Instant Genius - The intriguing science of phages, with Tom Ireland

Episode Date: June 29, 2023

Even before the global COVID pandemic, simple mention of the word ‘virus’ was likely to send shivers down most of our spines. But it turns out not all viruses are nasties. Ever heard of a phage? They are a type of virus that infect bacteria. Despite being one of the most common forms of life on Earth we still only know very little about them. However, current research suggests they may just be one of our greatest allies in the fight against superbugs. Learn more about your ad choices. Visit podcastchoices.com/adchoices

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So you can experience exceptional sound at home. Music just as the artist intended. Visit name audio.com to learn more. Hello and welcome to Instant Genius, a bite-sized masterclass in podcast form. I'm Jason Goodyear, commissioning editor at BBC Science Focus magazine. Even before the global COVID pandemic, simple mention of the word virus was likely to send shivers down most of our spines. But it turns out not all viruses are nasties.

Ever heard of the phage? There are a type of virus that infect bacteria. despite being one of the most common forms of life on earth, we still only know very little about them. However, current research suggests they may just be one of our greatest allies in the fight against superbugs. In this episode, we catch up with Tom Island,

science writer and editor of the biologist, the bi-monthly magazine of the Royal Society of Biology. He tells us about the fascinating discoveries he made about phages while writing his book, The Good Virus, the untold story of phages, Your book, The Good Virus, is all about something called a phage. So I think a lot of people will be unfamiliar with this term. You know, it's quite an interesting word, phage, just it sounds quite nice, isn't it?

But is there a strict definition of what a phage is? Yeah, so they're unusual in that they are viruses, but most viruses are just called viruses. You have animal viruses, plant viruses, human viruses. for some reason phages have their own kind of term. So the term bacteriophage means bacteria-eater. So it's essentially a virus that infects and kills bacteria. There are other single-celled organisms that are quite similar to bacteria, but not quite the same, called archaea.

And you get phages that can infect them as well and kill them. But essentially, it's a microbe of a microbe. It's a virus that kills bacteria. And the reason they have their own kind of term is that the guy who discovered them was a bit of an eccentric, a bit of a maverick. And he actually sort of discovered phages when people didn't really know anything about what viruses were. So he gave them this name, Bacteria Eater, as that's what he kind of observed them doing. So, yeah, it's probably led to them being seen as more obscure than they actually are. I think if they were just called bacterial viruses, we'd all know what they were.

It would be kind of self-explanatory. but yeah, they've got this quite cool, mysterious name, Phages. So the field of studying Phages is relatively young. So you mentioned how they were discovered. So who was responsible for the kind of early pioneering work on Phages and how were they discovered? So there's this really interesting character called Felix Derelle. So he was French-Canadian, but some people say he was Belgian. He changed his name a lot.

People say he falsified his qualifications to get a job at the Pasteur. Institute, which was the big kind of microbiology Institute at the time. And, you know, this was at a time when microbiologists were kind of hugely powerful, famous people. Louis Pasteur was virtually a saint in France. He'd invented this, the system of pasteurization to help stop food and drink spoiling. But microbiologists was suddenly able to kind of help save people from infectious diseases, which had never been done in history before. So it was a really important time for microbiology. And Felix Dorel, as I said, he was a strange character. He was very spiky, who was self-taught. There were questions about his background. And he announced one day that he had discovered

a microbe of a microbe that could kill bacteria. And he discovered this by essentially having plates of bacteria and observing that there were little tiny holes in this, of uniform lawn of healthy bacteria. And he could take a little sample from one of these holes and transfer it to another plate of completely healthy bacteria. And the same thing would happen there. A hole would start appearing as if the bacteria were just disappearing. And what he did was quite clever.

He kept diluting that substance over and over and over again. And so if it was just some kind of chemical that was causing the bacteria to die, that effect would get weaker and weaker and weaker. But actually, he could dilute it a million-fold and then just drop it onto a plate of healthy bacteria and the same thing would happen. It was an infection spreading among the bacteria. So, I mean, this was all done before electron microscope.

So he couldn't see, he couldn't look at whatever was happening on this plate as we can now. The phages are up to 100 times smaller than a bacterial cell. so it's completely impossible to see them with a light microscope. He did all this with just brilliant experimentation and reasoning. And essentially, these kind of titans of microbiology at the time just didn't believe it. It just didn't believe that this guy had discovered something so momentous

with such huge ramifications. And so really there was sort of decades of squabbling among microbiologists where some thought this was really exciting and worth looking into. kind of dedicated their careers to like disproving that this was actually a microbe of a microbe and they had all sorts of competing theories that this was something the bacteria were doing to themselves. And so his character was kind of trashed by other scientists for literally decades and then he eventually sort of moved to the Soviet Union, which was recruiting scientists that wanted to defect from the West and he's essentially just had enough of being

criticized by his colleagues, but he was the first one, not only to discover phages, but to think about the potential using them in medicine as well. So he actually did experiments on himself and was the first to essentially just give a big vial of phages to a young boy who was suffering from dysentery. Again, one of these diseases at the time, long before antibiotics, where if you had a really bad bacterial infection, you were done for, really. And he went into a hospital in Paris, told some doctors that he had discovered a cure for dysentery, gave this young boy a vial of phages, and he recovered within a few days and left the hospital without symptoms eventually. So he had this strange kind of dual life where he was being criticized

by the medical establishment, but he was also able to sell these remedies, which used phages to cure bacterial infections. He eventually moved to the Soviet Union, became completely sort of isolated by the West. And then, unfortunately, Stalin was, he's running one of the most brutal, murderous regimes in the history of civilisation. So that further kind of enhanced this reputational phages as being a kind of controversial and strange element of microbiology that just had all of this baggage with it, which continued all through the 20th century. So, as you say, they're bacteria eaters or bacteria killers. So what do we know, about how they do that. I think it's quite interesting. Because bacteria are quite different to kind of

human and animal and plant cells, they're a lot tougher to infect. And so bacteriophages are actually sort of way more interesting and sophisticated than the viruses that infect us, which tend to be, I know, if you look at images of them, they tend to be kind of spiky blobs. Bacteriophages, you know, some of them look like little nanomachines or little spaceships. They have these kind of capsules where they keep their DNA, and then they have these long tail-like appendages, which they use to kind of clamp on to the outside of the bacteria, and little kind of spidery legs as well.

They really are amazing-looking things. They sort of bind to the outside of the bacteria and punch a hole in the outside and inject their DNA into the bacteria. and then that DNA then kind of hijacks the bacterial cell. It reprograms it to essentially become a phage factory. So all of the metabolism of the bacteria is no longer focused on reproducing and feeding. That bacteria just starts producing more phages and nothing else, essentially. And then the really neat thing is that the phage programs the bacteria to produce a special kind of suicide model.

molecule at the end, which just blows it open and all these new clones, these new phages go off into the world and repeat the process in another cell. So I think one point worth mentioning is there, you know, maybe a lot of people haven't heard of phages, but they're incredibly prolific, aren't they? Yeah, in terms of abundance, yeah. And that's another really interesting thing is that it was only sort of 30 odd years ago that scientists realized that they are the easily the most abundant. sort of biological entity on the entire planet.

So it was thought, understandably, scientists have concentrated on viruses that kill us and maimers and that kill our animals and our crops. So people hadn't really gone out into the environment looking for bacterial viruses, to be honest. They had been used as kind of tools in laboratories. They're quite useful for doing experiments with. But no one had ever really gone out and looked for bacterial viruses in the environment and thought about how many there were.

Right at the end of the 1980s, early 1990s, a group of Norwegian scientists decided to do something quite random, which is just take some samples of water from open water, what would be considered quite clean water. So it was from a fjord on the very northern tip of Norway and from a big bay on the east coast of the USA. And they were the first people to just take these tiny samples of water, look at them under an electron microscope and count anything that looked like a virus.

And the numbers that they got was just completely wild. They were talking about millions, billions of phages in every sort of milliliter of water, which just didn't make any sense because everyone would always assume that you would find viruses around human beings, you know, in sewage or in hospitals. But for there to be that many viruses just floating in the ocean, that didn't seem to make any sense. So, you know, other groups started looking at it and they found the same thing. You know, they'd take samples of water from a briny marsh or from a hydrothermal vent or from some soil. And everyone was coming up with the same figures, you know, millions, maybe even billions in every milliliter or gram of soil.

And when you add up all of the milliliters of water on the whole planet or how many grams of soil there are on the whole planet, you get this astronomical number. There's a number that's often quoted by phage scientists, which is a completely wild guesstimate. It's a real back of a cigarette box calculation, but it's 10 with 31 zeros after it. that's how many phages they think are on planet earth, which is essentially sort of a trillion phages for every grain of sand, someone put it. So yeah, extraordinary abundance, trillions of them in our guts on our bodies at any one time, trillions of them all around us in the soil that I'm looking at in my garden at a moment.

And that also is something that's really exciting and interesting because it means they're driving ecosystems, they're driving diversity, among bacteria, and they're just there for the taking. If we want to find a phage that is potentially medically useful that can kill bacteria that we want to kill, we just have to go out and dip a beaker into some water somewhere, which I've done myself, and there's some amazing stories in the book about ordinary people,

even young kids going out, scooping up some water from their local stream, and finding, with some help from people in the lab, that the phage that they've found can kill some of the most dangerous bacteria on the planet. So, yeah, they're absolutely everywhere, and we know hardly anything about any of them. Yeah, so coming off the back of that, obviously studying them is a huge challenge then, as they're so abundant, like you say. So what's there, you know, is there any sort of methodology that current researchers use to study phages? So the way that you discover a phage is actually sort of,

unchanged since Daryl, the guy from the 1910s, 1920s. He essentially, he got a plate of healthy bacteria, you kind of wash whatever you, you wash some water over it. And if these holes appear in the healthy bacteria, then you have something that's killing that bacteria. So the process is pretty much unchanged. The thing is every different strain of bacteria has a different phage that infects it. So there's potentially billions of different types of phage out there. What scientists tend to do is look for phages that infect bacteria that they're interested in. So for example, when I was looking for my own phage, I took some samples of water. The scientists at Exeter University had a kind of a range of, say, half a dozen bacteria that are

causing lots of problems in health systems around the world because they've become very resistant to antibiotics. And they took my samples of water, they filtered them with these very, very fine filters that remove every sink that's bigger than a virus, essentially. And then they just wash that water over those bacterial samples, leave them for 24 hours, come back. If there's any of these little holes appearing in that healthy,

opaque lawn of bacteria, then you have a phage that's killing that bacteria, and then you can cultivate that phage and create solutions of, you know, more and more concentrated phages as it replicates in those bacteria. So you mentioned there the idea of antibiotic resistance. I think that's quite a key point, and that's worth sort of digging into a bit more deeply. So are you able to explain what exactly do you mean by antibiotic resistance, how it's arisen and how bad the current situation really is?

Yeah, antibiotic resistance is when bacteria, become less affected by antibiotic drugs. So this can happen over many decades or it can happen quite quickly. Essentially, some bacteria just need to have a small mutation in their genome and they suddenly have a way of resisting a certain antibiotic. So we have lots of different types of antibiotic that kill bacteria in different ways. And bacteria have lots of different ways that they can deal with those, antibiotics. Some have little pumps that kind of pump them out of their cell. Some have

chemicals that can neutralize the antibiotic. And antibiotics, remember, are a lot of them are based on natural compounds. So bacteria will have evolved mechanisms to overcome these kind of natural compounds that other fungi use to kill bacteria. These mechanisms to resist antibiotic drugs come at cost to bacteria. So they're often kind of quite costly in terms of if they switch on one of these mechanisms, it kind of affects their growth and it affects their ability to replicate. But when we constantly bombard bacteria with antibiotic drugs, eventually they evolve to become more resistant because it's worth their while.

Essentially, if they have some kind of way of resisting the antibiotic, then they become the only bacteria left in the gene pool. So this resistance becomes stronger and stronger and stronger. And this used to be a problem in just hospitals where you had very sick people with lots of bacteria, coming into contact with lots of antibiotics, and this helped to kind of breed strains of bacteria that could resist the antibiotics.

But actually now, antibiotic use has become so widespread. They're given to livestock, willy-nilly, you know, people are being prescribed antibiotics, even when they may not have an infection that's actually caused by bacteria. Antibiotics are literally washing into waterways, into, you know, off farms, into rivers, into soils. And so this is actually an environmental problem now. You have these low levels of antibiotics in the environment now at all times. You can measure the amount of antibiotics being used around the world by the ton now.

it's ticking up by the ton. You may only have micrograms in each pill, but the amount of antibiotics being used, especially in farming, is measured by the ton now. And so you're creating an environment that's conducive to drug-resistant bacteria, and you are getting bacteria

that are not just resistant to one type of antibiotic, but lots of different types of antibiotic. And now, in the hospital setting, you're seeing bacteria that are resistant to every single type of antibiotic, even the last resort ones that are kept in the locked cupboard, you have bacteria that can resist everything we've got in our arsenal, basically.

That's a really scary thought because not only does it make the infections really, really difficult to treat, some people have no other options left. And what starts off as a quite simple infection, an abscess or something, or an ulcer, just becomes this whole body, disastrous

infection. And this was always seen as a problem for the future, but actually some recent work published in the BMJ, I believe, suggested that in 2019, two million people worldwide

died of antibiotic resistant infections. And millions more, their treatment was made more complicated. So this is a kind of problem for the present, actually, and it's only going to get worse. Ambition comes in all shapes and sizes.

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are kind of invisible allies in the fight against bacteria. You know, they are a way of killing bacteria that has evolved over billions of years. They are bacteria's kind of natural foe. And of course, we don't want to kill all bacteria. Lots of bacteria are completely essential to our ecosystems, but these are viruses that we can use for good. So there's been a long history of phages being used in medicine, mainly in the Soviet Union, but also increasingly as antibiotic resistance becomes a massive problem. People are rediscovering this idea in the West as well. At the moment, the system of regulation means that you can't really even try this

until someone's on their last legs. And then drug regulators tend to say, okay, you can try phages now. But that's changing. And people are trying to work out a way of getting this into mainstream medicine. Firstly, to prove that it works, it's been very difficult to actually prove that you can do this en masse. you have to find the specific phage for the specific patient, so it's not really like using antibiotics at all. And so, yeah, that's why I've called it the good virus.

It's this idea that they can help us, rather than our traditional concept of a virus being just something that kills and harms us. There's also other amazing uses for phages. You know, they've been central to many of the massive breakthroughs in molecular biology in the 20th century, so we wouldn't have genetic engineering. we may not even know that DNA is the kind of genetic material if it wasn't for phages. You know, they've got this amazing role in molecular biology as a kind of lab tool. And there's also other really interesting potential uses for phages,

using them as little drug delivery vehicles in the body, for example, as well. There are perfectly evolved kind of nanomedicine, essentially. What they've evolved to do is find a very specific type of cell and inject something into it. And if we can sort of reprogram them so that they're not just looking for bacteria, they might be looking for tumour cells instead. And instead of injecting their own DNA into the cell, they're injecting an anti-cancer compound, then you have this amazingly evolved system for binding to a particular target

and breaking it open and injecting whatever you want into it. Yeah, so sort of going further into the idea of the use of phages, therapeutically. You've got several really interesting case studies in the book. And you know, you mentioned there that they're often used as a last resort. I think that that's really interesting when, you know, when all other, basically all other attempts to cure the infection has failed. Is there any particular one of those case studies that stands out as you as particularly impressive? Well, I think they're all very dramatic, especially when they've been used in the West. The one that obviously stands out to me is Steph Strasty and her husband, Tom Patterson,

So I think this encapsulates everything about how difficult it is to use phages, because Steph Strathie is like a director of, she was a director of global medicine at San Diego University. So she was already well steeped in healthcare systems and infectious disease. And her husband picked up an infection when they were on holiday in Egypt that very quickly became very, very serious. And he was evacuated home, very ill, had a terrible drug-resistant infection, and was essentially sort of put into a medically induced coma. Even she didn't know anything about phage therapy, but as her husband essentially lay dying, she started Googling anything that might be able to help with this bacteria that had become resistant to all-known

antibiotics. And she came across this idea of phage therapy and couldn't quite understand why there was these articles about it being used in the Soviet Union, but absolutely no literature about it being used in the West. And she kind of single-handedly pulled together a team of people, some phage scientists that aren't medics at all, but just study phages in their labs, a doctor that was willing to give it a shot in the hospital where a husband was being treated, some people in Georgia and Russia who had experience of actually using phages on people. Obviously, she had to pull in the drug regulators in the USA, the FDA.

She managed to pull together this big team of people and essentially come up with this kind of impromptu version of phage therapy, get all the paperwork signed off to say, nobody's going to be held responsible if this doesn't work. There was all sorts of pharmaceutical work that had to be done to actually purify the phages once they'd found the right ones. And then they injected them in literally, it was at the last minute. His kidneys were failing.

He was really, really ill. And he recultly made a full recovery. It's important to say this isn't, you know, this isn't anecdotal evidence. That wasn't a clinical trial. But it's certainly like just one of many amazing single patient cases where phages have been used as a kind of last resort. and the results are kind of spectacular and fairly instantaneous as well. Obviously, the Soviets have loads of these examples,

and in places like Georgia, former Soviet countries, they're still using phages. You can walk into a pharmacy there and get phages. So it's more of an everyday thing for them, and they don't tend to have such spectacular cases. It tends to be people having maybe a stubborn ulcer on their foot or a diabetic ulcer on their foot that hasn't healed, and it gets cleared up by phages.

Equally interesting to go over there and see how they just essentially dish out phages like we would dish out pills and you can happily go and swig a vial of this, of a trillion or so phages if you have a food poisoning or whatever bacterial ailment is affecting you. So taking that sort of body of evidence into account then, what's the current state of phage research, you know? Is interest growing? There's been waves of interest, but the problem is it's really hard to, firstly, it's really difficult to prove that these therapies work within the confines of how we normally test drugs.

So our clinical trial system has grown up around the idea that you take a chemical, and you know exactly what its formula is, and then you test it on an increasing number of patients and look at whether it's safe and whether it works. And you can't do that with phages because for each different patient, they're going to have a different strain of bacteria, and you're going to have to find a different phage. And so it doesn't quite work in that traditional clinical trial system. You can't just say, hey, we've found a really nice phage that works like an antibiotic,

and we're going to test it on a thousand people. The trials just don't work like that. So it's been traditionally, it's been really hard just to prove that this is something that can be used in mainstream medicine. It's also, just the administration of it is really difficult. As I said, you've got to match a particular phage for the patient's exact strain of bacteria that's causing the problem. So you can't just reach for something off the shelf.

Every time you treat someone with phages, you have to do some quite intense lab work, which is another reason why this has always been sort of an idea that, doesn't, people don't really believe in, right? So the current status, though, I think, is that we're reaching a point with antibiotic resistance where actually we really, really need to start looking at this properly. And there's, there's probably about a dozen clinical trials that are underway at the moment. They've been specially adapted to the particular characteristics of using phages. There's been decades of failed clinical trials where, as I'm, for reasons I just spoke about, you just can't take one phage and try and treat a thousand people

with it and see what happens. It's just never going to work. So there's lots of trials ongoing at the moment. There's probably more momentum now than there ever has been behind the idea of phage therapy. And there's also these kind of offshoots of phage therapy that could be really promising. So one idea is to actually just take that enzyme that I mentioned earlier that causes the bacteria to explode, we can just take that from the phage and perhaps use that as an antibiotic. Other groups are actually just taking the tail parts of the phages and growing a concentrated solution of the tails and using them as kind of like nanoscopic syringes that could be used to inject things into bacteria. Offshoots of phage therapy that are being researched.

I think ultimately the research is suggesting at the moment that a combination of antibiotics and phage therapy is probably going to be the most promising way to deploy this in the future. When you do get drug-resistant bacteria, if you bombard them with phages, then they often lose their resistance to the antibiotic because they can't handle all of these different attacks at once, and then they may develop some resistance to the phage, but then they'll lose their resistance to the antibiotics. So a combination therapy is likely to be the way forward. There's just a real need for it at the moment and lots of funding going into it. So I think we're going to see over the next few years some interesting trial data

coming out and also the NHS has appointed its first kind of phage therapy specialist. So we're going to start seeing it being rolled out in the NHS in a less kind of last resort haphazard way, but hopefully at an earlier stage in people's infections before they get to the kind of critical stage. In the course of the book, I spoke to several people that, you know, because they can't really get access to this type of treatment in the UK or in America or in Europe, they're having to sort of take this trip over to Georgia, which is a long way away. It's nestled between the southern tip of Russia and Turkey. And yeah, it's really strange. You go over to these clinics and some of them are, you know, the equipment is fairly outdated.

It's a very strange environment. People don't speak great English and they're having to go over there to get, get treated with viruses. It's a terrifying experience, but, you know, hundreds of people now are doing it every year just because they have these infections that Western antibiotics can't treat. And some of those therapies are successful? Yeah, I mean, again, it's really difficult to say because these clinics are just treating people. They're not necessarily doing randomized clinical trials.

So they have some impressive statistics, but that's not clinical trial data to us in the West who want to see real clinical trial data, robust clinical trial data, and also sort of molecular information about what the phages are that are being injected into people. They don't do that kind of thing over there because it's just, they just do it in a quite a rough and ready way. You know, they are finding phages in the local river, in the sewers, purifying them and working out a sort of a batch that seems to work well on particular bacteria and giving them to patients without really doing a huge amount more of kind of scientific study.

It seems to work over there, but the data from those Georgian clinics is not really of standard that's of use to people in the West. So what we really need then is some some proper robust clinical trials. Yeah, and some collaboration, I think. I think you want a combination of the expertise of the Georgians and the modern molecular-based studies that you would expect in the West when you're thinking about characterising a virus that you're going to inject into someone. You want to know exactly what genes do what and whether that that virus has changed after you've injected it into the patient and whether the bacteria has changed. And you want to be able to really characterize that host parasite relationship that's

going on inside the body in a lot of detail if you're really going to start using it on lots of patients. So yeah, that's the future. I think another thing to mention is this idea that you could genetically engineer phages or even synthesize completely man-made phages. And that might actually, even though it sounds kind of a bit scary, that actually might be a safer way of doing it in that you can sort of create a phage and you know exactly what's in it, you know what each of its genes do

because you've designed it. And regulators actually might be more comfortable with a phage, not that's been plucked out of a sewer or a stream, but that's been actually designed in a lab for this specific patient. So that's an interesting route forward perhaps as well. That was Tom Island, author of The Good Virus, the untold story of Phages. Thank you for listening to this episode of Instant Genius, brought to you from the team behind BBC Science Focus.

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