Phage Therapy as a Medical Treatment

Welcome to Zoe Science and Nutrition, where world leading scientists explain how their research can improve your health Palm lies motionless on a hospital bed, sweating, hallucinating The body riddled with bacteria is rapidly failing. Days earlier, he'd been enjoying a holiday in Egypt Now he's close to death An antibiotic resistant super buug is coursing through his veins Every antibiotic has failed Bleak tale plays out every day as antibiotic resistant bacteria become increasingly common But what if science already has an answer to this deadly problem And it comes in an unusual form A virus that is harmless to humans, but deadly to bacteria Thankfully Tom's wife was a scientist who had heard of these phages. with the help of laboratories around the world She managed to procure some of these magical bacteria killers Three days after treatment You're woke from his coma and his recovery began But if these viruses are truly the answer to such a deadly problem, Why aren't they widely available? What does this mean for your gut health? Because right now The lining of your gut wall is stuffed with trillions of these viruses O immune system is coordinated Tay. I'm joined by Marth Cloke afessor of microbiology at Lesteron University and one of the world's leading experts on the mysterious phage O the last twenty years pioneered research on phage therapy as a revolutionary approach to treating infections without antibiotics We'll explore how these overlooked viruses could end the use of untargeted antibiotics that can wreak havoc with our microbiome. and replace them with targeted therapies to destroy only the specific bacteria that is making us sick Martha, thank you so much for joining me today. Thank you for having me Tim, great to have you here too Likew So Martha, we have a tradition here at Zure where we always start with a quick fire round of questions. And I know you said you've listened quite a few times. So this is your chance to do it. And you know, we have these very strict rules for scientists. you can say yes or no or a one sentence answer if you have to. Okay Are most viruses harmful to humans? No Is it healthy have viruses in our gut? Yes, very much say we need them bacteria make up the majority of our gut microbiomees They make up the majority in terms of abundance, but viruses are the most numerous. Could the viruses in our gut help keep our microbiome healthy? Yes, absolutely Finally What myth about viruses do you hear most often I think that viruses are bad Many viruses as we'll discuss are good and much needed Most of us have heard of viruses. What are they and how are they different from bacteria So the main difference between a virus and a bacteria is that a virus does not have its own metabolism. So in order for it to be alive as it were, it needs to infect another cell So we're used to viruses that infect us, don't we know about flu and COVID Tteror, interestingly, they have their own viruses that infect them. So they're highly highly specific, but they only become alive as it were when they're attached to an infecting bacteria Are there a lot of viruses out there Yes. Viruses are the most numerous biological entities on the planet. So for each bacteria, it's thought there's at least ten bacteria phages. So that adds up to a very, very large number of ten to the thirty one. So that's far more stars than there are in the visible universe, for example. It's an extremely large number. If you lined up all the little bacteria phages ad to tell, head to t, head to t tell, you'd make a path two hundred million light years long. So it said while ago million light years long. made up of Little viruses that only actually attack crteria. Yeah I heard some statistic how many there are even in the sea. Yes. So we think of the sea as a sort of sterile place just with a bit of salt in it It's absolutely full of these tiny viruses. Yeah, that's right. That's where I started my journey with bacteriophages actually more than twenty years ago. I was studying the bacteria oceans and there's a million bacteria in a teaspoon of sea waterater. They're mainly just fixing the light and making a living like that. And each bacteria there has ten bacterophages that infect it So they're really, really numerous in the oceans and actually it's studying the bacteria in the oceans has then allowed us now to look at them in other environments closer to home, such as the human gut. So you're saying there's ten million viruses in a teaspoon of seawater? Absolutely You've jumped straight into bacteria phages, but this is one sort of virus. Could you maybe paint the overall like what are viruses for? How do they exist and then help to understand these particular bacteria phage viruses? Yes, of course. So a virus is a small parasite. It just it consists of genomes, an RNA or a DNA genome, sometimes a bit of a protein head surrounding it or some lipids. so they're the ultimate parasites. Now, the fviruses interestingly that infect bacteria tend to be a bit more complicated. They're much larger. they have a more complicated structure, bigger genomes, although they infect very small things. they're a more complicated form of a virus. So all viruses are like predators really, aren't they? And I think there's some debate about whether the viruses came before 's not quite resolved as I understand it, but they're these killers really. that can only win by gaining entry into someome other organisms cells and they might be trained against bacteria, in this case, the ones we' have discussed today or human cells or other animals any animal cells Yeah All plants and animals and fungi, we all have viruses They're the ultimate predator. So they're just small chunks of a genome that replicate they need something else to be able to replicate them. so they don't have their own machinery So even plants can get viruses? Yeah, yeah, plants get there anybody who gardens will often see their plants suddenly look terribly sad and often that's due to viral infection. And they're on the leaves of most of the plants we're eating as well aren't they? So every time we're having a salad or something There'll be viruses on it as well as bacteria Totally freaking me out now. It's fascinating So the viruses are sort of like these attackers. they need to plug into some other sort of cell. And you're saying it's not just an animal, which I think is how I've always really thought about it, but it could also be a plant or a bacteria And I think you're also saying that Going back to those quick fire questions, like one virus T plug into me And it could alternatively plug into bacteria? No, they're highly highly specific. So even within bacteria, a virus that infects one type of bacteria won't infect another. And even often within this species, they're very, very specific within that. So there's no way that a virus that infects a bacteria would infect a human Probably most of us never thought about viruses very much until COVID. and then obviously suddenly we all sort of got a bit of a crash course on understanding what they are. But I think we understood, o, okay, so there's viruses that maybe can infect other animals and at some point there's a mutation and then it can be a problem for humans. and of course we then saw the way that COVID virus sort of was mutating, right and changing Why is it that you're saying so confidently that these viruses for bacteria couldn't be harmful for me? So a virus has to gain entry to a cell in order to do damage. So COVID the virus jumped from one species into humans and then became problematic when it could enter our human cells. So bacteria phages, they can only enter bacteria because the surface of a bacterial cell is very different to the surface of a human cell They might be able to go inside a human cell, but even if they did, they wouldn't be able to do anything when they got inside it because again, they've evolved to work with the specific machinery inside a human cell. So they can't gain entrance. and then even if they did somehow get in through some other means, they wouldn't be able to do any damage because they can't exploit the human machinery. they need a bacterial machinery in order to be able to operate I'm now showing my age and thinking about The world before everything was on the cloud and you know I've got my DVD or my VHS tape or whatever and I have to have the right machinery to play this on. Yeah Is that the analogy?aly. That's really nice because first of all, even within bacteria, a lot of the whole the battle between the bacterop phages and the bacteriia is all about that surface So that's where they're very, very specific within which bacteria they can actually enter in the first place And then if you think about the outside of a human cell, it's just very composed of completely different material to a bacterial cell. So it couldn't get in. And I'd like your analogy even if it did get in, it's got the wrong equipment, it would just be probably eaten by the human cell So we're talking about these bacteria phages. That's a fancy word for viruses that work on bacteria. So phage just means eat it's Greek from the Greek to eat. So bacteria ph e is just a bacteria eater. Oh, so this is a virus that eats bacteria. Yeah. Now I think I'm starting to get a hint, what happens if this virus like gets into a bacteria So what they do is they go in and they hijack that machinery of the bacteria and they turn it into a virus factory or a phage factory. So they essentially make perhaps ten or maybe a hundred or more bacterophages. So that pooral bacteria is just happily living, doing what bacteria do. The virus comes along and all of its genetic machinery gets turned into making more virus so it copies the virus And then it turns that information into the viral proteins and then eventually in a very timed where they all burst out. So you'll have a hundred new bacteria. What's your worst zombie nightmare, Jonathan. So that basically they're taking over your body And then it's like there's suddenly hundreds and thousands of zombie Jonathans. should be running around. I think that might be your worst nightmighting. Definite defefinitely down. I feel rather il now You've emphasized, firstly that these viruses don't cause any harm to humans We've also talked about them being like distinct to individual bacteria. F feels like it would be much more efficient if that virus could just stick ono every bacteria. It would find many more ways to go and create this plague of more viruses. If you're anything like me then at three or four o'clock in the afternoon Your brain starts thinking about only one thing. a snap And for years, I followed a very simple routine Id feel tred and hungry Stop work, go to a nearby shop and buy the nearest snack bar that promised to give me energy And if it seemed to have some nuts or raisins in it or had any health claims on the wrapper thenen I had the added bonus that I was eating something healthy Now if you're a regular listener to this podcast, you've probably been on the same health journey that I've been on And you'll know that those snack bars are jammed full of added sugar and artificial additives. So they spiked my blood sugar through the roof every time I ate them And sure enough I ended up hungry again a few hours later as my blood sugar crashed So imagine my surprise when Zoe's chief scientist, Professor Sarah Berry, came to me a year ago and said that the Zoe science team had completed a massive study of our data. It revealed that ninety five percent of us snack every single day that those snacks make up a hidden fourth meal that accounts for twenty five percent of our daily calories. However What it shocked Sarah with something else Her data showed that forty percent of people who eat a healthy lunch gone to eat a poor quality afternoon snack In other words, they're working really hard to eat healthy during their main meals, and then their snacks were sabotaging their gut health I was definitely in that category The good news Sarah told me she thought we could solve this. and create a snack that was actually good for your gut health while also tasting delicious Obviously, I said let's do it And then I waited. And I waited But finally, after a year of work with Zoe's Gut hellsciatists Sarah came back with a Zoe Gut Health bar Turning that snacking blind spot into a win for your gut I find that it's delicious and satisfying to eat while also containing a huge diversity of plants All carefully selected by Sarah and her team preserves the cell matrix of the plant. which we talk about so often on this podcast and it's designed to feed your gut microbes It's got seven grams of plant protein a huge eight grams of fiber twelve to thirteen plants in each bar, depending on the flavor My favorite is of course the seventy percent dark chocolate bar But my cofounder, Tim Spector prefers the raspberry and Gjibererry flavor Phaps I'm bias But I think our gut health bar is delicious And I love the fact that it takes time to chew instead of being hyper palatable and stuff full of artificial additives. I think it's time to stop giving in snacks that don't serve your health And if you feel the same way, why not head to Zoe. com slash snack bar and try for yourself That's Zoe. com slash snack bar Y' g Well, thank you Yeah. I mean, it's interesting, isn't it? It's just if you think about the fact that bacteria have been on Earth for three point nine billion years We live in a sort of microbially dominated world. In general, we tend to just think about the ones very often that are associated with us. But bacteria have been evolving for a very, very long time And with them, their own bacteriophages have been endlessly in a sort of almost like a dance and continuous evolution with them. So the bacteriophages are actually very useful for the bacterum in many ways, which seems a bit counterintuitive, doesn't it? becauseuse they kill them? But they also are capable of interacting with them in different ways. So I largely study these ones immediately they go in and kill, but some of them can go in and kind of hang out And when they're hanging out, they can make the bacteria better as a bacteria. They can make the bacteria more toxic perhaps or it can make it better at surviving certain situations. Like for example, in an anerobic gut, they can have useful things in there that help the bacteria survive. Certain chemicals, can't they? They're metabolites that could be helpful for us humans as well. Yeah, absolutely.'s like. You can think about the bacterophages as when they infect in that way, they have to pay their rent, okay So it's a good strategy for a bacteria phage to be able to just make a partnership with a bacteria. So while it's in there, it has to do something useful for that bacteria to give it a bit of a selective advantage compared to all the other bacteria. So you have this whole world really where all bacteria are being shaped by their bacterial predators. and it's sort of the phages are always trying to get in and the bacteria are kind of they want them there, but they don't want them to be too much there. So they're trying to block them and then the phages cant evolve and then the bacteria cannt evvolve. So you end up with all of these different trajectories of huge huge numbers of viruses. Can I make sure I understood that for a second? You're saying A lot of these bacteriaia phages, they just go in and they immediately kill the bacteria. But actually It's more complicated than that. There's a whole bunch of these viruses. that inject themselves into the bacteria, they don't kill it. and actually potentially giving it almost like superpowerers we wouldn't have otherwise. we think about taking some medicine or something we talk often about particular food, right? which helps our health or indeed having bacteria inside us And so you're saying that these viruses aren't always bad, which I'm finding very radical as a thought. They're not. They're sort of The viruses are doing lots of things for the bacteria. So from our perspective, they're just they're controlling the bacteria, they're determining which bacteria are actually there. So they're killing some, which means others can then grow up and then they're releasing stuff. And then other bacteria can then come in and grow there. So we've got bacteria phages just really controlling that biology, they're actually determining which bacteria are there One analogy is like they're acting as gamekeepers Pf of the fact there are lots of them. There are lots of instances aren't there when you get an overgrowth of some bacteria in your gut. And if they did overgrow, they would probably outlive their food supplies that would die off. So actually what these phages are doing pruding them back a bit like, you know, a coal If there's too many deer in a forest, you introduce wolves. keeps them down so that they're actually healthy and then that whole environment is much healthier. So that's another way to look at it. acting like you would in an environment that this ecology that's evolved to be the most efficient. Yeah. so when bacterial numbers get really high, that becomes advantageous for the bacteria. There's more likely that a bacterialhage will be able to infect them. so they will bring that abundant thing down. So they're really helpful in general for any ecological system because they're controlling the balance of what's already there I think of them entirely as a bad thing. so this seems quite radical. Is it only bacteria that can benefit from viral infections? Yeah, well, it was interesting, we don't really have a very good idea at the moment of whether bacteriophages are good or bad for us. What we know is that within a healthy gut, we have a high diversity of bacteria and a high diversity of bacteriophages we're just starting to work out now in particular diseases, this balance seems to change. So for example, in Crohn's disease and inflammatory gut disease, we know that the amount of bacterophages and the diversity, the types of bacteriophages reduces And we also now know as well that in other diseases, there seems to be a correlation sometimes between both particular bacteria and phages. So in certain settings, they are driving disease and in other settings, they are clearly playing a role in keeping the natural sort of diversity because when you see a disease state We see the bacteria phages and the bacteria out of balance. Yeah, we've done some studies in twins And it does seem that the diversity of these viruses how many different species and types there are, correlates with the diversity of the normal gut bacteria, which we know correlates with health So again it seemes to be the more different ones you've got the healthier you are overall. I mean these very early findings, but it seems to be behaving the same way as we' arere perceiving gut bacteria, we want more of them more different ones. We don't just want one strain that takes over, that would be very bad news This variety does seem to be beneficial I've read that there is evidence when viruses are in your mucus layer in your gums and things like this They've shown to be definitely protective for a chemical that's fighting infections particularly and they might also do the same in the gut. is that? Yeah, no, that's absolutely right. It's thought that bacterophagers can sit in the gut and protect us from the invasion of bacteria that causeesease So bacterop phages are covered in these little domains called IG domains. They're a bit like antibodies. So they sit in the mucous lining of our gut. and then if a bacteria comes along that would cause us an infection bang. They'll protect us against it. So they're part of our sort of defense system to bacteria that would otherwise cause us some disease symptoms Now just as you describbe that, now you're talking about these viruses actually inside our gut. Can I just take a moment because I think you were just saying the evidence is like the more variety of different phages is your shorthand in your propective these particular viruses, these phages. The more different viruses I have in my gut actually seems to be positive for my health. Is that right? It does seem to be that's the case. Yes. I have in my mind that whenever my body sees a virus, it just goes out and kills it. So what's going on that you're saying that my gut lining is like full of all of these viruses just resting there? Yeah, so from a very early age As we become colonized by bacteria, we're also colonized by bacterophages by phages. So for every different bacteria cell that's there, there'll be ten bacterophages. Now they're in both of these life cycles that I told you about, so some of them are infecting and killing, others are infecting and hanging out. They're shaping what's there, they're changing the biology of what's there, and then they're also living within our guts are just sitting. But our immune system is effectively trained to see them as friendly. Yes, that's right't pick them up as like a a gastroenteritis virus, which would trigger our immune system. These ones are you know your friends and foe Most of them are friendly and From early age, babies or immune systems are being trained. Every time they eat food or take anything in, they're getting viruses and that just says, okay, relax we're on your side and so they don' you don't get a reaction against it. So our immune system knows that these viruses, these phages are actually safe and actually helpful. and so it says, I'm not going to attack you. Yes. I think we're all familiar with the idea that there's unhealthy bacteria that I can eat, and that's why we tend to wash our hands What about viruses Oh yeah, you can easily get viruses that make us sick and Teric viruses will make us sick of our human viruses. So our body will definitely imagine immune system when they see them. The phages are quite different in terms of their relationship with us. It's not that we can't see the viruses in our gut. Like our immune system absolutely can see them. and then it's like, Ohh, I know you're safe ome other virus comes along that can make me sick and it's immediately pouncing and attacking. Yeah, exactly. So in the same way that we don't mount an immune response to our commensal gut bacteria. We don't mount an immune response to our bacterophages. They're just part of us. So a lot of the work in my lab is finding phages that we can use to treat bacterial disease. So for example, we've done a lot of work in Salmonella Now if I wanted to find salmonealipphages, I was originally going to sick animals and sick people. We didn't find any because at that point, is escaped. But if you just go to healthy animals, healthy pigs, healthy chickens, healthy sheep, you'll find in there species, really good viruses that kill Salmonella Part of one of the reasons why we're healthy is that we have these phages that kill things that invade us You have your defense system, so nobody attacks you. and so you're saying if I've got all of these bacterophages ready in my gut I don't get the salmonella. but if I didn't have those and I'm overrun with salmonella, you're like, well, that's because there is one of these phages to protect me. Yeah, exactly. So the phages are just part of our natural defence that's keeping us healthy. But it can be overrun if there's too many of the salmonella bacteria which just overwhelm the system ca course toxins and all the other kind of havoc they can wreck or person is unwell for other reasons. and We know that general sickness reedduce the number of these normal healthy phages in your gut That's why older people and people who have other diseases are more prone to these bacteria you get in food Could you help me to understand that a little bit more? Yeah of course. If you look at the viral diversity of people as they age, we know that when you're born, you don't have bacterial phages and your' g that gets colonized in the same way it gets colonized with bacteria. And we can see that that diversity goes, it starts to go up and then it stabilizes at the age of two. And then again, it goes up a little bit more through your teenage years. And as you get old,'s what Tim is saying, the amount of phages for some reason, goes down, so you lose your diversity with age. So we have a sort of relatively static phagome in the same way we have a relatively static microbiome in general But with age, the diversity drops One of the things that's happening as I'm getting older and worrying about obviously maintaining my health, you're saying this like diversity of viruses that are protecting me is falling away and therefore I'm more at risk from infections than I would have been when I'm younger I don't think we know quite enough to know that yet, to be honest, but I think that certainly there's a lot of variety in terms of the component and what they're doing. And I mean amazingly really, theres so little known actually about what those viruses are encoding So if you think we've got perhaps a billion bacteria in each gram of gut material, there'll be ten billion bacterop phages No They're really unknown. So about eighty percent of them, we have no idea what they encode, how they act, what they're doing, how they're behaving. So's in terms of discovery space that there's so much to try to unpick. Yeah, I mean if we compare it to what we knew about the microbiome, it's about twenty five years behind. Yeah. So you've got to try and imagine what we knew about the microbiome twenty twenty five years ago, and that's the sort of state of play of what we understand about these gut viruses. but We have the advantage of knowing all the things we know about bacteria so that we can project a lot that we didn't know. So we're having to sort of guess a lot at the moment because they're really, really hard to study I was told that I have to ask you about the healing waters of the river Ganges and why they might actually be healing waters. Yes, this is really fascinating. The Gangis of course, are a long history of being a very spiritual place and it's known that people go to the Gangis and get healed from things. But interestingly enough, the very very first observation of ed out to be bacteriialhages were seen in the Ganjis. So in the late nineteenth century, there was a British biologist. he was there, Hankkin and sankin his name was. and he was looking at the water and he realized there was something in the water that killed bacteria and he didn't know what it was, but he knew that if he boiled the bacteria he didn't get this effect anymore. What's happened is I think that the ganges is a really interesting place for bacteria.ople It's a lot of connection with humans. there a lot of human bacteria there from us. Also it originates in the Himalayas, there lots of natural bacteria washing in from the soil. So a huge diversity of bacteria. It's a big diversity of bacteria phages. So if you have a bacterial ailment and you go into the ganges, it could easily be that you'll find a natural phage that will then cure you that some of those healing properties. You have to be, I would say, quite brave. I did go to the Ganges for there was a big religious festival there. and people were jumping in and drinking the water. Yeah. Thousands of people going in there. And at the same time, I'd witnessed that morning burning bodies on the banks of the Ganges and you had dogs You I still sniffing around these bodies. So there's human remains in there. There's all kinds of things that you don't want to really comprehend. So the idea of drinking Gangji's water to be healthy. It's a big leap of faith, but it is interesting that they keep doing it. so they can't really be getting that ill. So it's not on your twenty twenty six habits to adopt Tim is drinking Gangjes's water No no, I'm sorry, Jora. I'm happy to sponsor your trip there and see if I'm thinking if you're not willing to do it, then it's definitely outside of anything I'm gonna. I chickened out. I was offered some gange' water But I did turn it down. But maybe know the science will support me next time and I'll be brave enough. Have you tried it, Martha? I have been to the Gangis. I was there last year. I was at a phage meeting in Faranasi where my collaborators had actually purified phages from the Gangis. and they were actually using them already to treat patients. So they were treating patients with really bad multi drug resistant infections, that could not be treated with other methods. So they were actually using Gangi' phages. So I think P purified gantesephages is probably a different thing to drinking the actual water itself I would love to talk about that Can you start by helping me to understand what antibiotic resistance is And I've definitely heard that somehow this is a really potential rule danger for us We U antibiotics for all aspects of medicine, don't we? If we have a bad chest infection or a skin infection, we will go to the GP and we'll get antibiotics anivertics also underpin all surgeries, cancer treatments and so on But what's happening is because they've been overused, bacteria are capable of becoming resistant to them. So they just evolve different ways of being able to exist with them. So normally an antibiotic will kill the bacteria and they have many different ways that they can just actually become resistant to them so they can survive in the presence of it. So that means that the antibiotics are not working anymore. So there is more and more bacterial diseases that are literally resistant to every single antibiotic that we have available to us. So it's an incredibly worrying situation is already it's estimated more than a million people dying every year from an infection that can't be treated and also several million more associated with these infections.ould you say more than a million people are dying every year from infections that can't be treated by antibiotics. And because there's lots of different types of bacteria and lots of different diseases, it's somehow not given the attention that it should, but it's incredibly serious already. We need to do something now because it's estimated that if we don't do anything, we'll perhaps have ten million people dying every year, so it'll exceed the number of people that are dying from cancers. Yeah the overuse of antibiotics in the public for colds and viruses It's also in our food supply It's used in low levels in a lot of food production For example, chickens grow faster and you know cut out infections in animals and it's used preventively. In Europe, they've managed to cut this down a lot, but a lot of the world, it's still very prevalent and fish farms still use it. So it's a real global problem So can I just clarify, you're allowed to give antibiotics to animals? even if they're not actively sick. In Europe now they've for about ten years, they've changed the rules. So Um, you can't give it Totally preventively. but if you just say one of my animals is sick out of ten thousand You can then give it to the rest of them So it's not completely black and white, but it's pretty different from what we do with people. I can't be like I met himim this morning. I told me he had an infection, so I'm gonna pop antibiotics. And everyone you know. Yes I know. Yeah, that's the equivalent. So it's still lacks. And many countries haven't signed up for this. so it's a global problem Yeah, so about seventy percent of all antibiotics are used are used actually in agriculture. They're used in the production, particularly of poultry, swine and fish farming ye. we literally put it into the water. Yeah. I should say that I've done a lot of work with a poultry in the UK and our UK poultry farmers, they actually stopped using them for this purpose even before it was banned. So there are our community led initiatives within the industes to stop this happening. but in many countries, it's a major problem. So we have to really think about our antibiotic resistance, where it's coming from and how we can stop it. So you can see we really need to understand a one health approach. It's not just the antibiotics that we given to humans. If we give antibiotics to the animals that we eat, we will then get these resistant organisms. And we have a lot of listeners in the US. What's the usage of antibiotics in animals there I think the extent of the problem in that area is still not fully known, but it's known that there are transmission risks. And the thing is once it's present, bacteria are super good at swapping and telling another bacteria, hoy, this is how you do it. They're really good at spreading resistance amongst them. So once you've evolved that resistance, it can spread really rapidly. I think anywhere where there's mass agriculture where you're putting thousands of animals together Whether it's in fish farms or these cattle lots, you're going to get problems of antibiotic overuse And this is a problem for everybody. So even if we stop now still in a quite perilous state of having not enough antibiotics to treat these common conditions. And so things that We thought impossible, you know, it's peopleeople are looking at if we fell over in the street in ten years time cut our leg There might be no antibiotic that would stop us getting se and dying from a simple cut. And I think the thing is it's happening now, even in the UK, it's estimated there's more than seven thousand people a year are dying of an infection. I never solicit this information because we're doing the research on bacteria phages to make sure we develop the correct ones. But I get emails all the time from doctors who write tell me that they can't treat their patient because their patients have got an infection that's resistant to everything. So it's a problem now, a major problem now something sooner rather than later. So could we now come back to this magic gange water and the phages in it? I think you've described this rather terrifying idea that we're handing this out like candy, not just to humans, but to animals to make them grow faster? this magic Gange' water help us? Well, it's not just the Gangess water. mean that was just where they happen to be seen first of all, but anywhere where we have high numbers of bacteria, we will have high numbers of phages. and phages can be developed as a treatment against antibiotic resistant bacteria So actually, it might surprise you that they were developed before antibiotics. So more than a hundred years ago, phages were actually isolated in nineteen fifteen by a British person, Frederick Tort, and a couple of years later by a young French Canadian called Felix D'al So phages were isolated. and Felix Durerell actually started to use phages to treat people in the twenties and thirties and forties. So they were actually used for a fair chunk of time before antibiotics were discovered. And then antibiotics, because they're simpler and easier to develop, they sort of overtook in terms of a treatment they're marvelous and they became our cornerstone of modern medicine. And then this whole area of bacterophage science as a medicine in most parts of the world was terminated. And so why was the antibiotics better than the phages? Well, an antibiotic is a simple compound can kill lots of different types of bacteria. So for a start, it's much less specific. You don't really need to know what you're killing. you just need to know it something making your gut sick. and then you can give the antibiotic roughly. So they're much broader in terms of their specificity than bacterial phages are So you're going to need to know what the target is really for your phages to work So this is sort of like I'm stretching my analogies a bit here, but the antibodot is sort of like a nuclear bomb. It like blows all of this up. That right. Where as you're saying, the phage is, it literally has like the photo of the exact bacteria that it's looking for and it lets everything else go until it finds within that analogy It's like a sharp shooter. So if you want to use a phage you need to have one that is perfectly matched to the bacteria that you need to try and treat. Yes, that's right. So actually the country that is most developed in this whole area is Georgia. So the former Soviet Union was really big on pages in general. that's because this first person that found the French Canadian, he trained the young Georgian scientist And whilst most of the world stopped using phages therapeutically, the Georgians carried on So I think one of the things that I know from personal experiences that if you take big I think they call them broad spectrum antibiotics, they can sort of wreak havoc in your microbiome. you know If I was to take these phages, would it have the same effect of knocking out my whole microbiome? No, not at all. When we've looked at the addition of phages in our different largely doneet in animal studies, we can see that they don't the phages would just will take out that one species. They don't and they protect the rest of the microbiome is left intact So they have a much less detrimental effect on the whole of the commment, All the good bacteria are maintained, basically Are there any examples of this phage therapy actually working in humans? because in a way, this sounds really exciting, but I think one of the things I've slowly learnnt over almost ten years now at Zoe is sometimes there's a very long way from speaking to a scientist doing research in their lab or talking about something in animals to like this thing is actually like real and works in human beings. Yeah, so they're used, as I say, they're used routuni in places like Georgia, where they treat thousands of patients every year They're largely used at the moment in worst case scenarios where there's nothing else has worked. so therefore phages are allowed to be used So there was a very nice paper published last year from Belgium and the military hospital there where they just treated one hundred patients and they wrote a paper of how they'd use the phages and how they'd combine them with antibiotics. So there were those types of cases where they're used. There was one very interesting case with a man called Tom Patterson. So he was a psychiatrist, he was from San Diego and he was on holiday in And he managed to get himself infected by a multi drug resistant bacteria. So they couldn't treat him, infected his kidneys. He tried to get treated in Egypt. they couldn't treat him there. He went to Germany, they couldn't treat him. And he ended up in a coma and very, very ill in San Diego. Now, Tom was lucky enough to be married to a woman called Stephanie Straty ground was in epidemiology and viruses. so she knew a lot about microbes in general. And she managed to get hold of bacteria phages from various places and they were able to find some different phages that were able to treat his infection. So he was basically dying and given ch very, very low chances of survival. and they managed to find some phages that they used to treat him. Did he recover? Yeah yeah he's perfectly fine now back So he's completely better and he was The doctors have basically given up because The infection he'd picked up in Egypt was resistant to all the different like literally every antibiotic that exists. Yeah, exactly. So it was resistant to everything. He was very ill,. Stephanie I' met her Stephanie several times. she's great. and she told me that she basically said to him, if you want to live, squeeze my hand and he did. And she managed to get phages from the American Navy, from there's an institute in the States where she also got them from one of the big phage centers there And then from some other private companies, she got a hold of all the phages she could different types and they gave him the phages and he lived. So that was one of the first sort of high profile cases in the states where bacterop phages were used. Do you think we should still be going to Georgia to stock up on our supplies in case we get ill I think there's a lot we can learn from Georgia for sure. I think what we need to do is understand bacteria phage biology to the point where we can make it mainstream in this country and where it's not just used as a last resort. It needs to be brought much earlier into the intervention. Ideally, you'd like a GP to be able to access both phages and antibiotics It used to be possible to buy bacteria phages in Boots the chemist in the UK until about the nineteen sixties. and then they stopped stocking them. but you can see in Boots records, they did used to sell them here Wow, that's really interesting. Yeah. So it's a traditional medicine here. We just forgot about it like fermentation and other things. What are your thoughts as we're talking about this, Tim? Is this like really niche sciences can be very hard to translate into something real or Is this a real way forward to avoid this sort of broad spectrum antibiotic usage I think it's pretty much the only approach to counteract the fact that we're running out of antibiotics and the millions of people that are going to be dying every year is going to increase. We are realizing that this antibiotic resistance is real and This is the number one treatment that we, you know, that we've just had, you know, has been used quite widely retty safe. That's the other thing. It sounds really scary. to drink a vial of viruses, right? You don't look very comomfortable try. We' maybe get you to try it afterwards with your tea, but You know, it is pretty safe because they're so specific You know, they're only going to go after these specific bacteria that are in you and they're not going to attack anything else. So I think once we get over this psychological barrier, of using viruses or drinking viruses as treatment then we can make big progress. but We can see how it's really hard to get these sort of medicines into our very conservative system. really needs to change, but I I think as well as the antibiotic resistance, I was talking to some colleagues about cancer treatment. that the very nature of these phages is that You can target these phages to attack essentially cancer cells Yeah, you can actually you can change their specificity and use them as delivery vehicles so they can recognize the outside of a cancer cell and re differentiate that from a healthy cell and deliver a drug. So that's one way that we're looking at sort of even taking them into a different area outside of the bacterial phage is very specific and finds the right bacteria. So what we can do is we can modify that so it doesn't recognize the bacteria anymore, but instead it recognizes cancer cell. When a cell becomes cancerous in the human body, again, the outside of it changes within the whole mass of a human body, you can get the phage to go to that cancer cell and then you can previously have engineered it to have what we call a payload. So instead of it injecting a bacterial genome, it will inject a cancer treatment. So it's one of the ways that we can use phages. when we understand them better, we can use them both to manipulate the microbiome, but potentially also to deliver things Because they' these specific assassins. They're so targeted that they make it really safe. And so you could, you know, drink a whole bucket of them and they'd only be going after that cancer cell. They would leave all your other cells alone. And so very little collateral damage unlike antibiotics. And I think that's what's so exciting about them And so is this entirely theoretical or in labs are they actually able to create these sorts of phages that can actually go after a cancer and a human being? Yeah, so phage engineering is again quite in its infancy. But what we've done, for example, in our lab is make phages that can attach to human gut epithelial cells. So therefore you could use them potentially to deliver something to the gut There aren't products at the moment. This is still very much in the research phase In regard to cancer, another really interesting thing is one of my colleagues, he's a surgeon treating lung cancers, and he's shown that he can predict whether or not patients will respond to his cancer treatment based on the human microbiome. So he can tell from the fecal the gut microbiome if that patient will or will not respond to cancer treatments So you can imagine use of phages in the future isn't going to be just the uses we've been talking about just taking out one bacteria, but it's potentially modifying that gut to a state that's appropriate and receptive to another treatment So we can use phages as a kind of If we understand how they're manipulating the gut, we can then influence them and push the gut microbiome in to a sort of composition that makes it amenable to other treatments. how the gut microbiome is really important for these immmune modulating drugs and cancer. Yeah. So that these new treatments for melanoma, kidney cancer, lung cancer So what you're saying is that these phages could be an addition to that. Yeah. So they rather than just giving people fiber and probbiotics and prebiotics. You could also give them phages, which was sort of help the immune system fight the cancer. Exactly there be part of that mixture might happen faster because you could be more general. we could try the Georgian mixture, for example, in some of these cancer cases. ye. Amazing. If you know someone who's working hard to improve their gut health and microbiome Why not share this episode with them right now they can start thinking about gettinget those healthy viruses into their gut too I'm sure they'll thank you What do we know if anything about how these viruses might be influencing our gut bacteria today if you're you know listening to this shard. So we know that we have a lot of viruses in our guts, and what those viruses will be doing is they'll be killing certain bacteria And that means that when those bacteria die, they'll be burst open and food will be provided for other bacteria to grow in. So the viruses are actually already determining that composition. So we're eating food, the bacteria eating the food that we eat, and then the viruses are then eating them and then sort of shaping them So we know that that's what the viruses are doing naturally Now if we eat a ice, diverse set of food, We'll have bacteria that will be growing in a particular way which makes it more likely for the phages to then come in and then burst them open. So really we've got the sort of diet affecting the bacteria and the state of the bacteria affecting the way that the bacteriaop phages are then interacting with them. So that's sort of what's going on amongst us the whole time a static microbiome. Yes, the way I see it viruses are mirroring the state of our gut health so the healthier our gut are The more diverse they are, the more diverse our diet is the more diverse set of saages you have then able to really sort of do the forestry and the husbandry correctly so that Our immune system is working really well and everything's in nice balance. because I don't think there's any particular foods or anything that affect viruses and not. that I'm aware of. mean It's not a very researched area. There has been a little bit. There was an interesting paper that subjected hundreds of bacteria in our guts to lots of different types of food. and they could see some quite interesting things. like there seems to be a positive correlation between phage types and coffee, which I thought was interesting We could see that people that drank coffee regularly, they' particularly high on a set of phages within their gut People who are drinking coffee tend to have more of these phages than people who don't Yeah, we don't know. they're probably good phages. They're certainly not bad phages. just it's very, very hard to turn correlation into causation when it comes to many aspects of the gut microbiome, including the phages. So what people have done, there just this one particularly nice study and they showed that some foods seem to make the viruses pop out of the bacteria. Aually one of the most potent things was Stevia. I think you've discussed that on some of your other podcasts. So it's a sweeten another that comes from a plant And that seemed to those viruses I talked about that were hanging out with the bacteria just in there. they popped out. they didn't like the stevia So what about if I wanted to get more of these phages into me? And I think one of you was saying something about potentially they're living in Like the plants that I might eat. couldould you explain that to me? Yeah, well, we know that if we eat vegetables that are grown just in that haven't been packaged in artificial atmospheres, they're covered in bacteria and they're covered in phages. And so if we just by part of a normal healthy diet where we're eating plant material, Do pesticides and herbicides affect? They will affect it. Yeah ye, they they're reducing num a significant way The same way that they reduce the bacteria, they will reduce the the number of the diversity of bacteria and the diversity of phages alongside that. Yeah There was a study that showed that if you eat lettuces that are just grown in your own garden or small market gardens, they had a much higher number of probiotic bacteria and phages associated with that compared to bagged salad So we will get phages from our diet from the natural plants that we eat I think what we know is that if we have a large diversity of plants and starting material, we will have a larger diversity of bacteria and with that we'll have a large diversity of phages. I don't think we have really the concept of what makes a healthy phage and really which phages are going to drive our guts in the right direction. I think it's just part of a natural Mediterranean or a naturally non artificially based diet appears to be good at promoting that phage diversity as well as the bacterial diversity. I think we can say that We're realizing that as well as this diversity of bacteria, we've got this whole extra sort of layer of the phages sort of directing all aspects of that bacterial biology. And as we unpick that more and understand it more, we'll be able to know how we can drive things in one direction or the other But I think for now is mainly just knowing that we've got lots of good friendly viruses in our guts as well as for good useful bacteria I mean, one thing I'm really struck by Marttha and I I always think this is a sign of like speaking to the real scientists who do the research rather than You know, some sort of social media influencer is that there are so many things about our human body where we just don't understand yet what's going on and we don't have all the answers. And I think phages are particularly new. I mean the fact that we just don't know eighty percent of the content in our guts, I mean we can send men to the moon, but we don't know what's in us. But I think that is exciting is even a decade ago, we wouldn't have had the tools to be able to get that genetic information and make sense of it. So we've been developing new bioinformatic tools to make sense and to understand this novel diversity. So if phages are so so diverse, I can still find them, look at them and not recognize anything. but now I can go into what we call structural space. We can predict how they might fold and how they might look that can help us understand how they work So I think it should be a really exciting time now in this area because for the first time we've actually got the techniques and the tools to be able to, first of all, understand it and then make use of it. I mean, these phages have been they're the perfect bacterial predators. We sort of ignore understanding them at our own peril really If I was going to ask you like what's the one thing that you're most excited about in terms of like the future or phages in human health, what would it be I think being able to actually go from Kning that they're there in huge abundance and they're playing roles, actually being able to use them in ways that are useful to us, that is really exciting. We'll be able to use them to stop infection, to prevent infections and in a multitude of other ways to control our microbiome. So I think we're on the cusp of that actually, being able to do something useful with this knowledge It's incredibly exciting I love your analogy, to us, Martha, you know, we can go to the mooon and se all these things And we don't understand so much of what's inside our bodies Yeah, no it's We've always gone outwards instead of inwards and that's generally the human fallacy really, but looking at the stars and not looking inside us. I think I have enormous potential to get us out of this terrible mess that overuse of antibiotics is less of us with. And I think that's me the really big hope and that's why we need to be putting more funds and money behind this field, which actually we've been very slow on You know, I don't think we really grasp this and it's been very hard to get grants and they, you know I failed a few times to get some grants in this area. Yeah, I think you're right. It'sort of seen as being niche and sort of in, which is ridiculous really. And also it's seen as being risky, but we actually need to do the work to show how they work to be able to d risk it Amazing I would like to do a quick summary And I'm just starting with the things that I've been most struck by. The first is There are like trillions of viruses in my gut and apparently that's good for me, which I think is the exact opposite of like everything I've been taught my entire life that Maybe drinking Ganges's water might be good for me because it's full of all of these amazing bacteria phages, these phages who've talked about these viruses that attack bacteria. So actually if I was really sick Perhaps drinking the Ganges would make me better. But if even Tim isn't willing to do it, I'm probably not going to experiment there I think you also shared this thing that in like one teaspoon of sea water, there's a million bacteria and ten million of these phages, these viruses. Y makes you realize how much we're coexisting with all of this life and we have done throughout like our evolutionary history and we just don't realize This area of science is new, but we do know that actually when you look at a healthy gut, it has a lot more diversity of these phages than an unhealthy gut. So just like we talk about with microbiome and wanting to have a lot of these different good bugs. L similarly we want to have a lot of these these phages. And then interestingly, our own immune system is like trained to keep these. So you're saying that like in my gut right now, there'll be trillions of like these phages that my body is aware of and keeping there because actually it might attack if I get salmonella or something like that. So actually part of my own immune system almost is to keep these phages ready to attack these bacteria. Just as we talked about like the bacteria is almost been part of our body and part of our system. you could actually even extend that The viruses of the bacteria to help sort of protect us is wild And then I think we talked about This amazing story about Tom Patterson like getting so sick in Egypt with something that couldn't be treated with antibiotics. he was going to die and he was healed by taking these phages. So this is real, it can be transformative. and that's important because A million people die a year from antibiotic resistance bacteria, but it could be ten million, one hundred million, it could be a billion. We need to have a solution here We can even be using this in cancer in the future, as Tim was saying. So that's incredibly exciting Now in terms of actionable advice, it's early So it's hard to like give lots of detailed advice. but what I heard is very much The advice you're following to get a sort of diverse healthy microbiome is probably the same advice to get sort of this diverse and healthy set of phages. So it's the same thing of like eating plants and variety. And then I heard specifically maybe a couple of things, which is we can measure whether there are phages around on the food that we eat. So if you're eating food that you know hasn't been packed in like an atmosphere, you know if it's more organic or less pesticides, you're going to get more microbes on it and you're going to get more of these phages with it And finally, Tim's going to be really happy because apparently coffee drinkers have more phages and Tim is on a campaign always to tell me that I should drink more coffee. And so there's just yet another argument for how coffee is actually good for us rather than b Its brilliant sorry. love Professor Sarah Berry here.