Bonnie Bassler on Talkative Bacteria and Eavesdropping Viruses
Bonnie Bassler, a molecular biologist at Princeton University, helped to revolutionize views on the sociability of bacteria by showing that they choreograph their collective actions through nuanced chemical conversations. In this discussion with host Steven Strogatz, Bassler describes how exquisitely sophisticated these conversations are, how bacteria wait to act until the numbers are on their side, and how viruses eavesdrop on the chatter. This episode was produced by Dana Bialek. Read more at Quantamagazine.org. Production and original music by Story Mechanics.
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Transcript
Bonnie Bassler: So, bacteria are the tiniest living organisms on the Earth. They’re the most ancient living organisms on the Earth and they are very — seemingly very primitive. They’re single cells, they don’t have very many genes. They look kinda like little blobs of goop if you look at them under a microscope. And yet — okay, I think they’re beautiful, but still…
Steve Strogatz: Only a mother could love the blob of goop.
Bassler: Bingo, right, exactly. You see how this is gonna go today. So anyway —
Steve Strogatz (narration): From Quanta Magazine, this is The Joy of x. I’m Steve Strogatz. In this episode, Bonnie Bassler.
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Bassler: What we know about bacteria, what we’ve known for a long time, is that they can cause disease and they can kill us, make us sick — kill us, plants, animals, humans. What we’re increasingly learning is that they’re also vital for life to happen, because of this magical microbiome which we now know exists. These bacteria that live in and on us and provide us beneficial traits that make us alive, okay? So those are facts: Bacteria can kill us, and they can give us life. So, what my gang wants to understand is how can they possibly do that? They’re so small.
Strogatz: So, I’m a mathematician who has been obsessed with synchronization, how individuals of any kind can get into sync and all do the same thing at the same time. This is a big story for Bonnie, too, because when her bacteria all do the same thing at the same time — release their toxins at the same time, for example — they can overwhelm the immune system of something much bigger than themselves.
Bonnie’s work is very provocative in that for so long, I and everybody else thought bacteria were incapable of much of anything resembling intelligence. They are the simplest organisms on Earth; they don’t have brains; they don’t have nervous systems. You know, what can they do? How can they cooperate in any interesting way? We never really thought about bacteria as having any social life whatsoever, but Bonnie has totally overturned that wrongheaded vision.
What Bonnie is doing is revolutionary for science, but it also has potentially really big implications for medicine and public health, too.
Strogatz: People didn’t really appreciate the social life of bacteria before you, but you did something special.
Bassler: Well … but I had a mentor. I was working on a bacterial project and I got to go to my first science meeting, which was in Baltimore, where I was a graduate student. You know, I just had to drive down the road, it didn’t cost anything, I could just attend this science meeting. And this guy, Mike Silverman, gets up and he gives this short (I don’t remember) 20-minute talk on this glow-in-the-dark bacterium. That he knew there was a molecule [as a signal], right? That they only turn on light at high cell density and they do it together. So, he had begun to figure out the components: the enzyme that made the molecule — the receptor for the molecule, and then the genes that turned on.
I’m sitting there with hundreds of people. This guy gets up. I had never heard about glow-in-the-dark bacteria either. He tells this story. I had been working on bacteria since I was 19, right? I think I know everything, because of course at that point in my life, I’m super arrogant too.
Strogatz: Sure.
Bassler: I’m about to get my Ph.D.
Strogatz: Yeah.
Bassler: And he says this thing about these bacteria, and they’re doing this together. And I am sitting there and I’m like, “Either that is the most amazing thing I’ve ever heard or this guy’s a crackpot.” Right? Because this was 30 years ago. There was such a snobbery, including all of us that worked on bacteria, that bacteria were these asocial reclusives, you know? And they were good for finding out parts — DNA, RNA, proteins. I mean, bacteria gave us all of that.
Strogatz: Yeah.
Bassler: But not behaviors. Behaviors, collective behaviors, you know, communication. That’s about higher organisms.
Strogatz: Right.
Bassler: But in that moment, this captivating talk, in the midst of all these talks that I literally wanted to drive a metal stake through my head while I was listening… You’re not actually gonna put this on the radio, are you?
Strogatz: I’m totally gonna put that on.
Bassler: But anyway, I… So, I’m listening. This guy gives this mesmerizing talk.
Strogatz: Let me paint the picture in my head a little more. Do you remember anything of the feeling in the room? Like, were other people with their mouth hanging open?
Bassler: No.
Strogatz: No, it’s just you.
Bassler: I remember sitting there thinking, “Holy shmoly, those bacteria…” You know, we didn’t use the word “talking” but they’re doing this thing as a group.
Strogatz: Right.
Bassler: I wasn’t the person I am now. You know, I had zero successes or — but somehow in that moment, I’m like, “You just have to let me be your postdoc.” It was so impulsive.
Strogatz: Do you remember how he looked at you after that approach?
Bassler: Oh, in horror.
Strogatz: Horror.
Bassler: In horror, right, because he’s an incredibly, almost pathologically shy person and they had forced him to come, you know, to give this talk. He never traveled. I think they threatened to take his grant away if he didn’t show up for this talk. And he’s real short and I’m really tall, and I towered over him and I’m — of course, he doesn’t know me from Adam.
Strogatz: Right.
Bassler: And then eventually, he said yes. You know, he is just this amazing person in my life that gave me — he taught me to be a scientist and he gave me my career. Because the first day I walked in the lab, he said, “I’m not gonna tell you what to do,” and I thought “good.” He goes, “But what you get is what you take.” I mean, he was so generous. I still see him every year.
One year I said, “You know, why’d you hire me? I didn’t know any genetics; I hadn’t had a genetics class; I assaulted you at this meeting,” and I go, “Why’d you hire me?” And he goes, “Because you asked and no one else did.” I was like, really? Right. And so, like, when I got there, there was nobody, it was me and him. You know, it was just amazing. Like this lab had one other person in it. I can’t get how it lit me up, ha ha. That’s, you know, like why it did what it did to me and why back then people weren’t crawling all over him. But that’s because I think it was considered this anomalous, obscure bacterium that no one had ever heard of.
Strogatz: It’s a totally fringe topic.
Bassler: Correct. Back then, it was this one kind of goofy, weirdo bacterium that turned on light, wasn’t harmful, you know. And so, I kind of understand it in retrospect, and I don’t know why it particularly fascinated me, but I’m so glad I did that, and I don’t know why I did.
Strogatz: I love listening to that from Bonnie because it does reveal so much about her character. First, that she says she doesn’t know why she did it. She is still questioning, even now, questioning. Wondering is such a big part of who she is, and she’s asked such brilliant questions over the years. And then I think of her courage, her nerve. You have to try. You have to gamble, actually.
Bassler: So, I have spent my adult life trying to understand bacterial languages and their chitchat. We certainly understand, or think we’re learning about, how they communicate, that they are multilingual, that the ability to communicate allows bacteria to tell each other both how many of one another is around, who is around. And then they can carry out group behaviors based on whoever is in the vicinal community.
Strogatz: What does it mean for bacteria to talk to each other?
Bassler: We’re always trying to understand how bacteria get any bang for their buck. And so, what we’ve shown over many years is that the way bacteria get their power is that they communicate with a chemical language. They count their numbers and then they recognize when they have the right number of bacteria locally that, if all of them change their behavior in unison, they can carry out tasks that they could never accomplish as individuals, because individually they’re too small. And so, that process of communicating and orchestrating collective behaviors, we call that quorum sensing, right? They sense when there is a quorum, and then the quorum makes these decisions together.
Strogatz: It’s incredible. So, they send — somehow they do this talking to each other by — what, they emit chemicals?
Bassler: Chemicals. So, bacteria, the way that they reproduce is that they grow and divide. You know, one cell becomes two, becomes four, becomes eight, right? So, they’re growing and dividing. And as that’s happening, each cell produces and releases, dribbles out some of these chemical “words.” So, they are chemicals, they are small chemical molecules. Then, as the population is growing, since all of the cells are contributing to producing these chemicals and releasing them into the external environment, the more cells there are, the more of these chemicals there are outside.
And when the chemical hits a particular level, the bacteria detect it, and they infer that they must have neighboring cells around. And so, they don’t actually know each other is there, they can’t actually count, they can’t see. They’re measuring the concentration.
So, when the molecule hits a particular level, the bacteria detect it. And they all respond by changing their gene expression, which then changes their behavior. And they begin to carry out these group tasks.
In my analogy, it’s kind of like perfume, right? Yeah, they release these molecules, you know, maybe you can’t smell it, but then eventually, if there’s a lot, everybody detects it, right? They’re using the concentration of a chemical to infer something about the number of cells present and it depends on everybody making a share of the chemical.
They’re responding to a chemical, and they change their gene expression, but the consequence is that all of them change their gene expression together and they begin to act like a multicellular organism. And what’s fun is, lots of times, bacteria, they get a stimulus, and they do something: stimulus; do something. We do that too, right, as an individual. But in this case, the tasks, the genes that turn on that drive, these quorum-sensing controlled behaviors, they’re unproductive if a bacterium does it alone.
So, we can trick the bacteria. We can put them by themselves. We squirt the chemical —
Strogatz: Okay. I wondered about that.
Bassler: We can make these chemicals in the lab. We squirt the communication chemical on, and the bacterium reacts. Yeah, yeah, yeah, you can just trick ’em, right? But out in nature, you know, if this bacterium starts pumping out, you know, all of these products and doing all these tasks, that you need lots of cells together, like to be virulent, like to make a biofilm, like to secrete an exoenzyme that you’re never gonna get your own back. Your neighbor gets yours; you get theirs. Like all these public goods, if a bacterium does that by itself in nature it’s doomed. Only when the community does it together do they all profit.
Strogatz: The big lesson of Bonnie’s research over the past few decades is that when bacteria team up they are formidable. I mean, they can do things as a collective through teamwork that are astonishing — both for good and evil — but individually, they’re tiny and sort of namby-pambies, they can’t do much. An individual bacterium is not a terrifying thing but, you know, a swarm, a collective, a biofilm, all these different ways that they can aggregate, they can be little monsters.
Bassler: So, then the question is, well, what’s a bacterium do in a group.
Strogatz: Right.
Bassler: We don’t understand all the genes. And of course, different bacteria, different species of bacteria need to do different biology, depending on where they evolved and what niche they live in. But the sort of general rules, if you will, are the kinds of things they do as a quorum are activities that, if one bacterium did it by itself, the activity wouldn’t work.
So, virulence. So, if you think about when a bacterium, you know, is in a host, an animal, a human, and it wants to make a successful infection because it wants to stay, one of the ways bacteria do that — two of the ways is, they make biofilms, which are communities of bacteria adhering to surfaces. So, like your intestine, your skin. They adhere to surfaces and they live in these groups. So, you need lots of bacteria to make a biofilm, to cover a surface and colonize, so that’s a quorum sensing controlled behavior.
And then also, in pathogenic bacteria, they secrete virulence factors. So, these are poisons, the kinds of products that bacteria make that make us sick, but what they do for the bacteria is, they get them goodies. Like, they make enzymes and toxins and things that allow them to make you vulnerable, to give them food, the bacteria. And the way that they do this is, they have to release these products into the extracellular environment.
So, you’re a huge host. If a couple of bacteria get in me and they dribble out a couple of these poisons or toxins, nothing is gonna happen. But if they wait and they count themselves and they recognize that “if all of us secrete these poisons together,” like an army, then these exoproducts, these proteins will have consequences to the host, right? And they might be able to overwhelm your immune system, which has evolved to look for invading bacteria, hunt them down and kill them.
Strogatz: Yeah, yeah, yeah, yeah, right. So just one lone bacterium out there is gonna get —
Bassler: Yeah, how is that gonna hurt me?
Strogatz: Yeah.
Bassler: Every one of my cells is a thousand times bigger than every bacterial cell.
Strogatz: Okay, good to know.
Bassler: So, this is sort of David and Goliath.
Strogatz: Uh-huh.
Bassler: And yet, these bacteria do it. And they do it not like David and Goliath; they do it by acting as groups, and then they release their poisons together. That allows them a toehold in the host. It makes the host vulnerable. It might provide all these bacteria nutrients from the host.
Strogatz: I always sort of wondered what are they trying to do? Like, why do they want to make us sick? You’re saying they elicit good food sources from us?
Bassler: Yeah, for themselves.
Strogatz: Really. So, like, what, what are the words that I should know? What nutrients do we give by having them make us sick?
Bassler: Iron, amino acids. Lots of times, bacteria have to consume substrates, you know, foods that are solids. And so, a bacterium is small, a solid is big. So, a strategy bacteria use is to release an exoenzyme that will cleave a solid substrate into smaller bits that they can — that are chewable, like bite-size, you know. And then these become not-solids. They’re soluble. They can be transported… They’re small enough, they can be transported across the bacterial membrane, and the bacteria will eat them. Like cellulose, like a tree, like a tree. So, bacteria can digest, you know, tree bark.
Strogatz: They can, by squirting stuff out that chops it up and makes it digestible to them?
Bassler: Yeah.
Strogatz: Wow.
Bassler: Correct. So, the polymer that makes a tree or plants is called cellulose. And so, they can chop up the — they can make enzymes that chop up the cellulose into smaller bits that they can take up and consume. All kinds of solid substrates. And so, the way bacteria do this is, they make a biofilm, they sit on the solid substrate, they release exoenzymes that digest the substrate into smaller bits, and then they consume the smaller bits.
We do it too. Like, you don’t eat a whole corn on the cob, you chew it up into little bits and —
Strogatz: Yeah, okay.
Bassler: It’s the same idea. So then to go back to quorum sensing. Whenever a tiny, itty-bitty little bacterium releases this exoenzyme to chew up cellulose, to chew up any kind of solid material, or mucin — like, the mucus that covers your intestine — like, stuff in the dirt, when a bacterium releases an exoenzyme, you know, it’s just a protein, a tiny protein, it never gets its own back.
I release it. The world is big and I am small if I’m a bacterium. So, if I release a protein out into the world, it’s gone. But if everybody does it together, I have a chance of getting your enzyme and you have a chance of getting mine, and ultimately, we the community succeed.
So, we know public goods, you know, from economics. There’s all kinds of public goods in biology, and when the community tries to use those collectively, they — then the community profits. So that’s quorum sensing. Quorum sensing is about when bacteria give things away to the world, and they gotta get something back, right.
Strogatz: Yeah.
Bassler: So, it’s very often about biological processes that we would claim are public goods.
Strogatz: Okay.
Bassler: You know, quorum sensing controls those.
Strogatz: Yeah.
Bassler: And so, secretion of virulence factors, biofilm formation, you know, exoenzymes, all of these kinds of activities, many of them could be considered public goods.
Strogatz: So, bacteria working together can do all sorts of things. Suppose they want to make a sticky film, you know, like the plaque on our teeth or, like, when they coat the lining of our intestine or — actually these biofilms are all over the place. I learned from Bonnie, they’re on our skin, they’re on our hair, they’re on every surface around us. But to make a biofilm, they have to make certain molecules. And so, there is this interesting problem, if I am making some of the molecules to help this biofilm matrix, you can benefit from them and you don’t have to produce your fair share.
So, this is a big concern. What happens when bacteria are doing things for the good of all, but then there are others who are cheaters, who are taking advantage? But it seems that they can do certain chemical tricks that have the advantage of shutting down the cheaters.
For instance, when they’re making these biofilms, they can make them thicker so that the beneficial molecules don’t diffuse as far away. So, the only bacteria that get the benefit of your hard labor, if you’re one of these producer bacteria, are the bacteria right next to you, and they tend to be your kin. You know, they are clones, they might be bacteria very closely related to you, so you don’t mind sharing with them.
Bassler: What I told you already is that these bacteria communicate. They make and release these chemicals, they measure the level of the chemicals, and they recognize something about “I must have neighbors around. Instead of doing tasks A, B and C we should do D, E and F.” So that’s quorum sensing.
What we’ve learned in the past, let’s see, decade or so is that it’s more than one chemical. So, what we now think is, to have a proper quorum sensing conversation, it takes multiple chemicals, and the bacteria have to decode the blend. And so, for sure the chemicals have something about cell number — you know, more chemicals out there means more cells are around. But also, the chemicals encode information that not only says somebody is my neighbor, but they say something about who my neighbor is. So, there are molecules that say, “You are my twin, right, you are my clone.”
Strogatz: Okay.
Bassler: Right. There are molecules that say, “You are my cousin. No, you’re not exactly identical to me, but you’re related.”
Strogatz: Yeah.
Bassler: And then there’s molecules that say, “You are not related to me, like, you’re the enemy.”
Strogatz: Oh, oh, yeah.
Bassler: There’s also — we think now — molecules that say, “You’re not a bacterium, you’re a eukaryote.”
Strogatz: Okay.
Bassler: And so, what we think is that the bacteria do this remarkable, sophisticated computation, which is they have to decode that blend to understand who is in the minority and who is in the majority. Like, you could imagine, right, this blend of molecules the different bacteria are making, and you as an individual want to know, “Is it mostly my kin or is it mostly the enemy?” Because you want to do different things depending on who is winning or losing in these situations.
And so, what we think the bacteria do is, they can actually decode how many bacteria are around. Is it mostly me, is it mostly something else? And then they actually tailor which quorum sensing-controlled genes they turn on or off, depending on not just the number of bacteria but actually who is in the neighborhood. Which is what we do.
Strogatz: But what did you mean when you say that we do it too?
Bassler: So, you can tell — in human terms, you can tell self versus other. I know this is my twin sister, my cousin, somebody I don’t know —
Strogatz: Right.
Bassler: Something I don’t like. And I am willing or unwilling to do things based on my understanding of who those people are. You know, I would throw myself in front of a car for my kid, for my sibling, you know, but I might not for a stranger or —
Strogatz: Yeah.
Bassler: We have wars.
Strogatz: Right.
Bassler: You know, we not only don’t help “other,” we try to kill “other,” right? And so, the bacteria aren’t that different, okay? You know, I mean we came from bacteria, right, we know that.
And so, the idea is that these, what we consider these “magical” traits, you know, that sound so human — that actually the “skeletons” of them, that the bacteria evolved this first, right? And sure, we have eyes, and we have voices, and we have chemicals. You know, maybe we have more of a repertoire, but I think that the origins are really there, of discriminating self versus other, friend from foe, group behaviors. We do group behaviors all the time, specializations of jobs. You know, the bacteria have it all over us. So, I think it’s really — it’s amazing that these social behaviors are embedded in these single-celled 4-billion-year-old organisms, right.
Strogatz: Boy, that’s a wild idea because, you know, you often hear people say something like, “ooh, it’s in my DNA.” But now if hear you, it’s more like, “it’s in me because I am a 4-billion-year-old version of bacteria.”
Bassler: Yeah, because your DNA came from a bacterium.
Strogatz: Yeah, it’s not really that it’s our DNA, it’s in our bacterial mindset or something.
Bassler: Yeah, ancestors.
Strogatz: Ancestors.
Bassler: Ancestors, yeah.
Strogatz: Huh.
Bassler: What we hope we’re learning by studying bacterial quorum sensing are the principles that transcend all of evolution, right? To — and certainly they get more complicated and possibly more fascinating in higher organisms, but we think we’re really learning something about: What does it take to have a collective behavior? What does it take to know self from other? How do you avoid cheaters and free riders? I’m talking to you; these are public goods; who are the little molecular police that keep this thing working?
And so, I think by studying bacteria we can understand principles that maybe will help our colleagues that study things like this in higher organisms. Your tissues work as collectives. It’s not like your kidney cells and your heart cells just decide what they’re gonna do every day. They have these jobs, and they do them and they do them together and that’s driven by chemicals. And so, we think that some of those principles might be in these bacteria.
Strogatz: Bonnie’s point of view is so all-embracing. It’s just wonderful, this tension that she highlights between the individual and its role in a larger collective. It actually goes across all parts of biology. It even comes up when we talk about subjects outside of biology, like politics or sociology, economics. In that way, it seems like a great frontier across all of science. It’s this deep, unsolved problem. How does the individual fit into a larger system? How does one small piece work in the whole? Wow, it’s really profound.
But that’s just for starters. Bonnie told me about new findings in her lab, about work that she’s been doing with her grad student, Justin Silpe. Well, after the break you’ll hear — this is just knocking my socks off because what she told me has staggering implications. It’s so deep.
It’s about a kind of chemical intelligence that viruses have. And given how profoundly mysterious viruses are — just think about HIV or the new coronavirus — well, understanding that news about how viruses work could have gigantic implications. That’s coming up.
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Bassler: I wish that I knew I had wanted to do this all my life, because I feel like I got the happiest, luckiest life in the world, to get to make discoveries and think about things nobody’s ever thought about before. That’s an amazing job. I wish more people understood that, how cool it is to be a scientist.
Strogatz: Let’s talk about how cool it is to be a scientist.
Bassler: I mean, this is not going to come as a surprise. We have this strange, nerdy stereotype and everybody asks me — I say I’m a microbiologist. They say, “Oh, you sit in a dark room by yourself and look in a microscope all day.” And that’s exactly what I don’t do. I never even had a microscope until a few years ago. I think, like, if people understood that what we do is, we work in these big rooms and it’s typically all young people who are trying to find out how the world works, on whatever project they’re working on. They laugh and they work together, and they talk, and the music is on and they have a basketball pool.
And it’s not like, you know, a professor has a great idea and points to some underling and says, “Go do that.” I mean, that’s not how knowledge happens, you know. It happens from the collective, from the group, from interacting. And then of course from asking questions, thinking of a way to ask a question with an experiment that gives you an answer that’s either no or gives you the next step to do.
And sometimes I don’t think people understand how exciting it is every day. Your job is to try to think up something no one has ever thought about before, and then go prove you’re right or you’re wrong. And like, that’s a rush.
Strogatz: It’s wonderful, it’s a rush, that’s beautiful.
Bassler: And I worry a lot about young people… That it’s challenging, and of course it’s challenging, or we would already know all this stuff. When somebody doesn’t get an A in their math or their science class or they find it really hard, I think that’s really good. Like, I wish that if a young person gets a B in organic or biochemistry, that he or she thinks, “Wow, this could be something that, you know, kicks my butt for my whole life. Wouldn’t that be great?”
Every day people try to make you be better than you were the day before. It is really hard. You know, these bacteria have had, in my case, four billion years to keep their secrets from me. You know, I have been working on it for 30 — of course I can’t figure this out! There is this view of science as boring, and as too hard. And those are not true. Like, it’s not boring.
So, I think the first thing I would say, and this is maybe to younger people, is like: I don’t want a job that I don’t think about after 5:00 at night and I go home and watch reality TV, right? I want a job that fuels me for my entire life. And what’s so amazing to me — this is my 25th year at Princeton, I think — I still come running to work every day because I can’t stand not knowing and finding out what’s going on. And we’re like the pioneers of the 21st century.
We know the world is round now, so we don’t need a boat. But what we don’t know about is this invisible world of molecules and chemicals and … plants, me, bacteria, how they work, and it’s really like being an explorer.
You know, when we read books about explorers, we romanticize it. “Oh, my goodness, it must have been so amazing to find these things, to discover things.” That’s what we’re doing, and we do it every day. We do it with people we like. The conditions aren’t that bad. You know, right?
And I have to say that we always thought we were working on something bigger than what you’re pipetting into that tube at that moment. But we were never so smart as to think, “Oh, there’s gonna be multiple molecules, you know, the molecules are gonna have different things, you know, it’s gonna be all these bacteria, people are gonna try to make therapies out of this. You know, like, if we can disrupt communication, maybe we can make new medicines. You know, like, I wish we were so smart!
Every time, when we get these moments where we have, like, sort of a transformational leap in our understanding, like, you know, “Oh, they’re multilingual. Oh, they can tell self from other. Oh, we could disrupt this.” You know, like when we have these moments, we spend half of the day patting ourselves on the back, like we figured it out. And then we spend the other half, like, “Of course, why did it take you so long?”
We get now that viruses eavesdrop on quorum sensing and they hijack the information to kill their bacterial hosts —
Strogatz: What? Wait a second. This is totally hot off the press.
Bassler: Yeah, it’s hot off the press. And —
Strogatz: I haven’t heard this.
Bassler: Quorum sensing transcends all domains on Earth, right? From viruses —
Strogatz: Oh my God, there’s a lot of conversation.
Bassler: Yes, to bacteria, to higher organisms, right? Then we think, well, of course they do, they have evolved together for billions of years. In fact, it took you 26 years to figure it out. You know, it’s like — I think that’s sort of the phenotype of a scientist, where you’re —
Strogatz: Yeah.
Bassler: Super happy and super depressed, you know, all at the same time and you have to admit to yourself that you like living like that and you like that feeling, right, and that it’s okay. We don’t spend very long in the “aha!” moment because the moment after the “aha!” moment is “you should have figured that out a long time ago.”
Strogatz: That’s so true. That is so true.
Bassler: Right.
Strogatz: But I want to hear a little more about this. So, you’re saying the viruses, what are they trying to do?
Bassler: Well, I think the viral thing is — that’s like totally insidious and wonderful. I think it’s a dialogue. So, we had found a new quorum sensing system in a bacterium and we found that the molecule, the chemical that’s the quorum sensing molecule, seemed to be broadly made among bacterial species. But the receptor that detects the molecule was very restricted, only particular bacteria have it.
A graduate student named Justin in the lab, so Justin was like, hmm, how — why is there this asymmetry between production of the molecule and presumptive detection of the molecule? So, he was hunting around in databases and he found one more receptor, but it was in the genome of a virus.
Strogatz: Sure.
Bassler: Viruses, we know, they infect us. You know, you get the flu virus, but viruses infect bacteria. Bacteria are bombarded by viruses. It is a war. Bacteria have defenses against viruses but in this case what Justin found was that this virus that infects the bacterium, it has the receptor for the quorum sensing molecule. And so, what happens is that the virus infects the bacteria, and viruses, when they do that, they have to make a decision: Stay or go, stay or go, right? “Am I gonna stay in this host and just be carried through generations or am I gonna pop the bacterial cell and try to get into other bacterial cells?”
And so, when should it go? You know, so if a virus doesn’t get into another host cell it’s a goner. So, when would be a good time to decide to go? Well, how about at high cell density when there’s lots of other cells around for you to infect. So, what —
Strogatz: [LAUGHTER]
Bassler: Yeah, right. It had to be that way, right. Anyway. So —
Strogatz: This is so great.
Bassler: Right. You get it in one second, come on! This is 26 years of my life, right?
So anyway, what Justin showed is that the viruses encode the quorum sensing receptor. So as the bacteria are growing and getting to high cell number, the [viruses] are tracking, they’re monitoring the population density of the bacteria, and then they launch their lysis, their killing behavior, exclusively at high cell density, which maximizes infection of the next cell.
Strogatz: They’re geniuses and they’re not even alive.
Bassler: They are — and they’re not even alive, exactly, they’re geniuses. And then, you know, I’m like, well, of course they’re doing that. No, yeah, so —
Strogatz: So, you know, if we think of the bacteria as tiny compared to our own cells, which they are, there is something a whole lot tinier than the bacteria, which are viruses. Viruses are really mysterious and bizarre in that they are not even considered alive. They can’t reproduce themselves. They have to hijack the machinery of something else that’s alive, either like our cells, animal cells or bacterial cells, just to reproduce.
Now, what was so astonishing is that the virus is actually listening the whole time, like a lurker, you know. We talk about them on the internet, someone who has an account but never tweets, they’re just listening. So, there are viruses that are doing that, too: They’re just in the background, listening to the bacteria talk about “Are there enough of us yet to undertake come collective action?”
The calculation, if you want to call it that, that the virus has to make is, “When do I stay and just live in my host bacterium and when do I replicate, make hundreds of copies of myself and burst out and pop that cell and try to find new homes for all my offspring?” And if there aren’t enough bacteria around, that’s going to be a bad idea, right? You’re gonna pop and there’s gonna be no homes for all your kids.
So, this is the crazy thing. I mean, I make it sound like the viruses are thinking about it, but these are little bits of chemistry. They don’t have any brain, they have no nervous system, they have nothing.
It’s like the simplest form of intelligence I’ve ever heard of. This is almost like chemical intelligence. We’re not even talking about biological intelligence. This is through natural selection at the level of chemistry and biochemistry. These viruses can do something that looks pretty darn intelligent.
Strogatz: So, we didn’t talk about horizontal gene transfer, but there is this thing that happens in the world of microbes — I know you know this, but I mean for anyone who hasn’t heard about this — that genes can be swapped. Certainly, bacteria swap genes a lot and have forever, and I assume viruses …?
Bassler: Mm-hmm, absolutely.
Strogatz: Is it possible that the viruses are picking up the ability to do this, or they gave it to the bacteria, or what do you think is going on there?
Bassler: Okay. So once Justin made this discovery, then he is, like, “Why don’t I look more seriously at all these genomes out there?” And it’s really clear that all these viral genomes are loaded with these quorum sensing components.
Strogatz: Yeah.
Bassler: And I’m thinking, why didn’t anybody else find that, right? And so, it’s really clear that in many cases the viruses are just stealing them from the host bacterium.
Strogatz: There you go.
Bassler: But in the one case, the first case, the one that we really fleshed out and figured this out, it turns out that the gene, the receptor gene on the virus is not from the host bacterium and it’s not a viral gene.
Strogatz: Oh, come on.
Bassler: Yeah, I know, exactly, right. So, it came from somewhere. So, either there is an intermediate that’s not — its sequence isn’t out there, or it doesn’t exist or it’s extinct.
Strogatz: Oh, that is freaky. Wait a second, can you do some kind of giant computer database search to see if it’s like anything in Archaea or anything else?
Bassler: We did, we did.
Strogatz: I know, I know you would have done it.
Bassler: Yeah, we did, yeah, of course, we — yeah, no, I don’t mean to be — of course, we did that, yeah.
Strogatz: It’s not anywhere?
Bassler: It’s nowhere.
Strogatz: Oh.
Bassler: Like, when I started in bacteria, I got into it by this crazy way that I told you, and I wasn’t very sophisticated and I wasn’t thinking, like, “What’s a great career to have?” You know? But at the time, say 30 years ago, bacteria were thought to be solved. They absolutely gave us, you know, DNA, RNA, proteins, gene regulation. And then there was kind of a feeling that only the dumb scientists worked on bacteria, you know? Because the big mysteries that bacteria had to reveal had been solved.
But then some of us just love bacteria. And we kept working away and working away, and then it turned out, you know, that it’s a renaissance. The microbiome, these bacteria live in us and on us and they give us life and they metabolize our medicines and whether or not you — you know, a medicine has side effects, or a medicine works, or it doesn’t work, you know, and what all your biochemistry is doing. And you get them early in life, you know, and all this stuff, like, that’s happening right now.
And the idea that we could make brand new kinds of antibiotics by disrupting quorum sensing or other behaviors, that’s something the world urgently needs. And it’s possible because some of us just fell in love with bacteria, lots of us, and thought there were mysteries there. You know, we never can seem to manage to understand how sophisticated and wonderful and mysterious they are, but if somebody is thinking that maybe they like bacteria, boy, the horizon’s bright.
Microbes are the things that actually kill people on this Earth and microbes are actually what are going to save us in terms of health, the environment. The microbes are going to come to the rescue. Don’t give these bacteria short shrift.
Strogatz: I want to say period, exclamation point, exclamation point. That was just marvelous. When I think about this conversation with Bonnie, I think of conversation at two different levels. There is the conversation among the microbes themselves, the bacteria talking to each other, the viruses listening in. So, there’s all this conversation in nature.
But there is also the conversation happening among scientists — and maybe sometimes not happening — that sometimes we get to feeling that we know things. Like, we thought we understood bacteria. And when we get that smug, when we start to think we know things, and we stop asking questions, and we stop listening, we miss out on so many amazing surprises.
[MUSIC PLAYING]
Next time on The Joy of x: physicist Frank Wilczek on what it felt like to crack the riddle of the strong force and to be told you’ve just won a Nobel Prize.
Frank Wilczek: The whole time I was on the phone — it was 20 minutes — I was dripping wet and naked because I had just gotten out of the shower. But I didn’t want to interrupt the conversation, so we just kept going and my wife sort of dried me off.
Strogatz: The Joy of x is a podcast project of Quanta Magazine. We’re produced by Story Mechanics. Our producers are Dana Bialek and Camille Petersen. Our music is composed by Yuri Weber and Charles Michelet. Ellen Horne is our executive producer. From Quanta Magazine, our editorial advisors are Thomas Lin and John Rennie. Our sound engineers are Charles Michelet, and at the Cornell University Broadcast Studio, Glen Palmer and Bertrand Odom-Reed, though I know him as Bert. I’m Steve Strogatz. Thanks for listening.
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