Bonnie Bassler on How Bacteria Talk and Work Together | Mindscape 361

[00:00:00]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. Um I'm not exactly sure when it's going to come out. I I'll let you know when when I do. was supposed to come out around now but that didn't happen since obviously I was very late getting in the actual book but uh 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.

[00:01:16]But more is different is the motto that is usually thrown around here coined by uh physicist Philip Anderson. And the idea that as a system whether it's an ant colony or you know sand in a sand pile uh 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. uh 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 uh by Woody Hastings and other people. But the world's expert in quorum sensing is Bonnie Bassler who is our guest today.

[00:03:02]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 its kind of interesting ways. But then when you get enough of them in a region and 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. Uh, as we will discuss in the podcast, there's a lot of bacteria that you carry with you. uh 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. It's a really fun topic in in just about every possible way. Uh 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, you know, a really fun and educational podcast. Let's go.

[00:04:52][music] >> [music] >> Bonnie Bassler, welcome to the Mindscape podcast.

[00:05:11]>> Thanks for having me, Sean. I'm delighted.

[00:05:12]>> I got to start. Uh, 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? It's like were you a young girl saying like it's bacteria for me?

[00:05:25][laughter] >> As I'm sure you've guessed. No, that would be a hard no. No. Uh it's a it was an accident. When I went to college, I thought I wanted to be a vet, you know, because I like animals. I like nature.

[00:05:39]And so I started on that curriculum, but it turned out I don't like gore at all.

[00:05:44]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 chemist 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 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.

[00:06:21]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 [laughter] know, and I still work on bacteria. And so the truth is is that in that undergraduate experience.

[00:06:37]Um I just found bacteria to be these 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 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 just beyond the the rapid the how fast you could do experiments and get results.

[00:07:08]>> The I thought then it was um the bacteria represented something that I could understand. I [laughter] 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.

[00:07:25]And again to long answer to your short question, it was such a remarkable lucky accident.

[00:07:33]>> 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."

[00:07:47]>> 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?

[00:07:55]Because what I love is making discoveries and and then I don't do this as much, you know, working with my hands, you know, doing experiments, trying to put these puzzle pieces together. So I do always wonder if you know, put me on that cancer project.

[00:08:09]Maybe I'd be working on cancer. But anyway, lucky lucky me.

[00:08:12]>> 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 [laughter] 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 qu if you're doing it right, it leads you to your next qu why that your next question, but um I do like that part of it where 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 and Yeah. And so that [laughter] yeah, I think I I love being at the bench.

[00:09:21]>> Yeah. So what do uh 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 your cells but um 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 always trying to figure out.

[00:09:59]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.

[00:10:11]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.

[00:10:30]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, >> you know, 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. But 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, right? And so we call this process of bacterial communication in group behavior quorum sensing.

[00:11:25]And I and I guess I'll just I'll tell you how it works. So the way it works, actually, you know what? Don't tell me how it works now because we're going to we're going to get there.

[00:11:34]>> I want to I want to like, >> you know, because the the 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?

[00:11:57]>> Yeah. Yeah. They Okay. I wasn't actually there, but they arrived arrived. They evolved on Earth right after oxygen, right? So, they're bill they have been on this earth for billions of years, like four billion years. They are we think earth's first mo first first living organism right and so they are the most ancient living organisms that we know of and um they are all single-sellled 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 when they were first observed by Van Leen Hook, you know, who was like a microscope maker. Anyway, >> yes, molecules. Yes, exactly. And so, you know, he's scraping stuff off his teeth and doing stuff like that. So, anyway, so they've been known for almost 600 years. We've known they cause disease for 150 years.

[00:13:04]>> [snorts] >> Um but they've always until about 30 or 40 years ago when this notion of quensing 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 ukarotes 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 thing that's all in higher organisms and so there was some kind of snobbery including among us the bacteriologists right that that they just didn't have the wherewithal to communicate or to do things as groups because those seem like very evolved olved 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.

[00:14:14]How could we have thought for so long that a tiny little bacterium could do all of that, right? you know, and [laughter] so now I have to say, you know, now that quorum sensing is an established field. We get that bacteria work in groups. And when you let me, I'll 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 I 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. But of course, that's that's after a discovery gets made.

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[00:15:44]And so it's it's kind of simultaneously amazing to me that the idea of bacteria, the this domain of life has been there from the start, right? You know, bacteria don't go away when other species uh come on board.

[00:15:57]>> Um but we don't know what the earliest bacteria looked like and and you mentioned they have thousands of of genes in them. Uh, so we probably have lost the f like the first bacterium didn't have thousands of genes in them.

[00:16:12]So we probably have uh little idea what the most primitive bacterium ever really looked like.

[00:16:18]>> No, probably not. I mean, the the notion now, right, is that these these organisms, this domain that we call the archa, right, old, are were the are the ancestors of the first living organisms on Earth. And that is because those microbes live in really hostile environments.

[00:16:39]Like they live in thermal vents or really cold places or dry dusty places.

[00:16:42]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, bubbling volcanic plots and things like that, right? And so we think that those are the the current ancestors of whoever were those first living replicating organisms on Earth that were presumably m were microbes, >> right?

[00:17:10]>> Yeah.

[00:17:10]>> And the >> so they they're sort of vestigages and they inhabit these you know places like in Yellowstone, right? Where the geology is not done. That's where these archa live.

[00:17:19]>> But archa are different than bacteria.

[00:17:22]>> They are indeed. So there are three domains of life. Yeah. So archa gave rise to both bacteria proarotes and ukarotes and archa archa genomes actually look more [laughter] like ukarotic genomes than bacterial genomes.

[00:17:36]Yeah. But then but then those archa 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? Almost everything you have that exists on earth you have not seen with your eyes.

[00:17:58][laughter] Right. So even most ukarotes are microbes.

[00:18:02]>> Right.

[00:18:03]>> Yeah.

[00:18:04]>> Right. And so you know like if you look at I wish we people could see us because I'm using my justiculating 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.

[00:18:19]The ark are a little few branches. is ukarotes are a lot of branches but only one tip of one little branch of those ukarotes is every bug and animal and uh plant and person and tree that you have ever seen. Right? So the world is microbial and it's mostly bacterial.

[00:18:36]>> All right. And yeah, we have a very uneven view of the world unless we're professional bacteriologist >> and and I guess I was going to say and I guess you see my bias, right? [laughter] So yeah, but I'm right.

[00:18:46]>> You have numbers on your side and >> correct. 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.

[00:18:58]We're a little bit symbiotic.

[00:19:00]>> 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 in you and on you, right?

[00:19:18]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 an honest bad microbes, you know, can't, you know, if 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 bofilm of your microbiome that keeps that that like a suit of armor that keeps bices 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. Kama to your point we do have this the 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 a in real not 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 m 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 know pasture 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 an honest honest scientists thought they were just passive writers. You know it's only recently you know with the advent of all the technologies and and genomes and the the understanding we have now about the natural world that we're learning about this this mysterious microbiome. Right?

[00:20:57]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.

[00:21:14]>> Yeah.

[00:21:14]>> 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? And like you said, a lot of bad press.

[00:21:30]>> There's more cells of bacteria in our bodies than human cells. And the trick is not all cells are the same size, right? By mass, we're mostly human.

[00:21:40]>> Correct. So, right. So, a human cell is you know 500 or thousand times bigger >> than a bacterial cell. So, yes. So the idea is you have 10 the current numbers and these change a lot uh you know as we learn more and more but the numbers you have 10 times more bacterial cells than human cells in you or on you 100 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 you say I can't lose that last 5 pounds you can't >> it's the bacteria [laughter] now >> you're excused you don't have to you can't All right. Okay. That's extremely helpful. But still 5 lbs [laughter] is something that's that's not trivial.

[00:22:22]Okay. There's a lot of bacteria in me.

[00:22:23]Good. U Good to know. I'll try to I'll try to be nice to my uh to my gut microbiome.

[00:22:28]>> And uh Okay. So now I'm going to let you off the leash a little bit. Um we 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.

[00:22:46]>> Correct. In my view. Yes. And not just my view. That's a fact. But that is also my uh 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 the 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.

[00:23:23]And and 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, the be 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 that change their behaviors and they begin to in synchrony carry out these group behaviors, right?

[00:24:20]So they don't have a clue. The bacteria really have no clue how many other cells are around. They're using these the buildup of these molecules as a proxy for cell number. And 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 few cells present, they can accomplish when they're together.

[00:24:51]>> Right? And so >> good. So the molecules are their words, if you will.

[00:24:56]>> So it's a phase transition. Can I call it that as a physicist? Is that fair?

[00:24:59]Sure. Okay, good.

[00:25:00]>> Yeah, you. [laughter] Yeah, sure.

[00:25:03]>> And 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 exquisitly nice way that you see why people would think it was intelligently designed, right? [laughter] >> Yeah. I don't think that >> but Well, 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?

[00:25:42]>> Yeah, I I think so. I think that probably, [snorts] you know, a gaz a billion years ago, whatever this when when when quensing evolved, we know these molecules, they're very simple. They're very cheap.

[00:25:53]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 bacterium evolves a receptor, right, that detects that molecule and and you know, and they're off to the races in terms of quorumsensing, right?

[00:26:12]And so, um, yeah, I don't I think that they probably were leftovers at the beginning, you know, and and but being able to detect them in the fact that every cell makes it share, you know, that that that the concentration of these molecules, we call them auto inducers, you know, because they auto induce the bacteria to do something.

[00:26:32]>> That's what we call them, you know, that those those increase in proportion to cell density >> because of because of biochemistry, right? because of the way they're made.

[00:26:42]>> Do they decay away eventually?

[00:26:44]Otherwise, I would think they would just sort of accumulate.

[00:26:46]>> Yeah, they Well, they do. So, they first So, um [laughter] 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 they're not they don't last forever.

[00:27:06]They're signals. So, they and and different some of them are more delicate than others. So presumably bacteria want longl lasting and shortlasting signals you know and so what I should tell you before I get to that is that um 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 bacterium makes. So that molecule says you are my twin. Okay?

[00:27:40]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 mi 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?

[00:28:14]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 large s 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 that kill off their competitors. And so um 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 rel relate closely or distantly I am related to my neighbor.

[00:28:59]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 ones that it takes lots of bacteria to make the behavior successful. So, let's go back to the traditional one, pathogenesis.

[00:29:23]So, when a harmful bacterium or a few of them get in me or you, if a couple 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. 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 one bacterium it's inconsequential the amount of anything it can make. But together I get the it's public goods. I get the benefit of what you do. You get the benefit of me doing and then these bacteria succeed. the ukareote, meaning the human or the plant, you know, may get sick or may get healthy, but the bacteria succeed in their task, right?

[00:30:16]We're the ones that say the task is good or bad, right?

[00:30:19]>> For them, these tasks are all good, right?

[00:30:21]>> If you personally um got a bacterial infection, would you feel a little betrayed?

[00:30:26]>> Oh, yeah. I really No. Whenever I get have a cold like I I also work on viruses of bacteria. So whenever I get a cold or I get a vir I am just I I'm just like my life's work. [laughter] >> Right. So I should be immune to all of that but I'm not. Yeah.

[00:30:44]>> And so yeah. Yeah. So you started to go down the the path of like so what do they do when they do sense all of their friends like you mentioned that they help with our uh digestion and there's these biofilms. Are these the kinds of things that are triggered by the quorum sensing?

[00:30:58]>> Yeah. Yeah. So bofilms are how bact 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 goop and so the bofilm 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 bofilm it has 600 species of bacteria it is architected right every day you get a cavity they're just eating right and and thriving right and so those are bofilms but Their skin is covered with bofilm.

[00:31:31]Every surface on earth, animate or inanimate, is covered in a bacterial bofilm, right?

[00:31:38]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 it it, you know, it locks them to the surfaces and makes them resilient. Those are all community behaviors. you know, one bacterium can't make a bofilm, you know, and then collectively these biofilms can make all these products, you know, toxins or beneficial products, you know, that these communities make.

[00:32:08]>> Okay, wait a minute. Say more about the fact that every surface in the world is covered by a bofilm. I didn't quite know that.

[00:32:14]>> There's nothing more to say about that, Sean. Every surface on this earth.

[00:32:20]>> Absolutely.

[00:32:21]>> The piece of paper in front of me is covered with a bofilm. Well, if probably when it 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. [laughter] Yeah. Certainly. Yeah. Everything.

[00:32:36]>> And does But the ones the one on my skin, I'm getting like the creeped out here, but okay. There's like bacterial bofilm on my skin and that's helping me.

[00:32:46]It's it's it's a suit of armor like you said.

[00:32:49]>> Correct. It is. So you can get a skin infection, you know, when you have an invader there. But no, that bofilm 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 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 that keep us healthy.

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[00:34:41]So going back to the evolution story, um you said [clears throat] that making the chemicals is pretty cheap, but I I don't know quite know how to quantify that. I mean at some point the way that evolution works as far as I can tell is they they started making chemicals without any benefit and then they realized there was a benefit to it.

[00:34:58]So it's sort of locked in genetically.

[00:35:01]>> 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.

[00:35:08]though 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 they we know we know, excuse [clears throat] 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 that every organism has, right? Right? And so they're kind of cheap and 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.

[00:35:47]It's just a leftover. But over time, it got co-opted by evolution >> to be a signal because it's leaked out.

[00:35:54]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?

[00:36:03]because these molecules were leaking out. The more cells there are, the more of these molecules there are, right?

[00:36:11]Then you can evolve a signaling system to have information encoded in those. I mean, that's the guess, right, about how quorum 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 a zillion genomes, right? Corm sensing is the norm in the bacterial world. Like so when I was first we were first discovering the first of these quorms 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 corpses.

[00:36:51]You know we can see these genes throughout the entire bacterial kingdom domain right and so it's not a one-off.

[00:36:58]And so I think that in ev 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 ger and the librarian.

[00:37:15]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 quum 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 ukarotic organ, I mean, you know, our own cells, you know, your kidney cells work together, your liver, you know, work together and herds of wilderbeast work together and wolves hunted, you know, and fishes. So, you know what I mean? and and and 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 know, 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?

[00:38:14]>> They were there first. Yeah, they get credit, right? Yeah, >> they get the priority claim. Um, >> and it's a 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.

[00:38:30]>> Correct. And it it's Yeah. 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 >> Yeah.

[00:39:00]>> a boss, right? Yeah.

[00:39:02]>> Do those chemicals do anything else that we know of? Uh the little molecules.

[00:39:08]>> 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 that's what we think. They are dedicated quensing signal molecules.

[00:39:28]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 ways, so thing you might be getting to, there's cheating and freewriting 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 auto-inducers 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 [snorts] 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 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 try you know because there's a lot there's all kinds of in these systems that 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 quorms sensing systems there is all kinds of [laughter] attempted and cheating and freewriting and eavesdropping because like the one good thing 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 where where different species that live together you know make a make mimic or trickery, you know, and so so somehow there's got to be little itty bitty policemen 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.

[00:41:48]>> It sounds like a perfect thing to study using game theory. Do people do that?

[00:41:52]>> For sure. So the you guys and your types love this for 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 you know like these ideas of these that 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 it bacteria are really great to study those kinds of things because you can do it on a peachy plate you you can actually do a real experiment. It's not just some public park or it's not a [laughter] right that that goes to heck, right? You know, when 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, [laughter] >> you know, it is game theory, right?

[00:42:50]Well, 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 uh um good and evil games, heroes and villains here, cheating and cooperation >> for sure. And I think another reason that that 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 trait We can make a guy that's deaf, right, that can't detect them. And we can then ask in a real experiment [snorts] who's harmed, who 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 [laughter] or you know you know or 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 um like get answers right so [laughter] 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?

[00:44:50]>> Right. About how these things work. And so that's been that's so so I think that quensing has been um a real boon to these kinds of cross-disciplinary um collaborations. So I've collaborated with Ned Winreen who's a theorist who should has never picked up a pipet nor should he and um yeah for 25 years on like how this system works for exactly the reason that you're saying.

[00:45:18]>> Have you ever visited Santa Fe Institute?

[00:45:21]>> I've never been Oh yeah, I have. I did.

[00:45:22]I went to one of those physics meetings and I've gone to the physics meetings in Aspen. Yeah, I have a card chewing. I have a little gold star.

[00:45:29]>> Yeah, physicists want to be. Yeah.

[00:45:31]>> 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 is probably my favorite example. It should be it's the founding example [snorts] right so it is the founding example on which the quorum sensing field was built right so remember bacteria and 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 corystein 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 uh almost everything in the 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, the uh a fabulous scientist sadly now deceased, Woody Hastings, uh 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 corn sensing, but bioluminescence. Like how could biology make light, right? You know, it's so I mean we love fireflies, right? 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. 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 me you know how 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 they that bacteria were doing something together right and so that's how this field started was because these bacteria made this visible output of quorm 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?

[00:48:14]But that was the the way in.

[00:48:17]>> Do [snorts] 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?

[00:48:31]>> Oh, yeah. Right. So they have an enzyme that we call luciferase which when it does its so there's a little fatty acid there's like a fat that's the substrate and when luciferase does its reaction right it um which is just a biochemical reaction it lets off a photon of light one one out of every 20 times right and 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 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.

[00:49:18]>> Is it a quorum sensing story in fireflies?

[00:49:20]>> So it is not. No, that's about sex. And so um right so [laughter] so what's really interesting is that we think that 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 luciferas need oxygen as one of the reactants but um yeah so fireflies are trying to find girlfriends and boyfriends they have a they have a uh timing you know so fireflies emit yellow light which is what you see at dusk, right? 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.

[00:50:01]>> Okay, good. Thank you for that. And okay, back to the bacteria who are the stars of their story. Um they also though as as I understand um 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 of the battlefield of bacteria is uh certain weaponry is turned on and off via quorum sensing. Is that right?

[00:50:24]>> Absolutely. And so I think though so for sure so we know all of these clinically relevant globally important pathogenic bacteria the baddies that if they don't have quensing you know like if we make mutants that that either can't talk or can't hear which we can make right they are completely avirulent because their repertoire of virilence factors toxins poisons you know things that let them enter into your cells those are all under quensing control, right? Because for the reasons we just talked about it that 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 quensing, you know, if a bacterium is going to give something away to the world, a toxin or a good something good, it never gets its own back. You know, the world is huge and bacteria. So if I release something, you know, a toxin, it's gone.

[00:51:26]And so the only way I as an individual bacterium can get the benefit of that toxin is if I 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 um listeners who I know are very sophisticated and like science for the sake of science. You know, there's a real industrial, biomed, agricultural part to this, right? Which is scientists have now learned about quensing, >> good or bad, right? So if we can beef up quenssensing in beneficial bacteria either in humans or industry or agriculture or we can interfere with quenssensing 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 sand.

[00:52:35]>> We're allowed to save the world, too.

[00:52:37]>> Playing in our sandboxes, but we actually do want to be dogooders. So, >> so is 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.

[00:52:53]>> Yeah. So, we've made molecules that look like the quorumsensing auto-inducers, 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? And and those shut down vir in animal models, right?

[00:53:10]These aren't in in real medicine yet, but in our labs, right? If we either make bacteria that just can't do quensing or we make synthetic strategies to shut down quorum sensing, make them so they can't make the auto-inducers, make them so the receptors get blocked, they they they have their entire um repertoire of virilence 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? 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 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 and um in humans and in industry we use bacteria to make us all kinds of stuff and to do all you know they they do bio remediation they clean up oil spills right if you could make quensing better right you can imagine all kinds of medical and industrial and agricultural you know things products >> well like 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 I really don't understand. So, I just ask you, does [clears throat] what's happening in my microbiome affect my mood or my like state of mind in any way?

[00:54:43]>> 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 um there's a lot of let me call this mounting evidence right remember these bacteria and I'm not talking about quensing 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 their little machines that do biochemistry right and so there's a lot of um 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. You 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 that do that and that's how why a salad is so healthy.

[00:55:42]You should thank your microbiome, right?

[00:55:44]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 um degrades the medicine. So you know how some people a medicine works on some doesn't work on others somebody gets a side effect somebody else doesn't that could 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 to my knowledge not proven yet but whether I'm a funny person I'm a happy person [laughter] you know I'm a you know uh 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 gob of molecules, there's 10 times more of them than your human cells. And these molecules are definitely, you know, we know that they're in our body. We just don't it's just such a um huge new horizon for scientists, you know, and and then again, remember Sean, your microbiome is 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? 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 >> 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 um intensively studied but hard to answer.

[00:57:42]Okay, >> we just did a podcast with Jeff Coller here at um Hopkins on using mRNA uh techniques to do bespoke therapies for rare diseases and >> exactly >> biology is hard. That's why I'm a physicist because like all these things [laughter] are related and talking to each other and it's it's very scary to me. Um but look, you know, I 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.

[00:58:12]>> 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 that's good little frontier there. Um 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 um bacteria are programmed to die and quorum sensing plays a role in that.

[00:58:44]>> Yeah. Yeah. That was kind of a that's a was a wonderful posttock in the lab that um that perhaps that he did he found it's a fact in these particular bacteria that we found when they make these beautiful bofilm structures he found that quensing regionally like in a region in you know you have to think of this as like a big community right adhered 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 core 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 this the community they all die and it's quensing controlled right and maybe what they do is they spill out all their nutrients. It's kind of like, you know, um cannibalism, right? It's a little bit like that. And then that that >> sacrifice, you know, allows the younger members of this community to hopefully survive a little bit more till maybe better times come along, right? So that was a crazy not crazy, it wasn't crazy, it was a really good project, [laughter] but it was a surprise. I mean, everything I'm going to tell you is a surprise. So yeah, he dis Amea was this postto that found that >> uh 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, um, right? That's a programmed cell death process, right? That gives you, for example, your fingers and toes.

[01:00:41]There's others, right? And again, programmed cell death was thought to be in ukarotes, right? So we don't really know in this case. We don't actually know if this quorms sensing trait is actually programmed cell death. It sure smacks of it.

[01:00:58]>> Okay. For so let me be more clear. For corsensing we know these bacteria are carrying out collective behaviors. We know that aa found that these cells do die. They die in this regional way. They quensing controls it. We hinted in the discussion of this paper that perhaps just like quensing was, you know, the original collective behavior. Perhaps bacteria also have programmed cell death mechanisms as do ukarots. You know, now I'm going to sound like a broken record. The bacteria were here first. Why wouldn't they have involved that if it's helpful in some situations?

[01:01:33]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. They split in two.

[01:01:43]So my naive physicist brain said how can one be older than the other? How could you have old bacteria and young ones?

[01:01:49]But apparently the materials split off asymmetrically. So there is like an older half and a younger half.

[01:01:55]>> Yeah. And there's an older side. Yes.

[01:01:57]Exactly right. And are they immortal? uh that's a little bit too [laughter] for me but yes but 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 maybe 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 jinned up way that we do experiment.

[01:02:31]>> Maybe I don't know Sean how much longer you want to talk to me. I can obviously I like communication. [laughter] >> Let's communicate. Yeah.

[01:02:39]>> Why don't me tell you what we're really working on right now?

[01:02:41]>> Let's do it.

[01:02:41]>> Okay. I'll tell you one more story. So So we've been talking about quorum sensing about bacteria, right? But what we've learned in the past couple 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 ukarotes and the viruses are participating in these chemical conversations.

[01:03:04]>> I was going to ask that. This is perfect.

[01:03:06]>> Oh, good. That's good. Okay, good. I want you to ask that. So, we'll pretend you asked me that and I'll act act like I'm a gracious um guest instead of, you know, [laughter] bossing you around. The bacteria might not have a boss, but I I am bossy. Anyway, let's see. So, two things. So for for the ukarotes like we found now that like your human gut cells make molecules that are almost identical to these bacterial qumsensing molecules, right? And so the bacteria perceive them as quensing 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, 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 corsync 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 ukarotes make gormsensing mimics right that bacteria respond to. So that's the ukarotes 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 that infect bacteria, we call them phages.

[01:04:46]>> Okay?

[01:04:47]>> Right? So bacteria have to protect them.

[01:04:49]Bacteria have immune systems that protect them from phages. And so what happens when a virus, a fagee gets in a bacterial cell, the virus, okay, I'll call it a fagee.

[01:05:02]The fage, that's a bacterial virus, right? The fagee 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 is infected right by the fagee or the fagee 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 dormcancy that's called lysogyny or lis so good when a virus gets into a bacterium it's got to decide lysogyny dormcy or lis right and so um >> and sorry the same virus can do either one depending Mhm.

[01:05:41]>> It's got to choose one or the other and they can switch between, right? So, right. So, you can have a lysoggen, you know, that's gone down many, many generations and all the sudden it says that's it. I'm out and it can go into litic 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 fage you know particles and try to infect naive cells that are in the population.

[01:06:11]Okay. So if the fagee decides the second like I'm going to lice my current host make more myself and then I'm going to spread and try to infect other cells. If there's no other cells there to infect that fagee is a goner. Right? So, when's a good time to >> to choose Aha. [laughter] So, when's a good Yes. Right. So, when's a good time to to be litic? 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, if you pop out of that current house and you kill it, you want to have maximally transfer the next cell. So what we've found now is these bacterial viruses have captured or evolved quensing receptors. So what they do is as the host bacteria are growing, they're releasing these auto-inducer molecules. The viruses are eavesdropping. They're surveilling the quorumsensing molecules, right? And then they recognize when there's lots of host cells around and then that that corner sensing turns on the decision to switch from being dormant to go litic. Right?

[01:07:19]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?

[01:07:29]So now we get that this corn. So this is what my lab might what we're interested we're not so interested in discovering the next quensing system. were very interested in this idea of quensing spanning from ukarotes to bacteria to viruses and like viruses they're not even like they're more different than right like viruses aren't even >> 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 fage 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 um are tuned in. That was a and afterwards again going back to something we said before afterwards were like you know people have studied fagee fagee 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 fages tune into corn 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 a fagee needs more victims right so of course they you know and of course I think I spent my whole life just going like shouldn't we have figured that out sooner right yeah but anyway that's something I'm also very excited about in my lab like I don't think that this sound like a Montipy python movie we're not dead yet I don't think the quensensing 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 quensing 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, exactly. And so near the end of the podcast, we always allow ourselves to be a little bit more speculative and uh let our hair down and this is the time. So uh 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 um 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 ukarotes or the origin of multisellularity 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 multisellularity even though it it mostly happens in ukarotes >> yeah I think okay So there's a debate about that like everything right and so um so for sure you know these biofilms or these groups right 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 multisellularity right these cells these groups they're coordinated they're doing things together I mean that is what happens both in multisellular organisms, but also just in organs, you know, in, [clears throat] 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 can and I'm talking about the bacterial cells, they can live on its own, right? So if I scramble that bofilm up, right, and release it, right, every one of them, those cells can live. Now if I do that to your kidney >> right [laughter] or Yeah. Right. And so like so again in your body or in a multi a real multisellular organism >> every cell has a vested interest in every other cell being healthy right in a bacterial biofilm or a bacterial community they they're all fine on their own. You know if everybody else dies it's kind of what we got back to. there still I can still a an and individual still can still divide and make the whole thing again.

[01:11:26]>> Right.

[01:11:26]>> Right. And so so there's something fundamentally different I think this is just my opinion you know that that there are the traits of multisellularity the collective behaviors you know they they they do know in a bofilm 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 It's 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.

[01:12:06]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 could build that bofilm again, you know, by dividing, right?

[01:12:19]>> Yeah.

[01:12:20]>> But and that's just different, right?

[01:12:23]like if I kill all your kidney cells, you are in a huge amount of trouble, >> right?

[01:12:27]>> But so I'm wondering, you know, again, what do I know? But I'm wondering uh you're you're so it makes perfect sense.

[01:12:33]The bacteria don't need each other to survive on their own. And that is an important difference. But so could we envision 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.

[01:12:56]>> Yeah. And we'd call that a ukarot, right? And uh Yeah. And it go and and again, you know, we already know that happened. Your mitochondria, right, or a chloroplast in a plant cell, right? Those used to be free-living bacteria, >> right?

[01:13:10]>> Right. That got somehow engulfed or whatever. And then they they have so few genes left, but they do all these really important, you know, they're the little engines of our cells, right? And so we have a not an it's like an analog of what you're asking me. I think we, you know, you know what I mean? Like, right?

[01:13:27]And so, >> yeah. [laughter] >> Okay, good. So, here's the final question, then. Um the uh we started by saying that there's more the number fluctuates, right? The number of bacteria in our bodies, they used to say 10 and they said it's about the same and maybe it's a little bit more.

[01:13:46]>> Um is there some future moment when we're just going to say, you know what, those are all human cells. Like our bacterial cells are still our cells and we should count them. [sighs] >> Right? So I think that if you're me um you believe that being a human or for me a ukareote means a community you know and I mean you know like I collective >> think of myself as >> this marvelous I don't mean that in an ego maniacal way I mean like this marvelous collection >> of cells right and and just like you I don't notice my bacterial cells either right but my human Well, and I can't be human without them.

[01:14:30]>> Mhm.

[01:14:30]>> Right. You know, unless I guess I lived in a bubble, you know, you you know what I mean? You know, so you can't be without them. So, you need them, you know, um to keep you alive, to keep you healthy, to protect you. Um I mean, don't get me wrong, you could be bor, you are born, you could be born, you could kind of live, but not for very long [laughter] without them, right? So, you do need them. But my human genome is my human genome, [laughter] >> right? And I have and I do have a brain, >> right? And they don't.

[01:15:02]>> Yeah.

[01:15:03]>> Right. But they are um But you need them, right? And so >> are we giving too much credit to the genome is my question. Like are we are we >> whose genome? Theirs or ours?

[01:15:14]>> Ours. Are we privileging?

[01:15:16]>> Oh, for [laughter] sure. Definitely. Oh, please. Yeah, of course. Yeah. Oh, for sure.

[01:15:22]But [laughter] but but then again, right, we >> 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 these things that that individually they don't have or even collectively they don't have.

[01:15:41]>> Are the bacteria in our gut microbiome etc. are they just temporary or are they there for our whole lives?

[01:15:48]>> Yeah, you get colonized. uh they change throughout your life. You get colonized, you you start sterile, you get colonized on your way out of the birth canal and you mostly get them by slopping goop, you know, from your family, right? For 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 plummets and we think maybe that's about aging or you know health and also if you eat live in an industrial world or a polluted world it's different you know so they can change like as you move around as your health when you take antibiotics but ultimately you will have a m you will have microbiome bacteria throughout your whole life right >> but so if I if you live with uh somebody your microbiomes intermingle They do a bit. Yeah. You look, 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 kids.

[01:16:56]Yeah, a little bit. No, probably [laughter] not. Extremely romantic place to end. So, Bonnie Bass, thanks so much for being as a dinner companion.

[01:17:05][laughter] >> I don't talk about bacteria nearly enough. That's the lesson I'm getting.

[01:17:10]So, thanks very much for being [laughter] on the Mindscape podcast.

[01:17:13]>> Oh, Sean, please edit this.

[01:17:16]>> No, can't do it. Sorry. [laughter] >> Anyway, no, really, actually, it was thrilling. You really made it uh fun for me to get to talk about all these wild topics. I hope it was helpful and that people like it.

[01:17:27]>> Oh, I think they will. All right. Thanks very much.

[01:17:29]>> Thanks. I'll see you, Sean.

[01:17:34][music] Yeah. [music] Heat.