A cure in our lifetime?

Dr Anna Williams from the Centre for Regenerative Medicine at the University of Edinburgh discusses her latest research findings with Al Jazeera’s Stephanie Scawen.

Al Jazeera: So, Dr Williams, tell me a little bit about the work you are doing here at the Centre for Regenerative Medicine and what you are hoping to achieve.

Dr Anna Williams: The thing that we’re very keen to research is to improve the brain’s system of repair. So in MS this is the oligodendrocytes that can form new myelin sheaths around nerves…

AJ: Which is the stuff that gets destroyed in MS and what you need to send messages.

AW: Exactly. You can think of it like the insulation around wires. The insulation falls off, but the brain is good at putting that back. [In people with MS], it’s not hugely efficient, so what we need to do is improve the efficiency of this. And the idea is that if we can put the myelin back, we can protect the nerves from dying back. And we think that it’s the nerves dying back which causes the progressive symptoms of MS.

AJ: Just remind me, oligodendrocytes, explain to me what they are.

AW: So they are cells in your brain and they make myelin, so they make the insulation of the nerve. And they actually do this by putting out their membrane and wrapping the membrane round, a bit like a Swiss roll. So if you have an area of demyelination, then these oligodendrocytes activate and start making more of themselves and they will go and try and repair the brain.

MS has two phases. Most MS patients have relapses – a bad spell that then gets better, initially…

AJ: Yep, that’s me.

AW: … but what happens with time is that the disability doesn’t go away completely, it get’s stuck. And then it starts getting worse on its own, without having relapses.

AJ: I have to say that I’m worried that I might be at that point

AW: But you might still be in the relapsing phase. Initially in the relapsing phase, you’ve got a lot of inflammation going on in the brain. But in the progressive phase, it’s what we call neuro-degeneration, where the nerves and cells are dying back. And the drugs that we have at the moment which are good for MS – and they really are good for MS – are good, are reducing relapses, but they don’t work in this second, progressive phase.

AJ: Why don’t they work in that phase?

AW: Well, they don’t work because they act on inflammation and they don’t help neuro-degeneration. And so we have to have a complete mind shift, a complete change in thinking, about MS. We’ll still be using anti-inflammatory drugs, but we’ve also got to use things that stop nerves dying, which we call neuro-protective therapies. And so this is very much what our centre is concentrating on – trying to build ways to protect nerves.

Now oligodendrocytes are the cells that make the myelin, the protective sheath around the nerve cells, and if the myelin falls off, the nerve cell (axon) is a bit more vulnerable and it starts dying away and we can’t regrow nerves. So what we can try and do is to either protect these nerves to promote their survival or we can try to get the oligodendrocyte system to work better and make the myelin come back.

AJ: Okay, so if you can create a system where you can get the myelin to regrow, will that help the nerves that have died off, or shriveled grow back? Is that possible, or you don’t know yet?

AW: Initially we’re not trying to get them to grow back. What we want to do is stop them dying in the first place. Because clearly prevention is better than cure. What we do know is that if we put the myelin back, it will protect the axons. Because as well as just being an insulation on a wire, myelin actually nourishes them, it provides energy to the axons. So if we can put myelin back, we can protect nerve cells from dying back and it is always better to do that than to try to regrow things.

AJ: Isn’t it the case that when you have an attack and you get de-myelinated areas in the brain or spinal cord, that eventually the attack dies down and the myelin starts to regrow. But eventually that regrowth stops happening at all, or as efficiently?

AW: It seems to fail more with age, but everything repairs less well with age, so it may be partly that. And it may just be because there’s a lot of damage around, that this might actually stop the oligodendrocytes from working so well.

So what we’re trying to do is to improve their efficiency. You need these cells to survive and produce more of themselves, to proliferate and migrate into the areas of damage and actually mature and put down the myelin sheath. And there’s been a lot of work recently trying to find molecules that will improve the maturation and actually make myelin. And we’ve also been doing some work here in the Centre about how to get these cells to go into the areas of damage quicker.

AJ: So if they can get there quickly, then they can start waving the flag, “get here, get here”?

AW: That’s exactly right. And that’s why they are called ‘semaphorins’, using the semaphore analogy.

AJ: So there was a breakthrough about a year ago with the RXR molecule. I’m not quite sure what that is.

AW: So RXR, this is one of the factors that if you manipulate it, you can get the cells that repair, the oligodendrocytes, to work better and you can speed up re-myelination. So this is a breakthrough, because we’ve shown – at least in mice and rats – improved re-myelination after damage.

And the next step is to take this further into drugs for people. And there’s a big list of other targets, other factors that if you can manipulate them, again, you can improve repair of the brain and semaphorins as well. So far the only one in clinical trial at the moment is the first one, anti-LINGO antibodies. So that’s in clinical trial, but the key is to move RXR to clinical trial and some of the others, to enhance our chances.

AJ: So you’ve identified the key elements that we need to focus on. How do you get from saying okay, that’s what we need to look at, to making it into a drug? I have no idea how long that takes or even what the process is. What do you do?

AW: Well if we take one of these factors, let’s take RXR. So we think that if you manipulate the levels of this receptor then you can change how well it re-myelinates. So we test that with oligodendroctyes that we grow on their own, to see whether you can get them to work better. You try them with slices of brain in culture, and then you test it in animal models, and we use mice and rats. And once you’ve convinced yourself it works for that, then you can say, this might work, let’s try and develop a drug for humans.

And there’s various ways of doing that. You can try and do that in the academic world. And there are libraries of drugs that you can just try out, to see if they work. Or you can try and do it with pharmaceutical companies who can have libraries of drugs, who can have high throughput screenings, they can test thousands of drugs very quickly to see if they can act quickly against this receptor. So you can do that, but you have to interest the pharmaceutical companies in doing this.

And then if you make a drug that works, you have to think how to get it to the bit of the body you want. For example, if you take it by mouth, will it just come out the other end, which would make it no good.

AJ: Of course.

AW: So you’ve got to get it into the brain. And that’s very hard to do, because the brain is a very protective bit of the body. We’ve got what we call the ‘blood brain barrier’ which basically blocks things going to the brain, and it will also block drugs. So we have to design drugs that will get across that barrier and get to the brain to tickle the ogliodendrocytes to get them to do what they should be doing.

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AJ: I walk with a stick. Can you and your colleagues here in the UK or anywhere else in the world for that matter find the magic bullet, the holy grail, to make me throw this flipping thing away? And if you can, how long is it going to be?

AW: I think the thing is to have sensible steps. So what we want to do with promoting re-myelination is to slow down people’s need to have a stick, slow down their deterioration, and that’s got to be the first aim. And then we’ve got to improve re-myelination so much that we can stop people getting worse. And ultimately we would love to be able to reverse it so you can throw away your stick, but that has to be third down the line. We’ve got to be realistic.

AJ: So I have to keep my expectations low?

AW: I’d say realistic rather than low. This is very exciting. It’s very hopeful that we can reduce people’s disability in the future. But we have to do it one step at a time. We’ve got to make sure the drugs work, that we get them where we want them to, and they’re safe. For example, there’s no point giving you a drug that helps with re-myelination, if it also gives you cancer.

AJ: I know, why take a drug that makes you sicker in some other area, and that’s just crazy to me.

AW: Exactly. And that’s why it does take time from being able to sort out a mouse, to finding a drug, to making sure a drug is safe for humans and making sure it works in humans, and it does take a long time. You know, anti-LINGO antibodies are the first out of this group into clinical trial. But that’s because they discovered that molecule first and it’s over five years since they discovered it in mouse, and it’s going to human. But it’s still only at the very early stage – is it safe?

AJ: And it might not even be the number one drug that you want?

AW: I think it’s probably unrealistic to think that there’s just one magic bullet here. We will clearly need the drugs for the inflammation, so we will clearly need this. But we’ll clearly need neuro-protective strategies as well. And if you think of it like a two-pronged attack. We’ll need anti-inflammatory drugs and we’ll need neuro-protective drugs, but you might even think it’s a three or four-pronged attack where you might need one anti-inflammatory drug and a neuro-protective drug working that way and a neuro-protective drug working that way.

AJ: Just as a matter of interest, when I was first diagnosed, the neurologist was saying at the time, it might go away but take Vitamin B because that will protect your nerves calm down. He was just calling it myelitis at the time.

AW: Vitamin B was used in the past. I think the one that’s taken over is Vitamin D.

AJ: Yes, we’ve heard a lot about that up in Orkney.

AW: Yes, because I think that Vitamin D has more than anecdotal evidence that it is useful in managing your immune system. So it seems to be useful in directing the immune system into knowing what’s self and what’s foreign. Because what we think is one of the problems in MS is that the brain thinks the myelin covering is foreign and it attacks it. So Vitamin D is helpful for that. And I’m certainly recommending it to all my patients, that they should take Vitamin D living in Scotland.

AJ: The weather was terrible!

AW: I’m sure. And between November and March, we do not get enough UV light to make vitamin D in our skin, and so probably most of the population is deficient in Vitamin D. And of course it’s great for bones as well as MS – and it might also be useful for other auto-immune diseases. So I suspect that we will all end up taking Vitamin D, and I suspect that is useful. What I don’t know – and I don’t think happens – is that I don’t think Vitamin D helps to protect your nerves. I think it is more anti-inflammatory.

AJ: It’s more for the initial stages of the disease?

AW: Exactly. And so I think we need to have at least a two-pronged attack. Yes we need to damp down inflammation, but we also have to promote nerve care, protection of your nerves. And that’s where I think it is going in terms of the very new and exciting research that can improve people’s quality of life in MS. And I think realistically we’ll do it, but it takes time.

AJ: Is it going to happen within my lifetime? Assuming that I live to say, 80.

AW: I think we’ll have drugs that will help this phase of the disease within your lifetime.

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