In Our Time - Penicillin

Episode Date: June 9, 2016

Melvyn Bragg and guests discuss penicillin, discovered by Alexander Fleming in 1928. It is said he noticed some blue-green penicillium mould on an uncovered petri dish at his hospital laboratory, and that this mould had inhibited bacterial growth around it. After further work, Fleming filtered a broth of the mould and called that penicillin, hoping it would be useful as a disinfectant. Howard Florey and Ernst Chain later shared a Nobel Prize in Medicine with Fleming, for their role in developing a way of mass-producing the life-saving drug. Evolutionary theory predicted the risk of resistance from the start and, almost from the beginning of this 'golden age' of antibacterials, scientists have been looking for ways to extend the lifespan of antibiotics.WithLaura Piddock Professor of Microbiology at the University of BirminghamChristoph Tang Professor of Cellular Pathology and Professorial Fellow at Exeter College at the University of OxfordAndSteve Jones Emeritus Professor of Genetics at University College, LondonProducer: Simon Tillotson.

Thank you for downloading this episode of In Our Time, for more details about in our time, and for our terms of use, please go to BBC.co.com.uk slash radio four. I hope you enjoy the programme. Hello, in 1928, the Scottish bacteriologist Alexander Fleming noticed something odd on the petri dish he'd left out in his laboratory, St. Mary's Hospital, Paddington. The dish was covered with bacteria, as expected, except for one area around some mould. He realised that something coming from the mould had killed bacteria. Fleming named the Mold's active substance penicillin.

He won a Nobel Prize of Medicine for his discovery in 1945, along with Howard Florey and Ernst Chain, who had seen the potential for penicillin and turned it into the life-saving drug it became. From that point on, scientists tried to understand how penicillin does what it does, and from there to find new antibiotics, to kill a broader range of bacteria

and deal with the ever-present threat of drug resistance. With me to discuss penicillin are Lora Pidoc, Professor of Microbiology at the University of Birmingham. Christoph Teng, Professor of Cellular Pathology and Professorial Fellow at Exeter College at the University of Oxford. And Steve Jones, Emeritus Professor of Genetics at University College London.

Steve Jones, before the 20th century, what did doctors use when they tried to kill bacteria? Guesswork, I think, is the word. People have known about fevers, of course, for a long time. And the assumption was it was an imbalance in body chemistry, the famous four humours. And the assumption of a fever was you had too much collar, too much blood. So what would you do?

It was the universal remedy. It was the penicillin of its day. You did bloodletting. You took a lot of blood out. Now, that probably did no good at all. In fact, it probably did more harm than good. There were some treatments in early times which probably did some good. People used to dress wounds with honey.

It seems an odd thing to do. And honey is sweet when it takes away the pain. But it could well be that that... sucks water liquids out of the bacteria that are in the wound and might just kill them off, but it's a might just thing. But there were various minor, almost random treatments. For syphilis, for example, which is a bacterial disease, they use mercury, which is fine.

It kills the bacterium, but often killed the patient as well. And then they moved to an arsenic salt, which did the same. So they're really groping in the dark, But I think things really began to get moving with chemistry, with dye stuffs. And it's a classic example of how science goes in unexpected ways. People in the 19th century and before had learned that you could stain tissue samples with particular chemicals that lit up particular parts of the tissue or particular kinds of bacteria. And Ehrlich had the brilliant idea of asking, well, maybe if it stains this tissue or this bacteria,

it's sticking onto it. And maybe some of these chemicals might actually kill bacteria. bacteria and huge research money was put into this. What dates are talking about? We're talking about the 1920s, the 1930s probably. And such drugs began to turn up. I mean, there were things like Salvasan, which is actually rather earlier, that was in the 20th century, which is very active against syphilis.

And then the buyer company, German company, started doing it. And they got a whole family of drugs, the sulphur drugs, and then came penicillin. What was Fleming interested in? in the 1920s that led to this discovery. What was he doing in his laboratory when this accident happened? Well, Fleming had been at the front in the First World War, and

what happened at the front, it happens in many wars, of course, that many more soldiers died from either infectious disease, infectious diseases of various kinds, very often from infected wounds. And there was really no effective treatment for that. You didn't finish since many more died than died

from bullets. Than died from bullet wounds. And there was no effective. treatment for that. It was noticeable that the infections seemed to come in some sense from soil because they were in the mud of the trenches and so on. And Fleming began to interest himself in possible cures and he noted that

various bodily fluids such as tears contain an enzyme which is called lysosine which kills off bacteria in culture. And he thought this might be useful but he couldn't find it didn't work in clinical terms. And then he made his famous... Not enough tears or not enough tears really.

Well, not just, it's in other fluids too. It's in snot as well. So it's not the ideal. It's not the ideal source. But there wasn't much of it. It didn't really work in clinical terms. It was broken down rather quickly. And then he made the famous observation, which you've mentioned on a petri dish,

which is a round, small dish with agar in the bottom, which you can grow bacteria on. Accidentally, he left some open. They grew some bacteria, as he would expect it. He was about to throw them away. And he noticed, as you said in your introduction, that on a few of them, there were spots where the bacteria couldn't grow. And that was around this mould, which was called penicillium.

And he put two and two together and made, really only made three rather than five. Because he thought this was very interesting, but then he didn't push it any further. He thought it was like lysosium. It wouldn't really work. It was broken down quickly in the body. Apparently, he was frequently referred to as the worst lecturer anybody had ever heard. And that's rare praise indeed, as any academic will tell you.

He also never really published his result. He mentioned it almost in passing in other scientific papers. So he came to nothing until finally he was picked up by Florian Chain in Oxford. Can we take that story up, Laura Pittock? So he's found this, but we still haven't quite got what he was looking for with these petri dishes. So it really goes back to just before the First World War where he was already a microbiologist at St. Mary's Hospital. and he was recognised as a good scientist, but he was also part of the army.

So he was in the World War I as a field hospital, and he was shocked by the number of patients who died because of the blast wounds. And this is the first time they'd been blast wounds. We recognise them in modern warfare, which blasted in bacteria, which then got into the body called sepsis and died. Into the bloodstream.

into the bloodstream. And they had very early times where they could put antiseptics into the wound. And he found that whilst the antiseptic was very good on the surface, it actually did a lot of damage when it got into the wound. It actually stopped some of the body's healing processes from working. So at the end of the war, he went back to St. Mary's into his lab and started a long period of work looking for antibacterial substances, made first of all in bodily secretions, which led to lysosine, which you've just mentioned, but also led him to look in all sorts of other ways for antibiotic-type substances.

We're talking about bacteria. We are 90% bacteria. How do you distinguish them that's trying to get us and them that aren't? That's a very good question. And we still struggle with it today because we well recognise friendly bacteria and bad bacteria. The reality is bacteria can be both.

and we need bacteria inside us for our gut to work properly to be able to digest our food properly. We need it for defence as well. They often perform a barrier and on our skin. So the real when they bad is when they get somewhere they shouldn't be, such as in the bloodstream, for instance. So a body site, we would not expect a bacterium to grow in. Steve has referred to previous methods of treating this.

one was dyes. Can you develop that a little bit? How far the spin-off from dyes, how well that was doing and the work on that in the 20s and 30s of the last century? Well, it was fairly well advanced. Chemistry was pretty good by then. And so, as Steve just said, they noted that some dyes had an antimicrobial effect, including against some bacteria and other,

small parasites as well. And there was then this chemical development of a dye on to making what we call the sulfonamite class of drugs. drugs and they were used right up into World War II and indeed sometimes they're still used today. So the ways that antibacterial drugs were looked for, the screening, the type of activity, that was fairly well developed, even doing tests in mice with specific bacterial species, Streptocarchae, Staphylococci, which Fleming also worked on. So it had fairly robust lab ways of working with non-executive,

new antibiotic molecules to take them from the test tube into a drug to patients. So we're talking about the 20s and 30s, as it were, getting a focus, the chemistry, which is in a boom area at that time, getting its focus on this problem. Yeah. So Fleming, when he made his observation on the plate, his, what he has, his discovery really was that there was this diffusible substance coming out from the mould growing on the plate that clearly stopped the bacteria on the plate. flakokai from growing. So what he went on to do was to try and grow the mould in liquid

culture. So it's like a mat growing on the top of like a broth. We call it a broth in labs. And was able to get the penicillin, as he called it, to then be active in the test tube. But he struggled to get a stable version of penicillin. It wasn't stable in liquid. It wasn't until the fluorine chain and others then worked on it. They found it was only stable when dry. So Fleming decided that it wouldn't be stable in the body, although he did do some mouse experiments because

he didn't think it would last long enough. And Christoph Tang, what I, let's stick with Fleming and this petri dish because it's an important moment. I think one of you says it's one of the great moments in chemical discovery and medical discovery. So what

is it about this petri dish and why nobody found that before and it seems so obvious you mold grows where you have bacteria in a particular location. I'd like to narrow it down. I mean, obviously, like I'd just sort of get a key to it. Well, I think the important thing to consider is how diverse the moulds are around that are in the air. And in fact, the chances of a mould which was producing something which is chemically useful,

something which could kill bacteria and landing on a plate next to bacteria or growing on a plate would be vanishingly small, so it's a remarkable coincidence that this mould landed on the plate. In fact, the sort of story goes that he'd left his window open, he'd left some plates open, and this mould sort of floated in on the air as a spore from the street outside the lab in St. Mary's, but it's very unlikely. I mean, I don't think any self-respecting microbiologist would leave their plates open or leave an open window for the risk of contamination. It's much more likely this mould actually came up through.

a lift shaft in the building at St. Mary's from a lab below, which was studying moulds. So we're talking about an accident? Incredible accident, remarkable accident, it transformed history, really. There is a tendency among scientists I'm fearing to tread here. If he hadn't done it, somebody else would have done it.

But is it the nature of this accident that it was perhaps an unrepeatable accident? I don't think so. Actually, if you go back in the medical literature, there were occasional accounts in the late 1800s of people, researchers in France. researchers in Italy who've noticed moles having similar antibacterial effects. I mean, what the problem was then was one of information technology.

I mean, now it's quite easy to find out what people have done. You go on a computer, do searches through the medical literature. Then it was an issue of painstaking going through printed literature. And for instance, if you're working in London, your access to medical texts produced in Italy or produced in France was very limited. And so many people struggle to find out what had been done before. And just before we leave Fleming, Steve said he was very bad lecturer and he was, didn't say much about Penicillian. But whatever did he make?

Did he see this could be something very, very important? I'm going to try it this way. What did he do? We'll move on in a moment. It's a very interesting question which people have considered. Why didn't Fleming take it on further? And I think I don't think he had the, when you look at it,

go back and read the original paper, he clearly didn't have the insight that you could actually use this to treat a systemic infection. He'd seen these local infections, the law had mentioned wound infections, and he was interested in using penicillin as an antiseptic, something you would put on an injury or something like that.

But actually using it as a drug, he didn't do that. He did do some experiments. He did do some trials on, some of his colleagues at St. Mary's. He grew up the mould in liquid culture. He got one of these colleagues to eat some crud, some molders grown up. Somebody had a sore throat. It didn't really help them.

Same person had some mold juice instilled their nose when they had sinusitis. Again, they were really half-hearted attempt. He didn't really have the conviction of what he'd seen to take it through to become a drug. But there was enough, Steve, in those side notes, for this to be picked up 10 years later. Yes, it was done, needless to say, at the University of Oxford,

which has always got its eyes firmly fixed on the financial payoff, needless to say. I'm going to ignore that. That's all right. If we weren't live, we were fixed on. Nobody would keep it in. No, but Florian Chain had read about this stuff, and they went at, they... These are two Oxford biochemists,

and they saw they had the insight to see what it could do. And they really almost industrialized the production of penicillin remarkably quickly, very efficiently. And it was clear it was going to be desperately needed during the Second World War. And the story goes that Fleming actually turned up in their laboratory. And one of them said, in an astonished voice, My goodness, Fleming, we thought you were dead. Now, whether that's true, I don't know.

But it just shows the gap between the sort of dreamer and the realist. And that gap, I have to say, between practicing scientists in biological sciences, in biology and clinicians, is still there. And desperate attempts are made to close it, often without success. Can I just be going to that a little more closely, Laura, so 10 years on, these two men, Australian, they see these notes, these few notes, and that's enough while they're searching. Why did they want a search to do anything with penicillin anyway? How was it around if he dropped it and nobody else knew anything about it? Well, he dropped it because A, he thought it was unstable, and B, he really couldn't get any chemists to join him

to successfully purify it to do anything further. So for several reasons he felt it was not a productive line of research. Florian Chain were carrying out a systematic analysis of antibiotic-type compounds. And Chain read the paper that Fleming had published about penicillin, and he wrote to Fleming and obtained the mould from him. By that time... Just a second, when Fleming turned up a few months, they said they thought he was dead.

Yes, well, it is an apocryphal story, I think. Well, one of them's apocryphal. The paper was published about a decade before Florian Chain started working on it. You just said they wrote to him. It doesn't matter. Get on it. And then they're five. So the story, yeah, but not only did they get the mould that made penicillin, Fleming had also sent it to lots of other people, including someone at Sheffield, who was a doctor treating eye infections.

He used to make pulses with it, which were pretty effective. So it was something that was known about. But because Florian Chain were having this systematic analysis of what was there and what could they work on, it was Chain who really picked up that this was something they could work with and do something quite different with. So they got it in the lab. They confirmed the bacterial species that were killed or the growth was stopped by penicillin. Fleming had already indicated that the spectrum of activity, i.e. the number of different species that penicillin would kill,

was somewhat limited. And there were certainly, they already knew that some species would not be killed. But the key thing was World War II. and the fact that men were being injured again and again they were dying of the infections and that really is what was the catalyst to the biggest ever international collaborative scientific effort to go from the test tube into patients

and I think the other thing that really led to that was because Florian Chain had worked out how to grow it and get more of it. They were the people who found out the penicillin was stable when dry. They could concentrate it 1,000-fold and they had a preparation they could inject into patients. Wasn't only the two of them, though, was it, Christoph? There was Hietley and Hodgkin,

but they didn't give them Nobel Prize to those two, man and woman, because they thought five people were too many for a Nobel Prize. Three were something like that. Anyway, what did Heathley and, we're still in this at Oxford Group? Yes. And it'd be lovely to know even more about how they drove it through. Well, Flory was appointed to become the chair of Pathology in Oxford in 19, which was about three years before they started working on penicillin.

And he was an unusual individual. He was a fairly abrupt, abrasive Australian character. But he was very driven and highly ambitious, and he knew exactly what he wanted to do in science. And at that stage, pathology was really the study of tissue down a microscope and recording what you would see down a microscope in disease. Florey had a very different view of what he wanted to do. and he wanted to understand the mechanisms by which disease occurred.

And to do that, he realized he needed a multidisciplinary team. So he went looking for chemists. He went looking for people with technical skills. And that led him to chain. So he recruited Chain, who was a chemist. An Emmer Grey from Germany had trained within the German chemical industry, so he was highly skilled. He then Chain knew Heatley, who you mentioned, a very important character here, an extremely fine scientist, ingenious, inventive.

And actually, the other thing that Heatley brought to this was he was a craftsman, he was a master craftsman. And he could make many things out of the very limited resources which are available in the Second World War. As Laura says, this was all happening in the context of a Second World War. Laboratory equipment was scarce, was difficult to get materials. And Heatley made system for purifying penicillin out of old bookcases, out of pieces of tubing. I mean, there are remarkable pictures at the Dunn School of milk urns,

which were used to store some of the mold juice, of the bathtub, and this remarkable contraption, which was built from a bookcase. So Healy was absolutely central to this. And in fact, it's been said by Henry Harris, who worked at the Dunn School, without Fleming,

no chain, without chain, no flory, without Flory, no Heatley, and without no Heatley, no penicillin. So that really shows how critical Heatley was for the development of the... And we still haven't brought in Dorothy Hodgkin. So Dorothy Hodgkin's very interesting, and I think it would be wrong to say that Dorothy Hodgkin

should have been awarded the Nobel Prize in 1945. Dorothy Hodgkin was a remarkable character. She was a structural biologist at the time when structural biology was really at its infancy, and she used x-ray diffraction to try and solve the structure of important biochemical and biological molecules. Penicillin. What did she bring? So she solved the structure of penicillin. Why was that important?

Because it happened in 1940. Well, it was important, but it happened in 1945 and the award of the Nobel Prize for Florey, Fleming and Shane was in 1945. So she couldn't have received the Nobel Prize. But why was it important? Let's stick with the penicillin business. Why was it important? Yes. Well, I think at the time, there were large arguments about the structure of penicillin, sitting at the heart of the penicillin molecule, really at the active center of penicillin is this structure called the beta-lactam ring, which is a small four-membered ring made of carbon and nitrogen. And many chemists thought such a small ring couldn't exist because it was so unstable. And this instability was really what dogged efforts to purify penicillin in the first place. But once she solved that structure, chemists were able to modify the structure to make new penicillins to extend their activity and extend their use. Steve, Steve Jones, can you tell us how penicillin works?

Well, like many antibiotics, it can work in several different ways. One of the important ways it works is it binds onto the cell wall of the bacterium. And the cell wall of a bacterium isn't like a plant cell wall, which is kind of a, at first sight, looks like a rather uninteresting static thing, which is solid and thick and protects the cell. The bacterial cell wall is the interaction between the bacteria, in the world outside.

And actually there's a famous book called What is Life by Schroenegger. The physicist Schroeniger. And he made the excellent point in the 1920s that what life is, is small pools of order in the universe of disorder. And that life has got an inside and an outside. And what a bacterium must do, and what he must do, is preserve its internal order against the disorder outside.

And to do that, it needs to import fuel, foodstuffs and various kinds, an excrete disorder waste. and that does that through its cell wall, and one of the things that penicillins and other lactams do, is to disrupt the constant shuffling and reforming of the cell wall, particularly the various pores, specialized pores, which are in the cell wall, and these can be blocked by penicillin.

There's another approach which the... So it kills them, really? Yes, basically, it kills them, unless they evolve resistance, of course, which I'm sure we'll come to later. That's the main thing they do. They can also get into the cell and disrupt various cellular processes too. But there are various ways of which the modified penicillins,

which grew from the understanding of its structure, they work in a great variety of ways, as do other antibiotics, to destroy the ability of the bacterium to call order, order on its internal self. Laura, you put it in. So it's really interesting. It took many years, decades, to really understand how penicillins and the similar drugs that came on afterwards, the beta-actam class worked.

And they knew from its structure that it was similar to a natural product within the bacterial cell. And when it got into the 1960s, they started to understand how the cell wall was made in bacteria. It was made of a structure called peptideoglycan, which is quite a complex mesh-like structure that confers shape, rigidity on bacterial cells

because some of them are different shapes. and the structural analogue theory came out that penicillin was the same shape. It mimicked the natural structure of a molecule that's in the end stage of sealing up gaps in this peptideoglycan mesh. So in the presence of penicillin, the cell wall fell apart,

and then the cell contents leaked out and the bacterium lised. Moving into the 70s, Brian Spratt had radio-labeled penicillin and he interacted that with subcellular, parts of bacteria and showed that actually there were several proteins that penicillin and similar molecules interacted with and that these were the enzymes involved in different parts of making this mesh. So what we then, they knew really from Fleming's time onwards that bacteria

take on different shapes in the presence of penicillin and really that all then tied together that at very low concentrations of drug, one shape happened and one type of enzyme was inhibited, going to higher concentrations, which then became sidel or kill bacteria. Why is it that there are some types of bacteria on which penicillin doesn't work at all? So penicillin and most penicillin-type molecules

that are still good drugs today are very good at things like staphlococci and streptococci. And these are what we call gram-positive bacteria. goes back to the dyes. Gram positive bacteria go a different colour when you expose them to what's called the gram stain. And they go purple.

And gram negative bacteria, like E. coli, go a pinky colour. So it's been known that penicillin and the earlier similar drugs worked very well against gram positive bacteria. And the main reason that is they can get into that cell and they've got ready access to the targets, those proteins that penicillin interacts with.

gram-negative bacteria, the penicillin has to get through an extra barrier. There's an extra membrane on the outside of things like E. coli. And it's a bit of a double whammy because not only do the drugs have to get in to then interact with those enzymes, but gram-negative bacteria have a three-part machine that spans the inside to the outside of the cell, which is basically a vacuum cleaner and it hovers, noxious compounds out of the cell, including penicillins. So even when the drugs can get in, they're promptly taken out.

Christoph, Turing, what became possible with penicillin that hadn't been possible before? Well, I think the major, most obvious impact that penicillin has was in the treatment of infectious diseases. And this was in the wartime, clearly, and a lot of effort was done to undertake the early clinical trials into a drug which could be applied in the front line of the troops. and as Laura alluded to earlier on, soon after the early clinical success, Heatley and Flory went to the US to try and enlist the help and encouragement and work from the US drug companies. At the time, the UK drug companies were really taken over by the war effort.

They were making vaccines, toxoid to treat their own group. They approached welcome a couple of times unsuccessfully. But it was really the US drug companies who weren't involved in the war effort at that time who really took this on. It was a huge undertaking and in many ways you could consider it similar to the Manhattan Project, you know, the project which led to atomic bomb. This is across multiple companies, about 20 different companies were involved and they ramped up production from essentially a cottage industry which happened at the Dunn School to growing vast amounts, vast liters of fungi within huge stainless steel vats which they were using for production

of other materials. it rather a risky venture? Well, I think people had seen the clinical trials and had seen the published data and they were really convinced by the potential effect of this and a huge amount of money was invested in it from the war effort in the US. Steve, Fleming warned in his Nobel Prize speech

warned the spectrum of drug resistance. What grounds you have for saying that, first of all? and then if you could develop the idea of resistance? Well, it was known well before penicillin came into clinical use that there were particular cases where the penicillium mold didn't inhibit the bacterium. And Fleming, I think, referred to this as training. The bacterium was somehow learn to avoid the effects of the drug. But it wasn't that.

It was straightforward, banal, Darwinian natural selection. And it's worth reminding ourselves that the drug, it's, penicillin is not new. It's been around for millions, probably hundreds of millions of years in the soil. And it's because the moles protect themselves with it. And in fact, you find resistance to penicillin

in the most unlikely places. You find it, for example, in corpses from before Columbus in the new world that are penicillin, if you cut them open, and you find in there, you find bacteria which you can revivify in there, then it turns out that some of them are penicillin resistance.

That shouldn't be a surprise because there's penicillin all around us. And I think that Fleming was well aware of this. I don't think anybody had the slightest idea as to how serious this problem would become. And, you know, as more and more bacteria-sized antibiotics were discovered, then resistance became a real problem. There's an interesting parallel actually with the other Manhattan Project, which was DDT, which was against another kind of infection carried by insects. tremendous progress, enormous progress, then suddenly resistance.

And people were surprised. They shouldn't have been surprised. They should have read, as every biologist should, they should have read the origin of species. It's going to happen. And now we know that it's going to happen. Whatever we do, there's almost certainly going to be resistance. So people knew it was going to happen. People were considering what they might do, but I think nobody had the slightest idea of the size of the problem. Do you want to come in, Christy? Yeah, see. I mean, I mean, Before penicillin was actually used, Shane had shown that bacteria can produce an enzyme

which actually destroys penicillin. They'd grown simple E. coli from our guts. They'd taken the filtrate of the cultures, and they showed within that filtrate, there was a molecule which could actually break open the penicillin. I mean, I've got a sort of personal interest in this because when I was eight, which I'd admit it, was in 1952, when penicillin

was coming into general use. I was eight. I mean, you're eight. You don't worry about anything when you're eight. And I got a, I've sort of got a mark on my little finger, actually. It's not very big, but I got an infection that, which blew up into a boil, which blew up. My hand blew up, my arm blew up, and I had a fever. I was taken to hospital.

I don't remember much about it, but I assume I was given penicillin injections. And it simply went away. And it never crossed my mind that I'd been in danger. If it hadn't been for penicillin myself, and millions of other people in that situation would quite likely have died. So really, it gives you a fresh interest in this question of resistance. I mean, every hospital used to have a septic ward before antibiotics were available, and these were not very pleasant places.

I mean, the name septic ward tells you something about what they were like. There's a great line from Lister. He talked about the stench of surgery. People, surgeons used to think it was great that there were sepsis. They could smell it. They could tell their work as well. going ahead probably. So this, I mean, essentially led to a fear of anybody doing anything. The surgery was used as the last resort because people were frightened of infection.

The sort of cancer chemotherapy, which we currently use to, which immunospress people, we couldn't possibly consider that without use of antibiotics. So not only has penicillin opened the door for treating people with infection, it's also essentially paved the way for modern medicine, modern interventional medicine that we benefit from now. Laura, I'd like to ask you something, but you want to come in on this, I was just going to say because of the massive development

in the first five, six years of the 1940s, that paved the way for all modern antibacterial drug discovery in development. The ways of screening... This was in war, the development in war. So post-war... And this was to do with, sorry, my IQ... I mean, they were going for two things,

they were going for gonorrhea and syphilis and then they were going for blood infections. Yes, so during the war, yeah, the primary aim was to get men fighting again as quickly as possible. And sexually transmitted diseases were a huge problem, and they still are in any war situation. But they realised very early on,

and in fact, there's a book from the 21st Army of all the use of penicillin, and they had very well by 1945 uses of penicillin where men were injured at the front, and in the forward front, they put penicillin powder and originally with a sulfonamide powder, but they dropped that

because they found penicine worked really well. that stopped wound infections really progressing and then when they were taken back to the field hospital or even evacuated home to the UK they were then given injections of penicillin and they were given hundreds of thousands of units of penicillin and it was remarkable they said they did not expect men to die

by the end of the Second World War from their wounds whereas at the beginning it was very common I'm still interested in this development of resistance Can we develop the development of resistance? I did more, Laura. Yes, so there was the discovery of penicillinase, but also it been observed by Fleming that if penicillin wasn't given for what he called long enough

and at a high enough dose that the bacteria would survive, we now know this as resistance. And this is what led to the statement he made in his Nobel Prize winning speech. So because the chemists were so good, and we now had the structure of penicillin by the mid-late 1940s, what that allowed the chemist to do was to take the natural part of the penicillin molecule,

the beta-lactam part, and add bits to it, to start making it less susceptible to things like penicillinases. And this led to a whole wave of new penicillins, and in fact it led to another group of beta-lactans called cephalosporins. And these came for another mould,

the cephalosporium mould. So there was a lot of screening of, soils for natural products and a lot of development. So by the 1950s there were lots of different types of drugs. And all of that has underpinned modern medicine. We wouldn't have transplants. We wouldn't have knee replacements, hip replacements, cancer patients being treated without the discovery of penicillin

because it opened the door to what could be done. But in terms of resistance, of course, it opened the door to resistance as well. So there was the idea that you could prevent infection by using penicillin. And again, this was tried out in sex workers in Asia. The idea if you could prevent the sex worker carrying gonorrhea, they wouldn't then give it to the soldier who would then be debilitated. Unfortunately, what they did was they bred penicillin-resistant gonorrhea, which then disseminated.

Well, let's go back to this resistance thing, Steve, because it's fascinating. So does it automatic, you think, because of Darwin and your well-known... obsession with Darwin, quite rightly too, if you're going to have an obsession. Does it automatically follow that resistance will develop, yes, but does it automatically follow that it will become dominant? Well, it depends on the circumstances, really. And the thing about resistance is that it's, because it's evolution, it's a mess. And what is it? What is Darwin's machine, natural selection,

inherited differences in the ability to reproduce, such as what natural selection is. it's really a series of successful mistakes. And that's part of the problem of dealing with resistance because if you look at the way that bacteria become resistance, they do it by changing the membrane, by enzymes, by pumping out antibiotics, including penicillin, by breaking it down.

Some of them do bizarre things. They change their own mutation rate, their errors in their own DNA and produce hundreds or thousands of strange errors which normally wouldn't survive in nature, but some of those managed to knock off the antibiotic so they can survive and the others die. And some even cut great sections out of their DNA,

great chunks of DNA just thrown away because that allows them to copy themselves more quickly. Now, without penicillin, they would never survive. So that generally speaking, most bacteria are penicillin sensitive, most positive bacteria, Pemisotin sensitive. But once you start using the antibiotic,

it's pretty certain that you're going to get resistance. And we still have possibly one antibiotic, which everything is more or less susceptible to with very few exceptions. But now we realise the dangers. People are using these last-ditch antibiotics much, much more cautiously than they did before. And we're really almost at the end of that road of drug development, which is a real worry.

What's the real worry then? I mean, the real worry is that we are not making new antibiotics. Because I think you, Christoph, in your notes, say, and drug companies, I'm more interested in producing compound chemicals now, which don't cure, that they keep you alive for longer, rather than the penicillin things, which cure and stop, but only last for a few days. In other words, it's more commercially, much more commercially valuable to develop the compound things, and therefore they're easing off on the research to the original antibiotic penicillin.

It's quite clear if you look at the number of companies over the last 30 years that are investing and researching in antibiotics, it's been dwindling. I mean, the number of companies involved in antibiotic research has dropped by about 20, 25% each decade for the last three decades. And the financial drivers, as you say, are quite clear. For antibiotics, you produce a medicine, and I guess we're used to having antibiotics cheap. We're used to be able to pick up antibiotics for pence. you have a therapy which lasts for maybe a week or a couple of weeks, whereas company is much more interested in having a drug which they can sell for a lifetime. And it's a bit like the analogy I have is of Starbucks.

You know, what would encourage Starbucks to make a coffee you would drink or a product you would drink for a week and would stop you needing to drink Starbucks ever again in your life? Ideally, they want you to have a coffee every single morning on your way to work. And so drugs for hypertension, drugs for diabetes, diabetes, you know, companies invest a lot in that sort of area. So I think there need to be real financial drivers set up for the companies to encourage development. Is there a sense, and we get into the end now, see if I know, is there a sense that which we became awash with drugs, drugs, penitence and going to animals, going to too many, too many being recommended,

too many being given away for too many things that they couldn't cure anyway. And that, our own foolishness or carelessness have got us into what is, let's say, a mess. think the clear answer is yes. Everybody knows that penicillin was given for colds. Well, that's silly. I mean, it's a virus. So that stopped. Actually, the amount of drugs used in the last year or so has begun to drop.

The one thing which is really shocking is the use of these things, penicillin once included, in agriculture. And there's a strange link with the BBC and indeed with myself again. There was a guy called Michael Swan, who was my tutor in Edinburgh, for Sir Michael Swan. We used to say that

the local home he was swan upping because he was always going higher and higher in the hierarchy and as you know became chairman of the BBC in time. But in 1969 he produced a report on the use of drugs in agriculture as growth enhancers as they were called, including penicillin

and so on. And there was a massive use of these drugs, which there still are. And of course this leads to resistance. Now this, an attempt to control this, which is fundamentally failed and we're addicted to these drugs. You can get away from them. Farmers in Denmark no longer use them and they don't need them and they haven't lost any money but somehow

because they do this magic stuff. Farmers are still using them particularly in the States where it's used is far greater than in medicine and resistance is spreading as a result. What's the consequence then Laura? Well the consequence of using animals is only going to be relevant for infections that actually come through animals particularly foodborne infections like salmonella or campylobacter. but because we have used these drugs so widely, then we have allowed lots of different types of resistances to develop and we have also spread them around our environment. So because we've used them everywhere from patients, hospitals, GP practice on farms

and antibiotic type molecules that might not be drugs are used in toothpaste and shampoos, we have lost sight of the value of this crucial. set of medicines. And it's dangerous? I think the short answer has to be yes. I mean, it's terrible to think of going back to the days of blood poisoning, but we could well do that.

Well, Somba now to end on. Thank you very much for that, Steve. Laura Piddick, Christoph Tang. Next week we'll be talking about the Bronze Age collapse in the 12th century BC. Thank you for listening. And the In Our Time podcast gets some extra time now with a few minutes of bonus material

from Melvin and his guests. I feel terribly depressed all of the social. I would think you're still on by the way just in case you don't know this is the sort of post script for the podcast I'm more optimistic

What makes you more optimistic and Steve might not take a lot to be more optimist Well because we know so much now about what not to do so the recent AMR review

has made a series of recommendations about use to increasing hygiene We're going back to hygiene. Many countries have a real problem with infections by resistant bacteria as well because they don't have access to clean water, they don't have closed sewers. So people are living in a swamp, as it were, of drug-resistant bacteria

because it's cheaper to go and buy a drug from a market than to see a doctor. But why am I optimistic? Because we now know what the problems are and there are lots of ways in tackling them. And whilst drug companies may not be discovering new antibiotics that could become drugs the future, there's a lot of activity in universities, research institutes and small companies. The whole model for finding new drugs has changed completely. Chris, I think we're also living in a golden age of biology. I mean, if you consider we have the genome sequence, a genetic blueprint of every single pathogen that can affect man.

We have the genome sequence of all the strains of moulds and bacteria which produce antibiotics and there's clearly a lot hiding within those genomes which we haven't yet resourced. And we can really study microbes in incredible detail and understand a lot about their life. So I think by understanding the bacteria, we can really begin to find ways to attack them in novel ways. Yeah, it's interesting because if you look at the human genome project, there were crazily optimistic statements about gene therapy. and so on, which hasn't really happened. But what it's done for humans

is to turn genetics into an extremely important diagnostic tool of early onset cancer and so on. And the same is, of course, true infectious disease. What you find is very often one particular strain of bacteria contains a gene which would break down or will defend against

a particular antibiotic. And of course, you can now sequence, read the message of the bacteria in hours or less and immediately know which one to use. And it's noticeable, for example, for example in the famous and notorious case of MRSA, metastrian resistance, staphylococcus warriors,

which spread like wildfire from a single mutation in Germany across Europe in just a few years. Now we know exactly what's going on there. And ironically enough, it's begun to drop in frequency. Because of a new antibiotic? No, because people now wash their hands. And if you go to hospital now, you'll find every doctor, every patient,

every doctor, every nurse, many patients, will constantly be doing this, washing their hands. And that's blocked the movement of this particular bacillus. And it takes us back to Semmelweis, who was the great Austrian, Austro-Hungarian doctor in the 1840s, who discovered that women who had their babies in the street on the way to the clinic survived much better than those that got to the clinic.

And he thought there must be something in the clinic. What are we going to do? We're going to wash our hands. And tremendous improvement, nobody took the slightest bit of notice. So maybe the simpler, will be part of the solution. Laurie, would you? Yeah, the other reason I'm optimistic

is that when we have the whole genome sequences of the producing organisms, there are lots of cryptic pathways. In other ways, pathways for making products that could be antibiotics, but they're turned off or the pathway is broken. And now those pathways can be manipulated to make those molecules.

And there's a lot of activity for getting natural, products from microorganisms from oceans or from plants. So there's a lot of interest. And also, as Chris has just mentioned, we're not stuck with just the targets we thought we were, like the ones that penicillin worked against in the cell wall. We're now, because we understand the bacterial genome,

we're identifying other targets, switches that will turn the pumps off, for instance, as we do in my team or Chris's team understanding how bacteria cause infection and trying to attack that system. So we're very creative now because we have so much more information than we had at the time of Fleming or Florian chain So I am optimistic Here's the producer with his message from the front

It's a cup of tea or coffee That's really what would you like We're on Twitter at BBC In Our Time There are more than 700 programmes to download and listen to for free from the In Our Time website We'll also find a reading list for this episode Thank you.