Bacteriophages

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Hello, early in the 20th century, scientists noticed that something in their labs was making bacteria disappear.

They called 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 they're the most abundant life form on the planet and with further research they could be an answer to the growing problem of antibiotic resistance.

With me to discuss bacteriophages, or phages for short, are 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 Klaus Kirkeheller, historian and charge de research at the French National Institute of Health and Medical Research's Sermet-Trois 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 principle, some kind of lysing principle where cultures get destroyed.

And one of the first reports that seemed to indicate the presence of phages came out of India in 1896 by a bacteriologist called Ernest Hankin.

And he notices when researching the water of the Ganges River that cholera bacteria are being lysed and killed when exposed to this water, as opposed to after this water has been boiled or well water.

So, what does lysid mean?

It means that the bacteriophage destroys the bacteria culture.

It explodes the bacterium.

Now, during this time, Hankin and many others 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 Twart.

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 micrococcus 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 through a very fine-poured filter called the Chamberlain filter that is so fine-poured that bacteria cannot pass through.

So he realizes that what he's dealing with is an ultra-microbe or something that can passage through this filter.

Then there was this Félix Dehrell, a French-Canadian.

He took this further, I understand.

Yes, DeRrel is a Franco-Canadian researcher who, two years after Twart, independently discovers bacteriophages.

And he's also the person who coins the name bacteriophage, bacteria eater.

Derel 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 colorful 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, he 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 Derel starts this, 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, See sal agave into alcohol, and he makes his first big discovery, which is to use Corcilo Soterelle, 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 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 suffer 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 pharge.

And it is in 1916 that he identifies the bacteria pharge when he holds up a broth that he's incoculated 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 comprehensible.

Thank you very much indeed.

Martha, can you take us to Georgia now?

Rather unusual leap, but 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, Georg Eliava, who had the fortune really of joining forces with Felix Durrell.

So he was actually, he was born in 1882 in Georgia.

He wasn't quite as colourful as Felix Durrell, but nonetheless he was a very keen sportsman.

He loved literature.

He loved horse riding.

He was 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 the 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 Félix Durrell, he sort of thought, oh, that's interesting.

I wonder if it's the same phenomenon.

So he actually repeated Félix Durrell's experiments.

And not everybody, even within the Pasteur Institute, believed Durrell.

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 Elijah Institute that many people have heard of.

But initially, again, it was the first thing they did in this institute was build um 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 he 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.

In this year, Stalin executed about 15,000 people in Georgia.

So he was executed for being an enemy of the people, for for spending so much time in France.

But he had ceded enough technology and ideas that the Institute could continue.

This is where the story of Alexander Fleming and penicillin 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 penicillin.

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, a 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.

It actually, 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 channelled on that and was investigating this.

And they 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 these, 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 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, yeah.

James, can you tell us precisely what is a phage?

Sure.

Bacteriophages or phages are essentially viruses that are 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 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 there are trillions of bacterial cells in our guts, so they outnumber even that.

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, well, you don't give up, but

I'm riding on your back now.

Away 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 metre 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

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 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 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 neighboring 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 life 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 the consequences of this?

The consequences are that these lysogenic phages can then become litic again.

So they can actually then start destroying the cell.

If, if, for example, that genetic information is 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 onpicking of phages seems to have had 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 Marf has 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 building 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 bacterial phages 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 principle, litig phages specifically, to elucidate the statistical mechanisms behind heredity.

And there's a link with James Watson here, 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 in 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 devised the iconic blender experiment, where they use raised O 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 3, 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 have 10 bacteriophages in order to kill all the different subtypes of E.

coli 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 litic 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 evolve to be able to target them and so on.

So So, it's a sort of classic predator-prey relationship, is what is what you see with these delicate wars.

It's basically a battle that's been raging ever since bacteria.

Nobody

won.

No, no, they're sort of codependent, and perhaps it's 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 that bacteria.

They can make it better at being

a pathogen, for example.

They can confer useful properties until they then kill it.

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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 sort of late 1940s when French microbiologists started looking at bathing waters.

But we tend to monitor drinking water historically using groups of indicator bacteria.

And these bacteria are shed by all warm-blooded mammals.

So although they can show us that water is contaminated fecally, 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 are 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 behaviour of other enteric viruses such as norovirus or adenovirus, which can also be circulating in impacted drinking water supplies.

So they're very powerful tools.

Klaus, how have phages been used to map a microbial environment?

Phages work brilliantly as therapeutics, but because they also lie only specific bacterial strains, they're also brilliant diagnostics.

And clinicians start using this from the 1920s onwards when in hospital settings you just infect a bacterial plate you're dealing with with a phage 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 that bacterial culture, it's bacterial culture phage type one.

That's a really simple principle, but it was of huge use during the Second World War when phage typist 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 epidemics 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 typists do 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 bacteriological 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 who will die across the globe every single year.

And this isn't some just esoteric number.

It's already happening already.

And 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 this has 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 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 has 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 bacteriophages a lot better.

James, James Ebden,

in your work, why is it easier to test for phages linked to the bacteria that cause the disease rather than to 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, 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 sewage 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, and James can still pick up the bacteriophages that infected it.

So that's why it's their evolutionary strategy that makes them so useful.

Exactly.

And we we can find them in the environment, we look for them, we find them in shellfish, for instance.

Shellfish are bioaccumulators and they're 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 any sense in which the dominance of the phages 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 upon 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 interest, long-term interest, to wipe out that host if it's not in a very good state, if it's stressed, if the bacterium or that 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 Direl, who actually thinks of phage as a part of the immune system because phage becomes more abundant in recovering patients.

So, he actually conceives of it as a kind of infective immunity that you can pass on.

It's obviously later debunked in the way that he formulates it, but the observation makes sense.

Marva.

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 it will build, so they're disadvantageous to the bacteria, but they don't ever hurt the human host.

So they're sort of a nerd.

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 around if you're a bacteria.

But for a human host, we can think of them as being the enemy of the enemy.

I see.

Klaus,

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

still exist in certain places around the world, such as the Pasteur Institute.

There are also important collections here in London and Collindale.

And they contain really observations of the rapid shifts of the microbial biosphere that

have happened over over the last hundred years with the antimicrobial era starting, but also climate change happening, etc.

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?

There 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 of as 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 that we 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 Martha's 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 phages to the rainforest.

Can you tell us why?

Yes.

So given that, as we've been hearing, the phages are the most abundant biological entities on Earth, we still know relatively little about their diversity.

And so just as rainforests represent hotspots 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, the phage have been dancing with their bacterial hosts.

And we see this amazing ancient sort of record.

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 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 ten times more of that of bacteriophages.

And then when you look inside the genomes of them, we can recognise nothing.

So this is unheard of.

If I talk to other microbiologists and I say, I found a new organism, and none of the genes look like anything that's known,

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 lytic phages, either for therapy or with the phage group to map bacterial genetics.

So there hasn't been a lot of interest, historically speaking, in phage diversity, ironically, even though they are one of the most or the most abundant form of

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 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 are as well.

Well, then, yeah,

you're shaking.

Well,

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 uts, 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, en masse 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 over-reliance 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 uroutine operations.

Now this all 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.

My patients are dying.

But we really need to do this underpinning science.

So with sufficient resources, there's a lot of talent.

We can get this right, I think.

And I think the final thing to think about is that phage also don't work on the market like antibiotics do.

As Martha said, you need tailored phages.

That means a patient needs to have a laboratory confirmation, the phage needs to be tailored, the phage needs 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.

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 EU context.

But how do we fit these 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 characterise 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 can confer toxicity to bacteria so we just need to be very careful with the the phages that that we do select for for use but we've got very important we've got tools now that we didn't have before that allow us to to select those and and artificial intelligence is a 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 a cusp.

Yeah,

I think that bacteriophages were really abandoned due to their complexity.

But I think now it's the complexity that we need to use.

We need to unravel it and use it appropriately.

So you see that we're a big,

might be at the beginning of a glorious dawn in this.

I think we've been there before.

The glorious dawn was in 1920 when everybody said this is the magic bullet against bacteria.

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, you know, 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 bacteriages 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 antibiotics have stopped.

They can actually be used to allow us to keep using our antibiotics.

Come into 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 War, that was specifically how phages were used alongside antibiotics as 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.

So they are, 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 Cloakie, James Ebden and Klaus Kirkheller.

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.

I was just scratching my head, but I will come here before.

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 antibiotics resistance in more economically developed countries, that we are making sure that we're 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 are most needed, whether that's for dealing with water, sanitation, and hygiene challenges in low-resource settings, emergency settings.

But we definitely need to make sure that the benefits of phages are shared by all and that 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,

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 already strong existing research and therapeutic traditions.

Phage therapy never went away in large parts of the world, and using phage's diagnostics didn't go away either.

So, 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 body you're trying to treat, you can use bacteriophages.

For example, you can nebulize them, the way 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.

And the important thing with phages, once they've arrived at their target, is that they actually start multiplying.

So the amount that's, it's not like an antibiotic where you take a tablet and they reduce over time, the phage is actually increasing at the site, at the target site 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 bacterial bacteriophage 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 Farschbanks 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 Derel or Iliyava, 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.

Although I think,

whilst I totally agree with what Klaus just said, there was a massive dearth of funding in phage research for a very long time.

When I started working on bacteriophages in about the year 2000, I was considered to be very unfashionable and I was told, no, 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

labor-intensive this

yeah bacteriophage research is really labour intensive especially for hard bacteria so as i said um about most of the bacteriophages 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 labor costs differently in different parts of the world.

If you have low labor 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 Marf, obviously different parts of the field are more popular or less popular at different points in time.

But underlying it all is I think a consistency of working with phage to a certain extent across different communities of microbiology.

I think our producer Simon Tillotson is pouring a bit.

No, does anyone want tea or coffee?

Melvin, your last one of the season?

Tea, tea, can you please?

I'd love a tea.

Come on.

Coffee.

Thank you very much.

In Our Time with Melvin Bragg is produced by Simon Tillotson and it's a BBC Studios audio production.

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