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I'm trusting T Mobile.

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They have the best network.

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I don't trust my carrier that much.

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We'll just use your phone as a flashlight.

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Kiana (Shopify Testimonial)

mobile.com I'm Kiana and I leveled up my business with Shopify. Once I figured out that Shopify was a thing, I never turned back. I can create a site with my eyes closed. Shopify thinks ahead of us, you know, and it thinks about the customer more than anything. Every day I'm thinking about some other new business, but Shopify is doing it to me because it's so easy to use. It's like I can't stop. I'm addicted.

Sean Carroll (Host)

Start your free trial@shopify.com hello everyone and

welcome to the Mindscape Podcast. I'm your host, Sean Carroll.

As I am recording this, I just this week finally sent in the manuscript to my publisher for book three of

the biggest ideas in the universe called Complexity and Emergence.

I do apologize to everyone who's been waiting for this book.

I'm not exactly sure when it's going to come out.

I'll let you know when I do. It 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, thinking about what they

do, and they come together to form something a little bit unanticipated. Of course, anyone who thinks about emergence and complexity knows that it's very difficult

to define exactly what you mean by

unanticipated in those contexts. But more is different is the motto that is usually thrown around here, coined

by physicist Philip Anderson, the idea that

as a system, whether it's an ant colony or sand in a sand pile, you can get behavior at the collective level that you would not have thought

of just by thinking about the individual

units that are coming together. And so I felt like in writing

this, it's a topic that I've known, I know quite a bit about, but

not nearly as much as one could because it's a sprawling, gigantic topic. And I felt that very, very strongly while writing about it. Like the things that I did say in that chapter, which again, is the culmination of the book I loved, I

liked everything I said, but you had

to make choices about what to exclude, what kind of arbitra classifications to invent to make this sprawling landscape of possibilities more coherent, etc.

We'll see how that goes over.

I'm thinking about this and saying this right now because today's podcast is a classic example of self organization and one

that I was not able to include in the book, even though I had really thought about it.

The units in question are bacteria, so just about the simplest living organisms that you can imagine. And nevertheless, they have enough complexity to come together in interesting ways and do things as a collective that you wouldn't have guessed they were going to do as individual cells. And the mechanism for them doing this is something called quorum sensing. Quorum sensing was discovered back in the 1970s by Woody Hastings and other people. But the world's expert in quorum sensing is Bonnie Bassler, who is our guest today. Bonnie was really the one starting the 19 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. 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. As we will discuss in the podcast,

there's a lot of bacteria that you

carry with you, probably at least as many, if not more bacterial cells in your body as there are your cells

in the sense that your cells have

your DNA in them. And there's a symbiotic relationship. Those bacteria are doing really, really important things for you just as you're providing a home for them. And so the dynamics of the bacteria working together and also how they fight off threats and how they symbiotically interact with other subsystems of your body are crucially important. It's a really fun topic in just

about every possible way.

It's intrinsically important because it's important 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,

Foreign. Bassler. Welcome to the Mindscape podcast.

Bonnie Bassler

Thanks for having me, Sean. I'm delighted.

Sean Carroll (Host)

I gotta 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

Bonnie Bassler

sure you've guessed, knew 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, I 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 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. 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 fantastic model system, you know, these stripped down versions of us, if you will, that I could wrap my head around. And you're going to see during this hour, I'm very, and you already know me, I'm very fast talking, I'm very high energy. And so, you know, like you could have a surprise in the incubator every eight hours, you could spill it the floor and it didn't really matter. You could do it again the next day. And so it 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. 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.

Sean Carroll (Host)

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.

Bonnie Bassler

Yeah. And I do wonder, like, to that question, I think, if they'd have put me on a fly project or, you know, maybe I would have loved that too. Right? Because what I love is, is making discoveries. And, and then I don't do this as much, you know, working with my hands. You're doing experiments, trying to put these puzzle pieces together. So I do always wonder if, you know, put me on that cancer project, maybe I'd be working on cancer. But anyway, lucky, lucky me.

Sean Carroll (Host)

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. In particle physics, that takes decades. Right?

Bonnie Bassler

Well, and in cosmology, you guys don't even get to do an experiment, right? Not really. Right. And So I do think. And then of course, for me, that's very satisfying. Right like that. And that is the attraction to me, is that you can ask these questions and get seemingly definitive answers. Obviously, they give you your next question. If you're doing it right, it leads you to your next question. 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.

Sean Carroll (Host)

So what do we need to know about bacteria for the purposes of this conversation? And especially the bacteria that live in our bodies, which apparently there's quite a number of them,

Bonnie Bassler

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 communicate. To be more serious with you, what I think will prob. Spend a lot of time talking about today is what my gang is always trying to figure out. So if I can just go back for a second to really answer your question. What my gang has always been trying to figure out is how 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. They 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. 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. And so we call this process of bacterial communication in group behavior quorum sensing. And I guess I'll just. I'll tell you how it works. So the way it works is actually,

Sean Carroll (Host)

you know what, don't tell me how it works now because I'm going to get there.

Bonnie Bassler

Okay.

Sean Carroll (Host)

I want to, like, you know, because the idea of quorum sensing does come as a surprise in some sense. Like, it's a pretty sophisticated thing. So I want to make sure we soften up the audience to let them be surprised by talking about just how primitive bacteria are. Like, arguably they're the most primitive life forms. Is that at least a plausible perspective?

Bonnie Bassler

Yeah, yeah, they. Okay, I wasn't actually there, but they arrived, arrived. They evolved on Earth right after oxygen, right? So they're. They have been on this Earth for billions of years, like 4 billion years. They are, we think, Earth's first living organism. Right. And so they are the most ancient living organisms that we know of. And they are all single celled, Right. They're, you know, microbes. You must have a microscope to see one. Right. 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 Von Lee and Hoek, you know, who was like a microscope maker. Yes, animalcules. 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. But they've always, until about 30 or 40 years ago when this notion of quorum sensing, and we can talk about how that happened, sort of came about. They were always thought to be these 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 bacteria gave us the parts list. We got DNA, rna, proteins from bacteria, right? But the cool stuff, behaviors and development and thought and all those kinds of things, that's all in higher organisms. And so there was some kind of snobbery, including among us, the bacteriologists, right, that they just didn't have the wherewithal to communicate or to do things as groups, because those seem like very evolved behaviors, right? But then if you think about it, right, we all came from bacteria, you know, where you think this stuff comes from. And then again, going back to what I said that started this is, if you think about all the profound, profound things bacteria can do, Good or bad, how could we have thought for so long that a tiny 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. 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 in retrospect. Now it actually seems obvious now. But of course, that's after a discovery gets made.

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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. 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. We probably have lost 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.

Bonnie Bassler

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. Like they live in thermal vents or really cold places or dry dusty places. So they seem to be able to thrive in. In places currently on Earth that are the closest to what we think Earth was like, you know, billions of years ago, you know, as 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. Right? Yeah.

Sean Carroll (Host)

And the.

Bonnie Bassler

So they're sort of vestiges and they inhabit these, you know, places like in Yellowstone. Right. Where the geology's not done. That's where these archaea live.

Sean Carroll (Host)

But archaea are different than bacteria.

Bonnie Bassler

They are indeed. So there are three domains of life. Yeah. So archaea gave rise to both bacteria, prokaryotes and eukaryotes. And archaeal genomes actually look more like eukaryotic genomes than bacterial genomes. Yeah. But then those archaea are. They are relegated to these hostile places that are currently on Earth. And then the bacteria came and they are nearly all of the biodiversity that exists on Earth. Right. Almost everything you have that exists on Earth you have not seen with your eyes. Right. So even most eukaryotes are microbes, right?

Sean Carroll (Host)

Yeah.

Bonnie Bassler

Right.

Sean Carroll (Host)

Okay.

Bonnie Bassler

And so, you know, like, if you look at. I wish we 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 can make because we have genomes and you see all the bacteria are huge. They are KR 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. So the world is microbial and it's mostly bacterial.

Sean Carroll (Host)

All right? And, yeah, we have a very uneven view of the world, unless we're professional

Bonnie Bassler

bacteriologists, and I guess I was going to say. And I guess you see my bias, right? So. Yeah, but I'm right.

Sean Carroll (Host)

You have numbers on your side and.

Bonnie Bassler

Correct.

Sean Carroll (Host)

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.

Bonnie Bassler

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. Every other organism on Earth lives in this magical, wonderful consortium with microbes in you and on you, right? And they are contributing their genes and their proteins to keeping you alive and healthy, right? So first of all, they take up all the real estate. You know, in an honest, bad microbes, you 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 that. Like a suit of armor that keeps bad ropes 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 keep 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 a. 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 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 are trying to figure out microbes, how could they possibly know that we had these microbiomes? And for a long time, once it was recognized that there were bacteria in an honest, 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 mysterious microbiome. Right. It's a new field of study. And so it's not. So there's a reason that for as long as people have recognized bacteria as pathogens, they never associated them with the good stuff they do. Because bacteria are invisible.

Sean Carroll (Host)

Yeah.

Bonnie Bassler

No plant can grow without these bacteria in the soil. I mean, 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, making a lot of bad press.

Sean Carroll (Host)

There's more cells of bacteria in our bodies than human cells. And the trick is not all cells are the same size. Right?

Bonnie Bassler

Correct.

Sean Carroll (Host)

By mass, we're mostly human.

Kiana (Shopify Testimonial)

Correct.

Bonnie Bassler

So. Right. So a human cell is, you know, 500 or 1,000 times bigger than a bacterial cell. So.

Hiker 1

Yes.

Bonnie Bassler

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. 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 say, I can't lose that last five pounds, you can't.

Sean Carroll (Host)

It's a bacteria now.

Bonnie Bassler

I know.

Sean Carroll (Host)

You're excused.

Bonnie Bassler

You don't have to. You can't.

Sean Carroll (Host)

All right, that's extremely helpful. But still, five pounds, you go home and eat dessert thing, that's not trivial. Okay. There's a lot of bacteria in me. Good. 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. 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, Correct?

Bonnie Bassler

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. And so the way it works is that bacteria, they consume nutrients from their environment. They. 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. So they just divide asexually. 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, 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 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. 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 presence, they can accomplish when they're together.

T-Mobile Announcer

Right.

Bonnie Bassler

And so.

Sean Carroll (Host)

Good.

Bonnie Bassler

So the molecules are their words, if you will.

Sean Carroll (Host)

So it's a phase transition. Can I call it that as a physicist? Is that fair?

Bonnie Bassler

Sure, yeah. You. Yeah, sure.

Sean Carroll (Host)

And it sounds like you're already anthropomorphizing, which is fine, I think. I think we're sophisticated enough to know what it really means. But there's also this question. I sometimes tease my biologist guests because sometimes nature does things in such an exquisitely nice way that you see why people would think it was intelligently designed. Right?

Bonnie Bassler

Yeah, I don't think that.

Sean Carroll (Host)

Well, exactly. Neither do I. But this is kind of like the opposite. This is 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?

Bonnie Bassler

Yeah, I think so. I think that probably, you know, a billion years ago, whenever this one, when quorum sensing evolved, we know these molecules. They're very simple. They're very cheap. They probably just leaked out. They were like just byproducts of metabolism. They leaked out. As soon as you leaked them out of a cell, there is a number component, Right. Because they can build up. And then bacterium evolves a receptor. Right. That detects that molecule and. And, you know, and they're off to the races in terms of quorum sensing. Right. And so, yeah, I Don't. I think that they probably were leftovers at the beginning, you know, and, and, but being able to detect them and the fact that every cell makes its share, you know, that the concentration of these molecules, we call them auto inducers, you know, because they auto induce the bacteria. 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.

Sean Carroll (Host)

Do they decay away?

Eventually.

Otherwise I would think they would just sort of accumulate.

Bonnie Bassler

Yeah, they, well, they do. So they do, 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. But they do, they don't look, they', they don't last forever. They're signals. And some of them are more delicate than others. So presumably bacteria want long lasting and short lasting signals. And so what I should tell you before I get to that is that there are multiple words in this lexicon. So it's not. So of course we don't know everything about every bacteria, but in these model systems that we study, there are molecules, for example, that one, and as far as we can tell, one and, and only one species of bacteria makes. So that molecule says, you are my twin, you're my clone. Then there's a molecule that all the bacteria in a family make. So they say, you're my cousin, so you're related to me, but you're not my twin. Then there's a molecule that all bacteria make. It's sort of a universal language that says other. And so not only are the bacteria measuring the buildup of these molecules, they're actually measuring the ratios of these molecules when they're in these consortia with lots of different species present. And so what we think they're doing, they're asking first how many bacteria are here? Then they're asking, who are they? Is it me and my kin or is it the enemy? And then they actually change their behaviors based on who's in the majority and who's in the minority. So like when you and your kin, your siblings are all together, the bacteria make all these public goods, they release all these goodies, everybody shares in this largesse 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 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 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 aud 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. 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, it's public goods. I get the benefit of what you do, you get the benefit of me do. And then these bacteria succeed. The eukaryote, meaning the human or the plant, 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.

Sean Carroll (Host)

Right.

Bonnie Bassler

For them, these tasks are all good.

Sean Carroll (Host)

Right. If you personally got a bacterial infection, Would you feel a little betrayed?

Bonnie Bassler

Oh, yeah. I really. No. Whenever I get. Have a cold, like, I also work on viruses of bacteria. So whenever I get a cold or I get a virus, I am just. I. I'm just like, oh, my life's work. I should be immune to all of that, But I'm not. Yeah.

Sean Carroll (Host)

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 digestion. And there's these biofilms. Are these the kinds of things that are triggered by the quorum sen?

Bonnie Bassler

Yeah, yeah. So biofilms are how bacteria are how we think are the predominant way. We think that bacteria live in nature, which is adhered to surface 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. It has 600 species of bacteria. It is architected. Right. Every day you get a cavity, they're just eating. Right. And thriving. Right. And so those are biofilms, but your skin is covered 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. It locks them to the surfaces and makes them resilient. Those are all community behaviors. 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.

Sean Carroll (Host)

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.

Bonnie Bassler

There's nothing more to say about that, Sean. Every surface on this Earth, my skin, covered in it. Absolutely.

Sean Carroll (Host)

The piece of paper in front of me is covered with a biofilm.

Bonnie Bassler

Well, if. Probably when it.

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It.

Bonnie Bassler

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.

Sean Carroll (Host)

Yeah, okay.

Bonnie Bassler

Certainly. Yeah.

Sean Carroll (Host)

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 a suit of armor, like you said.

Bonnie Bassler

Correct. It is. So you can get a skin infection, you know, when you have an invader there. But no, that. That biofilm that you can't see or feel that's on your skin is covering up all of the surface and keeping bad bacteria that happen to land on you that you also can't see or that you run into from getting any real estate. And now your skin's a funny thing. Your skin, you know, you make new skin cells and you schluff them off all the time. That's part of your defense against predatory bacteria, right? But your skin gets colonized again and again and again, you know, by these bacteria that keep us healthy.

Hiker 1

Awkward time to ask this, but. Hey, did you download the trail map?

Hiker 2

Yeah. No, I don't need to.

Hiker 1

I don't understand. You're trusting your signal out here?

Hiker 2

I'm trusting T Mobile.

Bonnie Bassler

They have the best network.

Hiker 2

And if we end up in bumtots nowhere, well, we've got T Satellite for backup.

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Whoa.

Hiker 1

I don't trust my carrier. That much.

Hiker 2

We'll just use your phone as a flashlight.

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Sean Carroll (Host)

every Home so going back to the evolution story, you said that making the chemicals is pretty cheap, but I don't know quite know how to quantify that. I mean, at some point point 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.

Bonnie Bassler

So I think that. So when we look at the what, again, we don't know what all the molecules are, right? I need a job. So try to figure this out, right? But the molecules, they're not like fancy molecules with lots of parts. They're very simple and they we know, excuse me, how many of them are made, the ones we've discovered. And they're made from very ancient substrates like amino acids, you know, fatty acids, very ancient central substrates that every organism has, right? And so they're kind of cheap. And when you look at them, they look kind of like, you know, these reactions were happening to make something and this was the leftover and it probably got leaked out like it was garbage, right? 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, the bacteria basically swimming in it, right? And so if you can evolve a receptor that binds it and sends information into the cell, right? Because these molecules were leaking out, the more cells there are, the more of these molecules there are, right. Then you can evolve a signaling system to have information encoded in those. I mean, that's the guess, right? About how 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? Quorum sensing is the norm in the bacterial world. Like so when I was first, we were first discovering the first of these quorum sensing, we're like, wow, you know, is this some crazy anomaly of some obscure bacterium? Well, fast forward 30 years, we look through these genomes, right? There are tens of thousands of cases of quorum. We can see these genes throughout the entire bacterial kingdom domain, right? And so it's not a one off. And so I think that 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? I think that that's an amazing step in evolution. And of course, you know, we know that in eukaryotic organ, I mean our own cells, you know, your kidney cells work together, your liver cell, you know, work together, and herds of wildebeests work together, and wolves hunted, you know, and fishes, you know what I mean? And like we understand the value of collective behaviors in organisms that we see with our eyes or even in cells in a higher organism. And of course, we came from bacteria. So these rules you're how to make collective, you know, why wouldn't they have evolved billions of years ago? And yeah, you and your liver cells and kidney cells have a few more bells and whistles than my bacteria do. But the bacteria made the rules shot, right?

Sean Carroll (Host)

They were there first. Yeah. They get credit, right? Yeah, yeah, they get the priority claim. 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.

Bonnie Bassler

Correct. And 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 rele these molecules as part of the biochemistry that happens in these simple single cells. Right. And so you can get this emergent behavior without a boss. Right? Yeah.

Sean Carroll (Host)

Do those chemicals do anything else that we know of the little molecules?

Bonnie Bassler

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. But for sure, in some ways. So 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. When it builds up to the threshold. But other bacteria, if they tune into it, it's actually an antibiotic. So it kills them. Right. So. Right. And like you, so. So that. That's just based on the structure of the molecule, that, that it's deadly. It's toxic to one bacterium, but not to another. Right. But you can imagine that that's a really good molecule to make because you can kill your competitors. Right. Who are. You know, because there's a lot. There's all kinds of. In these systems. So that's a dual function molecule. Right. Because in these systems, remember, these bacteria mostly don't live in test tubes in Princeton, New Jersey, you know, in these pristine. Right. They live out in the wild west. And so there is in these quorum sensing systems, there is all kinds of attempted and cheating and free riding and eavesdropping because like the one good thing to do is I make the molecule, but I Don't turn on the genes that are really expensive, which are all the public goods in the task, right? Or I, you, my competitor, make a molecule that you're trying to count your cell numbers, and I, your competitor, make an enzyme that I clip that molecule in. 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 trickery, you know, and so somehow there's gotta 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 lab, you know, where these creatures are actually living together, you know, each with their own priorities that may not match.

Sean Carroll (Host)

It sounds like a perfect thing to

study using game theory.

Do people do that?

Bonnie Bassler

For sure. So the. 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. 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 bacteria are really great to study those kinds of things because you can do it on a petri 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, when. 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? Because it has the features that they like to think about, usually about humans. Right. But in fact, you know, it is game theory, right?

Sean Carroll (Host)

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, so bacteria might be like the simplest things that have little coordination

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and

Sean Carroll (Host)

good and evil games, heroes and villains here, cheating cooperation, for sure.

Bonnie Bassler

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. How did cooperation and cheating and what does it take and what are the rules evolve on Earth? What's great about bacteria is that we can make mutants, right? You can't do that with humans, Right? So we can make a cheater, right? You're not supposed to. Yes, okay. But we can make a bacterium that only makes the molecule, but doesn't turn on the traits. We can make a guy that's deaf, right. That can't detect them. And we can then ask in a real experiment 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, in bottles, right? And we can add molecules when we want and which molecules and blends. And so their bacteria are just so fantastic to work on because you can at least begin to get at the kinds of questions that would be absolutely unethical to try or, you know, you know, or you can't do it. Like, you can't. Like there may be a lazy lion in a lion pack. Right. But how do you actually study it and get, you know, right here we can do that and like get answers. Right. So, so, so, so. And then again, to the point about the physicists, right. Is that it's really, really attractive because we can amass data, you know, experimental data that they can put into their models. Right, right. About how these things work. And so that's been. That's so, 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.

Sean Carroll (Host)

Have you ever visited the Santa Fe Institute?

Bonnie Bassler

I've never been. Oh, yeah, I have. I did. I went to one of those physics meetings and I've gone to the physics meetings in Aspen. Yeah, I have card queuing. I have a little gold star. Yeah. Physicists want to be.

Sean Carroll (Host)

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.

Bonnie Bassler

It should be. It's the founding example. Right. So it is the founding example on which the quorum sensing field was built. Right. So remember, back to not remember, that sounds. I don't mean to say 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 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, common in the ocean, right? So they make blue light. You know, fireflies make yellow light. Blue light travels far in the water. So things, creatures in the ocean make blue and green and purple light, right? And so almost everything in the. 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? 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? 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. 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 assuming, 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 quorum sensing, you know, and now, again, going back to what I said, we know it's the norm. We have all these ways to measure genes and behaviors and things that we didn't have in the 1970s when Woody Hastings discovered this. Right? But that was the. The way in.

Sean Carroll (Host)

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?

Bonnie Bassler

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, there's like a fat, that's the substrate. And when lucifera rays does its reaction, right. It. 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 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.

Hiker 1

Awkward time to ask this, but. Hey, did you download the trail map?

Hiker 2

Yeah. No, I don't need to.

Hiker 1

I. I don't understand. You're trusting your signal out here?

Hiker 2

I'm trusting T Mobile.

Bonnie Bassler

They have the best network.

Hiker 2

And if we end up in bumtots nowhere, well, we've got T satellite for backup.

Kiana (Shopify Testimonial)

Whoa.

Hiker 1

I don't trust my carrier that much.

Hiker 2

We'll just use your phone as a flash.

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Sean Carroll (Host)

mobile.com Is it a quorum sensing story in fireflies?

Bonnie Bassler

So it is not. No, that's about sex. And so. Right. So. 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. 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 and there's a pattern and they're following that light to be able to mate.

Sean Carroll (Host)

Okay, good. Thank you for that. And okay, back to the bacteria, who are the stars of their story. They also, though, as I understand, the quorum sensing comes in when they want to do something bad to us, right? Like when they want to attack or maybe when they want to defend. Like part of the, of the battlefield of bacteria is certain weaponry is turned on and off via quorum sensing, Is that right?

Bonnie Bassler

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 quorum sensing, you know, like if we make mutants that either can't talk or can't hear, which we can make. Right. They are completely aviralant 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, that you have to have the army do it together to have an effect on the host, whether the host is an, an 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. You know, the world is huge and bacteria. So if I release something, a toxin, it's gone. 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 listeners who I know are very sophisticated and like science for the sake of science. You know, there's a real industrial, biomedical, agricultural part to this, right. Which is scientists have now learned about quorum sensing, good or bad, right? So if we can beef up quorum sensing in beneficial bacteria, either in humans or industry or agriculture, or we can interfere with quorum sensing in these harmful bacteria. Right? Those are applications that are being made now based on, you know, learning about these crazy bioluminescent bacteria really that started this, right? And now there's a very, there's many, many People, scientists working on these applications, you know, based on what we've learned. Right. So I do want to make a little plug that we're not just playing in our sandbox.

Sean Carroll (Host)

We're allowed to save the world too.

Bonnie Bassler

We are playing in our sandboxes, but we actually do want to be do gooders. So.

Sean Carroll (Host)

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.

Bonnie Bassler

Yeah. So we've made molecules that look like, 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. And 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 the 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, 1, 2, 3, shoot, right. They don't know to do it. And so you're just trying to buy time for the immune system, you know, to get rid of them, which is what your immune system is doing all the time. It's doing surveillance. It's just that these few pathogenic bacteria have, you know, have a leg up on us. And so if you could thwart them by just getting them not to be able to launch these harmful attacks, there's real promise to that. And then again, I want to talk about these good bacteria. Like, in agriculture and in humans and in industry, we use bacteria to make us all kinds of stuff and to do all, you know, they do bioremediation, they clean up oil spills. Right. If you could make quorum sensing better. Right. You can imagine all kinds of medical and industrial and agricultural, natural, you know, things, products.

Sean Carroll (Host)

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 what's happening in my microbiome affect my mood

or my, like, state of mind in any way?

Bonnie Bassler

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. So 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? All kinds of. That's what bacteria do. They're little machines that do biochemistry, right? And so there's a lot of energy, let's call it that, in this idea that for sure, you know, for sure they're making. Just let me start with facts like you cannot digest plant food whenever you eat a vegetable or a salad or anything like that. Your human genome does not have the enzymes that allow you to digest that food and get the calories, nor the nutrients. So the bacteria in your gut provide the enzymes that 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, that, that degrades the medicine. So you know how some people, a medicine works on some, doesn't work on others. Somebody gets a side effect, somebody else doesn't, that could. There's a lot of evidence, and I mean, data that shows your microbiomes playing in that whether they can affect your mood, that people think that's a possibility. That is my knowledge, not proven yet. But whether I'm a funny person, I'm a happy person, you know, I, I must. You know, there's like, ideas that maybe if you're a better. Depending on your microbiome, you might be a better athlete. That's way out there, okay? But it's not crazy, right? Given that these bacteria make a 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 is different than my microbiome, you know, and what you eat, how 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 intensively studied, but hard to answer. Okay.

Sean Carroll (Host)

We just did a podcast with Jeff Collar here at Hopkins on using MRNA techniques to do bespoke therapies for rare diseases and.

Bonnie Bassler

Exactly.

Sean Carroll (Host)

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. It's very scary to me. 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.

Bonnie Bassler

Those are Molly. Molecules.

Sean Carroll (Host)

Yes, they're 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. A little frontier there. Another frontier, I think, that you've been working on recently, I mean, depending on

how you define recently, is cell to death.

Like the poor bacteria are programmed to die. And quorum sensing plays a role in that.

Bonnie Bassler

Yeah, yeah, that was kind of a. That's a. Was a wonderful postdoc in the lab that. 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 in. You know, I 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, of course, it seems high cell density, lots of cells there. And so then maybe maybe some of these elders, because it is the oldest part of this, the community, they all die. And it's quorum sensing controlled. Right. And maybe what they do is they spill out all their nutrients. It's kind of like, you know, cannibalism, right? 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. It was a surprise. I mean, everything I'm going to tell you is a surprise. So, yeah, he just. Ameya 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 wide webbed. Right. And then the cells that are in between your. Excuse me, your toes and your fingers. Those cells, as one example, those cells die and you get your digits. Right. That's a 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 traitor is actually programmed cell death and sure smacks of it. Okay, so let me be more clear for quorum sensing. We know these bacteria are carrying out collective behaviors. We know that may have found that these cells do die. They die in this regional way. Quorum sensing controls it. We hinted in the discussion of this paper that perhaps, just like quorum sensing was, you know, the original collective behavior, perhaps bacteria also have programmed cell death mechanisms, as do eukaryotes. You know, 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

Sean Carroll (Host)

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. So my naive physicist brain said, how can one be older than the other? How could you have old bacteria and young ones? But apparently the materials split off asymmetrically. So there is like an older half and a younger half.

Bonnie Bassler

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. 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. 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.

Sean Carroll (Host)

Let's communicate.

Hiker 2

Yeah.

Bonnie Bassler

Why don't we tell you what we're really working on?

Sean Carroll (Host)

Yeah, let's do it.

Bonnie Bassler

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 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.

Sean Carroll (Host)

I was going to ask. This is perfect.

Bonnie Bassler

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. The bacteria might not have a boss, but I am bossy anyway. Let's see. So two things. So for the eukaryotes, like we found now, that like your human gut cells make molecules that are almost identical to these bacterial 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 our human, 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 hundreds of thousands of years, maybe your human cells want to be controlling what those bacteria do. Right? And so by making autoinducer, 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 that bacteria respond to. So that's the eukaryotes 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.

Sean Carroll (Host)

Okay?

Bonnie Bassler

Right. 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 called a phage, the phage, that's a bacterial virus, Right. The phage can do One of two things. It can just be dormant and be passed down through generations. So every time the bacteria divides, the daughter cell gets the is. 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 lysos or lysis. So when a virus gets into a bacterium, it's got to decide lysogeny dormancy or lysis. Right.

Sean Carroll (Host)

And so, sorry, the same virus can do either one, depending.

Bonnie Bassler

It's got to choose one or the other and they can switch between. Right. So. Right. So you can have a lysogen, you know, 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 the lytic mode. Right. Okay. So both ways, the virus wants to just infect cells. Right. So you can do one by one by one, one 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. 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 switch? To choose.

Kiana (Shopify Testimonial)

Aha.

Bonnie Bassler

So when's a good. Yes. Right. So when's a good time to do B Lytic? Well, it's when there's lots of other bacterial cells around. So if you pop out, you and your. All these virus particles that you may, if you pop out of that current helicopter and you kill it, you want to maximally transfer the next cell. So what we've found now is these bacterial viruses have captured or evolved quorum sensing receptors. So what they do is as the host bacteria are growing, they're releasing these 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. So they only make viruses, they only kill their host cells when there's lots of other hosts in the environment to infect. So they're eavesdroppers. Right. So now we get that, this core. So this is what my lab, what we're interested. We're not so interested in discovering the next quorum sensing system. We're very interested in this idea of quorum sensing spanning from eukaryotes to bacteria to viruses. And like, viruses, they're not easily even. Like, they're more different than. Right. Like, viruses aren't little machines.

Sean Carroll (Host)

Yeah, yeah.

Bonnie Bassler

And like, like, it's. So anyway, I think that's been really, really fun. And then, of course, because of that, we can like, trick these viruses and make phage therapies. Right. That could be useful, you know, by getting them to kill or not kill on demand. But anyway, that's pretty fun for us, is that these viruses are tuned in. That was. And afterwards, again, going back to something we said before, afterwards, we're like, you know, people have studied phage. Phage, bacterial viruses that founded the molecular biology field. Like, that's what scientists were working on. They were working on bacteria and phages. And of course. So that's like 80 years ago. And so now we've discovered that phages tune into quorum sensing. And then afterwards you think, well, of course they did. It only makes sense to kill the host when they're, you know, the phage needs more victims. Right. So of course they, you know, and of course, I think I spent my whole life just going like, should we figure that out sooner?

Hiker 1

Right, right.

Bonnie Bassler

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 Monty Python movie. We're not dead yet. I don't think the quorum sensing field is dead yet because we have the microbiome that we don't understand. And then now we have this idea of cross domains, you know, communication with quorum sensing, and then again, like a treasure trove of applications that are waiting, you know, to be made for humanity and for the Earth. Earth.

Sean Carroll (Host)

Yeah, exactly. And so near the end of the podcast, we always allow ourselves to be a little bit more speculative and let our hair down. And this is the time. So. But this leads right into where I wanted to go, which is, you know, there are these interconnections you get in biology. Right. Things start talking to each other and we don't understand perfectly the origin of life, but we also, as far as I can tell, don't understand perfectly the origin of eukaryotic eukaryotes or the origin of multicellularity. And I'm wondering whether, I mean, obviously bacteria play roles here.

Can we think of quorum sensing as a tiny little step toward multicellularity Even

though it mostly happens in eukaryotes.

Bonnie Bassler

Yeah, I think. Okay, so there's a debate about that. Like, everything, right? So for sure, these biofilms or these groups, these. There are many, many cells in them, right? But in some. And so people. Scientists want. Wonder. Let's call it that. Wonder is this the first step in, you know, a first step in multicellularity? Right. These cells, these groups, they're coordinated. They're doing things together. I mean, that is what happens both in multicellular organisms, but also just in organs, you know, in. You know, like your heart cells do the same things, right? And. And your kidney cell, you know, and so we wonder really different, though, because each one of those cells, I'm talking about the bacterial cells, they can live on its own, right? So if I scramble that biofilm up, right. And release it, right. Every one of them, those cells can live. Now, if I do that to your kidney, right. Or. Yeah, right. And so, like, so again, in your body, or in a real multicellular organism, every cell has a vested interest in every other cell being healthy, right. In a bacterial biofilm or a bacterial community, they're all fine on their own. You know, if everybody else dies, it's kind of what we got back to. There's still. I can still a. And individual cell can still divide and make the whole thing again. Right, right. And so. So there's something fundamentally different. I think this is just my opinion. You know, there are the traits of multicellularity, the collective behaviors, you know, they do in a biofilm, just like in your body cells that are identical, bacterial cells that are. They have the identical genomes, they take on different fates. Just like all the cells in your body have the identical genome. Your kidney cells, your heart cells, your blood cells, they take on fates. They do different jobs. That is clearly happening in a bacterial biofilm, that in one region, you know, the bacteria are doing these jobs, in another region, they're doing those jobs. We know that. But nonetheless, right. If I scramble it up, every one of those cells, like, they're sort of like the ultimate stem cells. Every one of those cells could. Could build that biofilm again, you know, by dividing, Right? Yeah, but. And that's just different, right? Like, if I kill all your kidney cells, you are in a huge amount of trouble, right?

Sean Carroll (Host)

So I'm wondering, you know, again, what do I know? But I'm wondering. So it makes perfect sense. The bacteria don't need each other to survive on their own. And that is an important difference. But so 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.

Bonnie Bassler

Yeah. And we call that a eukaryote, right? And. Yeah, and it go. 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? 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. Have not an. It's like an analog of what you're asking me, I think. You know. You know what I mean? Right. And so. Yeah.

Sean Carroll (Host)

Okay, good. So here's the final question then. The. 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.

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.

Bonnie Bassler

Right? So I think that if you're me, you believe that being a human, or for me, a eukaryote means a community, you know? And I mean, you know, like, I collective think of myself as. As this marvelous. I don't mean that in an egomaniacal 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 cell, and I can't be human without them, right. You know, unless, I guess I lived in a bubble, you know? You know what I mean? You know, so you can't be without them. So you need them, you know, to keep you alive, to keep you healthy, to protect you. I mean, don't get me wrong, you could be born, you are born. You could be born, you could kind of live, but not for very long without them. Right? So you do need them. But my human genome is my human genome, right? And I have. And I do have a brain, right? And they don't. Yeah, right, but they are. But you need them, right?

Sean Carroll (Host)

And so too much credit to the genome is my question. Like, are we. Are we.

Bonnie Bassler

Whose genome, Theirs or ours?

Sean Carroll (Host)

Ours.

Are we privileged?

Bonnie Bassler

Oh, for sure, definitely. Oh, please. Yeah, of course. Yeah. Oh, for sure. But, 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 these things that individually they don't have or even collectively they don't have.

Sean Carroll (Host)

Are the bacteria in our gut, microbiome, etc. Are they just temporary or are they there for our whole lives?

Bonnie Bassler

Yeah, you get colonized. They change throughout your life. You get colonized, you start sterile, you get colonized on your way out of the birth canal. And you mostly get them by sloppy 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 you're health, when you take antibiotics. But ultimately you will have a. You will have microbiome, bacteria throughout your whole life. Right.

Sean Carroll (Host)

But so if I. If you live with somebody, your microbiomes intermingle.

Bonnie Bassler

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. Beginning. Right. And then you begin to look more like whoever you're cohabitating with.

Sean Carroll (Host)

Including your.

Bonnie Bassler

Over time. Yeah, a little bit. No, probably not. Anyway.

Sean Carroll (Host)

Yeah, romantic place to end, so. Bonnie Bassler, thanks so much.

Bonnie Bassler

Yeah, you should never have me as a dinner companion.

Sean Carroll (Host)

I don't talk about bacteria nearly enough. That's the lesson. I'm good. So, thanks very much for being on the Mindscape podcast.

Bonnie Bassler

Oh, shot. Please edit this.

Sean Carroll (Host)

No, can't do it. Sorry.

Bonnie Bassler

Anyway, no, really, actually it was thrill. You really made it fun for me to get to talk about all these wild topics. I hope it was helpful and that people like it.

Sean Carroll (Host)

Oh, I think they will. All right, thanks very much.

Bonnie Bassler

Thanks. I'll see you. Sean.

Hiker 1

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Hiker 2

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Bonnie Bassler

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Kiana (Shopify Testimonial)

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