The earth is 4.6 billion years old, but we humans have been here for just the blink of an eye. 200 thousand years, only. Compared to the vast length of time that the earth has been the earth. Bacteria on the other hand, have been on this planet long before us In fact, for most of the time on earth, bacteria were here, they were here before us. They breed the life into our world, made it possible for us to evolve, and we know about the age of bacteria, we know they are about 3.6, 3.5 billion years old, the first bacteria arose. We know this because of places like this, this is shark bay in Australia, you can see these beautiful structures. They are called stromatolites, and they are caused by communities of bacteria that form thin mats, and these trap settlements, and then they precipitate Calcium Carbonate, and you end up having these stacks, and these are preserved very well. In the fossil record, so, this is a relatively young fossil, it is only 3.5 million years old, but you can see the tell tale patterns of the stromatolite, and we’ve been able to find stromatolites that are 3.5, 3.6 billion years old. So I think you are getting the picture, the bacteria are very old, and we draw a timeline like this, I struggled, because it is almost impossible to put humans on the same timeline as something that is 3.6 billion years old. I stuck it at the end there, a few pixels. 200 thousand years ago, compared to this vast expanse of time. Now when we came on the scene as Eukaryotic cells, we were single celled organisms, we had a nucleus, felt pretty good about that. Bacteria did something very strange, they bestow bestowed upon us a gift, and that was that they invaded us. Physically invaded our bodies and gave us the means to produce energy, and the first person who came up with this endosymbiosis theory, actually was probably someone you have not heard of, Schimper in 1883. He thought, you know there are bacteria out there, that look suspiciously like those organs that we see in plants, that are called chloroplasts, and people after him noted that well there are bacteria out there that look like mitochondria, which are the things inside us that make energy. So here is a bacteria that looks suspiciously like a chloroplast, and there is a chloroplast, I don’t know if you agree with Schimper. And this is a bacteria called Rickettsia, which looks very much like a mitochondria, as you can see. So although a lot of people formulated these hypothesis and developed them, Lynn Margulis, she usually gets the cut of this discovery, in 1967. well deserved, she gave some great evidence. But Schimper, nobody knows his name, and that is because, he put his theory in a footnote. So the moral of the story is, if you have a great idea, don’t put it in a footnote. Okay, so bacteria are ancient, they’ve been around, they’re friendly ostensibly, they gave us energy, We’ve been living, and in love with them for so many years, but there are 5 million trillion trillion bacteria on this planet. That’s more than the number of stars in the universe, if you can believe it. and on our bodies, and in our bodies, not counting those mitochondria, 100 trillion bacterial cells, right now, as we speak. That means that you are all 10 times more bacteria than human. If you find it a sobering thought. So we are vastly outnumbered, so given that, it’s not surprising that we often wrangle with bacteria. We have problems with them, they infect us, they make us sick, and they kill us, quite frequently, and with alarming regularity. Okay, so we know that bacteria have been infecting us for as long as we’ve been human, and before, animals get bacterial infections too. So bacteria have always been with us and making us sick. The oldest known infection that we’ve been able to see scientifically, is from 9000 year old bones. These are bones that were, this is brilliant actually, they were in an underwater city, off the coast of Israel. So these are underwater bones, a drowned city of Atlit-Yam. And you can see on these bones, the tell tale marks of Tuberculosis infection. They may just look like a bunch of holes to you, but if you are a scientist, I’m not one actually, that knows about this sort of thing, these are definitely TB holes. But you might say, okay, I need more evidence than that. And despite the fact that these bones were underwater, for 9000 years, they managed to pull out some forensic evidence, of micro-bacterium tuberculosis. What you can see here is a chromatograph, you see that 5 peak signature, which is a particular lipid that’s only found in micro-bacterium, they found it on a woman’s left rib, woman’s right rib, and an infant’s bone. And you can see the standard underneath, showing that those 5 peak superimpose. This is prove, that this lipid, found only in micro-bacterium tuberculosis, was present on these 9000 year old bones that were underwater. That is an amazing story, science is amazing. This is the culprit, micr-bacterium. It’s useful just to show this, because it shows you how small these things are. These things are 2 microns in length, and a micron is a millionth of a meter. And, despite the fact that they are so small, they can reek untold devastation on our species. and you probably all know about, 2nd pandemic of bubonic plague, in the 13 or 14 hundreds, it’s estimated, any where from 1/3 to 1/2 of Europe, depending on the statistics that you believe. And this illuminated manuscript from a contemporary bible, shows, basically, the fact that there is really nothing you can do, if you have bubonic plague. You’ve got religion, you’ve got fairy dust, and you’ve got wishful thinking. But, they didn’t understand, what caused it, they didn’t know why they were sick, they didn’t know how to cure it, they couldn’t cure it, they couldn’t prevent it. It was a devastating disease, and this just goes to show you, how really devastating a bacteria can be. And I like this picture because, you can’t get DNA or lipids off of this illuminated manuscript, but you can, the artists were so good back then. Look at the detail on these buboes, which are inflamed lymph nodes, characteristic of bubonic plague, and look at a modern day case, of bubonic plague. You can see, I think, that it really is bubonic plague. And this is caused by Yersinia pestis, which is a bug that lives in the hind gut of a flea, and this is actually inside a flea’s hind gut right now. Great camera work there. So it is still with us, Yersinia pestis, this bacteria still causes the plague, in isolated places. And it’s under control, for now, because of antibiotics, for now, hold that thought. Okay, so why are we all here, why aren’t we all dead? We should’ve been extinct millennia ago, this doesn’t make any sense. Well we have defences, you all know that we have a very robust immune system. I’m teaching immunology to some students now, I think some of them are in the audience. Immunology is incredibly complicated, we have dozens and dozens of different cells, that patrol around, looking for invaders. We have specific proteins and compounds that are specific for all these different bugs. You can get memories, so when you see the same bug again, you can fight it better. It’s the most amazing system, but still, it’s not enough, to concur a lot of bacteria. Here is the picture of an antibody, just to show you how beautiful these structures are, these are these patrolling proteins that can find bits of bugs that are alien, and go after them. Okay, so why doesn’t our immune system do the job? we are highly evolved creatures, you know we are top of the food chain. Why can’t we fight a bacterial infection alone? And the reason is, because of what’s known as cat and mouse evolution, this is more coyote and roadrunner evolution. But, the basic truth is that, all though we come up with these elaborate defences, bacteria can evolve, very quickly to outsmart us, to subvert us, to get around us. So no matter how many interesting and wonderful things we develop in our immune system, the bacteria are always one step ahead. Okay, and I’d like to illustrate this concept of subversion. By showing you an example of, a bacteria that I work on. This is, I work in urinary tract infection, which doesn’t sound so good at cocktail parties. It’s a very serious disease actually, it is the most common infection disease with the elderly. And were it not for antibiotics, this disease would be devastatingly fatal. At the moment, it’s under control. So UTI, is caused by several different kinds of bacteria. This is Escherichia Coli, E.coli, you probably all heard of him. He lives in your gut, he’s friendly, he’s suppose to be friendly. He digests your food, he comes out the other end. So E.coli, normally, is free living. So this means, they like to live on top of our cells but they don’t go any deeper than that. They hang out on the top of our cells, and in our gut, this is all fine. But some times, these bacteria get into the bladder, I’ll leave it to your imagination why they get into the bladder, but females have a bigger problem with this than males. It’s because of the anatomy, and the proximity of these bugs to the bladder. So when the bacteria gets to the bladder, something really really strange happens. Very unusual, and it was totally unexpected when this was discovered, about a decade ago. So, this is a micrograph, this is from a lab in St.Louis, the ? lab. Beautiful micrograph of a mouse bladder. It’s very smooth, well it’s a bit bibbly bobbly, but, by in large it’s quite smooth. You infect this mouse, with E.coli up the bladder, look at that. This is what’s called a pod. The scientists do have a sense of humour, this is technically called a pod, it looks very science fiction, and what it is, it’s the bacteria, have physically burrowed into the bladder. Inside the cells, and they’re going in there, they’re regrouping, they’re multiplying, they’re doing their evil things, they’re getting really big, there is a huge colony, it’s getting bigger and bigger and bigger and you can see, that it’s so big that it’s just distending the cell, it’s making a blister. Some people might have these inside you right now, actually. So, women get lots of UTIs, women get lots of infections like this, and between infections, they think they are okay, but a lot of them have these things going on. You can probably guess what happens next. These things can burst open, and reinitiate an acute infection. So it’s really heard to treat these bacteria. When they are in that pod, they are nice and safe, the immune system can’t get to them, antibiotics can’t get to them, and they are all very cozy, and then they burst open. In my lab, we’ve shown that, other bacteria can do something similar, this is Enterococcus, which is very common urine pathogen. This is a red, side view of a bladder cell in red, you can see lots of blue bacteria on the top of the cell, but you can also see in the side view there, there are lots of Enterococcus inside that cell. And they are doing very similar things to the E.coli. So this is a common strategy, that uropathogens use to evade the immune system in the bladder. And just for fun, I’m gonna show you this video. This is from, the Justice lab in the States, it’s kinda cool. So this is the slow release pod, leaching these bacteria into the inside of the bladder. okay, now once they’re in there, in the bladder, they’re vulnerable again, the immune system can immediately get them, then who’s gonna get them? It’s these guys. These are, these purple things, macrophages, monocytes. They’re all fancy words, they mean, big cells, that eat bacteria. Hoover them up, they don’t care what they are, they’re tasty, they’re gonna eat whatever is in there that’s not suppose to be in there. This is MRSA bacteria being hoovered up, by a monocyte, but it could be anything. So when these E.coli burst out of their pod, into the bladder, they’re in trouble, because these guys are patrolling. So what do they do, well this is really interesting. So, some scientists and some colleagues have shown, that normally E.coli is a capsule shape, it looks like a tic-tac. And on the top panel you can see, the characteristic tic-tac shape of an E.coli. But underneath, is what happens when that pod explodes, these bacteria shape shift. They actually elongate, and they form these long spaghetti like structures, which have two functions, the first function is, basically mechanical. So if you were in the bladder, and your host urinates, it’s like being in a firehose. And because you are so small, and the pee is so forceful, so the spaghetti shape is been shown, to allow the bacteria to cling on in there, when the host is urinating. So, they don’t want to get washed out, they want to stay right where they are. So that’s an adaptation. The second thing, is truly amazing. The spaghetti shape appears to impart, almost a cloak of invisibility, to these filimentus bacteria. And this is a really cool video, from the same lab, that showed the pod, the Justice lab. What you’re looking at here, those dark, grey capsule shaped things, are normal shaped E.coli. The big green thing, has been false coloured in green, so you can follow it. It’s a long filamentous form of E.coli. And the blue things, are the big angry macrophages that are chewing up the bacteria, or they are trying to anyway. So let’s see what happens here, the video so they are hoovering them up, they’re are hoovering them up, they’re are hoovering them up, hoover hoover hoover, but they cannot seem to swallow that green thing. They try they try, They’re either not tasty, or they’re invisible. or both, we don’t actually understand, this strange thing that happens. But it’s very advantages, if you’re a pathogen. So, those are just two examples, of strategies that bacteria use to evade us. And there are, countless others. Because there are so many different kinds of bacteria, and there are so many different strategies. I could talk for hours, I would never get through them all. So what I want to talk to you about now, is I want you to picture the world, if we couldn’t control these bacteria. And this world used to exist, so, 1900s, United States for example, there are statistics suggesting that, from every 10 people who died, 3 of those people died from a bacterial infection. So 30 percent of people, who are dead, were dead because of bacteria, or complications from bacteria. That’s a very high number, imagine what it would be like if you you had a child who, fell on the pavement and scraped her knee. And the next day she was dead. Because she had an infection that you couldn’t stop. Imagine that you prick your finger on a rose, in the garden, and a week later you’re dead. Because you just… there’s nothing you can do. Nothing, imagine what that would feel like. And keep that in your mind. So, this is our saviour. Penicillin, you’ve all heard this story, it’s worth saying again isn’t it, because Alexander Fleming actually gave a discourse, I’m honoured to be here, where he once stood. He did it, had the famous accident. And this is actually a photograph of his petri dish. The famous petri dish that was growing bacteria, and accidentally got a spore of mold on it. That’s the thing on the top, the bid white thing. The small white things are bacterial colonies, and the big black hole, between them, is the zone of exclusion. where the bacteria could not grow. Because the mold was secreting something that stopped them. They killed them. And that was of course penicillin, his famous discovery. But Fleming really couldn’t do anything, Well, he tried, he published it, he tried to work with it, it was very complicated, and he eventually abandoned it. I just want to point out that, similar techniques are still used today. It’s very quaint, but, the zone of exclusion is still used in diagnostic labs. What you’re looking at here is the petri dish, that has been spread with a sample from a patient. And each of those white disks, is impregnated with a different antibiotic. And then the plates are allowed to grow, and you can see what happens, some of the discs cause bacteria around them to die really well. And those bacteria are sensitive to the antibiotic, other parts you see are completely rubbish. They are doing nothing, and some are sort of mindle, fairly mindling, you wouldn’t what to use that in the clinic either. So this is antibiotics, and the discovery. So, what is an antibiotic? Well it is a chemical, its structure, it’s a chemical compound that’s produced by a mold or bacteria another living organism. And, this is penicillin G, it’s a beautiful molecule, it’s very very simple. Some antibiotic are very complicated. This one is very simple. You can see the most salient feature here, I want you to look at it, is that 4 membered lactam ring in the middle, I think you can see it. So this is penicillin G, It was a real bear. It was hard to isolate, it was hard to make useful. And Florey and Chain, shared the Nobel Prize with Fleming, For the discovery of penicillin, because without those biochemists and their teams, we never would’ve been able to mobilise this drug. And actually, if it wasn’t for pharmaceutical companies, and sort of the war effort, we wouldn’t have got penicillin out as quickly as we did, in the 40s. So that’s penicillin, how does it work? well, it’s a kind of a very nice strategy. So, what you’re looking at here, is the cell wall of a bacteria. So bacteria are enclosed by a rigid cell wall, and this cell wall needs constance maintenance, constant DIY. And that is because, bacteria are not static. They have to divide in two. So the cell wall is always shifting and changing, and you need somebody there to make sure that the wall is always sealed. And that’s what this protein called DD-transpeptidase does. It’s a long word there, it’s just that grey shape. DD-transpeptidase, what it does, Is it morphs together the bricks of the cell wall, and it’s always on duty, making sure that there is no holes in it, because if there are any holes or chinks, on this armor, the bacteria will die. very important job. Okay, so what does Penicillin do? Comes along, it’s this, yea this orange thing in this picture. It simply docks the DD-transpeptidase. in a particular place, and gums up the works. And that enzyme in now no longer able to maintain the cell wall. It’s a simple, binding and blocking strategy. Very clever, so penicillin goes in, blocks all the transpeptidase, the cell wall looses it’s integrity, and the bacteria dies. It’s really nice. Um, that’s just one antibiotic. We have lots of them, there’s lots of potential targets. So if you’re a bacterial cell, you’d have to do certain things to stay alive. And we know what does things are, you need to metabolise, you have to reproduce your DNA, make proteins. And, you do need to maintain those cell walls. So, this is a bit of a scary picture you don’t need to be able to read it. This is just demonstrating, the different kind of antibiotics that we have, and where they are targeting a bacterial cell. You don’t have to be able to read it, just appreciate that there’s a wide variety of antibiotics, all going after different aspects of what this cell finds crucial for survival. I have to point out, that the cell wall is a great target. because it’s on the outside, it’s like the ramparts. And also, it’s quite difficult to get drugs inside some bacteria. So the cell wall is an obvious target, but there are other targets as well. So after the discovery of penicillin, there was this guy, have you heard of this man, Selman Waksman? Most people have not heard of him, he is a hero, he discovered single handedly, 20 different antibiotics. In the golden age of antibiotic discovery. Which is between 1940 and 1960. This guy was a soil guy, he liked the soil, he liked the bacteria in the soil, he liked the molds, he was a biochemist, he put together strategies and methods for isolating antibiotics from the soil microorganisms. Not making antibiotics himself, but finding natural products that were out there. And if it were not for this man, many of us might not be in this room because our patents and grandparents wouldn’t be alive, he discovered Streptomycin, which is the most amazing antibiotic. And he discovered many many more. Selman Waksman, don’t forget his name. So now what I’d like to do is, I hope I can read this cos I’m a little bit farsided. I would like to read you from Alexander Fleming’s Nobel lecture, because it has a little story, that’s very prescient and very pertinent. Okay, and this is because Fleming was already a little bit worried about this amazing discovery. He was worried that it wasn’t gonna work for very long. So I’m gonna have to, I’m afraid I have to back off and read this. But I would like to sound one note of warning, penicillin is to all intents and purposes non-poisonous so there is no need to worry about giving an overdose and poisoning the patient. There may be danger, though, in underdosage. It is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same has occasionally happened in the body. This is in 1945, just want to remind you, the time may come when penicillin can be brought by anyone in the shops or off the internet I added that bit, I’m sure he would have said it if he knew and there is a danger that the ignorant man may easily underdose himself, and by exposing his microbes to non-lethal quantities of the drug make them resistant. Here’s the hypothetical illustration. Mr.X has a shore throat, he buys some penicillin and gives himself not enough to kill the streptococci, but enough to educate them to resist penicillin. He then inffects his wife, Mrs.X gets pneumonia and is treated with penicillin. As the streptococci are now resistant to penicillin the treatment fails. Mrs.X dies. Who is primarily responsible for Mrs.X’s death? Why, Mr.X whoes negligent use of penicillin changed the nature of the microb. Moral, he says, if you use penicillin use enough It’s a brilliant story and I fell a little bit sorry for Mr.X, it’s not completely his fault. But his fear, this is 1945 his Nobel lecture speech, came true the same year, a little bit afterwards. As war starts to filter down from the fronts of WWII, that soldiers were picking up resistant strains of gonorrhoea and syphilis, from ladies like this. They look friendly, they look clean but they are not. So penicillin was released to the community as a drug, and instantly resistance developed. Okay, how does this happen? It’s just evolution basically, you have a petri dish or body, infected with a white bacteria one of these might mutate to become a resistant to a drug, if you treat with that drug, all the white ones will die, and the red ones will propagate. It’s actually very simple, and it happens in the lab all the time. So what is the molecular nature of resistance? It is different for every different antibiotic, because every antibiotic is different, lets go back to our friend penicillin G. Recall it has that lovely four membered ring in the middle, some bacteria produce an enzyme called β-lactamase. and β-lactamase has a very simple function, it just snips that ring open. just like that, penicillin floppes open, it’s no longer the right shape, and it can no longer dock with DD-transpeptidase, and gum up the works. One little clip, penicillin is neutralised. And it’s really easy for this enzyme, the gene that encodes it to be passed around. So β-lactamase is a serious problem. It has made a lot of penicillin family useless, to some patients. Now, there’s more than one way to be resistant to penicillin, there’s another way, and this is employed by MRSA, which is of course the evil hospital acquired methicillin resistant staphylococcus aureus, which is all over the news, and it is very common in hospitals, and it’s…some times has a β-lactamase, but it has an additional defence against penicillin and their family members. What it does, if it says okay, you’re gonna gum up my DD-transpeptidase, um, I don’t care, I’ll make another one. I’ll make a different DD-transpeptidase called MecA, that’s exactly the same as the original version, but it’s slightly different. And then penicillin can no longer bind there, so the only difference between MecA, and DD-transpeptidase is that region where penicillin binds and gums. So, it basically circumvents the whole problem, by producing lots of this other protein. So it’s really devious. So antibiotic resistance, you hear about it in the news a lot, and we will talk more about that in a minute. You might think it’ something that we caused. Because you do hear a lot that it’s our fault. But actually, antibiotic resistance is ancient. just as ancient as antibiotics. Before we were even on the planet, there were bacteria communicating with each other, fighting with each other, producing antibiotics, and producing antibiotic resistant genes, it was all going on before we even got here, so it’s ancient. And the oldest antibiotic resistance gene that we were forensically able to identify is 30,000 years ago. and back then, that’s what our ancestors were doing, they were making tools like that. And just as an aside cos I this it’s interesting, it may be that antibiotic are not actually weapons. they may be more communication signals, because it turns out, that in the wild, in the soil, the doses of antibiotics that are in there are really low, and they are actually no enough to kill things. so it could be their primitive form of communication, and antibiotic resistance might be a ping, you know ping back from that communication. Interesting aside. But we are able to exploit that, for now. To kill bacteria. So how did these genes get around? They do get around very very rapidly, how does this happen? well there’s a number of different mechanisms, so these are two bacteria having sex. and they are connected by a structure, and they are freely passing DNA back an forth. including resistance genes, probably. Bacteria can also pick up free DNA that’s just been left in the environment when a bacteria dies, it spews all it’s DNA out, other bacteria can just soak it up. Another really interesting way bacteria can get DNA from other bacteria, is through viruses. So, bacteria actually have their own viruses, they’re called bacteria phages, so if you are British, bacteria PHAges. I’m gonna call it bacteria phages, so phages for short. So phages are basically glorified syringes. They go around, um, injecting DNA into bacteria and trying to kill them. And this is been going on for long before we were here as well. There all are ancient battles that we have just stumbled upon later. So, in doing this, sometimes they don’t kill the bacteria, sometimes they just inject DNA from another bacteira it’s kind of like if you get a mosquito bite, and it’s bitten your neighbour, and now it’s coming, and it’s bitten you and you might get infected by malaria. It’s a very similar process. Okay, obviously, once you have a resistant bacteria in a patient or a person, on the tube, or on the bus, you can spread that bacteria to your friend, your neighbour, your lover, patient next door, the nurse who didn’t wash his hands, between patients and this is another great way that antibiotic resistance can spread through the population. And obviously in hospitals it’s a lot easier. So, lets talk about hospital acquired infection, this is a very complicated diagram, but I’ll just walk you through it. There are two kinds of MSRA, is Resistant Staph aureus, it’s the Super Bug, that you hear about in the news. The one on the bottom, is in the community, it’s actually not a hospital bug. It’s resistant to methicillin, which is like penicillin pretty much. And it is resistant because it is of this blue gene, down at the bottom there, makes it resistant to methicillin. It’s basically MecA, which I told you about already. So this is a sort of, relatively benign tamed form of resistant bacteria. But looked at the guy on the top, this is from a hospital, he is got a very similar genetic structure, but his got more things in it. It’s a coset of resistance. Not only do you have methicillin resistance, but you have another gene that can confers resistance to another antibiotic. You’ve got this guy here, confers resistance to 4 different antibiotics. So, you get 6 resistances with the price of 1, if you’re infected with this guy. So this is why MSRA is so dangerous, it can no only pass resistant genes, but it can pass entire cosets of resistant genes. And bacteria are doing this all the time. Okay, get’s worse. It’s gets worse. The other problem with bacteria, if they replicate so very quickly, and just to get your head around that, I made a little video. In my lab, I put some bladder cells in the petri dish, nice warm petri dish, with some medium. And I dribbled a little bit of E.coli on top. And I set up the time laps video, and I just film them. So these bacteria, are dividing at their normal rate, which is once every 20 minutes, and you can see that, with time, this is a 10 hour video, the bladder cells below become invisible, they’re so encrusted and covered with bacteria. They are just overwhelmed. Now there is no immune system in this dish, and crucially there is no antibiotics. And this is what could happen in a patient, if there is unopposed…if these bacteria are not opposed somehow. So, a colleague of my, Dave Spratt, his a microbiologist, has a really nice way of thinking about it, about how do you get your head around this time scale. Because the more you divide, the more you replicate, the more you can mutate, the more you can pass on genes, the more you can, get around us. He says, okay, 10 day ago, where were you, you probably can remember, you look in your diary, 10 days ago, was actually 500 generations for bacteria. Where were you 500 generations ago, anyone know? You were in the Ice Age, so this gives you a sense, of how quickly these bacteria can adapt. They just got all the time in the world compared with us. So, ladies and gentlemen, antibiotic resistance is accelerating. So it’s been around for millennium, but, it’s accelerating at a very scary rate, and just to illustrate this, this graph is a little bit complicated, I’m gonna walk you through it, What we have is the time that an antibiotic was released, um, that’s the blue triangle. or time it was discovered. And the, sorry that’s the red. And in the blue triangle is the time that the resistance was noted in the population. You’ll see penicillin actually was resistant before it was even released as a drug. Because it was in a laboratory, when they were working with it, they noted resistance. Penicillin did really badly, but actually, the next few to come along the pipe line were alright, you had 10 years of grace, before resistance was noted. The one exception there is a penicillin family member, so it’s too similar to penicillin. The bacteria already knew that one. They’ve seen that joke before. So, what happened in 1980? suddenly, for every new antibiotic that was produced resistance developed very quickly, within a year. Sometimes simultaneously. Suddenly that 10 year grace period was gone. What’s happening here? There’re several reasons. One minor reason is that we try to get clever, in the 80s and 90s, we thought well we understand science now, you know, molecular biology, genomics, lets design our own antibiotics, forget the things in the soil. Lets be clever and come up with our own, you know we were rubbish. We made antibiotics, but their resistance developed like that. Because bacteria, they’re all over that. You know, these are ancient molecules, you don’t mess with them. The other thing that happened, I think you all know. This story, it’s kind of sad. Antibiotics are being misused at an alarming rate. You hear this all the time, you hear this so much, that it almost doesn’t sink in anymore. This whole antibiotics crisis thing, we hear it all the time, and we’ll get back to that too. We’ll talk about that later. We can get antibiotics very easily. If you don’t fancy taking your chances with a Canadian pharmacy online, you can go back to your GP until she says yes. And people do do this. A study was published this year I think, that showed that, um, British GPs, often bow to pressure, and prescribe antibiotics when they weren’t necessary. And then once you get the antibiotic, maybe you feel better in a few days and you stop taking the full course, and that’s the worst thing you can do, because you are, like Mr.X and Mrs.X, you’re educating those bacteria to resist you. If you don’t take the full course, if you don’t kill them all, some of them will survive a little bit, they’ll be a bit sick, and then they’ll evolve that resistance. And then the game is up. We also have, we are soaking our planet with antibiotics. Aquaculture, agriculture, life stock, there are antibiotics everywhere they are dripping into the soil, they are in our water supply. They are educating the whole world’s bacteria, how to resist our weapons. It’s like we are giving away the secret plans, of our army, to the enemy. We just say, here it is, take it. Evolve resistance to it. And we now have, a perfect storm scenario. Where we have, many bacteria becoming resistant to all known antibiotics, and the discovery pipe line is completely stalled. It’s a little bit difficult to read this I think, what you can see here, is that, in the golden age of discovery, between the 40s and 1960s, 20 new classes were discovered. There has not been a new class of antibiotic discovered since 1987. Except for the one that was reported last week, which I’ll tell you about, it’s great timing. So, 3 new classes of antibiotics, since 1987. and keeping in mind it takes a very long time to go from mouldy petri dish, to tablet. It can take 10 to 20 years, to make a drug. out of a discovery. This is the discovery void, there has been no new classes discovered. It’s scary, there’s nothing. And this is mirrored by approval rates of new antibiotics, as you can see here, year by year, the number of antibiotics that are approved go down, and actually, most of these antibiotics that were approved in the past few years, they are not interesting new antibiotics, they are just ripping off the same old penicillin, or the same old formula, they are just tweaking the side chains of it, the chemists, not making something novel. So the bacteria can evolve resistance to them easier, cos they have seen something like it before. So, last year, you may have seen this alarming report from the WHO. I encourage you to read it, it’s free online. Makes for some scary reading. Keeps me up at night sometimes, it basically surveyed all the WHO regions, and asked, okay you guys, in this particular country, how may of your bacteria are resistant to X? how many, and here’s an example, The top, you can’t really read this but, 5 our of 6 WHO regions are reporting that 50% or more of E.coli are resistant to the front line antibiotics choice, In hospitals, 25% out of hospitals, so it’s 50% of them. Here in the UK, E.coli that causes urinary track infection, 50% of them are resistant to the front line antibiotic. So that’s really scary. And actually, the future that we are all worried about, is already here. I don’t know if you know this, but there are now bacteria, that are resistant to all known antibiotics. This is only a very recent thing, if you look at the CDC report from 2013, It’s claiming 25,000 Americans dying of infections that can’t be treated. You’re sent to the hospital, they do that panel I showed you with all the different antibiotics, nothing is killing what’s in you, there’s nothing left. They’re cashed out, there’s nothing left. These people die, usually. and it’s going to get worse and worse, because the problem is growing. And we are not doing anything about it, which is the theme of this talk. So why aren’t we doing anything. Why is it so hard to make new antibiotics. And the reason is MONEY It all comes down to money, antibiotics are cheap you wouldn’t pay 10,000 pounds for an antibiotic drug, like you would for a cancer drug. You don’t take it every day like a Statin or a Beta blocker, you take it maybe once a year, once every 5 years, and you take it for 2 weeks, you don’t take it every day, for the rest of your life. So it’s not a very profit orientated thing, and people like to trash pharma, for not being altruistic enough to do things, but you know, without money, you can’t do research. And the vast majority of drugs, you develop as a company don’t even make it onto the market at all. And the net, the stats here shows that basically the antibiotic is worth negative 15 million dollars, at the onset. It’s not their fault. And also regulations, are really bad, they have been really bad. There’s a lot of red tape, it’s not easy to get new antibiotic onto the market, there was a few scarcities a while back, and there was an overcompensation, and basically it’s very difficult. And also, to be fair, as a scientist, it’s hard. We found all the easy fruit, the low hanging fruit, Selman Waksman nicked them all, with his 20 antibiotics. Those were the easy ones, and it wasn’t easy I’m telling you. It was hard. But antibiotics are hard, they are hard to purify, they are hard to make. They are hard to find. So we need new ideas, and now we’re quite desperate for new ideas. So what’s coming down the pipeline. Well there’s combination therapies, you probably hear about co-amoxiclav, have you heard of this? co-amoxiclav, it’s basically 2 antibiotics in 1. It’s a penicillin like drug, but it also has an acid. That stops the β-lactamase from clipping that ring. So if you put them in together, you restore the ability of the antibiotic to work, It’s a nice idea. This is kind of retro, so phage therapy, have you heard of phage therapy? So, last century, we all decided in the West to go down the antibiotic route, very expensive, the Soviets couldn’t afford it, so they decided to look at bacteria phages as a way to fight infection. And people have noted, that if you bathed in the Ganges, which is very polluted, you got really sick, but then you were resistant suddenly, to a lot of different bacterial infections, and people realised that phages were out there, killing bacteria. And this is a really cool idea. So in Georgia, in the former Soviet Union, you can go to the doctor, and get prescribed PYO bacteriophage. Which is a bottle full of bacteriophages. Really, I’m not kidding, dozens and dozens of them in a bottle, and it’s so funny, because the bacteria are evolving resistance against bacteria phages very quickly, they replicate even faster than bacteria do. so twice a year, these guys in Georgia, have to refresh the recipe. They have to go out and find the latest phages. Throw away the old bottles, make new bottles, it’s almost like our flu vaccine, every year we have to change it a bit. Twice a year, you’ve go to change these bottles. I think it’s a really nice idea, and a lot of people are looking into it, because we are running out of other ideas. Okay, this is a little bit more science fiction, this is CRISPER-Cas, which is a fancy name, for a DNA that you can design, that will go into a bacterial cell, and find an antibiotic resistant gene, and nuke it. So suddenly, the bacteria is missing it’s resistance gene, Agh and then you can kit it with an antibiotic, so you are basically curing them of resistance. This is a little bit further down the road, because we have to work out how to get those DNAs into the bacteria, it’s gene therapy so a little bit difficult. You have to design these really specific DNA, you have to understand all biology, but it’s a really nice idea, and this came out last year. To a lot of headline news which you may have read. But really, people are thinking you know we need to go back to the soil. There are so many bacteria out there, and I don’t know if you know, but, how many bacteria in the soil can actually be cultured in the lab? Any guesses? Percentage wise? 1% 99% of moulds and bacteria, and things in the soil, won’t grow in the lab, imagine how many antibiotics that might be hiding in there, these treasures that we cannot grow. So this was a gift to Friday evening discourse speaker, last week in Nature, a new class of antibiotic was discovered, after, you know, since 1987. and it was the most amazing paper, it’s a beautifully written paper, it’s actually quite technical, but I think you might even be able to get a grim if you read it yourself. It’s been made open access so every body can ready it, cos it’s so important, A new antibiotic, kills pathogens without detectable resistance, how did they find this antibiotic? They did, it was amazing, I wish I thought of this, it’s such as simple idea. They took a lot of soil bacteria, instead of growing it in the lab, they just buried it, in the ground. And left it there. And then they dug it up, and lo and behold, all this bacteria were growing, all these moulds were growing, all these things were growing, that would never grow in the lab. It sort of like, dagh, what a great idea. And, then they were able to use very classic methods to quickly isolate, I assume it was quick, quickly isolate brand new species of bacteria and brand new antibiotics. And this is, this one here, this is they call the soil hotel, this is a soil hotel. Over laid with Staph aureus, look for that zone of exclusion and isolate the compound. Teixobactin, you’l probably hear this word again, it’s a beautiful, very complicated antibiotic compared with penicillin, a lot of them are. The beauty of this guy is that it fights bacteria in a different way. It doesn’t fight proteins, like β-lactamase, proteins are really easy to evolve resistance to, cos you just need a gene. It fights a lipid. Lipids are not encoded by genes, to inactivate a lipid you have to make a lipid, you have to do use of different genes and lots of metabolism. And it’s really complicated, it’s hard to find one place where you can actually fight that. There is another antibiotic out there, called vancomycin, have you heard of this? Vancomycin was an amazing, was, an amazing antibiotic, cos it’s resistance seemed never to happen. Because it’s against a lipid as well. It fights a lipid. And only recently, Vancomycin is now become resistant, resistance has arisen, and it was a bit of a flick accident actually. It’s a long story, I won’t tell it, but this guy also fights lipids, and it’s great hope. Because the authors tried to find things that were resistant to this antibiotic, they couldn’t find anything, they looked every where. Not a sausage. So, hopefully if we treat this antibiotic with care, it will last us a good 10, 20, 30 years. And, unfortunately it only acts against a certain kind of bacteria. The Gram positives, which leaves a big gap for the Gram negatives like E.coli and other big killers. But hopefully the strategy can be used generally. Maybe not just with soil, maybe we can go to the deserts, under the oceans, all different environments, and find all these new bacteria, grow them in their environment, where they will, where they like to grow. So this is a brilliant discovery, I’m just, I’m so happy that I was around to see it. Okay, so another problem that we have, with, this has nothing to do with resistance, it’s biofilm, so have you heard of biofilms? I mentioned biofilms at the beginning. These stromatolites are caused by mat formed biofilms. If you scrape your teeth right now, something comes off, that’s a biofilm, of dental bacteria. Slimy rocks, that’s a biofilm. Biofilms are everywhere, it was only recently appreciated, that most bacteria are living in these communities, and they’re not free living at all. And, this is just a schematic showing that these bacteria come together, in groups, very complicated groups. And they form these primitive organs almost, they secrete this slime, and slime protects them from antibiotics, and other things. And it’s estimated now that, in the US, It’s causing a massive problem with health care, because these things grow on catheters and in dwell in medical products, and they are actually involved in a lot of infections, and they’re very difficult to treat, cos they are slimy, and you can’t get the antibiotics in there. And the other thing they do, is when they’re in that community, they’re exchanging DNA, lots, so they are exchanging resistance and they are making the problem worse. So we need to solve this problem as well. So just for fun, my lab is growing biofilms in the lab, this is a beautiful video from one of my students, as you can see, what you’re looking at, is just a thin section of biofilm. Top, these red things are metabolically active bacteria, the green things in the middle are sort of structural, things that aren’t growing very much, and there’s this channel, can you see this blue channel, water, nutrients can come through. It’s a really beautiful structure. And what we are trying to do now, I’m collaborating with engineers, in Oxford and at UCL, we are trying to make nano-capsules and micro-capsules, that can penetrate biofilms, because, it’s no good having an antibiotic that works, if you can’t get that antibiotic inside, to where the action is. So I think that, collaboration between biologists and physicists and engineers, are another thing that we need, to get out of this mess. So, we are in trouble as a species, I think maybe I’ve convinced you that we’re in trouble. But, I’m interested, just to finally, in the final few minutes of my talk, where has this complacency come from? Is not that we haven’t heard about this hundreds of times before, if you look at this media survey, 1961, in Good Housekepping, which is a girly mag, they were talking about antibiotics resistance, and oh, don’t overuse them, for casual reasons, and every generation, since now, and then, has sounded this alarm. Fleming sounded the alarm. Everyone was having hysterical head lines, guys we are in trouble, and nothing happens, this happens in our country too, so in 2013, chief medical officer said, guys, it’s like climate change and terrorism rolled into one. A few headlines, all went quiet. The next year, David Cameron, ah, medical dark ages, few head lines, went quiet. And Cameron, he said this thing which just made me laugh, he has announced to review into why so few antimicrobial drugs have been introduced in recent years. We don’t need a review, we know, we’ve known for generations, that it’s difficult, they have the incentives, the money, we know. We don’t need a review. What we need is money, and effort put into this problem. And the US congress is doing great things with, agh, cutting red tape to help, and also we’ve got initiatives, they EU is throwing money on it, UK has annouced a strategy, So, I’m sure it’s very good, and of course, the Longitude prize is giving prominence to antibiotics. But what we really need, Mr.Cameron, if you want to write to your MP, you can tell them what we need, is money. Because scientific research is very expensive. And we spend hardly anything on it. If you look at this lovely graph, from scienceogram, you can see that, the UK is at the bottom, out of the developed nations, for spending money on science, it’s 0.57% of GDP. And even the 0.79% that’s a G8 average, it’s a pitiable amount of money to spend on research and development. For something as important as science, because we need science not just for antibiotics, but for climate change, and for food security, all these problems that we have, to solve. And we need science to get us out of this mess. And we are spending pennies on it. So I think you should all write to your MP, and tell them, you’re gonna vote in the next general election, what do you think about science. So, just in conclusion. keeping in mind, it takes 10 to 20 years, from discovery, to tablet, we have a discovery void, aside from this wonderful nature paper that ruined my story, no new classes are discovered since 1987, we are still in trouble with Gram-negative organisms, given that, we need to put more effort and we need to stop just shrugging it off, I think we have too many crises stories, oh, the bacteria are coming, the bacteria are coming, I’m not helping, I know, but it really is time to get serious. We don’t want to go back to that age, when we are all dying, bacteria are one step ahead of us, and we need something to catch up, now. That’s it, Thanks.