361 | Bonnie Bassler on How Bacteria Talk and Work Together

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1:35Over 4 million businesses have skipped the line with Stamps.com. Join them to save up to 90% off carrier rates from your computer or phone right now. Print postage for certified mail, registered mail, and packages in seconds. Then schedule a pickup right from your home or office. For a limited time, go to stamps.com and use code podcast for a free welcome gift. Taxes and fees apply. 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.

2:13I 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 was 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.

2:57And 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.

3:33And 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.

4:07We'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.

4:42And 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 Bassler, who is our guest today. Bonnie was really the one starting in the 1990s who explained, discovered, and then explained to 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.

5:15But 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.

5:48As 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, you know, how they fight off threats and how they symbiotically interact with other subsystems of your body are crucially important.

6:25It's a really fun topic in just about every possible way. It's intrinsically important because it's important to 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.

7:04Bonnie Bassler, 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, no. That would be a hard no. No, it was an accident. When I went to college, I thought I wanted to be a vet because I like animals.

7:34I like nature. 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, biochemistry classes. And I loved the curriculum. But I didn't know 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. I thought I would try that. And he did let me. And he had two projects, a cancer project and a bacterial project.

8:06And, of course, I was 19 years old. I wanted to cure cancer. That sounded 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 this

8:37fantastic 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 can have a surprise in the incubator every eight hours. You know, 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 rapid, how fast you could do experiments and get results. I thought then it was the bacteria represented something that I could understand.

9:12I 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 academia forced you to try something new. And you're like, oh, my goodness, this is it. Yeah, and I do wonder, like to that question, I think if they'd have put me on a fly project

9:48or, you know, maybe I would have loved that too, right? Because what I love is making discoveries. And then I don't do this as much, you know, working with my hands or 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

10:20just 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. 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

10:50seemingly definitive answers. Obviously, they give you your next question, if you're doing it right, it leads you to your next, 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, yeah, I think I love, love being at the bench. Yeah. So what do we need to know about bacteria for the purposes of this conversation, and

11:22especially the bacteria that live in our bodies, which apparently there's quite a number of them? More cells than your cells. 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, they, they communicate to be more serious with you. What I think we'll probably spend a lot of time talking about today is what my gang is

11:53always 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 do bacteria get any bang for their buck, right? They are so puny. They are so primitive, right? They're single cells. You can't even see 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.

12:24They keep plants alive. They clean up the environment. They do all these fantastic and terrible things. And so those are facts. And 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. And so 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.

12:58But if they have used collective 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 is so- Actually, you know what? Don't tell me how it works now because we're going to get there.

13:30I 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. Like, arguably, they're the most primitive life forms. Is that at least a plausible perspective? Yeah, yeah, they, they, okay, I wasn't actually there, but they arrived, arrived, they evolved

14:00on 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, first living organism, right? And so they are the most ancient living organisms that we know of. And they are all single-celled, 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

14:30in 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 when they were first observed by von Lienhoek, you know, who is like a microscope maker. Anyway, and, yes, animalcules, yes, exactly. And so, you know, he's scraping stuff off his teeth and do stuff like that. So anyway, so they've been known for almost 600 years. We've known they cause disease for 150 years.

15:01But 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 asocial recluses, 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 eukaryotes. 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

15:36things, 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 seemed like very evolved behaviors, right? But then if you think about it, right, we all came from bacteria, you know, where you think this 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

16:12tiny little bacterium could do all of that, right? You know, and so now I have to say, you know, now that quorum sensing is an established field, we get the bacteria work in groups. And when you let me, I'll tell you how it works. I will. 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 spend a lot of my time thinking like, why did it 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.

16:44But of course, that's after a discovery gets made.

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18:44$50. That's 50% off your first year at MONARCH.COM with code MINDSCAPE. Sure. And so it's kind of simultaneously amazing to me that the idea of bacteria, this domain of life, has been there from the start, right? You know, the bacteria don't go away when other species come on board. But we don't know what the earliest bacteria looked like. And you mentioned they have thousands of genes in them.

19:15So we probably have lost. Like the first bacterium didn't have thousands of genes in them. So we probably have little idea what the most primitive bacterium ever really looked like. No, probably not. I mean, the notion now, right, is that these organisms, this domain that we call the archaea, right, old, are the ancestors of the first living organisms on Earth. And that is because those microbes live in really hostile environments.

19:47Like 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, you know, billions of years ago, you know, it was a bubbling volcanic plots and things like that, right? And so we think that those are the current ancestors of whoever were those first living, replicating organisms on Earth that were presumably were microbes.

20:18Right. So they're sort of vestiges and they inhabit these, you know, 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. So there are three domains of life. Yeah. So archaea gave rise to both bacteria, prokaryotes and eukaryotes. Got it. And archaea genomes actually look more like eukaryotic genomes than bacterial genomes. But then those archaea, they are relegated to these hostile places that are currently on Earth.

20:52And then the bacteria came and they are nearly all of the biodiversity that exists on Earth, right? Almost everything you have that exists on Earth, you have not seen with your eyes, right? So even most eukaryotes are microbes. Right. Yeah. Right? Okay. And so, you know, like if you look at, I wish people could see us because I'm using my gesticulating 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

21:24genomes, you know, and you see all the bacteria are huge. The archaea are a little few branches, the eukaryotes are a lot of branches, but only one tip of one little branch of those eukaryotes is every bug and animal and plant 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 professional bacteriologists. And I guess I was going to say, and I guess you see my bias, right? So yeah, but I'm right.

21:55You have numbers on your side. 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.

22:26Right. 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 us. Bad microbes, you know, can't, you know, if you eat them, you know, the real estate in your gut is taken up by what we call your microbiome. Your skin is covered in a biofilm of your microbiome that keeps, like a suit of armor that keeps bad microbes from being able to get a toehold. You know, they do all these functions that our own genes and our own bodies can't do to

22:59keep us alive. Comma. 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, not my emotional feel, like your physical, you feel your microbes when you're ill. It's not like you get up every morning and you thank your microbiome for helping you digest your breakfast, right, or for keeping you alive. Like the only time you noticed that you, that microbes are part of your existence is

23:33typically when you get sick. And of course, if you think back to 150 years ago when, you know, Pasteur and all these people were 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 and on us, scientists thought they were just passive riders. You know, it's only recently, you know, with the advent of all the technologies and genomes and the understanding we have now about the natural world that we're learning about this

24:04mysterious 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, right? No plant can grow without these bacteria in the soil. I mean, they, you know, nothing happens on this earth without these bacteria, but since you can't see them, you only really think about them when something terrible happens, right?

24:37And like you 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 by mass, we're mostly human. Correct. So, right. So a human cell is, you know, 500 or 1,000 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 number is you have 10 times more bacterial cells than human cells in you or on you, a hundred

25:07times 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're excused. You don't have to. You can't. All right. Okay. That's extremely helpful. But still five pounds. Yeah. Okay. You go home and eat dessert. That's not trivial. Okay. There's a lot of bacteria in me. Good. Yeah. Good to know. I'll try to be nice to my gut microbiome. And, okay, so now I'm going to let you off a leash a little bit.

25:42We have all these bacteria, but any one bacterium can't do that much. 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.

26:13And so the way it works is that bacteria, they consume nutrients from their environment. They 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 asexually.

26:32And then what they also do is that they make and release small molecules that you can kind of think of like hormones, right? And so as the bacteria are growing in number, you know, more cells, 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, they get above the threshold that the bacteria

27:06can 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 that 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 the buildup of these molecules as a proxy for cell number.

27:37And so if I can anthropomorphize, which you already 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 a few cells present, they can accomplish when they're together. Right? And so... Good. So the molecules are their words, if you will. So it's a phase transition. Can I call it that as a physicist? Is that fair? Sure.

28:08Very good. Yeah, sure. And it sounds like you're 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. But, well, exactly, neither do I, but this is kind of like the opposite.

28:40This 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, whenever this, 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.

29:11And then a bacterium evolves a receptor, right? That detects that molecule and, you know, and they're off to the races in terms of quorum sensing, right? And so, yeah, I think that they probably were leftovers at the beginning, you know, but being able to detect them and the fact that every cell makes its 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.

29:41That's what we call them. You know, that those increase in proportion to cell density because of biochemistry, right? Because of the way they're made. Do they decay away eventually? Otherwise, I would think they would just sort of accumulate. Yeah. Well, they do. So, first of all, 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.

30:11But they do, they don't, they're not, they don't last forever. They're signals. So they, and 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

30:42tell, one and only one species of bacteria makes. So that molecule says, you are my twin. Okay. You're my clone. Then there's a molecule that all the bacteria in a, in a family make. So they say, you're my cousin, you know, 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

31:17of 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 in this, in, in this largesse and they all succeed. But like when they're around their enemies, sometimes they flee or sometimes they try to

31:49kill the other guy. They make antibiotics that, that kill off their competitors. And so they do different things. So what we think now is that these molecules encode something about the number of cells that are present, but also something about how closely or relate or closely or distantly I am related to my neighbor, right? 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,

32:24ones that it takes 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 of bacteria dribbled 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.

32:55The 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. 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 what you do, and then these bacterias 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.

33:28For them, these tasks are all good, right? If you personally got a bacterial infection, would you feel a little betrayed? Oh, yeah. I really, no. Whenever I have a cold, I also work on viruses of bacteria, so whenever I get a cold or I get a virus, I'm just like, oh, my life's work, right? It's so ungrateful. I should be immune to all of that, but I'm not, yeah. And so you started to go down the path of like, so what do they do when they do sense

33:58all of 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 quorum sensing? Yeah. Yeah. So biofilms are how we think, are the predominant way we think the bacteria live in nature, which is adhered to surfaces, you know, covered in this goop. And so the biofilm you know about mostly is the one on your teeth every morning, right? You brush that gudge off and it's back there the next day. That is a bacterial biofilm.

34:28It 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 with biofilm. 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

35:00surfaces and makes them resilient. Those are all community behaviors. You know, one bacterium can't make a biofilm, you know, 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. Say more 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. My skin, I get. Absolutely. The piece of paper in front of me is covered with a biofilm?

35:32Well, 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. Okay. Certainly. Yeah. Everything. And does, but the ones, the one on my skin, I'm getting like creeped out here, but okay, there's like bacterial biofilm on my skin and that's helping me. It's, it's, it's a suit of armor, like you said. Correct. It is. So you can get a skin infection, you know, when you have an invader there, but no, that

36:03biofilm that you can't see or feel that's on your skin is covering up all of the surface and keeping bad bacteria that happened to land on you that you can't also can't see or that you run into, um, 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. That's part of your defense against predatory bacteria, right? But, but your skin gets colonized again and again and again, you know, by these bacteria

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37:37Whether you want more privacy, better light control, or to upgrade your home with motorized or smart blinds, 3-Day Blinds has thousands of options to fit any style or budget. So for a free, no-charge, no-obligation consultation, head to 3dayblinds.com slash podcast for our buy one, get one 50% off deal. That's the number three, dayblinds.com slash podcast. So going back to the evolution story, you said that making the chemicals is pretty cheap, but I don't quite know how to quantify that.

38:10I mean, at some point, probably the way that evolution works, as far as I can tell, is they started making chemicals without any benefit, and then 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 I'm still trying to figure this out, right? But the molecules, they're not like fancy molecules with lots of parts. They're very simple, and we know how many of them are made, the ones we've discovered.

38:45And 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. But over time, it got co-opted by evolution to be a signal because it's leaked out.

39:15The bacteria are 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.

39:47You know this. We have the human genome. We have a zillion genomes, right? Form sensing is the norm in the bacterial world. Like, so when I was first – we were first discovering the first of these form sensing, we're like, wow, you know, is this some crazy anomaly of some obscure bacterium? Well, fast forward 30 years, and we look through these genomes, right? There are tens of thousands of cases of quorum sensing. You know, we can see these genes throughout the entire bacterial kingdom domain, right?

40:17And 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 quorum sensing. I do some work, you do some work, and we all succeed more, right?

40:50I think that that's an amazing step in evolution. And, of course, you know, we know that in eukaryotic – I mean, you know, our own cells, you know, your kidney cells work together, your liver cells, you know, work together, and herds of wildebeest work together, and wolves hunting, you know, and fishes. 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.

41:20And, of course, we came from bacteria. So these rules, your 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 rules, Sean, right? They were there first. They get credit, right, yeah. 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.

41:51Correct. And it's – yeah. But – so there has to – yeah. So they're just doing it, you know, so are there leaders and followers? We think about that a lot, right? 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.

42:23Right? Yeah. Do those chemicals do anything else that we know of? Yes. 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 want 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're still just leftovers and nobody's figured out to eavesdrop on those.

43:00But for sure, in some ways – so the thing you might be getting to, there's cheating and free riding 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 autoinducers, 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 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?

43:40But you can imagine that that's a really good molecule to make because you can kill your competitors, right, who are – 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 and the task, right?

44:23Or 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 where different species that live together, you know, make mimics or trick – you know? And so somehow there's got to be little itty-bitty policemen around that are, you know, making a punishment for cheating, right?

44:55And 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. So 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.

45:28You know, think about like when these – like you have these population crashes or tragedy of the commons, right, where you're making public goods. Like bacteria are 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 – I don't know if that's making sense. But yeah, I think the physicists have loved this stuff, right?

45:59Because 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 because 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. And so bacteria might be like the simplest things that have little coordination and good and evil games, heroes and villains here, cheating and cooperation.

46:36For sure. And I think another reason that – and again, this goes back to you asked me how did 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.

47:06We can make a guy that's deaf, right, that 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.

47:42Or, 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 – 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.

48:13And so that's been – so I think that quorum sensing has been a real boon to these kinds of cross-disciplinary collaborations. So I've collaborated with Ned Wingreen, 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 the Santa Fe Institute? I've never been – oh, yeah, I have.

48:43I did. I went to one of those physics meetings, and I've gone to the physics meetings in Aspen. Yeah, I have. I'm card king. I'm the 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 quorum sensing, but I'm not sure if I gave you the chance to, like, really go through some of the fun examples. I know that bioluminescence is probably my favorite example. It should be. It's the founding example, right? So it is the founding example on which the quorum sensing field was built, right?

49:16So remember bacteria – not remember. 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 quorum sensing get missed for the 500 years 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?

49:48So 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 because 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?

50:19And everything is twinkling and making light in the ocean and so he just loved bioluminescence, not corn sensing, 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 of a sudden all the bacteria would turn on light together.

50:54And what was so powerful about that is that it made the invisible world visible to the scientist, right? You know, he's like – I mean, I'm just – you know, why don't they make light? Then 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 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.

51:25You 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 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 its – so there's a little fatty acid.

52:00There's like a fat that's the substrate. And when luciferase does its reaction, right, which is just a biochemical reaction, it lets off a photon of light one out of every 20 times, right? And that photon, the wavelength of it happens to be blue, right? 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.

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53:48So for a free, no-charge, no-obligation consultation, head to 3dayblinds.com slash podcast for our buy one, get one 50% off deal. That's the number 3dayblinds.com slash podcast. 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.

54:20And 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 timing. 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 mate. Okay, good. Thank you for that. And okay, back to the bacteria who are the stars to their story.

54:51They 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 of bacteria is certain weaponry is turned on and off via quorum-sensing. Is that right? Absolutely. And so I think, so for sure, so we know all of these clinically relevant, globally important pathogenic bacteria, 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?

55:28They are completely avirulent because their repertoire of virulence factors, toxins, poisons, you know, things that let them enter into your cells, 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 bacterium is going to give something away to the world, a toxin or something good, it never gets its own back.

56:05You know, the world is huge and bacteria is gone. 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. You know, 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.

56:40You 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?

57:18So I do want to make a little plug that we're not just playing in our sandboxes. We're allowed to save the world too, that's okay. We are playing in our sandboxes, but we actually do want to be do-gooders, so. So do I get it that, yeah, 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 autoinducers, but they're what are called antagonists, right? So they're inhibitors, so they slot into the receptors, but they block the real molecules, right?

57:51And those shut down virulent, in animal models, right? These aren't in real medicine yet, but in our labs, right, if we either make 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 autoinducers, make them so their receptors get blocked. They have their entire repertoire of virulence factors intact, you know, it's command and control, it's like the army, if you don't say, go one, two, three, shoot, right?

58:22They 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?

59:00If 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 I just ask you. Does what's happening in my microbiome affect my mood or my, like, state of mind in any way? 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 can do everything.

59:38So there's a lot of, let me call it 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? They eat 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.

1:00:10Like, 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 why a 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 degrades the medicine.

1:00:43So you know how some people, a medicine works on some, doesn't work on others, somebody gets a side effect, somebody else doesn't. There's a lot of evidence, and I mean data, that shows your microbiome's 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'm a, 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?

1:01:14But it's not crazy, right, given that these bacteria make a gob 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 don't, it's just such a huge new horizon for scientists, you know, and then again, remember, Sean, your microbiome's different than my microbiome, you know, and what you eat, how you live, every medicine you've ever, not every, medicines you've taken that I have. You know, all of those have affected your microbiome and your own human genome throughout your life, right?

1:01:48And so 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, 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.

1:02:22Those are intensively studied, but hard to answer, okay? We 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 realm of—

1:02:57Those are molecules. Yes, they're molecules. 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, I mean, 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.

1:03:30Yeah, yeah, that was kind of a—that 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, you have to think of this as like a big community, right? Adhered to a surface, you know, like a blob, right? It regionally controls the death of certain cells.

1:04:05Like the idea being almost altruism, which is that I spill out all my gut. You know, this community is getting kind of old. There's not enough food around. That's when this happens. You know, quorum sensing is high cell density. There's lots of cells there. And so then maybe, maybe some of these elders, because it is the oldest part of 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? 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?

1:04:46So 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, Amea was this postdoc that 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 programmed cell death processes in human cells. So for example, when you're an 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?

1:05:23That's a programmed cell death process, right? That gives you, for example, your fingers and toes. There's others, right? And again, programmed 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 programmed cell death. It sure smacks of it, okay? For quorum sensing, we know these bacteria are carrying out collected behaviors. We know that. Amea found that these cells do die.

1:05:53They die in this regional way. Quorum sensing controls it. And 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 programmed cell death mechanisms, as do eukaryotes. You know, and now I'm going to sound like a broken record. The bacteria were here first. Why wouldn't they have evolved 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 guest explained it to me, but bacteria, like you say, they reproduce asexually.

1:06:28They split in two. So my naive physicist brain said, how can one be older than the other? How can you have old bacteria in young ones? But apparently the materials split off asymmetrically, so there is like an older half and a younger half. Yeah, and 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.

1:06:58And 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 that gave rise to all the others. That's in this ginned 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. But want me to tell you what we're really working on right now? Yeah, let's do it. Okay, I'll tell you one more story.

1:07:29So we've been talking about quorum sensing is about bacteria, right? But what we've learned in the past couple of years, like, and what is 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 you, this is perfect. Oh, good. That's good. Okay, good. I want you to ask that. So we'll pretend you asked me that. Act like I'm a gracious guest instead of, you know, bossing you around.

1:08:03The bacteria might not have a boss, but I am bossing you. Anyway, let's see. So two things. So for the eukaryotes, like we've found now that, like, your human gut cells make molecules that are almost identical to these bacterial quorum sensing molecules, right? And so the bacteria perceive them as quorum sensing molecules. And so what we think then is, remember, your gut is where a 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, meaning humans, have evolved with these bacterial microbiome for all of these, you know, years, you know, hundreds of thousands of years, maybe your human cells want to be controlling what those bacteria do, right?

1:08:50And so by making autoinducer, you know, these quorum sensing 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 quorum sensing mimics, right? The bacteria respond to. So that's the eukaryotes. And so we're super excited about cross-domain communication. And then on the other side of these domains are the viruses.

1:09:21And 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 that protect them from phages. And so what happens when a virus, a 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.

1:09:52It can just be dormant and be passed down through generations. So every time the bacteria divides, the daughter cell 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?

1:10:22And so— I'm 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 a sudden it says, that's it, I'm out, and it can go into 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.

1:10:56Okay, so if the phage decides the second, like I'm going to lyse 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— I see where this is going. Yes, right. So when's a good time to 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 made, if you pop out of that current house and you kill it, you want to maximally transfer to the next cell.

1:11:34So 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 autoinducer molecules, 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 quorum-sensing turns on the decision to switch from being dormant to go lytic, right?

1:12:05So they only make viruses, they only kill their host cells when there's lots of other hosts in the environment to infect.