Alzheimer's drug breakthrough, and sugar in space

0:11Hello,

0:17welcome 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. I'm Chris Smith. Coming up, a drug designed to block Alzheimer's disease enters trials. What makes this one stand out from the crowd though? Also, in super quick time, a new Ebola vaccine emerges from Oxford's labs to help to tackle the crisis in the Democratic Republic of the Congo. So how did they move so fast? And why the discovery of sugars in And space, in the Milky Way no less, is a giant leap for mankind.

0:59A major trial is set to begin for a potentially game-changing drug called trontinemab, which has the potential to halt Alzheimer's disease before symptoms show. Research suggests that the next-generation drug, which is a therapeutic antibody, can clear toxic brain plaques in just three months and has been specially engineered to enable it to penetrate the brain much more efficiently. It comes at the same time as a blood test, which could detect those at higher risk for developing Alzheimer's disease, is being rolled out on a test basis to patients in some parts of the UK. Tara Spies-Jones is director of the Centre for Discovery Brain Sciences at the University of Edinburgh, And she's just been at a conference where the new trial looking at trontinimab's ability to prevent Alzheimer's in people who don't yet have symptoms was announced.

1:52Yeah, it's an exciting time to be an Alzheimer's researcher. This is one of many new drugs that we've been discussing over the past few weeks. And this one is called trontinimab and it's an antibody. So it harnesses the power of the immune system to remove toxic amyloid from the brain. So amyloid plaques are one of the pathologies. It's a toxic protein that clumps in the brain in Alzheimer's disease. And this antibody gets in and removes it. And it's even cooler than that. So it also has what they've called a brain shuttle. So one of the problems with antibody drugs is they don't get past your blood brain barrier very easily.

2:24So trontinimab, this antibody, recognizes 8-beta, but it also recognizes a receptor on the blood brain barrier that gets it through into the brain. So in theory, then, it should do two things. One, it should do what it set out to do and help to dismantle the plaques that we think are linked to the disease process. But also, it should get to the site of the action across the blood-brain barrier with greater efficiency. So in theory, we may see greater efficacy. Yes, and it should be safer because it's not going to be causing damage to the amyloid on the blood vessels. And even better than that, this trial is new in that it's targeting people who don't even have symptoms yet.

3:05So this drug is already in phase three trials for people with mild Alzheimer's. But now the new announcement is they're trying it in people who don't have any symptoms, but who are at high risk, which is amazing because if it works, it will prevent people from ever having symptoms. Now, just tell us a bit more about the benefit to the blood vessels, because is this linked to the problem we saw with the prior agents, denanimab, lucanimab, which are also antibodies that target beta amyloid, that they have had as a side effect brain bleeding. Is that because there was damage to blood vessels caused inadvertently by these antibodies?

3:42Yes, we think so. So one of the things that happens in Alzheimer's, you get the plaques and you get the tangles, which is the tau pathology, but you also get amyloid, the same stuff in the plaques, that line some of the blood vessels. So we think that these other antibodies, lukanamab and dananamab, cause dangerous side effects, at least in part, by removing that amyloid from the vessels. And certainly by being concentrated near the vessels, we think that's part of the problem. So the canimab and denanimab very effectively clear amyloid from the brain. But one of the reasons we can't get them here in the UK on the NHS is because they're risky for a relatively small benefit.

4:16So they only slow disease progression by about 30%. And they have this rare but really serious risk of brain bleeding or brain swelling. And so far, the data on trontinamab in earlier phase trials looks like it's much safer. and because more of it gets into the brain with this shuttle, it's also going to be more effective, we think. So it's in two trials for people with mild AD and now this prevention trial, we don't know for sure until these trials finish, but it's looking very promising. How do they know who to give it to? Because if the idea is to intervene early, because we think that the sooner you start, the bigger the benefit will be, that's the rationale.

4:51But how do we know that the people we're treating were destined to get Alzheimer's at all and therefore whether we've really made a difference? That's another really hot topic that's been discussed at this conference, and that's around blood tests. So there's been huge advances in the past decade in being able to take blood samples and detect early brain changes indicative of Alzheimer's. So there's a test that looks for phospho-tau. So that's tau, the protein that clumps and tangles, not plaques. But interestingly and unexpectedly, when you have increased levels of phospho-tau in blood, it actually reflects really accurately whether you have plaques in the brain that's one of the scientific mysteries we're working on in the lab but with that test you're able to identify people who have plaques even before those plaques cause symptoms because plaques accumulate in the brain for decades at least 20 years before symptom onset in alzheimer's so we know who therefore might be at higher risk the idea being then we go in with this treatment and then follow them up to see if it changes the course of the disease in those people?

5:53Yes, so they're looking at whether it prevents or delays the onset of symptoms. And one of the problems with prevention trials is they're very long, because Alzheimer's is a very slowly progressing disease. Like we just talked about 20 years of pathology building up, and that's a long time to be in a trial. But what they're doing is taking people with very elevated levels of P-tau on this blood test. So they're likely from other data in the field to probably progress to symptoms within six years. So they're going to give this drug and see if they can delay past that six years when you would expect people to develop symptoms.

6:27Therefore, Tara, if you and I have an eye on our risk for the future, what age would we need to probably start therapies like this if we were to reduce our risk of Alzheimer's going forward? It really varies by individual because your risk for developing Alzheimer's is a combination of your age, but also your genes and what's happened to you and then your lifestyle. So everybody progresses a little bit differently and there's a wide range of onset ages. Typically Alzheimer's disease onset is after age 65, but the pathologies start to develop for years before. So for a typical person, this would be somewhere in your 50s, maybe even late 40s, but it really does vary.

7:08So these people are going to be a little bit older. They're going to be people who have that positive signal, a very high P-tau signal. But that's where the blood test comes in, presumably, because you could then get some kind of disease risk readout and know where you stand on that scale and therefore whether you've shifted the balance in favour of doing something like this at an earlier age if your particular makeup dictates it. Yeah exactly right now this is not available in the UK but just this week up in Scotland they started rolling out this blood test to GP practices to try and understand how GPs could incorporate this blood test into diagnosis of people who are worried about their memory.

7:47So it is coming in the future. It's going to be transformational because as you say, we can all go in our early fifties, mid fifties, have this test, look at our genes and look at our risk factors like diabetes and obesity and head injuries and things like that, and have a pretty good idea about our own risk. And one of my colleagues who actually is a psychiatrist who sees people and he says he wants this to be like when you come in and you get a high cholesterol test, he wants it to have that same lack of emotional response. You just say, oh, you've got a touch of amyloid. We're going to give you one of these drugs and it'll really stop you from ever developing Alzheimer's.

8:19That's the goal for the future, is really to prevent symptoms altogether. Tara Spires-Jones at the University of Edinburgh and Tara apologised for her croaky voice this week. She said it was caused by enthusiastic discussions about trontinimab at her conference, although she didn't deny that enthusiastically supporting the World Cup might also have had something to do with it. Now scientists at the University of Oxford have developed a new vaccine to tackle Ebola and the UK regulator has given permission for clinical trials to take place. The researchers began developing the vaccine in May when a public health emergency was declared in the Democratic Republic of the Congo.

8:57The driver for the initiative is that the outbreak there is caused by a different form of Ebola virus which is not catered for by our existing arsenal of vaccines So we needed to make a new one, which the Oxford team have managed to do in record time. Bahuma Tatanjee is an infectious diseases specialist and a virologist at Emory University. I asked her to bring us up to speed. The Ebola outbreak is still continuing with more cases being recorded. And right now we have had over 2 ,000 confirmed cases and over 700 deaths. There have also been cases in neighbouring Uganda. So far 20 cases, all of them with links to importation from the DRC across borders.

9:42And so far with the Uganda outbreak, they've been two deaths. There's still no treatments or vaccines for this Ebola outbreak and containment really relies on contact tracing and being able to isolate and treat those who are diagnosed with Ebola. This is because it is a different strain of Ebola than the one that caused the biggie about 10 years ago. That is absolutely correct. So the strain of Ebola virus that is causing the current outbreak is the Budimbukyo Ebola virus strain, and it is actually one of the four strains that have been known to cause a disease in humans. However, as opposed to the Zaire Ebola virus that has caused a majority of previous outbreaks, this current virus has only ever caused two previous outbreaks prior to the ongoing outbreak in the DRC and in Uganda.

10:37So while it is an Ebola virus, we don't have quite as much experience with it. And we also do not have as many vaccines or we don't have any vaccines for it or any treatments that have been proven to be effective against this particular Ebola virus. And is that because although they're a big family of or a family of Ebola viruses, the individual members, like this one, the Zyostrain, they're sufficiently different to each other that it won't work like we can use, say, the vaccine against smallpox also protects against the monkeypox virus. It's not going to work like that necessarily. So we need a bespoke vaccine for this variant.

11:16Because the family of viruses is one large family of viruses, people often assume that we would have one vaccine that is capable of effectively protecting against the four Ebola species that cause human disease. But like you have mentioned, these viruses are quite different in their genetic makeup. And the Budingbugio Ebola virus is actually about 35 percent different in its genome compared to the Zaire and Sudan viruses. And that difference is enough to actually make it be a completely different species, which means that if you were to develop a vaccine for it, you would have to develop a specific vaccine that targeted that virus.

11:59So what have the Oxford team done that might get us over that hurdle? The Oxford team has actually leveraged the platform that they used for their COVID vaccine that is based on something called the chimp adenovirus, which is a benign virus that doesn't cause disease, but it's actually used as a carrier virus to be able to carry the protein target of the buding bugio virus and deliver it in the form of a vaccine so that your body can generate an immune response to it that would hopefully be protective. And the reason why they've been able to do this is because they already had an existing platform that has been demonstrated to be capable to deliver a vaccine effectively.

12:46So essentially, they've just swapped out the target and replaced it with the protein target of the budding bugio virus. And how will they test it? They're currently underway an approved phase one study and phase one studies are really focused on demonstrating that the vaccine is safe and that it can stimulate an immune response. So that is the very base entry level of assessing whether a vaccine can then progress to additional studies to check whether it's actually protective. and the goal will be to assess whether this vaccine is safe and well tolerated in humans and the second goal will be to assess whether it generates an immune response.

13:30The Serum Institute of India has already pre-stocked and produced about 620 ,000 doses of the vaccine pre-emptively and 4 ,000 of these doses have been donated for clinical studies. Ah, right. So they're not waiting for the green light on the safety trials to actually make the stockpiles. They're racing ahead so that as soon as the green light comes on and we've gone through safety trials, they're ready to go. So that should minimise the delays. Nevertheless, is this going to be fast enough at the rate at which this Ebola outbreak is progressing? It is very difficult to tell how quickly we will be able to get these vaccines into phase three studies, which are the actual studies that are meant to assess whether the vaccine itself generates a protective effect and can actually prevent people from acquiring Budeng Bugio Ebola virus.

14:26because there are regulatory requirements within the countries where these vaccines will need to be rolled out. And sometimes these regulatory processes can take several months. However, I think it's very encouraging to note that we're just 57 days since this outbreak was identified, and we're already rapidly moving into a phase one study, which then sets the scene and the stage for moving into a phase two study if the phase one studies are shown to be positive and the vaccine is shown to be safe. Is there the right resource on the ground to do this though? Because there's a reason why we've got this problem in the DRC and it's been as bad as it has, which is there's been conflict, there's been political instability, and we know these are one of the worst provoking factors to drive public health disasters.

15:22You need a good public health system to get vaccines on the ground and into people at risk. So is that actually going to really frustrate things? We can have all the vaccines in the world and if the politics isn't there, we're still no further along the track? Well, you know, the challenges that you mentioned are very real regarding the landscape where this Ebola outbreak is unfolding with the mass displacements of people related to conflict and the multiple rebel groups operating in the area, as well as the limited public health infrastructure. But we must remember that in the 2018 to 2020 Zaire Ebola outbreak in the DRC, that also occurred in a very difficult to navigate part of the country, that particular outbreak still saw vaccine studies as well as treatment studies that were executed during the outbreak.

16:20And actually, the existing vaccines for Ebola Zaire were utilized in the context of this 2018 to 2020 outbreak to effectively help with containing that outbreak. Behuma Tatanji at Emory University there. The Naked Scientist podcast is produced in association with Spitfire, cost-effective voice, internet and IP engineering services for UK businesses. Find out how Spitfire can empower your company at spitfire.co.uk.

16:57This is the Naked Scientist podcast with me Chris Smith. Still to come, sugar and space and all things nice. We'll hear from scientists who've just discovered clouds of the sweet stuff out in the Milky Way which might also point to how life got started here. But first, pneumonia affects millions around the world every year and it's a huge killer. The prognosis for someone who ends up in intensive care with the condition can be grim. Strangely, some people seem to do better on some treatments, while others fare less well, leading to a poor consensus in the literature about how best to manage the condition.

17:31It occurred to doctors at Addenbrookes Hospital in Cambridge that perhaps there are different types of pneumonia, each with different disease mechanisms that demand different optimal treatments, and that's why some therapies seem to show inconsistent results. The findings published in Nature Communications and confirming at least three different pneumonia processes exist could open the door to developing much more tailored ways to treat the condition. I went to meet Vilas Navapurka from the John Farman Intensive Care Unit. I look after with my colleagues lots of patients with pneumonia and it is the commonest cause of infection for patients in intensive care and is worldwide the commonest infection cause of death, killing about two and a half million people per year.

18:21And those patients that survive are usually left with severe disability. And there's been no evidence that shows an impact or benefit across a range of different patients with pneumonia. So we wondered whether there were in fact different types of pneumonia and that this idea of looking at pneumonia as a single disease may not be appropriate. So we're lumping all pneumonias into one under one umbrella term pneumonia but in fact it might be a bunch of different diseases in disguise. They're all manifesting as pneumonia but in fact the diseases are different and therefore the treatments they need are different.

19:05That's what you're arguing. That's right and actually on the surface they all do look the same with similar kind of clinical picture and yet the responses to treatments are different. So you might give the same treatment to all of them but half of people do well, the other half do badly and we just assume it's down to bad luck and actually what might be the case is that we've given the wrong treatment. that's exactly right that it may well be that we're giving treatments that may not be appropriate for a particular type of pneumonia whereas if we had tailored it better to a particular type if it existed then they might have done better and it may well explain why some treatments do benefit some but in the studies they're cancelled out almost by other patients not doing so well with the intervention.

19:56So it's very difficult to tell who you're treating properly. How did you go about it then? What did you actually do to see if there are different types of pneumonia and therefore mechanisms of pneumonia that you're suggesting may exist? What we did was to take the fluid from patients' lungs, because pneumonia is an inflammation of the lungs, and we looked at the patient's genes to see which ones were being turned on more and which ones were being turned off more to see whether there was a pattern or different patterns in these patients. And if there are different disease processes then you're going to see different patterns of gene changes mapping onto those different diseases.

20:43I suppose that's your hypothesis. That was indeed the finding and we identified three different discrete clusters of genes and when we superimposed the clinical diagnosis they did in fact match to different mechanisms of injury in the lungs. What are the different types of pneumonia that this tells you about then? There are different types of pneumonia or pneumotypes as we've called them and we've labelled the three that we've clearly identified although there may be further types as pneumotype 1, pneumotype 2 and pneumotype 3. Each different pneumotype has got a different population of genes that are switched on the most and switched off the most.

21:24That means the injury mechanisms to the lungs are different for those different groups, which would explain why treatments for one group may not be appropriate and in fact may harm, and treatments for the other group may be better and more specific and they may do better. And that's the advantage of this new knowledge that there are different mechanisms for different types of pneumonia. Are the different types caused by different infecting organisms or are they caused by completely different processes? No is the answer to that. At the moment, we believe that one of the types is caused by infection and they do the worst.

22:09The other type is probably caused by abnormal activity of cells, patients' own cells that suppress the patient's immune system. So instead of fighting infection, the patient's immune cells are causing an injury. And the third group does not seem to be an infectious group at all. and in fact could be called a healing group and they don't need any form of treatment. And do those three map onto obviously different treatment pathways? So if you said, right, I've got a group one pneumonia here, this person needs this sort of treatment versus a group two which would need this sort of treatment and the group three person, you've got to have the confidence to say let them heal themselves.

22:57That's where we believe we're heading, to say that the group with the bacterial infection could in fact be treated in a different way to the other groups, i.e. using antibiotics and using blocking agents for proteins that are released by the patient's immune system. The other group, we believe that if we can modulate the immune system without antibiotics, we may well decrease the injury. and the third group we don't believe they need any form of intervention because they are in the healing process and intervening may well have a deleterious effect. Have you thought about when you consider that two and a half million death toll that you mentioned earlier how big a dent you could make in that if you were to deploy this sort of approach?

23:50We've done some very early preliminary health economic modelling, we have got some guesswork that we could move into the thousands upon thousands of lives saved and harm decreased. But it's at the moment way too early to say, but that's definitely something we believe will have an impact on, as well as using the antibiotics that we have currently better, much better antimicrobial stewardship and save thousands of our lives going forward. ITU consultant Vilas Navapurka there at Addenbrookes Hospital. To another groundbreaking study now, where scientists have detected large amounts of a sugar in deep space, which seems to have managed to form there, despite temperatures near absolute zero and in a near vacuum.

24:40The same sugars, constructed from four carbon atoms and known as erythroloses, crop up naturally in fruits here on Earth. They're also used in some sun tanning liquids. And this has led to the tantalising hypothesis that their delivery here billions of years ago, not in the sun cream, from clouds out in space, might be why biology adopted very similar molecules as the backbones for DNA and RNA at the dawn of life on the early Earth. Isaskhan Jimenez-Serra made the discovery at the Centre for Astrobiology in Madrid. We have found a sugar with four carbon atoms, which means that it's one of the simplest sugars that we know of.

25:20And we have detected it in the interstellar space between stars within our galaxy. How did you see a sugar in deep space? So we see it because each molecule has its own fingerprint. And this fingerprint is characterised by light. Because these molecules are in vapour state at the very cold conditions of this nebula in space, the only thing that they can do is rotate and when they rotate they emit light at radio frequencies. So by using our radio telescopes we can measure these fingerprints and that's how we know these sugars are present there. How did they get there in the first place? Why is there a cloud with sugar in it in deep space?

26:05So that's the interesting thing even under the extreme conditions that we can find in these huge clouds of gas and vapour, we can form these complex molecules that are relevant for life. So that's one of the main results of this work. Even under those extreme conditions of very cold temperatures, very close even to the absolute zero pressure conditions of vacuum, these kind of molecules can form. What actually is the sugar you found then? You said it's got four carbon atoms in it. So what is it? And do we understand the chemistry that must have gone into making it? So this sugar is present in red fruits and in particular in raspberries.

26:51And it can also be found in these self-tan cosmetics that maybe some of you have used. I would never use a self-tanning cosmetic. I just go to a nice country like Spain where it's sunny and it's amazing. I use it in the UK. though so i think sometimes it's useful true true but where did it come from out in space and how does it actually get built so raspberries can make it yes it's in biology here on earth but out in space in space so the way they are formed is on the icy surface on the cold surface of a very small particles that we call interstellar dust particles and these particles are very very tiny.

27:33So they are of a size of a bacteria. They are covered by these ices, very cold ices. And then these sugars can form on top of those ices because they can meet, they can join together, and then they can form. So in particular for the sugar with four carbon atoms, we start from two kind of Lego blocks of two carbon atoms. They meet, they react, and that's how we make the sugar with four carbon atoms. Where did the simpler molecules come from in the first place though? Because you're saying you build a four carbon sugar by joining a couple of two carbon elements together. Where do they come from?

28:13They come from even simpler molecules and the simplest one of them is carbon monoxide which is basically a carbon atom and an oxygen atom. That molecule is on these ices, on top of these ices and then by adding hydrogen atoms on the surface because these interstellar gas particles, they act as a catalyzer. So that's how these more larger structures start forming by adding hydrogen atoms and other carbon atoms subsequently. Where does the energy come from to kickstart the reaction though? Is that light or do they just naturally want to react to form these sugars? That's the interesting thing. So because the temperatures are very low, are very close to absolute zero, the energy available is really, really tiny.