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Can we repair the ageing brain?
Professor Brian Cox and our expert panel explore the science of Alzheimer’s, Parkinson’s and other conditions that cause dementia.
More than 55 million people around the world are living with dementia, with the number set to rise in ageing populations. How close are we to effective, affordable treatments? What are the genetic risks? Can we prevent it developing?
The panel takes a deep dive into dementia research and where it’s headed, from early detection to the latest drug trials and whether diet, exercise or even doing puzzles like Sudoku really make a difference.
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Brian Cox: Hello, I'm Brian Cox and this is "A Question of Science" here at the Francis Crick Institute. In each episode we assemble a panel of world-leading experts to tackle your questions about some of the biggest scientific challenges we face today, from who owns space? That's really one of them. Who owns space?
To the nature of consciousness, the future of fertility and the science of ageing. And today we're talking specifically about the ageing brain and what happens when that ageing process goes wrong. It's currently estimated that there are around 55 million people in the world living with dementia. But that figure is set to triple by 2050. To put that into context, that means that someone develops dementia every three seconds. Today I'm joined by a panel of experts who all look at different aspects of this vast subject as we ask, can we repair the ageing brain? So let's introduce our panel.
Bart de Strooper: Hello, everybody. Nice to be here. I'm Bart de Strooper, and I'm a professor in Alzheimer's research. I work here in the Crick, and I try to understand how this devastating disease initially starts with little changes in the brain and what connects the different steps to each other.
Julie Williams: Hi, I'm Julie Williams, I'm a professor in Cardiff University, and I've spent most of my career trying to identify genes that increase your risk of developing Alzheimer's disease. And more lately I've been looking at what those genes tell us about mechanisms and potential therapies.
Rory Cellan-Jones: Hi everyone, I'm Rory Cellan-Jones. I used to be a BBC technology correspondent for many years. Now I write about health and technology on a Substack called "Always On." And I co-present a podcast called "Movers and Shakers" which is all about living with Parkinson's, which I've been doing since 2019.
Sonia Gandhi: Hello, I'm Sonia Gandhi. Thank you for having me. I'm a professor of neurology and I'm a clinician scientist, so I look after people with neurodegenerative conditions, including Parkinson's. And here at the Crick, I run a research programme that tries to build models of the human brain and try to understand what causes Parkinson's and how we might more effectively treat it.
Brian: And this is our panel. Sonia, could I start with, it's a simple sounding question. I suspect the answer isn't simple, but we'll start with the definition. What is dementia?
Sonia: Yes, not so simple. So I mean, as we age, we know that there are changes that happen to the brain. There are structural changes, there are changes in the network and how the brain is working, and that at a cellular level there are changes in how the brain's trying to adapt to the many years that it's been functioning. And age is a risk factor for dementia. And what ageing does is make us vulnerable to dementia. So what is dementia, then?
Well, dementia is really an umbrella term we give to when there's a change in memory or reasoning or language or behaviour that really changes our daily life. Now, that's an umbrella term given, though, to a number of conditions that cause dementia. So the four conditions that really cause maybe 99% of dementia are Alzheimer's disease as the commonest, what we call vascular dementia, which is when the small blood vessels of the brain can clog up. That's closely followed in frequency by dementias associated with Parkinson's disease and its related condition dementia with Lewy bodies disease. And then finally a less common one, but one that causes problems with language and behaviour, is frontotemporal dementia.
Brian: And, Julie, is it inevitable?
Julie: No, I don't think so. I think what we're finding is that there are predispositions and we can identify those through looking at the genetics and in combination with environmental factors, that pushes you into a liability to develop these diseases. So not everybody will develop these dementias and there will be individual susceptibilities, and we're now beginning to understand more about what they are.
Brian: And, Rory, you mentioned you've been living with Parkinson's since, what, for about six years now?
Rory: Yeah, yeah.
Brian: Could you say a bit about your experience?
Rory: I first noticed something wrong in the summer of 2018 when I was on holiday with my wife in Italy and I kept dragging my right foot, and she, being quite a brisk woman, said, "Pick your feet up, boy." And then we began to realise it might be something more significant.
And in the following January, I was diagnosed with Parkinson's, which, I love this word, progressive. It sounds cuddly, doesn't it? But it is progressing. I've got a tremor, and one of the things that happened was I was live on breakfast television. I didn't know it at the time, but my hand was shaking. It shakes worse in moments of stress. It shakes quite a lot at football. I'm a Brentford supporter, and they make me shake.
For the first few years, I kind of thought, well, this isn't so bad. The last couple of years, it's begun to affect my gait a lot more. I've begun to develop that sort of slightly rigid look sometimes and shuffle a bit. So it is progressing, but it's managed with drugs.
And the good thing about it is it's given me a whole new interest. I spend a lot of time talking to people like Sonia, trying to understand what's happening inside my brain and what might be done about it.
Brian: Well, thank you. And, Bart, just before we go to the audience questions, we've used this term, dementia, and defined it in a clinical sense. Is it helpful? And I suppose I'm thinking scientifically, is it helpful to just use a single word?
Bart: Yeah, I think, in fact, it has put us on a very wrong foot for many, many years, this focus on dementia, which is in fact a symptom. And so people want to cure dementia, people want to understand dementia. We have a programme on dementia. And so that deviates you, in fact, from the question, what causes dementia?
For instance, clinical trials for drugs, it's a request from the government that they show an effect on the dementia. And the consequence is that all these drugs are tested in people who live with dementia. Even an early form of dementia is a late step in the disease. And so then the therapy doesn't work, but the therapy is focused on a process which is in the beginning of the disease, which we start to understand. And at the time that the dementia is there are 10, 15 different processes busy. And so you silence one process, but you don't do anything with the other ones.
And so in that sense, the research has been misled, the therapeutic developments have misled. I'm happy that we have these debates, in fact, because dementia has been for a long time a taboo. People didn't talk about it.
Brian: That leads us quite nicely, actually, to the first question, which is a question about how or when the brain begins to deteriorate.
Rae Kane: Hello, everyone, my name is Rae Kane, and I want to know if it's too late to prevent or delay Alzheimer's or dementia after a certain age, say, from the age of 55 onwards, if someone thinks they've had mild cognitive impairment symptoms for quite some time.
Bart: Yeah, I think it's never too late, but it's a very good point and it fits with what I said. What you basically want to do is to prevent the damage on the brain. So if you can interfere before neurons die, or when, before synapses, the connections between the neurons are dying, if you can do that, then you will probably maintain people completely normal, cognitive normal.
So if you are already in a phase that there is damage, then the aim should be to stabilise that. And so even with the therapies, which mainly work in the beginning, if you give them at a later stage, it's not like in your brain all these things happen in parallel. So the places where there is some initial damage, you could block the process. You will keep those neurons longer.
Rory: But what I don't understand is how you identify people who are going to develop serious symptoms before those symptoms are evident.
Brian: Julie.
Julie: I think over the last 10 years, the genetics of Alzheimer's disease has taught us many lessons. And we can actually predict with about 80% accuracy those that are going on to develop Alzheimer's disease. So you can do that at the age of 30, 40. What we don't have are the preventative therapies yet to get in there before there is damage.
Sonia: I mean, I think we need to move away of thinking that these are conditions of older age. They're not. They're diseases of middle age that manifest with their symptoms at older age. So, of course, what we're seeing at the older age is the end of the process.
That's really important because biologically you can't engage with the end of the process. You can only engage with the beginning. So mild cognitive impairment, of course, is one of the earliest stages, but there's a stage even prior to that.
So our challenge, I think, for Alzheimer's, but especially also for Parkinson's, is to be able to identify people before they've presented to a doctor. Now, we know that, we call this the prodromal phase, that there's a collection of high-risk symptoms that affect sleep, or how your bowel works, your sense of smell, that together tell us the risk of converting and developing a condition like Parkinson's. And in that phase, there isn't significant neuronal loss in the brain. And those are the phases that we would need to focus on for treating.
Brian: And that actually really does fit nicely with the next question, which is about diagnosis.
Veera Panova: Hi, I'm Veera Panova, and my question is, will the signs of neurodegeneration be less noticeable and therefore more likely to get ignored in people of high intellectual ability?
Bart: Absolutely. I mean, that's really something which I say every time I engage with the public. It's sometimes said that people who got higher education have a protective reserve in their brain.
The cognitive tests you do for Alzheimer's are little exams. You get a question, you need to answer. And so people who do university and higher education are trained to follow- to solve this type of exams.
And so I think if you would ask a taxi driver instead of filling in an exam and ask him the way in London and do a test there, they would be saved from Alzheimer's disease for many years. But of course we think that it's more important to be able to answer what day it is and four words after each other.
So it's absolutely a mistake. I think that we need to come away from that type of thinking and that we need to try to objectivate what happens. So measuring the changes in the brain quantitatively, measuring electrophysiological activity, instead of doing these exercises, we need measurements of your brain function.
Rory: One of the huge problems I've learned about Parkinson's is actually measuring it. The doctor makes you walk up and down outside his corridor, he pulls you back, he makes you get up out of the chair. It's very crude, and without better objective forms of measuring the condition, it's for instance, very difficult to get a drug through the clinical trials.
So the difference between the drug and the people who are taking the placebo group, their results can sometimes be quite close, and you know, without a precise measurement, we're never going to get anywhere in deciding what works and what doesn't.
Brian: What technologies are you talking about that would give you an objective view?
Bart: If you think about Alzheimer's, it's defined by accumulation of strange proteins in your brain which are called amyloid plaques. And that's followed by a second strange accumulation of proteins which are called tau tangles.
And so we can measure that now with imaging. But so what we see is that people who go from this accumulation of amyloid, which doesn't give you signs, towards the accumulation of the tau, that all of a sudden in your blood there is a protein which appears, phospho-tau 217, and you can measure that.
And so there are indications in the drug trials, if you have patients which have not evolved into this tau phase already, that you can lower that phospho-tau, so you can basically see the effect of your drug without having any measurement of cognition, etc.
The other side is what you are asking for is can we develop better objective systems to measure brain activity so that we can measure inside the brain? And the answer was always no. And then I'm saying, we can measure signals from a zillion years ago from the cosmos, and we wouldn't be able to fine-tune these activities.
Brian: 3.8 billion.
Bart: Exactly. But I didn't dare to say how difficult it was. But so, I mean, we need to have these electrodes on the head, and we need to be able to see how your brain works at 40 and then at 50, because the brain is extremely good in misleading us.
The third thing I have to say, and then I will stop, is that, yeah, it's my hobby actually. So the third thing is that you need to follow that per individual, because there is nothing more different than a brain.
Brian: Let's turn now to what might be causing these diseases, and specifically one area that's gained a lot of attention in recent years, our immune system.
Fiona Petit: Hi, my name is Fiona Petit, and I'm wondering what role our immune system plays in causing dementia and whether targeting inflammation could be a game changer in prevention.
Brian: Julie?
Julie: Yeah, I think one of the major things that the genetics, the genetic results have shown us, and we know we have 90 genes that we know confer risk to developing Alzheimer's disease, is one of the big things that came out was that our immune system was implicated and different aspects of our immune system, inflammation, what we call the complement system.
There are several genes that implicate that. And there are people now that are using drugs that are already used for complement in the body to get it over the blood brain barrier, which is a challenge, so it gets into the brain. There are other elements also that are coming out of the genetics, but the immune system.
So I think Alzheimer's disease, to me now, has a large autoimmune component, because it's our own immune system that is actually destroying some of the synapses and tissues that we see. And I think that gives us scope for multiple treatments. And a lot of the genes that we have found are expressed in this cell called a microglia, which is a clever little cell. It has its own little patch of the brain that it keeps clean and tidy, gets rid of toxins.
So there are differences in the way this cell operates that has direct effects on Alzheimer's disease. And we are now beginning to understand what those look like. They affect the amyloid plaques. They make them more compact and less inert if you have a protective factor. They are associated with protecting the synapses, which we have talked about as the connections between the nerve cells.
So we are now beginning to get a handle using the genetics as a basis, understanding disease mechanisms that we can look at treatments.
Brian: Sonia.
Sonia: So when we think about inflammation in the context of neurodegenerative diseases, it's a little bit different. It's not the a typical immune system disease, but what we do know is that ageing that we've thought for a very long time has been more about, and it still is, how we generate energy and how that declines over time, or how we clear misfolded proteins from the brain and how that declines over time.
In actual fact, there's a concept called 'inflammageing', which is this low level of chronic inflammation which affects us as we age. And it means that we don't respond quite so well to the environment. We may mount an inflammatory response, but we don't recover it back to baseline, which means that when we see another inflammatory insult, an infection, surgery, for example, our immune cells, such as the microglia, don't respond in quite the same way.
So we've come to understand that actually aberrant inflammation happens in ageing and then in the immune system of people who are susceptible to neurodegenerative conditions, there is this interplay between inflammation, as Julie just talked about, but also protein misfolding, which Bart talked about, which is a really major feature of all degenerative conditions, where proteins start to become insoluble and collect and misfold. We're seeing this interplay between protein misfolding and inflammation in all neurodegenerative conditions, actually.
So the genetic basis is much stronger in Alzheimer's, but actually even in Parkinson's as well at the earlier stages, we're seeing that misfolded proteins and environmental insults lead our brains to develop these inflammatory responses, which we think are abnormal. One thing we haven't discussed yet is that everybody's very different with their different condition. We've talked about dementia being a progressive illness, and there's more and more loss of cells in the brain over time. But that trajectory of progression is very different from individual to individual.
And so we need to understand what drives certain people to have fast progression, develop cognitive problems earlier, for example, versus the ones who are actually going to have slow progression and be fairly well protected and can be managed differently over time.
Brian: We do have a question now, actually, about genetics, or, to be more specific, the heritability of different diseases.
Roberta Tiberi: Hi, my name is Roberta Tiberi, and I want to know how concerned should I be about developing Alzheimer's or Parkinson's, given that several relatives on my mother's side were diagnosed with these conditions in their 80s. Are these diseases mainly genetic, or are there steps I can take now in my 50s, to reduce my risk?
Brian: This is your field, Julie.
Julie: So there are probably thousands of genes that confer susceptibility to, let's take Alzheimer's disease. So the fact that members of your family may share some of those genes, they will not share only a proportion of those with you. And because Alzheimer's disease, from the genetics we can see, is made up of multiple components, I mean, everybody in the audience or some of us, may have one of those risk components, risk pathways. Some may have two, but you may need three or four to develop the disease. So it's by no means definite that you have a family history that you will get the disease. In fact, the majority of people that present with common Alzheimer's disease don't have a family history.
Sonia: Just coming in for Parkinson's disease, so we think about the genetics in two ways. There is the form that runs through families because those families will carry mutations in a gene that is passed down from generation to generation, but that only accounts for 5 to 10% of all the cases of Parkinson's.
And then there are the common changes that we all carry in our genome, which puts us at risk in the way that we inherit our risk to high blood pressure or risk of diabetes or risk of asthma. And that risk probably accounts for another small percentage.
So we think in the Parkinson's world that heritability is roughly 30%, whether it's the small risk or the large risk. And that means that the rest of it, 70%, is about our environment. And because that's a huge proportion, I would say that all of those, hopefully someday will be modifiable.
Brian: We have a question now from Dee Kemp. The question is, does physical exercise have an impact on brain health?
Sonia: I would say for Parkinson's, which starts as a motor condition, then the question in our field really is, is it disease-modifying? Can it actually change the brain and the brain structure and the abnormalities in the brain in a tangible way that actually reverses or prevents progression? Clearly those sorts of studies are very, very difficult to do. Exercise-based trials are really difficult. But there are some signals that exercise, especially sort of strength-based exercise, switches the way in which the brain metabolism works. And that in itself is protective for brain health.
Brian: And beyond the general, I suppose live a healthy lifestyle is good advice in general, but because we hear things, don't we? People will say, "Well, I could take this supplement or I could eat these particular foods and that will help brain health, or do these puzzles on the iPad or whatever it is." Is there any sense, Bart?
Bart: Well, it's a very dangerous part which makes people paying for things, and based on non-scientific claims, I would like to stay very far away from it. It's obviously good to do some exercise, it's obviously good to have balanced food. And all these things are just general advices to keep yourself healthy. And so the brain is part of a body, and if you keep your body healthy, your brain will be more healthy.
And so don't go in any direction at this moment fanatically. Don't start to take one type of vitamin, for instance, because every study tells you that variety in what you do and in what you eat is the best way to keep your body healthy. So I'm very sceptical about all those studies. They're also much more easy than real science.
Sonia: I think. I mean, it's the commonest question I might get asked in clinic is about, should I take vitamin X? Just to highlight the difficulty that we have as clinicians and scientists in resolving this. So somebody goes and measures the level of a vitamin, or in a whole load of people with Alzheimer's or Parkinson's and say it's low, and that generates a hypothesis that is that low level causing the condition or is it a consequence of the condition?
Then what we might do as a group of scientists is take it to a model system, a cell in a dish or an animal model, and give that vitamin X back, and say, "Well, look, it protects," or, "It's toxic." But then we do the most difficult and messy experiment, usually not very well, which is then to give vitamin X to the human, which, with a condition and measure some very late stage phenomenon such as memory. And we do this in an underpowered and not very useful way, and we end up with just terrible evidence.
There are lots of papers suggesting vitamin X is very helpful, but in reality, we're unable to make the recommendation because that science has just not been conducted in a way that's robust enough for us to be able to put it into policy or advise people.
Bart: There's a beautiful paper just published about lithium. That's a good study. That's interesting. I'm actually thinking to take some lithium, but it's also for other conditions.
Brian: Rory, I mean, so Bart said there that as a scientist, he reads papers and he did see one and he thought, "Oh, lithium, I might take lithium. That's interesting." As a journalist, did that lead you to do research into your condition? Have you become interested?
Rory: Yeah, I mean, what is very frustrating for people with Parkinson's is that every time there's a story in the news, our inboxes fill up with lovely relatives and friends saying, "Look, there's this." And you go, "It's deep brain stimulation with a new twist. So what?" You know?
What's really frustrating is how long it takes to get anywhere. There was a drug that there was a whole lot of hope for, called Exenatide, an existing diabetes drug that got to phase three which is the final phase. Huge expectations. And then last autumn, the results were it failed. And I looked back and this existing drug, tests had started on it in 2008. So 16 years to get nowhere. And that does make one tear one's hair out.
Bart: But it's part of the nature of science, huh?
Rory: Yeah, but if enough money is thrown at a particular- I mean, look at what's happened with HIV. There, a huge effort was made and it had results.
Brian: Yeah.
Bart: I agree with that. My mother had Alzheimer's disease. And then people, which are always very friendly, they say, "Wow, that must be frustrating that you didn't find anything. You work your whole life on this disease."
And I was thinking, yeah, there is some truth in it. It's very frustrating. And then why do we see all these revolutions in cancer?
I went to the big database of all published literature, and I put in cancer. I got 5,400,000 publications. I did the same with neurodegeneration. I got 350,000, and I checked it two or three days ago. It's still the same. That means that we know 18 times more about cancer than about neurodegeneration. And there are equal numbers or even more people with dementia.
So that's decades of underfunding, which explains this, and that's the root of the problem, that if we would do the same type of investment as we have done with the war on cancer, then I would say that we would have already a panel of medications. And that's something which is not said a lot, but it's the truth.
Sonia: And we know that to go from a discovery in a laboratory to an effective clinical treatment is roughly 15 years. 15 years is a very long time in anyone's condition. And it doesn't always have to be slow. So we call that process translation, of going from a discovery through to it seeing its impact. But translation can happen rapidly.
And we know that because during the pandemic for SARS-CoV-2 and COVID-19, okay, it's slightly simpler. There's one pathogen, one virus causing one disease. But at the same time, when there's the will and the funding and the team effort, you can make a diagnostic test, you can make a prevention, and you can find some curative drugs within a year.
Bart: But it's not only the science. The reason that this clinical approval takes so many years is the risk aversion in our societies. The last thing you want to do in a clinical trial is having somebody dying. So over the years, we have made a very complicated legislation to follow that.
And that's a big, big slowing down of research. And I don't know how to solve it, but it has created kind of monopolies for the big pharma to do these clinical trials because they are so expensive.
Brian: I think you should become Prime Minister. Please solve it.
Julie: There may be an opening.
Bart: I think I would be quickly fired.
Brian: We have another question on ways in which the environment might contribute to the onset of these diseases.
Sarah Adams: Hello, I'm Sarah Adams. The digital dementia hypothesis suggests that an over-reliance on digital devices can impair cognitive function and therefore increase dementia risk. What does the current evidence suggest about digital habits and the causes of dementia?
Brian: Rory, actually, maybe as a technology correspondent, you have something to say.
Rory: As someone whose wife is always telling him to put his bloody phone down at the table. I'm very, very dubious about this. It just seems incredibly convenient. There is a huge moral panic about screens at the moment, some of which is okay, but, well, I'm not a scientist. We've got three, four amazing scientists here. God, I nearly fouled up there.
But I suspect also it's far too early in the development of these digital gadgets for there to be evidence that they give you dementia. But I would be extremely sceptical.
Brian: And Bart, I guess your answer is going to be the same.
Bart: Yeah, I think it's, first, much too early to decide anything. Second, it's a good fashion at the moment to bash on all these apparatus. Brain is a big organ which allows us to interact and communicate with other people and to keep our body working.
And so while you are sitting here, you do much bigger exercises for your brain than whatever puzzle or whatever equation you are solving. At this moment, you are breathing, your brain is controlling that, you are listening. That's a miracle. You have to think about what happens here. I'm moving a little bit of air that goes to your ear, that's converted into some vibrations in your ear. These vibrations are converted into electrical activity. This electrical activity goes somewhere in your brain. It's processed, it goes to another place, and then all of a sudden that other place transforms this electrical activity back in words and in understanding.
You are all doing that, hopefully. On top of that, you see me a bit more moving with my hands. It's my Italian background, I like to think. That's all happening at the same time. On top of that, a little bit of exercise is not going to change. So my advice is, if you want to keep your brain healthy, interaction, communicate is the best exercise.
Brian: Well, I think you also said that just living is such hard work.
Bart: Yeah, exactly. No, it's funny, it's fun, but it's the best exercise.
Brian: Let's go to a question now which we partially touched on.
Bala Patel: Hi, my name is Bala Patel. As people are living longer, the chances of developing dementia from an ageing brain are greater. What medicines are in development and how will they work?
Brian: So, Sonia, I mean, we mentioned that it's painfully slow sometimes to develop drugs, but in terms of drugs that are now in development, maybe close to market.
Sonia: In the Parkinson's field, we have, there's been a huge development in symptomatic therapies, which can be surgical or developing stem cell transplantation and so forth. And we restore the neurotransmitter that's lost, which is dopamine.
But in terms of slowing the disease process, that loss of neurons, what we call a disease-modifying therapy, there are many coming through the pipeline that are addressing these biological mechanisms. So about 20, 30 years ago, we only knew of about one or two molecules that were causing the condition. Now we know at least 100. So we're closer to developing therapies that either remove the notorious misfolded protein, in Parkinson's it's called alpha-synuclein, or therapies that are targeted towards inflammation, or therapies that are trying to address the way in which the brain's metabolism works, so insulin resistance. We have different classes of drugs now coming through the pipeline.
They're at phase two. Phase three is the stage at which we would test it on hundreds of people to get what we call a randomised control trial against standard of care to get the result that would allow that drug to progress into the clinic. So we're still a little bit far from that because there are very few phase three trials globally. But there are many of these drugs targeting these new mechanisms that we're finding in the laboratory at phase two.
So I think that's quite hopeful, in my field in Parkinson's. I think the Alzheimer's field has opened up really a huge amount.
Bart: I really think that we have seen the first breakthrough in that field. These are antibodies. So it's a very expensive way of developing therapy which you inject in the bloodstream and infuse, and then they go to the brain, and they bind to the amyloid plaques in the brain, these protein accumulations which initiate the disease.
And by a trick that enhances this inflammation response, that starts to help these cells, the microglia cells, which we mentioned already, to start to clear these amyloid plaques. That works in 90% of the patients which get that medication. And if you get that treatment early in the disease, there is a good chance that you will be stabilised for several years. If you get it later in the disease, when you have already clear symptoms, then you can postpone the disease and slow down it.
The mean in the study was 20-30% slowing down. So they declined still. But that's a mean. And so that's why I'm optimistic. If you can move it forward, we will see probably a bigger declaration between these two. So that's the situation at the moment. So these are the first drugs which do something on the disease. That's very clear, that's proven, but the effect is too little that we also agree, but it does something on the disease.
America and Japan have it on the market, China also. In UK, they have been approved earlier to be used on the market, but again they can only be used in private clinics. So that means that a whole group of people will not be able to use it. And so the problem with that is how much do we win with such a slowing down of the disease? Is that keeping people longer out of the hospital, et cetera, can we save on care, et cetera. And if that is in a good balance, then these therapies will be made available for everybody.
But I find it a very interesting societal discussion. I think if this would happen in cancer or in another area, a drug which works and which is not offered to everybody, that would have a bigger discussion than we see in the Alzheimer's.
Brian: Do you share Bart's frustration? Eloquently expressed frustration. Not only at the amount of investment in the R&D, but the trials process. Is that unanimous on the panel? Because it's interesting to me, if it is unanimous that we're too slow at bringing potentially useful drugs to market, too risk averse, let's say, who is it who needs to speed that up? Because you're the professors.
Sonia: One of the inherent problems with clinical trials is that everybody declines in the trial. And what we're looking for is for people to decline less. And in fact some of those targets are 30% less. So you can imagine that's an incredibly difficult thing to do.
The other thing we haven't talked about is the conditions are slow. Actually deterioration is quite slow. So you have to run the trial for quite a long time before you can see that slight difference in progression. They're actually quite a lot harder, for example, than cancer trials are, to do. The way trials are generally run is there's a large gap between each phase of the trial. The company running the trial will dismantle all the machinery around the country and then wait a few years and build it up again to do the next phase of the trial. That can take 10 years.
So the whole clinical trial system is a bit broken, but there are changes. And certainly in the UK, what we're trying to do very much is, for example, run phase two and phase three close together, where we can engage what we call platform trials, which are ways of testing multiple drugs at the same time against one control or placebo arm. And in those trials where you have multiple arms against one placebo, you find the answer a lot quicker.
And then there are innovative trial designs, we call them adaptive trials, which learn as they go along. So you might stop it at one year, and then pause and see if there's an effect, and if there isn't, you drop it out and take a new drug on board. So we're launching these very large trials for Parkinson's, but it's been a very, very slow process to get funders and people to come on board with this. But the biggest solution to the trial would be what you have in Alzheimer's disease, which is an objective biomarker, to know that the drug that you've given is improving something other than the patient's symptoms.
Brian: We've almost run out of time, but I'd like to get one more question in. So we've been talking about drug treatments, but this is a question about different potential treatments.
Harry: Hi, I'm Harry, and I'd like to know which of the following therapies show the most promise going forward: stem cell therapy, focused ultrasound, or deep brain stimulation?
Rory: I've written about all three of them. And stem cell therapy, there is an extraordinary tale because it begins in the late 1980s, and it's a continual roller coaster of, "Hooray, it's working!" "Oh, no, it's not." "Hooray, it's working!" "Oh, no, it's not." And just at the moment, we're in a hurray, it's working stage.
So that is hopeful, but it's incredibly expensive and it's been going a long time. Focused ultrasound is really aimed at more benign essential tremor than Parkinson's, as far as I can see, or at least it's for only a subset of people with Parkinson's. And it's a kind of substitute for deep brain stimulation.
Deep brain stimulation is probably the most interesting thing that's come along besides Levodopa over the last 50 years. These people will tell me whether I'm right or wrong. And it's getting more sophisticated. They're now getting something called adaptive DBS, which means it sort of modulates itself. And that is a good advance. But am I right in thinking that, I mean, none of them is disease modifying, is that right?
Sonia: So what happens in Parkinson's, there's a circuitry failure that begins in the midbrain and that projects neurons to the striatum, which is part of the brain that deals with movement. But that's not the only part. Parkinson's is a multi-system condition.
We know that if people live long enough, they will go on to have the condition affecting parts of their brain that deals with memory and thinking as well. Not everybody, but a percentage will.
So deep brain stimulation stimulates that circuitry that deals with movement. And it's pretty effective for suppressing tremor and also for managing some of the involuntary movements that people can develop called dyskinesias.
But what it can't do is modify what will happen to other parts of the brain, the non-motor features, for example, the cognitive impairment or the sleep disturbances, or any psychiatric phenomenon. Now there are stimulators that can sense the brain's natural electrical rhythms and then adapt the amount of stimulation they give in a very personalised way. So actually the technology for deep brain stimulation is really progressing, but it's a symptomatic therapy.
Stem cell therapy, we've talked a lot about, one of the biggest problems is it's just too late. Once neurons have died, you can't restore a neuron. A neuron is there from birth. It will survive for as long as it's going to survive, 80, 90 years. But once it's dead, there is no drug that can bring that back. So that's caused the circuit to break down, if you like. So the idea of stem cell therapy is that we use stem cells which have the capacity to become any cell in the body, and we make them into the precursors of the dopamine neurons or the neurons that specifically have died in Parkinson's. When you inject that into a part of the brain, some of them go on to form the circuit that's been lost.
So it's pretty amazing, right, that we can even do that. And it's looking very, very promising that some of that change in circuitry, what we call restorative or regenerative medicine, is actually beneficial. But again, it's beneficial for the motor symptoms. Doesn't change the overall course of the condition as it plays out over 20, 30 years.
Brian: Julie.
Julie: Well, I think there is another therapy that we should mention, which is gene therapies. And there are gene therapies out there, mainly for single-gene disorders like Huntington's for example, with Huntington's you get a sort of stutter in the DNA. If you have 30 stutters, you get Huntington's disease basically. And there are therapies out there to cut this gene in the right place, and you've got apparatus that tells you where to cut it.
That may work, but these are going to be for single-gene disorders. For common disorders like Alzheimer's and to some extent Parkinson's, gene therapies are going to be very difficult because you've got genes, a very small effect, you're going to have to put combinations in and that's going to be too challenging.
Brian: You're essentially switching off or indeed removing a particular gene.
Julie: The cause, you see. So that's what's attractive about it. If you can identify a bit of DNA, a variation in there, that is increasing your risk substantially, if you take that out and replace it with the normal form, you've solved that bit of the problem.
Brian: So how far are we away from really truly understanding that or being able to deploy it, let's say?
Julie: Well, I think at Huntington's, there's a guy in my lab, Vincent Dion, who's doing it. He's trying to get some money together to get it into a commercial clinical trial. So I think it is feasible.
Bart: There's approval in ALS for antisense therapy, which is a genetic therapy for a rare form of ALS. It has been approved actually. So, I mean, it's not only science fiction, it's happening.
Brian: In a previous episode, actually, we talked about cancer research, and that often gets framed. Can we cure cancer? Can we prevent cancer? So in this case, neurodegenerative diseases, can you see a point when these become either entirely manageable to the end of someone's life or indeed you end up being able to just switch them off, essentially? Is that anywhere on the horizon?
Julie: I think with some you will be able to switch them off. Not everything we found as the components of disease are treatable, but on the other hand, you don't have to treat everything to delay the onset to age 90. So I think the combinations of treatments that we will see coming out in the next 10 to 15 years, we will see a reduction in these diseases.
Sonia: I think what we're finding is there are major commonalities across the conditions. So some treatments that are working, protein removal methods that are being deployed in Alzheimer's will still be helpful in other conditions, quite possibly Parkinson's, where you develop later cognitive changes. There's going to be a lot more cross-talk talk across the different conditions to really try to share some of those therapies across them, and I think that will help.
But treatment wise, we're still stuck in the era of one size fits all, and that's not going to work. For cancer therapies, it's a little bit easier in the sense you can take the cancer out, see what an individual has, what type of biology that cancer has, and then target your treatment to that.
Someday, as our biomarkers are improving, we're going to be able to do the same for an individual, to delay, slow down those conditions considerably, and also when we can give them in middle age. I think that's the critical thing, the timing.
Brian: Rory, do you tend to be optimistic about, can you see these treatments, increased understanding on the horizon?
Rory: Well, we all try to be optimistic. I go to a lot of research meetings, and sometimes at the end, somebody puts up his hand and says, basically, "Why can't you all just bloody well get on with it?"
Bart: Exactly.
Rory: And that, I think that is the general feeling. Could you please hurry along?
Brian: Just to finish, the sense I get from you, Bart, in particular, but maybe everybody, is, there is a path to hurrying along, and it's a combination of funding and regulation and so on.
Bart: There is no doubt. It's like the medieval cathedrals. If all these people would have thought, "It will not be in my lifetime," we wouldn't have had these cathedrals. And so the same with this medication. If people like us do not believe that we will achieve this, then it will never happen. And it's maybe a little bit too pessimistic, because I think we are really at the door of breakthroughs. It will really go fast now.
Brian: The cathedral is almost finished.
Bart: The emotion of investing in something which is important for a long term, not because of yourself, but because it's important. That's what's going to drive these diseases to a solution.
Brian: Thank you. I think that's the perfect ending. We've run out of time, sadly, so I'd like to thank our panel, Bart De Strooper, Julie Williams, Rory Cellan-Jones, and Sonia Gandhi. And to you, our amazing audience. Thank you for listening. Goodbye.
