Slime Moulds

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If you scroll down the page for this edition, you can find a reading list to go with it. I hope you enjoyed the programme. I'm a professor of quality of cell biology at University College London, and Merlin Sheldrake, biologist, writer and research associate at the Braille University in Amsterdam, and Oxford University. Jonathan Chubb, what is slime mold? It's actually quite a vague fuzzy term that encompasses a lot of different species. They superficially seem very diverse, but there are some common features. Often a free living single cell stage that goes around eating usually bacteria, but these organisms also have the ability to make spores, which are environmentally resistant and dormant and can last for years before they germinate and generate single cells again. Now there's a tremendous diversity. Some of these things are really a tenth of a millimeter in size. Others can be a meter across. These are the big things you see on a decaying wood. Some of the forms are incredibly beautiful. Things like wool, smoke, looks like German Christmas biscuits. There's also the dog's vomit or better known as scrambled eggs mold, which looks exactly like that. It's a very very successful type of species that is evolved multiple times during evolution, whereas as far as I'm aware, there's probably only one hominid branch. Even some bacteria have life cycles that resemble slime molds. Mixer bacteria, which also have a single cell stage, which can aggregate to form spore-containing structures. How does slime mold relate to other organisms such as plants, animals, and fungi? Putting aside the bacteria, if we can oversimplify the tree of life into two branches, which I'm going to get slapped for, but there's the branch that's a bit more plant-like, and there's a branch that's a bit more animal-like and fungal-like. Now, the slime molds appear on both branches, so there's some of them that are a bit more plant-like, and there are some that are a bit more animal-like. For example, the acracids are much more plant-like. They include certain human pathogens like necleria, whereas the more animal-like ones include the amoebazoa. That includes a big spectrum of acelular slime molds and cellular slime molds. But within these different groups, you have, for example, animal-like ones like amoebazoa, looks very very similar to plant ones like the acracids. So there's this motif, these features have propped up many times during evolution. How many species are there? I guess we probably don't know the extent that there's at least over a thousand, many of the sort of acelular form. Yes. When did people come across them? Well, to the best of my knowledge, the first one named was Woolsmilk in the 1600s, and it was as early as the 1700s, actually, that someone realised this wasn't initial reaction was this was some kind of fungus, but it wasn't till another century later that they realised just based on morphology that it was something a bit different. It doesn't look like a mushroom. Yes. Thank you. Merlin, Merlin, so great. Can we develop where these slime molds are found, and whether we see them on what they look like, just give this as a visual map of what they're sitting on, looking at, or scraping off? So you'd find them in damp, often shady places like you'd on ford and logs or on ford and leaves when walking through a forest. And in different stages, they look like different things. And in their single cell phase, you might think of them as being, if you had a microscope, as being signed shape-shifting blobs, a little bit like your white blood cells that we have in our bodies. So shape-shifting single-celled beings. But then they come together to form networks of slimy, tentacle-like veins, which could be pinkish, yellowish, orangey. And these networks are shape-shifting as well. But they're exploring as a network, their environment. And they're the ones that look a bit like sometimes can look like dogs form it, or scrambled eggs, or tapioca pudding. But then they come together when they produce reproductive structures. You'd see those as very fine stalks, a few millimeters high, with a spherish kind of structure balanced on top of the stalk, or a sausage-y structure balanced on top of the stalk. And they're really remarkable looking. I mean, they're ones that look like little planets, or like single fish eggs, or like the seed pods of a very unfamiliar plant, or like corals that have erupted from small sacks. It's remarkable. There we're told, and there are around a thousand known species of slime mold, which forms a two main type, cellular and a cellular. What are these? Let's start with cellular. Cellular slime molds spend much of their life living as single-celled organisms. And when times get tough, food gets scarce, they come together to form a multi-cellular structure. But the individual cells retain their identity as an individual cell. So it's a little bit like imaginary or playing with bubbles as a child. Those bubbles can sometimes stick together, but they remain. You can see the different bubbles in a kind of clump of bubbles. Now, the A cellular ones, when they come together, because they also come together from a single-celled state into a kind of merged state. And when they come together, and they form one giant cell, so it's a bit like those bubbles have joined to form one big bubble with one outer membrane. So it's quite a different way of leaving a single-celled state and coming into a merged state. Hello, hello, Tomson. Let's keep banging on about this. Digging in might be a better way to talk about this cellular slime mold. Trying to give a listener an idea of what they are. What's you made up of? Is it very similar to our own cells, their cells? Okay, so the cellular slime molds are the ones that we know particularly well, because there's an example of them which we are using a lot in scientific research. So in the 1930s, an organism called Dictistelium Discoidium was discovered on Dung, and it's an amoeba. It's a eukaryotic cell, so it's a complex cell type like our own, which gives us an idea of the preservation of cell features over evolutionary time, because this is an anciently evolving branch of organisms that has cells that look very like our own. In this scheme of things, in this your scheme of things, does it surprise that their cells are like human cells? No, because so I'm really interested in what's maintained over evolutionary time in cells, and so one sees it all the time. So bacteria, in fact, do many things that more complex cells can do. We always think of bacteria as being very simple, but they make up most of life on earth. And then our poxy eukaryotic branch, these complex cells that end with this tiny little twig of multicellular complex life with humans and animals on it. The thing that's special about the amoebae for us and makes them nice to use as a model in the lab is because they're very like human cells in not having a cell wall, and we'll perhaps talk about the genetics as we go on. Yes. How does it behave at different life stages? Okay, so cellular slime molds, as Merlin said, maintain a unicellular life habit, but they're able to join together to form a multicellular organism. So they have this amazing, fascinating life cycle where they can graze their prey microbes in the environment. So they go around engulfing bacteria as a food source, but then as they reach very high numbers of cells and they start to run out of food, they signal to each other with a chemical signal that tells them that it's time to move on and make spores. So single cells signal and when one cell signals to another, another cell signals to other, and you get this propagating wave of chemical signals that then brings together waves of these single cells into a mound. And then the mound is able to sort of rise up and it topples over and then again the amoebae, they sound so glamorous. We call this toppled over multicellular organism, we call it a slug. So every aspect of this is made to sound really unexciting, but clearly it is because we have these identical single-celled organisms which come together to become a multicellular slug. And then this slug is a true multicellular organism which is able to move to a place where it can produce the next generation of spores. That's the point of the slug. But in doing that, we've differentiated. So these independent living cells turn into different types of cell within the slug and then they turn into a base, a stalk, and a sport head. And the amazing thing about that is that only some of the cells are in the spores and so sacrifice becomes part of this dictustilum life cycle. When did they come into your area of knowledge about what was going on in life? I was given dictustilum as a leaving present when I left the lab where I did my postdoctoral research. I was working on a particular set of components of cells and some very lovely colleagues in the dictustilum community gave me some dictustilum cells to take with me when I set up my own new lab. So I've had them for about 10 or 12 years. How they behaved in that time? Yeah, mostly okay. They are a really lovely organism because they're just so interesting. They're a really brilliant teaching tool. And when we have visitors to the lab who aren't necessarily scientists, they're a lovely thing to show them. What do you share them? Well, so the unicellular form of dictustilum is not visible to the naked eye, but you can see where it is on agar plates because if you put dictustilum cells on to what we call a lawn of bacteria, it will graze those bacteria and produce very little sweet areas of grazed out bacteria, so zones of clearing that you can see on a plate, so that bridges the microscopic to the macroscopic. And then the multicellular stages, you can actually see with the naked eye, so you can see the store can fall head. So even though it's a microbe, visitors to the lab can actually see this thing. Jonathan, let's talk about the A-cellular kind. What's that made of and how does it behave differently from the cellular? I mean, it has a slightly more complicated life cycle. It can exist and feed. There's both this large thing that you see on rotting logs, but also as small cells, which can either be amoeba like the cellular slime moles or flagellate, which means it's a cell with a tail, think sperm cells. So I think the most remarkable phase of the life cycle of this organism is this thing called the plasmodium, which is these things are visible to the naked eye. Sometimes they can be a meter in diameter. They're these flat structures that you can see in the soil or in logs. These are in some senses quite unusual because normally when our cells divide, the cells copy the DNA and they segregate that into two nuclei and then the whole cell divides and each cell has a nucleus. But with these plasmodial or A-cellular slime moles, you get the nuclear division, you get the whole growth of the cell itself doesn't divide. You've actually got a single cell, which can weigh as much as 20 kilos, which is it's a very unusual strategy. We have some cells like that in our bodies. For example, muscle fibers are often fusions between multiple cells, but a single fiber is nothing like the scale of the A-cellular slime mole. So one of the other remarkable features about this in a cell that large, moving material around is really rather hard. For example, in our bodies, we have a circulatory system that can move oxygen and nutrition around. In a single cell, that becomes a problem, but these slime moles have developed an internal circulation, which we call cytoplasmic streaming. So if you want to imagine how that works, imagine squeezing a sausage in the middle and when you squeeze the sausage in the middle, the contents will move to the other side. So the cell has these proteins, which basically wrap themselves around the tubes and they squeeze much like if you were squeezing a sausage and that causes flows of fluid along various channels within the cell. Thank you, Merlin. How does it make decisions? We said early on, they have no brain and yet they're very intelligent. Now, can you enlighten us on that? Well, I think it's helpful to think about some of the behaviors that we're trying to explain. So one of the very famous slime mole, the plasma module or A-cellular slime mole behaviors is the ability to navigate labyrinths or mazes. And there are some very well-known examples of this with researchers recreating a Tokyo subway network, but others have done it with the network of Roman roads in Italy or the American highway system, where if you put lobs of fuel oats, they love oats, they love rats of the plasma module slime mold world love oats. So you can put oats on a big dish and then the slime mole will find the most efficient path between the oats, having explored the dish. They can also find the shortest path between two points in the labyrinths. So the question is, how are they so good at searching space and navigating complex environments? Actually, they're so good at this. I have a friend who's an artist and he always got lost in IKEA stores, giant IKEA stores, and he had a stable of slime molds at home and he told me once that he'd made a scale model of the floor pan of the IKEA store with all of the obstacles and routes that were available to him as a human with a brain. And he unleashed the slime molds in the slime mold sized IKEA store and they were able to find the shortest path to the exit. Fast as he could, even though he had access to shop assistants to help direct him, so he would always say, look, they're a cleverer than me. So the question is, how then can they navigate? How can they find shortest paths? How can they do this? And it comes down to what Jonathan was saying, where these rolling waves of contraction move the cellular contents along these slimy vein-like protrusions or tentacles, a little bit like tentacles. And so when one of these arms or veins reaches some food, then it generates a stronger contraction along that arm of the network and the stronger contractions move more cellular fluid along that arm. And the shorter the path, the more will pass along that arm. So what this means is that the stronger arms, the more, if you like, successful arms, the ones that are touching food, are strengthened at the expense of the arms that aren't touching food. And in this way, the slime mold can redistribute its body, orienting to new food sources and and sensitively navigate through landscape. I mean, I've been taking it back, but I mean, you know, this is the world you dwell in. This is the world that's completely new to me. It sounds almost like a magical world. I don't know, again, and Jonathan, both of you. What can we gather about these slimyles, social behavior in communities? How do they communicate? How do they interact with you, Oliver? OK, well, if we follow on from the development of the unicellular to the multicellular organism, there are two particular features of that that we haven't mentioned so far. So one is the sacrifice that's involved. So 20% of a multicellular dichyostelium, in the case of this cellular amoeba, will become dead stalk cells. So there's an element of self-sacrifice. It's almost a philosophy of science that comes in here. How do you decide which cells will become the spore and which will become the stalk cell? So the communication and control of that. And then the thing that really makes the hairs stand up on my arms still when I describe this is the presence of cheaters in the community. So in the population of cells that all look the same as each other at the beginning, they're aggregating to the multicellular organism. There are quite a lot of changes that can happen that will ensure that you become a spore. So some cells will make jolly well sure that they're in that spore head. And so we can learn a lot from dichyostelium about the messages that go between cells that make those things happen. How's that decision made you say they decided to move there or there? Well, this is where knowing things about science makes the science sound more boring. So there's self-sacrifice. So there's another element of this which is kin recognition. So dichyostelium spores have been found to be more likely to be relatives of each other so that they can recognize one another. And these features are surface features. So there's a green beard, is the theory, isn't it? So the idea that you will choose somebody with a green beard to join your community. So a dichyostelium cell that recognizes a relative is more likely to aggregate with something that has that component on its cell surface. Not about green bears, but I think these cheetahs that seem to become spores and not sacrifice themselves. So there's a limit to what the population can take of those. So they're very good at following the signals that allow them to become spores. But if you have too many of them, the population, you get an overall loss of fitness that is a break on how far they can actually permeate in a community. Yes, what is a cellula slime mold? What are you useful for? You look taken aback. I'm just trying to be diplomatic. I'll give a very personal answer and possibly in the minority of one, but for me, I think the idea that its intelligence is a very human view of the proceedings. I think for me it shows from our perspective very, very complicated behavior using very, very simple rules. I think that's what we have to take from this. What are those rules? Then think about how that can relate to more human types of questions. For example, you've got this vast network that's making this decision on which way to go or which path to strengthen. I'm talking about the slime walls mimicking the establishment of rail networks and things like that. In practice, we would never set up a rail work network like that. The way they do it is they send out this big flanks of material almost at random and that would be like building a railway every few meters in hoping that one of them would actually find the destination you're aiming for. But the branch that actually gets to the outflake is the one that stabilizes and all the others are retracted. So in terms of designing rail networks, I'm not sure this is really that useful at all, but in terms of understanding what is effectively a complex behavior and understanding the basic rules of that, I think it's extremely useful. I mean, our brain is also just a net work of cells that are communicating, and using similar types of, the same types of cell biological processes to underline the structure of this network, just our networks are bigger and more complicated and have more sub-departments. Yeah, so the way that they find these, or navigate space and find these routes is very different from the way that we would do this, because we're centralised organisms, now if we were dropped off in the middle of a desert and we had to go and find water, we'd have to pick one direction and we'd try that one direction, we might be successful, we might not be, and we'd have to keep looking one route at a time. But slime molds, these asylilous slime molds, a bit like fungi, are able to grow out in all directions at once, which means they can search space quite efficiently, but when they get to the point of interest, say it was us in the desert finding water, but for the slime molds finding an oak flake, then they can strengthen that line and retract the parts of their enquiry, which didn't lead anywhere. So it's just a different way of navigating space, and so what that means is that you can, so when researchers have done these experiments where they've recreated road networks, or there are some that have used slime molds to calculate the fastest fire evacuation routes from buildings, what you're doing is asking the slime mold to find the shortest path to the oak flake, which you've positioned at the exit, if you're trying to find the fire exit. So we might design in a slightly different way, but these are partly demonstration and partly a way of trying to understand these different strategies that all Muslims have to navigate a changing and varied world. And what's amazing in these cases, to me, is that they're able to solve this kind of problem without a centralized place to do so. We're used to thinking of our bodies in terms of centers, we have heads, we have hearts, we make capital cities, we have heads of state, the centralization runs all the way through our societal metaphors, but slime molds don't, their coordination takes place a little bit everywhere at once, and a little bit nowhere in particular. And so, I think it's important, as an example, as a way of life, because it illustrates that one doesn't need a brain to solve problems, and that. You mean none of us need a brain to solve problems? So I think one of the things that illustrates is that, you know, we're used to thinking about brains as being totally key to problem solving, because we have brains and we're proud of our brains, and rightfully so, but there are lots of ways to solve the problems that life presents, and slime molds illustrate some of these other ways, and in jolting us into remembering the many ways that there are to solve problems. I think they've done us a great service, at least none of them science a great service. Start your day with fully cooked breakfast sausages from Amy Liu, 365 brand frozen waffles with no bleached flowers, and of course Whole Foods Market eggs, which are all cage-free or better. In the evening, bring home a build your own family meal that feeds four for just $35. Use one entry and two sides. Shops smarter, not harder, at Whole Foods Market. Hey, it's your ceiling vent, so I'm dripping. Could be the rain, could be the upstairs bathroom, eggs. You could hire the guy your neighbor recommended, but I'm pretty sure that's just his cousin. Do we know if he's licensed, or does he just own a ladder? Listen to your home. Go with Thumbtack, upload a photo or voice note, and we'll diagnose your project and match you with the right pro for the job. Thumbtack, we know homes. Hire the right pro today. Before Achilles found glory and Odysseus eventually found his way home, someone had to compose the Iliad and Odyssey, but was their credited author, Homer, even real? Hi, I'm Greg Jenner, host of Your Dead To Me, the comedy show that takes history seriously, and we are travelling back to 8th century BCE to trace the origins of the Iliad and Odyssey, epic poems that became backbones of Western literature. Join me and my fantastic guests as we unpack the stories of ancient Greek culture, war, and triumph, and have a laugh while we do it. Listen on BBC.com, or wherever you get your podcasts. Thank you. Bye. I think there's a lot of examples where even some of the more complicated, emergent behaviours that are shown by the cellular slime molds are happening in our bodies and during development. The primary example would be how the cells talk to each other when they're in the single cell state. So, they talk to each other with this chemical called cyclic AMP, and that chemical, it's like a relay. So, one cell releases cyclic AMP, and the next cell sees it and goes, "Oh, I'll release cyclic AMP, and then that passes along this chain." So, what happens is a bit like one of those Mexican waves, you get at a football match, where everyone just sees what their neighbour does, and it goes around the whole stadium. So, you get these waves and waves and waves, propagating across the population. So, that type of emergent behaviour is occurring in several aspects of our own physiology. So, if you have a cut, the cells that are surrounding the edge of the wound will have similar types of wave as they coordinate the closure of the wound. You see similar patterns. These waves, certainly on a two-dimensional surface, they form these beautiful spiral patterns. So, you can see these, just making recordings of electrical activity in the brain, you see these very similar patterns of activity. So, the contractions within our heart show the same types of what we call excitable behaviour, where you have one cell, signaling to the next and so on and so on and so on. What can you develop that a bit? I would say that if you wanted to study a lot of fundamental problems about, certainly, from my perspective, developmental biology and how you build structures in an organised fashion, biologists like to think of some sort of central control element that directs things or some sort of blueprint. But the more and more we look at how embryos develop, there's so much more which is about self-organisation and adaptation to the environment and then almost finding a structure and then modifying it to suit the environment and to suit the associated structures. Do you want to add to that? Yeah, I think it seems to me that one of the central problems of biology that's been around for a very long time is how parts come together to form complex holes and how these holes can be nested within even greater holes. And you think about our bodies, we have cells of certain types which come together into tissues which come together into organs, which come together into a coordinated feeling, wild, wet, you, you know, and that can explore the world into here talking about life. So these are nested systems of organisation and it's such a puzzle on so many levels, you know how do these cells communicate with each other, how the cells know what to become, when to stop becoming what they're going to become, how do they then coordinate with all the other cells. So in the sense that this is a big persistent question in biology, I think slime moulds, especially the cellular slime moulds can really help us to have a kind of model system where you can see the journey from a cell into a complex morphology which can differentiate into different cell types and regulate it as an integrated organism and so much for science is playing around really and I think they can really contribute to this endearing question of how the organisms acquire form and how the organisms develop into complex forms. And can we talk about how useful these slime moulds have proved to be for scientists? I'll talk about the cellular slime moulds if that's right. That's right, yes. So I think a lot of people who study slime moulds study them because in the single cell stage the cells look very much like the cells of our immune system, cells like neutrophils and macrophages. The job of which is to maraud around the body looking for bacteria and other things to eat and then going to a wound and stopping infection getting in. It's very difficult to study these cells such as neutrophils and macrophages. You can take them out of your blood but they're often dead within a few hours whereas you can slime moulds just grow on the bench but actually the overall cells themselves the way they move, even the chemistry, the biochemistry explaining why they move is highly related to these immune cells. And in particular the two features of immune cells that matter which is finding your prey which is identifying where the bacteria are and which a process we call chemo-taxis and then killing the bacteria, eating the bacteria which we call phagosytosis. So cellular slime moulds are experts of this. Can we talk a little more detail about how scientists are using these cellular slime moulds? To research diseases like cancer Alzheimer's, Parkinson's, epilepsy, bipolar disorder. They seem to be everywhere and they seem to be ever effective, can you give us a summary of that? Yes, I can. There are probably three parts to this answer and the first is probably the most boring part but it is what Jonathan has alluded to which is that we can grow the cellular slime mould, the amoeba, dictustelium very easily in the lab and we have strains of dictustelium that we can grow in flasks shaking about in an incubator which means we can grow lots of cells which means that we can look at the chemistry of something much more easily than we could have a look at a nerve cell or a component of us. There's a second part which allows us to really start to study complex things like disease in us which is that dictustelium was sequenced very early in the sequencing era and so it became apparent very soon that dictustelium through a slight freak of evolution actually has retained an enormous number of genes that correspond to our own. So there's cellular equipment that dictustelium has. Yes, so the reason I say that is because yeasts are a very nice eukaryotic microbe. They have complex cells like ours that they're fungi and you can grow them very easily in the lab but they seem to have lost a lot more of the human-like genes, although up on the tree of life I think even a dictustelium biologist would agree that you would think that fungi will be more similar to human cells but it just happens that dictustelium has an unusually large number of genes that correspond with ours and therefore if you're interested in a particular disease pathogenesis, how a disease progresses you can study it in dictustelium by looking at the gene in the amoeba that goes wrong in human disease. And then the third part of the answer is that dictustelium also has many parts of the way it behaves and its life cycle that are analogous to aspects of human disease. And I can list those, if you like, or income. - Okay, so some things that correspond really nicely with human disease in us are the migration, the motility of cells. So that's relevant to cancer cells when they metastasize. So we can study the adhesion of the amoeba, dictacy, them to a surface, and why it adheres and why it doesn't. And we can study how cancer cells might move and spread using that system. The migration of cells is also seen in wound healing. So we can study the good and the bad of disease. I mean, there are many aspects of dictastydium that mirror disease. But the neurodegeneration, one that you mentioned so Parkinson's and Alzheimer's, it has a couple of things where it's particularly relevant. In the case of Alzheimer's, dictastydium seems to be very resistant to the protein aggregation, the plaque formation, that's very characteristic of Alzheimer's disease. So some research is trying to find out what aspects of that you might employ to fight Alzheimer's. And then in terms of Parkinson's, which is the second most common neurodegenerative disease of aging, and many diseases of aging in human come down to a problem with the energy generation of the cell. So the mitochondrion, the compartments of the cell that makes energy. And dictastydium has a sort of fun feature, which is that if it has a defect in its energy generation, you will often see dictastydium amoeba cells that can't respond to light very well. And they don't develop very well in their life cycle. And when they do develop, they often have little short fat stalks. And so if you have dictastydium that has these particular appearances, characteristics, it's been found that the genes that go wrong are often ones that go wrong in human neurodegenerative diseases as well. So we can explore those cell and genetic pathways in dictastydium a whole lot more easily than we can in a human cell. These strange little objects seem to cover most of the territory, don't they? Do you want them computer scientists using them to ascending them into space? Who's going to take that on? I can have a go. The experiment I want to see done in space hasn't been done, which is to take a huge bucket of dictastydium or slime mold spores up into space and just release them and see do any live ones come back and can they actually see life somewhere on Earth? If we can label them and somehow, can we actually get spores to come through the atmosphere? I think this could be a useful way of colonizing future worlds, it was a bit far out. But in terms of what's actually been done, both the cellular and A-cellular slime molds have both been up to space. The cellular slime molds 20 years ago went up on a NASA expedition to look at the effects of both gravity on their formation of their three-dimensional structures, but also the effects of ionizing radiation on the organism. And actually they've found that the cells didn't really care very much, they did their thing. More recently, A-cellular slime molds fizzaram have been on the International Space Station again to look at behavior of these very large cells in a low-gravity environment. It was found that they have a more 3D-like structure, whereas if you see them on the log, they tend to be quite flat. So there was something learned about that. I mean, I think the most important thing is that these cells, they like surfaces. So I'm not sure how informative for the biology of this organism that's actually is, but it was quite interesting. It was a massive collaboration with a lot of school children who made the Earth's side measurements of fizzaram. How important is the slime mold for very small microbes? Cellular slime molds can teach us a lot about microbiology. They're a really good example of the complexity of microbial life. So I think perhaps there's an idea, in general, that we're incredibly complicated and super beings, but when we look at something like dictistelium, we start to understand just how sophisticated microbial life on Earth is. And if we look at the tree of life whole, not as Jonathan did at the start, but we really, if we include the bacterial groups, and we see how early off the tree of life, the amoebae that include dictistelium branch off, and we see that the fungi and the algae and animals are at the top. We have this illustration that even something is sophisticated as dictistelium is a microbe, and it's on a microbial branch. The world is microbial. And dictistelium also lets us study what's microscopic, because we can see stages of dictistelium. So I guess it makes that microbial world visible to us as well. Jonathan, what do we not yet understand, and by slime mold? I think for the last 40 or so years, dominated by technologies of molecular biology, we've amassed a huge amount of data. And we're drowning in data, really. I think the challenge really is to try and make sense of all that, to try and integrate all that information. And my feeling is that, and this is a problem for a slime mold research as well, but I feel that slime mold research has a manageable level of complexity, where we can actually answer big questions without drowning in information. So I think the challenges I see, for example, are how does cells really integrate information? We know that we have some good answers for how cells can integrate information from one signal, but cells are bathed in different signals all the time. The thing is like walking down Houston Road during rush hour, there's all these sites and sounds that are completely hitting them. And how does that single cell process all that information? I think that seems to be the biggest challenge. I mean, more generally, I would say, what you have here is a very, very successful mode of living. This idea that single cells can either aggregate or generate a very large cell, which makes spores. A beautiful example of this is, some of you may have seen the Terminator movies with Arnold Schwarzenegger. So in the later generations of the terminators, there are terminators that are made of liquid. So when their arm gets cut off, it forms this pool of liquid on the floor, which over the next 30 seconds to a minute regenerates the arm. So it gives the good guys time to get away. But what are the limits to this type of self-organizing emergent behavior? Could it build more complexity? Is there a restriction on this complexity? It's obviously a very successful form of life. Maybe it doesn't need to. It's very adaptive. I mean, that would be the more philosophical question, you know, what are the limits to this approach? And can we evolve something that could have more functionality? Merle, I'd like to come back to something we touched on earlier. And I think, listen, we're very intrigued to know, how do slimes change our understanding of massive things, like memory and intelligence and individuality? We said at the beginning, they were without brains, but they seem to solve brain problems, more impressive with the human intelligence in some ways. So can you give us your view on that? I think there are a few very interesting ways that they teach us about memory. And they're a cellular slime molds in Nepler's module stage. So these slimy vein-like networks have been challenged with all sorts of experiments. And in one memorable experiment, these networks were given an opportunity to cross a salt bridge, a salty channel leading to a plate of food or something delicious. And they didn't like to cross the salty channel. It's salty, it's uncomfortable. It's not something they would choose to do. But over time they explore, and over time, the ones that explore reach the plate of food on the other side of the salty channel. Now, given the chance to explore this similar sort of obstacle course again, the ones that had crossed the salty channel to get to the food, they were quicker to cross the salty channel again. They had somehow learned and had an enduring memory that this was something that they could expect in their way, some kind of response where they'd remembered that the salty channel was something that might lead to food. So what's interesting then, it's interesting, first of all, that they can learn in that way, associative learning, we might think of it as, although there are potentially other ways to think about it. But then when a slime mold that had learned was exposed to a slime mold that hadn't been exposed to the obstacle course, so you might say a naive slime mold, and they were given the chance to form a connection for around an hour, and then separated, the naive slime mold was quicker to cross the salty channel to the plate of food. And what's funny about that is that this, we usually think of memory as needing a subject, the subject in our cases, us, in my case, me, is the owner, if you like, of memories, the seat of memories, and it's something to do with my past experience that I'm recalling when I have a memory. But in this case, a self, the slime mold, naive slime mold, which had not experienced this challenge, did have the memory. The memory had somehow been transmitted from slime mold to slime mold. Without the second slime mold, the naive slime mold, needing to have that experience. So I think that raises all sorts of questions about selfhood, about the nature of memory, of how memories might be transmitted between different organisms, and certainly dislodges some of our assumptions about memory that we might have if we stood only looking at humans and other animals with brains. Does it dislodge our ideas of intelligence? What you're talking about is something that if we weren't using the word slime mold, we would say, "That's very intelligent." That's very intelligent. And so on. So you see slime molds that I can't list sort of pre slugs that getting in the way of me accepting that. I accept it, of course, I do. It's imagining how they can do without a brain, as you keep saying. What they do, which in some ways, sounds as if it's as intelligent or more intelligent, or things we do. I mean, the word intelligence has undergone some discussion in recent years within biological fields, and it used to be a word that were applied to the sort of behaviors that humans can do, because the cognitive scientists placed humans at the center of their inquiry, naturally, 'cause I try to understand ourselves. But over time, this is definitions of intelligence have deepened and expanded, and now I subscribe to view that intelligence refers not to something, it's not a property that one has or one doesn't have, that there are behaviors, which you might think of as intelligent behaviors, different types of intelligence. behavior that one might possess to a greater or lesser degree and you might think of those as being able to make decisions between alternative courses of action. You might think of them as being able to adapt to changes in one's environment. You might think of them as the ability to solve certain kinds of problem. And when you think about it like that, almost all organisms have some degree of intelligence because all organisms have some degree of intelligent behavior because they all live in a changing world. We all live in a changing world. We all have to solve different kinds of problem. The kinds of problem that humans have to solve are quite different from the kinds of problems that a plant has to solve. So we might miss the ways that the plants are sensitively responding to their environment in problem solving ways. If we only use human categories, so I'm very interested in how that debate has expanded and how it leads us into thinking about life from the perspective of different organisms and stepping outside our own human-centric perspective. I add something to that. The idea that an organism can know how related it is to its neighbours is something that we can see happening in these amoebae. But we can also see it in bacteria. So if you've got a different subspecies of a very common skin bacterium called Staphylococcusorius, that a community of those bacteria will know how. Millions of bacteria. Millions of bacteria will know whether their neighbours are related to them or not and will make decisions, according to the relatedness of the bacteria around them. There's another bacterium called pseudomonas aerogenosa, which is the one that infects you when you have cystic fibrosis, but it's a very common environmental organism. Iron is often a limiting nutrient in the environment, and pseudomonas aerogenosa will cooperate and produce a chemical that will grab the iron together as a community. So again, just this idea of intelligence in cooperation, it's our definition that's problematic as we learn more and more about life on Earth. We're coming to the end now, but still, Eleanor, what do you think this investigation into the effectiveness of slime-mills has had on the whole? How has it changed your view of how the world works? Well, I have two microbiology degrees, so I've spent decades bigging in terms of the complexity of life on Earth, but I love to think that our, well, Merlin's done an amazing job telling the world about fungi and how complex and interesting and widespread they are, and it would be great if an exploration of the amoebae, which sounds perhaps even less exciting, would make people understand that we live in this fantastic microbial world. All life on Earth is really microbial and complexity in life started really early on the evolutionary tree and we can use it to simplify our understanding of our own bodies in many ways. So I'm a great proponent for microbiology and I hope on that level that our understanding of these systems helps people appreciate the world that we're living in a bit better. From my perspective, I think that I've been working with slime-mills now for nearly 30 years. Before that, I was very, very welded to this almost religious view of embryology and developmental biology that there is a blueprint or a pre-plan for how an embryo is constructed, and I think I'd probably still be there without that exposure to a completely different way of doing things. In fact, for about 20 years, most people who worked on slime-mills believed in the blueprint model. I think revolutions in mammalian biology have very much allowed us to relax and believe what we want to believe again, which is that I think emergence is really, really important. Finally, last word from you? I study fungi a lot, which are network forming organisms that are capable of complex behaviors in this kind of bottom-up way that we've been discussing with slime-mills. And for me, slime-mills make it so clear they're really poster organisms for kind of brainless problem solving in my mind. And they illustrate something really fundamental because so many biogeochemical processes, so many processes that have really shaped the world over hundreds of millions of years, have been overseen and conducted by network forming organisms that have analogous behaviors. And so slime-mills for me are a gateway into a whole other way of being a whole way of living, which is not only vitally important today, but which has shaped the very conditions for existence. Well, thank you very much. Thanks to Merlin Sheldrake, I learned Thompson, and Jonathan Sharp. Next week, we take a break and we'll be back on the 16th of January with the Battle of Baume in 1792. We saved the French Revolution and cemented the Marseille-Eyes out of the National Anthem of France. Thanks for listening. And the In Our Time podcast gets some extra time now with a few minutes of bonus material from Melvin and his guests. What did you feel you didn't have to have to say that you were like to have said? Jonathan, what about you? Is it okay if we talk about slime-mills sex? I think we'll get that there with green flag. So it's probably more arcane than anything in the Julie Hooper novel, and I'll be brief. No, it's funky at the worst. What do you do at your time? So slime-mills get in the mood usually when it's dark, and they're starving, but in submerged conditions. So what that encourages them to do is that I should start by saying there's actually three mating types in the slime-mold I work on, so that's one more than us. But it almost doesn't matter which mating type you are, but when they decide that they're going to mate, they all come together and form this giant cell. And then in that process you get the nuclear fusion which characterizes any normal mating process. And then the fused nuclei segregate into little cells on their own. And then they proceed to eat all the cells around them. So this would be like this first matrimonial event being eating the whole village. So it's completely bizarre. Anyway, after eating the whole village with all that nutrition, they then form another type of resistant sport called the macrosist, which then sits around for a few months until conditions are better. What about you? Well, I think that slime-molds are a beautiful gateways into some of the so many strange ways to be alive. And there are so many phenomena, and even in animals, that are reminiscent of some of the things that slime-molds can do. For example, with flat worms, and you can teach flat worms tricks, they can be taught to learn something. If you cut off their head, they regrow a whole new head, a whole new brain. And they can still remember tricks that they've been taught with a new head and a new brain. So the question is where is the memory in their body then? Moths and butterflies can learn a new food plant as an adult, so they can they'll lay their eggs on a new food plant. And with moths and butterflies, caterpillars can be exposed to for the first time to a new food plant. And then they completely liquidate their body and reform into an adult butterfly or moth with wings. And they can somehow remember the new food plant from this earlier stage of their life, despite the fact their bodies got undergone a massive liquidation and reconstruction and reformation. And so this is a kind of phenomenon. I think opens our eyes a little bit more to the wild witness of life. And perhaps this lodges us a little bit from some of these more top-down views of development like Jonathan was talking about earlier with this kind of the single blueprint highway to an outcome approach. There are lots of ways to get where one needs to get in life. And so slime molds open up that world for me and I think a really helpful reminder of the many ways there are to be alive. There's another aspect to the the weird and wonderful behaviour of Amoebi that we've discussed today that is how many aspects crossover with the fungi and with the algae. And these are some of the really difficult groups in evolution that we've had real problems classifying them. And today there are still arguments being resolved as we get gene similarity across these different groups. But I think that almost the difficulty in understanding Amoebi and understanding fungi and understanding algae and what they are is a really nice way of illustrating that all of life on earth originates from one cell, you know, one point. So life on earth has evolved from a cell that had a set of properties and even though we have convergent evolution in many characteristics across we see similarities in many organisms that's not evolutionary preservation of genes. But this continuum of behaviour that we see in the Amoebi and across other groups really shows us that similarity. Yes, probably the last thing I would want to say is that because these modes of existence have occurred so many different times during evolution, they're obviously doing something right. So what is that? Can we learn from that? I mean. Do you think they're on the path towards perfection? That's a bit of a jump. Sorry. Well, we can roll with that. There's certain things that they do do very well. One is there's clearly distributed thinking. It's not I'm the leader that you do this. When they've exhausted their local environment they form spores and just chill out for a few years and wait for conditions to improve. You know, there's a limit to how much they can exploit. That's interesting when thinking about fungi and what evidence we have of fungi in the past. You see fungal networks which look very, very similar to modern fungal networks. So the morphological long history of fungi is one of kind of consistency, as if they hit on this way of life very early and haven't needed to do much to it. But look at the animal, the fossil reservoir animals. And you see a huge variation in form. This is a total like raccoco efflorescence of biological possibility in different ways of being different numbers of teeth and wings and all sorts of weird and wonderful ways to be. And so yeah, I like the idea that they sort of stumbled on this quite early on and haven't needed to do that much over all of these hundreds of millions of years. In our lists of the utility of digital stadium in the lab, so the uses of maybe in biomedical science, we didn't talk about drug development and understand. standing, how drugs affect our bodies. So of the many features of Dictastelium that are useful, having so many components of cells that are the same as ours, mean that if you have a drug and you treat Dictastelium with a drug, you can sometimes work out the mechanism of action. So that's been done in bipolar disorder and epilepsy. And looking at an epilepsy drug like sodium valproate, one of our colleagues has tried to screen new drugs that are less toxic using Dictastelium. So there's a whole area of not using animals for research here. So if you've got new drugs that target the same pathway that sodium valproate targets, there's a high chance that they might be just as toxic as that is and perhaps produce birth defects in the way that that drug can do. And then you, if you find anti-epileptic drugs that don't target that pathway in Dictastelium, you've saved yourself a whole load of very, very early biological research, admittedly. But it can be a really useful first screen for the genetics, the molecular biology, the protein biology, before you start to move higher up. I do anything to say about that, John, as long. I mean, I'm fascinated by the fact that this thing has influenced on these massive diseases, which you keep reading about very difficult to cure. We've gone one step forward in Alzheimer's. We don't quite know where we are with this, that and the other. And I just wondered how they went about it. I can give an example of a quite a devastating condition called acute, respiratory distress syndrome. That's caused by some information of your lungs. And this is caused by immune cells being overactive. So what happens when you, normally, if you've got healthy lungs, then it's not usually an issue. But if you have information in your lungs, caused by smoke, usually, or vomit, or something like that, then the first cells that get there are these immune cells called neutrophils. Now, they're a bit like, imagine suicide bombers, basically. They go there, and they kill, they start acting. And if there's any bacteria around, they'll eat those bacteria. But they're also pretty non-specific. So they'll start causing a lot of damage to the tissue. And of course, when you have more damage to the tissue, you get even more information, which means even more immune cells. So then this whole thing just sort of cascades out of control. So neutrophils on their own, for example, if you have a carton, you have this little yellow bit of pus, that's what they are. It's not usually a problem. Because what happens is that the next generation of or the next round of immune cells called lymphocytes come in, and they're much more specific. So they can mop up the bacteria without causing tissue damage. They also send signals out to the neutrophils, saying, go away, go away. So the whole wound then becomes a much more controlled environment. Now, one of those signals, it's called APR, is something that the slime walls use. So in the capacity they use it, is when they're feeding on a nice plate of bacteria, when the cell number increases so much and the amount of bacteria drops, they start releasing this chemical, and it's basically saying disperse, disperse, disperse. And it's the same molecule, and this molecule was identified in the slime mold, and is now being used in clinical trials for this horrible respiratory condition. Well, thank you all very much. That was a cracker. Thank you all very much. I really need a drink after that. Mind learning, discussion. So what would you like more of into your cooking? I thought you were going to say a whisky, or a pasta, a German tonic would go down there. I don't know. And then, what would you like? So you need the-- They need to be-- Yeah, yeah, yeah, yeah, yeah, yeah, yeah. I'll talk it to you later. 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