We see evolutionary arms races play out all the time. Take COVID, for example. A strain would run through the population. We built immunity from vaccines or getting it. And then another strain, mutated and adapted to get around our defenses, would come along and be successful, and the cycle would start all over again. That's evolution, and there's obviously nothing new about it. Bacteria have been in this kind of evolutionary arms race with viruses for as long as they've existed, billions of years. Evolution is a mad scientist, but it's also very demanding and, in the end, pragmatic. Mess around just a little bit and you might go extinct. And when evolution finds something that works, it tends to run with it. Welcome to the Quanta podcast, where we explore the frontiers of fundamental science and math. I'm Samir Patel, editor-in-chief of Quanta magazine. It seems like the more we learn about the way that evolution operates, especially at the molecular and cellular levels, the stranger the story gets. In a recent piece in Quanta called The Ancient Weapons Active in Your Immune System Today, science journalist Vivian Callier explores a surprising evolutionary connection across billions of years. And on the occasion of our 50th episode, she's here with us to talk about it. Welcome to the show, Vivian. Thanks so much for having me. So Vivian, what's the big idea? So the big surprise here was that some of these bacterial defenses against phages exist in our cells too. And they really haven't changed that much, even though we've been separated from bacteria for billions of years, evolutionarily speaking. And the reason that this is surprising is that arms races tend to drive the evolution of novelty, of new adaptations, because a species is always trying to stay ahead of an evolutionary challenge. And so immunologists had believed for a long time that these arms races would drive very idiosyncratic solutions in different lineages of life. So every lineage would find its own solution to defend against infection. But what we're finding is that that's actually not true. And the same solutions seem to be used again and again all over the tree of life. So we're talking specifically about immune responses to infection. Like we talked about COVID earlier. I think listeners might be familiar with the human immune system, that we have a whole series of cells that come along and change things. But it's obviously different for bacteria, right? We're talking about bacterial immune response to use the word phages, which is the term for the kind of viruses that infect bacteria. So when we talk about an immune response or a response to infection in bacteria, can you explain for us a little bit what that means so that we can establish a little bit about how it's different between bacteria and us, for example? When a bacteria gets infected with a phage, so a phage is a virus that infects bacteria, one of the things that happens is the bacteria can detect that there's some foreign DNA that shouldn't be there. Then it has a couple of choices. One, it can try to stop that virus from replicating. For example, by making nucleotides that are similar but not exactly the same as the ones that viruses use. And so it terminates viral replication and therefore stops the virus in its tracks. So that's one way. Sometimes the simplest solution is for the cell to kill itself. and that prevents the virus from spreading to its neighbors. Now, when we compare that to, say, a human or mammal immune system, we have different responses to infection, but we also have cellular-level mechanisms as well to respond to viruses. Yes. So in humans, this is a vast simplification, but there are basically two branches of immunity. The more ancient branch is innate immunity, which is what we're talking about today. The other branch that's more recent evolutionarily is the adaptive immunity. And this is probably the one that people are more familiar with because during the COVID pandemic, we learned a lot about antibodies and things like that. So that's all part of the adaptive immune system, where our immune system can produce antibodies that are specifically targeted to a particular pathogen. The innate immune system is nonspecific, so it just recognizes general patterns of this looks like a pathogen, this looks like viral DNA. So it's not specific, but it responds quickly. So it's the first line of defense against infection. The adaptive immune system takes longer to kick in. So the bacterial immune system is this kind of innate immunity you're talking about. And you mentioned a couple of mechanisms by which that happens. Is our innate immunity similar to that? What did we know prior to the most recent research that I think we're going to talk about, about the way that innate immunity works in humans? We knew that, for example, there's cells like macrophages and neutrophils that are specialized in kind of going around and engulfing things that look like pathogens. So that's part of the innate immune system. And we had known about the pathway called sea gas sting, a mechanism that our cells used to detect foreign DNA in basically all multicellular organisms, plants, animals. Our cells have a nucleus and our DNA is in that nucleus. If there's DNA outside of the nucleus, that's usually a red flag that something has gone wrong, right? Or you have a virus that has come in or something like that. So that rings the alarm bells. And there is a protein called C gas that senses this DNA, and it produces these small signaling molecules called cyclic dinucleotides. They're just small molecules that are then sensed by a protein called sting. And then sting goes on to activate a whole suite of immune genes. And then you get this immune response. In 2008, the sting part of the pathway had been figured out. So people knew how sting activated an immune response. But there was a question as to what is activating sting. And when you say an immune response an innate immune response in a human cell is that the same process that you were describing in the bacteria where they either block the replication of the virus or they commit cellular suicide Well, sting will activate immune genes, so cytokines and other immune responses, so basically triggering inflammation. But it can trigger, for example, cell death. So if a cell in the body is infected, it benefits the body as a whole for that cell to self-destruct before the virus gets into any other cell. So it will trigger cell death. And it can also stop the virus in its tracks and just stop it from replicating without necessarily self-destructing. Right. Okay. So 2008, the sting pathway is identified and it does initiate some kind of immune response in a human cell. Okay, so go on. So in 2013, James Chen at the University of Texas Southwestern, he's a biochemist, he discovered how does C gas actually sense DNA and then produce these signaling molecules that then activate sting. So then we had the full picture of how does this pathway work. And by pathway, what we mean here is how does a human cell respond to foreign DNA that's somehow in the cell that shouldn't be there, that's outside the nucleus? What does this have to do with bacteria then? So after this discovery, Philip Kranzuch, he's a microbiologist at the Harvard Medical School. He thought, how would this pathway have evolved. It just seemed a little mysterious to him. And so he went looking for other proteins that make these cyclic dinucleotides. And he wanted to know, are there other proteins anywhere in the tree of life that do the same thing or that produce these nucleotides? And then what's their job? What's the context in which those would be found? At the time, John McElanos' lab, also at Harvard, they had identified a bacterial enzyme that makes cyclic dinucleotides. So Kranzich decided, okay, let's figure out what the structure is for this bacterial enzyme. He found that this bacterial enzyme had basically the same shape as the human sea gas enzyme. And that was a big surprise because if you look at the sequence level of those two proteins, they share only a handful of amino acids. They're really different. If you just compare the sequence of amino acids, you wouldn't necessarily know that they were related or that they were doing the same thing. But their structure is so similar and they're both making these cyclic dinucleotides. So then he found other proteins that were also making cyclic dinucleotides that turned out to be all in the same family of C-gabs, and then things snowballed from there. Okay, so let's bring this together a little bit, right? We're talking about protein sequences and protein structures, right? So just a little 101, which you can back me up on. Protein is a big molecule made up of chains of amino acids, which are smaller molecules, And the sequence is what order those amino acids appear in. Now, as a result of the amino acids that comprise a protein, once it's made, it essentially folds into a structure. And that's what we're talking about, right? It becomes a three-dimensional structured protein. What you're describing, though, which is really weird, I think, is we have a protein in human cells that folds up into a particular structure. and it's part of this pathway of responding to foreign DNA. And we have in bacteria a whole different protein sequence, a different protein entirely, but it folds into the same structure and does the same thing. Is that what I'm hearing? Yes, and it is very counterintuitive. Yeah, that's legitimately weird. And I think there's probably a couple of things that I think I got from reading your story that you might help us unpack a little bit. Like we were just talking about evolution and immune response to COVID or for any infectious disease, right? That sounds to me like probably a pretty rapid process. That's evolution on fast forward. But what we're talking about now is a particular immune pathway that is conserved from bacteria, billions of years of evolution, into our own cells today. It strikes me that's the surprising part of it. What did the researchers make of this idea that you've got this exact same structure of molecule, totally different proteins making that same structure, serving the same function in something as simple as bacteria and as complex as a human cell? What did they think when they found this connection across billions of years of evolution? I think they were very surprised. And I think that was conceptually the hardest thing for the field to accept. I remember Kranzich telling me that the biggest challenge here wasn't solving the protein structure. It wasn't a technical thing. It was really convincing people that this mechanism of sensing foreign DNA and then producing these cyclic dinucleotide molecules as an intermediate signal and then onward to the sting protein, convincing people that that was conserved. You know, it totally changed how people thought about the evolution of immune systems. People had previously thought, oh, because immune systems are engaged in these arms races, they're probably going to find different idiosyncratic solutions to defend against infections in the different lineages on the tree of life. Everybody might find a different solution. Literally whatever works. Right, right. Whatever works is what's going to be carried on generation to generation. That's the pragmatic side of evolution, right? Yeah, for sure. But in this case, this C-gas-to-sting process in bacteria, that is an idiosyncratic solution to whatever problems they were facing, and yet it is preserved across billions of years of evolution. I mean, our relationship to bacteria is extremely remote. Those are single-celled organisms that don't have a nucleus. The idea that that same cellular mechanism would be preserved, even as the protein that produces it has changed dramatically, that does seem pretty surprising. What's even more surprising is that it's not just C-gas sting, right? So sea gas sting was the first immune mechanism that was discovered to be conserved between bacteria and human cells But after that people started looking and finding more and more and more And that was even more surprising You mentioned it changing the way that people imagine that immune systems evolved and that it was thought that they would be this idiosyncratic, whatever works sort of mechanism. How did we used to think the innate immune system evolved in humans and plants and animals and multicellular creatures? And say, what is this doing to our idea of how immune systems came to be? The innate immune system has gotten a little bit of a short shrift. If you look at most immunology textbooks, there could be maybe one chapter about innate immunity and then like 16 chapters about adaptive immunity and all the amazing things. the adaptive immune system does. So there was sort of a collision of fields that really opened up this whole avenue of research. People have been interested in bacterial immunity for some time. And then, of course, in the 2000s, CRISPR was discovered. People might know about CRISPR as a gene editing tool that has been in the news a lot, but it actually is a bacterial immune system that cuts DNA at a particular sequence at a very precise location. And that's what makes it useful as a genome editing tool. And so CRISPR became very important, not just as a bacterial immune system, but also because it was then adapted as a tool, which many labs now use for all kinds of things. There's a microbial immunologist called Rotem Sorek. He's at the Wiseman Institute in Israel. And he was a postdoc in the mid-2000s. And he thought CRISPR is very interesting, but not all bacteria have CRISPR. So what are those bacteria doing to protect themselves against infection. He started to think there's got to be other immune mechanisms hiding there. He started looking at bacterial genomes. And the interesting thing about bacterial genomes is they're pretty small and genes that have the same roles tend to be close together in the genome. That's different than our genomes, which are much larger. And you can have functionally connected genes or genes that are involved in doing the same job together. They might be in different parts of the genome. They might be on different chromosomes. In bacteria, genes that work together tend to sit next to each other. And so what he found was that immune genes in bacteria tend to cluster together in what he called defense islands. And there was another evolutionary biologist, Eugene Koonin at the National Library of Medicine at the National Institutes of Health. And he published a paper in 2011 showing these defense islands. And he had suggested that some of the unknown genes within these clusters were probably also related to immune defense. That makes sense. In general, bacteria put the functional parts of their genomes together. than the material around one that is a working mechanism that you know of, it stands to reason that that would be a great place to look for other immune systems, right? Yeah, that was exactly their thinking. And so Eugene Koonin proposed this in 2011, and Rotem Sorek was also working on these defense islands. And he basically built a computational pipeline to identify more of these unknown genes within those defense islands. And then he created an assay in the lab where he could basically set up duels and test whether that given unknown gene would defend a bacteria against a whole array of phages. He could just challenge them with lots of different phages and see, does that gene help the bacteria survive or not? And so he screened many, many, many of these new proposed immune genes and found that, yes, many of those did help those bacteria survive against phage attacks. And so that really confirmed this hypothesis that there are these unknown genes in the defense islands that are helping prevent infection. So that was pretty cool because now we've suddenly got hundreds of bacterial defense systems. And just to put that into context, before that, there were really just two known bacterial immune systems. So in the 1950s, the restriction modification system was discovered. And then in the 2000s, CRISPR was discovered. That was the second one. Then we get to 2018 and all of a sudden we're discovering, oh, there's hundreds. So we have many, many more to discover. We went from two basic mechanisms for bacteria to defend themselves and then through a bacteriophage thunderdome. They just discovered hundreds more of these mechanisms. And I'm assuming they're spread wildly among different kinds of bacteria. and this does lend itself to this idea that you were talking about where there is a whole ton of idiosyncratic ways to respond to infection and these bacteria that are obviously evolving rapidly in response to this arms race with the viruses that want to infect them. I guess it makes sense that this is the model that they would just produce whatever kind of molecular tricks work to stop the viruses from infecting them. So it's a huge thing that we would go from two known mechanisms to literally hundreds of them. Yeah, if you're a bacterial immunologist, it's very exciting. But the reason that people outside of that field care, the reason that this is even more broadly relevant is some of these bacterial immunologists started to think, well, what if instead of looking at human immunity and then finding those same mechanisms in bacteria, can we look at all these new bacterial mechanisms that we're uncovering and identify new human immune mechanisms. And so they started to make these predictions, looking at bacterial immune systems first, and then trying to find them in humans, but also other lineages, other animals, and also in plants. And they started to find just so many examples of these connections. That's really where the excitement comes from because studying bacterial immunity can tell you a lot about immunity in animals, plants, all kinds of lineages. So the relevance is suddenly much greater because bacterial immunity is helping you understand immunity across the tree of life It really does seem like a significant change in the way that we would think about innate immunity to say that this is basically shared by bacteria and the rest of the living world. From an evolutionary perspective, obviously there's billions of years and so many changes that separate us from bacteria, for example, whatever kind of immune relationship we have with viruses, it's happening faster in bacteria, I would guess, right? Which makes sense then that they would evolve a whole lot of different ways to deal with viruses. How do we end up getting those same mechanisms in human cells after billions of years of evolution and very incompatible cellular environments? How do these mechanisms get conserved between bacteria and us? So I'm not sure the answer is fully known, but there are some ideas. Let's think about the bacteria for a second. So the bacteria live in these communities, and we are discovering now that there are hundreds, maybe thousands of different bacterial immune defenses. But not every single bacteria has all of those. Right. It's useful to think about these defenses almost as like an arsenal that is a community resource. An individual bacteria can have a handful of immune defenses, and it can easily share them with its neighbors if needed. It can also easily borrow from its neighbors as needed through a process called horizontal gene transfer. So bacteria are really masters of horizontal gene transfer. They can very easily share genes, whether it's something that they need from somebody else in the community or whether it's something that they have that somebody else needs. No problem. They can all share. And this is a major part of the way that evolution works that wasn't necessarily well-known. Like horizontal gene transfer, huge part of our modern understanding of biology these days, at least. Yes. Now, in multicellular animals like ourselves, we reproduce over much longer generation times. We have sexual reproduction. So the frequency of horizontal gene transfer is much lower. There's evidence that it happens, but not as easily or frequently as it does in bacteria. So the question, and this framing is really coming from Eugene Kuhn-In, Because when I asked him about this, I said, how did these immune systems get into different eukaryotic lineages? And he said, if you give lineages enough evolutionary time, it's not that hard to acquire a gene through horizontal gene transfer, even if you're a multicellular eukaryote. We're starting to get a picture, and I think the way you described it in the story was that bacteria as a whole are kind of like a maker space. It's a place where a whole lot of creative evolution takes place. And then through these mechanisms that we don't necessarily fully understand yet, but we can understand how it happens in broad terms. through these mechanisms. When evolution lands on some useful way to deal with viruses, there's a fair chance that that mechanism from the creative space of bacterial immunity will end up in other species, whether it's through horizontal gene transfer or some kind of endosymbiosis. That immune experimentation, essentially, there is a way for evolution to play it out and make it a much more widely used pathway for dealing with viruses. Our understanding of evolution is constantly evolving, but this does seem like one that I haven't necessarily heard before, that bacteria are like these engines of our own innate immune systems. And that seems really cool. Yeah, for sure. I think bacteria, because they have such short generation times and because they are masters of horizontal gene transfer. And they're under just such strong evolutionary pressure. They are constantly battling viruses. And this has been going on for almost 4 billion years. They have just gotten so good at evolving solutions. And animals like ourselves, we can't evolve so quickly. You know, multicellularity has lots of advantages, but there are also trade-offs. And one of them is we just can't evolve that quickly. And so animals are better off borrowing when they need new defenses. They're better off borrowing from bacteria. Well, thanks for coming on the show and explaining this to us, Vivian. I really appreciate it. Oh, thanks for having me. It was so fun. Before we let you go, we always like to ask our guests for a recommendation. So what's exciting your imagination this week? I want to talk about this book called The Power of Life by Jessica Riskin. It was just published in March of this year. And it's a story about a French evolutionary biologist, Jean-Baptiste Lamarck. It is just a wonderful book about the history of science. I also thought, what an interesting character this guy is. And I think other people who enjoy evolutionary biology would also enjoy the book. Well, this sounds like it's in my wheelhouse for several reasons, so I'm excited to check it out. Thank you. Also on Quanta This Week, you can read about the latest advances in so-called zero-knowledge proofs and an exploration of what actually initiates lightning. If you've been enjoying the Quanta podcast, please take a moment to rate the show and leave a review. We'd love to hear from you. The Quanta Podcast is a podcast from Quanta Magazine, an editorially independent publication supported by the Simons Foundation. I'm Quanta's Editor-in-Chief, Samir Patel. Funding decisions by the Simons Foundation have no influence on the selection of topics, guests, or other editorial decisions in this podcast or in Quanta Magazine. The Quanta Podcast is produced in partnership with PRX Productions. The production team is Ali Budner, Deborah J. Balthazar, Genevieve Sponsler, and Tommy Bazarian. The executive producer of PRX Productions is Jocelyn Gonzalez. From Quanta Magazine, Simon France and myself provide editorial guidance, with support from Samuel Velasco, Simone Barr, and Michael Kenyongolo. Our theme music is from APM Music. If you have any questions or comments for us, please email us at quanta at simonsfoundation.org. Thanks for listening. From PRX.
