Alzheimer's drugs & tackling HIV

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1:00Without further ado, this is the Naked Scientist. Hello, welcome to the Naked Scientist podcast. The program that brings you the biggest breakthroughs and talks to the major movers and shakers in the worlds of science, technology, and medicine with me, Chris Smith. And this week, fresh analysis claims breakthrough Alzheimer's drugs don't work, but not all scientists agree. Also, a Norwegian man, known as the Oslo patient, is cured of HIV and a meteor shower to look forward to in the night sky. New analysis has suggested that a pair of recently approved breakthrough Alzheimer's drugs, the Nanimab and Lacanimab, are actually unlikely to offer significant clinical benefit to patients. Researchers said that the impact was well below what was needed to make a difference to dementia patients' lives. But there have been some criticisms about how the study's been conducted.

2:01Tara Spies-Jones is a professor of neurodegeneration at the University of Edinburgh and she's also division lead at the UK dementia research institute. These drugs are for treating early Alzheimer's disease and they're really exciting scientifically because what they do is they actually remove one of the toxic proteins from the brain. So these drugs that were analyzed in the study are all antibodies, so they use the body's immune system and these antibodies target a protein called amyloid and that's one of the two proteins that builds up abnormally in the brains of people with Alzheimer's. So these drugs get into the brain and suck that amyloid out, clearing it from the brain. And what evidence have we got that that makes a difference to the dementia in those patients? There are two of these anti-amyloid drugs, one called the Canimab and one Nanimab. And the evidence for these is that both of them very successfully remove amyloid from the brain and both of them slow-disease progression significantly in gold standard phase three clinical trials. And what that means is people are still losing cognitive functions

3:02or their memory's still getting a bit worse, but people who are taking these drugs that happens more slowly. The problem is it's not a cure, it's not even something that stops the disease. It just makes you get worse a little bit more slowly. And even though they do work technically they're much better than placebo, they're significant, but there's also the risk of side effects. So some people can rarely have brain swelling or brain bleeding with these drugs. So they have risks and the benefits are small. And the new analysis that's been done, who's done it and how have they done it and what did they conclude? So this is a new analysis by a group of scientists in Italy and they didn't generate new data but they looked at the clinical trial data from seven different anti-amyloid drugs. So the two that worked and also five that failed their phase three clinical trials. And what the scientists did is they looked at the data from the clinical trials and they asked when you lump all of these trials together, do amyloid antibodies have a clinically meaningful effect? Are they going to really slow disease in a way that you would notice?

4:04And what they found is that when you look at all these drugs together, they don't have what they consider to be a clinically meaningful effect. In a way, it's a little bit unfair in my view to lump the ones that didn't work with the ones that did, because these drugs aren't exactly the same. They all target the amyloid, but amyloids not just one thing, there are lots of different versions. There's little tiny oligomers stuck together, so we know that two of these actually do work and do slow progression. The other five don't. And when they put them all together, they see that they don't work. But I think there were a little bit of issues with how they analyze the data. Indeed, some commentators have likened the situation to, well, if I was looking at blood pressure medication, there are lots of ways to treat blood pressure. And the end goal is lower blood pressure, which if we look at that, we get a reduction in stroke risk, we get a reduction in heart disease risk. So it's not unreasonable to their mind to say, well, if we look at all drugs that target amyloid in the brain, we ought to get a reduction in Alzheimer's risk. I think that that's a fair point, and there is a lot of genuine scientific debate in the field amongst scientists,

5:06like myself, about should these drugs be our focus and do they actually work? The problem is that they're not all exactly the same, and we've evolved over time. Some of the trials have gotten better and better and better. So one of my colleagues who's a practicing neurologist as well as a scientist said his analogy was, we shouldn't be throwing the baby out with the bath water because just because five of these didn't work. And two did the best estimates that I've seen are that even though they're definitely not perfect, don't get me wrong, these drugs slow progression and the best estimates I've seen are that that would be equivalent of about five more months of maintained cognition before you progress to the next stage. And you can see if you're living with dementia, that might be meaningful to you, right? To have that maintained ability to do some of your activities that you're used to every day or the memories that you have, even five months, although they're not perfect, might be meaningful for some people. So saying there's not a clinically meaningful benefit is tough because it's a subjective term, not objective, like the clinical trial results where you measure cognitive ability, and that's definitely slowed.

6:07Saying meaningful is a bit tougher and there's not a standard and not a really a gold standard for that. Others have pointed out that many of the people we recruit into trials like this actually already have Alzheimer's disease. And were we to have intervened in much younger people who didn't have symptomatic Alzheimer's or be early Alzheimer's disease, then we might have had a different outcome, a much bigger one, and therefore we wouldn't be in this position. Yeah, and that's one of the reasons that the more recent trials probably succeeded, whereas some of the older ones, in addition to being slightly different drugs, we've gotten better and better at identifying who is in that very early stage of disease. You may have heard of the news there, now blood tests that are pretty good at predicting whether you have this amyloid protein in your brain. So yes, I think that it's likely, and most of us in the field think that it's likely that earlier treatment is better, but you do have to balance that with the idea that these drugs aren't completely safe. So do you want to be giving a drug that could have very serious side effects to somebody who for all intences purposes is healthy? But it's a really excellent point because that amyloid builds up in the brain for at least 20 years before, even before symptoms.

7:12So the earlier we can get at the better, we might be able to prevent the disease entirely. And I think in the future we will get there actually preventing people from ever getting disease symptoms in the first place. Is there a risk that an analysis like this could torpedo the field in the same way that about 20 years ago a vaccine was developed for Alzheimer's disease, it led to clearance from the brain of the beta amyloid that's linked to the disease, but it also led to inflammation in some patients and as a result, the trial was stopped. And it caused a lot of hold up in further development of these sorts of therapies, a little caution. Now we've got to be cautious, obviously, but is there a risk that with an influential result like this, it could lead to people backing away, withdrawing investment, withdrawing confidence, and it holds the field up. And in fact, there would have been promise had we persevered. So I hope not. It's so interesting. You brought up that 20 year old vaccine study because all my computer, which you can't see because it's, you know, radio, but podcasts.

8:13I'm actually looking at brains from some of the people who participated in that early trial. And there are many reasons that trial failed. One of them being that about a third of the people in the trial didn't have Alzheimer's. They had a different kind of dementia because we couldn't detect it back then. Anyway, to your point about whether this could torpedo research, I really hope not. I think right now we have a moment in Alzheimer's disease and wider dementia research that's incredibly hopeful. We have the approval of these two new, relatively new anti-amoloid drugs that did past phase three. And they're approved for use in many countries around the world and being used to slow albeit not stop disease progression. By regulators, yes, but not by funding bodies. The National Institute of Clinical Excellence, Nice in the UK, did not give this seal of approval on the grounds of cost effectiveness. But the MHRA, the medicines to healthcare products regulatory agency, they did say, well, this is okay, but they can't go further than that and advise it's used. No, absolutely. And I think those are very good reasons for that because they aren't hugely effective and they are costly and they have risks.

9:13But the next generation of these anti-amoloid drugs that are in trials now are even better and safer and more promising. And we've moved as a field beyond amyloids. So we're not only in my lab, we're in any lab around the world. We're not only focusing on only this amyloid. There are a lot of us looking at other targets that are incredibly promising. So I'm actually for the first time in my career, I've been in Alzheimer's research and dementia research for about 25 years. And I'm really optimistic that we will have really meaningfully life changing treatments in the next decade or so. It's hard without a crystal ball, but the science is really coming along. Tara Spies Jones at the University of Edinburgh and the UK dementia research institute sounding an optimistic note there, despite that slightly despondent response from the Cochrane review about the Alzheimer's drugs earlier this week. To Norway now, where a 63-year-old man known as the Oslo patient has become one of only a tiny number of people to be considered cured of HIV. The patient received a bow marrow transplant from his brother who serendipitously also carried a genetic mutation called CCR-5 Delta-32

10:19that made his immune cells resistant to HIV infection. The study which is published in Nature Microbiology showed that two years after stopping anti-HIV therapy, the man remains free of the infection. The results, as well as similar findings in several other patients from around the world since, are actually making clinicians re-evaluate how we think these sorts of transplants might be curing patients. Historically, we believed it was the genetic mutation that protected the new immune system. And while that might be a contributory factor, as Marius Troside, his infectious diseases doctor at Oslo University Hospital and part of the team behind the new study explains, it's more likely that the new incoming bone marrow derived cells attack the existing virus-infected immune system wipe out the HIV reservoir. So the Oslo patient is a man now in his 60s. He was admitted to our hospital because not because of HIV, but because of a bone marrow disease, so a pre-stage to blood cancer, hematological cancer,

11:25and he needed treatment for bone marrow disease. The first line treatment with, you know, cytotoxic or immunotherapy didn't work, so he needed a bone marrow transplant. So in a bone marrow transplant, you need to get a new immune system from a donor. When our blog specialists were planning to do this procedure, they also looked for a suitable donor in an attempt to also cure his HIV. Tell us more about that because why would a bone marrow transplant cure HIV? So when the Oslo patient was transplanted back in 2019, there were two cases worldwide having been potentially cured for HIV. These two patients had both received bone marrow transplant with a certain mutation and a certain genetic variant that alters the surface on the immune cells. And the fascinating thing about this is this alteration makes it impossible for the HIV virus to enter the immune cells.

12:28So there was a search for a donor with this kind of mutation also for the Oslo patients, but it was impossible to find in the registries in Europe. It was decided that he should get a transplant from a suitable donor for his bone marrow disease and it turned out to be his brother who was compatible with the patients. And on the day of the transplant, it was actually found out quite coincidental that his brother actually carried this genetic variant, this mutation that locks out the virus from the immune cells. So you take someone with HIV, you destroy the immune system they have, and this is also to treat the blood cancer problem. And then you give them back a new immune system using cells taken from a donor, but that donor patient also, in this case, happened to have the genetic change that makes the immune cells impossible for HIV to infect. Right, so we believe it's the new immune system replacing the old one that is actually knocking down the virus in the body

13:37because HIV it hides in your DNA, so it really becomes part of your DNA, part of yourself. So you need to kill the immune cells that carries HIV and then replace it with a new immune system. So probably it's this process that drives down the virus and kicks it out and then you have these genetic variants or this special structure on the immune cells that also makes it impossible for the virus to enter the new immune system. So it's like an extra safety belt that keeps the virus out. So is that what happened in your patient that after the graft, after the new immune system comes in, the virus disappears from the bloodstream and has stayed away? Yeah, so after the transplant, he was still on antivirus medication for two years, but after two years there was no detectable virus in blood. We also looked for virus integrated in the DNA and it seemed to be away.

14:40The immune system was restored to normal blood cell counts. So it was decided then to try to stop his antiviral medication and see if the virus rebounded. And after following him two years without any drugs, we did very thorough analysis to really search for any rest of the virus or if his immune system seemed to recognize the virus. It's not possible to detect any viable virus. So we believe he's effectively cured. And you think then it is the treatment to destroy the existing immune cells that helps but the incoming immune system. You're arguing turns on any vestige of the old immune system and that also helps to just wipe the slate clean and get rid of any possible reservoir of virus.

15:40But when we started out, we thought there was this genetic mutation that would be key to cure. But after we started working with the OSTO patient, they have been two cases now being cured without this mutation. So we believe it's actually the new immune system replacing the old one that is key to cure in these cases. We also did very thorough workup on the OSTO patient doing analysis to see if the new immune system had completely replaced the old one in different organs. I mean, this has been shown in blood and bone marrow previously. But the main harbor for hidden viruses is in the immune system in the guts. The guts really carries the largest number of immune cells in the body. Also there we can show that the immune system have completely erased the old one. It's obviously impractical to treat 30 million people, the current reservoir in the population of HIV infection with a bone marrow transplant.

16:43It's also extremely dangerous as an intervention. You have to have some other major life threatening disorder to balance the risk up, don't you? But what does this teach us about the plausibility of using a strategy like this? Or does it give us clues as to how we might be able to cure people of HIV in the future? I think first of all, it's a step stone together with other cure patients that it's possible to cure HIV. I think that's important. I think we also with this cure cases shown that there are probably different mechanisms that could lead to cure. You have this mutation that I talked about. You're probably also then immune reactions against the viral reservoir, which we can try to mimic in different ways. And third, I think we and other cases have also tried to find log tests that you could take to make it most likely that you're actually cured for HIV. So it's everything from measuring the amount of hidden virus in different places in the body, but also to measure the immune reaction towards the virus.

17:52Really interesting. Marys Troside there at Oslo University Hospital. Have you ever been stuck on a weight loss plateau, trying everything and anything you can to lose that extra weight and reach peak health? We've all been there, but NUME's unlocked a secret to reaching the mountaintop. Go in micro. The NUME GLP1 Microdose program starts at $99 and is delivered to your door in seven days. Start your microdose GLP1 journey today at NUME.com. That's N-O-O-M. NUME. Microchanges. Big results. NUME GLP1RX program involves healthy diet, exercise, and support. Individual results may vary. Meds and personalization based on clinical need, not reviewed by FDA for safety, efficacy, or quality. No affiliation with NOVO Nordisk Inc., the only US source of FDA-approved semoglutide, not available in all 50 US states. The Naked Scientist podcast is produced in association with Spitfire, cost-effective voice, internet, and IP engineering services for UK businesses.

18:56Find out how Spitfire can empower your company at Spitfire.co.uk Music in the program is sponsored by Epidemic Sound, perfect music for audio and video productions. This is the Naked Scientist podcast with me, Chris Smith, and still to come, the Lyred Meteor Show is about to visit our skies. But where do these celestial displays come from in the first place? Before that though, industrialized lifestyles may be changing our gut bacteria in ways that affect how the body processes estrogen and specifically how the gut bacteria recycle and reactivate excreted forms of the hormone back into the bloodstream. Researchers dubbed this the Estrobalome, and looking at microbiome data from around the world reveals that the average westerner is recycling up to seven times as much of their own estrogen, and a formula fed baby twice as much as that of a breast fed baby compared with other populations.

19:58The consequences might be greater risks of certain cancers and effects on fertility. My name is Rebecca Britton, and I am a postdoctoral researcher at Yagen Lonean University in Krakow in Poland. The Estrobalome is a subset of the gut microbiome that can metabolize estrogen. Normally, when your body is ready to get rid of estrogen, it inactivates it in the liver, and it sends it to the gut to be excreted. And well passing through the gut, some microbes living in our guts can produce an enzyme that can reverse that process, so the estrogen becomes active again and gets reabsorbed back into circulation. So instead of leaving the body, it's essentially recycled. And why might that be important? That matters because our estrogen influences a wide range of things from our reproductive health and fertility, to growth and development, and even what we call our lifetime estrogen exposure,

21:04which is linked to certain types of hormone dependent cancers. So if the microbiome, if the Estrobalome, so to speak, is affecting our estrogen levels, it could have both broad and very important implications for our health and well-being. And where around the world were you considering? Anywhere possible we wanted to get industrialized and non-industrialized. We have hunter-gatherers, pastoralists, industrialized groups, and a few others. Right, so you've actually got a really broad brushstroke of how people live around the world. Yes. And when you then begin to look at that, what trends emerge? One was that industrialized populations had much higher estrogen recycling capacity than non-industrialized populations, in some cases up to seven times higher. We also found that formula fed infants, aged six months or younger, have about two to three-fold higher estrogen recycling capacity than breastfed infants.

22:06And then we also found that males and females have similar Estrobalomes within their population. And why do you think you see this in the first place? It could be a number of things. It could be diet, processed foods, physical activity or lack thereof, medicines. It could be early life exposures or lack of exposures to certain things. It could be a number of things or a combination of these things. So we have a current study that is underway right now that is following up on a lot of this and trying to pinpoint some of these factors. Why is it just estrogen, as well, or are there other things that are being recycled in a similar sort of way, which may also have health consequences? Yes. So it's not just estrogen. And in the enzyme that these microbes are producing is called beta glucoronides. And you will find this enzyme of great interest in the pharmaceutical world, because it's not just specific to estrogen. This enzyme is recycling a number of things.

23:09So what do you think the consequences might turn out to be? And why are the men and the women the same? I think that this is probably driven by diet. We can't know for sure yet. But I don't think it's driven by hormone levels. I think that diet is having a larger impact. Otherwise, we would expect even within populations for males and females to differ, right? And they don't. The first part of your question. Therefore, what the consequences might be, because if we've got more estrogen recirculation, including in males, does this perhaps contribute to other phenomena we're seeing in Western societies like declining fertility? There can be a lot of health implications, reproductive growth, development, risk of cancer. In industrialized society, we are already kind of thought of as high estrogen to start with. And then this increased recycling capacity could be a contributing factor.

24:10It could be adding to this estrogen as linked to fertility. If we have too high of estrogen and males that can be linked to fertility, we don't know that this higher estrogen recycling capacity is actually translating into negative health consequences yet. More research needs to be done, but it could have a number of implications. Growth, development, fertility, all kinds of things. So fascinating finding, isn't it? And we'll now have to wait with interest to see what Rebecca Briton's follow-up study is going to reveal. That work has just been published in the journal Proceedings of the National Academy of Sciences. Now, the lyrid meteor shower is one of the oldest of its kind recorded, offering a brief but significant displayed meteors every April, although mainly concentrated over the Northern Hemisphere. It's expected to peak in the coming days when the Earth passes through a stream of debris left behind by a comet called Fatcher, which was first discovered in the 1860s.

25:10I caught up with Meghan Argo, space scientist at the University of Lancashire, to talk about the phenomenon. The lyrid is one of a number of meteor showers that we see throughout the year. So we get the showers at the same time every year caused by a different comet or asteroid in each case. And the way I like to think of it, if you've ever seen something like the red arrows fly overhead when they've got the coloured smoke coming out of the back of the aircraft, when a comet flies around the solar system, it's a bit like one of those aircraft leaving a smoke trail behind it, except instead of smoke, it's little bits of dust and rock that get left behind. And just like those smoke trails dissipate, they get wider and wider and less dense and less dense until they just disappear altogether. These trails of debris do the same thing. And as those debris trails are left in the solar system with the Earth, sort of it happens to pass through one of them. Then those bits of dust and rock that are left behind in that trail hit our atmosphere. And as they do, they heat up quite dramatically, they heat the air around them. And they start to essentially disintegrate and burn up. And that's what we see as a shooting star in the sky. And the lyrids happen in April every year when we pass through the trail of one of these comets.

26:14And this year the peak will be on the night of April the 21st into the 22nd. That's when you'll stand the best chance of actually seeing some of these meteors. So as we see the lights coming down in the sky, we're actually seeing bits of comet burning up. Anything from bits of dust that are the size of grains of sand you might find on the beach, anything up to maybe golf ball sized, the bigger the bit of rock, the brighter the meteor, because the more material there is to burn up in the atmosphere. So the smaller ones tend to be the phantom ones. And in any of these distributions, there is always a range of sizes and a range of numbers of those sizes. So if you look at the statistics of the sizes of stuff, you usually see a lot more of the phantom ones, a lot more of the smaller particles and fewer of the bigger ones. So with any meteor shower, you'll see far more faint meteors than you will bright meteors. So the best chance of seeing anything is to get somewhere away from as much light pollution as you can, so you can see those phantom ones. Do they have specific colours? Does the chemistry of what is in the particle make a difference? Or is it just super heated air as it comes in an interest with the atmosphere,

27:15therefore colour isn't part of it? Colour does vary from meteor shower to meteor shower. Some of them are quite pronounced, so you get some meteor showers where you often see quite a lot of green and it's to do with the chemistry particles in the same way it is to do with the chemistry of what's in the air. So as these are burning up in the air, if you've got a big bright one, then there's lots of material there to burn up and depending on exactly what chemicals there are in the rock, you see different colours. Most often they look white, but sometimes you'll see green ones, sometimes you'll see more of a yellow tinge to them. And talking to the particles, do we know what the origin in cometry terms is of these particles? This particular one is from a comet, which is called comet thatcher, and it's a long period comet. We actually haven't seen it come back since it was first recorded back in 1861. So we know that it's got a long period, and we think it's about 422 years, because we've only seen it past once, there's some uncertainty in that orbit determination. So we're expecting it to come back in the year 2283, so none of us will be around to see it come past,

28:16but hopefully astronomers at the time will see it and we'll get a better determination if it's all but. Why have we not got showers and showers and showers of meteors going around? Why is it just the odd one that seems to do this? Or are comets much rarer than I'm giving them credit for? There are an awful lot of comets in the solar system, we do see them on a very regular basis, with the fact we're finding new ones on a very, very regular basis with some of the sky surveys, and some of the telescopes that stare at the sun off and there are comets that pass through the field of view. The reason we don't see as many meteors showers as we see comets is because the conditions have to be just right for us to see a meteors shower. The comets orbit has to intersect with the orbit of the earth, so that it leaves a debris trail at the earth will then pass through on its next orbit around the sun. Most comets do not directly cross the earth's orbit, they're going in different trajectories that mean they just don't intersect without a path around the sun at any time. And if they never do that, then we're never going to see meteors shower from that particular comet. Probably this is not going to happen for a very long time, but if it is on an earth crossing orbit, there is a small risk that on one of those 453 year-long orbital passes, it could hit us.

29:18It's a very, very small possibility, you're right, there is a risk there. But the comet has to be at just the right point in its orbit at the same time the earth is coming past the right point in its orbit. And given that we think the orbit of this comet, it takes 422 years to go around one complete orbit, and the Earth takes 325 and a bit days to go around its orbit, the chances of them being in exactly the same place are very, very, very small. I shall take some comfort from that. So just before you go, Megan, if people want to see this meteor shower, where do they look and when? It's active over a period of a few weeks, but the night when you're most likely to see a good rate of meteors is over the night of April 21st into the 22nd. The moon will be up, but it will only be about a quarter full. When the moon is brighter, it reduces your ability to see the faint rend of the meteor distribution. So you want ideally, unlike when there's no moon in the sky, but 27% is not as bad as it could be, it's a lot better than it being a full moon. What you want to do is get somewhere away from as much light pollution as you can.

30:20If you can't do that, then use buildings or trees or something to try and block out the lights that are around you. So you've got a better view of the sky above you. And the radiant, the place on the sky that the meteors appear to come from, will be, at least in the UK in the early hours, it will be in the northeast. The best way to observe meteors is quite a nice way to observe the sky, is to get something like a deck chair and a sleeping bag, a woody hat, and a flask of coffee, and just look up and just enjoy the sky. And if you're lucky and if you're outside for long enough, you'll see meteors streaking across the sky. So keep your eyes on the skies in the day to head. Megadago there at the University of Lancashire. Well, that's it for today. Dude, tune in on Tuesday, though. We're in partnership with UK Research and Innovation. We're going to be examining the problem of flooding. Why does this happen? Why is it dangerous? Is the risk worsening? And what can we do? Most importantly, perhaps to prevent it. Thank you, meanwhile, to those of you who show your support with donations to help keep our show on the road and help us to cover our running costs.

31:20If you appreciate the program and what we do for you each week and you'd like to make a contribution, do please head over to nakedscientist.com forward slash donate. We've made it really safe and simple. That's nakedscientist.com forward slash donate. We also welcome your comments and feedback. Thank you very much for what you're saying to us. If you have any questions, you can of course drop me a line directly to Chris at thenakedscientist.com. I'm Chris Smith. Thanks for listening and from all of us here at the nakedscientist team. Until next time, goodbye. My perfect day at sand saltwater and friends. But my moderate to severe plaques rises can take me out of the moment. Now I'm all in with clearer skin thanks to skyrizzy. Risen kism at Risa, a prescription only 150mg injection for adults

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