The Fly Brain
Hi. Welcome to the Brainfix podcast discussing all things brain. I'm professor David Brough, professor of neuroinflammation at the University of Manchester. And the first guest on the podcast is professor of neuroscience, Richard Baines. And today, we'll be discussing the use of fruit flies in neuroscience research.
Prof Dave Brough:So Richard, welcome to the podcast. I wonder if we could start with a little bit of background into your research career and what's brought you to your current research interests.
Prof Richard Baines:Well, thank you, David, for inviting me. My background has always been a neuroscientist, but one that's always worked with insects. And insects have, a very special property in that because their nervous systems are quite small, they have what we call identified neurons. That means we can actually give names to specific nerve cells and go back to the same cell time after time in different insects. You can't do that in higher animals like mice or, rats and so on.
Prof Richard Baines:So it gives us a level of resolution that's better than competing models. Now I started out with what we call big insects. So I finished my PhD back in 1988, which is rather too long ago for my liking actually, But I worked with locusts and I worked with cockroaches. They had big nerve cells, but they had no genetics. So in about the nineties when the molecular biology genetics revolution really got going, I made the switch to fruit flies, Drosophila, much smaller, but still have identified neurons, but now they had the capability to mix genetics and molecular biology.
Prof Richard Baines:And together, it's now a very powerful laboratory model system. Yeah. So I can see that, you know, mixing
Prof Dave Brough:in genetics makes a massive advance, but I guess how similar is a is a fly brain to a human brain, and and what can you actually model with it? Well, I get that question
Prof Richard Baines:a lot and, you know, my my first response is always to say there's only one nervous system on the planet. We all share a variation of it. So if you think about a fly, it's a lot smaller and, yes, its nervous system is a lot smaller, But flies still need to do everything that we do. So they need to be able to see. They need to be able to hear.
Prof Richard Baines:They need to be able to walk. And in the case of a fly, they fly, something we don't. They find food, they need to find a mate. So actually when you boil it down the fly is not so different to the human. Now if you take a fly and look inside and find the nervous system what you will find inside that nervous system is very recognisable from a human perspective.
Prof Richard Baines:The nerve cells use the same sorts of neurotransmitters, the chemical signals. They have the same sort of basic structure. The connections between them, which we call synapses, are the same. And so in many ways, a good analogy is perhaps thinking about a laptop computer being the insect and a supercomputer matter of scale that's different, but not the actual functionality of it. And the the advantage for that, for us really then, is that we have a nervous system which is composed of much fewer nerve cells, maybe a million nerve cells in the fly brain, whereas a human has 80,000,000,000.
Prof Richard Baines:We have nerve cells which we can identify and go back to, and we have nerve cells that we can manipulate the genetics of.
Prof Dave Brough:So in terms of your your current field, your current research interests, I know you've done a lot of research on epilepsy and trying to find new ways of treating it. How useful has the fly been in
Prof Richard Baines:this area? So in many ways, the the issue with epilepsy is it's a very common neurological disease, so one to two percent of the world's population suffer from epilepsy. So in The UK, that's six hundred thousand people. Now we have a lot of drugs in the clinic. There's about 25 or more drugs been developed over about the last seventy or eighty years.
Prof Richard Baines:But there are two key problems. The first is about thirty percent of people with epilepsy don't respond to the drugs we have. And even though we keep designing new drugs, that number doesn't change. The second is those drugs are not a cure. They will prevent or reduce seizure severity, seizure frequency, but the individual has to take those drugs for life.
Prof Richard Baines:And as we know, drugs come with side effects. And with epilepsy, those side effects can be very significant particularly for, women of childbearing age. They have very bad effects on the developing fetus to the point where women often have to make a very difficult decision to come off medication whilst pregnant, but then they lose management of their seizures. So we need new approaches, new ideas, and that's where things like the fruit fly come in. It's a laboratory test tube to allow us to experiment.
Prof Richard Baines:So a couple of areas that we've really explored in my laboratory are, one, how we could possibly design treatments for new targets, and the second, which I'll explain in a moment, is we've actually shown it is possible to cure epilepsy. So the first one, if you imagine the human brain, as I mentioned before, what 80,000,000,000 cells, they all have about a thousand connections each, it's something like a trillion connections in the brain, and they're changing all of the time. So actually the brain is a real chaotic place to be. It's not static by any means. And the brain has developed these sort of mechanisms called neuronal homeostasis to maintain activity within acceptable limits.
Prof Richard Baines:And that's really been an area that I've studied for twenty years now, how do these mechanisms work? And we realized some time ago that these mechanisms that the brain already uses to make sure most of us don't have seizures, could we boost them in people who did have seizures and epilepsy for a cure, you know, for a treatment? And so long story short, we've hijacked wannabe systems, we've developed a drug that promotes the brain's own mechanism, and when we've tested this compound in both fly seizure models and mouse seizure models, it's really very effective. And so we've got, a new drug target to develop, and it's early days but it's quite promising. So coming back to that second area we've developed, the sort of holy grail if you like and that's curing epilepsy, could we ever do that one day?
Prof Richard Baines:So flies have the same genes as humans and we can mutate genes in the fly which we find are mutated in people with epilepsy. So when we do that, we end up with flies. We we can, induce seizures in them. But we found actually that even if those flies have those mutations, if we manipulate the nervous system early in development when the nervous system is forming, we can actually sort of overcome the effect of the mutation. So the fly develops with the mutation, but never shows any seizures because we've allowed the nervous system to compensate.
Prof Richard Baines:So that's quite a, you know, an ambition. It has recently been reproduced in a mouse model, which is always the next step of the translational pipeline. But at least in the laboratory, it is possible to prevent the epilepsy process, and that really is, you know, where we would want to work towards because then you take take the reliance away from drugs. So the fly is never going to be a human. It's too far apart from it evolutionally speaking, but it's a real great test bed where we can generate new ideas and tinker around how do things work, we know that, and maybe we can intervene.
Prof Dave Brough:Yes. And those two examples are incredibly exciting. So fingers crossed that, you know, the future is really bright there. More generally, aside from epilepsy, are there targets or treatments for medical conditions that have been first discovered in the in the fly?
Prof Richard Baines:Yeah. You know, I think that's a harder thing to pin down, and in many ways, I think it's I could say yes, but I can't put my finger on the specifics. Let me explain why I think that is. So almost all that we know about human biology comes from studies in simpler animals like fish, frogs, flies, locusts, and so on. But before we can get them to the clinic in terms of new drugs, they have to go through preclinical testing and preclinical experimentation.
Prof Richard Baines:And the gap between the sort of early stage and the late stages can be ten, fifteen, twenty years. And so in many ways in science the sort of origins of stories get lost. So we all stand on other people's shoulders, but I think we sort of forget who we're standing on at times and so it's very difficult to pin it down. But I think let me perhaps illustrate this with one excellent example, a very personal recent example, and that is the biological clock. So we all have a clock that ticks away inside us.
Prof Richard Baines:It anticipates the alarm clock. It tells our body when lunchtime is and when the evening is, and it gets us ready for the different stages of the day. The basic mechanism of the biological clock was found from working the fly, And people in the clinic now, clinicians are very interested in using the knowledge of the clock to decide when to give people drugs because you will respond to the same drug differently at different times of the day. There are also other people looking to see how we could change people's, bilateral clocks for all sorts of reasons. It's a good link to cancer, for example.
Prof Richard Baines:But you know simply jet lag. Imagine if we could have a a pill which you could pop to stop jet lag, I'd be very happy about that and, there are people working on it. So basic science feeds the clinical science and so difficult to say a specific example, but I think it's implicit in all of it.
Prof Dave Brough:Okay. So I guess the the future for flies and research is quite is quite bright then. What do you think the the promise for the future in neuroscience is using fruit flies?
Prof Richard Baines:I think flies hold enormous promise. So the fly was the first complex animal to have its genome fully sequenced. The worm, C. Elegans, was the first, but it's a very smaller, simpler animal. The Drosophila was, in many ways, the the test for doing the human genome.
Prof Richard Baines:We also now have a complete wiring diagram of the fly brain. So we know which cell is connected to which cell, and that's a huge effort over the last twenty years. So I think it's fair to say the fly is probably the most well understood animal on the planet. And one of the beauties of having that sort of well characterised system is not only exploring biology, but we can use it as a a test bed for developing new methods, new ways to look at cells, new ways to manipulate cells, new ways to move genes around, and it's methods that drive science. So with the advent of the human genome project, we developed lots of different ways to make genetically modified animals, and that allows us to make disease models and so on.
Prof Richard Baines:I think one area starting to develop with flies is to use them as mini humans. We call it humanising. So for example, the the genome of the fly is not very different to our genome. We have the same genes, so it's possible to replace a fly gene with a human gene, and we could replace that fly gene with a disease human gene, one with a mutation, and the fly can then become a model system for testing drugs. We call them avatars.
Prof Richard Baines:So, we can very quickly grow up huge numbers of flies. Each female lays about 200 eggs. So you start with one pair of flies, and after a month, you've got thousands. We can they're all the same genetics. They might be carrying a human disease gene.
Prof Richard Baines:We could screen a thousand drugs against all of them very quickly. In the clinic, people are starting to, think about using this approach to identify the right drug for the right person. So, personalized medicine often means people respond to different drugs even though they may have the same mutations. And in some areas like cancer where time is of the essence, there's scope now to make a humanized fly of an individual's cancer mutation and screen it for various, chemotherapy agents to find out which one might work best, and that can be done relatively quickly and then move back to that patient in the clinic. So for
Prof Dave Brough:the basic science there's huge potential, but I think the applied science, how we can exploit the fly to help human, treatments is enormous. Thank you, Richard. I'm gonna start bringing the podcast to a close. So I just want to to say thank you for coming on and sharing your insights. That's been incredibly interesting and exciting, and clearly, there's a lot still to
Prof Richard Baines:be done, with fruit flies. Well, thanks, Dave. I've really enjoyed it. And, I think I'll just leave by saying one thing to the listener that if you, take nothing else from this podcast, next time you see fruit flies buzzing around in your fruit bowl during the summer, please resist the temptation to squash them. Just look at them as smaller relations.
Prof Dave Brough:Thank you. Thanks, Richard. This has been the Brainfix podcast. Any feedback on this podcast or for future content, or any sponsorship inquiries, please send, to the DNS inbox. That is dns@manchester.ac.uk.
Prof Dave Brough:I'll repeat that. DNS@Manchester.AC.UK, and please use the word podcast in the subject line. Tune in next time for more neuroscience.
