bears evolve to be different from normal bears - brown bears, all kinds of bears that do not live in the Arctic. Obviously, they're big, they're white, they can cope with cold so, clearly, they're quite different and it was actually confusing scientists because it didn't seem like they'd have enough time to evolve all these differences. We previously believed that they evolved from a brown bear about 150,000 years ago. It's when they split off from that heritage. Now, they've looked at better samples of DNA, not just mitochondrial DNA, but the rest of the DNA code as well, and that suggests that they've actually evolved five times longer ago than we thought which explains why they've become so different over that longer period of time.
Kat - So yeah, we thought they were some kind of evolutionary ninja that they changed really fast, but they've had 600,000 years to turn into polar bears. I also thought it was quite interesting it picked up that it's very difficult to do evolutionary research on polar bears. There aren't fossils because they tend to just die on the sea ice and then sink to the bottom of the sea. So, it's quite good that they've managed to get enough samples and use new techniques to make sense of it because the polar bears are under a lot of pressure at the moment, and poor things.
Nell - Yes, aren't they?
Kat - Are they going to evolve out of it? I don't know.
Nell - Well, we'd hope so. One thing they also found was that they're not very genetically diverse which is going to be a problem if they need to evolve to cope with less sea ice than there was before, encountering humans, putting up with pollution, all that kind of thing. So hopefully, this might, maybe give us some ideas of how to help them do that if we need to in the future.
10:49 - Tasmanian tiger diversity
Tasmanian tiger diversity
with Nell Barrie
Kat - And moving to another sad story, this one's about an animal that's already become extinct, the Tasmanian tiger. This is research that's published in PLoS One by Dr. Brandon Menzies and his team at the University of Melbourne, obviously in Australia where the Tasmanian tiger lived. Now, they've been doing a lot of research onto the evolution of Tasmanian tigers and looking at old samples and found that they have very poor genetic diversity. So for example, when you look at DNA changes in certain parts of the genome, dogs have like 5 to 6 differences between individuals. Tasmanian tigers only average about one difference there, not very diverse at all. And luckily or maybe unluckily, the Tasmanian tiger actually got hunted to extinction by bounty hunters before it could go extinct.
11:33 - Giant sex-crazed bees
Giant sex-crazed bees
with Nell Barrie
Nell - Yeah, this is giant bees in China and this was published in PLoS One. They're actually looking at isolated colonies of bees on an island off the coast of China and what they were trying to figure out is how these bees cope with being so isolated because you'd expect them to be again, not very diverse genetically because they haven't got a lot of options in terms of who they're breeding with. What they found is the way the honeybee queens cope with this is just by having sex with loads of males, as many as they can, which is a great strategy.
Kat - Really?
Nell - Apparently so.
Kat - Not yours.
Nell - Well, these are giant sex-crazed bees we're talking about so, who knows what they get up to. But this is good for them because it means that they are mixing up those genes as much as possible and that means that they're not becoming too inbred I guess.
12:22 - MicroRNAs in bee brains
MicroRNAs in bee brains
with Nell Barrie
Kat - Another nice bee story that I noticed in the journal Genes, Brains and Behaviour and this is from researchers at Washington University was about the role of microRNAs in bee brains. The microRNAs are kind of tiny little snippets of RNA. It's sort of the message inside our cells. For a long time, scientists have just thought this was maybe sort junk DNA, didn't really know what it did and now, it's turning out to be very interesting because in bee colonies, bees have different jobs. They're very stereotyped. Some bees are worker bees, some bees are nurse bees, obviously you get queen bees, you get drones. They think that these microRNAs at different times might be responsible for making sure that bees go into the right job. So, it's not just the genes, the actual genes being switched on and off. They think that this microRNA is controlling it and it's really fascinating, some of the roles that these microRNAs might have.
Nell - Yes, it's kind of like career advice for bees in their brain.I think kind of what's weird about this in ways that there is so much we still don't know because clearly, something must be controlling when these little switches are going on and off inside the bees' brains and in other animals too. We know they have roles in circadian rhythms for example and we just don't really know enough about yet, what they could be doing in human brains for example. So, it would be really interesting to see more research like this coming out in different species, I think.
Kat - Yeah, us humans make around 2,000 microRNAs and they started to be implicated in cancer, in neurological disease, so a whole field to be explored.
13:48 - Pigeon navigation
with Nell Barrie
Nell - And this is a little bit sad because it's the kind of crushing of an urban legend. People did use to think that pigeons actually had magnetic beaks and that this acted as a sort of compass, allowing them to do these amazing feats of navigation that we hear about. What this research in Nature has shown is that in fact this isn't true and it's a bit of shame really. They do, it turns out have cells in their beaks which are filled with iron and that was clearly the clue that led people to think that perhaps this was acting as a kind of compass. But in fact, they found that these are macrophage cells. They're white blood cells. So, there's no way they could be sending messages to the brain because they're not just designed to do that sort of thing, these cells. So, we still got to find a way, how are these pigeons navigating?
Kat - I love the quote from the researcher David Keays. He said, "We've put the cat among the pigeons now."
Nell - He did. Just couldn't resist that clearly.
14:48 - Breast cancer redefined
Breast cancer redefined
A joint team of researchers from the UK and Canada have rewritten the rule book on defining different types of breast cancer, publishing their findings in the journal Nature this month. Led by Professor Carlos Caldas from the Cancer Research UK Cambridge Research Institute, the scientists carried out detailed analysis of the genetic fingerprints of 2,000 breast tumours and found they grouped into ten distinct categories. Currently doctors only recognise four broad categories of breast cancer, but these new results help to explain why women who seem to have the same type of cancer respond differently to treatment. It will be some years before the fruits of this research filter into routine treatment, but the team hopes that their findings will start to be applied in clinical research by stratifying women taking part in breast cancer trials straight away.
15:35 - Genetic switch turns leaves into flowers
Genetic switch turns leaves into flowers
Scientists at the National University of Singapore have discovered the molecular 'switch' that makes plants produce flowers rather than leaves, publishing their results in the journal PLoS Biology.
Although it's one of the most important things that a plant does, the actual mechanisms underpinning how this happens are relatively unknown.
The researchers, led by Hao Yu, discovered that the protein FTIP1 is important for making plants flower at the right time under normal light conditions, while plants with a faulty version don't flower on time.
Manipulating FTIP1 or similar proteins in crop plants could be useful for increasing crop yields in different environments.
16:16 - Fitter frogs
In a paper in the journal Molecular Biology and Evolution, Juan Santos from the National Evolutionary Synthesis Centre in the US describes how fitter poisonous frogs have faster-changing genomes. The idea that animals with faster metabolic rates might have faster evolution was first put forward in the 1990s, but nobody could come up with good evidence to support it - but Santos thinks this is because researchers only studied animals at rest, rather than during physical activity. To test his idea, he put 500 frogs from 50 different species through a froggy fitness test, and discovered that the genomes of the fitter species were changing faster than their more sluggish relatives. While the reason for this isn't clear, it may be related to the production of free-radicals during exercise - damaging oxygen molecules that can cause changes in DNA.
17:07 - Brain evolution due to fat metabolism
Brain evolution due to fat metabolism
Scientists at Uppsala University in Sweden have discovered evidence showing that the evolution of human brains may have resulted from changes in the genes responsible for fat metabolism. Led by Adam Ameur, the researchers think a gene change around 300,000 years ago helped early humans to produce larger amounts of Omega-3 and Omega-6 fatty acids from vegetable oils in our diet, which are vital for brain development.
Intriguingly, the researchers only found the gene change in humans, and not in our primate relatives like chimps, gorillas and monkeys, or in early hominids such as Neanderthals. But there's a flip-side to this, as although increased production of Omega-3 and Omega-6 fatty acids may have helped our brains to evolve, today they contribute to the risk of diseases such as cardiovascular disease.
18:19 - Arabidopsis as a model plant - Dr Sean Cutler
Arabidopsis as a model plant - Dr Sean Cutler
with Dr Sean Cutler, UC Riverside
Sean - Because of its size, it's a very small weed and it grows relatively quickly, and also has a small genome. And because of those features, geneticists early on selected it as being a good model for lab studies, in the way that the fruit fly is a good model for a lot of other insects.
Kat - And how long have scientists been studying Arabidopsis?
Sean - The first studies go back longer than the '50s, but I would say, modern Arabidopsis research, where a lot of people started working on it in parallel with similar building tools and working together that really started I would say in the '80s.
Kat - And we know about model systems for studying animal biology, fruit flies, zebra fish, mice. Why do we need a plant model?
Sean - Well, plants feed the planet. We need to understand how plants use water, how they use nitrogen, how the different inputs that we give them are converted into the materials that we harvest for food or fibre, and now of course, for fuels as well. What we would like to be able to do is make those processes of modern agriculture more efficient and get by with less of the inputs that we use, so that we can feed our growing population with the available land and resources that we have.
Kat - So obviously, a big challenge with climate change in a lot of places in the world where we grow crops getting a lot drier.
Sean - Yeah, drought is a really big problem all over the world, but also, flooding is a really big problem. So the levels of floods and flood-prone areas are going up. Climate is becoming more erratic, it appears, with drought-prone areas getting longer droughts, more severe droughts and flood-prone areas getting more longer and more severe floods. And it turns out that plant biologists are getting a handle on how to make plants grow better under conditions of flood, how to make plants grow better when there's water limitation or other nutrient limitations.
Kat - So tell me a bit about the kind of approach you're taking, this chemical genetics approach. What do we mean by that?
Sean - So, classical genetics used to and still does, try to figure out how a pathway works by breaking it with a mutation. As if you're trying to understand how a car worked and you were from Mars, you would cut the line between the brakes and the brake pedals and the car wouldn't stop, and you would conclude that the brake pedal has something to do with slowing down cars and genetics has that same logic where you break genes and you look at what the consequences are for the organism, and try to infer their functions that way.
One of the things that we're realising in many organisms, but it's particularly true in plants is that, there are often backup systems. So, plants as a rule always have two brake pedals and if you're trying to do that experiment where you cut the line on the brakes, you might never discover the existence of a braking system. Chemicals often, for technical reasons that I don't need to get in to, chemicals can sometimes indiscriminately cut all of the brakes, instead of just cutting one particular brake cord in this, now overwrought, analogy. So chemicals provide an additional tool in the arsenal that a geneticist can use to help understand a pathway and they can be particularly helpful where redundancy may have been preventing a geneticist from fully understanding how a system works.
22:01 - Zebra fish ears - Dr Tanya Whitfield
Zebra fish ears - Dr Tanya Whitfield
with Dr Tanya Whitfield, University of Sheffield
Tanya - They don't have an outer ear, a pinna like we do, and they don't have a middle ear system, but they do have the equivalent of our inner ear and they do use their ears for both hearing, so they're sensitive to sound - although they're not sensitive to quite the same range or frequencies that people are. And they also use them for as a balance organ which is exactly what our own inner ears are useful too, so we remain upright partly because we're constantly sensing whether we're the right way up, using our inner ears.
Kat - And tell me about some of the work you're doing with zebra fish. How are you using zebra fish to try and find how the ears work?
Tanya - The subject I was talking about today was our work, looking for small molecules that can actually affect the way the ear develops and functions in the embryo. The fish particularly good for that because the embryos are small which means we can treat them with different compounds, different small molecules, and see whether those have any effect on the developing ear. Specifically, we've been using a gene expression marker which is abnormally expressed in one of our zebra fish strains to see whether we can restore the normal expression of that gene, after we've treated with chemical compounds.
Kat - So when this fish don't have their ears developing properly, they make this marker that you can see and then you're looking for things that will turn it back to normal.
Tanya - Exactly, yes. And we can do this in not a high throughput, but a sort of medium throughput format, so we can screen plates of about 80 chemicals at any one time and so, we've completed a screen of over 2,000 chemicals and of those, we found 40 different compounds that give the effect that we want.
Kat - So, what are some of the similar problems in human hearing that mimic what you see in your fish and do you think any of the things that you've discovered could be useful for human hearing or balance disorders?
Tanya - We're at the very basic end of research so it's very early days to say that yet, but the fish with the abnormal gene expression I was talking about actually also has swollen ears as a developmental defect and in fact, too much fluid inside the ear is a problem in some clinical conditions for example, something called Meniere's disease which is actually quite a common disorder and for which the causes a largely unknown and some syndromes such as Pendred syndrome which is an ion imbalance syndrome which causes problem in the ear and in the thyroid gland. But the idea is, a long-term goal is to identify new lead compounds that might be used in a drug development process.
Can medication change your DNA?
Answered by Marianne Baker, Barts Cancer Institute.
Most drugs act on proteins - the molecules in our cells that do particular jobs - so they don't change your underlying DNA. But some can act on DNA - for example many chemotherapy drugs, such as cisplatin, damage DNA and make cancer cells die. But they can also damage DNA in healthy cells too, causing side effects. Some other new cancer drugs in development are designed to change the molecular 'tags' on your DNA, known as methylation and acetylation, affecting how genes are switched on or off. While DNA-altering drugs will usually just kill cells in your body rather than just causing long-term changes, there are more serious consequences if women take them while pregnant. The controversial drug thalidomide can also affect DNA, causing birth defects if it's taken by pregnant women, and there are other examples of drugs that can also have this effect and must be avoided in pregnancy.
Does high speed travel change human DNA?
Answered by Marianne Baker, Barts Cancer Institute. There's probably no effects on DNA from high-speed travel itself, but there is a known effect on DNA from cosmic radiation at high altitudes - one long-haul flight is roughly the equivalent radiation exposure of a couple of chest X-rays. So if you spend a lot of time at high-altitude, rather than high speed, you'd be increasing the chances of damaging your DNA, and therefore slightly increasing your cancer risk. As SeanB points out on the Naked Scientists forum, if high-speed travel had an effect it would have been seen already - astronauts have to go at 12km per second to obtain enough energy to reach earth orbit as well, and, as they are probably the most studied people around, any effects would have been seen since the 1960's when the first people orbited the earth.
27:25 - Gene of the month - Callipyge
Gene of the month - Callipyge
with Kat Arney
Move over Kim Kardashian, because our gene of the month is the curvaceous Callipyge, Greek for "beautiful buttocks". It was first spotted back in the early 1980s on a farm in Oklahoma, when the farmer noticed some sheep in his flock with particularly big, muscular bottoms. Tracking down the Callipyge gene itself turned out to be quite tricky, because it is inherited in an unusual way known as 'paternal polar overdominance' - the only known example of this phenomenon in mammals. Animals only get big bums if they inherit a normal copy of the gene from their mother, and a version from dad that has just one single DNA letter change.
Agricultural researchers are very interested in Callipyge because the mutation enables sheep to convert food into muscle 30 per cent more efficiently than their small-bottomed siblings. And as well as the potential for breeding meatier livestock, scientists think it could also shed light on human size and shape, helping our understanding of the genes (with a g) that affect whether we can fit into our jeans (with a j).