A nasal spray for flu, and is this how life began on Earth?

0:16Hello, welcome to the Naked Scientist podcast, the programme that brings you the biggest breakthroughs and also talks to the major movers and shakers in the worlds of science, technology and medicine. I'm Chris Smith and coming up this week, an antibody nose spray that can block flu infection. Also, the origin of life is really one of the big kind of unsolved questions in both chemistry and biology. Have these scientists found how life began on earth and the bacteria that help oak trees to fight drought?

0:58We begin this week in the Netherlands, where researchers are developing an antibody nasal spray to help to combat influenza. And it's shown great promise in human clinical trials. It's hoped that the spray, which targets the parts of the virus common to all strains of flu, could also help to tackle future pandemics. Even more exciting is that the same technology could be turned on other seasonal lurgies, like the common cold. A company called Leiden Labs is behind this exciting development, and their CEO, Conrad Weidhalb, has been telling me all about it. We're developing nasal sprays that people can take during a flu season to be protected against these different viruses.

1:40these contain antibodies that can you know protect people against not just one type of flu but actually the whole set of influenza viruses and that's what we're developing. That's intriguing so effectively you have made in a lab the sort of immune response I would make if I caught flu for real and I'm spraying something similar up my nose on a daily basis and then if flu does try to invade those antibodies are there and stop it exactly what's also important by directly bringing these antibodies to the nose is also use unique antibodies that can protect against all these influenza types so we all know that you know every year there's you know we have to take another flu shot because every year there are different um flu strains that are attacking us But with this, we can really use one, which is important for the seasonal flu.

2:34But also, if we go back to our pandemic times that we can all remember, that we're also ready for a potential pandemic flu virus as well, like avian flu. These antibodies effectively hit bits of the virus that is invariable. So from one flu season to the next, this doesn't change. So you've got an antibody against that. It will always work effectively. Exactly. And that took decades of work to actually try to find these antibodies that are so broad that they can protect against all these influenza strains. But added to that, we bring that in the nose where these viruses attack us so that we stop the infection there immediately.

3:12While vaccines mostly work when the virus is already in the body. So it's, of course, easy to stop somebody just breaking into the house right at the door than trying to get them, you know, when they're already in the living room. I like the analogy. The thing is, there are lots of roots into the body for flu. It can even infect the surface of the eyes and give you conjunctivitis. Yes, you can sniff it up. You can also just breathe it in through an open mouth. So can you get enough protection from putting these antibodies just in the nose that this makes a clinical difference? Absolutely. And there maybe I've become a bit more technical, but these viruses indeed come in, you know, through the nose, but also through the mouth and sometimes through the eyes.

3:58What we're not trying to do is just stop them coming in in the first place, like a face mask. What we're actually doing is taking away the fertile ground that these viruses need to really replicate first when they come into the body. so they typically land in the back of our throats after they came in even if they come in through the mouth and that's where they replicate fast and and only then can they affect also the further body and the lungs for example and what we're doing with these nasal sprays is that we put these antibodies at that place so we take away the fertile ground for them to replicate in the beginning how long do the antibodies sit there on the surface giving that protection after you dose with them?

4:39So what we're working towards is that people can take a daily spray like for example you know I have seasonal allergies so pretty soon when spring arrives again I take my you know daily spray to be protective against these allergies so this would be the same that people can take the daily spray and during that time they're protected against these viruses that's what we're towards. And what sort of data have you got that that's achievable? Yeah so we very recently published data where we now see that this really can work in humans. So we have done clinical trials where we see that it's well tolerated so it has a good safety profile but then also we see that we can achieve these high antibody concentrations in our nose throat area to actually have that protection and that we can correlate with the work that we did before in the lab but also with other studies that we did where we see that that is enough to then also protect humans against these different virus so that's a clear breakthrough that we just published.

5:45Was this a challenge study as in you protect some people and then you throw a certain amount of virus at them to see if it breaks through or was this a natural experiment where you take a group of people, ask them to use the agent, and you know how many people you'd expect to catch the flu, and you compare that to how many actually do, and you can work out what the efficacy is. How did you actually generate that data? We actually are measuring the antibody concentrations in the noses, and then we take out samples of these noses, and we see that those samples are still neutralizing these different viruses.

6:22And that we could correlate with the work that we have done before where we know how much antibody is basically needed to protect against these different viruses. But that's still not a replacement for a person walking around in the real world, encountering flu for real and being protected. That's got to be the next step. That is absolutely the next step. So we're working through to start those kind of studies as well. And that's the next step to further develop this. Given you've managed to do this for flu, you think, and obviously we're waiting on the subsequent trials to prove that it does work in the real world.

7:01Can we then extend this into the realms of other nasties? Could you make a suite of antibodies against the commonest causes of the common cold and people could protect themselves against that too? We are working on an approach that would be able to protect against basically all airborne viruses. We're working on a product that can protect against coronaviruses, not just SARS-CoV-2, but also other coronaviruses. And about 20 to 30 % of our common colds are actually caused by coronaviruses. But then also looking at other viral families. Of course, the future that we want to work towards is having, you know, one spray that can protect against all these viruses.

7:42But we take it, of course, step by step. Nevertheless, it sounds very good, doesn't it? That was Conrad Weedhaub at Leiden Labs. Arguably, one of science's greatest unanswered questions is how life got started here on Earth in the first place, about 4 billion years ago. Our present best guess is that a cocktail of chemicals simmering in a warm rock pool spontaneously cooked up some of the molecules that are the building blocks of genetic materials like DNA and its close relative, RNA. According to that hypothesis, some of these building blocks then hitched themselves together into a chain that folded up in just such a way that it became a miniature machine capable of copying itself.

8:24Now the fly in the ointment was that although scientists had discovered RNA molecules that are capable of doing this, they're so large and complicated that the odds of them cropping up by chance in a warm little pool seem impossibly small. But now researchers at the MRC Laboratory of Molecular Biology in Cambridge have found a much smaller RNA molecule that can do this, making this RNA world hypothesis of life's origins that much more plausible. I went to meet Eduardo Gianni and speaking first his colleague Phil Holliger to hear how they did it. The origin of life is really one of the big kind of unsolved questions in both chemistry and biology, kind of how did this transition happen sometime long, long time ago on the early earth where chemistry turned into biology, so to speak.

9:18And one top candidate molecule for this transition is RNA, a molecular cousin of DNA. And it is thought that at some point in time, RNA acquired an ability to make copies of itself and sort of grow a little bit like cells in biology grow. And that is the key step in the transition. Nobody has found such an RNA molecule. So the question is, can such a molecule exist? And the task we set ourselves, can we build such a molecule in the laboratory? I suppose then you're saying, if you could make a molecule in the lab that could do this, it makes the likelihood that that happened four plus billion years ago here on the early Earth, that bit more likely.

10:09Yeah, that's exactly our thinking. How on earth did you do it, Eduardo? By the way. For many years, people have been trying to find a molecule that could make copies of itself. And already in the 90s, other labs had found an RNA that could copy RNA. The problem with it is that it's a very long RNA molecule. What that means is that for it to make copies of itself, the task is made much more complicated by the length. And also if we imagine a scenario on an Earth 4 billion years ago where an RNA has to spontaneously come out of chemistry and form, if the molecule is smaller, this process is more likely to happen.

10:50If the molecule is very long, this process is much less likely to occur. As Phil's saying, RNA is a chemical relative of DNA. It's a series of building blocks strung together and it winds itself up into interesting shapes which can then confer interesting chemical abilities, like you're saying, the ability to copy itself. But you're saying, statistically, the chances of something huge emerging just like that and having these abilities makes it that much less likely this happened. But if you had a short one that could do all this, we'd be much more convinced. That's exactly right. So what we set ourselves to do is look for a shorter one than the one we had been working with, because that would make the whole hypothesis of this RNA world much more likely.

11:36So instead of continuing in incremental work on the previously existing one, we set out to search for a completely new RNA molecule that's smaller from the get go. How did you hunt for Phil? It's a little bit like finding a needle in a haystack. We make a huge number, kind of millions and millions, well, actually trillions, kind of like of RNA molecules. And then we see through them looking for that capability to make itself. And there were a few molecules within that pool that could do that. And we could fish those out and then study them much more closely. And how big, Eduardo, is the one that you've got that appears to have this ability?

12:19So the one we found is 45 nucleotides, so 45 letters of RNA long, whether the previous generation was at least 150 nucleotides long. In essence then, if you make this molecule and you put it into a tube with a soup of the genetic building blocks of RNA, it will knock out more copies of itself just like that on its own. Kind of. We're not quite at the point where it makes a lot more of itself. It makes a tiny, tiny amount that we can start detecting, but it's the first time we can even see that first touch of self-synthesis, of ability of making itself happening in the laboratory. Can you look at the structure of it to understand what's special about it that's giving this tiny molecule the ability to self-replicate in this way?

13:06Does that give you clues about what else might be out there that might do this even better? We'd love to have a look at the structure. We don't know the structure yet. We've tried predicting it with AI tools such as AlphaFold, and it gives a sense of the size and the shape, but it's not quite producing the correct structure we think yet. Hopefully, once we have the structure, shall be very helpful in understanding how an RNA can fold up in a three-dimensional shape that allows it to have this specific activity. And we have guesses, but we still don't know. And back to where we began, Phil, which is you were saying, if we could create something that had this ability, it would convince us or be more compelling arguments that that's how life might have got started on the early earth.

13:55Do you think this nails it? I think it's a significant step to a better understanding how that crucial step kind of could have happened. Because what we've discovered just makes that whole process so much more plausible than it was before. Do we have the exact kind of molecule? Kind of like, no, we don't. But we have a sort of something that we can study by proxy. And, you know, maybe we can further improve its properties, maybe shrink it even further make it even smaller and we can start to study how this molecule might interact with other molecules that were there on the early earth and how you could have maybe some form of molecular symbiosis kind of going to to get life kind of sort of to bootstrap life kind of out of the primordial soup.

14:44Phil Holliger and Eduardo Gianni fascinating stuff they just published those remarkable findings in the journal Science. 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.

15:11Music in the programme is sponsored by Epidemic Sound, perfect music for audio and video productions. This is the Naked Scientist podcast with me Chris Smith. Still to come, how root microbes might help oak trees to adapt to drought in the future. But first, scientists are calling for a moratorium or at least very strict controls on research that could lead to the creation of so called mirror life. This is a form of biology built from molecules that have the opposite handedness of those used universally in nature. Our bodies exclusively use sugar molecules that are right-handed. Our proteins, meanwhile, are all constructed from left-handed amino acids.

15:53But, chemically, there is nothing to prevent a viable cell being built using the chemical mirror images of these substances. The risk, though, is that such an entity would potentially be entirely invisible to every other form of life. As such, it would have no predators and no means to be recycled. The impacts could be devastating. Kate Ademala from the University of Minnesota is the author of a report documenting those risks that was published recently in the journal Science. She is among those calling for an urgent debate around this issue. Every molecule that builds any cell in the real world has this property that its 3D structure points one way or another.

16:40It's very much like your feet. You have two feet. They can exist in a left or right, we call it configuration or chirality. And when you put shoes on your feet, the left shoe always only fits on the left foot and the right one only fits on the right one. And that's the same with biology. A left-sided or left-handed molecule only interacts with other left-handed molecules. And that's the concept of chirality in biology, is every molecule that makes cells can interact only with molecules that have the same three-dimensional structure as its partners, as it is itself. So left-handed interact only with left-handed and right-handed only with right-handed.

17:23And does life preferentially have a handedness then? Yes, life only uses one type of molecules in all of biology. So all living molecules are only of one type of handedness. And there is no exceptions in all of biology. All of our DNA, RNA, the proteins that make our cells, they all obey that rule. and I suppose that's part of the evidence for a common origin for life on earth isn't it that everything obeys that rule of biology therefore we all came from one common ancestor way back in history that made the decision to use one particular handedness for some of its molecules and we've all inherited that that's correct and there is no any specific biochemical reason why this particular handedness that we use ended up being chosen so it had to be an accident and it happened once and then everybody inherited that.

18:18And why are scientists interested in it then? If it's one of life's certainties, why are we considering it? We're very interested in the biological handedness because it guides how molecules interact with each other. And so if you make a molecule of the opposite handedness than it exists in nature, the life enzymes, other molecules of life, will be interacting with it, not at all or very different. And that's actually both a bug and a feature. We're using this property of the fact that opposite handedness molecules don't interact with natural enzymes to make molecules that are much more stable.

18:56So imagine you want to take a drug and that drug is metabolized in your body too quickly to work. But if you make that drug from the molecules of the opposite handedness, that drug is going to persist in the body, remain active in the body. And that is a great advantage if you want to make, for example, peptide-based drugs that people can swallow as a pill. And are we actually doing that? Is there evidence that that's not just blue skies thinking that could work? Yes, there is a lot of evidence. We've made molecules, including peptides, of the opposite-handedness. And we know for the fact that they do not get digested by the enzymes in your stomach.

19:33They do not get digested by other enzymes in your blood and they can have the correct function if you design them correctly, but they are very resistant. So that's experimentally validated fact and that drives this whole field of using opposite handedness molecules as drugs. What is not to like then? It sounds like that could be a huge advantage, but what are the disadvantages? The opposite handedness molecules by themselves are perfectly safe and we should all love them. The thing that we should not like is a whole cell made of opposite handedness molecules. So, you know, you can kind of make this logical progression.

20:12If I can make a molecule of opposite handedness, if I make enough of those molecules, I can put them together and build a whole cell of the opposite handedness. But that's a problem because cells replicate. Single molecules don't replicate. Cells can replicate. So if you have a cell that can replicate and it's of opposite handedness, it will not be regulated by the rest of the ecosystem. So that cell could potentially sneak past your immune system. It could sneak past predators and regulatory mechanisms in the environment. So it would be really dangerous and irresponsible to make a cell that's basically stelt to all the other biology.

20:50And what are you advocating for then? Some kind of moratorium on this to stop people doing that? We're advocating for a moratorium on making mirror self-replicating cells. We strongly support mirror molecule, biomolecule research for medical purposes, but we think we should stop, we, the royal we of scientists, should stop this work before we're capable of making a cell that's made out of mirror molecules that can replicate and live in the environment. Where have scientists got to so far? Are we at the stage where this is becoming a realistic prospect? and that's why you're saying we need these regulations and guidelines in place right now or is this so far away that at the moment we've got time to debate this?

21:36We definitely got time to talk about it, to think about it. Most people agree we're about 10 years at minimum, some people say more like 20, from being able to make a mirror cell. We talk about it now because we want to stop this work before it gets too close. We don't want to stop it a second before we can make a mirror cell. We want to stop the foundational technologies that allow us to even think about making mirror cells right now before it gets too close and before it gets to the point where a single person, single bad actor could do it. And predictably, Hollywood are already in on the action.

22:12The film Mirror Life came out last year. The story centers on a drug that reverses the handedness of genetic material and proteins. And would you believe it spawns legions of zombies? Well, let's hope it stays in the realm of science fiction. That was Kate Adamala. She's at the University of Minnesota. A new study has found that root microbes could help much-loved oak trees to adapt better to drought. The research, which was carried out in natural woodland, found that the trees showed subtle changes to their root microbiomes during warm and dry conditions. This suggests that the oaks are able to recruit beneficial bacteria when they're under stress.

22:49And if we can find out what those microbes are, it might be possible to use them to protect other vulnerable species in the future. The study's author, James MacDonald, is a microbial ecologist at the University of Birmingham. Trees are very long-lived. They're large organisms, so they can't move away from the extreme kind of environmental changes they're facing. And so microorganisms that live on the trees are one of the major adaptations that they have to cope. And so we're really interested in trying to understand which microbes are present in oak trees and how they might help them to navigate that drought stress.

23:24And if we can identify some of those organisms, there's potential that we could utilise those microbes to help boost the health of oak trees, particularly as we now look to plant large numbers of oak trees across the nation. And it's important that these kind of young saplings and seedlings that are planted actually established and grow into mature trees. How have you gone about this then, trying to find out what the magic mixture of microbes is to give the trees the greatest resilience? So working with mature trees is a real challenge. Lots of the research on plant microbiomes has been focused on very small, fast-growing herbaceous plants, like agricultural crops.

24:04Mature trees are extremely large and some of them can be 30, 35 metres tall. And this actually makes studying them a real challenge. So we were quite lucky in that we had access to a woodland where there was a large number, several hundred trees that were around 35 years old. And this was a great opportunity because it enabled us to conduct a large scale experiment on fairly mature trees where we could manipulate the experimental sites to kind of introduce drought onto those sites. So the way that we did this is we built, we call them rain shelters around the stems of these trees. so it was almost like a roof and a gutter underneath the canopy of each tree and there were ditches around the bottom so this basically stopped the rain from reaching the roots of those trees and another treatment that we had involved ring barking where we use a chainsaw to cut a small piece of stem from around the tree and this limits the transport of water and nutrients across the tree and again mimics one of the impacts of drought where they become nutrient dressed and water starved and we also had trees that we didn't impose these treatments on and which we could then compare them.

25:15And what you're looking at what that does to the assemblage of microbes that are associated with the tree in response to those challenges? Yes absolutely so what we then did was we took samples from the trees over a period of two years and we were able to extract DNA from those samples and sequence the DNA to look at which microorganisms were present so we predicted that in the trees where we had excluded the rain from reaching the roots that there would be drought stressed and this would drive changes in the composition of the microorganisms that you find in the roots of the trees and in the other parts as well.

25:52And did it stress the trees out doing this? It did stress the tree so some of the other measurements that were taken looking at the kind of physiology the biology of the tree showed that the drought and the ring barking was having an impact but what we were surprised to find was that the microorganisms that we found on those trees didn't change very much. And it took about five months for the bacteria to change and they only changed slightly. And it took about 17 months for the fungal communities and the roots to change. And this was the opposite to what we expected to find. And it suggests that the microorganisms that are found on these trees are actually quite stable and they maybe help the tree to kind of mitigate some of the stresses that they're experiencing.

26:32Could you see evidence that the trees were responding to the drought? they were becoming stressed but were they changing their physiology in any other way that was then in turn changing the relationship with the microbes the microbes are still there they're the same microbes but the relationships change perhaps the numbers has changed the density the relative densities of the microbes were shifting so although they're the same individuals it's a different crowd as it were in terms of relative proportions yes absolutely we did see this happen. So we know that the treatments had an impact on the trees because we could measure factors like stem humidity, which gives us a sense of whether drought is affecting the stem of the trees.

27:12And we know that that did happen. We could see changes in the leaves and the nutrient levels in the leaves as well. But interestingly, although there weren't major changes in the microbial communities, we did find that some bacterial species in the roots changed in abundance, so they became more dominant and when we looked into the other published literature on what is known about these species it was shown that they've been associated with drought tolerance in other plants like wheat and other tree species as well so this is an interesting finding and it suggests that it could be a number of things one explanation could be that these microbes are just better at surviving the drought conditions that they experience or it could be that the tree is actually directly trying to associate and recruit those bacteria to the roots to help tolerate the stress and it has been shown that this is the case in other plant species.

28:02Indeed so the tree is manipulating the environment around the root to enrich for things that give it the best chance of survival under those particular circumstances. That's right yes and it's already well established that plants secrete carbohydrates that they produce via photosynthesis out of their roots to recruit beneficial microbes to their root system, which help the plant to grow. So in the same way, the trees could be secreting some sort of metabolite or compound that actually recruits the beneficial bacteria to their roots and helps it to navigate this drought stress that they're experiencing.

28:41And do you get any sense that there are some trees that are better at doing this than others? And so if you look at the ones which are succumbing to more stress, are they less good at harnessing the right microbes to defend themselves? And is that one of their vulnerabilities? We don't have concrete data to support that idea, but I think it's a logical conclusion to make. And I think it does require some further research. James MacDonald on the bacteria keeping dry trees feeling oak-kay. That study's just come out. In cell host a microbe. thankfully the research is better than my jokes well that's where we have to leave it for this week do tune in on tuesday though when we're going to be examining cardiac failure with experts from the british heart foundation including hearing about a gene therapy technique that can repair broken hearts before i leave you i have to say a very big hello to laura rose your sister lauren says you're a huge fan and you deserve a shout out so thanks laura for being a listener and thanks meanwhile to all of you who are supporting and getting behind us here at the naked scientists with your donations this really helps and if you would like to make a contribution to keep the show going please head over to nakedscientist.com forward slash donate we're a reasonable way towards our target for the year if you can help to get us over the line we do have a very specific thing in mind that i can tell you a bit more about in future but we do need to get close to that a target so if you can help us nakedscientist.com forward slash donate every little helps please meanwhile follow us on linkedin and instagram and do leave us a review wherever you get your podcasts from including on spotify or apple it's great that we tell other people including us what you think of the program i'm chris smith thanks for listening and until next time from all of us here at the naked scientist team goodbye