The Joy of Why - How did Multicellular Life Evolve?

Episode Date: March 20, 2025

At first, life on Earth was simple. Cells existed, operated, and reproduced as free-livingindividuals. But at some point, things became more complicated once unicellular organismsfound a way to group and function collectively. This transition, known as multicellularity,formed a pivotal event in the history of life on Earth. Multicellularity created the means toincrease biological complexity, which sparked an incredible diversity of organisms andstructures.How life evolved from unicellular to multicellular organisms is still a mystery, though one thingwe do know is that this may have happened as a result of multiple independent events. To try tounderstand what could have happened, Will Ratcliff at Georgia Tech has been carrying out long-term evolution experiments in which multicellularity in yeast can spontaneously evolve andgrow. In this episode, Ratcliff talked to the Joy of Why podcast about what we know aboutmulticellularity, how his snowflake yeast model can investigate this, the surprises hisexperiments have thrown up, and how he has responded to scientists who are cynical of hisapproach.

Here's the thing, science isn't only for the PhDs of the world, it's for everyone. On the Shortwave Podcast, we dig into the latest research with a humorous touch. In under 15 minutes, it's serious science, even if it doesn't sound like it. Listen now to the Shortwave Podcast from NPR. I'm Steve Strohgatz. And I'm Jana Levin. And this is The Joy of Why, a podcast from Quantum Magazine exploring some of the biggest unanswered questions in math and science today. Hi, Jana.

Great to see you. Hey, Steve. How are you doing out there? Hi, Jana. Great to see you. Hey, Steve. How are you doing out there? Good. Welcome. This is season four. We're back. We're back.

Looking forward to this. Yeah, me too. This is going to be a really exciting season, and I'm so thrilled that we're doing it together. Yeah, and you're kicking it off this season. You have the first episode. Yeah, so I did. And the topic was one I had never thought about before. I wonder if you've run across it.

It's the question of the origin of multicellularity. Weirdly, I have thought about this. You have? Well, I found it fascinating that single celled organisms waffled for so long on the earth. And that just nothing was happening for a very, very long time, billions of years. And then something finally happened. I always thought that was just remarkable. But so I think of you thinking more about like black holes, space-time, astrophysical stuff. But why are you thinking about this? Because science is fascinating.

I like the science that other people are doing too. And sometimes I just want to hear about it. I'm used about things that I don't plan on working on necessarily. Okay. I see. So not from some astrobiology life on other planet type. Not yet. Huh. But you make the point about waffling.

That single-celled critters, like we have bacteria, maybe cyanobacteria in the oceans, taking them a long time to get their act together to go multicellular. And you said you wondered why it took so long. Yeah, right. I mean, if you ask about astrobiology, is that happening on other planets? It's just taken a really long time and they're just single-celled organisms

floating around out there? Right, what took so long? Yeah. And did it only happen just once? And apparently, and this came as a shocker to me, it did not just happen once. It happened something like 50 times, independently. That's shocking.

Yeah, why wasn't I informed? Yeah, why am I the last to know? Well, I think when we were in high school and they were teaching us biology, they didn't know that. But it's now understood that, you know, in all these different kingdoms, or whatever they call them in biology, so whether it's animals, plants, fungi, they all figured out their own way to do it, to go multicellular. But in any case, one question then is how does a

unicellular organism manage to make this transition in any of these cases? I mean, there's the historical question of how did it happen, but what's so amazing and really very courageous about our guest, Will Ratcliffe is his name. He's a biologist at Georgia Tech is that he wants to do this in the lab. He wants to induce a multicellularity transition in a single celled organism that we've all heard of yeast, like the yeast in making beer or bread rising, whatever, which normally lives as a eukaryotic single-celled organism. He has found a way to get them to act multicellular, to clump together into, are they a colony?

Are they trying to be a multicellular organism in their own right? Well, I really hope that stays in the lab. You don't want to see that thing coming at you in the street. I don't want it coming out of my kitchen sink drain. Like one of those crazy cyclops fungi. Well, we're not there yet. I can tell you that's not where the episode is going. But as we'll hear from Will, it is controversial. There are colleagues of his who feel what he's doing is irrelevant to the history of life on earth, and he's just doing something in the lab, and it may be telling us very little about what happened in real biology, whereas other

people think it's fundamental mechanisms that he's getting at. It's opening up a realm of possibilities for us to explore. Some may have occurred, some may not have occurred historically, but still it shows us what biology is capable of. Yeah. So you ready for a Will Rackless? Fantastic. I'm ready. Let's do it. Okay. Let's do it. Oh, hey there, Will.

Hey, Steve. How's it going? Good. I'm really excited to have you on the show today. Can we begin by talking about your hobby farm? I have to admit, I'm not sure I know what a hobby farm really is or what happens there. I think it mainly means that we spend much more money than we would ever gain from any proceeds from the farm. We have goats, we have chickens,

which lay more eggs than we can eat. We have peacocks, which haven't hit maturity yet. So my neighbors are still okay with them. The males, I think make a, like a call that is like a, but you know, a hundred decibels or more. And, uh, we'll see, we may be getting rid of those. Some natural selection there. Indeed.

Uh, so in addition to raising animals and plants though, you do, as we're going to be talking about today, raise yeast. But before we get to that, could we just talk about, more broadly, the question of unicellular life versus multicellular life? What are some of the basic characteristics of each type? Yeah, so, you know, life on Earth has a very long history. It evolved around three and a half billion years ago. And by then we had honest to goodness cells

with the things that you've probably learned about in your high school biology class, right? They have a nucleus which contains the DNA that encodes the genetic information that the cells use to perform their basic functions that, you know, then makes proteins that are the action parts of a cell. And so cells are these fantastic biological machines, right? In which you have this concentrated soup of highly functional macromolecules.

Now, life wasn't always cellular. Cells are like one of these great innovations of life. And once sort of cells evolved, they really took off. And it has been the sort of basic building block of life for the last three and a half billion years. Multicycle organisms are a kind of organism that is built upon the basis of cells, but where many cells live within one group and function essentially collectively. So we are a multicycle organism. We contain approximately 40 trillion cells, which divide labor and perform all these various functions to allow us to do things in the multicellular environment, run around, have eyes, see things, talk on podcasts that wouldn't be possible for

single-celled organisms. Right? So the evolution of multicellularity is a way of increasing biological complexity by taking what were formerly free-living individuals and turning them into parts of a new kind of individual, a multicellular organism. And it's evolved not once or twice, but many times. We don't really have a great number because we keep discovering more actually, but there's at least 50 independent transitions to multicellularity that we know of.

Whoa. That's not something I remember hearing in my high school biology class. That's something we only figured out, what, in the past few decades? Yeah, I think it's been a gradually increasing number, but I think as people we tend to be very animal-centric. But then there's a whole slew of things that are a little bit more esoteric. There's cellular slime molds that live on land that move around like a slug and then will grow as single cells

and come together like a transformer to then do something as a group, you know? So there's different flavors of multicellularity that have evolved in different lineages. And I think partly we've known about this for a while, but especially as we develop the tools to understand bacteria and archaea, the big domains of single-cell life that have been around for a very long time, we're finding more and more types of multicellular bacteria and archaea

that we just didn't know existed because unless you're looking at them with a high-powered microscope or using other advanced techniques, you can't just see it, right? So, one thing I was wondering about here is dates. We have reasons to think that cellular life exists around three and a half billion years ago. And Earth is only four and a half billion years old total, so it's fairly early in Earth's history as a planet.

But it probably happened earlier. And by that time, they've already done the things that are required to evolve cells and have all these basic building blocks of life, like DNA, which contains the sort of code of the organism. Uh-huh. Good. Yeah, this is very helpful because there are so many interesting transitions to talk about, each of them being astonishing. You know, the origin of life from non-life would be one, but the very famous one that everybody hears about is the Cambrian explosion. And if I'm hearing you right, that is not quite what we're talking about.

It's one of the transitions, well, let's put it this way. The evolution of multicellularity is broader than just animals. It's a process through which lineages that are single celled can form groups, which then become units of adaptation, evolutionary units that can get more complex through, you know, natural selection. And the Cambrian explosion is a incredible period where animals, which had already been around for probably a hundred million years or more, just start to figure out all of these innovations, which are hallmarks

of extant animals. Before the Cambrian explosion, things were soft and gelatinous and didn't have eyes or skeletons. It's questionable if they had brains. They don't have any of these things. And then in a relatively short period of time, just a few tens of millions of years, all of these things show up. And we think it's probably due

to these like ecological arms races where you have predators attacking prey, the prey start evolving defensive mechanisms. So, you know, you have just this explosion of animal complexity in what appears to be a very short period of time in geological terms. But that Cambrian explosion, when the animals start to figure out all these evolutionary innovations, that's later, right? Any estimate of how much later that is than the first appearance of multicellularity? Great question. So the interesting thing about multicellularity, it's evolved in very different time periods and different lineages.

So cyanobacteria were evolving in multicellularity with honest to goodness development and cell differentiation around 3 billion years ago. It doesn't take that long after you get cells that you start to get multicellular organisms evolving. So the red algae, which are a seaweed, they begin evolving multicellularity around a billion years ago. The green algae start doing it around then too.

Fungi, probably anywhere between a billion and half a billion years ago. Plants, we know that pretty well. That's about 450 million years ago. Animals, they really start to take off around 600 million years ago. Again, it's really hard to put an accurate date on that, so we have to be sort of, you know, hedgy. And then the brown algae, the most complex kelp, they actually only began evolving in multicellularity around 400 million years ago.

And you know, I think we should not think of it as one process, but something where there are ecological niches available for multicellular forms. And there has to be a benefit to forming groups and evolving large size. That benefit has to be fairly prolonged. And most of the time there isn't. But occasionally there will be an opportunity for lineage to begin exploring that ecology and not be inhibited by something else that's already in that space.

That might be why something like animals has only evolved once, because once you already have an animal, then it suppresses any other innovation to that space, like a first mover advantage. So what are the benefits and what are the things that would inhibit you from that transition? Yeah, so John Tyler Bonner is an evolutionary biologist who worked on multicellularity decades

ago. And he has this quote that I really like that, there's always room one step up on the size scale, right? So, you know, the ecology of single-celled organisms, that's a niche that's been battled over for billions of years. And there's lots of ways to make a living in that space. And that's why we are in a world of years. And there's lots of ways to make a living in that space, and that's why we are in a world of microbes. But once you start forming multicellular groups, you can participate in a whole new ecology of larger size. You might be immune to the predators that were eating you previously,

or maybe you're able to overgrow competitors for a resource like light. If you imagine that you're an algae growing on a rock in a stream, single-celled algae will get the light. But hey, if something can form groups, now they're intercepting that resource before it gets deep. They win, right? Or groups also have advantages when it comes to motility

and even division of labor and trading resources between cells. So there's many different reasons to become multicellular. And there isn't just one reason why lineage would evolve multicellularity. But what you need for this transition to occur is those reasons have to be there and that benefit has to persist long enough that the lineage sort of stabilizes in a multicellular state. It doesn't just go back to being single-celled or die out. You could imagine there's lots of ephemeral reasons to become multicellular and then they go away and then the single-cell competitors just win again, right?

Hmm, that is very fascinating. I actually took biology with John Tyler Bonner. That's really cool. He was a very sweet man too. And you know what else? He had a lot of interest in physics and I was a math and physics student and this teacher, Professor Bonner, started talking about scaling laws as creatures get bigger. How does their metabolism scale with their body mass and things like that? And it was suddenly there was all this math in biology class, so I felt at home.

But I'm bringing it up not just to tell my own story, but because I get the feeling you're some kind of math, physics, computer-ish kind of person. Is this true? No. I came to biology early and I came to computation and theory and physics late. But you're right that we use all of those different approaches. My longest running collaborators are with a physicist at Georgia Tech, Peter Juncker, and a mathematician in Sweden named Erik Libby, who is a theorist. And I've been working with both of them for 10 to 15 years.

All of my students, you know, basically work at the interface of theory, computation, experiments. I guess that's the space that we inhabit. We also throw synthetic biology into that pot which is one of the beautiful things about working with yeast. Wow. Let's go into yeast now. I think it's time. You've probably said it already, but what is the big idea underlying the research you've been doing now for some years? Big picture, we want to understand how initially dumb clumps of cells,

cells that are one or two mutations away from being single-celled, don't really know that they're organisms. They don't have any adaptations to being multicellular. They're just a dumb clump. How those dumb clumps of cells can evolve into increasingly complex multicellular organisms with new morphologies, with cell level integration, division of labor and differentiation amongst the cells. Just like we want to watch that process of how do these simple groups become complex.

And this is like one of the biggest knowledge gaps in evolutionary biology, I mean, in my opinion. But it's something where, you know, we can use the comparative record. We know multicellularity has evolved dozens of times. And the only truly long-term evolutionary experiments we'll have access to are these ones that happened on Earth over the last hundreds of millions or billions of years. But because they're so old and because those early progenitors, those early transitional steps, aren't really preserved, we don't really know the process through which simple groups evolve into increasingly complex organisms. So what we're doing in the lab is we are evolving new multicellular life using in laboratory directed evolution over multi 10,000 generation time scales to watch how our initially simple groups of cells, dumb clumps of cells, figure out some of these fundamental challenges.

How do you build a tough body? How do you overcome diffusion limitation when you after you've built a tough body and made a big group? How do you start to divide labor amongst yourselves when you only have one genome? How can you make that one genome be used for different purposes in different cells to underpin new behaviors at the multicellular level? Does this thing become entrenched in a multicellular state, which prevents it from ever going back, or at least going back easily, to being a single cell? And so we're watching this stuff occur with a long-term evolution experiment which we're now on generation 9,000 of what we

call the multicellularity long-term evolution experiment, MULTEE, multi, absolutely a pun. It's also named an homage of the long-Term Evolution Experiment, which is a 70,000 and counting generation experiment with single-celled E. coli, started by Rich Lensky and now run by Jeff Barrick. So we're basically trying to do something similar, but in the context of understanding how multicellular organisms evolve from scratch, how they can sort of co-opt basic physics and bootstrap their way to becoming organisms. Beautiful. That's great. That is incredibly ambitious. I mean, I hope the listeners get a feeling of the courage it takes.

And I'm sure your critics would say hubris or you're playing God or, you know. But still, this is a wild idea to try to make multicellularity happen in the lab. So maybe you should tell us, you said directed evolution. That's a little bit of an unclear phrase unless you're a professional. So what are you doing to encourage this transition? Yeah, so we start out with a single cell of yeast. We did some preliminary experiments

where we evolved them in an environment. This is a test tube that's being shaken in incubator, where it's good to grow fast because they have access to sugar water. And the faster you eat the sugar water, the more babies you can make. And it's, you know, scramble competition. Everyone has access to the same food.

And then at the end of the day, we put them through a race to the bottom of the test tube, where we just put them on the bench for initially five minutes, but as they get better and better at sinking quickly, we make that time shorter and shorter to keep the pressure on them. And here there's an advantage to being big,

because big groups sink faster through liquid media than small groups. This is just due to, you know, surface area to volume scaling relationships. Bigger groups will have more gravity pulling them down relative to the friction from their surface. You take the winners of that race to the bottom, the best ones, they go to fresh media,

and you just kind of keep repeating this very simple process. So you used to have a budding mechanism where a mother cell will pop off a baby from one of their poles, and then they can keep dividing and adding new cells to the same cell, right? So in our early experiments that were just open-ended, we got these simple groups forming that have this beautiful fractal geometry. We had this easy mutation, it turns out it's just

one mutation in a regulatory element of the cell, that prevents daughter cells from separating. Super simple. Every time the cells divide, they pop off a baby, but remain attached. And so you get this sort of growing, fractal branching pattern. Imagine something like a coral, or maybe like a branching plant.

They kind of look like that, and they end up becoming more spherical, these nice branches. We call our yeast snowflake yeast. And you have this life cycle where they grow until they start to have packing-induced strain. They run out of space, and now if they add more cells, they just break a branch. And so you have this emergent life cycle where they're growing, they're jamming, they're breaking branches, those little baby snowflakes

pop off, and they even have a genetic bottleneck in this life lifecycle in that the base of the branch that came off is one cell. So as mutations arise, they get segregated between groups and every group is basically clonal. Every cell in the group has the same genome. Let me pause here. There's a lot of things going on. I want to keep track of them, see if I got you.

So first of all, the big mutation is the one that doesn't let the daughter detach from the mother, right? That's the key thing for forming simple groups. Correct. Yep. So we figured out what this mutation was and when we started our long-term evolution experiment, we started them with basically one genotype, so one clone that already had this mutation engineered into it, but with replicate populations.

Because what we want to understand is, how do these simple groups of cells evolve to become more complex? And I don't want that to be confounded by the mechanism through which they form groups in the first place. So we have actually 15 parallel evolving populations that started out the same in the beginning. But we actually have different metabolic treatments for them.

So one of them is taking all their sugar and they are burning it up with aerobic respiration, using air from the environment to respire their sugar. One of them, we broke their mitochondria in the very beginning, so they don't get to use respiration. They can only ferment and they get a much lower energetic payoff from that, but they don't have to worry about oxygen diffusion anymore. So sort of a trade-off there. And then one of them can do both.

It first ferments and then it respires. Okay, so when you spoke of 15 different lines, they all have the property that their daughters will stay attached. But then you say some get to use oxygen in this advantageous way for their metabolism through respiration. Others have to use fermentation. Which is how you make beer, by the way.

Yeah. Okay, so we have different ways. And then you said some of them, at least, don't have to worry about oxygen diffusion. What's the worry? What is the scary thing about oxygen diffusion? So we thought initially that the ones that could use oxygen would be the ones that evolved the most interesting multicellular traits. But it turns out that they've actually stayed very simple for almost 10,000 generations. They haven't done that much in the last 8,950 generations. They peaked early.

They peaked early. And they're only about six times bigger than the ancestor. And we don't see any beginnings of cell differentiation. They're just simple kind of bigger snowflakes. The anaerobic ones, they have evolved to be more than 20,000 times bigger than their ancestor. What? Yes. Six in one case, 20,000 times bigger than their ancestors. What? Yes. Six in one case, 20,000 in the other case.

Yeah, yeah, yeah. And it turns out that this is because there's a trade-off that's introduced by oxygen. If you form a body, and oxygen is this valuable resource that if you get it, you can grow a lot more, but it can't diffuse very far into the organism, Then all of a sudden, the bigger you are, the smaller a proportion of your cells are able to access this really valuable resource and your growth rate just falls off a cliff. Wow, your interior is so small compared to your surface. Exactly. The bigger you are,

the larger your radius is, the smaller a proportion of your biomass has access to oxygen. In our case, the anaerobic line, they've done the interesting things because they're not being constrained by oxygen. They've evolved large size. They've evolved all these interesting behaviors and they're solving all these fundamental multicyclic problems. If I'm hearing you right, you're saying something like that the anaerobic ones, because they

don't get this sugar high from the availability of oxygen early on, they have to be resourceful. They have to come up with all kinds of other innovations and they do. So, yeah, I like the way you phrase that. But to be just a little bit more precise with our system. Yeah, please. The ones that have access to oxygen, as they get bigger and bigger, their slower and slower growth rates really push back against them and kind of act in the opposite direction of any benefits that come from size. But if you remove oxygen, now bigger is better.

The smaller ones go extinct and the bigger ones win. And then they figure out a way to get bigger. And they can really push the envelope on size and explore large size in a way that the ones with oxygen can't because they're getting pushed back on by growth rate. But then as they get bigger and tougher, they actually start to have real trade-offs that are created by forming big bodies. They're so big that now they're struggling to bring sugar in to these groups because they're actually becoming macroscopic. They're bigger than fruit flies now. They're large. Yeah. That's wild. Yeah. And they also face another constraint. Early I mentioned that they

grow and would normally break due to physical strain arising from packing problems. But they solve that by figuring out how to make tough bodies by making their cells long enough that they actually wrap around one another and entangle. This is now a vining procedure where if you break one branch of a vine, you know, the ivy is still not coming off your shed. I live in Atlanta, I'm tugging ivy on trees and sheds all the time. And it's very difficult because entanglement percolates those forces throughout the entire, you know, entangled structure.

And so now you don't just break one bond to break apart the snowflake yeast, you have to break apart hundreds of thousands. And it becomes much, much tougher as a material. And we even understand the genetic basis of this, all the way up to the physics. It's really cool to be able to watch mutations arising that change the properties of cells that underpin emergent multicycler changes, which natural selection can see and can act upon and can sort of drive innovation in that multicycle space. It's all very surprising, right?

Because he's got this hypothesis going on on the basis of what we believe about the importance of oxygen. And we even talk about it when we're looking for other planets and life on other planets. Will there be oxygen? And is there water? And all this stuff that we're really so certain is what's needed to really accelerate life and life radiating. But now he's amazingly saying, well, maybe that's just not the case. Here you have these oxygen hogs that got stuck. Oh, I love your exobiology perspective on this. I wouldn't have thought of that.

That's so interesting. I don't know what to make of it. To me, it sort of sounded like if you've got a hand tied behind your back and you're forced to ferment, you're going to be resourceful. You're going to be like that old folk saying about whatever doesn't kill you makes you stronger or something like that. And evolution, as they always remind me, is not just mutation. It's mutation and environmental pressure.

So it's the hostility of the environment in some sense that drives the mutation. Interesting point. We will hear more from Will after the break. Welcome back to The Joy of Why. We're here with Will Ratcliffe and we're discussing the evolution of multicellularity. I'd like to get into a question about clusters versus organisms. What would make an organism different than a colony? And how do you know which kind of thing you're getting through these selection experiments? It's a great question.

And it really cuts to the core of what do we mean by multicellularity. And I think a lot of confusion in my field for the last half a century has come down to poorly resolved questions of philosophy. But what do we mean by these words? And people inadvertently speaking at cross purposes. Okay, so part of this is that the word multicellular really means three different things and we're not very clear with our language.

It's treated as a noun in English to say, you know, multicellularity, but it's really an adjective which modifies different nouns. So you could have a multicellular group. That's just a group that contains more than one cell. You could have a multicellular Darwinian individual, and that is a multicellular group which participates in the process of evolution as an entity at the group level. So something which reproduces, where mutations can arise, which generate novelty in a multicellular trait

and which natural selection can act on and cause evolutionary change in a population of groups, that's adaptation at the group level. So that would be a multicellular Darwinian individual. And then you have multicellular organisms. And the sort of philosophical distinctions of what's an individual, what's an organism, there's been a lot of work done in the last 20 years and I'm pretty happy

with the results of where that field is right now, which is that organisms are functional units. Organisms have integration of parts and work well at the organismal level with, you know, high function minimal conflict. And so we are all three. We're a group, we're a Darwinian individual, and we're organisms. And so the distinction is, is that there are sort of progressively higher bars for how you get to these additional steps and they tend to occur sequentially. The first step would be forming a group. The second step would be making that group capable of Darwinian evolution. And then as a consequence of group adaptations, you can get organisms,

which would be functional integration of cells, which are now parts of the new group organism. And so a trait that would be diagnostic of that would be cellular specialization or differentiation, especially if it comes down to reproductive specialization. People love that in evolutionary biology because your cells give up their direct reproduction, they're no longer making offspring. That's something which is a behavior that you really can't ascribe to the direct fitness interests of that cell, right? So your skin cells will never make a new steeve, right? Never. They are entrenched in the, not on the line of descent, but it's okay because they are

helping you make your reproductive cells reproduce. And so the vast majority of our cells are not directly on the line of descent, but that is a derived state. Originally, every cell made copies of itself that were on the line of descent. Originally, simple groups don't have this kind of reproductive specialization. But over millions of generations of multicellular adaptation, you get organisms that have now cellular parts, or those parts work together to allow the organism to do things that it couldn't have done before.

And an important part of that is specialization. Just to make sure I get that point, what does it mean to be in the line of descent in relation to skin cells versus what, like gonadal cells? Yeah, sperm and eggs and this isn't a strict requirement, right? You could have something like plants that don't have this type of line of descent segregation. But nonetheless, you know, if you look at a tree, it makes flowers, it makes seeds, right? You have this differentiation into cells that will be the reproductive structures and those

that don't. If you're a wood cell, you just give up your life to make wood, right? Wood is basically a series of tubes. You differentiate into a tube, then you die. They're doing it for the good of the multicellular group or something. That's right. And it's also for the good of their own genome. And their genome. Because usually those that are on the line of descent are related to them.

And that's how you kind of square it. So there's apparent altruism at the level of the cell, but there isn't really altruism at the level of the genome. Because I mean, when you start talking about Darwinian adaptation at the level of the group, I hear Richard Dawkins' British accent in my ear drilling in that there's no selection except at the level of the gene. And then if it were Stephen Jay Gould talking to me, he would say there's no selection except at the level of the individual. Yes.

I think. I'm oversimplifying, but group selection is where people traditionally start yelling at you. That's correct. You're totally right. And I think there should be some sociological studies on this in evolutionary biology because it has been much more, do you believe the consensus rather than like actually rigorously thinking through it. And in the last 15, 20 years, I'd say the anti-group selection sentiment that was very powerful all the way up through the 2000s has mostly melted away as people have embraced

more pluralistic philosophies that like, there is sort of one evolutionary process. You can view it through different perspectives. Sometimes it makes more sense to use a group selection model. And I think if we're thinking about individuals in the GOOL sense, selection acting on the traits of individuals, for multicellular organisms, those individuals are groups. Of course, that's why it's always a little bit of a confusing distinction, right? I mean, the individual is made of other things. Yes. and people are happy to sort of round them up to just one, but there was a point where it wasn't just one.

It was a simple group, and it wasn't so clear that that group was an individual. Like a snowflake yeast, you can break off any cell, put it into its own flask of media, and then it'll turn back into another snowflake yeast, right? That wouldn't happen with one of my arm cells. Now, if you go for a really long time in my experiment that stops happening, but in the beginning, cells are just in groups as vehicles.

And over time, they gain enough adaptations as a consequence of selection, acting on the traits of groups and really caring about the fitness of groups. That cell level fitness outside of the context of groups starts to really take it on the nose. They don't do so well as being outside of groups anymore. And they're evolving the beginnings of division of labor, different cell states from one genome. This is unpublished work, so I wanna be appropriately hedged here, but we've done single cell RNA sequencing

and we can see new cell states evolving over the 5,000 generation time scale. We go from one sort of putative cell type to three and we think we know what they're doing. Like we think it's actually adaptive differentiation as opposed to just sort of noisy chaos. If this pans out, it's saying that the cells have differentiated in their gene expression. Is that what you're saying?

Exactly. Into different sort of behaviors. Well, all right. So you're saying? Exactly, into different sort of behaviors. Well, all right, so you're seeing these interesting transitions in your lab. You're inducing them through the selection you're putting on. But to what extent do we think these multicellular transitions that you're provoking shed any light

on what happened historically in the wild? That's a great question. I mean, actually, I love that question, because it's an important scientific question. It's something I've thought a lot about in the wild? That's a great question. I mean, actually, I love that question because it's an important scientific question. It's something I've thought a lot about in the sense that in order for our experiments to have meaning, they need to be somewhat generalizable. Now, I think the caveat here is that there is no one answer

to how multicyclic evolved. It likely evolved in very different ways and for very different reasons in plants and animals and mushroom-forming fungi. It's not a single thing. But nonetheless, the thing that does unite it all is this evolutionary process. You have to have group formation. Those groups become units of selection and they turn into organisms as a consequence

of group adaptation. And that evolutionary process, while it might play out in different ways in different lineages, some of these things are fundamental. So that transition to individuals that become organisms, that's universal. And size is universal. And the physical side effects that come with size,

scaling laws, challenges with diffusion, and the opportunities that come to break those trade-offs through innovations. Those things are all generalizable even if they take different paths in different lineages because they're all proximate creatures of their environment and their gene pool, right? And we've never seen those processes play out in nature. And I don't know that we ever will because they're historical things that we don't have the actual samples to see it. And one of the things that we can do is while we're not saying this is how multicyclical evolved in any one lineage, what we're saying is this is how multicyclical can evolve.

And this is how some of these things that may be looking in hindsight, you think you need really complex developmental control. Oh, actually, it turns out you don't because physics gives you all these things for free that are kind of noisy, but they work. And you can bootstrap those into your evolutionary lifecycle and build upon them without necessarily having to evolve those traits for a reason. So a lot of things in our experiment have turned out to be easier than we expected. And while the details may differ, I suspect that some version of these things that we're seeing in our experiment play out in the different transitions in nature. You seem to have some practice with answering that question.

You have thought about that one a lot. I like that answer. Thanks. Well, all right. You mentioned earlier a scientist named Rich Lensky who had done this very long-term evolution experiment with bacteria. And that that's been passed on now. Do you have a Jeff Baric lined up? You're not quite close to retirement yet, I don't suppose. But have you thought about this? Is this experiment going to outlive you, I guess, is what I'm asking. I would hope so. But first of all, I want to say, I would be remiss if I didn't say

that our experiment is actually run in my lab by Ozan Bozdog, who's a research scientist with me, who started the multi as a postdoc in 2016. And it's kept working and kept succeeding and he's making his career essentially running this experiment. So like without Ozan, I wouldn't be here and doing this. He's the one that kind of figured out how to really make it work.

So I'd actually be interested in doing this a little bit differently perhaps than the way the LTE has been run, which is I want to run the standard multi myself, but I wouldn't mind doing like a multiverse type thing and have collaborators or others that were interested in running their own version of the experiment. There's no reason that it has to be one timeline. I mean, you know, we could go all Loki. I see separate universes doing the experiment. Sure.

I mean, we already have kits that we send to teachers where they can evolve their own snowflake yeast or do experiments with predators. Wow. We're actually making a new kit this summer for these hydrodynamic flow behaviors that we've been observing that snowflake yeast actually act like volcanoes or sea sponges, pulling nutrients through their bodies and up and shooting them up at the center of the group, which totally overcomes diffusion limitation. But also, if scientists want to work on our system, then I think if we democratize this and make it a resource for the community, science benefits, right? So you've been very good about responding to what are some aggressive questions here?

Do you ever find it discouraging? And do you ever think about, you know, I don't need this aggravation? Not for a long time. I felt mostly like good vibes from the broader community for many years now. But when I was just starting out, I did have some experiences that were discouraging. Like Carl Zimmer, like it interviewed me for the New York Times and then got a bunch of critiques and then re-interviewed me and I, as a postdoc, had to like defend myself to very senior faculty

that I really looked up to. And that didn't feel very good. It felt sort of like I wasn't welcome in those communities where it seemed like at the time Maybe we were just bullshitting and trying to spin a good story and there wasn't much substance there That definitely affected my own approach to science and my own thoughts on inclusion and just being Really supportive of younger scientists anytime you critique a paper in my field, you might think you're critiquing

the senior scientists on the paper, but they usually have a graduate student or a postdoc who wrote the thing. It's their life for years. They're the ones that really feel their critique. Criticism is critical for science, and I love good, rigorous, critical debate. I hang out with

physicists and mathematicians in those communities it's a sign of respect to be direct to ask hard questions and to endeavor to get at the truth and I really like that but at the same time I love writing why I like a paper I love writing why I think this paper is important and how it changes the way I think about a field and so when I'm reviewing papers and grants, the first thing I do is write detailed review of why the paper is important and cool. Even if I have major concerns and questions, which I will get to, I always make time to acknowledge the importance of the work. And similarly, like in the context of multicellularity, I'm always trying to

bring new people into the field. Like we're pluralists, we want new people to come in, we want you to bring your systems and your ideas, there wasn't just one way of thinking about this. I think those early experiences that I had were fairly rough and made me sort of avoid interacting with those communities maybe for longer than I wish I had in hindsight. Do you think the harsh criticism or at least penetrating criticism, did it sharpen you

up? Do you think it improved the work? Did you write better discussion sections? Did you write more persuasive introductions? Perhaps. Well, you remember when you asked me, you know, what's the importance of your work? And I had a polished answer. And that's because I've been challenged on this enough times over the last 15 years that

I had to really think hard about that, right? And certainly thinking hard about it changes the way you do your science, right? You develop the areas that you think are more general and more impactful as opposed to just doing the next experiment. That being said, the criticisms, the sharp and penetrating criticisms I've always appreciated, because that makes your science better. The criticisms that are simply dismissive are the ones that I always have found the hardest,

the most frustrating because, you know, if someone says, and I've gotten this a lot, it's cool what you do, but snowflake yeast aren't multicellular. I mean, then I have to question, okay, am I going to spend the next 10 minutes explaining the philosophy behind what multicellularity is? Like, there isn't just one thing here, right? And so it's the sort of dismissive side of the criticism that I've found the least productive, whereas like sharp penetrating tough questions. I mean, we're scientists.

We kind of like that stuff. So good. Thank you, Will. I really appreciate it because you know, you have fielded, I've tried my best to sort of simulate those tough questions and give you a chance to respond to them So maybe in the future you can just play this for the some of those people save your breath Anyway, it's been really a great pleasure talking to you likewise so much. Thank you very much So we've had will Ratcliffe with us talking about the evolution of multicellularity, and

it has really been fun. Thank you. Thanks, Steve. What about that? Do you have any personal experiences with that? Or maybe you've seen it with your own students? Oh, man. I'm still a student of the subject.

And even now, it really resonated in that it can be very discouraging if someone's dismissive. He's exactly right. It's okay if somebody's like really critical and you're exploring together and you're going to get to the answer. If it's right, it's right. If it's wrong, it's wrong. But to be dismissive, that is something that it's not only hard to hear, it sort of engenders a little bit of distrust, I think, because there's something about that that doesn't feel like the program, you know? The person who would dismiss you,

you feel like I don't trust that person so much anymore. When I hear people being dismissive, it doesn't have to just be at me. I get a little suspicious, yeah. Uh-huh, like they have another agenda about self-promotion or something else? Maybe, yeah, you know, something, because aren't we here because we're driven by excitement and curiosity that so emanates

from him. And what a great colleague to have. I want to get a letter of review from him. I want him to review one of my papers. But what a great colleague. That's what you want people to bring to the table. And yeah, you want people to tell you, you know, this isn't the right direction if it really isn't, and to explain why and, you know, be able to navigate that. But that requires real engagement.

Something about his phrasing that to be dismissed is not productive. So that was such an interesting operational word to use. I mean, not that it's insulting or hurtful. It's not productive. Yeah, and it can take the wind out of your sails because then there isn't anything to discuss. Yeah. If you have something to hang on to and a point to respond to with a compelling, rational, mathematical, formal, experimental argument, whichever avenue is required, that you can keep going. It doesn't help you be a better scientist. It doesn't help you make new discoveries to just be dismissed like that.

Well, this has been so much fun talking to you about this episode. Always. I can't wait to review for the show. It helps people find this podcast. Find articles, newsletters, videos, and more at quantamagazine.org. The Joy of Why is a podcast from Quantum Magazine, an editorially independent publication supported by the Simons Foundation. Funding decisions by the Simons Foundation have no influence on the selection of topics, guests, or other editorial decisions in this podcast or in Quantum Magazine. The Joy of Why is produced by PRX Productions.

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