#1272 Arvid Ågren & Manus Patten: The Paradox of the Organism

00:00 Ricardo Lopes: Hello, everyone. Welcome to a new episode of The Dissenter. I'm your host, as always, Ricardo Lops, and today I'm joined by two guests, Doctor Arvid Ogren and Doctor Manus Patten. Uh, Doctor Ogren is a return guest. He's now assistant professor at the Cleveland Clinic Learner College of Medicine at Case Western Reserve University. And Dr. Patten is teaching professor in the Department of Biology at Georgetown University, and they are editors of the book we're going to talk about today, which is the Paradox of the organism, adaptation and internal conflict. So Doctor Ogren, welcome back to the show. Doctor Patton, welcome to the show. Really nice to have you on both.

00:42 Arvid Ågren: Yeah, thanks for having us.

00:44 Ricardo Lopes: Yeah, OK, so, uh, let me start by this. Uh, WHAT is the paradox of the organism? What does that mean in the context of evolutionary biology and the philosophy of biology?

00:58 Manus Patten: So, uh, I can take that one. The, the, the term paradox of the organism comes from Dawkins, as there's so many, uh, terms in evolutionary biology now. Um, WHAT he was referring to there was this observation that it's actually kind of a surprise that we have perfectly functioning, you know, perfectly good organisms, despite the potential for internal conflicts and selfish replicators inside of them. To undo them from within. Um, IT, it actually, it, it, it demands an explanation how you can have these organisms which are paragons of cooperation and internal harmony, at least at first glance, uh, despite the constant threat from selfish replicators within. So things like selfish genetic elements and selfish cells, the cancerous cells and the like. Um, SO perhaps not a paradox to a philosopher. I think philosophers would say that's not, that's not so much a paradox as it is an interesting observation and maybe a, a thing that needs explanation, but, uh, the, uh, you know, the thing that needs explanation about the organism doesn't make for as, as good a title as the character of the organism does.

01:59 Arvid Ågren: I think, and one thing you can kind of justify, call it the paradox in, in this more kind of way that biologists use it to just means something that we haven't explained yet, is that Dawkins pointed out that organisms have traditionally been just taken for granted, that they are there and they work. And kind of from his kind of selfish gene point of view, that isn't the fact, that isn't just something you can take for granted. It's there and it needs to be explained. Um, AND that is kind of like the, the entry point for us, uh, into this book.

02:27 Ricardo Lopes: But let me just ask you more, some, I guess, a provocative question here, but I mean, isn't it a paradox if we approach evolution through a gene's eye view of it through a gene-centric approach to it? I mean, if For example, as some people have suggested, we take as the unit of selection to be, for example, the entire cell or even, uh, organisms as individuals, wouldn't that paradox just not be there?

03:04 Arvid Ågren: And it, it becomes much more, it becomes, as you say, a paradox from the point of view of, of genes or, or replicators because, you know, the whole point of biology is to an extent to explain why things are the way they are and not just, And why not in another way? It turns out like life as we have it here on this planet is organized in this kind of complex ways with units coming together in, um, to, to build organisms. Uh, AND from a gene's point of view, then, why isn't it just, um, self-replicating molecules, um, persisting around on their own? Why do they come together, uh, evolutionarily to, to form these bodies, uh, as we see them? Um. And from that point of view then, is that what, why is it, why is it not just still, um, virus-like entities? Why do we see this kind of extraordinary diversity, uh, of complex life, uh, that we do?

03:56 Ricardo Lopes: Mhm. But what is an organism actually from the point of view of evolutionary biology? What does it mean exactly?

04:08 Manus Patten: I, I would say it's one of these bundles of biological activity. So, so Ar described a hypothetical world where biological activity is, is, is engaged in by the virus-like entities and that's all there is. You can, you can imagine such a world where biological activity is limited to just that, and yet on this planet, we see that activity come to be bundled into chunks, which we call organisms. Um, SIMILARLY, there, there's an analogy in economics where you can imagine just a bunch of economic activity. Just a, a marketplace where people exchange goods, um, and that's all there is, but instead, we find firms where people come together and some economic activities is arranged internally where there's an internal harmony and some internal logic to things. So, so organisms are these bundles of biological activity. They're bounded, they have some boundaries, um, and so, so, so we can off of that, that, that's the definition of organism. Not one without some problems, you get into some difficult, uh, uh, areas where sometimes you have to squint and, and decide whether that's an organism or not. Um, AND that's where it gets kind of interesting. I, I think any, any grade schooler could tell you what an organism is. It's a dog, it's a flamingo, it's a sunflower, um, but then as you get more educated, you actually get more confused about what an organism, uh, actually is. Uh, SOME of the problem cases arise in that case.

05:31 Ricardo Lopes: Yeah, yeah, that's why we have to define our terms here. So, um, but in the context of evolutionary biology as well, what is a conflict? Because we're going to talk a little bit about different kinds of conflict here, particularly focusing on internal conflicts because we're going to be talking about the organism. What is conflict and how does it apply specific to, uh, specifically to the organism?

05:58 Arvid Ågren: So conflict in, in evolutionary biology, we usually talk about that when we have two entities that have kind of conflicting fitness interests, and there you can kind of get an evolutionary conflict of, over how that, what, what may be good for one entity's fitness may be detrimental to the other entity's fitness. Now, this can, uh, we can Describe this in quite general terms, that this is usually something we think of individuals having conflicts with each other, um, over, uh, over something. Um, BUT as we kind of show in this book that these kind of conflicts, um, you can apply the same logic to lower-level entities. So cells within the bodies may have conflict with fitness interests. What's good in the short Term for a tumor cell, um, is bad in the short term for the, uh, for the full multicellular body. What is good for one, type of gene may be bad evolutionarily for another type of gene, uh, within the same, uh, body. Um, AND that is, when we say, when we use that kind of like what's good or bad, we're talking here in terms of, uh, fitness interests over evolutionary time.

07:04 Manus Patten: And that's it we're doing there you know that that's a move we're making like all the time and if you're reminded that not everybody thinks this way, uh, about organisms, uh, I, I, I think, I think everyone might think this way comfortably about organisms engaging in conflicts and cooperation, like organisms have behavior and there's a whole field of behavioral ecology about those behaviors, but I think what motivates behavioral ecologists, it's the same thing that motivates us, but we're not thinking about. Meerkats getting in, uh, you know, cooperative arrangements or conflicts. We're thinking about genes and cells doing that instead and applying some of the same intuition and some of the same models even to those internal conflicts.

07:44 Ricardo Lopes: And approaching things through the genes I view or through the point of view of genes, how do the interests of the different genes get aligned in an organism? I mean, how does that happen?

08:00 Arvid Ågren: It's kind of various, uh, ways. The kind of, the, the central way I would say is that they typically share the same route into the next generation, um, and they kind of, that, that route then is set up in, in what we, what we usually say is a fair way. So in a, in a, uh, sexually reproducing organism such as ourselves, um, we have two copies of each gene, but only one of them gets transmitted to the next generation. And the, the, the kind of the way that, uh, that is decided, which, which copy that is, is through what is essentially is a lottery, and the lottery through, of, um, meiosis. Now, uh, that works really rather well to, to align the interests of the genes of the body. However, then, there are, uh, kind of extraordinary number of fantastic examples where genes have evolved, um, strategies to, uh, circumvent that. And kind of uh bias a lot in their own favor, so instead of ending up in 50% of the, the gametes or the offspring, they end up in a much higher frequency uh than that, um. So that's kind of one of the central ways that uh genetic conflicts are uh managed within the body.

09:10 Ricardo Lopes: Mhm. And uh what about different uh levels of selection? I, I mean, first of all, what do you make of the, uh, multi of multi-level selection? I mean, do you consider the different levels of selection? Do you only consider the genetic level of selection? How do you approach that? And then, uh, what can conflict occur between different levels of selection?

09:41 Manus Patten: I, I, I think yes to all, um, uh, maybe I, maybe, let me back up and tell a little story here, uh, a little evolutionary tale to, to, to, to, to, to explain where these levels come from, uh, because we don't get these levels all at once, uh, so every kind of organism we can think of had to arise at some point. That way of organizing, uh, biological activity didn't exist always. It had to come into existence by some evolutionary process. We call these. Major transitions in individuality. So, one canonical example, one that's made familiar to us, is the transition from a world that was entirely unicellular. So if we go back a billion years, I think yeah, about a billion years, we'd be, we'd see nothing but unicellular organisms. There'd be no multicellular organisms, at least no big and charismatic ones at least. There, there's maybe some filaments and maybe some films, and those are definitely multicellular, no disrespect to them. But in terms of like the complex multicellularity that we uh display, that sort of thing didn't exist about a billion years ago. So, predominantly, things were unicellular. To get to a multicellular organism where biological activity is, is taking place in a multicellular blob requires some, some evolutionary transition. What it requires is for cells to come together and cooperate in a sense. Um, AND to, and to, to, to have a fitness of their own, not so much fitness of the parts. Um, AND that transition. It's, it's an interesting one. What it then invites for, for us, what we find interesting about it is that you have these entities, cells in our case, where if you back up the tape, a billion years, a few million years, you'll find those cells have fitness interests of their own, but then through a transition, we stop thinking about the cells as having a fitness interest or, or fitness at all. We think of the individual, the multicellular individual as being the bearer of fitness and also being the bearer, therefore, of adaptations. Um, AND so, what the major transitions in evolution perspective gives us is a story where in the beginning, we had adaptations at this level and evolution taking place at this level, but then you build up more complicated arrangements, um, and and belongs to these higher levels. Of course, for us, what we're interested in is, is the backsliding, right? This cooperation gets you these new and fantastic kinds of organisms, but the conflicts we find very interesting. They also get you a lot of interesting evolutionary elaboration as well. Um Uh, IN, in, in a sense, what, uh, what biodiversity is all about for us is how conflicts and cooperation, really how, how those conflicts have been settled, uh, and tamed by organisms.

12:20 Ricardo Lopes: But when it comes to multi-level selection, do you consider, uh, all the levels from gene selection all the way to group selection, or is group selection something that you, uh, Don't consider, I mean, I, I'm asking you this because I know that there's lots of discussion surrounding group selection and some people consider, for example, uh, cultural group selection but not genetic group selection and so on. So what is your take on that?

12:53 Arvid Ågren: Emma, so the, the, the kind of the, uh, relationship between the genes IVO evolution and, uh, what we now call multi-level selection, what has historically been called, uh, group selection has been quite, um, complicated and at times quite, uh, contentious. They have sometimes been, uh, conceived as kind of direct, um, kind of empirical rivals, making kind of either one of them is true and Um, the other one falls. I think these days, most people would kind of think of them, that that is the wrong way to think about their relationship, but rather they are a different way of conceptualizing the same, uh, process. And then you kind of, depending on your preference, you can model that using a multi-level selection, um, framework. Um, AND within multi-level selection, there are, uh, various ways you can do that, and people will have their own preferences. Uh, AND then you have a kind of a traditional gene selectionist way, and kind of related to that is the kind of inclusive fitness frameworks. And people can kind of, kind of choose their own, um, tools. Um, AND kind of I think where Man and I have landed that these are different tools of doing it. There's an interesting question, I think about When are the kind of assumptions you make within one modeling framework so different from another one that we should be worried about that maybe these can statistically give you the same prediction, but kind of closely, biologically, what, what is going on, uh, are now quite different, so we should be a little bit worried about that. Um, BUT what, what stems from that is that kind of the kinds of internal conflict that we, uh, study in this book can meaningfully be described as conflict between different levels in kind of a, in, in, in a hierarchy of, um, of, uh, of selection, if you, if done, uh, properly within kind of thinking about time and how you conceptualize, um, selection. There's actually one chapter in Specifically within the book by a philosopher Pierre Bra who kind of tackles that and kind of makes an argument that if you properly account for time scales, often these kind of conflicts will actually, uh, dissolve, that it doesn't really become meaningful to talk about conflict between different levels if done at the right kind of, uh, evolutionary time scale. But that being said, that kind of it, um, kind of put a particular time scale, it can be meaningful to be thought of, uh, as a conflict between, between levels.

15:02 Ricardo Lopes: Mhm. Yeah, I, I will have actually Doctor Brat on the show later this year, so I think I can talk a little bit more about that with him. Uh uh.

15:12 Arvid Ågren: Sorry, uh, wonderful, he's an excellent, uh, uh, uh philosopher and one who really understands, uh, uh, biological problems.

15:20 Ricardo Lopes: Yeah, yeah, yeah, for sure. So, uh, Doctor Patton, earlier you mentioned transitions in individuality. I was actually going to ask as well, what is individuality? I mean, again, in the context of evolutionary biology, what does that mean and how does individuality come about?

15:39 Manus Patten: Yeah, this is another one where if you ask a child what's an individual, they'll have no problem giving you an answer, like you're an individual, I'm an individual, that dog's an individual, that sunflower, that's an individual. Um, IT'S only when you get really educated that you could get confused about where, how to settle what an individual is. AND so I think when we look carefully at biological individuals, I, I think some of the, that, that's where we, we see some of this, this mess, uh, which is fun to work with. There are maybe two moods for describing and defining what biological individuals are, and one is rooted more in function and physiology. Um, AND so, so for example, one way to decide whether this is an individual or whether this is 2 or 3 or more is to let the immune system, uh, determine self versus non-self. And so if you come from that perspective, it's a, it's more of an organismal function definition. Um, SO, uh, organisms which are bounded by their metabolisms and the like, and their, in their, in their systems and their physiology, that's what makes a biological individual. So something like a, a human and its microbes. Arguably, you could say that that is an organismal arrangement because you wouldn't be quite the same, you wouldn't function the same if we were to give you a microbe transplant or wave a wand and eliminate all of your microbes. So, so by that definition then the human plus all those microbes, that's one individual because it's one organism. An alternative definition, which I think is more, be more important to us as evolutionary biologists down to evolutionary individuality, um, and how fitness, uh, uh, uh, payoffs are are paid out. Um, SO, so something that has a shared interest in maximizing some fitness or in having traits that maximize that fitness, we would say that is one single individual. So something like a human and microbes, given that the microbes can reproduce separately. That, you know, aren't aren't tied necessarily to the reproduction of their host, that would argue for the human and its microbes not being an evolutionary individual, uh, in that sense, and so not a biological individual. So

17:49 Ricardo Lopes: actually, I, I, I was just going to say actually, in our case, at least as humans, we need the microbes to survive, right? I mean, the, we, we need the gut microbiome, the, and, and other kinds of microbiomes in our body for it to function properly.

18:10 Manus Patten: I think that's right. If you were to remove all our microbes, we'd be in some distress. So organismally, the way we function relies on those as parts. You can think of them as parts of this overall individual, but evolutionarily, the microbes' fitness is not tied to ours, right? They can reproduce without us, and we can reproduce without them. We might not exchange, we might not transmit their, their progeny to our progeny in the same, in the same fashion as I transmit all of my genome to my progeny.

18:38 Arvid Ågren: And in, in, in a way it goes back to kind of the earlier point about how we, how we managed them. Internal genetic conflicts, it's kind of like whether two parts are kind of transmitted together is kind of a crucial part and when in a human and our microbes, yes, they're essential, but there's this difference in how things are, uh, reproduced into the next generation. But, and just kind of one more point on the, kind of the, um, the messiness of what a biological individual is. We have one chapter in, in the book by Ellen Clark and, and her colleague, uh, Will Morgan, but Ellen has, is also an excellent, uh, philosopher like Perry. She's written a whole book on the, the kind of concept of biological, biological individuality and really kind of drilling into all kind of possible complications, uh, that come with it, both kind of when you approach it from a From a biologist trying to make sense of what is it really that, that I study, but also kind of the, the numerous kind of philosophical, uh, issues, uh, that arise when you try to kind of individuate, uh, things. Um, uh, YEAH, so that, that, that came out just the other year and it's, it's, it's a fantastic read.

19:41 Manus Patten: One of the things Ellen uses in her notion of the, of the, the individual, the essence of the individual is this shared expectation of the future, which I think is something she, that that phrase, I think Dawkins uses that phrase in his organism paper talking about the, you know, organisms have a shared expectation of the future. That's why they function together, that's why they're not overcome by their conflicting replicators. So to the extent that things have a shared expectation of the future. You can expect low conflict, where there's not that same expectation like between me and my microbes. ME and my microbes, myself, my microbes might be in conflict given that we don't have a shared expectation of the future. Their fitness is not my fitness and vice versa.

20:21 Ricardo Lopes: Right. But since we have these internal conflicts and we've already talked a little bit about or alluded to some of them here, uh, earlier, like for example, conflict between different genes, conflict between, uh, cancerous cells and, uh, quote unquote normal cells and so on. Um, HOW do these internal conflicts allow us to get a better understanding of what an organism is?

20:51 Arvid Ågren: I, I think it brings a new perspective on it. It kind of is in line very much with that kind of evolutionary approach to, uh, individuality that it kind of turns the question about what an organism is, um, into one about kind of the alignment of fitness interests that to get the fully functional organism, you need, uh, an arrangement such that that a part of working towards the same goal. And again, that is something that I think traditionally has kind of been taken for granted or that of course the parts will do, but I think this kind of paradoxical organism perspective or inside view gives you is that um, Can makes you take a step back and say, well, maybe, maybe I can't just take this for granted. And here are kind of the kind of empirical observation about genetic conflict and cancers and, and, and so on. It's a good reason that, you know, we, we kind of have to like build it up from, from the ground. Why do these kind of align, uh, to begin with. Now, I think that it's kind of, there, there are discussions to be had about how important were conflicts and the origin of, uh, individual organisms versus they are once the kind of the organismality itself is, um, is established. But I think for us, taking this kind of paradox viewpoint is a, is a, I think a very, uh kind of tantalizing invitation to kind of make sense of this fascinating, uh, biology that we have kind of felt is often kind of brushed a little bit, uh, under the rug. And not really kind of taking seriously, uh, kind of what the significance are for, for evolutionary, uh, theory.

22:23 Ricardo Lopes: Right. And uh should we think about organisms as unified agents, and I guess in this particular case, we will also have to talk a little bit about what agency means in the context of evolutionary biology, but what is your take on that?

22:44 Manus Patten: I would say definitionally, you sort of have to take them as unified agents, otherwise, it's not really an organism, it's not a unified, if, if all the parts are in conflict, uh, and you know, and the knives are out. It, it's only an organism to the extent that there is this unity of purpose. Um, BUT empirically, our organisms agents? I, I think no, I I mentioned this, this sense we had that often these conflicts get swept under the rug. We have a theory about organisms doing things. But overlooking all the parts doing things too and having interests of their own fitness interests of their own, and even adaptations of their own, um, and so the book is really a Putting a spotlight on these internal conflicts. It's not that I, I, I don't think or I think that organisms don't exist. Um, AND then it's all just selfish genetic elements and selfish genes, um, uh, uh, and like, I think we're, I think we well appreciate that organisms appear to be these unified agents, um, and by definition have to be unified to a certain extent, otherwise we wouldn't call them organisms in the first place. But neither us thinks that the, that. Selfish genetic elements are a rarity or aren't important to the evolutionary process. I think we think quite the opposite and uh want to convince others to think quite the opposite too that there are uh big implications of selfish, uh, genetic elements, selfish cells, and all, all these internal conflicts.

24:08 Arvid Ågren: And it it's worth mentioning here also that agency in of itself is, is one of those words kind of like individual, individual or organism that, that means different things to different um biologists and different, um, philosophers. In this book and, and kind of in the work that Mannus and I have been doing, we've kind of very much worked within a tradition that takes, can talk about agents as being this fitness maximizing, uh, entities, and we've been kind of interested in what happens to that notion of agency when you have entities within that also can maximize their own fitness in conflicting ways. What, what is left of that kind of concept. Now, there's a, a different tradition and probably in many ways, a bigger tradition, I think. About agency, much more in kind of like what makes living organisms different from non-living things. And then you kind of, you draw upon different, uh, concepts. Now, I think internal conflict has a lot to offer that, uh, tradition, um, as well, but, uh, I, I would say that kind of like the work that we have done in this book and elsewhere have operated, much more in this kind of fitness-centric view, uh, of agency and, and not in this kind of light, the um, The, the, the kind of arguments about what makes living different from non-living and kind of what is are the kind of attributes of proper, um, biological agents and are those with a, um, A mind different than those without a mind and, and, and, and so on, that, that also exists. And so I guess just to be clear, we're not kind of talking about agents here, uh, in that kind of way.

25:40 Ricardo Lopes: OK, so, uh, just to get this point clear, from what you said there, I got the sense that then at least some of what you explore in your book can inform the discussion surrounding what separates the organic from the inorganic. Is that it? Did I get that right?

26:00 Arvid Ågren: Well, I, I, I, I think, I think, I think there's that big, uh, uh, debate. We have been much more centric on, on kind of fitness-related definitions of agency. I think that will be part of, of, of, of anything that, that, uh, defines, uh, living from, from, from non-living, but I guess on the whole, we have operated within a much kind of narrower definition of, uh, of things.

26:22 Ricardo Lopes: OK. So earlier we talked about, for example, the fact that we have uh microbiomes in our body like the gut micro microbiome, the oral microbiome, and I guess that, uh, we can already use that to Make a case that maybe our own organisms as human beings operate as ecosystems, uh, but, uh, can we think of organisms more broadly as ecosystems or not?

26:55 Manus Patten: I maybe, I, I, I, I don't also try to turn it around and ask, can we think of Ecosystems is, is organisms. I, I think there's a, you know, the Philippe Punneman has a chapter on this in the book, um, and, uh, took in a direction for us was surprising. He was thinking about ecology, so, you know, in the ecological literature going back a few decades. There was a classic dispute between Clemens and Gleeson over how to describe a community of plants. Is it, is it like an organism, uh, or is it just a happenstance collection of, of things kind of, you know, coming in and out, dispersing in, dispersing out, and like, and Clemens was much more in the, in the, in the mood of a community is, is like an organism. It has a, it has an ontogeny, it develops, um, and it has some state that it's developing toward, um. That that's one view of, of a community or an ecosystem that it's organismal in that regard. Um, But, and, and, you know, another question, you know, so, so in some, sometimes an organism can be like an ecosystem. An ecosystem has a function. Uh, JUST like organisms have functions, you know, things go in, things go out of an ecosystem. There are inputs and outputs, you can measure them, they're measurable. Um, OTHER times though, you, you might wanna describe an organism more like an agent where it has goals, and I'm not sure you can do the same thing with any old ecosystem. I'm not sure. I, I suppose Clements might have thought there were goals in terms of where the community was going, um, uh, but for us, the goals are always measured in terms of fitness. And so I think it's, it's harder to make the case that something like the human plus its microbiome has one single fitness interest. Given the, the room there is for different transmission routes. Um, SO, so hard to make a case that the human plus its microbes is one single agent, arguably an ecosystem, uh, in terms of, you know, things go in, things go out, you know, ice cream goes in, um, and maybe, uh, uh, uh happy digestion comes out or maybe not depending on one's microbiome. Um, SO it, it's definitely an ecosystem, but maybe not an agent. So I think what Philippe, uh, points to is this, this is acts as a variation. Organisms can be more like ecosystems perhaps, or more like agents. Um, I think when they're more agential, I think you're getting closer to an evolutionary individuality kind of notion of things. When they're more ecosystem-like, it's more like that organismal notion of biological individuality where functions, you know, a human plusus microbes, still that, that's what's required. Those are parts to that function. But they're not tied evolutionarily to one another. It's made more fruitful to think of them as an ecosystem instead.

29:35 Ricardo Lopes: Right. So, uh, going back to the notion of internal conflicts and now, uh, I would like to explore this more in terms of, for example, how we approach medicine nowadays in, and in Western medicine, particularly. I mean, what kinds of uh maladies, diseases can stem from internal conflicts? I mean, uh, in what sense can we apply this notion to uh our understanding of pathology?

30:10 Arvid Ågren: The, the first obvious example that usually comes to mind when, when talking about it in this kind of ways is, is cancer. We have mutations that happen. That means that there are some of the cells within the multicellular body, uh, who start to proliferate, um, uh, and, and while doing so, they grow, uh, in copy number, but then, in this kind of tumor grows, but that comes at a, at a cost to, to the rest of the, um, rest of the body. Um, AND this then, you, they, we say they proliferate, they do so kind of under by an evolutionary process by, by natural, uh, selection that some cells are dividing faster than the surrounding ones. And in that way, at that kind of within generation time scale, there's a conflict, what's good for, um, For the tumor cells and what, what is good for, uh, the rest of the, uh, the body. So I think that one has, uh, people have thought of, uh, uh, as a conflict for, for, for quite a while. Uh, PERHAPS more controversially, there, there have been kind of ways you can think about complications that can arise through, uh, pregnancy, where you, during the, the development, uh, of a fetus, you go from something being very clearly part of the, the, the mother's body to developing into its own, uh, biological, uh, entity. Um, AND while this is, of course, a very, um, cooperative venture, uh, on the whole, that does not mean that there are, um, opportunities for, uh, conflicts to, to, to arise, particularly about how much, um, uh, investment the mother should make into this particular, um, offspring. And there are ways you can kind of explain some of the complications that can arise, uh, during pregnancy, such as, uh, hypertension or high blood pressure and related kind of, uh, maladies as something that, that may arise through this kind of parent offspring, uh, conflict. Um, SO in kind of in, in the chapter, so this is a chapter that, that I co-wrote with, with, uh, Amy Body, who's a biological anthropologist who's been very interested in kind of evolutionary medicine kinds, uh, of problems, and we try to point out that in kind of in, in cancer, um, pregnancy-related, um, uh, illnesses, but also some of these kind of phenomena around microchimerism, where's this, which is this observation that you get the inheritance of cells from, uh, parent to, uh, offspring. And even kind of in the opposite direction that offspring cells, uh, is are transferred to, to the mother and from, uh, and, and where they persist. And kind of making sense of this from, from a kind of a paradoxical organism or kind of conflictty views can be quite, um, helpful and kind of, and makes us think about new ways that this can be, uh, treated, uh, rather than if you think of this as kind of a, uh, machine-like cooperative, uh, venture.

32:56 Manus Patten: And I'll, I'll, I'll add, it's again, we're doing something, we do it regularly, and I, uh, it comes naturally to us to think, think about all these angles, all these internal conflicts, these selfish elements. We've been, I've been described as a paranoid Darwinian, uh, and that I'm always thinking about what are these genes trying to do to me and these genes trying to do to these other organisms, um, and you, you can, you can actually, you can explain phenomena that would otherwise be overlooked when you're, when you're wearing the tin foil hat. So to speak. Um, uh, ONE example comes to mind, uh, is the humans and micro microbes. We don't actually, we don't have much about humans and microbes. Uh, IT'S just on my mind today, but We, we think of them, sometimes you, you hear about them being described as uh little helpers, like they help you digest your food. If you were to remove this species, you might suffer in certain ways. Another perspective on that though, instead of thinking that everything you have is part of you and is there to help you, if instead you have the tin foil hat like we do, and you think these parts of you might have selfish agendas of their own, if instead you think of there being this, you know, conflicting relationship between microbes and humans, if you remove something. Maybe what you're doing is exposing this past history, this antagonistic history, co-evolution between the microbe and the human under conflict. So now what you expose is how the, the human body is pushing back against whatever this microbe is trying to do to it. So by removing the, the microbial uh associate, you end up exposing this overshoot by the host, some comb of defense. So you end up being sick. Not because you've removed a part that was helping you, you actually removed the part that was harming you, but you're revealing this defense that then causes an overshoot. Some of these overshoots we also see um in imprinting disorders. So we have imprinted genes that are expressed either from the maternal side or the paternal side, and there is a conflict, an inherent conflict, uh, between the two halves of our genome. Um, OR described parent offspring conflict where mothers and offspring. Don't fully agree. There's a lot of cooperation there, but they don't, they're not perfectly aligned and how much resources should be transferred from mother to offspring. But it's even worse than that because even within the offspring's body, those two genomes don't agree. They're not perfectly aligned on how much resource should be transferred, and imprinted genes are the, the outcome of this evolutionary conflict. And when you have mutations to these imprinted genes, you often get overshoots or undershoots, and you get these imprinting diseases, and they can be quite severe because this co-evolutionary history. Of offense and defense and offense and defense, you can view it sort of like an arms race, has arms race dynamics to it. You get this escalation of offense and defense, and when you remove one party, you have a lot of defense for no offense, or, or you have a lot of offense and no defense against it, and you end up with, you know, with the, with the, the disease outcomes. So internal conflicts can maybe generate. And make the system very vulnerable to these kinds of outcomes. That's another perspective that the internal conflict gets you is that these might be prime sources uh of vulnerability to disease. So pregnancy is a very fraught time during reproduction, uh, during, during life, you would think evolutionarily, come on, natural selection, get that right. That's where fitness happens is that reproduction. But in fact, there's a lot of conflict there and conflict begets some of these, these outcomes, this vulnerability to disease. Mhm.

36:12 Ricardo Lopes: When it comes to cancer specifically, I mean, tell us a little bit more, or I want to ask you a little bit more about how we should understand the conflict between cancer cells and the entire organism or cancerous cells and other cells of the organism, because I mean, if I understand it correctly, cancer, I mean, it can be the result of genetic mutations, genetic mutations that occur through environmental influences, like for example, what you eat, exposure to the sun, and so on, to UV rays and so on. Or you can inherit some mutated genes that predispose you to develop certain kinds of cancer, and, uh, I mean, what happens is that cellular division, which is usually controlled. Uh, GO, uh, I mean, becomes uncontrolled and so cancerous cells continue to proliferate beyond what would be normal for within that organism that they inhabit and they start extracting also resources from other cells, other tissues, other organs, and so on, and I mean, I mean, so. Uh, WHAT, what, how should we understand the conflict because it's actually also a conflict between the genetic material of the cancerous cell not being perfectly aligned with the genetic material of the. Other cells correct or is that not that not one of the ways of understanding it?

38:01 Arvid Ågren: So with cancer, there is this kind of multiple things that are, that are, um, interacting, and I think you, you kind of hit on the, the, the key ones, right, that they, we Are used to talking about that there you get these new mutations that happen, uh, inside of you, and it presses worth stepping, uh, uh, back, uh, one step to say, well, why should that matter? Well, one reason why that matters is otherwise, the cells in, in our bodies, all the somatic cells, so the non-kind of sex cells in our body are genetically, uh, identical. So at birth, they are, OK. And then you start this kind of accumulation, uh, throughout your life that mutations. Happen in, in different parts of, of your body. Most of these mutations will, may not matter much, but every now and then eventually you can get these mutations. Uh, THAT causes, um, uh, cancers, um, behaviors to, to, to, to, uh, to begin. Now, as you also point out, we may have inherited genetic predispositions to this, so that we are more vulnerable to certain kinds of mutations that I say that if I've inherited this one, A predisposition, should there be a new mutation that happens in another gene, I'm more vulnerable to that than someone who did not have that kind of mutation that I was born with that I had inherited. And of course they also point out there is this kind of whole environmental thing that you may have exposure to sunlight or smoking or, uh or other things that are now well established to, uh, interact with these kind of genetics of it. Now, so what the situation arises with is that you have this kind of conflict that may, that we can think of a quantity then between the tumor cells that are genetically distinct from the rest of the body. So in that way, from a kind of an evolutionary genetics point of view, you kind of have a kind of a clear explanation why the fitness interests of those, uh, ought to be, ought to be different. Now, one thing that Amy and I point out in our chapters that one thing we've learned about tumors, uh, more recently is also that within the tumor, there may be kind of conflicts between different cancer cells within the tumor because they in turn may be genetically distinct. So it's not just that there are two kinds. Of regular cells and cancer cells. It may actually be regular cells, cancer cells, and within those cancer cells, you have many different kinds, uh, genetically different cancer cells within a single tumor. And they, in turn, may compete with each other for resources. So what's good for one. Kind of, it's kind of a cancer cell isn't bad for another, and that kind of is a dynamic that there are some of these, uh, more kind of evolutionary-minded kind of treatments try to harness that competition. So if, if you kind of can promote it within tumor competition, perhaps you can use that to slow down overall, uh, tumor, uh, growth.

40:41 Ricardo Lopes: Right. So, uh, there are, I have two more topics I would like to explore with you and they fall more or less under the same rubric of what we were already talking about here. Uh, IN the book, uh, at least in one chapter, you also explore the limitations of the body as machine approaching medicine. So what is that approach? What characterizes it, and then how would you contrast it to the Paradox of the organism approach to health and medicine and what do you think are the limitations of the body as a machine approach that perhaps we could overcome, at least to some extent if we take this paradox of the organism framework into health and medicine.

41:35 Arvid Ågren: Because the first thing to say about the, the, the, the, the body as a machine metaphor, which is kind of, is exactly as I say, to say that the body, um, is in a way a machine. It has machine-like features in that they kind of have these different parts that work together, and you can kind of understand the function of different parts of the body. Uh, BY, uh, thinking of it as being part of this machinery. And then, like, when an illnesses or maladies then arise when something breaks. So you kind of go in and you think, Well, how does this thing fit together with the others? Um, BUT as you can kind of see, underlying this metaphor is that, like, machines. There's no conflict within machines. If you think of our, our watch, maybe we can think of that having the goal to tell time and you can do that in an, in an analog way that we, we have to reset every morning or it can be in a digital way. But regardless, there isn't that there are some parts of the watch that does not want to show time or want to show a different time. They're all gonna have, we think of that machine parts have the same goal. And that, I think we would say is one of the weaknesses, that there's all these reasons, empirically and theoretically evolutionary. To believe that bodies are not like that. Bonds are distinct from machines in, in numerous ways. One of them being that, uh, because they are a product of evolution, they're gonna have these remnants of evolutionary conflicts almost built in to them. So if we always think that all parts of the body are gonna work towards the same goal, we're gonna miss out, uh, on a lot of, uh, interesting biology, but also, I think we're gonna, may, may end up misdiagnosing certain parts, uh, uh. Um, OF when, when, when things go, uh, when things go wrong. And that's why I think this kind of like, uh, evolutionary, uh, approaches that rely on trying to harness within tumor, um, competitions is so, is so, is, is so fascinating, both because it's a, it's a cool piece of biology, but also I think it's, it shows kind of like a kind of clinical or practical application of taking this kind of, like, more, uh, paradox perspective or the, the paranoid Darwinian, uh, perspective. Uh, I think that helps us. Understand that much more intuitively. That is not of course to say that people have to have this perspective when, when, when doing, uh, developing these approaches. They, they do not. Many people who have pioneered these kind of evolutionary minded approaches, um, don't take that, but I think that kind of taking this kind of paranoid perspective lends itself to seeing, uh, why that is, is a promising avenue of research much more easily than, than, than, than the alternatives.

44:01 Ricardo Lopes: Right. So, uh, one final topic I'd like to ask you about. When it comes to genetic conflicts, can they also get expressed on a psychological level? And if so, what kinds of ways can they get expressed?

44:20 Manus Patten: Uh, MAYBE, uh, there's a, there's a feeling that, uh, that possibly some of our internal psychological conflicts stem from and are a readout of internal genetic conflicts. Um, SO I think the internal genetic conflicts that we have in mind here are these imprinted gene conflicts where genes of maternal origin, genes of paternal origin are expressed differently, and they're expressed differently because they have different Interest in how the body should develop or how the brain should develop in this case. Um SO there were these really interesting experiments back in the 90s where they put together chimeric embryos made of a typical embryonic cell, but then also mushed together with a cell that had either two fathers, two paternal genomes, or two maternal genomes, and what you found in these chimeric mice is that their brains look quite different. Um, AND I, I'm gonna, I, I might get the direction of this wrong, but the The, the, the mice that had the gynogenetic, the, the, the, the two mother uh uh cells mixed in had a larger neocortex. The ones with the two paternally derived genomes had a larger, and again, I don't know the neurobiology well, lizard brain is how I would describe it. I'm sure that's not how a neurobiologist would describe it, but they, they, they were enriched, those cells were enriched in different parts of the brain, and the brains themselves grew to different sizes in different regions. Uh, AND an interpretation of this then is that what paternity derived genes are pushing toward is the development of more of that sort of, uh, impulsive, uh, limbic system kind of, uh, uh, brain. The maternity derived genome is pushing more for the deliberative cooperative neocortex, uh, uh, parts of the brain. Um, SO, because you have these different desires, different goals, uh, of the different, uh, genomes. You may, as you engage in life and and and make decisions, you may hear these different impulses to be a little more deliberative or a little more impulsive, um, and that internal conflict, one thought is that it may be is a readout of there being these different genetic interests, um. But there's no need. I, I think one of the things, uh, Samiro Kasha covers this in his chapter, um, uh, dance with this, with these models of, uh, you really don't need, um, you don't need to have a readout of the internal conflict genetically. You may just have a brain that develops and it makes a decision, uh, it's it's again developing under this tug of war between the different interests, but once you've got the brain developed, that's that. You don't need to listen. You don't need to generate the. The experience of those two conflicting impulses. Um, SO you need not get internal psychological conflict from internal genetic conflict. Uh, THERE'S no reason to expect that that would come out, unless what Samir does in his chapter, um, is, is think about how we think about, uh, internal psychological conflicts, you know, are they really, are there really two individuals there? Do you ever have such a severe internal conflict that you no longer have a single individual, that instead you have. Uh, YOU know, uh, uh, dissociative identity disorder, maybe this, this sort of thing where you in fact, don't have one individual there, you have multiple individuals because they have multiple interests, uh, in the same way that when you have different genes within a genome, they actually have different interests. The maternally derived, maternally derived genomes don't have the same interest. Uh, uh, THEY, they don't maximize their inclusive fitness under the same brain. So you have these internal conflicts genetically, if they were so severe. That the organism would, you know, cease to exist. That, that is an inherent possibility, but not when we observe often. Uh, IT'S maybe we can observe more often, um, in psychological conflicts where the internal conflicts are so severe, you might want to say that someone has, there are two individuals, um, residing in that one bundle of biological activity. So, so, so Okasha takes these ideas about organisms and their internal conflicts and turns the lens on psychological conflicts. Take some of the lessons we've, we've learned from, uh, organismal conflicts to, to that domain.

48:22 Ricardo Lopes: OK, but if that is correct, if Doctor Okash's sort of suggestion there is correct, then could that help us get a better understanding of at least potentially certain uh psychological disorders?

48:42 Manus Patten: I, I, I think it gives us a lens through which to view those, those particular disorders of internal conflicts. I, I'm not, again, I don't think it, there, there's no sense in which those disorders come from developmentally internal genetic conflicts.

48:56 Arvid Ågren: I mean, in, in a way it's kind of run through several of the chapters here that's like this. Kind of two questions that like Samir is, is interrogating. One is this kind of like empirical claim. Is there a core, is there a kind of actually a mechanistic link between genes that are involved in in internal conflict and the kind of psychological sensation of being conflicted as a As, as, as a self, and it seems like there, there isn't. Um, THAT being said, you can kind of still think of that kind of like feeling of being a divided self as a kind of internal content. I think that he showsis can be quite a productive, uh, way. But to the, to, to the extent that it, that it will help us improve treatments of it or our understanding of it, I think it will come through that kind of conceptual route rather than through the kind of mechanistic. Um, GENETICAL one.

49:41 Ricardo Lopes: OK, great. So I mean there will be many other topics that we could talk about here today, but we're reaching our time limit. So the book is again The Paradox of the organism, adaptation and internal conflict. I will be leaving, of course, a link to it in the description of the interview. And, uh, Doctor Ogren and Paton, would you both like to tell the audience where they can find you on the internet and the rest of your work starting with you, Doctor Ogren?

50:13 Arvid Ågren: Uh, SO you, um, you, you can find meratin, in, in two main, uh, uh, places. There's my, my own website which is Avidarren.com. Um, AND, and these days, um, with, with regards to social media, it would be Blue Sky, which is also, uh, Avidarren.

50:27 Ricardo Lopes: Uh, WHAT about you, Dr. Pen? The

50:29 Manus Patten: patent lab.com is how you can find me out. You won't find me on Blue Sky, and you might find me on Twitter, but you won't find me active on Twitter or X.

50:38 Ricardo Lopes: OK, great. So thank you so much for taking the time to come on the show. It's been a very interesting conversation.

50:46 Manus Patten: Thanks for having us.

50:46 Arvid Ågren: Yeah, thanks for having us. It's a lot of fun as usual.

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