Episode 8: Vital Connections in the Brain

Anna Rose: Thanks for downloading this podcast from the University of Portsmouth. In Life Solved, we're asking the big questions about our world from politics to technology, our bodies and our environments. One of the most remarkable things about the research taking place here is the scope for one area to give us clues in another. Departments take what's called a cross-disciplinary approach to help our academics and scientists connect the dots and find exciting solutions to human problems.

Anna Rose: Today, John Worsey talks to a man whose obsession with a certain type of cell led to some tantalising possibilities.

Arthur Butt: Glia are extremely important. If glia stop doing their jobs, neurones do not work right.

Anna Rose: Professor Arthur Butt's glia research looks set to make a real impact on our understanding of how our brains and nervous systems work, and perhaps even the way we understand some illnesses.

Arthur Butt: So we thought, well, instead of looking at all these individual little avenues and networks, we thought, well, lets hit this one and see what happens. So we thought, oh, we'll try with that lithium – it's off the shelf.

John Worsey: Yeah.

Arthur Butt: Everybody knows how it works. Let's try it. It had an absolutely profound effect on the glia. But not many people have considered the possibility that glia might actually be the very important and also drug targets.

Anna Rose: Arthur has been absorbed by neurophysiology since the 1980s. He actually did a marine biology degree but became fascinated by the science neurology and diverted down that path instead.

Arthur Butt: I knew nothing about neurophysiology. And when I read around it, pretty much not many people did know.

John Worsey: Right.

Arthur Butt: So I thought. That's the area for me.

John Worsey: Yeah.

Anna Rose: Luckily for us, Arthur turned his attention to research into cells that repair nerve connections in conditions like multiple sclerosis. These days he builds upon that knowledge and is focussed on the glia, a type of cell found in the nervous system. He runs a lab with colleagues at the University of Portsmouth.

Arthur Butt: We call ourselves the Glial Research Group, which is totally un-sexy. Britain is leading-- leads this particular area of research – I would say. Those cells, which I mentioned, these repair cells, so I was one of the people who helped discover those.

John Worsey: Yeah.

Arthur Butt: So we didn't know those cells even existed.

John Worsey: Right.

Arthur Butt: We had hints of it.

John Worsey: Yeah.

Arthur Butt: But we didn't know how many of them there were in the brain. And so some of the work I was involved in demonstrated this about how prominent they are in the brain and how they work. So yeah, and now we understand a lot more. So that's basic-- that's just fundamental.

Anna Rose: Before we begin, Arthur took us through a few basics to help understand the science. Brace yourself for a whistle-stop tour of your nervous system.

Arthur Butt: Your brain is made up of cells, so these are the building blocks and the way they work, the mechanics of how they work is called physiology. So if you think of how your car engine works, the mechanics of that it's equivalent to the before thinking, for example, but also it controls our movements and our behaviour and emotions and so on. It's the nerve cells – posh name neurones – and the glial cells. The nerve cells are the ones which do all the signalling. So you might be aware that there's electrical signals in your brain. And this is actually so we have electrical signals, it's how the nerve cells communicate with each other and then they'll transmit this electrical signal down your arm and you can wiggle your finger or whatever it is. But for them to be able to do that, they require a lot of support. So they're very, very sensitive cells. And if you alter their environment in any way, they stop working properly. So they exist in a very kind of gentle, passive kind of environment. And that environment is provided by glia.

Anna Rose: When Arthur began his research, very little was understood about glia cells, which were dismissed as simply connective tissues in the brain. It turned out they were actually much more important.

Arthur Butt: Some of the research that I've been involved in, underpins some of that of how these cells are actually allowing neurones to work. Most of the people working on neurones, as far as they're concerned, if something goes wrong in the brain it's because the neurone has gone wrong. Which is true. But what they neglect in, is the fact that the reason the neurone has gone wrong is because the clear aren't working properly. So actually glia are extremely important. If glia stop doing their jobs, neurones do not work.

Anna Rose: Well, there are three kinds of glia. That's an oversimplification, but that's the easiest way to think of it. One of the types is called an astrocyte. So you've got a nerve cell which is fired in a way, and then it transmits this signal.

John Worsey: Yeah.

Arthur Butt: This electrical signal is essentially coming down a wire.

John Worsey: Yeah.

Arthur Butt: That's why it's called an axon, which is just a big, long extension of the cell. So the electrical signals coming down there and it travels instantly. And the reason it gets there instantly is because of myelin. So myelin is the insulation around the wires in your brain.

John Worsey: Right.

Anna Rose: So one type of glia makes myelin, which is essential in instantaneous transmission of signals. That means if you decided to click your fingers right now, it happens without any delay. The mysteries of the glia seem to be an untapped resource for more information about neurophysiology. For Arthur and his colleagues, this can be frustrating. Although his research isn't directly looking for cures or treatments to medical conditions, he believes the discoveries we're yet to make could be fundamental in doing so.

Arthur Butt: They've been funding Alzheimer's to the tens of billions.

John Worsey: Yes.

Arthur Butt: The last 50 years and haven't come up with a single treatment. And it is kind of shifting. So they are starting to give some money towards it. But it's like a big tangle...

John Worsey: Yeah.

Arthur Butt: ...at sea. It's going to take a while to shift.

Anna Rose: The potential for connecting glial cells to our bodies behaviour under different conditions and diseases is fascinating. Arthur told us what we have already learnt so far. He explained this in the context of the myelin insulation that glia make.

Arthur Butt: Without this insulation, they don't conduct quickly. A classic example of this is the disease, multiple sclerosis. So multiple sclerosis, which is an area of research I've been involved in for the last 20 odd years, is when that myelin, that insulation is lost or degenerate/deteriorate. It is not lost everywhere. There's just little pockets. In the patient, persons with these with the M.S. will end up in a wheelchair. And this is because the signals are not being transmitted. So they can't control how their legs work, how their arms work. They also have cognitive changes. So they start struggling with mood.

John Worsey: Right.

Arthur Butt: Psychiatric changes as well. And also cognitive. So thought processes, the speed of thought. And this is all about losing this insulation. Essentially what it means is the electrical signals are not being transmitted properly in your brain. What happens is in the main type of multiple sclerosis is called relapse, remitting.

John Worsey: Yeah.

Arthur Butt: So you have a relapse of the disease.

John Worsey: Yeah.

Arthur Butt: Then you recover from it.

John Worsey: Yes.

Arthur Butt: That's called the remittance and then the relapse and remittance. This goes on for 10, 20, 30 years and it gradually gets worse and worse – in most patients it gets worse and worse. And what happens is during the-- the relapse, there's something called demyelination. So that's when you lose the insulation. And then during the remittance, there's a repair process which goes on that's called remyelination. And they can keep doing this throughout life pretty good. For reasons, we're not 100 percent sure of, ultimately, this repair starts to fail.

John Worsey: Right.

Arthur Butt: So in multiple sclerosis, the immune system attacks myelin, this insulation in the brain. And over the last couple of years, actually, we've started to understand a bit more why this repair is failing. If you go back about five years, that was my hypothesis, that's what we believed was probably happening.

John Worsey: Yeah.

Arthur Butt: And some recent studies, including the work in my own lab, is now being shown that-- certainly, that is exactly what is happening, but our brain becomes less capable of repairing itself.

John Worsey: Right.

Arthur Butt: Now, you superimpose that upon a disease like M.S., so you're losing myelin and we are losing the capacity to repair. So it means it just gets worse and worse and worse. So we have this disease process and lots of current therapies for multiple sclerosis, around that this immune attack. They'll slow down the immune attack. And these are proven very effective in quite a lot of patients, is not 100 percent effective in 100 percent of patients, but in a significant proportion of patients, it is effective. It's slowing down these relapses.

Anna Rose: In this kind of research, Arthur and his colleagues are not looking directly for a cure to MS, but instead are seeking understanding as to why cells behave in the way they do and how they respond to different drugs.

Arthur Butt: We are looking to understand why does the demyelination occur and what controls the repair?

John Worsey: Yeah.

Arthur Butt: And how we restimulate that repair process to stop the degenerative changes.

Arthur Butt: When it comes to repair and ageing, Arthur's work triggered another question for biomedical science. Age is a natural process, leading to a slowing in our brains and bodies. In dementia, however, this is accelerated.

Arthur Butt: One of the calls, or the focuses, is on ageing research because the population is getting older and older and what we want to be able to do is keep that population healthy. In my case, we're looking at the ageing brain. So the ageing brain gradually declines and this is cognitive decline. So basically we just get less quick.

John Worsey: Yeah.

Arthur Butt: This isn't pathology, this is that your brain slows down, the rest of your body will slow down as well. Your brain also slows down and there's lots of different reasons for that. One of them is that-- what we call plasticity of the nerve cells, so when we learn a new thing, we have to make a new connection in our brain.

John Worsey: Right.

Arthur Butt: So every time we learn something new, new connections have to be made. And your brain gets less good at making those new connections – gets less plastic. Because those glial cells I'm so fascinated with, they become less plastic.

John Worsey: Right.

Arthur Butt: Because it's their job to make sure those connections are made. So the nerve cell has to find this connection and then make it. And it does it because glial cells help them.

John Worsey: Right.

Arthur Butt: So the glial cells get less plastic and less helpful. The other thing which has to happen when that new connection is made is it has to have insulation. Otherwise, it's connected, but it's only conducting electricity very slowly. So we need new myelin, new insulation, as I mentioned earlier, that declines with age. The cells which make new myelin get less good at it as we get older.

John Worsey: Yeah.

Arthur Butt: And this is all about losing this insulation. Essentially what it means is the electrical signals are not being transmitted properly in your brain. So once you get passed around about the age of 50 or 55, 60, this repair becomes less.

John Worsey: Right.

Arthur Butt: And in recent studies, we've discovered – we and others have discovered – that in certain drugs which are available on the market, which can-- which can stimulate these ageing repair cells, to think they're young again. Not many people have considered the possibility that glia might actually be very important and also drug targets.

Anna Rose: So where does Arthur see the most potential for further research in Alzheimer's and dementia, for example? One of his funding sources is the BBRSC or the Biotechnology and Biological Science Research Council. The MRC or Medical Research Council then makes decisions based on these findings.

Arthur Butt: So what the BBRSC fund me for is to look at why does this-- these cells which make the myelin, why do they become less capable as they get older?

John Worsey: Gosh, yeh.

Arthur Butt: So it's very fundamental.

John Worsey: Yes.

Arthur Butt: If we found something very exciting in the basic research concept, but we think now we're on the verge of finding something which might-- we might be able to take a pill which is going to help us in ageing or in Alzheimer's and dementia or in multiple sclerosis. The MRC might say, OK, we found that.

John Worsey: Yeah.

Arthur Butt: And we'll give you some money to prove that you can improve your ageing and that this is relevant to some kind of pathology.

John Worsey: Yes.

Arthur Butt: I usually relate it to M.S. because I've been working on it for so long. I'm recognised as knowing what I'm talking about. But it's also relevant to dementia and Alzheimer's disease. So if you think of normal ageing cognitive decline, it's a natural process. In dementia, it's an accelerated process. So, you know, from possibly from the age of 50, 55, it gets worse and worse. And the pathology of that is mainly neurones. I think, again, the glial cells are massively altered in it. And I -- hardly anybody gets any money to research into glial cells in Alzheimer's, unfortunately. But the glial cells are altered and they would be a potential therapeutic target.

Anna Rose: That makes sense, but a discovery like this raises many more questions for a researcher to investigate. John asked Arthur where else his glia investigations had taken him and what real-life impact it suggested.

Arthur Butt: So the cells have got things called ion channels. It turns out these channels are really important in just about everything that the cell does. And we work on a particular kind of channel which is specific to glial cells. So we have been involved in explaining how these channels allow glia to keep that constant environment I was talking about.

John Worsey: Yeah.

Arthur Butt: What they do is keep potassium in the brain.

John Worsey: Yeah.

Arthur Butt: At a very constant level. And if potassium in the brain fluctuates, the nervous activity fluctuates. And we can't allow that to happen. And it doesn't normally happen. It only happens in diseases such as epilepsy.

John Worsey: Right.

Arthur Butt: Where we get to see synchronous activity all over the shop.

John Worsey: Yeah. And that's the-- that's the symptom of...

Arthur Butt: Other causes the seizure, the synchronised activity. That doesn't normally happen because the n--astrocytes to keep in this potassium. But when they lose this particular channel it stops working, we can get what's called focal epilepsy. So we get a wave of seizures coming from this point where the astrocytes don't work anymore. So a lot of the work that I did, fundamental work, describes how those cells actually regularly do that.

John Worsey: Right.

Arthur Butt: Of course, we know how-- what happens when it goes wrong. So somehow we have to figure out a way of stopping it from going wrong.

Anna Rose: Arthur also explained the role glia play in paralysis after spinal injury. He teamed up with spinal injury experts at King's College London to bring the two worlds together.

Arthur Butt: When you damage the CNS, the brain and spinal cord, a scar forms.

John Worsey: Yeah.

Arthur Butt: And that scar is formed by astrocytes, the star cells. They make the scar. The scars function is to protect the rest of the tissue.

John Worsey: Right.

Arthur Butt: Because otherwise what you get-- with the damage, you get this area which is damaged.

John Worsey: Yeah.

Arthur Butt: It releases toxins and that kills the cells next to it. They release more toxin and it just spreads.

John Worsey: Yeah.

Arthur Butt: So what the glia do is come in and they form this wall, a barrier to stop that from spreading. So it's protective.

John Worsey: Yes.

Arthur Butt: But the problem is that it also stops axons these wires from regenerating. So the research that we're involved in there is how can we control this scar? So so we thought well, instead of looking at all these individual little avenues, networks, we thought, well, this hit this one and see what happens. One of the key inhibitors of this is lithium. Lithium, we might know because it's the frontline treatment for bipolar disorder.

John Worsey: Yeah.

Arthur Butt: So we thought, oh, we'll try with that. Lithium it's off the shelf.

John Worsey: Yeah.

Arthur Butt: Everybody knows how it works. Let's just try it. It had an absolutely profound effect on the glia. And then when we delve deeper into it, we discovered that it was so basically new psychiatric diseases such as bipolar, schizophrenia and depression, etc. So this is an imbalance in the brain.

Anna Rose: And in the course of exploring the role of glia in one thing, Arthur and the team suddenly discovered a connection between astrocytes, one of the types of glia and a possible host of psychiatric conditions.

Arthur Butt: Because all of a sudden we've made this discovery with lithium, it was like this is relevant. And actually relevant in neuropsychiatric diseases. It's relevant to that spinal injury, which is why we got into it in the first place, which is highly relevant to neuropsychiatric diseases because one of the reasons we proposed that lithium works.

John Worsey: Yeah.

Arthur Butt: Is because it controls astrocytes. And nobody had ever thought about that. And then we came up with some drugs which mimic the effect it would come out the way we discovered-- the way – discovered is a big word but in this case, I think we really did. Before this, nobody had ever thought about it. We've discovered another enzyme in astrocytes which had never been identified before. And this controls how astrocytes respond and how they grow. And we've just published that.

Anna Rose: An incredible breadcrumb trail of discoveries all through Arthur's curiosity towards one group of cells. It makes you wonder what mysteries of our own bodies we are yet to discover and how science with the right funding can make huge leaps in our collective knowledge and understanding. Arthur's discoveries could have implications for so many people living with little-understood diseases as well as some of the biggest.

Anna Rose: You can find out more about Arthur and his glial research group at port.ac.uk/research. Next time on Life Solved from the University of Portsmouth, the humble sea creature that could save our coastlines, waters and marine environments.

Jo Preston: One oyster can filter 200 litres of sea water a day. The impact they can have on water quality is phenomenal if they're in the high enough numbers.

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