361 | Bonnie Bassler on How Bacteria Talk and Work Together

Hello everyone and welcome to the Mindscape Podcast. I'm your host Sean Carroll. As I am recording this, I just this week finally sent in the manuscript to my publisher for book three of the biggest ideas in the universe called Complexity and Emergence. I do apologize to everyone who's been waiting for this book. I'm not exactly sure when it's going to come out. I'll let you know when I do. It's supposed to come out around now, but that didn't happen since obviously I was very late, getting in the actual book. But it is going to come out. That is the good news. And so it's on my mind all of these issues of complexity and emergence. I've been writing about them quite a bit. And the last chapter, you know, the culmination of the book is on complexity. And a lot of that is about self-organization in different kinds of systems where you have a bunch of little things, whether they're cells or ants or birds or human beings or whatever, which have their individual motivations and dynamics and ways of thinking about what they do. And they come together to form something a little bit unanticipated. Of course, anyone who thinks about emergence and complexity knows that it's very difficult to define exactly what you mean by unanticipated in those contexts. But more is different is the motto that is usually thrown around here coined by physicist Philip Anderson. And the idea that as a system, whether it's an ant colony or, you know, sand in a sand pile, you can get behavior at the collective level that you would not have thought of just by thinking about the individual units that are coming together. And so I felt like in writing this, it's a topic that I've known I know quite a bit about, but not nearly as much as one could, because it's a sprawling gigantic topic. And I felt that very, very strongly while writing about it. Like the things that I did say in that chapter, which again is the culmination of the book. I loved, you know, I liked everything I said. But you know, you had to make choices about what to exclude, what kind of arbitrary classifications to invent to make this sprawling landscape of possibilities, more coherent, etc. We'll see how that goes over. I'm thinking about this and saying this right now, because today's podcast is a classic example of self-organization and one that I was not able to include in the book, even though I had really thought about it. The units in question are bacteria. So just about the simplest living organisms that you can imagine. And nevertheless, they have enough complexity to come together in interesting ways and do things as a collective that you wouldn't have guessed they were going to do as individual cells. And the mechanism for them doing this is something called quorum sensing. Quorum sensing was discovered back in the 1970s by Woody Hastings and other people. But the world's expert in quorum sensing is Bonnie Basler, who was our guest today. Bonnie was really the one starting the 1990s who explained, discovered and then explained the rest of us how quorum sensing works. So the idea is that you have bacteria and every individual bacterium does its thing in its kind of interesting ways. But then when you get enough of them in a region and a high enough density of bacteria, they are sending signals. So they realize, oh my goodness, there's a bunch of us grouped together here. We are now more powerful. We can do more things than we were otherwise able to do just as individual cells on our lonesome. So it turns out, this is not only cool and interesting to people who care about complexity and emergence for purely intellectual reasons. It's also super relevant to biology, including the biology of human beings. As we will discuss in the podcast, there's a lot of bacteria that you carry with you, probably at least as many, if not more, bacterial cells in your body as there are your cells in the sense that your cells have your DNA in them. And there's a symbiotic relationship. Those bacteria are doing really, really important things for you, just as you're providing a home for them. And so the dynamics of the bacteria working together and also how they fight off threats and how they symbiotically interact with other subsystems of your body are crucially important. It's a really fun topic in just about every possible way. It's intrinsically important because it's important what's happening in our bodies. It's intellectually exciting because self-organization and complexity is going on. And it's super fast moving and we're discovering new things every day. So I think this is going to be a really fun and educational podcast. Let's go. Bonnie Baster, welcome to the Mindscape Podcast. Thanks for having me, Sean. I'm delighted. I got to start. I don't usually start this way, although a lot of other interviewers do. But what is it that got you interested in bacteria of all things? Like were you a young girl saying like, it's bacteria for me? As I'm sure you've guessed new, that would be hard. No, no, it was an accident. When I went to college, I thought I wanted to be a vet. Because I like animals, I like nature. Sure. And so I started on that curriculum, but it turned out I don't like gore at all. I like live animals. So that didn't last very long, but what was lucky is I was taking biology classes and you know, about chemistry classes. And I loved the curriculum, but I didn't know what I, what one could do with that. And I liked my lab classes. So I went to a professor and asked if I could work in his lab. Thought I would try that. And he did let me. And he had two projects, a cancer project and a bacterial project. And of course, I was 19 years old. I wanted to cure cancer. That's how they're very important. Still sounds very important. But he put me on the bacterial project. And at first, I thought, oh, this is a trick. It's like you have to prove that you're earnest and hardworking. And then he'll take me off the fake project and put me on the important project. Well, it's a few years later, Sean, as you know. And I still work on bacteria. And so the truth is, is that in that undergraduate experience, I just found bacteria to be the fantastic model system, you know, these stripped down versions of us, if you will, that I could wrap my head around. And you're going to see during this hour, I'm very, and you already know me, I'm very fast talking. I'm very high energy. And so, you know, like you could have a surprise in the incubator every eight hours. You could spill it on the floor and it didn't really matter. You could do it again the next day. And so it's just beyond the, the repeat how fast you could do experiments and get results. The, I thought then it was the bacteria represented something that I could understand. And you know, still haven't figured it out. So that turned out not to be true. But it just ended up being the right system for me to ask the kinds of questions that I like to ask. And again, to long answer to your short question, it was such a remarkable lucky accident. It was an accident. But in some sense, it's an example of the system working, right? Like you didn't have a preconceived idea what you were going to do. The hack a DMEF forced you to try something new and you're like, oh my goodness, this is it. Yeah. And I, I do wonder like to that question, I think if they'd have put me on a fly project or, you know, maybe I would have loved that too, right? Because what I love is making discoveries. And, and then I don't do this as much, you know, working with my hands, you're doing experiments, trying to put these puzzle pieces together. So I do always wonder if it would have put me on that cancer project. Maybe I'd be working on cancer. But anyway, lucky, lucky me. And I remember vividly, you came years ago to give a colloquium at Caltech to the physics department. And afterward my grad students, like, you know, came up to me and said, and they were just amazed because like there's many amazing things. But one of them was it's so easy in biology to ask a question. We don't know the answer to and then answer it. Like in particle physics, that takes decades, right? Well, and in cosmology, you guys don't even get to do an experiment, right? Not really. Right? And so I do think, and then of course, for me, that's very satisfying, right? Like that, and that is the attraction to me is that you can ask these questions and get seemingly definitive answers. Obviously, they give you your next question. If you're doing it right, it leads you to your next quote, why that? Your next question, but I do like that part of it where, you know, it's not always clear cut and you have to do lots of experiments. But in the end, you get some clarity by the things you did with your own hands. And yeah, and so that, I think I love being at the bench. Yeah. So what do we need to know about bacteria for the purposes of this conversation? And especially the bacteria that live in our bodies, which apparently there's quite a number of them. More than more cells than yourselves. But yeah, so what you need to know for this conversation is that bacteria talk to each other. They are multilingual. Their language is chemical and they're very good at math. So they can, they communicate to be more serious with you. What I think will probably spend a lot of time talking about today is what my gang is always trying to figure out. So if I can just go back for a second to really answer your question. What my gang has always been trying to figure out is how to bacteria get any bank for their buck, right? They are so puny, they are so primitive, right? They're single cells. You can't even see them with them without a microscope yet. They do all these terrible things on Earth like make us and animals and plants sick, but they also do all these miraculous things on Earth like you just alluded to like they live in and on us and they keep us alive. They keep plants alive. They clean up the environment. They do all these fantastic and terrible things. So those are facts. What my group is always interested in is how can they manage to do that? They're so tiny, yet they have this remarkable power. What we've shown is that the way bacteria get their power is that they work in groups and they carry out tasks as collectives, as teams, that they could never accomplish if they acted alone because individually they're too small to make a difference. But if they have used collected behaviors and they all do things in synchrony, they can accomplish tasks that they never could otherwise. And so the way they manage to do that is to communicate with chemicals so that they know one another is there. And so we call this process of bacterial communication and group behavior, quorum sensing. And I guess I'll just tell you how it works. So the way it works. Actually, you know what? Don't tell me how it works now because you're going to get there. I want to like, you know, because the idea of quorum sensing does come as a surprise in some sense. Like it's a pretty sophisticated thing. So I want to make sure we soften up the audience to let them be surprised by talking about just how primitive bacteria are. Arguably, they're the most primitive life forms. Correct. Yeah. Yeah. They, okay, I wasn't actually there, but they arrived, arrived, they evolved on earth right after oxygen, right? So they're, they have been on this earth for billions of years, like four billion years. They are, we think, Earth's first living organism, right? And so they are the most ancient living organisms that we know of and they are all single cell, right? They're, you know, microbes, you must have a microscope to see one, right? And, and you know, they only have a few thousand genes, so a few thousand bits of information in their DNA to give them their physical form and their traits. And you know, people have known scientists have known about bacteria for almost 600 years and they were first observed by Von Lee and Hoke, you know, who was like a microscope maker. And, and, and, yes, and a male kills, yes, exactly. And so, you know, you scrape and stuff off his teeth and do it like that. So anyway, so they've been known for almost 600 years. We've known they cause disease for 150 years. But they've always, until about 30 or 40 years ago, when this notion of quorum sensing, and we can talk about how that happened, sort of came about, they were always thought to be these A social recluse, meaning that they were so primitive and so simple, that there was no way they could have what you just said, sophisticated behaviors. That was the purview of you, Kariots, like, like bacteria gave us the parts list. You know, we got DNA, RNA proteins from bacteria, right? But the cool stuff, you know, behaviors and development and thought and all those kinds of things, that's all in higher organisms. And so there was some kind of snobbery, including among us, the bacteriologists, right? That they just didn't have the wherewithal to communicate or to do things as groups, because those seem like very evolved behaviors, right? But then if you think about it, right, we all came from bacteria, you know, where you think the stuff comes from. And then again, going back to what I said that started this is, if you think about all the profound things bacteria can do, good or bad, how could we have thought for so long that a tiny little bacteria could do all of that, right? You know, and so now I have to say, you know, now that Cormson's thing is an established field, we get the bacteria working groups. And when you let me tell you how it works, but anyway, we get that they work in groups, we get that they, you know, carry out these tasks as armies, right? When you think about it in retrospect, I spent a lot of my time thinking like, why did you take us so long to figure that out? It had to be like that, you know, and so in retrospect, you know, now it just seems, it actually seems obvious now. But of course, that's after a discovery gets made. If you're like me, you like money, but you don't like dealing with money or thinking about it, why can't it just take care of itself? Sadly, that's not going to happen, but Monarch might just be the next best thing. Monarch is a financial management app that doesn't just tell you what you've already spent, it helps set goals, understand what you can afford, and see trouble coming before it arrives. Monarch helps you view all of your finances in one place, letting you see where the money comes from, where it goes, and that can help you understand your financial situation better, whether you're focused on coordinating with a partner or paying down some debt. You can use Monarch to help with everything from splitting the bill when you're out with friends to tracking your savings for a large purchase. 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We're talking automated lead routing for your sales teams, seamless AI integration, and an intuitive, point-and-click website builder. It's everything your business needs to scale, saving you time, headaches, and money. So stop piecing your software together. Go to odo.com/mindscape. It's simultaneously amazing to me that the idea of bacteria, this domain of life, has been there from the start. The bacteria don't go away when other species come on board. But we don't know what the earliest bacteria looked like. You mentioned they have thousands of genes in them. We probably have lost. The first bacterium didn't have thousands of genes in them. We probably have a little idea of what the most primitive bacteria never really looked like. No, probably not. The notion now is that these organisms, this domain that we call the archaea, old, are the ancestors of the first living organisms on earth. And that is because those microbes live in really hostile environments, like they live in thermal vents, or really cold places, or dry dusty places. So they seem to be able to thrive in places currently on earth that are the closest to what we think earth was like billions of years ago. You know, there's a bubbling, volcanic flats and things like that, right? So we think that those are the current ancestors of whoever were those first living, replicating organisms on earth that were presumably were microbes. Right. And the earth, what? So there's sort of vestiges and they inhabit these places like in Yellowstone, right, where the geology is not done. That's where these archaea live. But archaea are different than bacteria? They are indeed. Okay. So there are three domains of life. So archaea gave rise to both bacteria, prokaryotes and eukaryotes. And archaea, gene, archaeol, genome is actually more like eukaryotic genomes than bacterial genomes. Yeah. But then, but then those archaea are, they are relegated to these hostile places that are currently on earth. And then the bacteria came and they are nearly all of the biodiversity that exists on earth, right? So just everything that exists on earth, you have not seen with your eyes, right? So even most eukaryotes are microbes. Right. Yeah. Okay. And so, like if you look at, I wish we people could see us because I'm usually just articulating wildly so they can just imagine me, you're seeing me. But, you know, when you look at these trees of life that we now, you know, can make because we have genomes, you know, and you see all the bacteria are huge. Our care are a little few branches, eukaryotes are a lot of branches, only one tip of one little branch of those eukaryotes is every bug and animal and plants and person and tree that you have ever seen, right? So the world is microbial and it's mostly bacterial. All right. And yeah, we have a very uneven view of the world unless we're a professional bacteriologist. And I guess I was going to say, and I guess you see my bias, right? So yeah. But I'm right. That's all you say. And I do think that a lot of us have a prejudice that bacteria are things like that our main job is to wash our hands to kill them, right? But in fact, they're helping us along here. We're a little bit symbiotic. There is no life on earth without the bacteria. And again to your point, right? It's not so we can say so we every other organism on earth lives in this magical, wonderful consortium with microbes in you and on you. Right? And they are contributing their genes and their proteins to keeping you alive and healthy. Right? So first of all, they take up all the real estate, you know, in and on a bad microbes, you know, can't, you know, if you eat them, you know, the real estate and your gut is taken up by what we call your microbiome. Your skin is covered in a biofilm of your microbiome that keeps the suit of armor, that keeps back ribs from being able to get a toe hold. You know, they do all these functions that our own genes and our own bodies can't do to keep us alive. Come to your point, we do have this. It's changing now. Like people are starting to understand the magic and the health benefits of the microbiome. But of course, you only feel and I mean that in in not not my emotional feel like you're physical, you feel your microbes when you're ill. It's not like you get up every morning and you thank your mic your microbiome for helping you digest your breakfast, right? Or for keeping you alive, like the only time you noticed that you that that microbes are part of your existence is typically when you get sick. And of course, if you think back to 150 years ago, when you're past your and all these people are trying to figure out microbes, how could they possibly know that we had these microbiomes and for a long time once it was recognized that there were bacteria in an honest, honest scientists thought they were just passive riders. You know, it's only recently, you know, with the advent of all the technologies and and genomes and the understanding we have now about the natural world that we're learning about this mysterious microbiome, right? It's a new field of study. And so it's not so there's a reason that for as long as people have recognized bacteria as pathogens. They never associated them with the good stuff they do because bacteria are invisible. Yeah. And you can grow without these bacteria in the soil. I mean, they, you know, nothing happens on this earth, down to bacteria, but since you can't see them, you only really think about them. When something terrible happens, right? And like I said, there's more cells of bacteria in our bodies than human cells and the trick is not all cells are the same size, right? Correct. So we're mostly human. Correct. So right. So a human cell is, you know, 500 or a thousand times bigger than a bacterial cell. So yes. So the idea is you have the current numbers and these change a lot, you know, as we learn more and more. But the numbers you have 10 times more bacterial cells than human cells in your on you, a hundred times more bacterial genes than human genes. But you're right. Human cells are much bigger. So you have about five pounds of bacteria. So when you say I can't lose that last five pounds, you can't. It's the bacteria. Now I know. So you don't have to. You can't. All right. It's extremely helpful. It's still five pounds. Yes. Thank you. How many of you are serving? That's, that's not trivial. Okay. There's a lot of bacteria in me. Good. Yeah. Good to know. I'll try to, I'll try to be nice to my to my gut microbiome. Yeah. Okay. So now I'm going to let you all the leash a little bit. We have all these bacteria, but any one bacterium can't do that much. Right. So the secret to being an effective set of bacteria is that they can talk to each other and group up. Correct. In my view. Yes. And not just my view. That's a fact. But that is also my life's work. And so I do think that's how they accomplish so many. Of the good and the bad things and we know that for a fact. So that's quorum sensing. Right. And so the way it works is that bacteria. They consume nutrients from their environment. They, you know, double their size. They double all their components that are in them and they divide in half. And so one cell becomes two becomes four becomes eight. You know, so they just divide a sexually. And then what they also do is that they make and release more molecules that you can kind of think of like hormones. Right. And so as the bacteria are growing in number, you know, more cell since each of the bacteria is making a share of these molecules and releasing them into the environment. The amount of these molecules around the cells increases in step with the number of cells present, right. More cells, more of the molecules. And when the molecules hit a particular amount, the back that they get above the threshold that the bacteria can detect. And when the bacteria detect the molecules, they infer from that detection event that they must have neighbors around. And so in unison, all of the bacteria change their gene expression, which allows them to make new proteins to change their behaviors. And they begin to in synchrony carry out these group behaviors. Right. So they don't have a clue. The bacteria really have no clue how many other cells are around. They're using these the build up of these molecules as a proxy for cell number. And so if I can't antipromorphize, which you are, you know, I do because I already they believe, if you will. If these molecules are at high amounts, it must mean there are other cells around the quorum is there. And if they all change their behavior together, these tasks that they couldn't accomplish when they are when there are few cells presence, they can accomplish when they're together. And so good. So the molecules are their words, if you will. And so the phase transition, can I call that as a physicist? Is that fair? Sure. Yeah. Yeah. Sure. And it sounds like you already anthropomorphizing, which is fine. I think I think we're, you know, sophisticated enough to know what it really means. But there's also this question I always, I sometimes tease my biologist guests, because sometimes, you know, nature does things in such an exquisitely nice way that you see why people would think it was intelligently designed. Right. Yeah. I don't think that. Exactly. Neither do I, but this is kind of like the opposite. This is like exactly what you would expect if everything in nature was just working with what it had and throwing things together and seeing how things could work out. Is that fair? Yeah. I think so. I think that probably, you know, a billion years ago, whatever this one, when quorum sensing evolved, we know these molecules, they're very simple. They're very cheap. They probably just leaked out. They were like just byproducts of metabolism. They leaked out. As soon as you leak them out of a cell, there is a number component, right, because they can build up. And then a bacteria, me evolves a receptor, right, that detects that molecule and, and, you know, and they're off to the races in terms of quorum sensing. Right. And so, yeah, I don't, I think that they probably were leftovers at the beginning, you know, and, and. But being able to detect them and the fact that every cell makes it share, you know, that the concentration of these molecules, we call them auto inducers, you know, because they auto induce the bacteria to do something. That's what we call them, you know, that those those increase in proportion to cell density. Right. Because of because of biochemistry, right, because of the way they're made. They decay away eventually, otherwise I would think they would do sort of humiliate. Yeah. Well, they do. So they do the first foot. So they do decay away, right, or they get washed away or the bacteria get washed away and then they're alone again. And so, right. So they have to start making them again, but they do they don't look they're not. They don't last forever. They're signals so they end different. Some of them are more delicate than others. So presumably, bacteria want long lasting and short lasting signals. You know, and so what I should tell you before I get to that is that there are multiple words in this lexicon. So it's not so. Of course, we don't know everything about every bacteria, but in these model systems that we study, there are molecules, for example, that one and as far as we can tell one and only one species of bacteria makes. So that molecule says you are my twin, you're my clone. Then there's a molecule that all the bacteria in a family make. So they say you're my cousin. So you're related to me, but you're not my twin. Then there's a molecule that all bacteria make. It's sort of a universal language that says other. And so not only are the bacteria measuring the buildup of these molecules. They're actually measuring the ratios of these molecules when they're in these these consortia with lots of different species present. And so what we think they're doing, they're asking first, how many bacteria are here. Then they're asking, who are they? Is it me and my kin or is it the enemy? And then they actually change their behaviors based on who's in the majority and who's in the minority. So like when you and your kin, your siblings, you know, are all together, the bacteria make all these public goods. They release all these goodies. Everybody shares and is in in this large. And they all succeed. But like when they're around their enemies, sometimes they flee or sometimes they try to kill the other guy they make antibiotics that they kill off their competitors. And so they do different things. So what we see is that they're going to be able to do a lot of things. think now is that these molecules encode something about the number of cells that are present, but also something about how closely or distantly I am related to my neighbor. So there's a lot of information in these little molecules, right? And then I guess I should have said the kinds of behaviors, I didn't talk about that, that I think your audience is already inferring this, the kinds of behaviors that are controlled by quorum sensing are, as we've discussed, ones that take lots of bacteria to make the behavior successful. So let's go back to the traditional one, pathogenesis. So when a harmful bacterium or a few of them get in me or you, if a couple bacteria dribble out a few molecules of toxins, nothing would happen to me, right? But if they wait and they count themselves and they recognize when they have the right number, that if they all launch their toxins together, they can overwhelm my immune defenses and make a productive infection. The same thing goes for all these good things, like when they're making us our vitamins and they're making us all these products that we need in the microbiome, you get it, a one bacterium, it's inconsequential, the amount of anything it can make. But together, it's public goods, I get the benefit of what you do, you get the benefit of me doing, then these bacteria succeed, the eukaryote meaning the human or the plant, you know, may get sick or may get healthy, but the bacteria succeed in their task, right? We're the ones that say the task is good or bad. Right. For them, these tasks are all good, right? If you personally got a bacterial infection, would you feel a little betrayed? Oh, yeah, I really know. Whenever I get, have a cold, I also work on viruses of bacteria, so whenever I get cold or I get a bite, I am just like, oh, my life's work. Right? I should be immune to all of that, but I'm not. Yeah. So you started to go down the path of like, so what do they do when they do sense all their friends? Like you mentioned that they help with our digestion and there's these biofilms, are these the kinds of things that are triggered by the core sensing? Yeah. And so biofilms are how we think, are the predominant way we think that bacteria live in nature, which is adhered to a surface, surfaces, you know, covered in this group. And so the biofilm you know about mostly is the one on your teeth every morning, right? You brush that gouge off and it's back there the next day. That is a bacterial biofilm. It has 600 species of bacteria. It is architected, right? Every day you get a cavity. They're just eating, right? And thriving, right? And so those are biofilms, but your skin is covered up a film every surface on earth. Animate or inanimate is covered in a bacterial biofilm, right? And so they live like making those communities covering themselves in this like goop that keeps them from being desiccated. It keeps your immune systems away from them, keeps them, you know, it locks them to the surfaces and makes them resilient. Those are all community behaviors. One bacterium can't make a biofilm. And then collectively these biofilms can make all these products, you know, toxins or beneficial products, you know, that these communities make. Okay. Wait a minute. Same war about the fact that every surface in the world is covered by a biofilm. I didn't quite know that. There's nothing more to say about that. Sean, every surface on this earth is covered in it. Absolutely. The piece of paper you're talking about is covered with a biofilm? Well, probably when you took it out of the package, it went through some, you know, heated up horrible sterilization thing, but pretty soon it is. Yeah. Certainly. Yeah. Everything. And does, but the one's the one on my skin, I'm getting like the creeped out here, but okay, there's like bacterial biofilm on my skin and that's helping me. It's a suit of armor, like you said. Correct. So you can get a skin infection, you know, when you have an invader there, but no, that biofilm that you can't see or feel that's on your skin is covering up all of the surface and keeping bad bacteria that happen to land on you that you can't also can't see or that you run into from getting any real estate. And now your skin's a funny thing. Your skin, you know, you make new skin cells and you slough them off all the time. It's part of your defense against predatory bacteria, right? But your skin gets colonized again and again and again. You know, by these bacteria that keep us healthy. So going back to the evolution story, you said that making the chemicals is pretty cheap, but I don't know quite know how to quantify that. I mean, at some point, it's probably the way that evolution works as far as I can tell is they started making chemicals without any benefit. And they realized there was a benefit to it. So it's sort of locked in genetically. Correct. So I think that so when we look at the what again, we don't know what all the molecules are, right? I need a job. So try to figure this out, right? But the molecules, they're not like fancy molecules with lots of parts. They're very simple and they we know how we know, excuse me, how many of them are made. The ones we've discovered and they're made from very ancient substrates like amino acids, you know, fatty acids, very ancient central substrates that every organism has, right? And so they're kind of cheap. And when you look at them, they look kind of like, you know, these reactions were happening to make something. And this was the leftover. And it probably got leaked out like it was garbage, right? It just got leaked out. It's just a leftover. And over time, it got co-opted by evolution to be a signal because it's leaked out the bacteria basically swimming in it, right? And so if you can evolve a receptor that binds it and sends information into the cell, right? Because these molecules were leaking out the more cells there are, the more of these molecules there are, right? Then you can evolve a signaling system to have information encoded in those. I mean, that's the guess, right? About how form sensing started. And about being locked in, oh, it is. Because when we now we have bacterial genomes, you know this, we have the human genome, we have zillion genomes, right? Chorm sensing is the norm in the bacterial world. Like, so when I was first, we were first discovering the first of these Chorm sensing were like, wow, you know, there's some crazy anomaly of some obscure bacterium. Well, that's forward 30 years. And we look through these genomes, right? There are tens of thousands of cases of Chorm sensing, you know, we can see these genes throughout the entire bacterial kingdom domain, right? And so it's not a one off. And so I think that in, I'm guessing, you know, in evolution, the ability to have collective behavior, you know, it changes you from being a subsistence farmer to living, you know, in New York City, right? Where there's the car mechanic and the grocer and the librarian. You don't have to do everything yourself, right? I mean, that's a little bit exaggerated right here. If you can share and have, you know, I do a little work, it's Chorm sensing. I do some work, you do some work and we all succeed more, right? I think that that's an amazing step in evolution. And of course, you know, we know that in, you carry on it, organ, I mean, our own cells, you know, your kidney cells work together, your liver cells, you know, work together and the herds of wildebeest work together and wool, plant them, you know, in fishes. So you know what I mean? And like we understand the value of collective behaviors in organisms, you know, that we see with our eyes or even in cells in a higher organism. And of course, we came from bacteria. So these rules, you're how to make collective, you know, why wouldn't they have evolved billions of years ago? And yeah, you and your liver cells and kidney cells have a few more bells and whistles than my bacteria do, but the bacteria made the rule shot, right? Right. They're first. Yeah, they get credit, right? Yeah. They get the priority claim. Yeah. And it's a lovely example of self-organization, right? There's no boss bacterium that is telling all the other ones what to do, but they can work collectively. Correct. And it's, yeah, so there has to be, yeah. So they're just doing it, you know, so are there leaders and followers? We think about that a lot, right? But in the end, it's just, you know, again, I don't want this to be thought. I don't want this to be intelligently designed. They are making and releasing these molecules as part of the biochemistry that happens in these simple, single cells, right? And so you can get this emergent behavior without a boss. Right? Yeah. Do those chemicals do anything else that we know of? The little molecules? Yeah. So as far as we know, as far as we know, they are dedicated signal molecules in that the bacteria can't eat them. They don't, I'm going to be careful with this. They don't eat them. They don't grow on them. They don't have other functions. But so that's what we think. They are dedicated, quorum sensing signal molecules. They are now for counting. Now it could be that there's lots of bacteria that we haven't studied that maybe they have multiple functions or they, you know, they're still just leftovers and nobody's figured out, you know, to eavesdrop on those. But for sure, in some way, so the thing you might begin to, there's cheating and free writing and trickery. And so for example, when you ask me, do they do anything? So there are examples where one species of bacteria makes one of these autointucersia, a molecule that it and its kin tune into and they say let's do collective behaviors, right? Let's, when it builds up to the threshold. But other bacteria, if they tune into it, it's actually an antibiotic, so it kills them, right? So, right? And like you, so, so that that's just based on the structure of the molecule that it's deadly, it's toxic to one bacterium, but not to another, right? But you can imagine that that's a really good molecule to make because you can kill your competitors, right? Who are, you know, because there's a lot, there's all kinds of in these systems, so that's a dual function molecule, right? Because in these systems, remember these bacteria mostly don't live in test tubes in Princeton, New Jersey, you know, in these pristine environments, right? They live out in the wild west. And so there is in these quorum sensing systems, there is all kinds of attempted and cheating and free riding and eavesdropping, because like the one good thing to do is I make the molecule, but I don't turn on the genes that are really expensive, which are all the public goods in the task, right? Or I, you, my competitor make a molecule that you're trying to count your cell numbers and I, your competitor, make an enzyme that I clip that molecule in half. So you're trying to count, and I'm over here in the dirt trying to make you mute, because, right? And so we know all kinds of that were different species that live together, you know, make, make mimics or trickery, you know, and so somehow there's gotta be little anybody policeman around that are, you know, making a punishment for cheating, right? And so people are now trying to figure out how all of that can possibly work, you know, outside of an academic lab, you know, where these creatures are actually living together, you know, each with their own priorities that may not match. - It sounds like a perfect thing to study using game theory. Do people do that? - For sure. - You guys and your types love this. First information theory, like how much information is encoded in these, like how many bits of, you know, and game theory, and also like evolution, you know, like these ideas of these evolutionary biologists, which I am not, you know, think about like, when these, like you have these population crashes or tragic of the tragedy of the commons, right? Where you're making public goods, like bacteria really great to study those kinds of things, because you can do it on a peachy plate, you know, you can actually do a real experiment. It's not just some public park or it's not a right that goes to heck, right? You know, because nobody's in charge of keeping it, not, I don't know if that's making sense, but yeah, I think the physicists have loved this stuff, right? Because it has the features that they like to think about, usually about humans, right? But in fact, you know, it is game theory, right? - Yeah, it is. It's all, it's not intelligently designed, and it's all stuff obeying the laws of physics ultimately, and physicists love simpler things, rather than more complicated things. - Exactly. - And so bacteria might be like the simplest things that have little coordination and good and evil games, heroes and villains here, cheating cooperation. - For sure, and I think another reason that, that again, this goes back to you, is to be how you work on bacteria, that's so attractive about thinking about those kinds of big questions, you know, how did cooperation and cheating and what does it take and what are the rules, you know, evolve on earth, what's great about bacteria is that we can make mutants, right? You can't do that with humans, right? So we can make a cheater, right? You're not supposed to, yes. Okay, but we can make a bacterium that only makes the molecule, but doesn't turn on the traits. We can make a guy that's deaf, right? We can't detect them and we can then ask in a real experiment, who's harmed, who benefits, you know, what happens, how do you evolve a cheating strategy, right? Like because we can, and we can also make these molecules synthetically in, you know, bottles, right? And we can add molecules when we want and which molecules and blends. And so their bacteria are just so fantastic to work on because you can at least begin to get at the kinds of questions that would be absolutely unethical to try. Or, you know, or you can't do it, like you can't, like there may be a lazy lion in a lion pack, right? But how do you actually study it and get, you know, right here we can do that and like get answers, right? So, so, so, so, and then again, to the point about the physicists, right, is that it's really, really attractive because we can amass data, you know, experimental data that they can put into their models, right? About how these things work. And so that's been, that's, so, so, I think that Cormson Singh has been a real boon to these kinds of cross-disciplinary collaborations. So I've collaborated with Ned Wiengren, who's a theorist who has never picked up a pipette, nor should he. And yeah, for 25 years on like how this system works, for exactly the reason that you're saying. - Have you ever visited Santa Fe Institute? - I've never been, oh yeah, I have. I did, I went to one of those physics meetings and I've gone to the physics meetings and asked, "But yeah, I have a lot of cards, I have a little gold star." Yeah, physicists want to be, yeah. - Yeah, everyone is. So I think you started talking about, you know, the different things that the bacteria can do when they are cooperating in Cormson Singh, but I'm not sure if I gave you the chance to like, really go through some of the fun examples. I know the bioluminescence is probably my favorite example. - It should be, it's the founding example, right? So it is the founding example on which the Cormson Singh field was built, right? So remember, I'm not remembering that sounds, I don't mean to be, bacteria are invisible. So if they're doing something together or something alone, how could you know? You can't see them, you can't see their traits, right? And so you can ask how did Cormson Singh get missed for the 500 years of that we've known about bacteria? It's because it's all invisible, right? And so what was so remarkable about how this field started, is that it started in bioluminescent bacteria. So bioluminescent bacteria are very common in the ocean, right? So they make blue light, you know, fireflies make yellow light, blue light travels far in the water. So things creatures in the ocean make blue and green and purple light, right? And so almost everything in the ocean either makes or uses somebody else's light, 'cause you don't have to go very deep and there's no light, right? So the selection, the evolutionary selection for bioluminescence is really high in the ocean, not so much on earth. And so anyway, a fabulous scientist, sadly now deceased Woody Hastings, these guys were all at Harvard and they used to love to hang out at Woods Hole, right? And everything is twinkling and making light in the ocean. And so he just loved bioluminescence, not Cormson Singh, but bioluminescence, like how could biology make light, right? You know, it's so, I mean, we love fireflies, right? It's so captivating. And so he was studying Luciferase, which is the enzyme that makes light. And then he is the one that discovered in these bioluminescent marine bacteria that they would grow for a while, you know, in a flask, and they would make no light. And then all the sudden, all the bacteria would turn on light together. And what was so powerful about that is that it made the invisible world visible to the scientist. It, right, you know, he's like, I mean, I'm just saying, you know, why don't they make light that all of a sudden they do make light together, right? And so it gave us something we could measure. It gave us a trait we could follow, right? And it showed that the bacteria were doing something together, right? And so that's how this field started was because these bacteria made this visible output of quorum sensing. You know, and now again, going back to what I said, we know it's the norm. We have all these ways to measure genes and behaviors and things that we didn't have in the 1970s when Woody Hastings discovered this, right? But that was the way in. - Do we know exactly, okay, so the quorum sensing tells the bacteria to, it's time to light up, right? It won't be just a waste of your time because we're all worth in this together. Do we know how the individual bacteria make light? - Yeah, oh yeah, right? So they have an enzyme that we call Luciferase, which when it does, so there's a little fatty acid, there's like a fat that's the substrate. And when Luciferase does its reaction, right? It, which is just a biochemical reaction, it lets off a photon of light, one out of every 20 times, right? And so, and that light, that photon, the wavelength of it happens to be blue, right? And so it's, you know, and so it is similar to what fireflies are doing. So, fireflies have Luciferase and Luciferin is the substrate in fireflies and they carry out this biochemical reaction that photons of light get emitted when the reaction occurs. - Is it a quorum sensing story in fireflies? - No, so it is not, no, that's about sex. And so, right. So, what's really interesting is that we think that Luciferase, the enzyme that makes light, that that evolved twice on earth, once in the ocean and once on land. And so there's nothing in common between bacterial and firefly Luciferase, except that all Luciferase need oxygen as one of the reactants. But, yeah, so fireflies are trying to find girlfriends and boyfriends, they have a, they have a timing. You know, so fireflies emit yellow light, which is what you see at dusk, right? And so they're trying to find each other, you know, and there's a pattern and they're following that light to be able to to mate. Okay, good. Thank you for that. And back to the bacteria who are the stars of their story. They also though, as I understand, the quorum sensing comes in when they want to do something bad to us, right? Like when they want to attack or maybe when they want to defend, like part of the battlefield, the bacteria is certain weaponry is turned on and off via quorum sensing. Is that right? Absolutely. So I think though, so for sure, so we know all of these clinically relevant, globally important pathogenic bacteria at the baddies that if they don't have quorum sensing, you know, like if we make mutants that either can't talk or can't hear, which we can make, right? They are completely a virulent because they're repertoire of virulence factors, toxins, poisons, you know, things that let them enter into yourselves. Those are all under quorum sensing control, right? Because for the reasons we just talked about it, you have to have the army do it together to have an effect on the host, whether the host is an animal, a human, or a plant, right? And so again, I think the way to generically think about quorum sensing, if a bacteria is going to give something a way to the world, a toxin or something good, it never gets its own back, you know, the world is huge and bacteria is fun. So if I release something, you know, a toxin, it's gone. And so the only way I as an individual bacterium can get the benefit of that toxin is if you do it, right? And so synchronizing these behaviors where I get the benefit of your work, you get the benefit of my work, right? Because we're doing it as a collective, you know, we get that's like very common in pathogenic bacteria and in beneficial bacteria. And I guess I should do one plug for your listeners who I know are very sophisticated and like science for the sake of science. You know, there's a real industrial biomedical agricultural part to this, right? Which is scientists have now learned about quorum sensing, good or bad, right? So if we can beef up quorum sensing in beneficial bacteria, either in humans or industry or agriculture, or we can interfere with quorum sensing in these harmful bacteria, right? Those are applications that are being made now based on, you know, learning about these crazy bioluminescent bacteria really that started this, right? And now there's a very, there's many, many people scientists working on these applications, you know, based on what we've learned, right? So I do want to make a little plug that we're not just playing in our, we're allowed to save the world. So we're not playing in our sandboxes, but we actually do want to be do gooders. So, so is it, do I get it that the idea would be that we could imagine preventing pathogenic effects, not necessarily just by killing the bacteria, but by preventing them from talking to each other? Yeah. So we've made molecules that look like the quorum sensing auto-inducers, but they're what are called antagonists, right? So they're inhibitors. So they slide into the receptors, but they block the real molecules, right? And those shut down virulent at in animal models, right? These aren't in real medicine yet, but in our labs, right? If we either make a bacteria that just can't do quorum sensing or we make synthetic strategies to shut down quorum sensing make them so they can't make the auto-inducers make them so their receptors get blocked, they they they have their entire repertoire of virulent factors intact. You know, it's command and control. It's like the army. Don't say go one, two, three, shoot, right? They don't know to do it. And so you're just trying to buy time for the immune system, you know, to get rid of them, which is what your immune system is doing all the time. It's doing surveillance. It's just that these few pathogenic bacteria have, you know, have a leg up on us. And so if you could thwart them by just getting them not to be able to launch these harmful attacks, there's real promise, you know, to that. And then again, I want to talk about these good bacteria like in agriculture and in humans and in industry, we use bacteria to make us all kinds of stuff and to do all, you know, they do bioremediation, they clean up oil spills, right? If you could make quorum sensing better, right? You can imagine all kinds of medical and industrial and agricultural, you know, things, products. Well, like you already mentioned at the very beginning, the whole microbiome story is certainly super popular and people are very enthusiastic about it these days. I mean, do I understand? I really don't understand. So just ask you, does what's happening in my microbiome affect my mood or my like state of mind anyway? So okay. So the microbiome is even newer as we discussed, right? Because nobody knew they were there and then they didn't think they were doing anything. And now we get that maybe they could do everything. So there's a lot of, let me call this mounting evidence, right? Remember these bacteria, and I'm not talking about quorum sensing molecules, these bacteria are making molecules, all kinds of molecules that they are releasing into your body, right? All kinds of, that's what bacteria do. They're little machines that do biochemistry, right? And so there's a lot of energy. Let's call it that in this idea that for sure, you know, for sure they're making just, let me start with facts like you cannot digest plant food whenever you eat a vegetable or a salad or anything like that. Your human genome does not have the enzymes that allow you to digest that food and get the calories nor the nutrients. So the bacteria in your gut provide the enzymes to do that and that's how why salad is so healthy, you should thank your microbiome, right? So they give you that, right? And so they do all kinds of things like that, like whether a person, some people like take a medicine and they might have a microbiome bacteria that that that degrades the medicine. So, you know how some people a medicine works on some, doesn't work on others, somebody gets a side effects, somebody else doesn't. That could, there's a lot of evidence and I mean data that shows your microbiomes playing in that. Whether they can affect your mood, that people think that's a possibility. That is my knowledge, not proven yet. But whether I'm a funny person, I'm a happy person, you know, I must, you know, there's like ideas that maybe if you're a better, depending on your microbiome, you might be a better athlete, that's way out there. Okay, but it's not crazy, right? Given that these bacteria make a gobb of molecules, there's 10 times more of them than your human cells and these molecules are definitely, you know, we know they're in our body. We just, it's just such a huge new horizon for scientists, you know, and then again, remember shown your microbiomes different than my microbiome, you know, and what you eat, how you live, every medicine you've ever, not every medicine you've taken that I have, you know, all of those have affected your microbiome and your own human genome throughout your life, right? And so it's a, it's a problem of enormous complexity and excitement, right? And so the sort of simpler things like, okay, I digest your plant food, you know, like that we know, the more exotic questions like you're asking, right? Very, very fascinating. And certainly, certainly the topic, many topics, you know, and whether or not a medicine is going to work on you or not, you know, like this idea of personalized medicine that the microbiome is going to really affect what it means to get personalized medicine going forward. Those are intensively studied, but hard to answer, okay? I just did a podcast with Jeff Collar here at Hopkins on using mRNA techniques to do bespoke therapies for rare diseases and biology is hard. That's why I'm a physicist because like all these things are related and talking to each other and it's very scary to me. But look, you know, I mean, having a cup of coffee or a cocktail can clearly change your mood. So it is not at all out of the-- Those are molecules. Yes, those are molecules. So it's molecules that are ultimately getting the responsibility for this. So I'm not surprised at the prospect that the molecules that live in my body and work along with it could also have an effect in principle. So that's good, the little frontier there. Another frontier, I think that you've been working on recently, depending on how you define recently is cell death, like the poor bacteria are programmed to die and quorum sensing plays a role in that. Yeah, that was kind of a-- that's a-- was a wonderful postdoc in the lab that perhaps-- that he did-- he found-- it's a fact in these particular bacteria that we found when they make these beautiful biofilm structures, he found that quorum sensing regionally, like in a region-- you know, I have to think of this as like a big community, right? It's here to a surface, you know, like a blob, right? Regionally controls the death of certain cells, like the idea being almost altruism, which is that I spill out all my gut, you know, this-- this community is getting kind of old. There's not enough food around. That's when this happens, you know, of course, it seems high cell death, there's lots of cells there. And so then maybe, maybe some of these elders, because it is the oldest part of this-- the community, they all die and it's quorum sensing controlled, right? And maybe what they do is they spill out all their nutrients, it's kind of like, you know, cannibalism, right? Okay. It's a little bit like that. And then that sacrifice, you know, allows the younger members of this community to hopefully survive a little bit more until maybe better times come along. right? So that was a crazy, not crazy. It wasn't crazy. It was a really good project. It was a surprise. I mean, everything I'm going to tell you is a surprise. So yeah, he just, Ameya was this post-acted found that. Yeah, that was, and of course, again, and I think this is what you're alluding to, is that we know there are all kinds of program cell death processes in human cells. So for example, when you're in embryo, your feet and your toes are webbed, right? And then the cells that are in between your, excuse me, your toes and your fingers, those cells, as one example, those cells die and you get your digits, right? That's a program cell death process, right? That gives you, for example, your fingers and toes. There's others, right? And again, program cell death was thought to be in eukaryotes, right? So we don't really know, in this case, we don't actually know if this quorum sensing trait is actually program cell death and sure smacks of it. Okay? For quorum sensing, we know these bacteria are carrying out collective behaviors. We know that. Ameya found that these cells do die. They die in this regional way. They dechorum sensing controls it. We hinted in the discussion of this paper that perhaps, just like quorum sensing was, you know, the original collective behavior perhaps, bacteria also have program cell death mechanisms. As do eukaryotes, you know, and I'm selling a broken record, the bacteria were here first. Why wouldn't they have been all that if it's helpful in some situations? Just to clarify, because I think I was confused by this and I forget which kind previous podcast explained to me, but bacteria, like you say, they reproduce asexually, they split into, so my naive physicist brain said, how can one be older than the other? How could you have old bacteria and young ones? But apparently the materials split off asymmetrically. So there is like an older half and a younger half. Yeah, there's an older side, yes, exactly, right? And are they immortal? That's a little bit too, for me, but yes, but we can see, but so for example, what I can tell you in the experiment that we do, not getting to that sort of meta question, we put one cell down. So it's the founder. And so everybody that divides from it is younger, because they didn't, you know, we can track every cell in this community. So the founder has a baby, another baby, baby granddaughter granddaughter, right? And so we do know at least in the context of that experiment, who the first cell was, the gave rise to all the others. That's in this gined up way that we do experiment. Maybe I don't know, Sean, how much longer you want to talk to me? I can, obviously, I like communication. Let's talk. Let's communicate. Yeah. What do I mean? Tell you what we're really working on right now. Let's do it. Okay, I'll tell you one more story. So, so we've been talking about corn sense. Things about bacteria, right? But what we've learned in the past couple of years, like, and when it's the sort of frontier for my lab, right, is that it's not just all about bacteria anymore. So now we know that the eukaryotes and the viruses are participating in these chemical conversations. I was going to ask, this is perfect. Oh, good. That's good. Okay. Good. I want you to ask that. So we'll pretend you asked me that. Now act act like I'm a gracious guest instead of, you know, bossing you around the bacteria might not have a boss, but I, I am bossy. Anyway, let's see. So two things. So for the eukaryotes, like we found now that like your human gut cells make molecules that are almost identical to these bacterial corns in same molecules, right? And so the bacteria perceive them as corns in same molecules. And so what we think then is remember your gut is where are human and most bacteria come in contact. That's where most bacteria in the human body are. They're in the gut, right? And so if you, I mean, humans have evolved with these bacterial microbiome for all of these, you know, year, you know, hundreds of thousands of years, maybe your human cells want to be controlling what those bacteria do, right? And so by making auto-inducer, you know, these quorms and seen mimics, maybe your human gut cells drive these bacteria to carry out particular collective behaviors that presumably are useful to the humans. So on the one hand, we know now that eukaryotes make quorms and seen mimics, right? The bacteria respond to. So that's the eukaryotes. And then and so we're super excited about cross-domain communication. And then on the other side of these domains are the viruses. And so just like we are bombarded by viruses, bacteria are bombarded by viruses as well. So viruses in effect bacteria, we call them phages. Okay. And so bacteria have to protect them, bacteria have immune systems to protect them from phages. And so what happens when a virus of phage gets in a bacterial cell, the virus, okay, I'll call it a phage. The phage, that's a bacterial virus, right? The phage can do one of two things. It can just be dormant and be passed down through generations. So every time the bacteria divides, the daughter cell gets the is infected, right? By the phage or the phage can replicate like crazy, make many more of itself, kill its current host and go infect other cells, right? So we call the first, the dormancy that's called lysogeny or lysis. So when a virus gets into a bacterium, it's got to decide. Lysogeny, dormancy or lysis, right? And so sorry, the same virus can do either one depending. It's got to choose one or the other and they can switch between, right? So you can have a lysogen that's gone down many, many generations and all of the sudden it says that's it. I'm out and it can go into the lytic mode, right? Okay, so both ways, the virus wants to just infect cells, right? So you can do one by one by one, you know, like by being a lysogen, every daughter cell is automatically infected or you can make lots of different phage particles and try to infect naive cells that are in the population. Okay, so if the phage sides the second, like I'm going to lice my current host, make more of myself and then I'm going to spread and try to infect other cells. If there's no other cells there to infect, that phage is a goner, right? So when's a good time to choose, aha, aha, so when's a good, yes, right? So when's a good time to do, be lytic? Well, it's when there's lots of other bacterial cells around. So if you pop out, you and your all these virus particles that you may have, you pop out of that current health and you kill it, you want to have maximally transferred the next cell. So what we've found now is these bacterial viruses have captured or evolved, quorum sensing receptors. So what they do is as the host bacteria are growing, they're releasing these auto-induced thermolycules, the viruses are eavesdropping. They're surveilling the quorum sensing molecules, right? And then they recognize when there's lots of host cells around and then that that quorum sensing turns on the decision to switch from being dormant to go lytic, right? So they only make viruses, they only kill their host cells when there's lots of other hosts in the environment to infect. So they're eavesdroppers, right? So now we get that this course, so this is what my lab might, what we're interested, we're not so interested in discovering the next quorum sensing system, we're very interested in this idea of quorum sensing spanning from eukaryotes to bacteria to viruses and like viruses, they're not even, like they're more different than, right? Like viruses aren't eating, yeah. Yeah, and like, like it's, so anyway, I think that's been really, really fun. And then of course, because of that, we can like trick these viruses and make phage therapies, right? That could be useful, you know, by getting them to kill or not kill on demand. But anyway, that's pretty fun for us is that these viruses are tuned in. That was an afterwards, again, going back to some, we said before afterwards, we're like, you know, people have studied phage, phage, bacterial viruses, that founded the molecular biology field. Like that's what scientists were working on. They were working on bacteria and phages. And of course, so that's like 80 years ago. And so now we've discovered that phages tune into quorum sensing. And then afterwards, you think, well, of course they did. It only makes sense to kill the host when they're, you know, the phage needs more victims, right? So of course they, you know, and of course, I think I spent my whole life just going like, should we're seeing that out sooner? Right? Yeah. But anyway, that's something I'm also very excited about in my lab. I like, I don't think that this sound like a Monty Python movie. We're not dead yet. I don't think the quorum sensing field is dead yet because we have the microbiome that we don't understand. And then now we have this idea of cross domains, you know, communication with quorum sensing. And then again, like a treasure trove of applications that are waiting, you know, to be made for humanity and for the earth. So yeah, yeah. Exactly. And so at the end of the podcast, we always allow ourselves to be a little bit more speculative and let our hair down. And this is the time. So, but this leads right into where I wanted to go, which is, you know, there are these interconnections you get in biology, right? Things start talking to each other. And we don't understand perfectly the origin of life. But we also, as far as I can tell, don't understand perfectly the origin of you carry oats or the origin of multicellularity. And I'm wondering whether, I mean, obviously bacteria play roles here. Like, can we think of quorum sensing as a tiny little step toward multicellularity, even though it mostly happens in your care. Yeah, I think, okay, so there's a debate about about that like everything, right? And so for sure, these biofilms or these groups, these, there are many, many cells in them, right? But in some, and so people, scientists want wonder, let's call it that wonder, is this the first step in, you know, a first step in multicellularity, right? These solidities groups, they're coordinated, they're doing things together. I mean, that is what happens both in multicellular organisms but also just in organs, you know, in, you know, like your heart cells do the same things, right? And, and your kidney cell, you know, and so we wonder that, but there's something really, really different though, because each one of those cells, I'm talking about the bacterial cells, they can live on its own, right? So if I scramble that biofilm up, right? And release it, right? Every one of them, those cells can live. Now if I do that to your kidney, right? Or, yeah, right? And so like, so again, in your body, or in a real multicellular organism, every cell has a vested interest in every other cell being healthy, right? In a bacterial biofilm or a bacterial community, they're all fine on their own. You know, if everybody else dies, it's kind of what we got back to, they're still, I can still, A and individual still can still divide and make the whole thing again, right? And so there's something fundamentally different, I think, this is just my opinion. There are the traits of multicellularity, the collective behaviors, you know, they do, you know, in a biofilm, just like in your body, cells that are identical, you know, and bacterial cells that are, they have the identical genomes. They take on different fates, just like all the cells in your body have the identical genome, your kidney cells, your heart cells, your blood cells, they take on fates, they do different jobs. That is clearly happening in a bacterial biofilm that in one region, you know, the bacteria are doing these jobs in another region, they're doing those jobs. We know that, but nonetheless, right? If I scramble it up, every one of those cells, like they're sort of like the ultimate stem cells, every one of those cells could build that biofilm again, you know, by dividing, right? - Yeah. - But and that's just different, right? Like if I kill all your kidney cells, you are in a huge amount of trouble, right? - You're wondering, you know, again, what do I know? But I'm wondering, you're, so it makes perfect sense. The bacteria don't need each other to survive on their own and that is an important difference. But so it could be envisioned that there's a form of cooperation between primitive cells that just becomes so successful that you do so much better when you're cooperating, that you lose the ability to live on your own because that's just like extra capacity you don't need. - Yeah, and we'd call that a eukaryote, right? And yeah, and again, you know, we already know that happen. You might have a congeal, right? Or a chlorplast in a plant cell, right? Those used to be free living bacteria, right? They got somehow engulfed or whatever. And then they have so few genes left, but they do all these really important, you know, they're the little engines of ourselves, right? And so we have, it's like an analog of what you're asking me, I think, you know what I mean, right? And so, yeah. (laughing) - Okay, good. So here's the final question then. We started by saying that there's more, the number fluctuates, right? The number of bacteria in our bodies that used to say 10 and then they said it's about the same and maybe so bit more. Is there some future moment and we're just gonna say, you know what? Those are all human cells. Like our bacterial cells are still our cells and we should count them. - Right, so I think that if you're me, you believe that being a human, or for me, a eukaryote means a community. You know, and I mean, you know, like I think of myself as this marvelous, I don't mean that in an eagle maniacal way. I mean, like this marvelous collection of cells, right? And just like you, I don't notice my bacterial cells either, right, but my human cells, and I can't be human without them. - Mm-hmm. - Right? You know, unless I guess I lived in a bubble, you know, you know, you can't be without them. So you need them, you know, to keep you alive, to keep you healthy, to protect you. It took him a long, you could be born, you are born, you could be born, you could kind of live, but not for very long without them, right? So you do need them, but my human genome is my human genome. Right? And I have, and I do have a brain, right? And they don't. - Yeah. - Right? But they are, but you need them, right? And so. - Are we giving too much credit to the genome? Is my question like are we, are we? - Who's genome? There's our ours. Are we privileged? - Oh for sure, definitely. Oh please. Yeah, of course. Yeah. Oh for sure. But, but then again, right? We do have brains. We have thought, we have feelings, all of which are probably biochemical reactions, but still we do have, you know, these things that individually they don't have, or even collectively they don't have. - Are the bacteria in our gut microbiome, etc. Are they just temporary? Are they there for our whole lives? - Yeah, you get colonized, they change throughout your life. You get colonized, you start sterile, you get colonized on your way out of the birth canal, and you mostly get them by slapping goop, you know, from your family, right? From me now, it's probably from my cat, but anyway, but anyway, and they do, they change, it changes over your life like when you live with someone, right? And then as you get older, the diversity of them kind of plummet, and we think maybe that's about aging, or health, and also if you live in an industrial world, or a polluted world, it's different, you know, so they can't change, you'll have, as you move around, as your health add, when you take antibiotics, but ultimately you will have a, you will have microbiome bacteria throughout your whole life, right? - But so if I, if you live with somebody, your microbiomes intermingle? - They do, a bit, yeah, you start to look more, as far as I understand, and again, right? You begin to, you look a lot like your parents at the beginning, right? And then you begin to look more like whoever you're cohabitating with, - Including your cats. - Pre-eating cat a little bit. Now, probably not. - It's an extremely romantic place to end, so Bonnie Baxter thinks so much. - Yeah, you should never have me as a generic companion. (laughing) - I don't talk about bacteria nearly enough, that's the lesson I'm going to give you. So thanks very much to you, the Mindscape podcast. - Oh, Sean, please edit this. (laughing) - No, can't do that, sorry. - Anyway, no, really, actually it was thrilling. You really made it fun for me to get to talk about all these wild topics. I hope it was helpful and that people like it. - Oh, I think they will. All right, thanks very much. - Thanks, I'll see you, Sean. (upbeat music) (upbeat music) - Marketing is hard, but I'll tell you a little secret. It doesn't have to be, let me point something out. 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