The friendly virus

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0:42But they didn't care. I'm dying laughing. Making outrageous demands for money. They wanted millions. It was high tech and high stakes. The country is under attack. And it was highly secretive until someone exposed it all. Cyber hack season four, The Conti Files. Listen on BBC.com or wherever you get your BBC podcasts.

1:07What does snow leopard poo have to do with the biggest challenge facing modern medicine? According to some scientists, we're about to meet potentially quite a lot. The connection is our ability to harness the tiniest, most plentiful, almost living things on the planet, bacteriophages. Before we go back to the zoo, I think we need a little more on these tiny phages. What are they? Well, they're viruses. And if I were to look at some with an electron microscope, I'd see a curious menagerie of structures. Imagine the six legs of an insect with something a bit like a bolt screwed on the top of it.

1:51Or angular squids. These are bacteria killers. The word phage means to eat or consume in Greek, and bacteriophages are picky predators, infecting and attacking specific strains of bacteria, often unpleasant bacteria like E. coli or MRSA. You can think of them as our enemy's enemy, the friendly viruses. They have the potential to be our superpower in the battle being fought in every hospital, in every country on earth, against antibiotic-resistant bacterial infections. There is nothing else that's scalable. We need antibiotics for everything we do in medicine. So it's a problem that desperately needs to be addressed before we're just returned to the dark ages.

2:43We've known about phages for more than 100 years, yet there are no licensed products available in the UK. There is, however, a buzz about phages right now. Only last year, the UK Health Security Agency said phage therapy truly has the potential to transform the way we treat bacterial infections. So, what's stopping us? How close are we to using phages? The search for answers takes me back to Dudley Zoo on a cold but sunny spring morning. I'm Martha Clokey, I'm a professor of microbiology and the co-director of the Vecchymare Centre for Phage Research at the University of Leicester. Why are we at Dudley Zoo?

3:27We are collecting poo samples from the animals because we know that that's a really good source of bacteriophages. So we're stood outside the snow leopard's enclosure. Why is snow leopard poo interesting? Well, we sampled around about 80 different animal species. And the snow leopards, the cats in general, but particularly the snow leopards, we've got the most number and the highest diversity of pages from those snow leopard samples. So who are we going to collect today? I believe we are just off now to go to the giraffe enclosure to see what they have produced. I'm Emily and I'm a ungulate keeper here.

4:03And we're stood next to the giraffes. Can you point them out to me? Yeah, of course. So over on the right here, we've got Keira, who's our younger one. And then on the left-hand side here, we've got Josie Mum, who is 17. They are a pretty pair. Thank you. All right, so we're heading into the giraffe enclosure. Man with a bucket. I've got you some poops. Oh, bucket of poo. We have got a range in here, I believe. We've got a bit of Keira and a bit of Josie, because there are some smaller and larger ones in here. Martha bacteriophages are everywhere but why is there particular diversity interest in poo?

4:41Most of the abundance of our guts and the guts of animals is bacteria what most people don't know is that those bacteria are being manipulated by bacteriophages in different animals the phages and bacteria have evolved with time they've gone over their own sort of micro battles as it were so we can we can specifically see if there are phages associated with different animals that have got good features that might be useful for us in different ways. So phages are everywhere, but particularly wherever the bacteria they attack are found. Sewage water has proven a good source, but so are all animals' gut microbiomes.

5:18And Martha and her team say no one has systematically phage hunted from zoo animal poo. So these are unexplored territories, which is a more romantic way to describe a couple of olive-sized giraffe poos in my sample pot ready for testing in the lab at Leicester University. My name is Faisal Patel. I work as the Biobank Lead, helping organise and obtain as many phages as possible using the collection of poo that we've got in-house. As a special treat, the team have allowed me to put on lab coat and gloves and I'm going to process some poo. On the white rack to your left, correct, there's some liquid there.

6:04Yep. You're going to open that tube. You're going to aim for 20 mil. And now if you just get another wooden spatula... Mm-hmm. Mash up the poo. Mash up, basically, yeah. Oh, so good. You just got to... I can see lots of bits of grass that it's been eating. I'm so pleased this is a vegetarian animal. So that will go, we call it the ferris wheel of poo. So we're going to take it onto that and tomorrow we'll spin it down and actually start processing and testing it tomorrow. Great. For now, we say goodbye to Josie the giraffe's poo sample, but I'll check back in with the team at the end of the programme to see if they've collected any good bacteria-killing phages.

6:42In the lab next door, Professor Martha Clokey and co-director of the project, Dr Andy Millard, showed me what was in store for my sample as they process from poo to DNA sequence. So you can see here, this is a lawn, so it looks slightly yellow in colour. We take a spot, so a small drop of that, and we spot it on top to quickly screen to see whether or not there is any viruses present. And if there are, you can see we start to get clearing in the middle. A lot of our listeners will be very familiar with the idea of agar plates with some sort of bacteria growing on them, or penicillin even is a classic.

7:22You can see the mould growing on. What we're looking at here is actually the inverse of that, right? Yep, so the viruses are eating the bacteria from the inside. They're causing them to burst. As they're bursting, they infect the next cell next to it. So that's why we get these increasing circle sizes. You're looking at your enemy's enemy. Yeah, exactly. Phage therapy does have its sceptics, I should say this. There are people that are concerned that we're putting viruses inside us and that maybe they might be stimulating the patient's immune system in a way that's actually not good. What do you say to that?

8:00What I would say to that is we will get the clinical evidence that will alleviate people's fears. And you can see why people have those fears. People often say, well, phages have been around for ages. If they were good, they would have worked by now. But we didn't need to develop them, so no effort was really put into developing them. Okay, so is phage therapy safe? Yeah, phages have got an exemplary safety record. So we have a paper which we published last year in Nature Microbiology, where one of the things we did in this paper was show that all of the sequenced phages that have been used in therapy are actually found associated with bacteria associated with us naturally.

8:38I think unlike an antibiotic or another medicine, which is something very alien to what the body's used to, we're used to phages, they're in us, they're amongst us. So yes, we have to assess that risk. We have to assess and show that they're safe. But actually their safety record is really, really very strong compared to any other intervention.

9:00The excitement about the potential for phage therapy in Martha's lab is palpable. But Martha has been excited about phages for a long time. So why are things moving so fast so suddenly? Why is this happening now? Well, to try and answer that question, I've got up very early this morning and I'm currently on the train to Paris. Why Paris? It's a key location for the start of the curious history of these friendly viruses. But first, I want you to hear a story set not in France, but in the former Soviet Republic of Georgia. Crucial to the development of phage technology is a 100-year-old scientific institute in Tbilisi.

9:48The Eliava Institute was named after its founder, microbiologist George Eliava. In its heyday, it wasn't just a lab, it was a factory, producing and supplying phage medicines for soldiers in the Soviet army. These were life-saving phage mixtures, or cocktails, that worked against diseases like cholera and gas gangrene. When the Iron Curtain fell across Europe at the end of World War II, the phage research being done in Tbilisi was cut off from the accelerating research into antibiotics in the West. Whatever was meant to be good for Western people was, of course, criticised in the eastern part of the world and vice versa.

10:32So phages were counted as Soviet science and not to be trusted. Yes, yes, exactly. That's Nina Chanishvili, head of the Microbial Biotechnology Laboratory at Eliava. I met her in Tbilisi back in 2019, and I saw more than Eliava's research labs. I also saw the clinic where phages were being used. So coming in and there's a waiting room and there's half a dozen people in here from all over the world who've come to meet the doctors. People like Anya, who had come from Switzerland with a persistent stomachache that was making her life miserable. Everybody said it was in my head. Can I ask about your symptoms?

11:19Yeah, well, always cramps and like a balloon, very... Big stomach. Yes, big stomach and always hurting. Eating anything, it's just hurting every time, all the time. So you're in the middle of the treatment? Yes, and I already feel it much better. I just told her it's the first time for years that I'm hungry. Oh, wow. Because I didn't know what it means anymore. How does that feel? I'm normal. Really thankful. I'm not saying this place is a cure-all, but the research that has been published on phage therapies here supports Anya's testimony. Phage therapy can have remarkable consequences. And yet, the rest of the world had abandoned these viruses mid-century in favour of antibiotics.

12:14All so I thought. Back to my early morning train ride. I know that Paris played a part in Eliava's story. Now, we are currently gliding through the outskirts of this great city, and when I get there, the first place I'm heading for is somewhere where Eliava worked and discovered phages to see if I can find out more. Where are we going? Right here. I'm at the world-famous Pasteur Institute in Paris. Yes, that's Louis Pasteur of pasteurisation fame. This was the place for phage research, and it still is a hub, which is why Professor Laurent de Barbier is showing me around a refrigerated lab. Yeah, I nearly took my coat off and then thought, no.

13:05Can I just get you to describe the smell in here, Laurent? Well, it doesn't smell anything for me. I mean, what it's meaning is meaning the medium that we use for growing bacteria. So Laurent has got a big plastic box off the top shelf, and in it are hundreds of little glass vials. Those were actually produced in the 70s as a phage suspension for use in patients. Okay, so back in 1972, you could make a phage concoction here in the Pasteur Institute and give it to a patient. Well, they were producing that suspensions that were actually available for doctors to treat patients. To give to patients, yes.

13:48So why aren't they available now? Well, that's the long discussion. OK, let's get out of the fridge and then have that. Yeah, I think that would be better. So France has a long and entangled history with phage therapies and were making them for use alongside antibiotics until the 1990s. This isn't a case of Western versus Soviet science. An arrondissement over from Pasteur, in Paris's main medical teaching university, I'm meeting Klaas, a historian of medicine who's writing a book on the phage story. I'm Klaas Kichella. I'm an associate professor working for the French Institute of Health and Medical Research, INSEAM.

14:30Were phages discovered here in Paris? That's a bit of a controversy, and it's been one that's been raging for quite a while. So phages or phages, I think I'll refer to them as phages because we're in France, were discovered over 100 years ago, almost around the same time, one time in the UK and also the kind of second time here in Paris. The UK discoverer is called Frederick Twart, and he discovered them or published the paper on them in 1915. And there is a Franco-Canadian, Felix Derel, who published a paper on his discovery of bacteriophage in 1917. Derelle is the one that gives the name to bacteriophage.

15:07Back in 2019, I was lucky enough to travel to Tbilisi in Georgia, and I went to the Eliava Institute, named after George Eliava. He first worked with phages here, though, right? Yes, he was at Institut Pasteur in the 1920s, like many Russian microbiologists, actually, who had their training here in Paris. Derelle has already discovered phage. And Derel, this is the other crucial thing, has already started experimenting with phage therapy. And Iliava actually meets Derel here in Paris and later on actually invites him over to visit and help him set up the kind of major phage production facilities in Georgia.

15:47As clinical trials developed, antibiotics produced more impressive results. But fringe phage therapies persisted. Klaas shows me a graph from Pasteur Records showing a steady stream of cases from the 1950s right through to the 90s of phage medicines produced for French citizens fighting particularly nasty bacterial infections. They did it on a no-cost basis. They were just charging the hospital for as much as it cost the technician to produce the phage. The Pasteur Institute experienced a financial crisis like many other scientific and public health institutes in the 1990s, and as a result, the therapy service gets cut.

16:28For just a few years, the phage pipeline in France dried up, which, as Laurent de Barbier explained to me, meant that all the regulation to start using them again needed to start from the beginning. There was probably a delay of maybe 10 years, maximum 20 years, between the time where we drop it and the time where we realised maybe we need it. It feels like phage therapy is always is happening soon but not now and it's been soon but not now for a while how soon how soon yeah well it's never soon enough for the patients i understand that i've been you know in contact with some of them uh yeah they are always in in a situation that is i would say disesperate when you read this letter that you receive on you could i could you help me really people people write to you to tell you that they've got infections that won't go away yeah and can you send them something i cannot there is no phase there is no phase i mean there is it's not that the phase doesn't exist it's that there is no phase that have been produced quality control and is available i think it's time we heard from a couple of uk doctors about the front line of untreatable bacterial infections.

17:55My name is Dr. Samir Maudafzal and I'm a consultant in virology, microbiology and infection. Hi, I'm Dr. Steve Montgomery-Laird. I'm a consultant physician in medical microbiology at University Hospital Cogntree, New Hampshire. There are two times in my career as a doctor where we feel absolutely helpless. One is when someone comes into ANE really septic, frail, and actually a few years ago we would have had antibiotics which would have kept that person alive and woken them up like magic. The second one really would be in patients who need antibiotics for a very, very long time to treat really complex infections.

18:40With time, the antibiotics may stop working. They don't necessarily have to be elderly. I've seen people my age come in with children dying from sepsis and knowing that they've got a resistant infection, which no antibiotic can treat, and then seeing them die in front of us. It's very, very distressing. And if it's distressing for us who are meeting the patient for the first time, imagine what it's like for the family and for everyone else who knows that person. The reality is that by 2050, every three seconds, somebody in the world will die of antimicrobial resistance. When you think of it, one, two, three, dead.

19:20And that could have been preventable death. What we want is alternatives which are safe for our patients. I strongly believe that all my colleagues are very keen to try and address the problem for antimicrobial resistance.

19:41Phage science is back in the spotlight because we need new treatments now. The UK is reviewing protocols on personalised phage therapies. But that's a big shift. How might this work in practice? In a leafy Parisian suburb, I'm visiting yet another phage lab. A final phage lab where maybe I'll get answers. Well, looky, there's something wrong in here. Excellent. This is Dr Adele James, co-founder of biotech startup Phagos. She's already given me the tour of the R &D labs downstairs, where there's the usual relaxed bustle of a working laboratory. The upstairs lab has fewer people and more PPE. So Adele, I've put on the safety gloves, hair cover, shoes, jacket in order to come into this lab.

20:37Here it's an extra level of security so that we have to follow according to regulation as well to be sure that we produce in the cleanest way. And then the first thing that we're staring at is this enormous glass beaker with bubbles bubbling through it. So we are in our production lab where we will go from a few milliliters of phages to a few litres of highly concentrated and pure phages. So this is what you see here in the bioreactors. I watch the phage mixtures being bottled and labelled. Then they are couriered to chicken farms in France and added to the animals' drinking water. This is the start, a trial with farms.

21:24But as CEO Alexandros Pantelis explained when he joined me and Adele, Fegos have bigger, bolder plans. Our mission at Fegos is to end bacterial disease. We believe that starting in animal health is super important, since this is also where you have a high volume of antibiotic consumption. Okay, and that story starts with a call from a desperate oyster farmer, right? Yeah, I did my PhD on oyster farming and the pathogenic bacteria infecting those oyster farms in France. In some cases, they lose up to 100 % of their production due to bacteria. It was a test case. We went on the farm, got some nasty environmental material and dead oysters from there.

22:14And just with this rudimentary material, Adele managed to build a proof of concept phage cocktail. And there was 40 % less death in the batches with phages. For context as well, these guys, they were so desperate. They were using antibiotics for veals. So the oyster farmers were using like cows antibiotics and sticking them in the water. They were trying stuff, you know, they had no solution. Nothing was working. Operating since 2025, but still in its trial period, Phagos calls itself the only licensed phage therapy platform. Regulation is modelled after antibiotics and, you know, chemical substances, which are always the same.

23:02But here with phages, given their precision, you have to have different cocktails. So what we suggest is that instead of looking at phages as a single product, you look at the thing that doesn't change. And that's the platform. That's the process of production. It's a new dawn for phage therapy, and it's true, it's a good time to be in phage therapy, I think. And here we get to another reason why phage therapy hasn't taken off yet. You can't patent a virus. But what about the process? Both Martha Clokey's team in the UK and the Phagos group use AI to speed up their phage work. The Phagos team are confident that their platform is the bit that can be monetised.

23:47Another way might be to create synthetic phages. That's a question I put to Martha Clokey and Andy Millard once back in the UK when I called them to see whether the giraffe poo I collected at the start of this programme contained a bacteriophage that might help us fight the bacteria that cause us harm. I had a great time in Paris. There's some really nice work. I'm in Plasture. It's a fantastic place. Laurent showed me his sewage collection. And then phages, like, you know, I've got a sort of a drawer full of cables that I'm never going to use, but I'm not going to throw away. And his equivalent is kind of these tiny vials.

24:26Yeah. So, did my giraffe poo sample yield any phages? It did. We're happy to say. Oh, that's fantastic news. What have we got? Faisal did the screening against lots and lots of bacteria and he found one putative plaque. Depending on the bacteria you're looking at, we often don't find phages, so it's good that we found one. So when you say a plaque, do you know what kind of bacteria the phage was killing? It was on an E. coli. So one of the things we're really focusing on here is on E. coli that cause urinary tract infections. So what we're doing at the moment is assembling all the phages. And then what we'll do over the next few weeks is work out the host range.

25:07You'll be able to know exactly how useful this phage may or may not be. So much of this feels like it's about building a model, building a process that's safe, right? Yeah, absolutely. I think we'll be building the whole of the ecosystem necessary to do this. what people have done with bacteriophage therapy is they've taken a more personalized and a smaller scale of approaches they test if phages can actually affect the strains that patients have and then they go on and use them but what we're hoping to do is actually ask the questions like how do we make sure that those phages don't immediately drive resistance like antimicrobial resistance how can we learn from those mistakes of the past with these big standardized collections we can make sure by the time we get to do the clinical trials that are really needed to make phages mainstream, we're going to use phages that have got the highest chance of actually working.

25:56Okay. What about synthetic phages? Are there extra safety issues there if we're genetically engineering them? Well, there are. And I think we're of the strong opinion, yes, it's going to be great to engineer phages. We're brilliant. Andy's brilliant at engineering phages. He's got a big team of people doing it. But the thing is, again, you need to know what you're engineering. Okay, so Andy, you see with the ecosystem developing, it's going to be natural phages first and then synthetic phages as a later stage? Yeah, I think so. I think it's going to be really important that we understand the biology of the huge diversity of phages that are natural phages to start with.

26:32So there's a lot of fundamental biology to come, I think, first and then build upon that for the engineered phages. Yeah, I mean, nature's been doing this for 3.9 billion years. I always think it's funny that humans think we can come along, we can do it better. It's a great comfort to know that as the powers of antibiotics wane, that harmful bacteria can, just like us, get a viral infection. And that harnessing the power of those useful viruses is nothing new. What is new is a suite of tools, fast genetic sequencing and artificial intelligence algorithms to help us match the best cocktail of phages to fight the infection.

27:13Human trials that fit our stringent modern safety standards are just starting in the UK And who knows, maybe in a decade, every pharmacy will have a phage fridge Full of friendly viruses, ready to help sick patients

27:38Don't play games with us A vicious gang of hackers, causing chaos for businesses, councils and hospitals. What if I don't finish this treatment and this cancer grows? But they didn't care. I'm dying laughing. Making outrageous demands for money. They wanted millions. It was high tech and high stakes. The country's under attack. And it was highly secretive until someone exposed it all. Cyber hack, season four, The Conti Files. Listen on BBC.com or wherever you get your BBC podcasts.