Ep 102: Inherency in evolution (with Stuart Newman)

What is inherency? What are the potential flaws with our understanding of biological function?

On this episode, we talk with Stuart Newman, professor at New York Medical College. In his recent paper, “Inherency and agency in the origin and evolution of biological functions,” Stuart argues against the commonly held view that functions of traits necessarily arise from the process of natural selection. He instead advocates for an alternative called inherency, which suggests that groups of cells naturally possess traits that determine their potential morphology, which can then be modified further by natural selection. He supports this idea with examples of extant species - placozoans and sponges - that closely resemble the earliest animals. We discuss Stuart’s provocative paper, the concept of inherency, and its potential role in evolution.

Cover photo: Keating Shahmehri

• Episode Transcript

  Marty Martin 0:07

  So Cam question, let's say we lived on a planet where somehow living things were made up of little plastic bricks, just like Legos, you could mix and match them and snap them and break them to make all sorts of things? For the sake of argument, let's say that the smallest bricks were about the size of a regular earth-like protein. How would Darwin say that entities composed of these bricks would evolve?

  Cameron Ghalambor 0:27

  I think, as a gradualist, he'd say, if there was heritable variation, and some combination of these bricks had a fitness advantage over other combinations, then through small additions and subtractions of bricks, and enough time, natural selection would lead to complex groups of bricks, like maybe brick elephants, and brick jellyfish and brick palm trees.

  Marty Martin 0:52

  Good, fair story. Darwin would be proud. But here's the important thing that Darwin's thinking misses the only future thing any individual can be is an extension of that which came before?

  Cameron Ghalambor 1:03

  Oh, no. I don't think he missed that. That's just another way of saying there's descent with modification. That was his focus, right? Leave it to you to say something so obvious, and try to make it sound like it's profound.

  Marty Martin 1:19

  Fair, I have been accused of occasional hyperbole, but stick with me. What if instead of bricks, life on this fake world started with big globs of stuff, blobs of fatty acids, kinda like really little balls of grosser, greasier playdough? How then, would life evolve?

  Cameron Ghalambor 1:37

  Oh, boy, I know there's a trick here. But I'm gonna say the basic same way. Eventually, after enough time, there'd be shapes and sizes of different species. And in this case, they'd be made up of little fat playdough instead of ultra tiny Legos.

  Marty Martin 1:53

  In a general sense. That's probably right. But think about the rate and extent of extreme forms and such different systems, the force of gravity would be very different on a T-Rex made out of fat than one made out of bricks, right?

  Cameron Ghalambor 2:06

  Okay, I think I see where you're going. There could never be a big fat, blobby T-Rex, unless the fat blobs evolved into something more rigid. No species like that would ever get that big unless it stayed in water.

  Marty Martin 2:19

  Yes. And this is the basic idea of inherency. The focus of our conversation today was Stuart Newman, a professor of cell biology at the New York Medical College. Stewart says that the natural physical propensities of living matter enable systems to evolve differently than Darwin and other gradualists would have us believe. Just like the dipole of a water molecule allows it to absorb a lot of heat before it changes temperature, the materials that compose life on Earth imbue them with particular abilities to stay viable, and exploit opportunities.

  Cameron Ghalambor 2:49

  Okay, wait, isn't that just a fancy way of saying constraint? That evolution can only follow a path based on what a lineage presently has, and elaborating on the things that came before? I mean, we'll never find a lineage of sea cucumbers with backbones. No matter how long we look, cause new species have to be variants on a theme. They have ancestors. And on a similar note, you and Art always talk about body size constraints. Life forms, and processes are limited just because of simple surface to volume relationships. I think we already know that stuff. Do we need a new name for it?

  Marty Martin 3:23

  Well, Stewart says yes, and I kind of agree. If we think of size and phylogenetic history, just as limits on life, we might miss a potentially major factor in life evolution. Just because the first life on Earth was made of my cells, little orbs of fat molecules, major evolutionary changes were possible. New morphological, and even functional doors, were open just because life was originally composed of fatty acids, and not little plastic bricks.

  Cameron Ghalambor 3:48

  Okay, let's hear from Stuart himself on this. As you'll hear, I was a bit skeptical on some points, but it was a super interesting conversation. On today's show, we talked with Stuart about the potential role of inherency in evolution based on work he and others have done with placozoans.

  Marty Martin 4:04

  Placozoans are an extant lineage of organisms made up of just six to nine cell types that probably resemble the ancestors of all modern animals. Stewart says that the physical characteristics of these lineages have had really important ramifications for how evolutionary processes have unfolded. Let us know what you think.

  Cameron Ghalambor 4:21

  I'm Cameron Ghalambor

  Marty Martin 4:23

  And I'm Marty Martin.

  Cameron Ghalambor 4:24

  And this is Big Biology.

  Marty Martin 4:36

  Stuart, thank you so much for joining us on Big Biology. It's really exciting to talk to you about a paper that you wrote not too long ago on inherency and agency and the origins and evolution of biological functions. I think your main motivation you wrote about it in the abstract is such was to question a central aspect of evolutionary biology: the adaptationist selected effects notion of biological function. So that's a heavy duty concept, I think, can you tell us what this selected effects notion is? And what's wrong with the sort of perspective about that? In theory so far.

  Stuart Newman 5:09

  Yes, so it's come out of philosophy and biology, but it relates to standard ideas and evolution. And it's the idea that if you, if you see a function in an organism, like the ability of the heart to pump blood, or the ability of the lungs to absorb oxygen, that this has come about over long periods of evolution, because the organisms in the population were better adapted to some external challenges, and they acquire that function in a gradual stepwise fashion, according to changes in their genome, in which genes have small effects iterated over many, many generations.

  Stuart Newman 6:00

  And the philosopher Ruth Millikan, kind of initiated this and she, she said, proper functions or functions that have come up through that route, and that there are what you might call functions of organs, like the heart's ability to make sounds, you know, doctors can use them. But those aren't proper functions, those are maybe side effects or something, because they haven't come up through this kind of winnowing of natural selection.

  Stuart Newman 6:31

  Later on, the philosopher Karen Neander, hold that the selected effects model or theory of the evolution of functions. And I took issue with that. I had been looking at the evolution of morphology for many years, my initial entry into biology was through limb development, looking at physical mechanisms of pattern formation, and so on. I hadn't really thought too much about functional evolution. But I started looking into how differentiation occurs in present day organisms. And also the difference between prokaryotes and eukaryotes, between metazoans and other eukaryotes, it really struck me that some ideas about differentiation that had been long held, were also flawed.

  Cameron Ghalambor 7:39

  So Stuart, I read the paper and I was actually I wasn't familiar with a lot of the philosophical background on form and function. And, I was kind of, you know, pleasantly surprised by how rich and what I thought was a relatively straightforward, simple perspective, that form refers to physical-like structures, like bone, muscle heart that you were mentioning, but even cells. And that, you know, you look at these structures, and you can infer something about their function, you know, what they do, what they contribute to, if it's muscle, how it contributes to running, you know, what other measure of performance. But then, you know, as somebody who works primarily at the whole organism level, I was also still struggling with trying to see why this kind of more standard, maybe simplistic view of form and function is really problematic for, you know, people who work at the whole organism level, because I think it's a very common assumption for us.

  Stuart Newman 8:54

  Right, so, looking at present day organisms, we have extant, forms like sponges and placozones and everything that we can call them ancestors, but we can infer backwards and looking at the fossil record and looking at the genealogy of the genes, we can say that the earliest metazoans, the earliest animals, were something like placozoans, which are kind of sandwich like quite simple organisms and sponges, which are labyrinthine, relatively simple or morphologies. And we could say that the earliest animals were clusters of cells that took on certain forms, and they had cell types, but they didn't have many cell types. And sponges have, I think about 18 cell types, placozoans, some people say six some people say nine, but they're much simpler.

  Stuart Newman 10:02

  And then you can ask about those presumptively early organisms, what were their functions, what do these cell types bring to them? And they brought things like motility, and the ability to absorb nutrients from the environment. But particularly if you look at the placozoans, you can see that the cells are not organized into tissues, no tissues that are forming organs. But there are cellular functions like the fluttering of cilia, for example, that for a cell itself, often don't have exposed cilia, the exposed cilia comes in with more complex organisms, but cilia are kind of inversions of intracellular structures. So placozoans have them on the outside, and they move around, through the environment using cilia in a concerted way. They're really these waves of cilia that act like flocks of birds, and they create this concerted movement which you can understand, like physical models. So you can see how cellular, what I call functionalities, things that cells do, are kind of recruited or appropriated in the multicellular system to do more complex functions.

  Marty Martin 11:59

  We want to dwell on the placozoans, sponges as well, but really the placozoans, you make some fantastic cases about, you know, potential steps by which this happened and how complexity may have emerged from these inheritances. But not too long ago, Cam and our other co-hosts of the show Art Woods, they spoke with Nick Barton, about many different things. But one of the main themes was Ronald Fisher's infinitesimal model. And I think you mentioned that in your paper, the basic idea in the model is that most traits are determined by many, many genes have small effects. What did he say that meant for evolution? And what is your perspective on the infinitesimal model given the, you know, the ideas of cellular dispositions?

  Stuart Newman 12:43

  So Fisher was basing his ideas and his mathematical models on Darwin's theory of natural selection, very clever theory. It said that you can get arbitrarily complex forms by building them up little by little. And over long periods of time. And let's say, let's hypothetically say, that you have an organism that changes radically to another organism. What's the trajectory between the two? Well, Darwin has a gradualist trajectory. And he says that there's variation. And organisms are a little bit different. If they're more prevalent in the next generation, that's a step to become a little bit different from that, and so on. And you have this continuous trajectory. So that's basically, the infinitesimal model is like a mathematical rendition of that idea.

  Stuart Newman 13:40

  But in fact, developmental biology shows us that with small changes in the genome, you can have very large changes in morphology. And you can have large changes in even functions. So you can have genes that have large effects. And then the question becomes, could those survive if you have a population with some extreme outlier because of some developmental change? And Darwin knew about these things, he called them "sports," and he considered them just random occurrences, and that there was no rhyme or reason to, he couldn't explain them. And he said that they really didn't contribute to evolution. And that's Fisher's position. Fisher had another paper called The Geometric model. And he said that the mathematics of natural selection don't work if you have big changes, because they're not tolerated by the population and the environment the population is swimming in. So those two things together are very much in keeping with Darwin's model that I think that bringing development into evolutionary theory changes the whole terrain.

  Stuart Newman 13:47

  I kind of want to push back a little bit on that, because I think, you know, the idea with the geometric model is really more that if a population is close to its kind of adaptive peak, then any mutation of large effect is going to have a negative deleterious effect and kind of push them further away from that optimum.

  Cameron Ghalambor 15:31

  But I think what you're talking about is more at a sort of macroevolutionary scale, as opposed to sort of that that kind of local microevolutionary scale that both the infinitesimal model and the geometric modeler are kind of more concerned with and I, you know, I see this a lot in both historically and currently that there's a long history of skepticism about the importance of natural selection, acting on continuous variation on on genes have many small effects, and I guess, to me, one of the problems here is and when we want to when I think when we want to incorporate development into evolutionary theory, is that we have to also be cognizant of the mechanisms that are associated with generating variation. So genetic changes, developmental programs, some of which can have, without a doubt, large effects, rapid effects, with the process of selection, which is just acting on the variation that is available to it, I don't see the process of selection, kind of as a creative force here. It's just acting with whatever variation, genetics and development and physiology and behavior kind of put out there. So how do you see these two sets of processes- the processes that generate the variation versus the process of selection acting on that variation?

  Stuart Newman 17:04

  Okay, so let's say that we have some large effects change, and this could come about by maybe the import of a new gene into a lineage, you have some lateral transfer, and this happens with the head crest of pigeons, that you have different lineages of pigeons and a introgression of a particular gene, and that they head crest instantly. So, it can happen that way, or it could happen by the environment changing and different rates of existing processes change in relation to each other, and then you get some developmental alteration that gives you a new morphology. So there are many ways that you can get jumps, and then the population is faced with whether these things are going to survive or not.

  Stuart Newman 18:05

  Okay, so it might be variant groups can form, you know, by sympatric selection, you can have the possibility of compatible populations within a given environment that's possible, or organisms can kind of strike out on their own. If this happens to a group of organisms, somehow, their particular genome makes them susceptible to an environmental change. So that you have a novel subgroup with novel properties, they can stake out a different pitch. This happens in plants a lot. And the organisms are quite different from their parental population. And they just stake at a new niche.

  Stuart Newman 18:59

  And they, and this is where I kind of bring the concept of agency into evolution, and other people have too. Organisms don't just kind of sit there and say: "Well, I'm not really good enough for this niche that I've arisen, I'm just going to stay here and die." They'll just kind of explore the environment and find some way of kind of mobilizing their new properties so that they can survive and living systems have this drive to kind of prosper. So Richard Lewontin talked about the organism as the object and subject of evolution. And seems to me that the kind of standard natural selection idea says: "Here you have some novelty, the organism is sitting there as an object of selection. This doesn't kind of comport with the originating population's adaptation to its niche. So it just dies." Because it's the effect is too large. But the organism as a subject of evolution says: "Well, look, you know, I'm bipedal and my cohorts are not, you know, so what am I going to do with it? I'm just going to walk to a different place and be a different kind of organism." So, basically, that's the idea that developmental processes, if modified in various ways, can give you new kinds of organisms. And then the question is, are the organisms content to just be selected the way their cohorts are? Or will they just become new kinds of organisms by founding new niches?

  Marty Martin 20:54

  Yeah, I mean, I know Cam has strong feelings about the concept of agency, as do I, but we come at different. We come at that from different sides. Maybe we can say a little bit more about agency in a minute. But what I'm hearing you to say, Stewart is that, you know, I think Cam's question was whether selection could be a generative force, like, you know, where the variation where this new stuff is coming from. And I'm sort of hearing you say that, it kind of what Cam was talking about that where the variation comes from, is going to be from other processes, and you named a lot of them, but it's not so much that selection is generating the new force selection is acting as some sort of a filter.

  Stuart Newman 21:33

  Right.

  Marty Martin 21:34

  Okay. Okay. Maybe let's turn then, to this, getting into the details about, you know, this, the sources and kinds of this variation. And this, this word of word inherency, that we've mentioned a couple of different times. You say that multicellular aggregates, particularly those in plants and animals during development, have evolutionarily important natural physical propensities, physical propensities, do their nature is biological matter. And this made the acquisition of morphological motifs almost inevitable. So I think that's a beautiful sentiment and yet complicated. Can you explain what that is and how that means inherency?

  Stuart Newman 22:15

  Sure. So first, I'll use a simple physical analogy. So if you look at water molecules, water molecules have certain properties. But you wouldn't say water molecules have waves or whirlpools or anything like that; they're just molecules. But if you put them together forces, kind of chemical Van der Waals forces, and so kind of make them cohere. And then you have liquid water, and liquid water can just be a drop, or it can be a kind of a still surface. But if you disturb it a little bit, it can generate waves, or it can generate whirlpools or generate water seas, of kind of chaotic nature. So there are various sigh inherent seas of liquid water that you wouldn't have necessarily predicted from molecular water. And water at certain temperatures can also freeze, it's very difficult to make a branched structure from liquid water. But if you have frozen water, it organizes into crystals like snowflakes and branches and so on. So different forms of matter, have different inherencies and the inherencies create morphospace. So, if you look at water, you can't say that it's all those things at the same time, but you can put it under different conditions and it will express those different forms.

  Stuart Newman 23:55

  Now when you're looking at animals for example, they arose from cells that are called Choanozoans, Choanozoans are a lineage of single celled organisms or transiently multicellular organisms are and where they include animals. And when the metazoans which are the animal branch of the whole, its own lineage emerged, the cells became attached to each other by a protein that was newly acquired, newly evolved in some way. These are the coherence, classical coherence, and they allow cells to remain attached to each other and at the same time and move relative to each other.

  Stuart Newman 24:46

  So when you have a material whose subunits are simultaneously changing position, but remaining coherent, that has liquid-like properties. And if you look at plant cells, they have a solid matrix, cellulose, that connects them to each other. And they're not moving relative to each other. Those types of materials have different inherencies. And you could predict ahead of time by looking at aggregates, animal cell aggregates, that if you had subgroups that were differentially cohesive, that you would get layers. Or if you had some units that had polarity, you can get cavities inside the massive tissue. So basically, there are inherencies that came about when this material first appeared on the face of the earth and had certain inherencies. And if you wanted to ask, how could it evolve, you can make changes to it, if you maintained its nature, but made small changes, what could happen? Well, not everything could happen. But some things could happen. And it could take you into different realms, you could get segmented structures, you can get whole structures, if you get structures with appendages, you could get structures that had internal hard skeletal structures, you could get organisms that had external hardened skeleton structures, and so on. So if you can always generate the whole panoply of animal forms, by looking at the inherencies of the original metazoan aggregates.

  Marty Martin 26:31

  So I find this idea really fascinating, Stuart, but Cam, and I've talked, you know, we prepare for these episodes. And one of the things that came up in our conversation, and I think it was a great point- Cam, I'm going to speak for you, I'm just going to steal your thunder. Why is this not a constraint? Like, what's the difference between physical constraint versus inherency? Because of, you know, the underlying physics, is there a difference there that's important?

  Stuart Newman 26:56

  Well, I think that a constraint says that it's a limiting factor. If something is an enabling factor, like I, if I told you that a mass of tissue, if you just kind of returned some of the serve and metabolic components, you could get segments, would you say, well, segmentation is a constraint of a mass of tissue?

  Marty Martin 27:25

  Yeah, that's fair. That's fair.

  Cameron Ghalambor 27:27

  I think also, like in the in the evolutionary literature, you know, the term bias is also also used kind of in the same context that a bias may act as a constraint, but it also may enable certain outcomes over others. And perhaps inherency, then is kind of capturing both sides, the bias enabling side and the preventive side as well.

  Cameron Ghalambor 28:06

  So if I understand you correctly, you know, inherency seems to be a very important concept, because it means that the cells have certain properties that predispose them to make these particular types, I think, of structures, I think you refer to these as motifs, which in turn, are then modified during the evolutionary process. However, unlike water molecules, the cells have their own evolutionary history. And they have the ability to be dynamic and plastic, depending on the environmental context, or I think, you know, in reading your work in the type of organism that they're found in. So we think a lot about that type of context dependency in the framework of phenotypic plasticity. And I'm curious how you see inherency related to the concept of plasticity?

  Stuart Newman 29:01

  Yes, well, I think that it's very related. If you look at the capabilities with the inherencies of any mass of tissue, then you could say, under what circumstances will one or another of the inherencies be manifest expressed. Sometimes, you can take a particular organism and put it in a new environment, and it will manifest it. So if you look at our bodies, if you put us in water and you have turbulence and so on, our bodies don't change shape. If you take a jellyfish and you put it in water, its body changes shape. So basically, the physical properties of its body accommodate to the environment in a way that ours don't. We have ways of resisting those forces, those simple forces, in the environment. But if you look at the developmental process, you could look at how segments are formed, for example. Segments are formed by some oscillating gene expression process a nd that gets coupled with growth, and if growth as a certain pace and the oscillation has a certain pace, you'll get a certain number of segments, and that segmentation number is characteristic of whether it's mouse or human has a couple of dozen segments, or a snake, which might have a couple of hundred segments. But you can take organisms like centipedes, and they have a certain number of body segments. And you can change the temperature, and the number of segments will be different at different positions at a temperature. So there's a kind of a modulation, and that's plasticity. That's modulating some inherency to make the organism different under different circumstances.

  Marty Martin 31:05

  Okay, I want to come back though, Stuart is something that you said at the beginning, now that we've defined inherency in a more explicit way. And we've talked through some other things. One of the first things that came up was was function, these proper functions of Millikan. So in the context of, you know, inherency in generating morphological novelty, I can follow that. But what's a little bit less intuitive is inherency in function. Can you can you get us there? I mean, how what are examples of inherency leading to Millikan's proper functions?

  Stuart Newman 31:37

  Sure, well, it wouldn't necessarily be a proper function, in her sense, because her sense of the proper function is one that has arisen by natural selection.

  Marty Martin 31:49

  Okay, good point. Yeah.

  Stuart Newman 31:50

  But I would say that, if we just look at things that our bodies do, like we have muscles that contract and allow us to locomote. Or if they're smooth muscle, they may allow us to convey food down our digestive tract. Where did the muscles come from? And if you look at single-celled organisms, particularly the Choazoan cells that gave rise to the animals, they have contractile functions, cells have amoeboid motion. And if you look at amoeboid motion inside a single cell, it's mediated by actin and myosin, two proteins, and a number of accessory proteins like tropomyosin. And if you look at muscles, both skeletal and smooth muscle, and also cardiac muscle, the same proteins are involved, the ancestral proteins, but now they're involved in specialized cell types and tissue types.

  Stuart Newman 32:55

  So what's happened is that those cells differentiate, they give up certain properties that are common to most other cells, or even with the ancestral cells. So for example, ancestral cells use those cytoskeleton proteins to divide and to multiply more cells. Skeletal muscle doesn't do that; it gives up the ability to divide. Nerve cells, other differentiated cells, sometimes they don't divide. So what's happened here is that they're part of a more complex organism. And they're kind of carried along and sustained by circulation system, other things they don't have to divide to, to keep going. And they have a specialized function. Now, that's an appropriation of this ancestral contractile function. But now it is in the service of a more complex organism that is sustaining that tissue type in ways that it can't sustain itself. So it gives up something and it's appropriated something.

  Marty Martin 34:05

  One thing that I'm having a little bit of a difficult time with is, well, can you say something more specific about the original roles? Or what was it about actin and myosin or proteins like that, that sort of has this flavor of inherency? Because if they're sort of eventually, you know, the sacrifices made by those cells that eventually evolved to become muscle cells. Now they can do contraction, which used to be used in amoeboid cells for locomotion. Where did the inherency initially come in? Because the inherency part isn't really there. There's a legacy and evolutionary legacy, when we go from single celled to multicellular, but what was the inherently the very first step of inherency with actin and myosin?

  Stuart Newman 34:49

  So that I don't know I there in all of the things I've written about this, I tried to make it clear that I don't know how cells evolved. There are people that study the origin of life and the origin of cells. And there are people, particularly philosophers that talk about things like autophoresis or the organizational approach of Moreno and Lucio, that people talk about those things. And they're very few molecular models of how that works. But it's very clear that cells are self-sustaining systems that interact with the environment. That's not my area.

  Stuart Newman 35:35

  My area is the evolution of multicellular organisms. And when I talk about inherency, there, I'm not saying that the function of actin and myosin in single cells is an inherent process. But if I asked how did multicellular animals first acquire the ability to have specialized cell types that allow the whole organism to locomote, to move around? What I have concluded is that they did it by appropriating inherent properties of cells. Now, one of the inherent properties of cells is motility. So, motility is a property of cells. Absorption is property itself, excitability, the ability to bind oxygen is a property of cells, the ability to detoxify the property of cells. So when you look from the point of view of a multicellular organism, and you say, what can I use, based on what I'm made of that will allow me to do new things? Well, there are inherency of cells that I can appropriate to become tissues and cell types.

  Marty Martin 36:55

  Let's move to the placozoans, I just love some of the word choices that you have in this paper. So you talk about the placozoans as a potential ground state of animal identity. What does that mean, and maybe connected to the points that you're making about the different cell functions that have been embellished in modern forms.

  Stuart Newman 37:16

  So it's important to realize that different kinds of animals, and particularly the what has been identified historically, as the phyla, actually have objective differences from each other. The sponges and the placozoans are often called basal metazoans. I think that's not a good term, because these are extant modern day forms and basal to anything. So there's another term that's used which are called parazoic. And they're in contrast to the eumetazoans, the eumetazoans are things like chordates and mollusks and arthropods and so on. So those are all eumetazoans. And even, there's a kind of an intermediate, like hydra, cnidarians and ctenophores, which are called comb jellies. Those are they're eumetazoans. But they're diploblasts, they only have two layers, they're not triploblasts, they don't have three layers. And if you look at what's the objective differences between these different classifications, you find that there are certain genes that are present, beginning with the cnidarians and ctenophores, that allow layers of cells, which we call epithelium, to sit on a surface called the basement membrane, and the enzyme that produces the basement membrane from collagen. Collagen is a very ancestral molecule, it's present in all animals, but the collagen does not polymerize into a surface, into a substrate, up until you get an enzyme called peroxidase. Which only comes in with the diploblasts. Okay, so it's a little bit technical here. But the point is that there are new genes that kind of seem to appear suddenly, and they may have had a gradual evolutionary trajectory. There's no evidence that they have been laterally transferred from other organisms; they just are not found anywhere, but in the new organisms that have them. And in the case of animals, like us, triploblast, things like fibronectin didn't exist in earlier forms. And that's an extracellular matrix that's important for our connective tissues and so on. Things like hydra don't have connective tissues but triploblastic organisms like us have connective tissues. And that is accompanied by new genes that perform functions that were not present in the earlier forms.

  So getting back to the question about placozoans being the basal metazoans, they have, basically, two layers of cells. They're epithelial like layers. It's a top layer and a bottom layer. But they don't have basement membranes. So they're not what we call true epithelial, they're kind of flimsier, much flimsier. They can't make, they can't put out appendages, they can't make limbs, they can't make even hairs or projections, they just can't. You need a basement membrane to make appendages. So they're just two flat layers, but they're covered with cilia. And the cilia are present in ancestral cells. So they didn't have to evolve de novo in the placozoans, they were already there, they just appropriated. But they do new things in the placozoans, because they're acting in a kind of a concerted wave-like fashion, and doing things that were never foreseen in the individual cells, in which the cilia first evolved. So the thing is that, when you get onto the multicellular scale, you can appropriate ancestral functionalities to do completely new things, just because of the scale. It's like the molecular water, when it finds itself as part of a drop of water or a body of water, it can do new things, it can make waves and so on, that weren't possible before.

  Cameron Ghalambor 41:52

  So if I can like jump in, and kind of ground this in a particular species of placozoan, so there's Trichoplax adhaerens, is the species. And so this is a very small placazoan, maybe only a millimeter long. As you mentioned, it has like these two epithelium layers, and is only made up of like six or nine cell types. And so you were talking about the cilia? You know, I'm very curious then, like, what else do we know about the origins of these different cell types before they show up in Trichoplax? Can you talk about like other cells and their functions? And like, what their kind of like evolutionary history is prior to showing up in placozoans? Do we do we have a kind of a phylogeny of these individual cell lines that goes back to the unicellular ancestors?

  Stuart Newman 42:50

  Oh, yes. Very interesting thing I just want to say about the placozoans. So lots of people, well several groups that look at the genetics and relate them to the kinetics of non animal Choazoans, and one of the most prominent things about the metazoan sea animals is the use of enhancers to amplify gene expression. And enhancers are not universal in all eukaryotic cells. They're really used in a very special way in the animals. And they congregate in these expression hubs for amplified genes and the animals and they're kind of central to the development of cell types. And it turns out that nobody's ever found enhancers in placozoans. So placozoans have specialized cell types, but they're kind of a very primitive. Specialization is kind of the overproduction of certain molecules. So the placozoans have digestive cells, which means that they have degradative enzymes that they secrete to the environment that are similar to our digestive enzymes in some way. And they're similar to, to pre-existing lytic enzymes that were made by single celled organisms. But they're not, they're not digestive cells, like we have digestive cells. They're not as complex and they're just kind of the overexpression of certain genes. So there's a kind of an abortive attempt for differentiation in placozoans. And it's a bit of a controversy as to whether placozoans are a form that was from kind of a more complete metazoan repertoire that just lost the ability to use enhancers or something, or if they, in fact, are the primitive state. But in any case, placozoans don't really have genuine cell types the way even sponges do, because sponges do use enhancers, and all other all other metazoans use enhancers.

  The other thing about placozoans is that there's a pathway that's also almost universal in the animals with a notch pathway. And the notch pathway is very important in creating patterns of cell types that we see in tissues and organs. So the notch pathway, the cell expresses one component of the notch pathway, it will interact with a nearby cell and say don't do what I'm doing, just do something different. It's kind of suppresses the adjacent cell from following the same route as the notch expressing cell. And placozoans are missing some components of the notch pathway, it's not that they don't have it at all, but they don't have it, they don't have it as efficiently and do it as well. And this is also in an impairment in the ability of placozoans to take whatever cell types they have and turn them into organized tissues. And even sponges have some aspect of organized tissue. It's not as advanced as it is and they put less and so on, but it's there, but it's less there in placozoans. So there's a deficient in a number of things. And it's not clear whether their ancestors never had it, where their ancestors never or if their ancestors lost it. In any case with the placozoans, they have some cells that are called crystal cells that form little crystalline inclusions that allow a kind of gravity sensation. So they're kind of a primitive form of a sensory cell. And they also have kind of primitive neurosynaptic types of components. They don't form, they don't have nerves, they don't form synapses, but they have cell types that have some excitatory functions that you could see are the makings of what eventually became nerve cells in metazoans.

  Marty Martin 48:10

  So this is really cool. And I have so many questions about placozoans. And especially when you were talking about a minute ago with the evolution of this enhancer, sort of scenario for gene regulation. However, we'll have to save that for another time, because I want to get us, I want to stay in this area of inherency. And I want to bring in a new player to this conversation. I mean, literally new in the evolutionary sense, because this guy, Mike Levin, at Tufts University and his colleagues literally invented these new forms of life, what they call bio-bots. And you tell a really compelling story. And full disclosure, Mike has been a repeat guest on this show, so we're really really big fans of Mike's work. But how do you understand inherency? And what kinds of inherency have you seen in these bio-bots? Maybe for the listeners who didn't hear those shows, or don't know Mike's work. Tell us a little bit about what these bio bots are.

  Stuart Newman 49:04

  Right it's remarkable work, Mike's work on that, and also on the electrical field, scaffolding structures. It's really brilliant work. So with a bio robots, what they do is that they take cells from frog embryos, Xenopus embryos for the, it's called the animal cap, and it's a homogeneous population of cells, and they dissociate them and they reaggregate them into spheroids. And spheroids have externalized cilia. So basically, spontaneously, they take structures that might be active internally in the animal capsules, but they get externalized and these little spheroids can kind of scoot around, and they can find their way through mazes and things like that. And this is nothing that they do when they're part of the frog embryo, the frog embryo, they may have these capabilities, inherently. But they're those capabilities are suppressed in the surface of certain stages of frog development. So they're not doing that. But here, they're put in a completely new context. They haven't undergone any kind of Darwinian selection. But they're just cells that are in a new context. They're given sources of nutrients, which they navigate towards. So they act like organisms that never existed.

  Marty Martin 50:40

  So yeah, I want to really drive this home steward, because I think you know that what we've been talking about with choazoans and placozoans, this is great. This is what happened on the planet. This is really amazing, because these cells have never had the opportunity evolutionarily, to exist as these entities. And yet, when you put bunches of them together, you sit they navigate mazes. How is that? These are just embryonic frog cells. Can you say more about how Mike found that to be the case?

  Stuart Newman 51:10

  Well, I think that they just observe things carefully. And then they set of challenges to see if they could be the challenges. They've done similar things with Physarum, Physarum is a slime mold, which is. But I would say and I think Mike Levin would agree that their ability to do this is based on the fact that individual cells have an agency of their own, they have with what has been called primitive cognition, they basically exist in the world as living entities. And they're not simply passive. It's not like if you take a cell type, an individual cell, and put it in a new place, it will instantly die, because it's never seen it before. It'll figure out how to get away from toxins, it'll figure out how to get to something that might sustain its life. Living things have this impulse to live and survive, and that's what people call agency and agency doesn't have to be reinvented, every time there's an evolutionary step towards more complexity. So it's basically appropriated. And it, in this case, these spheroids, they're made of cells, cells have this impulse to survive and to nourish themselves, and they have the capability of doing it. So basically, agency is one of the inherencies of, of living cells. And do it, can we explain it? No. As I said, there are philosophers that have been pondering over it, but I haven't tried to explain it. But I've tried to see how it works, when it's placed in a new context. A new context can be the experimental context of the bio-bots, or the new context can be some novelty, that has arisen through the inherencies of the multicellular tissue.

  Cameron Ghalambor 53:36

  So Stuart, I kind of want to maybe push back a little bit on that because Levin's work with these bio-bots is really phenomenal. But I guess my confusion here is that these cells have a obviously an evolutionary history that we've talked about. And it's true historically, they're the environment and the context that they occurred in was, was embedded within the tissue of a frog. But released from that context, in the, in this new sort of environment of the bio-bot, because of this evolutionary history, the cells are, essentially have a form of plasticity. And so I guess what I call the capacity for being plastic is what you're referring to as as agency. How, how are those two different from each other?

  Stuart Newman 54:35

  Plasticity versus agency?

  Cameron Ghalambor 54:37

  Yeah, in this case, I mean, you take the cell out of the historical context, it's still a biological, you know, entity and it has amazing complexity that reflect you know, that's its long evolutionary history. And so in this new kind of environment, you know, without having to, I guess, invoke any kind of primitive cognition or anything, I'm sure that if you put any kind of cell in other kinds of context, they would do different kinds of things, just again, based on the mechanisms that are currently present within the cell.

  Stuart Newman 55:22

  Right, so plasticity, you could define plasticity, to include behavioral plasticity, and then you're basically overlapping with the concept of agency. But if plasticity was simply, if I take a cell, and the cell normally has a cuboid, of a shape in an embryo, and I put it on a flat surface, adhesive surface, and it becomes flat, well, I'd say that's morphological plasticity. I wouldn't call that agency. So plasticity is by analogy to certain physical processes. If you look at water, and say that it's a material with plasticity, it can form waves, or it can form whirlpools, or it could be still just flat. Well, that's physical plasticity, I wouldn't call it agency. So cells really have this kind of impulse to stay alive. And it sounds vitalistic. And I'm not a vitalist. But I understand that there are certain things about cells that we don't, we don't really have a good molecular and biochemical explanation for now. So you can kind of bracket that as a kind of practical vitalism but not a commitment to vitalism.

  Cameron Ghalambor 56:59

  Yeah, I think, I mean, from a, from an evolutionary sort of biology perspective, you know, we broadly defined plasticity as just saying, the capacity for any, like genetic background, to change its phenotype, whatever that phenotype might be, it could be behavior, it could be morphology, it could be physiology, in response to the environment, and that it is a predictable response to the environment, it's not a random response to the environment. And so if you go to a population, and you see that different individuals exhibit different responses to the same environmental cue, then we kind of think about that as a genotype by environment interaction. And it's that variation that that selection acts on. And so, you know, I think at the cellular level, I could imagine that in the past, cells that didn't respond in particular ways that were maybe adaptive to the environment would have, you know, been been eliminated, and those that, that did persisted and, and we see they're sort of offspring living today in modern organisms, so.

  Stuart Newman 58:15

  So let me push back against that. So if you have a population and the population cells have kind of little algorithms or computers in them, that have been evolved, according to the history of the species, to make the cells do a certain thing, then you can say the cells are little automata. And they may respond differently like a slime mold amoeba, a dictyostelium amoeba, will see a gradients of cyclic AMP navigates a gradient towards the high points. But certain cells in a population won't, and they're not necessarily eliminated. Maybe they don't have that computer in them, in a fully evolved form. But they remained in the population, and the difference can't be attributed necessarily to genetic differences. Cells just have different behavioral modes. There was a recent study of fireflies, and it was thought that fireflies blinked in synchrony, because of some mathematical property of some internal oscillator. And that if they are part of that collective that is blinking in synchrony. They'll blink in synchrony, and then they found that there's some fireflies that just don't do it and their progeny could do it, but they didn't do it. And basically organisms have quirkiness to them, and the quirkiness is kind of associated with just not following the crowd, sometimes. Maybe that's kind of a preadaptation to being able to exploit new environments if they turn up. So but the thing is, but maybe it's not, maybe it's just agency, maybe organisms just have different tastes and propensities.

  Cameron Ghalambor 59:54

  It could be, I guess, if you think about organisms, whole organisms that live in ecologically complex environments that are that are shifting, having a diversity of like personalities at the, at the whole organism level, you know, different kinds of behaviors, some individuals might do better under certain conditions, and then other individuals do better under other conditions. And so you can also maintain variation at a population level, you know, in response to kind of fluctuating environments that way. So, I think there's, you know, it's hard to know, obviously, but I do think of that as a fascinating question to, you know, move from the level of population of individual organisms to looking within the organism at a at a population of cells, or, you know, these different cell types that have to each have their own sort of functions. And as you use the term, the inherency, that they bring, but they but they also have to cooperate with one another at the tissue level, or at the organ level, and then certainly at the whole organism level to work together. And so, to me, that's also a very fascinating kind of levels of selection, kind of problem.

  Stuart Newman 1:00:57

  Right? Yeah, I would just question whether what was quirkiness? It's something I think it's a kind of a kind of a matter of almost a matter of faith to say that if you see some feature of an organism that doesn't seem to conform to the expectations of evolution, like the ability to have birds hybridize with each other, well, that kind of erases a species difference. So it seems to be kind of going against the standard evolutionary theory, but you create new species by hybridization. So are those propensities specifically about and what was the adaptive scenario that led to them to be discordant with the rest of the members of their population, have all possible adaptive scenarios existed to bring us to the point where all the latencies of possible futures are present in a population by natural selection, or is there just kind of an openness to the nature of organisms?

  Marty Martin 1:03:13

  What you guys have been talking about in the last couple of minutes, it really relates well, to something that Cam and I have been thinking about for over a decade. And the kind of bumper sticker version of this is whether organisms are in scare quotes "special" as a level of biological organization. Now, let me try to frame that in, in the words that you used in your paper, you wrote about organizational closure. And what you said was that organizational closure is this emergent regime of causation such that constituents of the system constrain the operations of others, but also collectively maintain itself via mutual dependence? Beautiful, I love it. But here's my question. So cells and tissues, I think, clearly do that. We've been talking about that it almost has to happen that way. Organisms probably do that. Do you think communities and populations do that? You started to speak about that with the hybridization example? But if they don't do that, does it mean that organisms are this kind of special level of organization?

  Stuart Newman 1:04:10

  So let me just say that, that what you quoted my saying that that's not the organizational closure comes from the philosophical work of Alvaro Moreno and his colleagues. And it's called the organizational approach and that's something that I've quoted and used in some of my work, but it's not, that's not my idea. But I would say that organisms have this cohesiveness to them as internal cohesiveness. And it actually goes back to the philosopher Immanuel Kant, who, who talked about organisms as natural purposes. He said that organisms will produce the means for their perpetuation, in a way that we don't see anything in the living world do. And that idea, which Kant acknowledged that he couldn't explain was taken up by Maturana and Verela, two Chilean philosophers, i n the concept of autopoiesis, and it's extended by Mareno and his colleagues in the organizational approach. So this is quite important. And it characterizes what people have tried to apply it to higher level entities, like societies, ecosystems, and so on. And my feeling is that those are different kinds of things. There are higher level things like eusocial societies, insects, that are organized in a way that is somewhat cohesive, or quite cohesive. There are flocks of birds that interact with each other in a way that looks like it's one cohesive entity, and so on.

  Stuart Newman 1:05:33

  My feeling about all this is, I'm very anti-reductionist, so I believe in different forms of matter. And each form has its own inherency. But I also, I don't believe that these things are irretrievably separate from each other, things like there are particles that form atoms, the atoms are different from the particles, but you can understand how the atoms emerged in the history of the universe from fundamental particles. So I'm not saying that there's no continuities between different forms of matter, but what I'm saying is that once you have a new form of matter, like the, you know, the hundred plus atomic elements, they have inherent properties that are very different from anything that preceded them. And there are also things that build on them, like cells and organisms are not reducible to the chemistry of the atomic elements. They are dependent on it, they're based on it, but new features come in, as you get new forms of matter. And I think that animals are a different form of matter than plants. I mean, we know that they've had common ancestors at some point. But they're different forms of matter, with different inherencies, so they have different developmental properties. So if you talk about an ecosystem, there are certainly kind of laws of organization, thermodynamic regularities. But I think that they're not reducible and not the same as the kinds of coherences and inherencies of individual organisms.

  Marty Martin 1:08:11

  Interesting. So what about the agency? Part of things? I mean, most of the argument was based on inherency. But like, the reason that I maybe I put up organisms, give them more credit than they're due, is that agency does seem to be concentrated at the organismal level, or is it? Is it meaningful and fair to say that communities have agency as well?

  Stuart Newman 1:08:33

  Well, there are people that say that and I think that there's incipient agency and communities, you know, maybe a beehive, as you know, has some kind of agency. But it's not the same thing. And it's more loosely organized. And when multicellular organisms evolved from single celled organisms, you also had intermediate forms, things like cellular slime molds, where you have kind of transient multicellular stages, things that kind of navigated around as a multicellular structure like the slug of dictyostelium. So these things, you could say that the slug of dictyostelium has agency, and the agency is somehow based on a domestication of the agency of the cells that it's made of, and then it disperses again into spores, and then the whole cycle starts again. So there are kind of more complex forms of agency, but they can be transient. And I think the mistake is to try to reduce one thing to another. You have these transiently new forms of matter, and they have new properties. that you just haven't seen anywhere before. You can relate them to the properties and the things they're made of, but you can't reduce them to the properties of the things they're made of.

  Marty Martin 1:10:10

  Yeah. Wow, that's well said.

  Cameron Ghalambor 1:10:12

  Well, I think on that, I mean, this has been a fascinating conversation. We always like to end by giving our guests the opportunity to say something that you know, anything else that you'd like to say that we haven't covered today?

  Stuart Newman 1:10:27

  Well, I just think that people should be open minded about the plurality of evolutionary mechanisms. And I know that a lot of evolutionary theorists are very loyal to Darwinian natural selection. And I think it obviously goes on, but I think there are more things in the world than even Darwin contemplated.

  Marty Martin 1:10:48

  Good. Well, I think we'll end on that note. Stuart, thank you so much for joining us. We really appreciate your time.

  Stuart Newman 1:10:56

  Thank you very much.

  Marty Martin 1:11:07

  Thanks for listening to this episode. If you like what you hear, let us know via Twitter, Facebook, Instagram, or just leave a review wherever you get your podcasts. And if you don't, we'd love to know that too. All feedback is good feedback.

  Cameron Ghalambor 1:11:17

  Thanks to Steve Lane, who manages the website and Ruth Demree for producing the episode.

  Marty Martin 1:11:22

  Thanks as well to interns Dayna Dela Cruz and Kyle Smith for helping produce the episode. Keating Shahmehri produces our fantastic cover art.

  Cameron Ghalambor 1:11:29

  Thanks to the College of Public Health at the University of South Florida, the College of Humanities and Sciences at the University of Montana, and the National Science Foundation for support.

  Marty Martin 1:11:38

  Music on the episode is from Podington Bear and Tieren Costello.