Alzheimer's drugs & tackling HIV

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0:34engine running. Absolute genius. Get this. Welcome. Welcome. This is the show where we bring you science. What that essentially means is discovery is advances. Research. Technology. Unbelievable. Without further ado, this is the Naked Scientist. Hello, welcome to the Naked Scientist podcast, the programme 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.

1:23new analysis has suggested that a pair of recently approved breakthrough alzheimer's drugs dananimab 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. Tara Spires-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.

2:04So these drugs that were analysed 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 canamab and one denanamab. And the evidence for these is that both of them very successfully remove amyloid from the brain.

2:38And both of them slow disease progression significantly in gold standard phase three clinical trials. And what that means is people are still losing cognitive function. So their memory is 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.

3:13So 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?

3:46Are they going to really slow disease in a way that you would notice? And 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 amyloid is 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.

4:14And 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.

4:45I think that that's a fair point and there is a lot of genuine scientific debate in the field among scientists like 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 bathwater 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.

5:29And 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. Saying meaningful is a bit tougher and there's not a standard and not really a gold standard for that.

5:57Others 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, albeit 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.

6:29You may have heard of the news there are 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 intents and 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, right?

6:58So the earlier we can get it, 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 lot of caution.

7:36Now, 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 on my computer, which you can't see because it's, you know, radio, but a podcast, I'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.

8:08They 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-amyloid drugs that did pass 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.

8:42But the MHRA, the Medicines and 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 there are very good reasons for that because they aren't hugely effective and they are costly and they have risks. But the next generation of these anti-amyloid drugs that are in trials now are even better and safer and more promising. And we've moved as a field beyond amyloid. So we're not only in my lab or 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.

9:16So 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 Spires-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.

9:55The patient received a bone marrow transplant from his brother who serendipitously also carried a genetic mutation called CCR5 Delta 32 that 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.

10:34And while that might be a contributory factor, as Marius Troside, who's 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 and 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 actually, but because of a bone marrow disease. So a pre-stage to blood cancer, hematological cancer, and 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.

11:22So in a bone marrow transplant you need to get a new immune system from a donor and when our blood 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.

12:13So 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 patient. and on the day of the transplant it was actually found out quite coincidentally that his brother actually carried this genetic variant this mutation that locks out the virus from the cells so you 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 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 you know knocking down the virus in the body because hiv it hides in in your dna so it really becomes part of your dna part of yourself so you you need to kill the immune cells that carries HIV and then replace it with a new immune system.

13:36So probably it's this process that drives down the virus and kicks it out. And then you have this genetic variant 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 uh after the transplant he was he was still on on uh antivirus medication for 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.

14:26The 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 rests of the virus or if his immune system seems 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 virus.

15:25Right. When we started out, we thought there was this genetic mutation that would be key to cure, but after we started working with the Oslo patient, they have in two cases now been 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 gut.

16:09the gut really carries the largest number of immune cells in the body and also there we can show that the immune new 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 it'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?

16:48I 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 have also with these cure cases shown that there are probably different mechanisms that could lead to cure. You have this mutation that I talked about. You have 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 blood 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.

17:38Really interesting. Marius Troside there at Oslo University Hospital.

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18:35music 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 lyrid meteor shower 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 dub this the estrobilome 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 breastfed baby compared with other populations.

19:28The consequences might be greater risks of certain cancers and effects on fertility. My name is Rebecca Britton and I am a postdoctoral researcher at Jagiellonian University in Krakow in Poland. The astrobilome 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 while 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.

20:17And 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, which is linked to certain types of hormone-dependent cancers. So if the microbiome, if the estrobilome, 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.

21:02Right. 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 threefold higher estrogen recycling capacity than breastfed infants. And then we also found that males and females have similar astroblomes within their population. And why do you think you see this in the first place?

21:48It 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? Yeah, so it's not just estrogen. And the enzyme that these microbes are producing is called beta-glucuronidase.

22:28and 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. So 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?

23:22There 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. It could be adding to this. Estrogen is linked to fertility. If we have too high of estrogen in 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.

24:07It's a fascinating finding, isn't it? And we'll now have to wait with interest to see what Rebecca Britton'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 display of 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 Thatcher, which was first discovered in the 1860s.

24:41I caught up with Megan Argo, space scientist at the University of Lancashire, to talk about the phenomenon the lyrids is one of a number of meteor showers that we see throughout the year so we get these 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 colored 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 the 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 if the earth sort of 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 lyreds happen in april every year when we pass through the trail of one of these comets and 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 the lights coming down in the sky we're actually seeing bits of 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 fainter 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 fainter 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 fainter ones do they have specific colors does the chemistry of what is in the particle make a difference or is it just superheated air as it comes in and interacts with the atmosphere therefore colour isn't part of it?

26:49Colour 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 of 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 of the particles, do we know what the origin in cometary terms is of these particles?

27:22This 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 pass 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 but hopefully astronomers at the time will see it and we'll get a better determination of its orbit. Why have we not got showers and showers and showers of meteors going around?

27:55Why 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. In 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 often there are comets that pass through the field of view. The reason we don't see as many meteor showers as we see comets is because the conditions have to be just right for us to see a meteor shower. The comet's orbit has to intersect with the orbit of the Earth so that it leaves a debris trail that the Earth will then pass through on its next orbit around the sun.