In Our Time - Bacteriophages

Episode Date: August 1, 2024

Melvyn Bragg and guests discuss the most abundant lifeform on Earth: the viruses that 'eat' bacteria. Early in the 20th century, scientists noticed that something in their Petri dishes was making bacteria disappear and they called these bacteriophages, things that eat bacteria. From studying these phages, it soon became clear that they offered countless real or potential benefits for understanding our world, from the tracking of diseases to helping unlock the secrets of DNA to treatments for long term bacterial infections. With further research, they could be an answer to the growing problem of antibiotic resistance.With Martha Clokie Director for the Centre for Phage Research and Professor of Microbiology at the University of LeicesterJames Ebdon Professor of Environmental Microbiology at the University of BrightonAnd Claas Kirchhelle Historian and Chargé de Recherche at the French National Institute of Health and Medical Research’s CERMES3 Unit in Paris.Producer: Simon TillotsonIn Our Time is a BBC Studios Audio ProductionReading list: James Ebdon, ‘Tackling sources of contamination in water: The age of phage’ (Microbiologist, Society for Applied Microbiology, Vol 20.1, 2022) Thomas Häusler, Viruses vs. Superbugs: A Solution to the Antibiotics Crisis? (Palgrave Macmillan, 2006)Tom Ireland, The Good Virus: The Untold Story of Phages: The Mysterious Microbes that Rule Our World, Shape Our Health and Can Save Our Future (Hodder Press, 2024)Claas Kirchhelle and Charlotte Kirchhelle, ‘Northern Normal–Laboratory Networks, Microbial Culture Collections, and Taxonomies of Power (1939-2000)’ (SocArXiv Papers, 2024) Dmitriy Myelnikov, ‘An alternative cure: the adoption and survival of bacteriophage therapy in the USSR, 1922–1955’ (Journal of the History of Medicine and Allied Sciences 73, no. 4, 2018)Forest Rohwer, Merry Youle, Heather Maughan and Nao Hisakawa, Life in our Phage World: A Centennial Field Guide to Earth’s most Diverse Inhabitants (Wholon, 2014)Steffanie Strathdee and Thomas Patterson (2019) The Perfect Predator: A Scientist’s Race to Save Her Husband from a Deadly Superbug: A Memoir (Hachette Books, 2020)William C. Summers, Félix d`Herelle and the Origins of Molecular Biology (Yale University Press, 1999)William C. Summers, The American Phage Group: Founders of Molecular Biology (University Press, 2023)

BBC Sounds, music, radio, podcasts. This is in our time from BBC Radio 4, and this is one of more than a thousand episodes you can find on BBC Sounds and on our website. If you scroll down the page for this edition, you can find a reading list to go with it. I hope you enjoyed the programme. Hello, early in the 20th century,

scientists noticed that something in their labs was making bacteria disappear. They call these bacteriophages, things that eat bacteria, and they turn out to be viruses, with countless real or potential benefits for understanding our world and treating disease. A century later, we know their most abundant life form on the planet, and with further research, they could be an answer to the growing problem of antibiotic resistance. We need to discuss bacteriophages, or phages, for short,

Martha Clokey, director for the Centre of Phage Research and Professor of Microbiology at the University of Leicester. James Ebden, Professor of Environmental Microbiology at the University of Brighton, and Claus Kirk Heller, historian and Charger de Research, at the French National Institute of Health and Medical Research's Cermetz Tuar Unit in Paris. Starting with you, Klaus. Who first noticed this phenomenon, and what did they make of it? Well, because phages are so ubiquitous in the environment, microbiologists probably always observed them

as soon as they started culturing bacteria, a culture that suddenly disappears, bacteria that won't grow. But it's in the 1890s with the rise of pure culture techniques that we start getting quite a few reports about bacteriologists noticing some kind of weird principles, some kind of licing principle where cultures get destroyed. And one of the first reports that seemed to indicate the presence of phages come out of India in 1896 by a bacterologist called Ernest Hankin.

And he notices when researching the water, the Ganges River, that cholera bacteria are being lised and killed when exposed to this water, as opposed to after this water has been boiled or well water. So what does Lissid mean? It means that the bacteriophage destroys the bacteria culture. It explodes the bacteria. Now, during this time, Hankin and many others, they have no modern notion of what a virus is, and many of the techniques used to study viruses are only just starting to emerge. So it's 20 years later during the First World War that we start getting the first systematized research on these litic bacteria-destroying phenomena.

And the first person to publish on bacteriophages is an English bacteriologist known as Frederick William Twat. He's a bacteriologist who works for the Brown Institute in London, and he's really interested in finding growth media with which to grow viruses. He's interested in the smallpox virus specifically. And on these growth media that he's trying to use to grow viruses, he notices the growth of a micro-cockus culture. And on this culture, he notices a glassy round dot. He's interested in what this dot is, and he realizes that when he uses, he touches this dot

and he transposes it onto another plate, the Lytic principle gets carried on. So it's something that is infectious to bacteria. It's destroying bacteria. And in the second step, he passages this three, a very fine-poored filter called the Chamberlain filter that is so fine-pour that bacteria cannot pass through. So he realizes that what he's dealing with

is an ultramicrob or something that can pass it through this filter. Then there was these Felix de Hale, a French-Canadian. He took this further, I understand. Yes, D'Relle is a Franco-Canadian researcher who, two years after what, independently discovers bacteriophages. and he's also the person who coins the name bacteriophage, bacteria, eater. Derell during this time, he is working for the Pasteur Institute,

and in 1917 he publishes a paper that he's identified an ultra-microbe that is parasitical to live microbes, and that is the microbe of immunity. He always uses quite spectacular language in his publications, and he's not just colourful in the language that he uses, his personality really puts a stamp on bacteriophage research for the next 20 years. And he's probably the most unorthodox microbiologist who's ever lived. He has no degree in microbiology, has no degree in medicine.

But through connections of his father, he's charged by the Canadian government of producing whiskey using maple syrup. This is a surplus commodity. The American market has crashed. How can you produce whiskey with this? So Derelle starts this and he later writes. And he later writes that he at this point decides to model his biography, his life's course on the biography of Pasteur, his great hero. To his great surprise, he manages to land the job of a microbiologist for the Guatemalan government

and moves with his young family to Guatemala in very liminal circumstances. And he spends the next 10 years shuttling around Central America and South America, fermenting bananas, sysal, agave into alcohol, and he makes his first big discovery, which is to use corzillo-bacillus Sotarel, which is a bacillus to target locusts. The financial and scientific prestige from this actually allowing them in 1911

to move his family over to Paris, where he works as an unpaid lab assistant at the Pasteur Institute. But in 1915, when the First World War breaks out, he's actually drafted into mass-produced vaccines for the French and Allied Unist. armies. And it's in this context that he observes bacteriophages. At this point, he's drafted in to investigate a big outbreak at Maison Lafitte amongst French cavalry soldiers who has suffered from a particularly virulent form of Shigella. And he is convinced that this is not only due to

the bacterium, but perhaps due to one of these ultra microbes, these filter passes. And he spends the next two years getting stool samples from across Paris, filtering them and testing them for fage. And it is in 1916 that he identifies the bacteria fage when he holds up a broth that is inculculated with the stool cultures that is cloudy and one that he's inoculated with the filtrates from the shigella that is blank. And that is what leads him to publish this 1917 paper. Well, that was very comprehensive and very comprehensive. Thank you very much indeed. Martha, can you take us to Georgia now? Rather unusual leap. We've had quite a few unusual leaps already to Tbilisi, what's happening there from the 1920s onwards?

Well, actually, there was a young Georgian scientist, George Eliava, who had the fortune, really, of joining forces with Felix Dorel. So he was actually, he was born in 1882 in Georgia. He wasn't quite as colourful as Felix Dorel, but nonetheless, he was a very keen sportsman, he loved literature, he loved horse riding, he's a very good pianist. He was the son of a doctor in Batumi. on the Black Sea in Georgia, and he did end up studying microbiology in University of Geneva.

And that led him to the Pasteur Institute. He was really interested in cholera, and he didn't understand why his cholera bacteria just kept disappearing when he was growing them. So when he met Felix Dorel, he sort of thought, oh, that's interesting. I wonder if it's the same phenomenon. So he actually repeated Felix Dorel's experiments. And not everybody, even within the Paster Institute, had believed Dorel.

So they became great, great friends. And he spent great periods of time at the Pasteur Institute, both in the 20s and then again in the 30s. And he could see quite quickly that if you had something that could destroy bacteria, this would be very useful. So his ambition was to take this technology back to Georgia. And he therefore founded the Institute of Bacteriology in Tbilisi, which then became the Elie Ava Institute that many people have heard of. But initially, again, it was the first thing they did in this. Institute was build, was make vaccines. So it started off with that focus. And then he was really, really keen to expand and be able to make bacteriophages for to treat different bacterial diseases.

He wanted to treat typhoid, which he could see was killing a lot more soldiers than the actual wounds themselves. So it was really keen to look at typhoid, diphtheria, the plague. So he managed to sell the idea to the Georgian government to establish a research institute there. Unfortunately, in 1937 he was executed. So it was a mass year, and this year Stalin executed about 15,000 people in Georgia. So he was executed for being an enemy of the people for spending so much time in France. But he'd ceded enough technology and ideas that the Institute could continue. This is where the story of Alexander Fleming and Penicillian could come in.

Can you tell us if it does where it does and what happens to it? Yeah, so the rest of the world was busy trying to figure out how to produce penicillum. So Alexander Fleming, famously Scottish microbiologist in Edinburgh left his plates open on the window that had bacteria growing on them. When he came back from a holiday,

he noticed that the bacteria had been killed by what turned out to be penicillium of fungi. And he knew that this was very important himself, but it took a long time to actually purify the very compound that did the killing. There was a lot of work done in Oxford and across in the United States. It took 20 years, more or less,

to be able to find a strain that produced a lot more of the penicillin itself and then to purify the compound. So the rest of the world became really channeled on that and was investigating this, and they eventually produced, eventually produced, high quantities of one of the earliest of antibiotics was incredibly revolutionary within medicine. What impact did that discovery of antibiotics have on the practical uses of phages? Well, in most places, after antibiotics were discovered

and could be produced in this pure way. It was just seen as the answer. It was very simple. You could produce a compound. So in most places in the world, bacteriophages were as seen as being very complicated. So why would you have to produce something that was complicated where you needed a very specific strain of a bacteria

and a very specific bacteriophage to kill it? That was just seen as something that was overly complicated when you could produce one compound that would kill many different types of bacteria. So really, in most places in the world, the idea to use bacteriophages to kill bacteria was not continued. I see. James, can you tell us precisely what is a phage?

Sure. Bacteropages or phages are essentially viruses that have specifically adapted to infect bacterial cells. So just in the same way that we as humans get infected by viruses, so bacteria suffer the same fate as well. And phages themselves, as we've heard, are the most abundant biological entities on it. Earth, and we find them from the depths of the ocean to the depths of our guts, where they outnumber bacterial cells by a factor of 10 to 1. But I understand the trillions of bacterial cells are our guts, so they outnumber even there. They do.

The imagination seizes, doesn't it? I can't comprehend these figures. I can't. So it's been estimated, not by myself, that there are a trillion bacteriophages for every grain of sand on the planet. So sort of mind-boggling numbers we're talking about. You give up. when you don't give up, but I'm riding on your back now.

There you go. So the phages themselves are essentially a piece of genetic information, so that could be DNA or RNA, that's wrapped into a sort of protein coat, a protective jacket, if you like. And phages range anywhere from 24 to 200 billionths of a meter in size or nanometers. So to sort of put that into some perspective, you could fit between 500 and 4,000 of them across the diameter of a human hair.

And they are regulating bacterial populations, both within our bodies, but also really importantly, within across the environment as well. So what they're very good at doing is regulating and controlling and shaping bacterial populations, making sure we don't see bacterial dominance occur. What's their life cycle? Bacteriophages can undergo one of two primary life cycles and they have very different outcomes on both the phage and the bacterium that's being infected. And the first one is what we term a lytic cycle. And in this case, an infectious virus, a phage, will land on the bacterial cell, much like a lunar module finding a landing site on the surface of the moon.

Once it's anchored onto the bacterial cell, it will then inject its gene. genome, its genetic information, into that bacterial cell. And it will effectively hijack it and convert it into a miniature sort of phage factory, where multiple phage progeny get produced to a point where they rupture the cell and then they go on to infect neighbouring cells in a sort of chain reaction. So very quickly we can go from having a single phage to suddenly having 100, 10,000 a million. So they can really quickly outmaneuver their bacterial. hosts. But the important thing with the Lytic phase or life cycle is that the genetic information from the phage remains separate from that of the bacterial cell, which for the second of the two

lif cycles, which is termed as a lysogenic life cycle, so it starts off the same, the phage will land onto the bacterial cell. But this time, the injection of the phage DNA or RNA will then get integrated into the cell itself. So on this occurrence, the bacterial cell will survive its experience with the phage, but it's been altered. It's been genetically altered. And the phage can then be dormant within that cell. And as the cell divides into daughter cells, then the phage is carried with it. What are the consequences of this? The consequences are that these lysogenic phages can then become lytic again. So they can actually, then start destroying the cell.

If, for example, that genetic information's rejected from the cell, then the phage can get nasty and start doing away with the cells again. So it's an important way of transmitting genetic information from one bacterial cell to another. Can I come back to you, Klaus, the unpicking of phages seems to find a massive impact. Yeah. I mean, from the moment that Derel publishes and the First World War ends,

there are three main trajectories of bacteriophage research. One of them focuses on therapy, as Marfa's already said. There's a big boom in the west of commercial therapy, but also on the Soviet Union. The second one is diagnostics. And the third one is the study of what viruses are, but also what studying viruses can teach us about bacterial genetics. In the 1930s, new groups of researchers start entering the field, and they're physicists and biochemists. and they're really interested in viruses as the basic buildings blocks of life. They think that viruses in some way explain the origin of life from inorganic objects to the rise of organic life

and that viruses kind of occupy a niche in this trajectory. And some of the people interested in bacteriophages actually go so far and claim that they are naked genes. So they are so simple and they are so small that by studying them, we can start elucidating hereditary mechanisms. and two big research groups emerge. One of them emerges in France at Answer to Pasteur. And then there's another big group emerging in the US, loosely structured and known as the American phage group. And they consist primarily of physicists who are interested in using phage as a really robust

and quickly spreading research principles, politic phages specifically to elucidate the statistical mechanisms behind heredity. And there's a link with James Watson here, and therefore with a double helix. What is that link? The phage group show in 1941 that bacterial mutations are not Lamarckian and acquired, but are actually Darwinian mutational. And then from that point onwards, they get really interested into what is the actual nature, the materiality of the gene itself. The French by this time have found out about lysogeny,

which means that phage can insert some kind of genetic material into a bacteria, which can be passed down to subsequent generations. And in 1952, Alfred Hershey and Martha Chase, devise the iconic blender experiment where they use ratio isotope markets to label the protein component of the phage and the DNA component of the phage. And they use this phage to infect a bacterium. They put it into a kitchen blender and then afterwards into a centrifuge. And they find that what the phage has inserted into the bacterium is DNA. Now, how does DNA work? How does it, you know, what is its structure? Well, they send one of their PhD students, James Watson, over to the UK, where he works

with Francis Crick and Rosalind Franklin, and they come up one year later with the double helix structure of DNA. So phage research here really gets to the heart of A, what is a virus, B, the Darwinian concept of bacterial genetics, and free the actual cornerstone of the genetic unit DNA. Thank you. Martha, it seems to be harder to develop phage treatments than to develop, say, penicillin. Why is that? Yeah, so it's difficult because of the exquisite specificity.

So James talked about how many viruses there are, all these trillions and many, many viruses that exist, 10 viruses for each bacterial cell. But their patterns of infection are quite specific. So if you want to use an antibiotic, that will kill perhaps many species of bacteria that might make you, give you a very upset stomach. Whereas with a bacteriophage, if you want to kill, for example, E. coli, a common bacteria you may wish to kill, you might need to. you might need to have 10 bacteria phages in order to kill all the different subtypes of ecoli that exist or might be circulating. So it's not easy on any level because you need to know what's causing that disease in the first place. You need to know with a lot more detail what actually you're trying to kill. So that specificity issue is really causing a lot of problems in terms of development.

You can't just have a generic product. How do the levels of phages and bacteria ebb and flow and why? what happens generally is different in different environments but essentially bacteriophages that are in this lytic cycle the cycle we're interested to use as a therapy what they will do is they will target all the bacteria they can and then the bacteria will ultimately evolve to escape so then all of those they'll wipe out the bacteriophages will wipe out the first set of bacteria the escaped ones will then become dominant so bacteriophages will like evolved to be able to target them and so on. So it's a sort of classic predator prey relationship is what you see with these delicate wars. It's basically a battle that's been raging ever since bacteria evolved. Nobody's even one. No, they're sort of codependent. And perhaps a battle is the wrong analogy. It's more like a dance. When bacteriophages are inside the bacteria, they can quite often confer quite useful properties to their bacteria. They can make it better at

being a pathogen, for example. They can confer useful properties until they're there. and kill it. James, can I come back to you? We have these trillions of bacteria. What knowledge can these phages bring to, say, drinking water? Phages have been looked at in the context of drinking water since the late 1940s, when French microbiologists started looking at bathing waters. But we tend to monitor drinking water historically using groups of indicated bacteria.

and these bacteria are shed by all warm-blooded mammals. So although they can show us that water is contaminated fecaly, what they aren't able to do is to show us the origin of that feces, the origin of feces. So bacteriophages are really useful, and we're isolating certain bacteriophages from the human gut that are obviously human-specific, and that can give us that information.

And that's important because being able to take a sample from an impacted river, for instance, and understanding that it's impacted by human fecal pollution allows you to start having mitigation methods that can target those human fecal inputs and also helps us understand liability, whether it's a local water company, for instance, or is it coming from other sources as well?

So being able to look at phages in this way is giving us a lot more information. And phages also tell us more about the behavior of other enteric viruses, such as norovirus or adenovirus, which can also be circulating and impacted drinking water supplies. So they're very powerful tools. Klaus, how have phages being used to map microbial environment? Phages work brilliantly as therapeutics,

but because they also lies only specific bacterial strains, they're also brilliant diagnostics. And clinicians start using this from the 1920s onwards when in hospital settings, just infect a bacterial plate you're dealing with with a phage to see whether it's the infection you think it is or not. Over time, people start realizing that phages can not only differentiate between bacteria at the species level, but actually below the species level, so that you have specific phage that only target one strain within a species. So by accumulating these very

specific phages into phage sets, you can start sorting the bacterial world according to its susceptibility to different phages, and this is known as phage typing. So the principle is, you've got four phages and you've got an unknown bacterial culture. You chuck all phages at it and if phage one lies as that bacterial culture, it's bacterial culture phage type 1. That's a really simple principle, but it was of huge use during the Second World War when phage type is started using this principle to really map large areas of countries, for example, like Britain, for microbial diversity. The reason for this was that people were really concerned about waterborne epidemic starting as a result of mass bombardment but also of bacteriological attack.

How do you know that you're being attacked by a bacterium if you don't know whether it's native to you or whether it's foreign? And what the phage type is due during this time is they developed sets for typhoid, for paratyphoid, for lots of other epidemic diseases. And they start typing each individual case. So there's a fingerprint registry of native typhoid types. And then they start seeing, does this type belong here or does it not belong there? And it's a hugely important neurological tool for national security purposes, but after the Second World War, also for really beginning for the first time to map the microbial cosmos outside of Western countries also. So these phage typing labs become huge infrastructures that almost function like data centers

for the mapping of microbial diversity around the world. Martha, why is there such an increase in the interest in phages now for human health? Well, unfortunately, the reason for us being interested in phages or for a lot more interest is not particularly good. It's because we're having increasing problems with antimicrobial resistance. So increasingly, doctors are not able to treat patients who are dying of infection. And it's estimated that unless we do something, by 2050, there will be 10 million people will die across the globe every single year. And this isn't some just esoteric number. It's already happening already in the most recent figures are showing that about

5 million people are dying every year with a condition that's associated with a bacterial infection. So it's like the population of Scotland just disappearing every single year. So this is really motivated doctors and researchers to think, where are we going to get something from that can actually help these patients as the antibiotics are not working? So many diseases that we could we could always treat like TB and pneumonia. If we knew what someone had, there would be an antibiotic. But these diseases are getting more and more resistant. So this is a motivated people to look at bacteriophages and look at this technology that was developed before and see, well, actually, could we think about developing it now within a modern era?

Because when it was developed before, we had no idea really what a bacteriophage was. But what's happened now is we have really good tools. So we can immediately go from finding viruses to looking at their genomes, to understanding a lot more about how they actually work, and to be able to compose a product that we know about So it's been a sort of coalescence of that great need with antimicrobial resistance and the tools to be able to understand bacteria phages a lot better. James, James Abden, in your work, why is it easier to test for phages linked to the bacteria that caused the disease rather than the bacteria themselves direct?

Looking for phages makes a lot of sense. A lot of bacteria are anaerobic. So when they get out into the environment, when they're shed in feces, they don't persist very long in the environment. They essentially are exposed to oxygen. But the phages themselves that are capable of infecting those bacteria are actually capable of surviving very well. They're shed by humans in tremendous amounts in our, particularly in our feces.

And something interesting that we see is that in typical sewage treatment, what we don't see, where we see bacterial indicators being reduced through the sewage treatment works, we can actually sometimes get higher levels of phages coming out of the serious treatment work than have gone into the treatment work as well. So they're highly abundant in surface waters that are receiving inputs of wastewater. Yeah, no, just to build on that, basically, because bacteriophages have evolved, to be able to infect bacteria, they need a strategy, that little protein coat is their strategy for long-term survival.

So the bacteria are well-dead when James can still pick up the bacteria phages that infected it. So that's why it's their evolutionary strategy that makes them so useful. Exactly, and we can find them in the environment. We look for them. We find them in shellfish, for instance. Shellfish are bioaccumulators and they filter feeders, and they concentrate these phages to very high levels. So we can actually go out and look at phages in shellfish as well

that help us understand their transmission through the environment and hopefully not back to humans as well. So there are lots of reasons why looking for the actual phage makes a lot more sense than looking for the bacterium. Is there a sense in which the dominance of pages is in itself a danger? As Martha alluded to, there's this dance going on, and there's this mutual relationship between the two. And as I touched on earlier, phages are regulating these populations.

And what we see in the lab, when we're growing a host, for instance, an e-coli host, is that the phages will only infect when the host gets to a certain density. It's not in their long-term interest to wipe out that host, if it's not in a very good state, if it's stressed if the bacteria are damaged. So there's this continual regulation of phage populations and bacterial populations that's going on. And that's really kind of controlling the environment. Which is quite interesting. I mean, it brings you back to Derell who actually thinks of phage as a part of the immune system.

Because phage become more abundant in recovering patients. So actually conceives of it as the kind of infective immunity that you can pass on. It's obviously later debunked in the way that he formally. it, but the observation makes sense. Marla? Yeah, so essentially, if we're interested in using bacteriophages therapeutically, in which case it's a bacteria that's causing us an infection,

and the enemy of that bacteria is a bacteriophage. So they'll, so they're disadvantageous to the bacteria, but they don't ever hurt the human host. So they're sort of a nut. We're full of, because we're so full of bacteriophages, we don't mount sort of strong immune responses to them. So they're not desirable to have a round if you're a bacteria,

but for a human host, we can think of them as being the enemy of the enemy. I see. Lars, meanwhile, there's this treasure trove of useful information in the old French records. There's now been over a century of research on bacteriophages, which means that we've had over a century of microbiologists using them to map the microbial world, but also experimental treatments. And these paper records, they still exist in certain places around the world, such as the Pasteur Institute. There are also important collections here in London in Collendale.

And they contain really observations of the rapid shifts of the microbial biosphere that have happened over the last 100 years with the antimicrobial era starting, but also climate change happening, et cetera. So by going back to these records, by understanding where certain bacterial populations were prevalent, how disease got transmitted, how new virulence, factors arose. These are incredibly important records with which we can start mapping the long-term and medium-term trajectories of our changing microbial environment. And it's not just the paper records, I should end by saying, it's also that many of these places have culture collections where they both store the original bacterial cultures and the original phage. So we've also got archives of evolution in the 20th century, which we can now start exploiting with new genomic methods. Martha, what are the prospects then for using phages?

are a lot of ways that we can use bacteriophages. The most immediate motivation is to do with these bacteria that are resistant to antibiotics. So we can find bacteriophages to treat lung diseases, we can use them for gut diseases, urinary tract infections. An enormous amount of people die in this country from sepsis. And about half of those sepsis cases actually start off. It was a urinary tract infection. So we could potentially use bacteriophages in that setting to stop those infections within the bladder to stop a lot of pain and discomfort and mortality and then to stop the other more serious infections coming along. But we can also use them in animal context as well.

So about 70% of all the antibiotics that we produce as humans are actually used in farming. So they're used in the animals that we could then consume. So what we're doing is we're driving antibiotic resistance in those sectors. So making the problem much more severe in terms of having these bacteria that then cause human diseases that we can't treat. So there's a good opportunity really to use bacteriophages in what we call this one health environment

so to use them in animals, to stop the disease there, and to stop that transmission. So to allow us to be able to have a lot of safe, sustainable food sources. And just to link Marfas and James research areas, phages are also making a big comeback as diagnostics. So slightly changed phages are so rapid in the way that they can bind to bacterial targets that they make for perfect rapid diagnostics. There's also since the 1970s been extensive use of phages and parts of phages for the biotech revolution,

where you take parts of the phage that are used to seal together parts of the DNA or to cut through parts of the DNA, and you splice that into the recombinant technologies that we rely on nowadays for large parts of the pharmaceutical sector but also for biochemical production. James, you've likened pages to the... rainforest. Can you tell us why? Yes. So given that, as we've been hearing, phages are the most abundant biological entities on earth,

we still know relatively little about their diversity. And so just as rainforests represent hot spots of biodiversity on earth, so the phages represent the largest cache of undiscovered genetic variation in the world. It's like an undiscovered rainforest. And we are beginning to get a sense of how big that is. So three billion years, phage have been dancing with their bacterial hosts. And we see this amazing ancient sort of records. So just in the same way in the rainforest, you still see the

primeval species. They exist within phages as well still. So it's an amazing archive and we're only just scratching the surface when it comes to it. Yeah. So we know over the about the last decade, a little bit more, we've been really understanding the diversity of our microbiome, the human microbiome and all these different things. We know that you or I have a thousand species of bacteria in our digestive system. And actually to then think we have another 10 times more of that of bacteria pages. And then when you look inside the genomes of them, we can recognize nothing. So this is unheard of. If I talk to other microbiologists and I say, I find a new organism and none of the genes look like anything that's known, they even they don't really believe

that this is the case. But there's so much undiscovered genetic diversity out there that it's a little bit hard to understand what it's all doing. So we've been developing tools to try to understand this diversity, to be able to compare bacteriophages, to be able to select those that are going to be useful to us in all these different ways that we've been discussing. I think one of the reasons for this is also really historical, because so far phage research has really focused on a very narrow spectrum historically of mostly lithic phages, either for therapy or with the phage group to map bacterial genetics. So there hasn't been a lot of interest, historically. historically speaking in phage diversity, ironically, even though they are one of the most or the most abundant form of, can we say life?

Yeah. Why is that? Because phage very quickly become tools. They become tools to map other things. We use them to map genetic heredity. We use them as therapeutics. We use them as diagnostics. But rarely did the researchers actually end up studying the phage themselves. So once the tool set was developed, there was little incentive to move beyond it. And I think, think with genomics now, it's much easier to do this than it was for previous generations. Yeah, so essentially you had one community of people that were trying to understand what bacteriophages were doing in the natural environment, and they were starting to sequence them and look at them and understand them. And then you had another community of people that were using bacteriophages, but just using them because they knew they worked. So what we can do now is bring those two communities together to actually try to understand how bacteriophages that will be medically relevant actually work, so we choose and use the right ones.

So you're optimistic about the future, then, in that sense? I'm extremely optimistic about the future of phages. To quote the author Victor Hugo, there's nothing more powerful than an idea of its time. And I think we are kind of on this cusp of a golden age of phage, where we've got the tools, we've got the will, we need to do it, we need phages to help us tackle some of these really big problems of our time as well. So absolutely, I'm optimistic and I'm hoping the other people around

the table hour as well. Well, then, you're shaking, well, are you going to be shaking your head about your head? I'm also very optimistic about the current wave of phage research. I think historically speaking, what's notable about the phage field, though, is a series of booms and busts of interest in phage research and also specifically in phage therapy. And I think phage have enormous potential as therapeutics, but I think that it's very dangerous to think of them as antibiotics or as an antibiotic as that's, as they're often marketed in the public sphere these days. They aren't antibiotics. They work very differently, and they also

can have ecosystems' impacts if we use them in a non-careful way, for example, on mass by spraying them into the environment. So I think what phage research has to square is both solving parts of the AMR crisis without replicating the problems that overuse of antibiotics and overreliance of antibiotics have created. Yeah, I think we have an opportunity now to get this right. We've really overused and abused antibiotics. They were such a powerful thing for doctors to be able to just be able to save their patients, to be able to perform your routine operations. Now this or we risk not being able to do these standard things anymore.

So with bacteriophages being the ultimate killers of bacteria, we have another whole chance. It's another whole set of things that kill bacteria. But we really have to get it right. We have to not just overuse them. We have to understand them. There's a lot of underpinning science to do. So we've gone from a situation where there was more or less no interest therapeutically, just in little pockets, to a situation where doctors are contacting me all the time saying, give me my phages and my patients are dying.

But we really need to do this underpinning science. So with sufficient resource, there's a lot of talent. We can get this right, I think. And I think the final thing to think about it is that phage also don't work on the market like antibiotics do. As Martha said, you need tailored phages. That means the patient needs to have a laboratory confirmation. the phage need to be tailored, the phage need to be applied, so they don't work off the peg like antibiotics do to the same extent. And that makes them very difficult to fit into the marketized development models we have for new drugs.

So developing... They're very case-specific, are they? They're very case-specific. They're also very difficult to patent if you're using natural phages. If you're using recombinant phages, that's another question. But these are really big regulatory issues we're facing at the moment, not just in the UK, but also in the US and the EU context. But how do we fit these, including? incredibly powerful tools into systems that have been developed around regulating and

financializing antimicrobials. James? Yeah, I think we need to be extremely careful. But we also, we were talking about this one health approach where we are all working together, whether that's for phage for clinical uses, whether phage in veterinary and agricultural uses and certainly for water quality monitoring. But I do think we need to be very careful about what we are, the phages, that we characterize the phages that we do use and that we make sure we're avoiding.

certain parameters such as antibiotic resistance genes and toxicity genes, so genes that confer toxicity to bacteria. So we just need to be very careful with the phages that we do select for use. But we've got very important, we've got tools now that we didn't have before that allow us to select those. And artificial intelligence is another way that can be used to understand the potency of phages, but also to understand that they are phages that are not going to go back into a lysogenic lifestyle

where they just hang out, that we are using the right phages. So I think, yeah, we are at the cusp. Yeah, I think it was... I think that bacteriophages were really abandoned due to their complexity. But I think now it's the complexity that we need to use, but we need to unravel it and use it appropriately. So you say that we're a big...

Might be at the beginning of allureus dawn in this. I think we've... We've been there before, right? The glorious storm was in 1920, when everybody said this is the magic bullet against bacteria. We've got Nobel, we've got Pulitzer Prize winning novels written about bacteria phages as the next big thing. And it just doesn't happen. And they're endlessly used as heroic solutions to huge problems. And in doing so, people make too strong or too big claims about what they do.

And it leads to a cascading disappointment. And I think the phage community has burned itself in the past. and at the moment there's a lot of caution about over-marketing them without in any way detracting from their huge potential. Yeah, I think previously when bacteriophages were exploited and they were developed, we had no real idea about how they worked in any way. So it was all done very, very blindly. So now we just have the tools now.

We can actually make sure that we have sufficient information about those bacteriophages. So we can make something that's pure, we can test it, we can get to the point where we're doing proper robust clinical trials. And I think it's important to say that bacteriophages aren't going to replace antibiotics. We can use them really well together to enhance antibiotics. So there was a very nice paper published a couple of weeks ago from doctors in Belgium who treated 100 patients. They didn't cherry pick. They just showed all the data.

And in most cases, when they combined antibiotics with bacteriophages, they were able to eradicate an infection that couldn't otherwise be eradicated. So bacteria, they shouldn't be seen as being something that's going to work when, just when antibiotics have stopped. They can actually be used to allow us to keep using our antibiotics. Coming to the final words, starting with you. And I think in that case, actually, history does hold lessons or insights for the future of phage therapy, because if we look back into the archives, this use alongside antibiotics is actually the historical norm. If we look at French hospital treatments for 60 years after the Second World,

that was specifically how phages were used alongside antibiotics. antibiotics as a niche to complement antibacterial management with increasingly sophisticated understandings of the ecological impacts in hospital wars but also broader. Phages can also improve the efficacy of antibiotics, of conventional antibiotics, in that they're very good at targeting biofilms. And these have prevented antibiotics getting to the target site. So, for instance, with implants, phages are very good at attacking those biofilms and allowing the antibiotics to get to their target.

Well, thanks to Martha Clokey, James Ebden and Class Kirk Heller. We take our annual break now and be back on the 19th of September. Please join us then. In the meantime, on BBC Sounds, you can listen again to the programmes we've made so far. There are more than a thousand of them. Thanks for listening. Have a good summer. And the In Our Time podcast gets some extra time now with a few minutes of bonus material

from Melvin and his guests. What did you not say that you'd like to? have had time to say. I would have liked to have talked more about how we will use phages in the future. So we've been talking about how we'll use bacteriophages to eliminate one particular disease causing bacteria. But actually, if we understand how they're working in the human body, we can perhaps use phages to manipulate the overall microbiome to a disease-free state. So a much more complex and nuanced way. So bacteriophages will allow us, for example, when people have severe breathing difficulties associated with things like cystic fibrosis, chronic obstructive pulmonary

disease, all these diseases, we know there's a shift in the number and the types of bacteriophages. And we know that this is interacting with treatments. So I think in the future, by understanding what phages are associated with disease, we'll have really good markers of disease, so that links to James's work and what class picked up on. And actually, we'll be able to have more sophisticated treatments where we'll be able to shape the microbiome that either it will be disease-free or it could then be susceptible to another treatment. So I think this is another really fascinating area of how we'll use phages in more complex and interesting ways in the future. Do you want to come in? Were you just scratching your head? No more. I was just scratching my head, but I will come in.

So for me, yeah, I think phages have this huge potential, but what we need to do is make sure that we're not just controlling antibiotic resistance in more economically developed countries, that we are making sure that we are controlling the spread of antibiotic resistance across the world, and that we are using these tools, including low-cost phage-based tools, in the parts of the world where they're most needed, whether that's for dealing with water, sanitation and hygiene challenges in low-resourced settings, emergency settings. But we definitely need to make sure that the benefits of phages are shared by all and they are felt by all and that can only really happen if we are using phages

in a more geographically inclusive spread. I mean, there's a bit of an irony here too, right? Because we're talking about bringing the benefits of biotech in an accessible way to the global south, so to speak. But phages were and were always a technology of the global south itself. If you look at the first mass uses of phage therapy, they happen in Brazil, for example. If you look at the persistence of phage typing, you will still find microbiologists in some parts of India, but also in, for example, in Kenya, in some cases, still using phage typing to this day.

So phage, because they are so local and so specific to local ecosystems, they are a local solution for local people, so to speak. So it's quite a nice way of thinking about it, isn't it, that these new technological advances that are there, they can link into a ready strong. strong existing research and therapeutic traditions. Phage therapy never went away in large parts of the world, and using phages diagnostics didn't go away either. So we can think of it as a kind of updating some of these competences. We know how antibiotics work. How do phages work?

How do you use them? The initial phage applications are via solutions. So you drink a phage cocktail and you swallow it for intestinal uses. Then people start using phages to apply them to topical wounds, and they also create tablets, phage tablets that you can swallow. But nowadays, the usage has evolved quite significantly. Yeah, so depending on which part of the body you're trying to treat, you can use bacteriophages.

For example, you can nebulize them, where you would nebulize an antibiotic or an asthma drug, so you can disperse them into the lungs to get to the lung infections. You can have them in capsules that will survive the passage through the stomach to get to the lower colon to sort out gut diseases. So you can use them in many different ways. You can inject them, although this becomes necessary to do quite a lot of other science because you don't want to use phages that promote a strong immune response.

But you can use them in similar ways to the way you would use other drugs. The important thing with phages, once they've arrived at their target, is that they actually start multiplying. So the amount that's not like an antibiotic where you take a tablet and they reduce over time, the phages actually increasing at the site at the target. sight within the body anymore? What has always struck me about thinking historically about phage is also how connected all of these different research strands are.

So when you read a book about the history of bacteria of phage these days, you'll either get the history of the bacterial genetic story. Often you'll get a tragic story of how phage therapy was forgotten and then got rediscovered. But as a historian, if you research the actual infrastructures of phage therapy, you actually see that they are remarkably consistent and almost form a backbone of microbiological. research in the 20th century. It's these central reference laboratories that use phage typing to accumulate these massive culture collections that we now rely on for our research on evolutionary interaction. It's the same institutes that combine the phage banks that we're now going back to when

we're looking for therapeutic phages. So what is really interesting here is that if we abandon these histories of these uber personalities like Derelle or Ilyava, if we abandon the notion of the forgotten Soviet viruses, what we actually see is quite a consistent tradition of phage research across all three areas of basic research, therapy and diagnostics in most parts of the world, actually, from the 1920s onwards. And avoiding the hype might be a good recipe for avoiding disappointment in the future when it comes to just building on these strengths that are already there. Well, I think, as I totally agree with, got class just said, there was a massive death of funding in phage research for a very long time. When I started working on bacteria phages in

about the year 2000, I was considered to be very unfashionable. And I was told, never, ever say you want to use phages. I published some books where I was basically trying to save the protocols from a whole set of phage biologists that were retiring. And they told me that they didn't have any other researchers that they had that were continuing their work. So it was seen, I think for a while, some strands were seen as being deeply unfashionable. So I think it's important to not forget those things of the past when we go forward as well. We have this opportunity to get it right,

but it will need resource. It will need government resource and resource from research councils for us to be able to do this research, to be able to translate. Is it more labour-intensive, this? Yeah, bacteriophage research is really labour-intensive, especially for hard bacteria.

So as I said about most of the bacteria, Phyrophages we have, the few thousand we have, are only isolated on 30 species. And that's because the other thousands of species, they're quite hard to grow. And if you can't grow your bacteria, you can't get your virus to bring your virus to life. So the techniques are very, very challenging, especially for bacteria that actually cause a lot of really difficult diseases. Which is interesting too, right, because labour costs differently in different parts of the world. If you have low labour costs in a country, phage are actually a really, good method to work with if, for example, you can't afford the servicing contracts of sequencing

machines or sequencing protocols. So you have this, I say, ebb and flow, I agree with math, obviously different parts of the field are more popular or less popular at different points in time. But underlying at all is, I think, a consistency of working with phage to a certain extent across different communities of microbiology. I think our producer, Simon Gillisterner's, pouring at the bit. No, does anyone want tea or coffee? Melvin, your last one of the season? Tea, please.

I'd love a tea. Coffee please. Thank you very much. In our time with Melvin Bragg is produced by Simon Tillotson and it's a BBC Studios audio production. Hi guys, I'm Ryland and this is How to Be in the Spotlight from BBC Sounds.

It's the podcast where together we're going to hear what it's like to be thrust into the public eye by those who've lived to tell the tell. In this podcast, I'm going to be joined by 12 fantastic guests who are going to share how they've learned to navigate the perks, pressures and pitfalls of fame. This is Ryland, How to Be in the Spotlight. Listen on BBC Sounds.