Microbial Megastructures

- So what I want to talk to you tonight about is, as I did in the previous lecture, about the invisible, about very small microbes, but tonight, I want to focus primarily on what these things create that we can see with our eyes, and in fact, what we can see in truly gargantuan fashion. I want to talk a bit about how tiny, invisible things can create the world around us and some of the largest structures on the planet. I'm going to start with this picture that you can see in front of you. So this, for anyone who's been there, is Shark Bay, in Australia, a very nice place to visit on holiday, and it's full of these structures in the water, which, in this image, look like rocks, but these are not rocks, actually, these are things called stromatolites, and these are one of the oldest and still, I think, most amazing microbial structures we have. They're very large, you can stand on one of these things, but if you slice through a stromatolite, you see an image that looks a little bit like this, layer upon layer, a bit like a tree ring, or some kind of layered pancake structure, and this tells you that a stromatolite is not a rock, it's not a boulder, it is something that has been created, and it's been created by microbes, because each of these layers is a layer of photosynthetic microorganisms that have sat, and they have photosynthesized, they have secreted and gained around them minerals that have, over time, formed into a stony layer, actually trapping the microbes and killing them, and then a new layer of microbes forms on top, starts depositing more minerals, and so the stromatolite grows. And over a long period of time, you get these really gargantuan rock structures that are entirely products of a microbial source. This is one of the oldest types of microbial structure we know about. And we know that stromatolites back billions of years ago actually were incredibly abundant. Today we see very few of them. And one of the reasons we think that may be is that later on during evolutionary time, animals evolved at eight that grazed these frozen synthetic organisms. And so they removed the layer before the stromatolites could get started, which is why today we only see stromatolites in certain geographical locations. But about one and a quarter billion years ago, these were incredibly abundant over most of the world. And in fact today their fossil stromatolites tells us a lot about the kind of microbial history of the earth. So this is one example of a microscopic organism creating something that is truly macroscopic and invisible to us without the aid of any instrumentation. So what I want to do tonight is start really with the very small scale and work through to the truly enormous scale and think a little bit at the end also about how we might be able to harness these microbial production facilities for human gain. But before I do that, I want to take you back into the world of microbes and tell you and remind you, I guess, about the fact that the world is actually very different if you're a microbe. So we, I think we are macroscopic individuals. We think of the world I think very often as being divided into two sorts of organism. There's big stuff, us, elephants, aardvarks, trees, things you can see and touch. And then we all know there are these microscopic things, some of which are quite good, like yeast that makes your bread or your beer. Some are pretty bad like Covid 19 virus, but they're all sort of invisible and small. But actually, if you are one of those invisible small microbes, there is still massive scale within your microbial world. And let me illustrate that with a couple of pictures. So this rather grainy image here is a Picornavirus it's a virus particles. So there are about, I dunno, 12 or 13 of these virus particles in this electron microscope image. And these are really, really small. They're about 30 nanometers across, so 30 millionth of a millimeter across in diameter. And they are microscopic. Clearly we can't see them but there are many other things that are vastly bigger that are still microscopic. So here is another microbe. This is E. coli, Escherichia coli, very common bacteria. You have this in all your intestines. It's a kind of laboratory workhorse. We use a lot for investigating microbes. This is about one micron long one, 1000th of a millimeter long, still far, far below the resolution of our eyes, but already 7,000 times bigger than one of these virus particles. So if you're an E. coli, this is your microbial world and everything else is huge. And then you can go a scale up even from that and this rather attractive chap here that is hopefully crawling across the screen in front of you, this is amoeba proteus. This is a typical single celled ameba, still a microbe. You still need a microscope to see this. And what we're seeing here is a microscope image of this guy very slowly progressing across the amoeba, it might have eaten me by tomorrow lunchtime. Moving across the screen, this is absolutely enormous relative to E. coli. It's about 200 microns across, still invisible to the human eye but about 200,000 times bigger than one of these. And therefore millions of times bigger than a Picornavirus. So even on the microbial scale, structures vary over log orders, over tens of orders of differences. And this is really important I think to think about when we think about microbes, all the things that are invisible are not all the same within this microbial world. There's massive variation in scale. It's really important to understand that. So if we dive into that microbial world and its that tiny world there, we can start to see some of these amazing structures. And one of the things I really want to get across to you is just how spectacular feats of engineering are at the microbial scale. Let's zoom in first of all, right to a single cell level. So here in front of you, you see two fungal cells, two different fungi. This one, the great black and white one is candida albicans. This is a yeast that is all too familiar to most of us. This lives on and in all of us all the time, we're all colonized by candida albicans. If you've just had a last minute run'cause you were running a bit late and you're sitting there thinking,"Gosh, I'm a bit sweaty and sticky." Your candida albicans are having a feel day and growing away on your skin and all your kind of mucosal membranes without any problem most of the time. But this is the organism that when it overgrows causes thrush, genital or oral thrush and so can be quite problematic clinically. Next to it and looking broadly similar although blue rather than black and white is cryptococcus neoformans, another fungal cell, single cell. This again is an abundant yeast found out in the environment. You've probably breathed it in actually as you came down the street towards this lecture. This organism also generally does us no harm unless your immune system is impaired, for example, by HIV or organ transplantation, at which point it can become very serious and indeed a fatal disease. But the reason for showing you these two fungi tonight is that these are masterpieces in microbial engineering. So if we zoom in on this, candida albicans, what looks like a kind of black line on the outside its cell wall. It's actually something that is remarkably elaborate. So here you have the inside of the candida outer sight. And this single cell wall, as you can see is composed of multiple layers, each layer with a different set of chemicals, including these rather elegant fibers on the outside which are extremely good at distinguishing things that should or should not go into that fungal cell. For example, resisting things like antibodies from a human immune system. If we look at the other example cryptococcus and we look at its cell surface, it produces this amazing caption on the outside which looks like a blue haze in this diagram, but under an electron microscope is truly spectacular as these incredible fibers. And in fact this really elaborate capsular structure is what is responsible for this fungus being able to avoid our immune systems, to avoid being eaten when it's in the soil by lots of different predators out there. And in fact, we're only just starting to learn that some of the chemistry in this capsule may have potential, for example as immunosuppressive drugs for medicine in the future. And so here at this single cell scale, you can already start to see some of the structures that these microbes are capable of producing. But to my mind, the most spectacular microscopic structure that many microbes make is the thing called the flagellum. And here I'm looking at the bacterial flagellum. Many, many bacteria produce these things. These are the kind of whip like structures at the end of some bacteria. And you can see them in this diagram here, these long green trailing things. Some bacteria have none, some have one, two, or many as is the case here. And these are responsible for propelling bacteria through fluid, through blood, through urine, through wherever they might happen to be swimming. And when we look at the ability of this flagellum to drive bacteria forwards, it's truly remarkable. So here's a very nice movie of a bacterium called rhodobacter. And you can just about see here these long flagella spinning around the back of this bacterium as it swims through its media in this case under a microscope. This is a remarkable piece of mechanical engineering because this motor is able to drive the bacteria at speeds that we can only dream of. In fact, if you scaled up that road back to the size of a human, it would be able to complete the London marathon in about seven minutes, which I think is pretty good going, I couldn't compete it in seven days. Imagine in seven minutes. So why am I telling you this about the bacterial flagellum? Because this is a piece of engineering that is far superior, anything that humans have ever created. And let me show you that in this diagram here. So if you can imagine now our rhodobacter is swimming down into the ground, it's tail is protruding right up here. And in fact on this scale, its tail will go right through the roof of this beautiful building and out into the London skyline. Sitting at the membrane of that bacteria is an incredible motor here that spins the flagellum and drives the bacteria forwards. It does that using a principle that is actually exactly like a human based water wheel. So inside the bacteria are chemicals, hydrogen irons, protons, little blue things here, the bacteria uses energy to pump those out and form a gradient. There's more of those here than in here. And then when it needs to move, it allows these to flow back through this motor and spin the wheel just like this. And in doing so, it spins this motor, the motor spins the tail, the tail rotates and it pushes the bacteria forwards. The amazing thing about this motor is it is absolutely precise. It has exactly the right number of subunit here. If it misses a subunit, it doesn't work. It has gears, it has rotors, it has channels to start and stop. And it does all of this in a way that is almost friction free. So it is far better than the motor that drives, for example your latest electric car. And something that we have not yet recapitulated on human scale. And yet millions and millions of bacteria have done this for for millions of years. And so I think there's a lot we can learn from these microbial feats of engineering, as we look forwards to kind of human engineering in the future. So these are all structures that you can only see with the aid of microscopes already advanced imaging techniques. But what I want us to do for the rest of lecture is think about structures that we can actually see, that you don't need any kind of advanced qualifications for or any sort of instrumentation. You can go out and see these products of microbial engineering in life. And the scale of some of these can be really, really quite remarkable. And we're going to start with an example that we can all have very close to hand here. And that's the example of the biofilm. So a biofilm is an accumulation of microbes, sometimes all the same one, sometimes a mixed bag of different microbes and they're living together in a community but not just kind of, ad hoc or ended up here together but in a structured ordered sort of way. And in particular what biofilms have that is fairly unique is their individual microbes. Here the bacteria are producing, secreting a kind of glue, a polysaccharide typically matrix that sticks them together. So they just didn't just end up here. They actually want to be accumulated together in a biofilm. Lots of microbes make biofilms and they do it for all sorts of reasons. They might want to stick to a rock in the sea to prevent themselves from being washed off. They might want to stick to your drainpipe and prevent the sink from getting or trigger the sink to be blocked up. And these biofilms are really important. They're important 'cause they're often a problem for us. Biofilms on intravenous lines in a hospital are a major cause of clinical problems. They're also good. They can create sort of ecologies whole ecosystems in very small areas. If you have a a fish tank at home and you've got fish tanks stick your hand, you have a fish tank at home, I thought no, a couple of people have fish tanks. So when you try, and ask this lady here, when you have your fish tank, do you just throw the filter away and that's it? Or do you take good care of the filter?- [Audience Member] Oh no. It's a massive problem with koi and we have to be really protective of the bacteria because of the koi you have to look after the water, not the koi.- Perfect, see, that's, there was not a scripted answer. You have to look after the bacteria because inside that filter is a biofilm, right? You've said a long time creating a mixture of bacteria and microbes in that filter that stick to the filter and purify the water. And they're doing that through the aid of a biofilm. We find biofilms all over the place. Some of them are quite problematic. One that we've probably many of you have probably encountered when you really didn't want to is this kind of biofilm. This is the one that you typically find when you go into your plug hole.'Cause your kitchen sink has got blocked up and outcomes. This yicky brown sticky goo, this is actually a spectacular microbial biofilm. What's probably not what you think at sort of seven o'clock on a Monday morning when the shower's clogged. But nonetheless it is a spectacular biofilm. When you zoom in on these biofilms, some of them have really remarkable beautiful structures. So here is an image of laboratory biofilm with multiple organisms in it, some fungi, some bacteria. And what you can hopefully see, we've colored them all differently, is they're occupying distinct zones. So the fungi in greener at the bottom, bacteria and blue are at the top. And there is a structure, there's an order to this community. It's not just that everyone's living everywhere, they know their own place, but there's a a place that we can see biofilms or at least experienced bio films on a daily basis. And I'm hoping I can rope up a volunteer, maybe somebody who's at the row. Would you mind volunteering? Excellent. Come and stand up here. What's your name sorry?- [Sona] Sona.- Sonam?- [Sona] Sona.- Sona. So let's stand here, smile at the camera. Millions of people are now witnessing you here. Hopefully you did tell people that you're coming to this lecture and they're not expecting you to be somewhere else. So could you give us a big smile? Please give the audience a big smile. Thank you. That's a brilliant smile. This is a prime example of a wonderful biofilm. Thank you very much. Do you brush your teeth? You look like you brush your teeth religiously well, yes, you nodded, very brilliant, well done. So even though you brush your teeth really well, which I hope everyone does, still within a few minutes of brushing, you have restored on your teeth a beautiful biofilm. Thank you very much. You can sit there, a beautiful biofilm. So when you have a smile like this, you think, "My teeth are sparkly clean," they're not sparkly clean. If we scrape away your teeth even immediately after brushing and stick it under microscope, what you end up with is something that looks like this. So if you look really carefully at this image, you can see it's just about moving. So this is a typical healthy oral biofilm from nicely brushed, well maintained human teeth, in this case mine. And so what you see under a microscope is, so this is a gum cell or a cheek cell, one of mine. But you can see around these big lumps of stuff, this is biofilm, these are bacteria, some fungi, maybe even some kind of amoebae that are living in between my teeth. The reason they have survived my best efforts to brush them is because biofilms are really sticky. They coat surfaces. They have evolved deliberately to live in an environment like the mouth that is washed really regularly. And you can just about see some of the little live things zipping around here. This is not a problem. In fact, this is quite healthy. Of course it is a problem if you don't look after your teeth well and if you end up really not looking after them well and get periodontitis, you end up with a biofilm that looks like this one, which I think you can immediately recognize is a lot scarier than this one. Particularly like the little zippy things in the middle here, zooming around. So these biofilms are whole ecologies, whole ecosystems living inside your mouth. They're also in all sorts of other sticky parts of your body that we won't talk about. But they are central to the colonization of humans and indeed all other animals by microbes. These are biofilms that are close to home. You can't usually see them without the aid of a microscope, but some biofilms you can see so spectacularly you can even see them from space. And here is a really good example. This is an algal bloom you've probably heard of algal blooms in the sea. When you get a sudden increase in the number of microscopic arguing, many of which stick together by those same biofilm forming characteristics that you see in a mouth for example. And you can see here in this image, this pale blue color, which is an algal bloom in the sea. And you can see already from the clouds. This is a satellite photo. The scale of these natural biofilms, however, can be truly spectacular. And you'll see that because when we zoom out and you see where I got this image from, you can hopefully recognize, at least those of you from the UK or listening from the UK that this algal biofilm stretches from the tip of the island of Ireland all the way to the bottom, hundreds of miles of microbial biofilm that has literally appeared within a couple of days and will disappear again a few days later. And yet this is a massive community of microbes sticking together. Living together can cause enormous problems. Blocking ship engines can also be incredibly important. This is the founding principle of lots of marine ecosystems because this biofilm allows larger organisms to colonize it. And so these biofilms are a fundamental part, if you like, of the global ecosystem rather than just the microbial one. Biofilms are very often an example of a symbiosis, multiple different species living together, benefiting each other kind of teamwork if you like, on a microbial level. Those kind of symbiosis have shaped much of what we remember about what we experience about the world around us. And I want to spend a few minutes talking about some of the really interesting symbiosis that have created structures that are probably quite familiar to most of us. And the first one I want to talk about is this one here. This is a plant root, okay, hoked out the ground, imaged under a microscope. And what you can see hopefully is the plant root here, but around it these very, very tiny filaments that look like their root hairs of the plant. But in fact they're not. This is a symbiotic fungus so-called mycorrhiza that is growing in really close association with this plant root. In fact, such close association that if you zoom in on the plant root microscopically, what you see is that the fungus here in blue has actually penetrated into the plant root, which are these large cells here. These are the plant cells, the fungus has penetrated in and in individual plant cells has grown into the cell and produced this structure that looks a bit like a bunch of grapes or a kind of tiny human lung or something. This is arbuscular mycorrhiza this fungus is a symbiote. It's growing in association with the plant and the plant has deliberately let it do this because these two organisms are trading off, plants as we know photosynthesize, they produce sugars, they are giving some of those sugars to this fungus across these really intricate intracellular structures. In return, the fungus is able to spread through the soil far further than any plant root can make it. It's particularly good at harvesting minerals, things like phosphates from the soil and it gives some of those minerals back to the plant. This is a true symbiosis and this is not unusual. In fact it's very far from unusual. In fact, we believe that these mycorrhiza plant associations are what allowed plants to colonize land, plants evolved in the sea. Like most organisms getting onto land is pretty tricky. If you're dependent on water, moving out of water onto land is not an easy obstacle to overcome. And there's quite good fossil evidence to suggest that a very early interaction was this association with fungi that allowed those early land plants to get nutrients out of this very difficult dry environment. And in fact, I think is reasonably fair to say that without mycorrhiza, the world as we know, it would not exist in the way that we know it today. Because we know that today about 80 to 90% of all land plants form these interactions, it's very rare not to have a symbiotic fungus living in your roots. And so this is what shapes the kind of plant life around the green planet around us. Some of these mycorrhiza interactions are absolutely critical. So if you are a fan of orchids, many of us I suspect have these growing at home. If you're a fan of orchids, orchids cannot germinate without this symbiotic fungus. If you have orchid seeds that are completely sterile, they will not germinate. So this entire family of all the beautiful orchids we know around the world are totally dependent on this fungal interaction. Perhaps slightly less critically, but really, really tastily truffles are also the product of a mycorrhiza fungus. This is the fruiting body of a hidden network of mycorrhiza in particular woodland habitats. And so for many of us, a significant, not a significant part of our diet side, a really nice part of our diet is derived from mycorrhiza products. But most fundamentally, some of the most beautiful, most important, most fragile ecosystems on the planet are totally dependent on mycorrhiza fungi. So if you go to the rainforest of South America or central Africa, you can find millions of mycorrhiza associations within just a meter of soil. And it's this that allows this incredible biodiversity to form on the planet. So here I think to a first approximation, we can say large sways of the, at least the terrestrial planet we live on, are products of a microbial interaction. The rainforest is pretty big, plants are pretty big. But a spectacularly even bigger example of a microbial structure is one that attracts millions of tourists. And many of us are sort of vicariously via Discovery channel, National Geographic type images every year, because one of the largest, spectacular structures on the planet is a microbial one. And it's this one here, the Great Barrier Reef in Australia, which you can see in this image. The Great Barrier Reef as we know is a coral reef. A coral is a kind of hard stony thing, but of course what produces the coral reef is not the stone itself but the organisms within it. So if you look at a typical coral reef like this one here, the each of these individual corals is produced actually by tiny microscopic animals called anthozoa. Which look a little bit like this in cross section, these are very small, but they're not specifically microscopic, but they are totally dependent on microscopic symbiont. So these coral themselves gain food by filter feeding from the surrounding sea, but that's usually not enough to provide the energy, the high energy they require to secrete the calcium carbonate that will go on to form these stony corals. They need more energy than they themselves can feed on. And so they are colonized by symbiotic photosynthetic organisms like these ones here, these little tiny algae live inside the anthozoa. They photosynthesize, they give some of the nutrients they gain from that to the coral, which uses them to build the coral reef. And in return the coral gives it a nice protected home away from predators for the rest of its existence. This really important symbiosis has created all of the coral reefs around the world. And we know it's fundamentally important because when it goes wrong, it goes spectacularly wrong. If the coral becomes stressed, if the coral organism becomes stressed, in particular by rising sea temperatures, but also by things like pollution, it responds to that stress kind of generically by throwing out the algae, it expels the algae, which is a pretty fatal mistake. Without the algae, it can't get enough energy and ultimately this coral animal dies and you end up with this a terrible phenomenon of coral bleaching in which the stony structure is still there, the skeleton is still there, but the animals are dead and the algae have gone. One of the most interesting twists in this tale I think is we've known about this coral symbiosis for a very long time, but very, very recently it's turned out this symbiosis is even more complicated than that. But it's just about two or three years ago now, a group investigated coral by DNA sequencing and discovered that within the coral is the algae, we knew that already, but also this unusual group of organisms not previously found that are now called corallicolids. And these, this is the little gray organism here, seem to inhabit many, perhaps all corals around the world. They are a microwave called an apicomplexa, which makes them quite closely related to things like malaria in humans. And as far as we can tell, these we think are parasites of coral, although it's very early days to truly know how they behave. And so even now, we've known about coral reef for hundreds of years, we've known by the symbiosis for many, many decades. But it turns out there's a whole new dimension to this relationship that we are only just starting to dig into. And it'll be really interesting I think, over the coming years try and work out what the role of corallicolids is in driving coral biodiversity.(glass clanking) So what I hope I'm kind of convincing you of is that microbes are actually fundamental to many of the world's largest structures. Many of the things that we often go on holiday and see actually, and some of those landscapes are, you wouldn't intuitively think of as being microbial, but they are, they totally depend on it. And here's one I appreciate. You might not go on a holiday to see this particular bit of a peat bog but bogs and tundra are something that is incredibly important to biodiversity, in terms of biodiversity and also in terms of very often of surrounding wildlife, in terms of ecotourism. And of course in terms of carbon capture, we now know that peat bogs are incredibly important in sequestering carbon and helping fight climate change. Peat bogs, as you probably already know, are composed largely of a single plant. This is Sphagnum Moss, okay? And it's this remarkable moss, which if you had a move of it, you can dip into water and it holds a huge amount of water, you can squeeze it out like a sponge. Sphagnum Moss is clearly not a microbe, but what I want to convince you of is that it's really dependent on microbes for its life because Sphagnum Moss is quite clever. It grows in very damp people conditions, it grows very tightly together and essentially creates a very anaerobic environment and the environment underneath it that is lacking in oxygen. This dramatically reduces the ability of other plants to grow'cause they can't handle the water load conditions, they can't handle the lack of oxygen. And so Sphagnum has the bog essentially to itself. That seems like a great idea, except that in a anaerobic damp environment, if you think about what happens if you leave a sort of, I don't know a few dead leaves in a bucket of water with a lid on for a while and then you come back six months later and open the lid and it's a pretty unpleasant experience'cause what has happened in there is this anaerobic fermentation. And that happens also in peat bogs. In this oxygen free wet environment. You have a group of microbes that rapidly colonize and live that generating methane. These are so-called the methanogenig archaea. These are a group of organisms that are closely related to bacteria, although fundamentally different. They have been around since the very earliest origins of life and they don't use oxygen. What they generate, they use nutrients and in in generating energy from nutrients, they release often things like sulfurous acid. But in this case, methane, many people know that methane is actually a really potent greenhouse gas, shortlived, but extremely potent in terms of global warming. So if you think about all the peat bogs around the world, if they're all producing methane rapidly, that sounds like a bit of a disaster. And yet we all know that peat bogs are really important for fighting climate change rather than creating climate change. So how can this be? And it turns out that's because of another microbe. So these archaea live under your Sphagnum Moss producing bubbling up methane. But a second group of bacteria, the so-called methanotrophic bacteria, see this as a kind of free buffet. They are capable of taking methane and converting it, gaining energy in the process, converting the methane to CO2. These methanotrophic bacteria colonize this habitat, convert that methane to CO2. That's already a great step in the right direction because CO2 is a much less potent greenhouse gas than methane, but it's still not great. We don't want to release CO2 as hopefully every single human being on the planet now knows. But that as a matter in a peat bog, because what happens is that CO2 is immediately used by Sphagnum Moss to grow. And then of course what happens over time is the moss will die or sediment out, the peat gets a bit deeper, new moss comes and you've captured all of that carbon and sequestered it away for thousands of years. And so this role of peat bogs in reversing or fighting climate change is driven essentially by this three way interaction between a plant and two different sorts of microbe, all of which depend on each other for their energy source, for their nutrition. And so large spectacular habitats like these upland peat bogs in Scotland are there because of these two groups of microbes that are supporting what is to us the visible plant layout on top. So my last mega structure example in this evening is one that's even bigger than a peat bog and it's triggered by some of the smallest microbes that we know of in the sea. These rather spectacular is rather spectacular. (coughs) Rather spectacular organisms in front of us are tiny marine photosynthetic microbes. This is a very, like you can just about see the scale bar here. So this is one micrometer. So this whole thing is maybe 10 thousandths of a millimeter across far below the site of the visible radar for humans but abundant in the ocean. In fact there are many, many of these kind of so-called coccolithophores living in marine environments. If we take a typical sample of seawater and look at it under an electron microscope, you see all these rather beautiful structures, each of which is a single celled photosynthetic, marine microbe. There are literally billions of these in every sort of teaspoon of of sea water. They photosensitize, they divide, they die. When they die, their shells which are composed of calcium carbonate or chalk fall to the bottom of the sea. In the right conditions they will accumulate because this is not easily biodegraded. And so bit by bit these organisms accumulate more and more skeletons. If you roll the clock back, this is about a hundred million years now we're going back. So this is definitely the age of the dinosaurs, okay? The world as we know it looked a little bit like this because of continental drift. Obviously most of the countries of the world that we know today were in different locations. And you can just about see here, those of you at the front perhaps this is what is now the UK. You can see South America you can just about make out Africa, although it's not in its current day position, it needs to move. But what you note in particular I hope, is that here what is is now today Europe, there are a lot of very small sort of inlets and very shallow warm seas. The world at this time a hundred million years ago, was a lot warmer than it is today. And so around what is now the UK and western Europe were a load of warm, tropical shallow seas full of these marine microorganisms that I've just shown you. Happily growing away, dying sedimenting growing a bit more. In fact, we know based on the fossil record that at this time about 0.5 millimeters of these dead bodies were laid down every year, roughly speaking, that's about 180 of those individual microbe cells stacked on top of each other. If you can think of that, each year half a millimeter is not very much. But if you do that for long enough, I.e millions of years, those skeletal bodies pack on top of each other compact down and form some of the most spectacular structures that we now see today. Like the White Cliffs of Dover, in this case the seven sisters down in Sussex, these huge spectacular white cliffs are essentially enormous collections of dead microbes. And in fact, you can see that if you take this chalk and look at it under the right kind of microscope, you can sometimes see these amazing clearly microbial skeletons in there. And so the next time you go for a kind of walk along, a beautiful white cliff, particularly on the south coast, think to yourself, "How many billions of organisms had to die for me to appreciate this amazing view that I get here." And this is not true just of course in in the UK it's right around the world. These kind of huge lime stain cliffs are all microbial products. And so between the great barrier Reef and the rainforests of South America and the chalk cliffs, I think it's fair to say that most of the structures that we see in the world around us are microbial in origin. So let me finish by thinking a little bit about all of these microbial structures that have been produced, these incredible feats of engineering and raise the question really, if microbes are capable of doing these things that we've never done before, they can build cliffs that are hundreds of feet high, they can create barrier reefs that are far more beautiful than any human architecture. They can make motors at an invisible scale that drive bacteria at speeds that we cannot match. Will we ever be able to harness any of this microbial engineering for our own benefits? And I think the answer to that is yes and in fact very early days, but it's starting to already happen. And let me give you a couple of examples. So most human building in the modern world is built essentially of one really dominant material, which is this one here concrete, okay? We're in a rare example of a building that is not concrete in Central London, but if we walk out of the door here, I can guarantee I'll find a lot of concrete within a few yards of the front door of Gretchen College. Concrete's great, it's flexible, you can make things, it's incredibly strong, you can go really, really high. It has a problem. And that that problem is that it often gets these micro cracks, over time as the concrete expands and contracts you can get very small fractures, very small cracks inside concrete and over time that weakens the concrete and ultimately the building that you've made with it. Wouldn't it be great then if we could come up with a way that you could fix these cracks in a building as they happen as opposed to waiting for 20 years and then having to pull the whole thing down because it's got too many micro cracks. One way you could think about doing that is by harnessing some of these microbial structures to achieve it. And that's exactly what some people have done with a material called self-healing concrete. And there are two things you need to know, microbiologically for that. The first is that many microbes as you've seen tonight, secrete these kind of stony products. These mineral products like calcium carbonate, they do that for their own purposes. They're not doing it to help us with our building problems, they're doing it because they might want to cement themselves onto a surface or cement to each other. But nonetheless they secrete essentially what is bacterial concrete. The second thing to know is that many microbes are capable of really extended periods of dormancy in some cases hundreds of years. So you can get things like anthrax spores, you might be familiar with anthraces, this very significant disease of humans and other animals. The organism that causes that, bacillus anthracis can produce a spore that is incredibly durable. So 50 years later that bit of soil that has a spore is still dangerous, that spore can wake up and cause disease. So many microbes can do that. So if you could combine these two things, the ability to produce something that's a bit like concrete and the ability to be dormant and to withstand lots of environmental stress, you could create self-healing concrete and that's exactly what has happened. So you can take concrete that looks like this, this is under a microscope, these tiny cracks up here within it. But if you have preloaded that concrete with these bacteria that can go dormant inside little capsules, they sit asleep if you like for a long period of time. The crack appears, if the building's outside rain will enter that crack and it will get damp, it will dissolve the capsule you've put those bacteria in and they will wake up because now the water is there and they will do what they were expecting to do anyway. They will start to multiply. They will produce the material they wanted to produce to stick to their surface, I.e this bacterial concrete and they will fill that gap remarkably successfully. And so you can build buildings which are primed and ready to heal their own cracks as they appear. And in fact, if you zoom right in on these healed cracks, you can just about see here, you can see these tiny little tracks which are actually like the footprints of the bacteria as they've borrowed their way fixing the crack that has appeared in your building. And so I think this is a great example of using invisible microbes to help fix human problems. I.e weakening of concrete buildings. So what else might we be able to do with these things, well, you could imagine really harnessing some of the most spectacular parts of microbial biology for our own benefit, not just for large buildings but for tiny structures too. One of the great attractions of microbes is they're invisibly small and yet incredibly accurate. So you could build things on a scale that we cannot currently get down to. We can't use instrumentation, we can't use lasers to get small enough, but we could potentially use bacteria or fungi to do that. This is really in its infancy, but I want to finish just with a couple of examples from a group in Germany actually who are doing exactly this kind of work. So here's the first one. Many bacteria are what's called phototactic. They swim towards light. If you are a photosynthetic bacteria, you need to be where the sun shines, otherwise you can't photosynthesize. So you are trained if you like, you behave by swimming towards light. So what we can do is we can take a bacteria that is producing something we want and is also phototactic, is also responding to light and we can shine a pattern on, so in this case a logo shined in a laser light, you can add your phototactic bacteria and in this case, if you leave bacteria for example, that produce a pigment and you come back a little bit later, what you see is the bacteria have swam to where the light is and they've done their thing and they've produced a very beautiful pattern. This is like kind of the photolithography that people use to make beautiful ceramics or something, but made by live organisms rather than by lasers or by etching. You could imagine a future in which we use these kind of lights to pattern things, perhaps in places we can't reach. What about patterning things inside human bodies? If you wanted to fix something that's in a pacemaker or an intravenous line or in someone's hip replacement, perhaps we could shine in fiber optic light and get bacteria to swim to the right place to fix that rusty patch or to remove some kind of debris that wasn't supposed to be there. And you can do the same thing in vitro to produce amazing structures that we can't currently engineer. So for example, here is a tiny flow device, you can see someone holding it, into this flow device. You can put bacteria that respond to the flow current as it goes through and produce something you might want. And so we can inoculate this with bacteria, we can flow liquid through it. The bacteria will respond to that and produce this matrix, this polysaccharide coating around them. And when they finish that you can remove it. And what you have is a thing that's a little bit like that coral reef I showed you. So it's a structure produced by bacteria in the pattern that they have swung into based on the flow you applied, this is obviously quite a large thing, this is several centimeters long. It's something that we could have produced by traditional means anyway, but you could imagine now doing this on a tiny scale. What about if you wanted to make really, really tiny pacemakers for newborn babies for example, what about if you wanted to make neural implants in a particular structure? Perhaps you could create a system that enables your bacteria to swim in the right direction, secrete the electrical cables you need to trigger a neural implant entirely naturally through a bacterial process without any need for kind of robotic implementation or something like that. All this very future gazing. But I think an example of how you might be able to harness microbial creative processes, biotechnology in the literal sense for human benefit. I'm going to finish there. I hope you enjoyed it. Thank you very much.(audience applauding)- Thank you so much Professor May for the fascinating lecture. We've got a question online and then we're going to go to the room. So the question online, I think in part you've already answered this, but what do you think the future holds for microbial mega structures and their applications? Or what's your favorite future? If you have one.- My favorite future, I like that. So I think there are lots, I mean I think it depends on the scale of future. So I think very close I think, is the prospect of doing materials perhaps that we can't currently make. So we know that microbes can generate some chemicals that we can't currently synthesize. For example, many of our antibiotics are produced by microbes rather than by factories. So you could imagine for example, harnessing some of the stuff we've been talking about here with that medical ability. And what about having a bacteria that was photo responsive and produced an antibiotic? You'd give that to somebody if someone's got a liver infection, you'd give it to someone, you shine the light in their liver, the bacteria accumulating the liver, deliver the antibiotic there, much lower dose, much more responsive and you could come back and do it again if the infection doesn't go, that I think is not very far away really now, much, much further than the future. But I think very exciting is the idea that many microbes live in environments that we cannot go to. So for example, you have microbes that can endure incredible doses of radiation. So you could think about using them to create structures on a moon base or Mars landing or all sorts of things. I don't think that's going to happen tomorrow, but you know, and probably not in my lifetime, but I think there's a really exciting prospect there for using microbes where we currently might use a robot for example.- [Audience Member 2] I'm just been working with a young researcher and we are looking into disposable replacing plastics with bio something or others and I was interested with your biofilm and wondered if there might be an angle there to connect it as a biodegradable form of plastic.- Absolutely, that's a great question and I think the short answer is yes, definitely. I mean humans, we are pretty bad at thinking long term. We've had all sorts of things that seemed like a really good idea at the time, like asbestos and then much later on you realize that wasn't so clever. Whereas stuff that has evolved, we've had literally millions of years to kind of work out how to deal with it. And so I think there's a couple of examples there, we can think about Chitin. So Chitin is the kind of polymer that produces, the hard bit of trees if you like the wood, currently there is no way to degrade Chitin other than through microbe. So microbes, fungi in particular can degrade Chitin, nothing else can. So they've figured out a solution to a problem that is millions of years older than the problem we currently have. There are groups actively working now to identify, and have had some success in identifying microbes that can digest many of the non-disposable plastics that we currently produce. It's pretty small scale but I think ultimately we'll come of that. The really exciting prospect is, what about if you can do both, if you can use those microbes to get rid of plastic mountains and turn it into something useful, either monomers that you could make more plastics out of, perhaps fuels, perhaps medicines. So I think absolutely is the short answer. I think there's a huge option there. And the last thing is I think there are also undoubtedly things that microbes make, like many of those polymers in the biofilms that we don't understand the chemistry of, that might be really useful for human applications once we figured out what they are and how they work.- [Audience Member 3] I want to ask you a basic question. Microbes, are they a form of life or how did they come into existence?- Great, so those are my favorite question. So the short answer is almost everything I've talked about tonight definitely is alive and definitely fits all the definitions of life. The only place where there is some debate microbially is around viruses. So one of my favorite essay questions to set students is, is a virus alive?'Cause a virus cannot live without a host and it's totally dormant. Many simple viruses are essentially just a stretch of DNA or RNA. So you can have a very good philosophical argument about whether a virus is alive, without a host. Does it become alive in a host? What happens then? But certainly bacteria and fungi and all those things reach definition of life, in terms of where they came into existence. And we talked to it in the first lecture, which you could find online about the kind of very early origins of life. And particularly there it becomes the further back you go, the harder it gets to be sure. We know quite a lot I think with real confidence now for example about how you carry it. So that's the cells that make ourselves, the cells that make fungi came about, harder to envisage how the very first forms of life came about. Lots of speculation about self replicating molecules that became encapsulated in a lipid membrane for example. And I think we'll probably never really know the answer because we're talking about 4 billion years ago and those things no longer exist. But I think in terms of the higher microbes, there is now quite a well-documented set of steps which went from very simple forms of microbes to some of the more elaborate microbes like the mycorrhiza that I talked about earlier.- [Audience Member 4] Do they exist in the moon or Neptune?- Oh did you say, so yeah, if you didn't catch the question. So do they exist in the moon? And actually isn't that a billion dollar question or a multi-billion dollar question? If you look at the cost, I think that's really exciting. I mean so far I think it is very clear there is no good evidence for any life on any other celestial body other than earth. People might be aware they have over the years been speculation about is a kind of a micro fossil from Mars rocks for example, that might possibly be bacterial, but very far from kind of solid evidence. But as you will probably know, many of the missions, both the moon and particularly to Mars, are deliberately targeted to work out whether there is any previous evidence of life on those planets. There is I think, no really good reason why this shouldn't be. And my personal feeling is if you look hard enough, far enough, you'll eventually find it. I guess the question is, is there going to be evidence of life on Mars which happens to be the closest planet to this one? That will be quite good luck, but who knows and maybe in my lifetime we'll be back here to celebrate it.- I've got one question from online, which I'm going to just disperse if that's alright and then come back to the gentlemen. So it says here, what are your thoughts on using microbes as an alternative to current carbon capture and storage methods?- So as an alternative, I think as well as rather than alternative is what I'd say, I mean I think it's incredibly clear that we need to do everything. So we need absolutely need to reduce carbon emission across the world very fast, faster than we even think right now. But we also need to sequester carbon and it's clear that as you all have heard from other Gresham lecturers, whatever we do in terms of stopping it, we still need to mitigate the carbon that's already been released, technology can get some of the way there. So capture of carbon and deep burial for example. But I think ecosystem change in principle is a really good opportunity. There are two parts that I think, so the first is absolutely, it's really critical that we preserve a lot of the biodiversity that's doing that now, like the peat bogs. But there's a bigger and slightly more controversial question about whether you'd actively intervene and the place that's been most touted is in oceans where many oceans are nutrient limited, iron limited in particular. And the idea is that you might be able to add iron, sprinkle iron, you'd get one of those algae blooms that I talks about. It would sequester a huge amount of carbon, sink to the bottom of the sea. And well, our problem solved and I think there's very good scientific reasons, I think that's quite exciting, quite powerful, also quite scary, that kind of large scale ecosystem change. I think human history is full of us having a really good idea about ecosystem change, like letting rabbits out in Australia, which didn't work quite the way we intended. So I think I'd be quite cautious about seeing something on that scale. But this is a global disaster and we've got to do something about it. So big ideas are important.- [Audience Member 5] You mentioned how specifically targeted that you could use microbes, particularly in medicine given that gene editing is still frowned upon, particularly by the EU, even with the introduction of CRISPR. Do you think that's going to be something that we could use microbes for in the future to be more targeted and specific?- Oh, there's a whole bundle of fun controversial questions in that one, aren't there? Okay, so in terms, so let's say, so in terms of genome editing, which is a type of genetic modification obviously, at the moment that is quite tightly regulators, you're quite right, particularly if it's going to be released into the environment, that doesn't mean it doesn't get released into the environment. You can do that and people might be familiar with, for example, trials at the moment of, genetic modified mosquitoes as a malaria intervention. I think there is huge potential there to do things. And one of the most exciting areas actually would be something like a live GM vaccine. So you could imagine a hypothetical example where you genetically modify bacteria to express a whole bunch of antigens. I know flu antigen and Covid 19 and a bunch of things and you deliver this safe bacteria, it primes your immune system, you gain immunity to six different diseases at once. And the real attraction here, you could perhaps design that bacteria to spread. So maybe I don't need to inoculate every single person in this room. I could give one of the, it spreads like a normal bacterial infection, but a harmless one that is inoculating people. Now you could imagine a great model there, where we suddenly inoculate the whole global population of humans by a naturally spreading natural vaccine. But there's a whole bunch of quite scary stuff there. You'd want to be so unbelievably sure about the safety. There's a whole ethical question there. What about if you don't want to have that vaccine but the thing spreads anyway and you can't avoid it? What about if there's a mutation in that bacteria and now it's not a vaccine anymore. All sorts of challenges there. So I think like many of these technologies, lots and lots of opportunity, but caution, really important understanding what you do with it and particularly really thinking about that cost benefit. I mean I think in the face of a, for example, imagine a scenario with a new pandemic, which we really could not control by any other means. Your decision on what risks you would take with that kind of approach are very different than the decisions we might take today on a reasonable November evening when naturally there's no pandemic hopefully around the corner.- I've got a question here from online. Is it possible that the microbes be used to build bone, skin or dental tissue?- Yes, absolutely. I think is the straightforward answer. So in terms of, I mean the structure of bone in particular actually is, I'm going to offend a whole bunch of people who work on bones. It's not that complicated. So I think it would be very reasonable to think of a microbial concoction, perhaps two or three species that together produce bone and one of the interesting things there is you could perhaps produce bone in shapes that we don't currently have. So maybe you could, generate a sort of bone replacement that was good for prosthesis. So that's absolutely possible. I think more complex tissues could be quite tricky. I mean, certainly when you start to think about things like muscle tissue or cartilage, that's more challenging, but not totally undoable. So yeah, that's a long way of saying yes.- And another one here. Does using microbes to repair micro cracks in buildings or to form small structures have any negative or adverse consequences?- Another good question. Not as far as we know at the moment. I mean, I guess self-healing concrete is a relatively new invention, so, but there's, at least at face value, it's hard to imagine a way in which that would be any worse than what we currently do to fix concrete. So, but it's an important question for any kind of microbial technology is, to think laterally, what else might this do? And is it all good?- [Audience Member 6] Is there like any pungent smells associated with it?- Are there any pungent smells associated with it, well, as a card carrying microbiologist, I would say there are loads of lovely smells associated microbes. My family might have a different view on whether they're lovely or not. So, yeah, so some microbes produce no smell at all. Some produce spectacular ones. Anyone who's baked bread at home or done their own beer, especially if you brewed your own beer and it's gone wrong, then there's a really pungent smell. As far as I know, self-healing concrete doesn't produce a particular smell, but yes, I know actually even in the, so if you think about the best example, perhaps if you walk outside after it's rained, it's been dry for a while, it's rain, you have that kind of really night, well, I think it's quite a nice smell that sort of soily smell that molecule that's dry net is called geosmin and that is produced by microbes in response to the rain after a dry period. And so that is a very good example of a microbial pungent smell that's signaling actually underground kind of construction that's happening, even though you're unaware of it.- [Audience Member 7] So what can you say about the future of food production that uses microbes?- So this is a subject close to my heart, and I could say I could go on for about three hours. So I promise I will keep it to 20 seconds. So microbes have a huge role in food production. Traditionally brewing, bread making, vara. More recently, many of us will have eaten products like corn, for example, which is a microbial product, essentially, going forwards. So things are enzymes. Many of the enzymes that we use in food production, if you've had cheese, most cheese these days is produced with enzymes that are microbial in origin, going forwards. Lots and lots of potential. I think you could imagine all sorts of exciting things. And one of the areas that's really very active at the moment is meat alternatives, where people are looking to create things that look, taste, feel like meat, but don't involve a cow or sheep. Some of those are very dependent on microbial products, either to produce the protein or to modify it in a way that makes it feel more like meat. So I think, yes, the short answer is a huge future I think for microbial food production. There is always this barrier of the yuck factor. If someone says, "Hey, here's your bacterial steak." It's not quite the same as the kind of eight ounce fill steak option. But we've seen historically people overcome that. I, well remember my grandfather being deeply skeptical about pasta'cause it was this weird food that was kind of stringy. Not many people are worried about pasta anymore. So I suspect, my children, my grandchildren probably won't bat island about bacterial steak. But who knows.- [Audience Member 8] What kind of microbes or microbial mega structures can you find in more extreme environments like hydrothermal vents?- Great question. So if you didn't catch that, what kind of structures, what kind of micro structures do you find in extreme environments like hydrothermal vents? Lots is the short answer. So hydrothermal vents that people don't know is typically deep under sea where the temperature's extremely high, where lavas but bubbling up, almost uninhabitable to most organisms except lots of microbes that apparently can live at these huge pressures at huge temperatures, often various acidic environments and often create structures, a little bit like those kind of coral reefs that I show you. So we know they can produce these hard calcium carbonate type structures in those environments. Deep rock, so deep miles underground, actually, you could find living microbes inside kind of granite structures, apparently engineering things in a way that's like the self-healing concrete. But these depths and pressures that are sort of unimaginable to us. So they are clearly capable of really impressive construction chemistry in environments that we can't even send robots to at the moment. And so that, I think going back to the original question is a really exciting opportunity. Can we harness that sort of construction ability to build things in places that we can't currently build things in, like on perhaps on other planets or the bottom of the ocean? It's a really exciting area, but very, very understudied at the moment. For obvious reasons, not many people want to go to the hydrothermal vent.- Thank you so much, professor May for such a fascinating lecture. And thank you to all our online audience as well as the audience in the room tonight. His next lecture, which you mustn't miss, is going to be on microbial Master chemists in January,

00 PM and I believe that's going to be here, but you can find out if you've gone to our website. Thanks so much for coming.- Thanks very much.(audience applauding)