Single-celled microbes underpin all life on Earth, and even complex organisms like humans retain a surprising amount of their microbial heritage. Life began when free molecules became encapsulated in a lipid membrane and transformed into a self-replicating entity. Subsequently, multiple cells came together, forming a remarkable symbiosis that ultimately led to all complex, eukaryotic, cells and laid the foundations for multicellular life.
Understanding this microbial legacy has some surprising implications, such as explaining why some antibiotics have unwanted side effects.
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A lecture by Professor Robin May
The transcript and downloadable versions of the lecture are available from the Gresham College website:
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- Thank you very much, Martin, and thank you all for coming tonight. For those of you joining me here in the room, good evening. For those of you joining me online, good morning, good afternoon, good night, wherever and whatever you are drinking, eating, doing whilst you're listening to this. It's a really great pleasure to be here. And what I want to try and do over the course of the next 45 minutes, and indeed over the rest of this series is to convince you that actually, all the really important stuff on this planet is invisible. And if you don't need a microscope to see it, it's probably quite boring. So, everything that we're going to talk about is microbial, invisible and still really, really important. And I want to see if I can try and illustrate that to start off with, with a subject that is very close to my heart and my stomach, which is food. So I hope you'll join with me in this and give me a quick show of hands if you have in the last 24 hours had a meal that includes soy sauce. There's a couple down here. Those of you online can't see the audience. Keep your hands up. Don't put your hands down. Okay, now add your hand if you've had an alcoholic drink, and are accepting to admit it. Okay, there's a couple. Yep, marvelous. Chocolate. Who's eaten chocolate in the last 24 hours? Keep your hands up, hands up. Marvelous. Doing quite well. Still a few people. Have you had a bread product, toast, sandwich, something else? Okay, those of you haven't put your hand up at all. Have you eaten a plant, a land plant in the last 24 hours? Yes. Excellent. I think everyone's put their hand up, right? All of those things require microbes to get to your stomach eventually. So chocolate, soy source, they're fermentation products. Their fermentation is created by microbes. Bread, as you know. Alcoholic drinks are also fermentation products of microbes. And almost all land plants require for really abundant growth a very close symbiotic relationship with invisible microbes in the soil, so-called mycorrhiza. So it's reasonable to say, I think, that without microbes, we would essentially have no food or at least no nice food. And that's a kind of really fundamental part of understanding the world around us. We've thought a lot, most of us, about microbes over the last couple of years, as Martin alluded to. They have unfortunately touched most of our lives in the most drastic and unpleasant way in the shape of COVID. But there are many, many really positive stories about microbes and I want to emphasize some of those as I take you on a bit of a journey about this. So food is obviously one of those really positive stories. Lots of these things. I didn't even mention cheese, one of my favorite foods. Lots and lots of cheeses, obviously yogurt, all these fermented dairy products are all microbial. If, however, we move away from food, if you've ever stood on the White Cliffs of Dover, or indeed any chalk upland in the UK or elsewhere in the world, you have also got microbes to thank for that, because you are literally standing on the dead bodies of millions, billions, trillions of ancient microbes when you stand on any kind of chalk cliff. If you've been to a rainforest, this is the Amazon rainforest, but any other rainforest, you've been probably admiring the trees around you, the bushes around you, unaware perhaps of the fact that actually all of those plants are intimately connected by an invisible web of fungi in the soil. And those fungi are really fundamental to the process of plant growth. So without those invisible microbes, we would not have that rainforest where you've been on holiday, or indeed where millions of people live and have their existence. And then of course the last, and this might have happened to you this morning, if you were racing for the door, you were a bit late for work or for school or for wherever, and you thought I'll grab an apple on the way, and you put your hand into the fruit bowl, and what you got was a kind of squishy brown unpleasant thing. Oh, I was going to say, "You probably thanked microbes." You probably didn't thank microbes actually. But microbes have done that. They have turned your pristine apple into a bowl of mush, because they are the ultimate decomposers. They create all the compost that we use in our gardens. And of course at the last, I think as a microbiologist, this is kind of a sort of satisfying feeling that at the very end of my life, I will be beautifully recycled into all sorts of other things by microbes. And all the bits of me will turn into bits of other people, earthworms, plants, all kinds of interesting molecules with the power of microbes to decompose and recycle. And indeed, it's been calculated that if we lost all our microbial life, we'd only make it about six days on before we drowned in our own level of rubbish. Because without that decomposition, we would almost instantly be overwhelmed by all the things that are currently being broken down around us. So microbes are really fundamentally important. The other really nice thing I think about microbes is that you can study them, you can learn a lot about them without even kind of leaving your home. If you study, you know, if you're a biologist who studies, I don't know, penguins or polar bears, you've got to travel quite a long way to see those in their habitat, and you have to dress up really warm as well. Whereas if you're a microbiologist, you can study microbes right here and right now. And I hope I can demonstrate that with the help of a volunteer. There'll be several calls for volunteers tonight. Please work with me. This is the moment if your, you know, wife, husband, children, parents, employer do not know you are here, don't volunteer. Otherwise, please do volunteer. So I'm hoping, could I have a volunteer for this first thing? I promise to return you unharmed. I can see a hand right at the back. Excellent. Come on down. Well done. Brave person. Can we have a round of applause for this brave soul?(audience applauding) Got to run your way down. I can't even see you yet with the lights, but here they come. Bravo. Come and join me on stage. You're about to be be seen by all those people watching this with their cup of coffee at home. Excellent. What's your name?- Brandy.- Brandy. Thank you, Brandy. You are an absolute hero. So, Brandy has kindly volunteered to be my first volunteer here, and I'm going to ask a very difficult question of the rest of you. You don't have to answer. What species is Brandy? Could I have a hand? Someone said Homo sapiens. Homo sapiens, yeah. Human, not really. Sorry, Brandy. Close, but not really. You know, superficially, yes, Homo sapiens. Actually, what you're looking at here is an amazing illustration of a fantastic microbial ecosystem, because what you see in front of you is not one organism, one Homo sapiens, but millions, in fact billions, approximately 39 trillion bacteria seething inside Brandy. It's not just you. Inside me as well. Inside all of us, okay? By our best estimates, the average human body has about 39 trillion live microbes at any one point, okay? That is undoubtedly more live microbial cells than you have human cells. So to a first approximation, I'm afraid, Brandy, you're not actually human. You're mostly something else, with a little bit of human on the surface. But on the other hand, you can be really pleased that you are a unique habitat, more unique probably than the Amazon rainforest. So, you know, people travel a long way and pay a lot of money to see that. But in front of you, you have a fantastic ecosystem. Don't go away. Hold on, don't go away. I've got one more task for you. So, one of the problems about this, this number, 39 trillion bacteria, it's a really big and challenging number. So let me help you visualize that a bit, and I'm going to pass this to you. So, in this envelope I have some poppy seeds, okay? Not illegal poppy seeds, by the way. They're just sort of the ones you put on there. I'm going to pass that to you, Brandy, to hold on. So those 39 trillion bacteria are very, very small, okay? This is a typical bacteria that you can see in front of you. This is E. coli, Escherichia coli. It's a very common bacteria found in intestines of all mammals, including ourselves. It's about a micrometer long, so about 1000th of a millimeter long. So invisible, okay? And it's very difficult to imagine what that might look like. So what I'm going to do is I'm going to ask you to tip out a few of those seeds into your hand, in a second, or take a pinch or whatever. If you spill them on the carpet, we'll apologize later, that's fine. So I've chosen poppy seeds just because they're quite small, but big enough for, I was going to say for everyone to see. You probably can't see them. Brandy can, right? They're quite small, right? About the size of a grain sand. So, you can show those to the audience. So I want you to imagine for a moment that each of Brandy's, 39 trillion microbes is the size of one of those poppy seeds, okay? So they're like this. How big would Brandy have to be, do you think, to accommodate her micros? Any guesses? It's the size of the room, someone said, I heard. This room? It's quite big. Any improvements on that?- [Audience Member] The size of England.- Five, what, sorry?- [Audience Member] The size of England.- The size of England. Not quite that big, you will be delighted to know. It's very difficult to buy clothes in that size. But you would have to be, if we grew each of your microbes the size of a poppy seed, we'd need to make Brandy about the size of five Olympic swimming pools to accommodate those microbes inside your gut. And so that I think is a kind of very visible reminder of just how diverse this is. Imagine looking out across five Olympic swimming pools filled with these tiny seeds, each one a unique living microbe that you're carrying around every day of your life inside your gut. Fantastic. Thank you very much. Now, you can keep the poppy seeds. You can sprinkle them on a window box and see if you get any poppies. Thank you very much. Round of applause for our first volunteer.(audience applauding) Everyone else in the audience is now thinking,"Oh my goodness, I'm not going to volunteer for anything anymore." Okay, so microbes are enormously important. They're incredibly tiny. They're amazingly diverse. Where then did they come from? So I want to start by taking you back just a day or two, about four and a half billion years to the start of the planet as we know it. And we obviously, by definition, know very little about what the early Earth looked like. But based on a whole variety of science, we know it was pretty hot. There was no life, obviously. There were, at that stage of time, a lot of energetic events, meteor strikes, lightning strikes, and a very, very different chemical composition, okay? This was an Earth completely unlike the Earth we have today. And as far as we know, for the first 600 million years, more or less, there is no evidence for life on Earth. However, during that 600 million years, stuff was happening, and we almost by definition cannot work out exactly what happened. But there are some reasonable assumptions we can make based on some pretty good scientific evidence. So we know under the conditions of the early Earth, it is possible to recreate relatively complex molecules, okay? From a very simple chemical soup with energy provided by things like lightning. So you can create things like amino acids, which are the building blocks of proteins. And I think a reasonable assumption for how life might have begun is when we consider that some of these simple chemicals can come together to form what's called a polymer, so a multiple linkage. A long, complicated molecule. And some of those long polymer compounds can undergo activities on themselves. So for example, we know of molecules called RNA Aptimas, which are long strings of molecules that are capable of cutting and sticking themselves. And so I think a reasonable assumption early on in this proto-planet, if you like, is that in that sea over 600 million years, the power of lightning and other energetic processes was creating molecules that could come together to form polymers like this. We also know that many of these polymers can self template. They can create, if you like, a mirror image of themselves, like a jigsaw puzzle. And so you can end up with a molecule that looks a little bit like this. And this, people in the audience might already be familiar with, looks a little bit like things like DNA, so the molecule that today creates all of our genetic material. And the very neat thing about these kind of polymers is that you can then strip them apart. And when you do that, you end up with two halves which can self template a new copy of themselves. And so I think you see in one go here that over a very long period of time, it's possible for spontaneous chemistry to create molecules that can copy themselves, and thereby lay the first kind of start, if you like, the principles that may go on to create life. But a self-templating molecule in itself is obviously a very long way removed from a microbe or even a cell. This is not life, this is just the basis of life. To move from a chemical in a soup to something that is alive, you need a second step. And that second step is you need to somehow compartmentalize it, okay? We don't live as diverse compounds spread across the Earth. We live as encapsulated entities, okay? Things that have a membrane, that have a boundary. So what does it take then to move from being a free living molecule into a cell, as we might know it? And what it takes is a membrane, something that will separate inside from outside, that will create something that is different from the environment around it. And so what you do is you can imagine taking these free living replicating molecules and encapsulating them in some kind of bags, some kind of membrane. And now you have something that looks a little bit like a cell. It has a different set of chemicals inside to the ones outside, and that seems like a relatively elaborate thing to do. So how might you create a membrane? I know that seems a bit kind of, you know, "Jackanory." But actually, this process is something that many of us do actually on quite a regular basis. If you've ever made an oil and vinegar dressing. Anyone made an oil and vinegar dressing? Yes. Excellent. Very good. So you take your oil and your vinegar. The oil usually sits on top of the vinegar and looks kind of, you know, greasy. And then if you're a good chef, you give it a shake or you give it a stir and you get, hopefully, these little droplets, right? Am I right? Yes. A bit of nodding. Those droplets of oil are kind of a large version of what's called a micelle. So the oil does not want to be dissolved in the water. It wants to cling to itself. It forms a little bag. And if you were to do that with some other molecules in your oil and vinegar dressing, that liked being in that environment, they would go into those little micelles, called partitioning. They would enter the micelle and they would sit in there,'cause they like that environment better. And you would then have created on the one hand a very nice oil and vinegar dressing, and on the other, the beginnings of a protocell, because you have created a membrane out of oils which is encapsulated within it a different set of chemicals to the ones outside. And this is precisely the kind of steps that we think happened in the early Earth. These oils and fats were created spontaneously. They don't like being a water matrix, so they come together, they cling to each other and they form little balls. Inside those balls, you can trap chemicals, including some of those self replicating chemicals, and now you have something that looks really like a membrane bound replicating cell. This is slightly speculation. We can't ever go back in time. We can't see fossils from this period, and even if we could see fossils, they wouldn't be there anymore because all the rocks from that long ago have long ago been melted down and reborn on the Earth. So we will never know for sure, probably, but there is very plausible scientific evidence to think this is how life started. The problem though in studying that is that all we have to go on is what we have today. So what a lot of people do is search for the simplest free living organisms we know of and try and understand from those what this early life might have looked like. And that has been an enormously successful strategy, and a lot of that work is focused in on this particular organism here. This is a lovely bacterium called Mycoplasma genitalium. And for those of you who are feeling very awake in the audience, you will realize that second part of its name suggests where you might find it. This is a sexually transmitted bacterium. That part is slightly irrelevant though. What's really relevant is that this is one of the simplest microbes that we know of today. So simple in fact that a group in the United States have taken the genome of this organism and they have synthesized all of that DNA in a lab artificially. They have put that entire genome into an empty cell and recreated this life from a machine built genome, which I think is an amazing achievement. But it's really important to realize that this, the simplest microbe we know of, is still vastly more complex than what would've been the early life on the early Earth. This is still an incredibly complicated organism. It has about 475 genes, okay? This is pretty simple. We have about 20,000 genes to make a human, so it's pretty simple. But even those 475 genes, they are written in the alphabet of DNA, in this so-called DNA base pairs or DNA letters. And those 475 genes, in total, that recipe is just over half a million DNA letters, okay? To put that into context, if you were to write this out as a book, that book to create this single bacteria would be about the same length as "Sense and Sensibility." I don't know if you've read"Sense and Sensibility," but you know, it's a great story, but it's not short. It's not the kind of thing you read, you know, in between three tube stops. And it's probably not where you started your reading, unless you were a real child prodigy. You know, when you were four, you probably didn't pick this off the shelves and start reading it. So thinking about how we build from modern life to understand early life is sort of like, you know, if you had never come across the written word before. There were no books in the world. You'd never learned to read or write, and the only thing you had to go on was a copy of"Sense and Sensibility." It'd be quite hard to work out how early language evolved. And so I often get questions from people saying things like, well you know,"If this is all true and all this early life was like this, then why don't we still see it out there in the environment now? Why can't we go and find these early life forms?" And you know, my answer to that is, it's kind of like, you know, anything in life. It progresses and as things progress, the older less efficient versions die out. You know, I don't know about you, but I haven't often seen people walking around in a loin cloth, for example, because clothing has moved on, and it's quite hard to find loin cloths. It's quite hard to find airplanes that look like the Wright brothers' airplane, because they're no longer fit for purpose. And for the same reason, we cannot find cells that are even simpler than this, because those simple cells have been superseded by these more evolved ones. And consequently, whatever we find as the simplest organisms today will always be much, much more complex than the early ones on the early life. So, hopefully I've convinced you that at some point about 600 million years after it formed, life arose on Earth. And let me take a little detour here to give you a brief history of life on Earth, and when I say brief, I say really brief. So this is a time chart of the history of the planet, more or less. It is not linear, just to point out. So right down here at the bottom, four and a half billion years ago is when we think the Earth formed. Right up here at the top is the present day. Just to put it into perspective, we're up here somewhere. I can come back to that in a moment. But what we've been talking about so far is this period of time at the start of the planet when there was no sign of life, about 600 million years. And then we're just getting into this part when cellular life first cropped up, what looks like a bacteria. This is also a very, very difficult thing to grasp, and so I'm going to borrow another volunteer, if I may. Can I have a different volunteer this time? Everyone's seen what happened to Brandy and they're like, "No, no." Please, anyone care to volunteer? I won't give you poppy seeds, I promise. I might have to pick on someone, if no one. Yes, at the back. Fantastic. Thank you, whoever that is. I can only see the hand.- [Emily] It's Emily.- Oh, it's a familiar volunteer. Well done, Emily. Thank you very much. (laughs) You missed the warning I gave to people that if your significant other doesn't know you're here, this is a bad moment. Thank you very much. Right, I'm going to pass you this very exciting thing, Emily. This is a nail file. You may extract the nail file. So, oh, I was going to say,"Whilst you do that, you can hold your hand out," but it's difficult to extract a nail file whilst you hold your hand out. Fantastic. Right, okay. And can you extend one arm like this? Brilliant. Okay. So I want you to imagine. I hope you've got good muscle strength. (laughs) I want you to imagine the start of life is roughly where Emily's nose is, okay? It's four and a half billion years ago, and we're migrating our way down the arm. What we've been talking about so far, the first 600 million years, no life at all, which is about from Emily's nose to her shoulder, okay? So there's no life at all. We had early bacteria life and nothing else for about another 600 to a billion years, right down to somewhere here on her arm. Okay, now I want you to take your nail file, Emily, and out here, humans were. Take your nail file and file one nail on this side. I won't do it for you. Yep, that's fine. Perfect. No, don't overdo it. (laughs) Okay, send your arm again. Thank you very much. Emily has just removed all modern humans. Okay, we've gone. That is the brief period of time that we have existed. If you can do it one more time. Don't over do it. Perfect, that's fine. Yeah, thank you very much. And now, we've removed everything back to when we split from chimpanzees. They've gone too, okay. That is the tiny fraction of time in which anything resembling, you know, really advanced life forms has been on the planet, whereas bacteria have occupied all of this chunk here. That's great, thank you very much, Emily. You can take the nail file as a souvenir. Bravo.(audience applauding) So we've had this vastness of time in which we're this tiny, tiny blip. But in that vastness of time, some really major and exciting events have happened, and one of the ones I want to draw your attention to is back here. For about 600 million years or so, bacteria kind of rocked around. They were using primarily chemicals in the early Earth to replicate themselves, to gain their energy, to build new structures. But then at roundabout sort of 3.4 ish billion years, we think, one of these bacteria evolved a mechanism to harness energy, not from chemicals but from sunshine, from light, okay? This is early photosynthesis. The first photosynthesis that happened was a very different sort of photosynthesis than the one we think about today in plants. This was using sunlight but not using carbon dioxide, not building sugars in the way that we think of today, but rather using chemicals that were abundant in the early Earth. Things like hydrogen sulfide, for example, which if you happen to know, that's the very unpleasant eggy smell you get from a rotten egg or lots of other unpleasant processes that we will not talk about tonight. You can use that molecule, that smelly molecule in a sort of photosynthesis to create energy. This went on for a little while, couple of hundred million years, and then in the next step, a microbe evolved a mechanism to take that same energy and use not hydrogen sulfide, but to use carbon dioxide in the atmosphere. This fundamental step was quite remarkable. So here, this is a modern picture, obviously. I haven't got a camera from three and a half billion years ago. But these are modern day examples of that first sort of photosynthetic microbe. These are things like green sulfur bacteria living here in Yellowstone Park in the US, okay. They are using sunlight to essentially eat hydrogen sulfide and other, to us, noxious chemicals in the hot springs. But in the pool, there are also more modern photosynthetic organisms that are using that sunlight to harness carbon dioxide in the atmosphere, like a plant does to create sugar. And this remarkable discovery laid a pathway to a completely different sort of evolution on the planet. And we can see that by using chemical means to look at the abundance of oxygen in the atmosphere. Because when an organism that is photosynthetic takes carbon dioxide and uses sunlight to build sugars, it releases a waste product, and that waste product is oxygen. Up until this point in the history of life, oxygen was almost non-existent, okay? The atmosphere had essentially no oxygen in it. And what happened early on, around here somewhere, so this is about threeish billion years ago, is photosynthesis occurred. It started to produce oxygen, but you did not get oxygen into the atmosphere, because at this point, the Earth had a large amount of iron around that was not oxidized. It was free iron. And as most of us will know, if you leave iron out in an oxygen environment, it rusts. It becomes yellow and orange. So what happened initially was these early photosynthetic organisms started pouring out oxygen and it didn't matter. The oxygen got eaten up by all that available iron and nothing changed in the atmosphere. But at a certain point, they ran out of iron, and now free oxygen began to accumulate in the atmosphere. And we're talking about a time here around 2 billion years ago, okay? If you look at this graph, you can see this is the level of oxygen in the atmosphere, and this is modern day up here. We're up at about 20% oxygen in the atmosphere. Here, 2 billion years ago, we're at less than 2% oxygen in the atmosphere, so only a 10th of what we have today. But nonetheless, this change was enough to cause catastrophic mass extinction, probably the first major mass extinction on the planet, okay. And I think there's a kind of slightly bitter irony about the fact that back here 2 billion years ago, microbes started putting a gas into the atmosphere and wiped out most other life forms on the planet. And now here in the modern day, we are also putting a gas into the atmosphere and doing a pretty good job of wiping out other organisms at the same time. So there's a kind of interesting parallel there. This early photosynthesis eliminated millions, billions probably, of early species. However, it also provided an atmosphere that allowed the evolution of a whole range of new species, and in many ways laid the ground for essentially everything we see today. Most organisms we study today rely on oxygen for life. And so this changed the course of evolution. So, so far in our journey through the history of life on Earth, we've had the evolution of first cells, we've had the evolution of photosynthesis, and now a really radical event happens. We had a major shift in the complexity of microbes, okay, from, and wait for it now. It's going to be a really big difference. From very simple organisms that look like this, to really incredibly advanced organisms that look like this, which I think you all agree look completely different, obviously. And you would immediately recognize to be vastly more complicated than these. These apparently similar organisms are the next major leap in cellular complexity, because these things on the right, this is Saccharomyces cerevisiae, the baker's yeast, the one that you put in your bread, or your beer, if you brew beer. This is a classical bacteria. This is actually Staph aureus, the thing that causes MRSA or wound infections. They're a little bit different in scale. They look very similar, but inside, they are radically different, because this thing here has complicated internal structures. Almost all bacteria have very little in the way of internal structures. They're a ball. They have some DNA to control their genes and they have lots of cellular machinery, but they have no compartments within them. Whereas all eukaryotic cells are subdivided inside them into different compartments, okay. They have things that look like this. Doesn't matter what they are. Compartments. The most obvious compartment of which is one called the nucleus, within which we store all of our genetic material. So if you look at any human cell, for example, you will see inside it a little compartment in which you would find your DNA. It separates your genetic components from other parts of the cell. And this was a major leap forward in evolution, because it allows all sorts of interesting biology that is not possible if you don't partition up your cell. This step, as far as we know, happened about 2 billion years ago, okay. So about halfway through our journey, if you like, from early Earth to modern day. And one of the most amazing, I think, discoveries of my life has been the process by which this happened, because it's truly remarkable to understand where these eukaryotes came from. And we think, in fact we are fairly confident now, that they came from a very unusual process called endosymbiosis. So if you think 2 billion years ago, there were all these different bacteria out in the environment, and in fact, there were two major types of microbe at that time, one called bacteria and one called archaea. And to most people, these things look absolutely identical. They're actually quite unrelated, but they look very, very similar. You need a microscope to see both of them. Today, we can still find this other lineage, these archaea, but typically, we find them in extreme environments. Places like hot springs under the ocean or deep inside rock faces. Both of these early lineages of bacteria likely survived on a mixture of gaining chemicals from the environment and eating each other, okay. This is not one of those bacteria, but this is the kind of typical example of microbes eating each other. You can see actually this is an ameba here that's doing a very bad job of trying to eat these little yeast that we're feeding it here. Lots and lots of microbes today live by eating other microbes. And indeed, it's very likely they have done that ever since the origins of life. And what we now believe is that about 2 billion years ago, one of these eating events went badly wrong or badly right, depending on your perspective, in that an early one of these cells, these archaeal cells progressed to eat one of these bacterial cells, the little red one here, and failed to kill it. And instead of having dinner, these two set up a sort of slightly unholy alliance, a so-called endosymbiosis. The bacteria continued to live within that archaeal cell, and they formed a symbiotic, so a mutually beneficial relationship. And this seems quite remarkable. It's even more remarkable when you realize that this has happened not just once, but actually several times in the history of life. Because subsequently, probably many hundreds of millions of years later, this process happened again when this dual partnership ate a third bacteria, a photosynthetic one in this case, and created the lineage that would eventually lead to all plants, okay. These endosymbioses events in which one organism starts to live inside another organism, and then very, very slowly over millions, hundreds of millions of years becomes unable to live independently, appear to be incredibly unlikely, right? It seems just vastly unlikely this would ever happen. But actually, they're nowhere near as unlikely as you might expect. And if we look today around the world of microbes, there are many, many examples where this happens. So for anyone, for example, who's been to the Great Barrier Reef, or indeed any coral reef, you have been looking at a great example of that, because coral organisms, many of them, live with obligate endosymbionts. So here's one here. This is one called Aiptasia, and inside this coral, you can see this little tiny red blob here, which is an endosymbiotic bacteria. And what you can see if I play this movie is this little little chap is rummaging around, and that bacteria is staying firmly ensconced within the coral microbe. And in fact, this is absolutely essential. This coral relies on the metabolic processes that that bacteria does in order to survive. And actually, this is a rather wonderful example, I think, because it turns out that it will sometimes throw this bacteria out and then take in a new one, and if it doesn't like the new one, it'll throw it out again. And it can tell whether the bacteria's going to kind of pull its weight or not. And if the bacteria starts to cheat, it gets booted back out again, which I think is very, very clever. This is the process by which most corals survive and produce coral reefs. Even cuter, I think, is a story from one of my colleagues in Birmingham who has been working on a fungal pathogen, so a fungus that kills people, actually. This is one called Rhizopus. It causes a disease called mucormycosis, which is a very, very unpleasant, fortunately rare, but extremely unpleasant tissue destroying disease, which kills people. This fungus, when it can get into your wounds, will germinate and it will grow like this, and it will eat your tissues, essentially, and lead to death. And one of the reasons that it's very difficult to treat is that this fungus has an amazing ability to avoid the human immune system. So whilst it's happily munching its way through your arm or your leg, your immune system is happily neglecting it, which is not helpful. And for many years we've been trying to understand, how can this be? How can this incredibly damaging fungus not to trigger an immune response? And it turns out it does that because it has a passenger that is helping it out. If you look deep inside these fungi, you see that inside each fungus cell in blue here are tiny, tiny bacteria, endosymbionts. These bacteria produce a toxin which deters the human immune system, and in doing so, of course, they protect their fungal host and therefore they protect themselves. And so this symbiosis is one, I think, which offers really important potential benefits clinically, if we can understand it, in terms of treatment. But again, a really elaborate endosymbiosis that has arisen probably very recently in history. So not perhaps that surprising that you would get these kind of endosymbiotic events that sometimes lead to stable evolutionary change. Okay, so we're still back down here, right at the bottom here. And you'll be pleased to know that I'm rummaging my way about as far as I'm going to go, because all this bit at the top is all big things that I'm totally uninterested in, that you can see with the naked eye. But there are a couple more steps that I really want to talk about. So we've just talked about these first eucaryotes. So, so far on our journey, we've had early bacteria, okay. We've had the evolution of photosynthesis. We've had that first big split, if you like, into the photosynthetic eucaryotes that will go on to become algae and land plants, and the non-photosynthetic ones, like our cells. But when we think about biological forms, different organisms, what we come to realize is that most of the ones we think about are actually not microscopic. They're large multicellular organisms. And that raises the second question of, how do these single celled free living things turn into large complex multicellular organisms? What is it that changes one for another? And that is a fascinating problem and one that I think gets to the heart of thinking about what we're about, because we think of ourselves, humans, as single entities. When we picked on poor Brandy at the start of this lecture, you know, and saying actually, we think of ourselves as one organism, but we're not one organism. And even if you take away all those trillions of microbes that live in or on us, we are still not really one organism. We are a very complex set of cells coordinating together. So how might those single cells grow together in a way that forms this multicellular life? And we can get some clues by looking at a modern microbe. So this is an organism called a Volvox, okay? And this is a multicellular organism but only just. What you see is that this is a colony of individual algal cells that live together, okay? It's one organism, sort of, but it's also hundreds of individual multicellular, single celled organisms working together. So that gives us a little bit of a clue about where these things might have come from. One of the most amazing things about multicellularity is that it has arisen not once, but multiple times. So all three of these rather ugly organisms on the board in front of you are multicellular organisms. All three of them though have arisen from a lineage which has independently acquired multicellularity. In fact, in the history of Earth as far as we know it, multicellular organisms have arisen 25 independent times, which is quite extraordinary. So the lineage which went from being individual yeast to complicated fungi, that multicellular step happened there, but it's completely unrelated to the step which led to a single celled ameba turning into something that looks quite frightening, like this chap in the middle here. These things have occurred again and again and again. And that brings us to this very challenging question, how can something as complicated as becoming a multicellular coordinated organism happen 25 independent times? That seems highly unlikely. But actually, it's nowhere near as unlikely as you might think, and in fact, it's so likely that it's possible to achieve that within a matter of weeks in a laboratory. And so this is a rather beautiful example from a group in the United States, Will Ratcliff's group, where they have essentially recapitulated the conditions that might allow single celled organisms to become multi celled. So they start with single celled yeast that you can see on the screen here in front of you. And then what they do is they set conditions that strongly favor multicellularity. And then you evolve this yeast in a laboratory, every generation trying to look for yeast that are a little bit more multicellular. And remarkably swiftly, when you do that, you end up with an organism that is quite fundamentally different, and here it is. So you can see in the top screen above me, here is a new multicellular yeast happily growing, no longer as a single celled organism, but as a multicellular colony. And in fact, if we do some fancy microscopy, you see these things are absolutely beautiful. This is a three-dimensional living organism now that has these kind of structures within it. And perhaps the most remarkable thing to me is when you look at the behavior of these, these are now acting like a true multicellular organism. So in the bottom corner, you see one of these colonies essentially growing, replicating, dividing like a large multicellular organism and no longer like a single cell, within a matter of weeks in the lab. And so I think this kind of process sets the kind of groundwork, if you like, the understanding for how individual cells might ultimately have evolved into all of these elaborate multi-cellular organisms. And explains to some extent why this process has happened 25 times and not just once in the history of life. And of course, it remains to be seen how different this might be in all the different lineages and multicellularity that we know of. And so these various steps that I've talked about this evening have together combined to produce the whole diversity of life that we have on the planet, what Charles Darwin referred to as these endless forms most beautiful. They've created structures that range from the truly invisible, absolutely minuscule viruses, up to enormous things like blue whales. And that great diversity is something that I want to touch on in the next lecture, when we're going to start to look at how microbes have shaped the kind of physical environment around us, and how some of these tiny invisible organisms have led to some really, really macroscopic changes. So I hope you'll join me then and have a look at some of these organisms. In the meantime, thank you very much for listening.(audience applauding)- [Tim] Hi, my name is Tim. First of all, thank you very much for this very interesting lecture. And I would like to ask you about one thing, what called is mitochondria. And we know what this mitochondria also was a bacteria, and now we know it's very important for our life. So my question is, how can I build more mitochondria in my body? Thank you.- Brilliant. That's a good start. Okay, so for people who might not have heard the question, the question was about mitochondria. And mitochondria are those first endosymbiotic steps that I talked about. When I talked about a bacteria engulfing a little red bacteria as the very first endosymbiosis, that little red bacteria is what turned into the mitochondria. And we have now in all of our cells of our bodies these little endosymbiotic mitochondria. They are essentially energy machines. They create the energy that our cells use. And if you don't have mitochondria, you lose your energy and your cell dies. So how can you create more mitochondria? Well, the easiest way actually is to do all those things that we get told to do a lot of and get really annoyed by, like exercise and eat well. Because the mitochondria will replicate independently of the cell. So you can have cells that have one mitochondria or cells that have hundreds, and that control is based on the kind of demand, if you like. So cells that you use a lot of energy have more mitochondria, and ones that don't use very much energy don't generally have many mitochondria. So when you drive energy demand by doing a lot of exercise, for example, you will start to get more mitochondria to meet that energy demand. You can also do things like, you know, altitude training, for example. When you go up high, your oxygen is less available, that will trigger more mitochondria. You can also go in the other direction. So you can reduce your mitochondrial number by being incredibly lazy. There are also some drugs that are particularly toxic for mitochondria that will reduce them. So your mitochondrial number is changing all the time. One thing that is particularly neat aside, but might be of interest to people, is that you inherit your mitochondria separately from your nuclear gene. So all of us in this room, you are a beautiful mix, whether you like it or not, of your mum and your dad's gene for all of your nuclear genes. But your mitochondria come only from your mum. So you have nothing to do with your dad's mitochondria. So if you're feeling like you have really low energy levels and you're blaming your mitochondria, it's your mum you have to blame, not your dad.- Looking back at those very, very early days, how much is hypothetical and how much can you generate from experiment? And how would you do that?- Yeah, that's a good question. So very, very early, I think it will always be inevitably hypothetical. So those early spontaneous chemical. I mean, what we can do in a lab is we can create conditions under which those chemicals form, and you can create chemicals which self replicate. So you can do all the steps in the lab, but whether that actually happened in that early Earth in that sequence, I think we'll never know. Endosymbiosis, I think there's such good data that it can happen and that it is an extremely plausible mechanism that I think that's not really disputed anymore about that process. So I think from that point on, most things are fairly robust. But that very early, how did you get a first cell, how did that first cell replicate, is I suspect always going to be slightly nebulous, although I'm dying to be proven wrong when someone comes up with totally incontrovertible evidence.- [Audience Member] Yeah, hi. Coming back to the point of the 39 trillion bacterial microbes in our body. How varied are they? Are they all one type or are they five types or 39 trillion types?- Yes, that's an excellent question. So the question is, how diverse are those 39 trillion bacteria? Very, very, very is the short answer. And the longer answer is, so we know essentially by doing DNA sequencing on poo, lots of poo, that people have amazingly complicated organisms. So we know, for example, that there are organisms for which we can find the DNA, which we have never grown in lab, which are unknown to science. So we're all harboring these unknown bacteria anyway. We also know that each of us has a very unique combination, so no two people are the same. And you might have come across a lot of interesting work on things like fecal transplants. There's a lot of interest in whether you can change people's microbiomes, that complement of bacteria by essentially swapping poo between people. And it works, it works quite well. But it's actually not just the body. So in fact, on your hand. I'll borrow Wendy. She's at the front here. Wendy, can I shake your hand? There we go. Marvelous. I've just contaminated Wendy horribly.- Thank you.- Thank you very much. Because on our hands we have about 300, 400 different species of microbes that live on our hands. Only 15% of those are shared with all of us in the the room. So whenever you shake hands with someone, you are scraping off all these unique microbes onto Wendy's hand and vice versa. The really good news is that very rapidly afterwards, the ones that are foreign die out and disappear. For some reason, your microbial compliment on your hand is kind of unique to you and is very difficult to displace. So we have these sort of unique, highly diverse ecosystems, which we really are just only just beginning to scratch the surface of.- [Audience Member] I rather wonder about the evolution of photosynthesis. It seems rather strange. It's not using the green part of the spectrum. It seems to use the red and the blue. But the green is the most active part of the spectrum. It's an evolutionary mistake, isn't it?- Yeah, yeah, yeah. That's an excellent question. So the question is, why green? Or indeed, and I remember many years ago as undergraduate being set an essay saying,"Why isn't the world black?" Because if you want to harvest light, it would seem like being black is a very sensible color to be, where you harvest all of the spectrum, rather than green, when you're by definition reflecting green. And I think there's sort of two possible answers there. So there are some pretty good reasons why you wouldn't want to be black, actually. So, which are largely to do with kind of overdosing and getting photodynamic damage based on too much light. But why green is a very good question. In fact, it's not always green. So there are red algae, for example, which are red, and there are lots of photosynthetic pigments which are not green, but the dominant one is green. And what you see is that that is actually very efficient based on the rest of the biology of the cell. But your point is a very good one that, of course, it's a bit like when you started to build a machine. If the first computer you buy is a PC, then you tend to stay with PCs because shifting over to Mac is quite a lot of work, and it's a little bit like that in evolution, I think. If the early machinery works well with what you have, evolution's put you on a path that will keep going that way. It's a very interesting question to wonder if we played the tape of life on Earth all over again, would we still have green plants, or might they be red, or orange, or some other color? So yeah, that's a very bad answer to your question. Thank you. (laughs)- [Audience Member] So at the beginning, well, towards the first third of your lecture, you said that the important criteria for the beginning of life as life itself was the development of a boundary for the formation of a cell. Would you say that's the most important criteria for considering life appeared? Or like a few other important ones. What would be the criteria for life itself?- Yeah, I mean, those are very difficult questions. It's a bit like asking someone whether their left leg or their right leg is more important to them. I mean, I think the membrane is absolutely a fundamental part of life, because it allows you to have different chemistry on one side from another. And what we see actually, so someone mentioned earlier about mitochondria, which generate energy. The way they generate energy is by having an internal membrane and separating things, a bit like a waterfall. So they have one set of molecules on one side and they let them through a kind of turbine to generate energy across that membrane. So the reason a membrane is so important is it allows you to do different things on one side from another. So I think it's fair to say that without a membrane, we would not have life. But it's also fair to say that without a self replicating chemical molecule, you wouldn't have life. And without an ability to harvest energy, you wouldn't have life. So I think all of these things are critical. But I think generating a membrane that allows you to enclose something must have been something that happened very, very early on. Whether it might even have happened before a self replicating molecule is an interesting question and quite possible. It comes to Martin's point about, will we ever know? But yeah, it's absolutely a fundamental step, definitely.- Do we know anything about when membranes ceased to be just an interface, but became an active structure? You know, 'cause they're involved in so much transport mechanisms, ionic exchange. What do we know about when that all started?- Yeah, very little indeed. I mean, there are now, if you look at modern cells, there are cells that have incredibly simple membranes. I use that kind of slightly cautiously. So a red blood cells, for example, that circulates in our blood is a relatively simple membrane, because that cell essentially has one purpose, which is to carry oxygen. And then you have incredibly elaborate membranes. So at the end of a nerve, so you know, when you're doing this, there are nerves firing and they're using just an incredibly diverse array of proteins at the end of their membranes to exchange molecules. So there are a whole range. I don't think there are any cells today that have a membrane that is as simple as it would've been, you know, the origins of life. But when a membrane changed from being just a physical barrier to something that had a kind of signaling role, I think it is, again, probably a question we will never know the true answer.- Some of the fungal mycelia have complicated communication networks which involve membrane transfer, don't they? So, we must know a little bit about that timing.- You're preempting. You have to come back for a future lecture, because we have a whole lecture on those elaborate membranes and fungal mycelia. But yes, which you can see, in fact, behind you here on the screen. Exactly. (laughs)- [Audience Member] Is it possible to imagine any mechanism by which acquired characteristics can be inherited? Or is that still believed to be simply impossible?- We're talking about the markers. So the question is, can acquired characteristics be inherited? And I think the answer actually to that is definitively yes, in some circumstances. So actually one example, very simple example would be prion diseases. So BSE in cattle, scrapie in sheep, or CJD in humans, where what you have is one protein that converts another protein into a pathogenic form, and then that carries on, that process carries on. Obviously in humans, that is a fatal disease. But you have an equivalent in yeast, a prion disease where those faulty proteins, if you like, can be inherited and go from one generation to the other. Probably a much more relevant example is around epigenetics. So when we express so-called express genes, and when your DNA is turned into something useful like a protein, that process can be controlled by chemical modifications on DNA that are not genetic but are nonetheless inherited. So for example, whether a gene is expressed or not sometimes depends on whether you've inherited it from your father or your mother, not because the sequence of the gene is different, but because it has different marks on it. And this is one of the explanations for why we see very interesting effects. So for example, in terms of diet, so you might be aware, this is very impressive data from the Second World War from the Netherlands where the population encountered extreme starvation. And the mothers who experienced starvation, not only their children but their grandchildren had differing birth weights, even though they themselves had never encountered that. So that kind of shock had somehow left an inheritable mark that has been inherited, and there are many more examples of that. I mean, I would caveat that by saying still overwhelmingly, almost everything about us is inherited in a typical genetic way, but there are some areas like that where it's undoubtedly important.- [Audience Member] My question is, because you touched how life on Earth started. You haven't said anything about viruses. Do you think viruses evolved from the bacteria cells? Or they were completely different life forms that evolved independently? Thank you.- Yeah, no, great question. So the fundamental feature of viruses is that they're not truly alive in the sense that they cannot survive without a host. They can't do anything without their host. They rely on a host to do something. And in terms of when, so my strong feeling is therefore that even the very first virus must have arisen after something else,'cause it needed something to predate upon. What we see today is that viruses very clearly arise from other, so often they are, for example, bits of DNA from something else that has kind of popped out as a free living life, and it acquires different genes as it goes along. So what you can sometimes see, for example, is that a virus might pick up a bit of host gene and add it to its genome, if it adds a benefit. So one of the examples is if it can pick up a gene that somehow confers the ability to evade the immune system, that's favored, and so the virus now has that. And so you end up with viral evolution by a kind of mix and match process of stealing genes from others. So, I think they were slightly later, but nonetheless, undoubtedly very early on. So almost all bacteria have viruses of them, so-called bacteriophages. So they're not a recent evolutionary event at all, I think, but they must, I think by definition, have risen after the very first life forms.- [Audience Member] I don't want to lower the tone of the lecture.- Oh, please do. (laughs)- [Audience Member] You did mention poo swapping. I can't let that go. You've also talked about, you know, hand shaking and what's transmitted through that and how it dies off, so.- Where do we go from that?- [Audience Member] I tried to.- No, I like that. Yes, I mean, so that's actually fascinating. So the place that this has been worked on most extensively is with patients with things like ulcerative colitis, Crohn's disease, where there is now pretty good evidence that the particular microbiome you have, so in some patients, the diversity of bacteria and fungi and everything else you have is triggering damaging inflammation. And so if you switch that microbiome in its entirety for a healthier microbiome, you can often get benefits. I mean, I should say it's not trivial. So first of all, you have to eradicate all the microbes in your patient by a really extensive course of antibiotics, and then essentially switch poo together with all its compliments from a healthy donor. And that has actually some quite profound clinical benefits in some patients. There is a lot of interest now in extending that to all sorts of other things. So you might be aware, there's a lot of media out there about obesity and to what extent is obesity, you know, driven by microbes. And there's quite good evidence actually that some people's microbiome is much better at harvesting energy, and therefore making you fatter for the same amount of inputs than other people's. And there's even some kind of emerging but quite exciting evidence that your microbiome might affect things that we think of as being very individual, like mood, for example. So, many mental health conditions, there are differences in microbiome content between certain people and people without those conditions. Lots and lots of caveats around that, but I think, you know, the compliments, your microbiome is probably doing an awful lot more than we think it does. I'm not aware of any data that your hands have a big impact. So Wendy, you're still safe, I think.- [Audience Member] I was just wondering what the conditions in the lab that we use to select for multicellularity.- Yeah. No, actually, very, very simple. So essentially what they did was they used a density gradient. So the bigger the clump, the faster it falls. And this is something that, you know, if you've done sort of home brew or something, you know, you wait for your brew to happen, then you let your yeast settle, and you take the white off. And so, if you do that in a way that you get the fastest falling, i.e. the biggest clumpier organisms, and you do it again and again and again, what you very soon end up with are organisms that only ever clump and never grow freely. And I think actually that's the kind of thing that might have happened also naturally in terms of early evolution, because being multicellular has benefits. So if you think about, for example, the shoreline, being a big, lumpy, sticky thing is probably quite beneficial if you can stick to a rock in a way that a single cell can't. But again, that's slightly speculation. But I think it's probably not that difficult to find conditions in nature which stimulate multicellularity.- Well, thank you very much. It's very nice to be able to conclude a lecture saying that it wasn't a load of poo.- It was.- I'd like to thank Robin for a fantastic lecture, and thank you very much.- Thank you.(audience applauding)