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Kevin Mitchell: Nature/Nurture, Genetics, Personality, Autism, Schizophrenia, Synesthesia, Free Will

Full episode transcript below. Beware of typos!

Nick Jikomes

Dr. Kevin Mitchell, thank you for joining me. Can you tell everyone a little bit about who you are and what your scientific background is?

Kevin Mitchell 4:32

Yeah, so I'm associate professor of genetics and neuroscience here at Trinity College in Dublin. My background is in Well I started in genetics actually as a student here in this department, and then did a PhD in developmental neurobiology at Berkeley and studying how the nervous system develops. So the question there really was what how are the sort of the the instructions in the genome decoded through the process? of development to actually wire up a nervous system, which is really complex process. Obviously, we were working in a very, very simple sort of model system, which was the embryo, the fruit fly, trying to figure out, could we find the genes that encode proteins that tell nerves to go this way or that way, basically. And so that was great. And I did a postdoc in a similar field in mice. So moving organism, but still asking the same question. Obviously, the mouse brain, which is where we were looking at is much more complicated. And then moved back here in 2002, and set up my own group, and we were doing that kind of mouse work. And started, I started to get interested in questions of the applicability of that knowledge. So if we could figure out the basic sort of genetics of how the brain gets wired. The idea that maybe mutations in those genes could lead to some kind of outcome. And it turns out that they can lead to things like psychiatric disorders, and epilepsy and autism and conditions like that. So that got me into thinking about humans, and working with some colleagues here in psychiatric genetics on psychology.

Nick Jikomes 6:14

Interesting. Yeah, I think a lot of what we'll talk about, is going to be to do with, you know, the extent to which what we what we do and who we become, and how we behave is, is determined by nature by things that are intrinsic and outside of our control, like, like our genes, versus to what extent it's due to nurture, as they say, or to what extent our environment and our culture, and our experiences, shape, how we develop and what we become. And, you know, people have been talking about the nature versus nurture dichotomy, since people have been thinking about anything, and then many, many words, and a lot of blood has been spilled over over where people sit and how they think about this dichotomy. How do you how do you think about the the idea of nature versus nurture? Is that a useful construct? Or is it potentially misleading in some way?

Kevin Mitchell 7:02

Yeah, I mean, I think both actually, in that it's useful in a very technical sense in the field of genetics, but it can easily be sort of misunderstood, and mis applied in it in unfortunate ways. So within genetics, what you can ask so so if you look at, you know, a range of organisms in a species, there's always some variation between them. And you can ask a question, what contributes to the variation that we see, you know, across members of the species, which first of all, is just a different question from what makes an individual the way they are entirely, right. So if you, for example, we're interested in variation in height, we're not asking the question, what makes humans about so high? Generally, right, we be asked, What's the what, what contributes to the difference in height between you and me say? So? So that's already a very specific question. And it's important to realize what it is you're asking a question about, just really about that variation. Now, if you're asking that question, it's necessarily a question about the population. Right? It's actually not a question about me, right? It's not where does my height come from? It's what causes variation in height across the population. And that's usually within the field of genetics. You can you can think about that. And you can dissociate causes or factors that contribute to that variation. And so people have been doing that, you know, practically in animal breeding and plant breeding for forever, basically. So if they want to know, you know, say they're working with cattle, and they want to know how, whether they should breed for some particular trait, say how much milk they produce, well, then it's good to know how genetic that trade is, right? There's no point trying to breed for something if the variation is just random, or it's just environmental. So they, they have developed a whole sort of framework to try and figure out for any trait like that how much of the variation you see is due to genetic differences in your population, how much is due to environmental factors. And of course, in animal breeding, plant breeding, you can control both the genes and the environment and the way you breed and so on. So it's, it's, it's perfectly valid to try and dissociate those sort of causes of the variance in a population. The problem is, if you think that you can do that in an individual, because those those different factors that make me the way I am, right, so that makes me the height that I am. So there's definitely a genetic contribution to that. And there's definitely environmental contributions and my own personal history and so on. But they can't be teased apart. It just becomes a kind of a nonsense question. It's not, you know, there's not 40% of my height came from my jeans. Yeah, it just, it just doesn't mean anything, to apply it to an individual And so, you know, so the typical usage of of nature versus nurture in in humans? Really, if it's about variation across the population, then I think it's fine. If it's about if it's applied to an individual, then you're just miss applying the concept. And unfortunately, it does get mis applied that way.

Nick Jikomes 10:20

Yeah, and, you know, I think a lot of people, a lot of non scientists, at least, they, they get confused when they think about things being either due to genetics, or due to the environment, and especially when you're thinking about genetics, with respect to the nervous system, so much, so much of it is experience dependent, you know, that the genes and the neurons and all these things are hardwired, to be changeable in plastic in response to the environment. And so you really do get a blurring of the lines there. Absolutely.

Kevin Mitchell 10:47

And I mean, for me, the key sort of, you know, concept to understand how genotypes that is, you know, our genetic makeup relates to our phenotypes, which is our whole sort of pattern of traits that we express, is that that's a that's a trajectory, right? It's not a fixed static, linear, direct relationship. It's not like a blueprint that says, if your genes like this, then this part of you will be like that. That's not the relationship, right. So it's more that the genome encodes rules and processes of development, that collectively will channel development into a kind of a range. But that's very much an ongoing trajectory. And that's true, especially true for the nervous system, because as you said, the point of the nervous system is to change in response to experience, right. And learning ability to learn is one of the huge benefits of what nervous systems get you. So, yeah, so we come pre wired to pre wired in ways that that are different between people, but also pre wired to respond to experience. Now, it's a little more subtle than that, because there's variation in how we respond to experience, right, so so there's this interplay, it's not like the genes do their work, and then they experience takes over, even in how we respond to things. genetic differences are still having an influence there. It's just an influence that continues to sort of manifest itself through life as we, as we learn from from our environment, from our prior experiences, we develop habits, we really develop our character. And that's absolutely an emergent kind of a thing. It's not just set by genes. It's not just, you know, driven from the outside by experience, it's an interaction of those things through time, and it's the through time bit. That is the key concept, I think to grasp.

Nick Jikomes 12:46

Yeah, one more thing I want to dwell on in this area for people that don't really have a technical background in genetics is, you know, you often hear people talk about genes, as if the genes are for specific traits. And for specific or for specific diseases, right. So you might hear people talk about a gene for height, or the genes for autism, or the genes for that this or that. What can you unpack for people? What, what are genes? Let's just start there, and what exactly are they encoding? And how does that relate to whether that those are reasonable ways to think yeah,

Kevin Mitchell 13:19

these are huge, huge questions. But I'm, I'm glad you asked because the the concept of a gene is very easily misunderstood, because it has multiple meanings. So the original concept from Mendel was, he could see that there were differences between his pea plants that he was working on it, some of them had, like, you know, smooth kernels, and some of them had wrinkled ones, and some of them were yellow, or green, or the plants were taller, or shorter or whatever. And in the traits that he chose to work on, well, first of all, he was quite selective about the kinds of things he worked on. Like he could see that, you know, the height of the plant was a continuous trait like height in humans, whereas the yellow versus Green was seemed to be dichotomous, it wasn't a range of color, it was either yellow or green. So those are kind of unusual traits. But anyway, he could see by breeding plants and looking at the inheritance pattern, so that there must be something that was being passed on from one plant to the next or put, you know, into the seeds, basically, through the pollen and the egg. There must be some physical thing that determined whether they were going to turn out to have yellow kernels or pod peas, whatever. Or green ones, right? Yeah. So he just called that a gene. And he didn't know what it was made of. He didn't know anything else. He just inferred the existence of it from from the inheritance patterns that he saw. So, so from the get go, a gene was a unit of inheritance. Okay, so if we hold that concept in mind, and then we get to molecular biology and an understanding of what genes are made of, then we Come back to explain what that is so. So it was known that you know that the genetic, there must be some genetic material. That's the physical stuff that's passed on. And when you look in cells, you can see all kinds of different stuff. And some of that is in the nucleus of the cell, these bodies called chromosomes, which it turns out are made of DNA. And protein, actually, they're sort of packed up in protein. So people didn't know whether the DNA or the proteins was the genetic material, but eventually was figured out that it's the DNA that does it. And now we know that DNA is made of this sequence of chemical bases. And it's that sequence that encodes the information. But, but it does that in two different ways. So if we think about the, the genome of a pea plant, it encodes somehow, the information to develop as a pea plant, and not as a potato plant, right? So, so somehow, in the whole genome, there's encoded the information for a pea plant to emerge. And basically, the science of developmental biology is trying to figure out what that relationship is. But if you look at the, at the genome, really what's what's sort of directly encoded is proteins. So all of our cells have, you know, the old enzymes, structural kind of proteins and stuff. All this sort of machinery of the cell is mostly made of proteins that do the work. And we have about 20,000 genes that code for about that many, well, actually many more proteins than that. And so, so now, if we think from a molecular biology point of view, okay, we've got a cell or an organism, that's going to develop a certain way, it's making all these different proteins, some of the tissues of the organism will express some of those proteins, and not so in us, for example, we have some proteins made in liver cells, different set made in skin cells, different set made in different nerve cells, and so on. Okay, so that's the molecular biology view and the developmental biology view. And then the question is, what does that relate? How does that relate to this idea of a unit of inheritance. And that gets back to what we were talking about earlier, which is that the idea that genetics is really about variation. So now we're trying to it turns out that if you have a gene for yellow versus green, really what that is, is a mutation, right is a genetic variation in some gene in the P genome, that encodes some protein. And maybe it's a mutation that, say, D activates that protein, so it just doesn't work. So now you've got two types of peas. Or they can inherit this this gene

that either say it works, or it doesn't work. And if it's working, right, maybe they develop green. And if it's not working, right, maybe they develop yellow. So a gene as a unit of inheritance, then is really a genetic variant, or a mutation. So we're talking about a gene for a disease, right? It's a a gene for cystic fibrosis, or Huntington's disease or something like that, you know, the purpose of the gene is not to make people diseased. Really what that what that is, is shorthand for a genetic mutation that has this effect of causing this disease. So, of course, some genetic variants will cause a disease like that many of them don't have any effect. And then there's a lot of them that just cause some variation. That's that sort of benign. It's just sort of part of the normal variation, like in height for. So yeah. Okay. So that's the broad scope, I hope that

Nick Jikomes 18:41

said, Oh, no, I think that's great. And I mean, the other thing I would love to get you talking about, too, is, it's really easy in my experience for people to think like, think that basically like there's one gene for one trait, one gene for one trait. So when we think about any trait, but I think height is a good example to dwell on, you know, my understanding is that most of these traits that we're interested in studying whether or not it's just normal variation, or it's a disease, there's actually many, many genes, each of which makes a small contribution to that trait. So why is that? And to what extent is that true? That's

Kevin Mitchell 19:15

so that's absolutely true. For most traits, we look at height and like you said, as a good example. So effectively, so you have the human genome in this case, right? So it encodes making an organism up that turns out to be about so high. Which is there's a whole interesting question about why, why so high? How's that, you know, how was growth stopped? How's that encoded? But whatever it is, so you've got tons of different genes all interacting in the in the developing organism, like I said, there's no it's not a blueprint. It's not one gene corresponds to one bit of the organism. It's a program of development that plays out with with all these 1000s of genes interacting in that process, so it really is a great big dynamical system. And over over evolution, so part of what happens in that system, once the proteins are made from the DNA, they they kind of jitter around, I mean, they diffuse, right, it's a really noisy environment at a molecular level. So the genome can't control that, and it has no way to, to really determine where those things should go after they're made. So, so it's a problem for the genome, it that has to be, it has to solve this problem to make an organism within a viable range, despite all this noisiness and the what evolution has done is build in lots of robustness, right, so there's all these proteins that are all sort of doing the same work, if maybe there's a bit less of them here, there might be a bit more of another one to compensate. So because of its, it's a dynamical system, it's very sort of fluid and adaptive through that, sort of, it's a self organizing system. So now paradoxically, because it's robust to this molecular variation that's sort of unavoidable. The consequence of that is it's actually robust to little genetic variations. So you can get little mutations that happen, not the big ones that really break the system, just ones that cause a little bit of variation in the system. And actually, the system is like, Yeah, that's fine, I can deal with that I'm a big self organizing thing, I can totally buffer the effect of this little thing, and still remain within a viable range. So what happens then over time, is that genetic variation just accumulates in the population, every time we make a sperm cell or an egg cell, we're copying the DNA, and some copy errors just creep in. And so as a result of that, then genetic variation inevitably accumulates in a population on on, and therefore it just contributes to variation in the outcome. It's not possible for the genome to encode the outcome really, really specifically, first of all, there's just not enough information in information, theoretical sense in the genome, to encode everything about the phenotype of a human being. But secondly, that variation in the in the population is, is unavoidable. So we're never going to get, you know, identical clones out in a population because of this genetic variation.

Nick Jikomes 22:27

So, basically, you know, a couple of things that are interesting here, one, if I'm hearing you correctly, even if you could somehow hold the environment perfectly constant, what you're saying is, you would still end up with genetic variation, because there is this stochasticity that exists at the molecular level is just completely unavoidable.

Kevin Mitchell 22:48

Well, yeah, so there's two things there. One is that, you know, for traits, like height across across a species, if there's, if there's no need for natural selection, to really narrowly channel that trade into very specific values, then it won't be about if genetic variation, if phenotypic variation is tolerated, then genetic variation will accumulate that that contributes to that. So if we think about the genetic, what we call the genetic architecture of a trait like height across a population, it's characterized by all these genetic variations that just exist in the population. And they can be quite common. So it might be you know that at a particular place in the genome, say, 70% of the time, it's an a, you know, the chemical base a, and 30%, it's a C or something like that. And maybe the A version is associated with a tiny statistical increase in height. And then there's 1000s, and 1000s of those. And so each of us has a distribution, we fall somewhere on the distribution across the population, so you might have just more of the ones by chance that make you a little bit taller than average or shorter. So that's the architecture of those traits. Now, on top of that, even if you had an identical genome, this developmental variability will still be in play, right? So even identical twins are not exactly the same height each other, they're obviously very, very similar, much more similar to any to other people, right, which shows the genetic effect. But even Yeah, raised and, you know, as close in an environment as you can get there, there's still going to be some phenotypic variation. And we, you know, we this has been known for centuries for people doing, you know, at least a century for people doing genetic experiments. In model organisms like fruit flies, or fish or mice are all kinds of things plants, where they're clonal, right? So they're all genetically identical. But, you know, we're just used to seeing the some variation still between them Even in the most highly controlled lab environments, so, yeah, so that developmental variation is unavoidable. And it's it's a third source of variance that's really overlooked, I think, because the sort of traditional framing of nature versus nurture has been translated into genes versus environment. Right. Right. But that suggests that genetic variation is the only thing that contributes to what we would call nature or, you know, innate predispositions or phenotypes. Which is not right, there's a third source, which is just developmental variability that's doesn't come from anywhere. Yes. Just it's just by the nature of the system has some, some randomness to it.

Nick Jikomes 25:44

Yeah. And I think it's an important point that, that people often overlook non scientists, especially even scientists, sometimes that part of the nature side of this, you know, when we think about the nature side, we tend to naturally think about the genes. And we think about them in a way that's very sort of specific and concrete and fixed. But part of the nature side of the equation is this noise and variation that's just inherently there. Yeah,

Kevin Mitchell 26:07

absolutely. And so you know, the genome encodes a potential individual, but the actual individual that emerges is like, sort of one run of that program that has some randomness to it. So like doing a, you know, a marble run, yeah. And sometimes it'll bounce over there. And sometimes it'll bounce over here for no reason. Otherwise, you know, that there's just some randomness that can't be controlled, within there. And so we're used to seeing that expressed in this I guess, you could say quantitative variation in traits, like the quantitative difference in height between identical twins, although occasionally, you can see it in quite dichotomous outcomes that still are kind of probabilistic. So for example, handedness is is a good example. So on average, about 10% of people are left handed. And it and usually strongly, so you know, do you usually either strongly left handed or right handed, there's some mixed a bit sort of in the middle. But if you have a history of left handedness in your family, so if your parents are left handed, then you have a higher probability of being left handed, but it's still a probability. And even an identical twins, you can often get one of them left handed one of them right handed. So in a sense, the what what seems to happen is that there's some point in development, where it can kind of either be channeled one direction or another. And if there's some little bit of variation, at some point, it just noisy randomness, it may just push the system to kind of go down this channel versus that versus this one, and then end up in because there's sort of self reinforcing aspects of that the further development along each of those channels, then you end up with these dichotomous outcomes. And the reason you know that you would have that for handedness is that it's important to be either left or right. Yes. Right. And, you know, it may be due to the need for fine motor control to be localized within one hemisphere, just so that it's fast. And you don't you're not having to send messages back and forth, for example.

Nick Jikomes 28:15

Yeah. Is this. So? Is this the concept of cannibalization? Yeah, so it's a

Kevin Mitchell 28:19

term that came from a guy named Conrad Waddington. And he has this beautiful visual metaphor of this of a ball rolling down a kind of an undulating landscape. But it could roll one way or another at certain points. And yeah, I mean, capitalization is not the most elegant term, but the idea is of a canal, right? It runs into a canal or a channel, there

Nick Jikomes 28:42

might be multiple possibilities, but you kind of get locked into one, because it's not useful to have sort of half of each.

Kevin Mitchell 28:47

Yeah, exactly. And there can be some times where it's, it's not so important, whether you're left or right handed. In fact, we don't really know why in humans, there's a bias, right? If you look in other animals, they're often they often have a preference. Even rats have a poor preference. But there's no bias in the populations like 5050. So we don't know the answer to that. But the important thing is to do one or the other. Not something in the middle, for that phenotype, at least. But it's a good example of a dichotomous outcome. Where the inheritance really is a probability, you don't inherit being left handed, you inherit a probability of being left handed. And actually, you see the same thing with the risk of a lot of disorders or conditions, psychiatric conditions for example, you inherit a risk of developing say something like schizophrenia, and we can carry it we can we can measure that risk or quantify it statistically speaking. And for example, if you have a, an identical twin who has schizophrenia, then your a statistical risk of being diagnosed with schizophrenia is about 50 Plus sent. Now, if you look at the offspring of two twins, one of whom has schizophrenia and one of whom doesn't, the risk of schizophrenia in their offspring is exactly the same. It doesn't matter whether the person actually expressed the that probability that as a phenotype or not, they're passing on the probability and, and it can be expressed than in the offspring. And there's so there's lots of phenotypes that are like that. It's a probabilistic Yeah. relationship that plays out through development.

Nick Jikomes 30:27

Yeah, it's really remarkable. When you realize this is true. Like, I think what you just said, two identical twins, identical genomes, essentially identical environment that they've grown up in. And despite the fact that schizophrenia is strongly genetic, technically speaking, in terms of its you know, how much of it is due to inherited factors, you can still have an identical twin, one of which has it, one of which doesn't, and I've still got it, you know, 50%, or whatever odds of producing a child that does or doesn't. And to me, what's the most remarkable is whether or not you express that, in part, in large part is due to some of that developmental noise.

Kevin Mitchell 31:05

Yeah, well, and so there's a, we think it is right, okay, so there's, what I want to say, I guess, is that it's often been assumed that whatever isn't explained by genetics must be explained by environment. And when it comes to things like psychiatric disorders, people have spent a lot of time looking for environmental factors. And this harkens back to the, you know, the early days of psychoanalysis, and so on, when it was just assumed it was an environmental experiential factor, typically blaming, you know, the mother in some way, for, you know, causing their child to be come schizophrenic, or autistic, or whatever the case might be. And so people have looked really exhaustively for that kind of experiential effect, or for systematic environmental factors that might contribute to these conditions. And there's a few sort of hints out there, but they're, you know, they tend to be quite small statistical risk factors, not enough to explain this non genetic component of variance. So, for me, the the inference, that actually the developmental variation can contribute to that is, first of all supported by the just sort of exclusion, right? You know, it's like, we're not finding these environmental factors. Plus, for example, there's no, there's no effect of the shared family environment. So you could do these twin studies or adoption studies. And see, you know, look at the risk of, say something like schizophrenia, and in adoption studies, it just goes with your biological relatives, right? Whether whether they have schizophrenia or not, that's the only family relationship that matters. It doesn't matter if you were raised in a, you know, adopted into a family where, say, one of your adoptive parents has schizophrenia, but you have no increased risk. And if you're adopted away from a family, where one of your parents had schizophrenia, into some other family, you have no decreased risk. And so, it the family environment is just not a factor in in contributing to who gets these conditions or not right, generally speaking. So, so the idea that there would be other factors that are kind of idios, more idiosyncratic, to me is a bit of an appeal to you know, there's no reason why an idiosyncratic experience would affect you, if a systematic one doesn't, there's no, there's just no logic to that, right. So, so for me, there's on that basis, there's a good reason to think that developmental variation is making a big contribution there. The trouble is, like experimentally, because you're looking at randomness, it's super hard to measure or control for anything. It's basically everything you have left after you control for everything you can. Yeah. So that makes it very challenging to really, definitively say it must be developmental variation. But to me, it's a good bet that there's a big kind of contribution there.

Nick Jikomes 34:00

Yeah. And that makes sense. To me. There's, you know, another interesting thing here that I like to think about, which is, you know, scientists and non scientists alike, we like neat explanations, we want to be able to identify those genes that contribute to the disease and those environmental factors. And, you know, I think everyone likes to be in control. No one likes to be out of control. And the idea that something is due to noise, I think speaks to this sort of instinct, basically, that we have that we want everything to be, you know, labeled and controlled, and I don't we don't want our lives to be dictated at all by randomness. Yeah,

Kevin Mitchell 34:35

absolutely. And I think it's kind of an affront to say some some things are just due to chance and it doesn't feel very scientific. It even offends people sort of sensibilities in a deeper way, because, you know, sort of suggestible, there's a limit to the lawfulness of the universe. You know, which, I mean, there may be actually but, but here the you know, the the word or that you hit on there was control. And that's why people want to find these factors, they want to find the genetic factors or the systematic environmental risk factors that they think might exist in order to be able to control them. And if the lesson that emerges from doing lots of this genetics and epidemiology is that there's a big component that is not explained by any of those things, and that is therefore not controllable, and never will be, it's not a very comforting thought, when it comes to conditions like that, it means there's something we just won't be able to control. My there's a flip side to that when it comes to things like, you know, psychological traits and personality and what kinds of things that make us who we are. In that, there will always be a component to that that's inherently unpredictable. In principle, not just in practice, not just, we have some limit to our genetic knowledge, or understanding of how environment shapes these things. There's just a an inherently random bit that will never be predictable. And, you know, in a sense, there's something sort of nice about that, that we're each completely unique, never to be repeated product of this idiosyncratic trajectory, that that was unpredictable and actually uncontrollable from the outset.

Nick Jikomes 36:16

Yeah, so like, um, you know, sort of circling back to the topic of like, how much of ourselves and you know, I guess we can, we can think about people for most of our discussion, how much of ourselves is due to nature, so to speak, you know, factors that are intrinsic to our being, and that we don't choose or that aren't part of our cultural environment. When we think about, for example, identical twins, same genome, they grow up in the same in utero environment, they grew up in the same family environment, unless they're separated at birth, can you start to talk about some of the I know that many twin studies have been done? There's lots of fascinating stories there, and a lot we've learned from them. But when we talk about identical twins, how similar are they on average? And what can you start to say about how much they can differ due to environmental differences?

Kevin Mitchell 37:01

Yeah, yeah. So it's the answer, like a lot of things is it depends. And in this case, it depends on what kind of trait you're looking at. And so if you look at height, they tend to be very similar, right? So they tend to be within you know, an inch or two in height, which is a, which is minor relative to the variation we see across the whole population. And so, so when we're saying how similar, we're always comparing the variants we see between them as a proportion of the variance we see across the whole population. So now, if you go to something like, you know, psychological traits, then they can be very different from each other. And there, you're getting into a whole different problem, because you have to say, well, if I'm going to put a number on that, I need to put a measure on this trait, right, I need to measure how similar they are to each other in something like extraversion, or conscientiousness, or honesty or bravery or kindness, or, you know, and some of those things, you know, psychologists have generated tools that let them put a number on a trait like that. But many of them are much more difficult to quantify the kind kindness is really difficult to quantify. People don't really study. So so there's a there's a whole sort of science of personality and trying to figure out how do these things vary across across the population? And in fact, what are the what are the dimensions along which human personalities bury? So if you just look at the way people interact with each other, in languages like English, there are about 8000 words we have that all refer to a slightly different style of behavior, usually, you know, interacting between people or say, you know, for risk aversion, you can have people who are reckless or cautious, or, you know, there's a whole load of words that you can think of that all kind of tap into the same construct, right? You can be stubborn or headstrong or obstinate or mule headed. You know, all of those things, you can see by looking at them you'd like, Okay, well, actually, that's not a 20 different things. It's 20 different words that are all kind of tapping into the same dimension of variability. So there's been a ton of work done to try and figure out well, how many dimensions are there? Along how many different directions do people bury? And then presumably, I mean, the important thing is that they could be independent, right? So you could be reckless and kind, or reckless and not kind, but you know, so, and those two things don't recklessness, unkindness, don't go along with each other. So there's a huge history of personality psychology trying to figure that out. And there's lots of ways you can chop and change do this kind of cluster analysis and then end up with these different traits and then you can say so say, You settled on these the The most popular ones are what's called the Big Five. Yeah, so it's extraversion, Openness to Experience conscientiousness, agreeableness, and neuroticism. And each of those captures a kind of a dimension, that that's recognizable enough. And usually the way that psychologists will then try to put a number on that is they'll just ask you a bunch of questions. Right? So there's do a questionnaire. They don't ask you how extroverted you are, right? Yeah, they ask you, how much do you like going to parties? How much you'd like to travel? Do you get energized in social situations? And there's a bunch of those things, which, I mean, those are sort of obvious ones, there's some less obvious ones that you wouldn't necessarily think tap into the same construct, but statistically, they correlate with each other. Or better put, there's some there seem to be some latent variable, that that correlates to all of the ice contributes to all of them. So then you can put a number on that, right. So you do a questionnaire you talk about score. And and then sorry, to make a long story, even longer, you finally get back to your question about twins, which is to say, How similar are they right? And really, the question is how much variation you see between them compared to how much you see across the whole population. And they definitely have less variation than across the whole population, but not as much less as for a physical trait like

Nick Jikomes 41:24

I see. So if you measure people's height, and that's right, that's very easy to do, you just get a tape measure and you measure the height, you've quantified that trait. There is variability between identical twins, but not as much as between two randomly selected people in the population. So in other words, identical twins will tend to be slightly different in height, but not exactly the same, even though they have the same genome. For something like personality. What you basically just explained is how psychologists have come up with the analog of a tape measure. Yeah, so they've come up with ways to quantify and put a number on some of these aspects of our behavior and our personality. And there's also variation between twins. And it sounds like there's more variation in those personality dimensions, and then something like height.

Kevin Mitchell 42:07

Absolutely. Right. Yeah. And a good bit more. Right. And it's interesting. So if you think about, okay, well, what could it be that that causes variation in those kinds of manifested behaviors? And And really, what those those statistical measures are a constructs that are inferring that there's some consistent thing that's contributing to variation and lots of different behaviors? And then the question is, okay, well, what is that? Right? So then you're getting to a neuroscience question, what could be different between the brains of these people that would manifest in in these ways? And really, if you're talking about behavior, essentially, you're talking about decision making? Actually. So if if I say, What do you want to go to a party tonight, and we talked about your, you know, going out later, then, you know, you would decide you've got a decision to make, do you want to or not, and you might make that decision differently from me, in this instance. But also, you might have a pattern of making that decision differently for me, or you might have a pattern of going to parties more than I do, say. Or you might have a pattern of being more cautious about certain things, and I might be less risk averse, whatever. So those are the things we call personality traits. But really, it's just summing up the way that you make decisions. Yeah, decision weights, yeah, over many times over many, many instances. So it's just a kind of a pattern across many contexts. The question that no, you know, so that gets us into the science of decision making? How is it that animals or humans make decisions? What are the parameters that actually feed into that? In any given moment? So if we're making a decision, say there's usually there's a bunch of options open to us? Usually, we have uncertain, ambiguous information, we don't have complete information, that's not always a right answer. What we're trying to do is optimize our behavior and the outcomes that we get from it by juggling, you know, many, many different sorts of parameters at once. And it might be, for example, that there's some opportunities here. That could be rewarding. But there's also some threats potentially in the in the environment, right? So now, I might in the same environment as you choose differently, if I'm more sensitive to rewards than you are, right, and there are neural systems that convey reward signals, I might make a different choice if I'm more sensitive to threats than you are, and there are different circuits that convey you know, threat signals and so on. And then there's a whole bunch of other kinds of parameters in there like how confident I have to be in the evidence that I get about what's out in the world before I'm happy to make a decision. And that kind of could manifest in impulsivity, for example, and even recklessness. So there's a lot of sort of neural circuits of decision making That can vary. And in fact, we know, you know, from work in animals where you see these circuits, you can go in, you can tweak them even on the fly in an animal that's trying to make decisions. And you can change the weighting of a parameter, you can make the animal more sensitive to rewards or less, more impulsive or less, right. So we know a lot about that. And we have in humans, then these measures of that are very broad statistical measures of behavior. What we haven't done yet is, is relate those two things to each other in any direct way. And not for want of trying, I think people have done, you know, hundreds of neuroimaging experiments, for example, trying to look for some variation in the brain that correlates with say, being more extroverted versus less or more neurotic versus less. There's no shortage of reports that have come out claiming to have found something like that, but they tend to be from, you know, small studies, and they just don't replicate. And in fact, there isn't really there's nothing in the brain that we could point to at this at the pretty crude scale of resolution that neuroimaging gives you, where we could say, you know, having a bigger amygdala makes you more neurotic, you know, that's just not right, it's the wrong

way, even to conceive of that relationship. Actually, it's not big chunks of the brain determining how, you know, one personality trait versus another, that's just a sort of an old fashioned idea. Yeah. But there may be some more subtle tunings in the, you know, say the reward circuitry, the threat circuitry, that confidence circuitry, that don't manifest as you know, you can't see it on a brain scan. But that would manifest as these different patterns of behavior. Now, when you think about what would cause that kind of variation in those circuits, it's the same kind of thing as would cause variation in height, it's the effect of variations in lots of lots of genes, probably, for the most part, so. So when we look actually physically at the brains of identical twins, now we can get a kind of an intermediate measure of the variability at the level of neuro anatomy or neural function. And there we see, actually lots of variability. So even when identical twins are really young, you know, as soon as we can image them, their brains are already different from each other. So the outcome of development up to birth, has already taken slightly different trajectories, some, there's some variation that we can see. So even prior to, you know, what we would call experience, those trajectories are already different. And then presumably, as they continue on their trajectory through through their lives, that variability sort of continues to increase in ways that reflect slightly different experiences, and also reflect the fact that their brains were slightly different ly wired to begin with. So if you're learning from experience, you're not learning from x happening to you, you're learning from how that felt, like the experience is not happening, the experiences in your brain and if my brain is, is wired in a certain way that I'm, I feel rewards more than you do, then I have just had a more rewarding experience than you have, even if objectively it looks like the same thing. So So then those those sort of initial predispositions that we might have this sort of tuning of those parameters of those different circuits, can can continue continue to influence the trajectory of our of our development of our character and behavior and our habits through our lifetimes.

Nick Jikomes 48:43

And you know, even even though we often don't have the actual details worked out to account for you know, why one twin will have a different personality than their other twin? I want to connect the physical dots here for people well, what is the kind of explanation that people can start to think about for what what would account for that variation? So if genes make proteins and the proteins do stuff that ultimately builds up to our personalities, when one twin has personality a maybe they're more extroverted, the other twins more introverted? At what level? Should people start thinking about that are proteins that say work at synapses, perhaps different such that one twin has synapses that are a little bit stronger versus a little bit weaker than the other one? Where do we where do we think about? Yeah, physical?

Kevin Mitchell 49:26

It's a super question. And I think, you know, a lot of the genetics of personality has been focused on the very kind of immediate proteins that carry these kinds of signals I was talking about, like reward signals, or punishment signals or things that monitor the outcome of behaviors, so that we can learn from them, things that convey, you know, goals and drives and the weight of those drives relative to each other. And those are things like neuromodulators, dopamine, serotonin, and noradrenaline, acetylcholine, and so on. And those have receptor proteins and enzymes that make those neuromodulators. And transporter proteins and things like that. All of which can vary, right? They can have, you know, slightly different versions between different people, sometimes it's the protein sequence itself that's a little bit different. Sometimes it's the genetic instructions for how much of that protein to make. So the protein could be the same, but I might have a little bit less than you have. So yep. And, you know, there's a reason to look there. Because we know that if we pharmacologically target those proteins, then you get changes in behavior. That's why, I mean, that's what drugs do, right, you know, both a lot of medical psychoactive drugs, as well as, you know, drugs that people use recreationally, you know, alcohol, and, and, you know, marijuana and other other drugs like that can target these kinds of, of receptors, right. So, it's not a, it's not an unreasonable hypothesis, to think maybe it's variation in those genes that encode those proteins, that's very directly alter altering these parameters of these decision making circuits. And it turns out not to be true. That's not That's not when you when you do the genetics of these conditions, and you look across, you know, humans and you say a trait like neurotic neuroticism. It doesn't really you don't use the genes that come up, when you find these these variations in across the whole population, ones that are common, they don't really target say, or they're not really enriched for like the serotonin pathway, which might have been a good one to think of. Now, there are very, very rare mutations in those proteins that cause big effects I see, that can manifest on these kinds of behaviors and personality traits. But across the general population, those you know, variation in those specific things is not particularly enriched. And there's an analogy to make their with, for example, height, yeah, where there are single mutations that dramatically affect height, right, they cause dwarfism, but they're probably selected against, it's they're rapidly, you know, selected against. And there's other ones that cause giantism. And, you know, those are mutations in genes that encode growth factors I see. Right, so they're really, really proximal, in a molecular sense to the phenotype that you're measuring. But for the when you when we look at the genes that have been found, that is the the genes that harbor variants that are statistically associated with traits, like personality ones, they don't tend to be so specific to those pathways. And the only thing you can say about them really is that they're enriched for neurodevelopmental genes. So so it changes the way we think about the genetics of or the underlying variability in those personality traits, rather than saying, the genes are directly affecting how this thing works at a biochemical level. It's this whole trajectory of development that can just go can just vary a little bit. And maybe, you know, maybe it is that there's collectively, you know, some more cells, some denser synapses, some differences in the biochemistry, you know, some differences in the metabolism of those cells, all kinds of right, that are not that not, they're not really specific. And so if you look at the effects of the genes, you may have a genetic variant that's associated with one of those personality traits. But it may also be associated with all kinds of other things,

Nick Jikomes 53:43

because maybe it's causing the neurons to burn 2% more ATP, and that affects everything.

Kevin Mitchell 53:48

Yeah, it can be all kinds of, of factors that that vary. So you know, we talked about Mendel earlier. And he gave this kind of a rosy view, a simple view of genetics, where, you know, it's possible to find these traits that are either like this or like that. And there's one gene that explains that difference. And most traits in humans are just not like that. And they're not, you know, the genetic causation. That is just really indirect. And it's really cascading actually. And that's especially true for our psychology. You know, we're talking about the the highest levels of human behavior, the most sophisticated cognitive things that we do like social interactions, you know, navigating those is a hugely emergent kind of a function or faculty of the mind and the brain. And, you know, the idea that it would be related very directly to how much of one protein or other you make. In retrospect, it's kind of a bit simplistic.

Nick Jikomes 54:50

Interesting, and so you mentioned neuro developmental genes, what would it neuro developmental gene be as opposed to a just neural gene? What did people think of well, so

Kevin Mitchell 55:01

there's a couple different ways to think about it. One is that you have genes that are directly involved in the processes of neural development. So they encode proteins that say, control cell division, proliferation, or migration, or the guidance of growing nerves, the kinds of things like where I started my career working on, or you know, who connects with whom, and the brain and that kind of thing. So those are genes where you would say their job is to do is to direct the processes of neural development. And variation in those genes can lead to variation in how the development plays out. However, development also requires all kinds of other things that those cells do, right, it requires their cytoskeleton to be normally requires that you know, certain levels of energy production and metabolism and all kinds of stuff. So there's another set of genes that you wouldn't look at the proteins that they encode and say that's for doing the process of neural development. Nevertheless, variation in that protein might affect how neural development goes, right. And that's the main sort of majority of these genes is that they're, when you're talking about the effects of mutations is a very different lens, than the function of the gene has to do X in a normal in a normative sense, or we say the normal gene is doing this job in cells or in the organism. But it relies on all this other stuff. And if you mess up all this other stuff, maybe this guy can't do his job properly, or the process just can't happen. So again, it's really it's sort of irritatingly nonspecific and indirect, and very unsatisfying with the goal of doing genetics is to figure out this biology. Well, it turns out the biology is just super, super messy. In a way, that's, it doesn't give you the clean answers you would want. Yeah, it's just sort of essentially uninformative. Yeah, it's not that it's not that we haven't figured it out. There's, there's no answer there after beyond a certain point. I mean, the answer for personality traits is interesting, in that they seem to reflect how the brain develops, as opposed to just how it acutely functions. That is, how it acutely functions is, is itself a function of how it developed. That was something we didn't know before. So there's an answer from genetics, it's just that it's a kind of a general answer, it's not a super specific one that we might have been hoping for.

Nick Jikomes 57:27

I see. And, you know, this starts to connect in a little bit to this distinction, that I've heard people make between neurodevelopmental versus neurodegenerative diseases. Yeah. And I think some of the things we're talking about with personality there and and neurodevelopmental genes get into, you know, thinking about things like autism, or schizophrenia, and how the aspects of our personality that, you know, these are basically we call them disorders or diseases, because the person diagnosed with it is not behaving within within the range of, of human behavior that's conducive to living, you know, living a normal life. So how does how do these neurodevelopmental genes tie into some of these psychiatric conditions?

Kevin Mitchell 58:13

Yeah, so it's a great question, you know, you raise the use of the term disorder. And, essentially, is something is a disorder, it's felt as a disorder. And there's not really any sort of better threshold, right, if someone if someone in a sense is suffering from having a condition, then it's, then it's a disorder. And that's just the, the way the term is used. And it's not judgmental. Beyond that. It's simply saying, this is something that is that this person is suffering from right now, in some cases, say for something like epilepsy, so you can see there's a physical thing that's happening, right. And it's, it's, it's a cause of danger and risk and ill health and so on. So it's not really a gray area, it, whether you're calling it a disorder or not, for something like autism, there's this massive range. And for some, you know, people with autism, they may be completely nonverbal, you know, really, really severely affected in the sense that they may need full term care for the rest of their lives. And then the diagnosis has been broadened over recent years, to include people who have, you know, this cluster of traits, which is sort of recognizable right as as a cluster, maybe a language, delay, social, you know, differences in social cognition and interactions, maybe repetitive interests and a few other things. And so that they sort of exist as a cluster that's recognizable and Label Label Label right. The question there whether you call that a disorder or not that now you're much more into the realm of it being a disorder just because society is not well set up to cater for those people, right? So. So there's this, there's massive range, right? Somewhere, it's a clear medical condition and others where it's a difference. And it's a difference that has potential functional consequences in the world. But that's, that's very much a relationship between the person and the world,

Nick Jikomes 1:00:25

the person may or may not be contented with having that argument. typic. Absolute stir.

Kevin Mitchell 1:00:29

Absolutely, yeah. So. So all of those right across that that range may reflect differences in the way the brain develops. And some of those are maybe just sort of general differences in where you fall on the range of these sorts of traits. Whereas others may be the outcome of a much more discrete kind of genetic causation, like a discrete mutation that causes the symptoms. So say, a condition like Fragile X syndrome, for example, it's a genetic condition caused by mutation in a single gene. And it's associated with intellectual disability, very high rates of autism, higher than normal rates of epilepsy, and then a bunch of other non neural related conditions. So there's a whole bunch of syndromes like that, like Rett syndrome, there's a bunch of 22 q 11 deletion syndrome, there's, there's a big long list of genetic conditions that are associated with a single mutation that confers very high risk of having this phenotype that gets you one of these diagnoses. And a question has been for psychiatric disorders. Generally, if you think about them as these known conditions, like Rett syndrome, or Down syndrome or fragile X syndrome. There's the known conditions that are kind of men Delian, right, they they follow this sort of simple inheritance of there's a single gene hit that causes the condition. With as it happens, that's too simplistic a picture, but we can come back to the, and then there was this big pool of what are called idiopathic cases, idiopathic just means we don't know the cause of it, right? But, but we can give somebody a label based on the symptoms that they manifest, and it's purely the behavioral symptoms. So obviously, autism, or schizophrenia, or whatever it is, so they go to a psychiatrist, psychiatrists will say, Okay, I recognize this cluster of symptoms. And we thought about this, and we come up with this label for it. So it's a, it's a construct, right? And there's a question, does it reflect what philosophers call a natural kind? Is it? Is it something that's real in the world that we're recognizing? Or are we just trying to impose orderliness on something that's actually a lot fuzzier. And from a genetic point of view, people have thought, well, maybe you've got these rare conditions that can increase risk of schizophrenia, or autism with these symptoms. But but those are different from this common pool. This is the real schizophrenia or real autism, it's kind of a hangover from the time of this sort of separation between Psychiatry and Neurology. So schizophrenia, almost by definition, is something that, you know, that has these these symptoms of, you know, paranoia, and hallucinations and cognitive difficulties and so on. That doesn't have an organic cause that explains it. And often that organic cause will say something like syphilis, right? So syphilis can manifest with those things. So if somebody came into the clinic had those symptoms, and you tested them for syphilis and a bunch of other stuff, and they didn't come back positive for that. Then they were labeled with schizophrenia. I see. So it's a diagnosis of exclusion. Yeah, it basically says, You look like this cluster. And it's unexplained. So we're going to call it schizophrenia. And oddly, when genetic started coming into the picture, once you got a genetic diagnosis, then it was like, Okay, it's not schizophrenia anymore. It has an organic cause that we can recognize, which doesn't quite fit, because actually, Schizophrenia is a genetic condition. It's a highly heritable, of course, it's going to have some genetic contributors to it, that doesn't mean the person no longer has schizophrenia, they still manifest those symptoms. So

so people have started to do a lot more genetics to try and tease this out. And what they're finding is both lots more of these single gene mutations that can cause high risk of some developmental neurodevelopmental disorder, or that manifests with psychiatric or cognitive symptoms. And at the same time, a big big pool of common genetic variants that contribute to risk more generally. And the question has been, how do we think about those things? How do we put those together? Are Are they really separate from each other? Is it really right to think that, you know, on the one hand, we've got cases of say autism that are caused by a mutation in fragile X syndrome, or the Rett syndrome gene or whatever, and we put them over here. And then we have other cases that are caused by this accumulation, this accumulated burden of these common variants. And and I don't think that's the right way to think of it at all. I think that common background part, what's called a polygenic background, is really reflecting the robustness of the system. And its ability to buffer these mutations that happen, because many of these mutations that are associated with, say, risk of autism or so on, they may be associated with like a 30% risk, right. But it's highly variable between people who inherit this mutation, some of them will develop the condition, some of them won't, some of them might develop schizophrenia, or ADHD, it turns out, the genetics of all these things is really overlapping. From a genetic point of view, the risk is actually really shared across these different categories. So so you've got genetic risk here, and then you've got outcomes, which are highly variable. And you'll have to explain why two people with the same mutation, excuse me, might end up with very different phenotypes. And part of the explanation for that may be that they have a different genetic background. So one person who has a kind of a high risk background, maybe unable to buffer the effects of this mutation during the development of their brycie, I see an end up being channeled down this route that manifests as autism. Whereas another person who has a, you know, a lower burden of these common genetic variants, may be able to buffer that insult of the big mutation, and end up within the normal sort of the typical cognitive behavioral range.

Nick Jikomes 1:06:57

So one, one mutation in one gene in two different individuals amounts to one mutation existing in two different genetic contexts. One of them might be able to compensate for whatever problem that mutation is causing during the course of development, and in a different genetic context. And different individual, you have the opposite. Yeah,

Kevin Mitchell 1:07:17

exactly. And which I think that kind of model can unite these different strands of looking at this, this big pool of background of common variants, and then the single, you know, variants that arise. But that's a model, right? You know, that's an empirical model, and it may need to be to be modified as we learn more, but to me, it makes the most the most sense. So, so yeah, so we have this, this sort of mystery. And to come back to the neurodevelopmental thing, what the genetics is telling us, when you when you look at either these rare mutations that we're finding more and more of in isolated cases, or a few cases, and this big pool of of genes that carry these common variants that contribute to this polygenic background. And, you know, so you could ask, Well, what kinds of genes are they? Right, what proteins they encode, as we talked about, for personality, and again, they're enriched for neuro developmental genes, very broadly, very generically. And you know, the hope, in doing the genetics of schizophrenia, was that it might point to very particular biochemical pathways that were disrupted very proximately, by these particular gene, say, and dopamine signaling or something, perfectly good reason to think that because drugs that target the dopaminergic system can act as antipsychotics. In fact, all antipsychotics that we know of that target dopaminergic pathways, and drugs that can induce psychosis can also target, you know, the those pathways or glutamatergic pathways and so on. So the pharmacology suggested, you know, maybe the genetics would be specific to those kinds of genes. But the answer, again, is no, it's not, there's lots of ways you can get the cause differences in the way the brain develops, that ultimately cause it to the developing brain to go into this regime of function, or dysfunction, a kind of a maladaptive regime that that we observe as the symptoms of schizophrenia. So it's, again, you know, it points to neural development as being the cause, but in a really generic, unhelpful, kind of a way, in that we're not going to, you know, it doesn't suggest, oh, I can target this biochemical pathway with a new drug, and, you know, meet this huge unmet need, clinically speaking, because, you know, for a lot of these conditions, they're very, very serious. They've been huge, huge impact on function. They're hugely, you know, detrimental. I mean, Schizophrenia is a horrendous, you know, condition and it's not very well treated for many people with it. So there's a big, you know, need to find better ways to treat it. Or either, you know, coping with it. I think there's a huge unmet need just in terms of supports, but also, you know, potential new therapeutics. And the hope was that genetics would point us very immediately towards those pathways. And unfortunately, that turned out not to be the nature of the relationship between genetic risk and the these emergent conditions.

Nick Jikomes 1:10:18

Yeah, I want to dwell a little bit on the fact that a lot of these psychiatric conditions are correlated in that, you know, if you're likely to get one, you're also at increased risk of getting another one. A lot of times I think, naively, you wouldn't think that right, right, we have, we have separate words for these things. There's autism, there's schizophrenia, there's epilepsy, it's natural, or very easy to think about them as completely separate. But you seem to be saying that a lot of the same genes that predict that neurodevelopmental genes that predispose you, if you have a mutation to one of them, can also predispose you to another does that start to connect with what you were saying with like, the different genetic context between people like one one mutation in a neurodevelopmental gene might predispose you to autism and schizophrenia, but the full context that mutation is in is gonna sort of dictate which way you go?

Kevin Mitchell 1:11:03

Yeah. So I think there's two elements to that. So first of all, it's true. Well, first of all, if we think about these things, again, are you know, are they natural kinds or not? And in terms of even just clinically speaking, they overlap a lot, right? I mean, I mentioned earlier that in fragile X syndrome, people have, you know, may have autism and epilepsy. So they, they, they're comorbid, in individuals quite a lot. And, you know, it's common to have, you know, ADHD, and schizophrenia, or you know, those kinds of things. So that's not uncommon at all. And in fact, it's not uncommon for someone to the diagnosis that they have to kind of migrate through their lives that these aren't necessarily static. Things, they're descriptors on their current state. At the same time, it's also true that the risk for them is clearly overlapping. And you can see that in across families. So if you have a sibling with schizophrenia, your risk is about 10%. Right? And the rate in the population generally is about 1%. Over the lifetime, so But statistically speaking, your risk of having autism is also higher, or intellectual disability, or even or even epilepsy, right? So. So you can see in Yeah, in different people, that the risk of these things is sort of globally shared. And then you can ask him more specific questions you just did. Imagine two people with the same mutation, one of whom may, you know, develop autism and the other may develop schizophrenia. And there, there may be an explanation that's partly due to the genetic background that they have that's different, you know, that you may have another mutation here, or just a background that buffers at better or worse, right, or we're differently differently. But even beyond that, there's also some variability, which is just this stochastic developmental variation that we were talking about earlier. So even monozygotic twins, who have these high risk mutations and obviously have the same polygenic background can manifest as you know, autism or not, yeah, ADHD, or epilepsy. Yeah. And really, you know, really quite dichotomous outcomes. That for me, you know, just highlights the fact that that what is being inherited, there is a risk or a probability of being channeled into one of these eventual phenotypes, you're not inheriting the phenotype, you're not inheriting a disorder is it's a risk. And how that plays out is going to vary even between genetically identical individuals, in the same way, as we talked about for handedness.

Nick Jikomes 1:13:37

Yeah. And I think it is really helpful to think about these, as you said before, as trajectories, not to think about them as sort of static, static things that aren't changing. And I love the analogy that you used earlier, I think of, you know, the marble game where you drop the marble in one spot with the pegs at the top and it goes down. And even if you drop it at the same spot with the same force every time, it's going to take a different path each time.

Kevin Mitchell 1:14:01

Yeah, absolutely. And like I said, that's there's a sort of an inevitability to that. It's not a,

you know, I was talking about earlier how it's difficult to prove that that's the case. But it's difficult to set because they come back as always, something like well, you're saying this is stochastic developmental variation, but maybe it's something from outside the animal. Yeah, or the or the person I use, you know, maybe one twin was on the top in the womb or something like that, right. And you can't exclude it right? So it's, you know, when you say it's noise, that's really just you, that's just you putting a label on your ignorance, which is a fair point, right up to a point up to a point. If you go looking for these kinds of variability, you never find anything that I've actually got to go, well, maybe there's nothing to find. Exactly. And the other thing is that even you can see at the neuro anatomical level, this kind of variability played out Yeah, right. So if we think that the the way the brain works reflects its structure then we can look directly at the structure and see you know what, there's noise here, that's nothing to do with from outside the organism. And the best place to do that is in experimental organisms, where you can see the same thing over and over and over again within the same animal. So harkening back to my work in fruit flies, we were looking at, in fruit fly embryos that have these abdominal segments. So the larva will crawl around, right, so they have muscles in their body wall. And each segment has exactly the same muscles, it's an array of 30 muscles that we, they have numbers, right, so we can identify them, their inner innervated, by about 40 different motor neurons coming from the nerve cord. Again, we know the names of all of them when we can see the same one on two sides of the animal for like eight segments at a time. And what we find is that ordinarily, if there's no mutations around, you know, this, this motor neuron here will with 100% accuracy make its way out of the nerve root along this branch detached from the nerve and innervate muscles six. But when you start to add mutations that affect some of the information that needs to get there, then it may only be able to do that 30% of the time. But when it does, it makes it perfectly fine. Yeah. So what you end up with is a clear expression of a probabilistic relationship on a single cell level with repeated observations in the same animal. And there I think you just have to say, well, that's, that's just a Catholic developmental variation. And I can't be anything else that that's what if that's what we're talking about. That's it. And so, in the end, you can see that, you know, in mammalian brains, you can see that manifested in sort of more statistical variability. But even there, you can get very dichotomous outcomes. The reason why is because neural development, especially, is very contingent on prior processes having happened properly at the right time. Yeah. Right. So so the developing brain has to coordinate all these processes, cell migration, and proliferation and axon extension. And it has to connect, you know, the axons from here have to reach this region, you know, and then their targets need to be there and to put them to connect with. So there's a really interesting example, which is in the formation of the connections between the two hemispheres of the brain, which is a big tract has millions and millions of axons in it, called the corpus callosum means the tough body because, presumably, top to cut through. And so ordinarily, that forms just fine. And the way it forms in embryonic development is that the two hemispheres, which are, you know, the neurons here are dividing separately from the ones on the other side, they have to fuse as a tiny little bridge of cells that fuses the two hemispheres, and at a very particular point in embryonic development, and then if that happens, fine, then some pioneer axons, nerve fibers will grow from one hemisphere to the next across this little bridge. And if they make it across, then everybody else can go across. But if this little bridge doesn't form, those pioneer axons can't get across at that particular point of development. And then nobody gets across. As the brain grows bigger and bigger and bigger, the two hemispheres remain disconnected from each other. So a little bit of noise, a little variation in gene expression right here, at this point, can lead to this massive outcome, where you know, you disconnected hemispheres of the brain. And again, you can see that you can inherit a genetic risk for that happening. And in lines of mice, for example, where this has been studied a lot, you can have different lines of mice with different mutations, where the probability of forming the corpus callosum is maybe 30%, or 40%, or 50%.

Again, when you breed those animals, the ones that either did or didn't make a corpus callosum, and they're all genetically identical, their offspring, it's also going to be 30% 70%. Doesn't matter whether their parents actually have the thing or not. The risk is what's is what's transmitted. So, so yeah, you can get this relationship between genotype and phenotype, that is absolutely an expression of the trajectory that the animal followed. And the way that that the the, the trajectory that they happen to follow. And that happenstance is that sometimes there's a bit of chance to it. And it can make a big difference in the outcome.

Nick Jikomes 1:19:34

One of I mean, we've been talking about diseases and disorders, and things going wrong, a fair amount, but it's also really interesting just to think about normal, if sometimes unusual types of phenotypic variation in terms of brain stuff like perception stuff and cognition, stuff among people. One way that we vary is the way that we perceive the Worlds. So a lot of what our sensory systems are doing just to set this up for people is, you know, we've got these different sensory sensory channels, we see with their eyes, we hear their ears and so forth. And they are parsing the incoming sensory data into distinct entities that we can then you know, manipulate and perform operations on. Right. So our visual system is parsing a pattern of electrical activity that comes from photons hitting the retina into objects. Our hearing system is doing that that to create the phonemes that compose our languages. When we think about perceptual variation, and variation, and how the sensory systems from individual to individual or parsing the world, it starts to get really interesting and know that you've, you've studied some visual stuff before. I'm colorblind, for example. So my sensory system is set up such that like, I'm not parsing the world into as many colors as other people are, people see more colors than than the average person as well. And you get interesting phenomena like synesthesia. Yeah. So when we think about this sort of perceptual variation, and where that comes from neuro developmentally, how do we start to think about that?

Kevin Mitchell 1:21:05

Yeah, so it's super fascinating, sort of area, and one that I think is underappreciated the amount of variation that we have, in literally how we see the world and or perceive the world through all of our, all of our senses. And you know, people will be familiar with things like color blindness, that's a well known one, they might be familiar with things like being able to taste certain things or not, you know, and some people find the taste of some things really disgusting, and other people can't taste it at all. And some of those, so, you know, perception starts with some receptor that detects something out in the world. And that might be receptors that detect, say, light of a certain frequency and compare them to allow us to kind of label things as with colors, right. And if you have a mutation in a gene that encodes that protein, then you you don't have that channel, basically, of color perception, or, let's say just frequency, particular frequency range perception that you don't, you can't make the comparison because the receptor is just not there. And similarly, for things that you taste or smell, you may not have the receptor, protein that allows you to bind this particular chemical. And so you just can't detect it, you're completely oblivious to it. And, of course, you know, across different species, the receptors that they have determined, they're what we call their sensorium. What it is, basically, the sensory world that they're living in, is completely different between different species. And you know, you may have seen things like these sort of general generations of pictures of what it's like to be a bee or a bird, or the kinds of colors that they see and flowers on things like that. But, so but there's also just variation within within species and including within us. And so you have this one class of things, which are pretty clear, like genetic conditions, there's a there, there's a mutation in this gene that encodes this receptor, and that explains the variation in ultimately in perception. That would be like my colorblindness. Absolutely, yeah. But of course, perception is not just sensation, you know, you refer to it, we we have to infer what's out in the world, we have to make sense of it in a way that we can then capitalize on. And so in visual system, where we're doing feature segmentation, object segmentation, and an object recognition, and the recognition part depends on our memory, right? It's not a passive thing that's happening when I'm recognizing something here. So you know, I came into the office, and I recognize this as a chair, and this is a table, part of that process is that I have a history of tables and chairs, I know what they are, I know what I can do with them, I know what they're for. And I bring all of that to the process of perception. So I'm linking the incoming signals, to my stored knowledge, to my concept of tables and chairs, and I and that then enables me to navigate through the world more effectively, and adaptively. And interestingly, there are some variations that we see in those higher order kinds of processes of perception, in concept formation, or linking, linking to memory. So the linking to memory one is a little easier maybe to think of, but so when we're processing objects in the world, we're doing that in a way that is sort of dependent on the salience of those things. So lots of things that we don't really care about much we don't even process them as an object, right? I mean, the side of that wall is, is effectively an object, but I'm not thinking of it in that way. Yeah. So one of the things we're really interested in is other people, especially people's faces, right? So we're highly highly social, hyper social species. And being able to recognize people from their faces is a perceptual skill. And it what it involves is the feature segmentation, understanding you sort of mapping where the future is our and then referring to kind of a memory store to say, yep, that's, that's Nick. That's whoever it is right. And some people just can't do that i There's a condition called face blindness or prosopagnosia, which was initially described as by people like Oliver Sacks, for example, as an acquired condition due to some kind of a lesion. So there's part of the brain that really specializes for detecting and processing faces. And if you lesion that part of the brain, you just won't be able to do it, you can see all the bits. It's not like you can't see the eye and the nose and the features, and you just can't link that to your memory of, of who the person might be. And so there's just a defect there. But there's also a congenital form of that. Also runs in families. And it's much more common, you know, maybe as many as 1% of people just can't do that.

Nick Jikomes 1:25:55

And there's also the natural variation. I don't know, people who are just they can do it, but they're not nearly as

Kevin Mitchell 1:25:59

good. Absolutely. Absolutely. So there's a range. Yeah. All right. And then there's people who have a discrete kind of thing where we could say, within a family, we could track this person has it and that person doesn't. Yeah, this person does. So and again, you know, that's like variation in height, versus dwarfism. You know, there's a discrete kind of a form or variation in intelligence versus intellectual disability. Yeah, yeah. So there can be two kinds of genetics happening at the same time. There's a parallel in in music, actually, in tune deafness, where people can hear the notes of tune, but they can't really link it to a stored memory of say, a melody, even maybe, one that they've heard before, or one that they're hearing for the first time. But even people, most people hearing one, for the first time, very rapidly develop a short term memory of the way a melody should go and can detect whether a note is out of place, for example. And there's a whole bunch of people who have this tune deafness, it's often called called tone deafness, but it's that they can hear the tones just fine. They can discriminate between tones, no problem, it's just linking this overarching kind of comp, it's almost a conceptual kind of a thing. So, so there's a bunch of variation like that, again, this is that's a genetic, you know, difference, at least. And then you get to two. So there, what you're doing is you are having a difficulty linking particular perceptual information to the concept of something or a broader kind of schema, if you will have up something right. So when I see your face, I'm not seeing the individual elements, I'm developing a schema of the overall way they're related to each other, right. And so our knowledge of things naturally entails their properties. In fact, it almost only entails their properties, it's not, there's nothing else to know about a thing, then the properties that it has the relation. So this table has the properties of of hardness and being about this taking up this much space, and being something I can put things on and so on. Now, when it comes to some kinds of percepts, it seems that some people with this condition synesthesia, tack on some extra attributes of those particular things. And sometimes, that's a very kind of a florid perceptual experience that they're having right in the moment. So for some people, for example, they sound will produce a color person, so their auditory information, triggers in their brain, not just the experience of the sound, but it triggers an additional experience of might be a cloud or some sort of visual shape.

Nick Jikomes 1:28:45

And when they just had a curiosity when they describe the phenomenology of this, do they tend to do they do they describe it as like, the room is literally, like filled with blue light? Or is it more of like a mental imagery thing? Or how does that yeah, so

Kevin Mitchell 1:28:59

it varies. So some of them will literally experience the thing out in the world, and they could point to it and say there's a pink cloud there when I heard what you know, when I when I heard the cutlery jingling in the drawer behind me, I saw a pink cloud appeared right there. And, and others may, you know, they may see little flashes of light, they don't tend to be very complex kind of phenomena. It's not like being on LSD where you're seeing, you know, people or objects or stuff like that. It's tend to be simple sort of, often, you know, sometimes geometric kind of little things object's individual, individual experience not

Nick Jikomes 1:29:36

interfering with their ability to behave and act in the world. But it is a genuine sensory percept of some kind.

Kevin Mitchell 1:29:42

Yeah, it's a it's a vivid sensory percept in the moment that the interesting thing about it is it tends to be really specifically paired with so when I you know, if I heard cutlery again, jangling, I'd see that pink cloud again. I wouldn't see something else right? So, so there tend to be these really specific pairings between sounds. You know, for people with musical synesthesia, you might be particular notes have particular sounds, or the key of the instrument, or the tambor or something like that, that that is almost kind of color coded and that sense. Color is an is a frequent percept. That's a sort of additionally experience. But it can be other things you can have sounds as an extra percept, you can have smells, tastes, and so on that happen. So, so there's that kind of manifestation, which we call projector, synaesthete in the sense that there is clearly an internally generated percept. But the experience of it is, in a sense, projected out into the world, right. And really, what that reveals is actually all of our experience is a projection out into the world. But there's another sort of set of people who don't necessarily have that kind of florid, vivid percept, but they have a very strong knowledge that the attribute of the thing that you're talking about has a certain characteristic. And the most common ones are those are people who have colored alphabets. I see. So they may, you know, if they're looking at letters on a page, some, some people will actually see them as colored. So a, maybe red B, maybe blue, C may be green, whatever. And they'll actually see that, for other people, they just know it, right. So they know that that's an attribute of that thing, just as much as they know that the the letter A visually is associated with the sound a light, so that's part of the schema of the letter A. And another attribute that it has is that it has a color, and that color will be very, usually quite idiosyncratic. The sorts of colors that people have for their for their alphabets, but stable for that person, often completely stable through their lifetime. And many of them will say this, it always had that I didn't, they didn't even realize other people didn't have a color for, you know, letters of the alphabet or numbers or didn't think of months, the month of the year as being, you know, having a spatial location, or, or whatever it is so. So it's an interesting link between the processes of perception that naturally involve conceptual categorization. And the idea that that entails a schema of the attributes of an object that make it that thing for you, and that somehow in people with synesthesia, they're adding in this extra attribute. And so the question that is, why, why. And so it is a heritable condition, you know, runs in families, sometimes in a way that looks like it might even be caused by mutations in a single gene, nothing, genetics is really still unknown, although the people working on it. But it clearly seems to be neurodevelopmental, in the sense that these are developmental and origin. I'd like you know, these people say they've always had it. And the way we think about it is that there's maybe some kind of cross wiring between streams of processing in the brain that normally are run separately from each other. So those might be between auditory and visual stimuli, for example, where the auditory pathway normally runs like this. But in people with synesthesia, maybe it just literally anatomically cross connects and drives the visual pathway. So when you hear something, now you're, you're, you're processing the sound as normal, but you also have to your brain has to interpret this extra activity. And ordinarily, if it's in the visual pathway, in your experience that's been driven by red things, say, and so now your brain goes, Oh, that's red. And then so either you're, you're having that experience right now. And a vivid percept. Or even if it was like that, even if that's not happening anymore, the fact that it was happening, in your experience, as you were learning, say the alphabet means that the colors are not part of your concept, even though you don't see them out there, you know, that they're part of that attribute of that object.

Nick Jikomes 1:34:06

Yeah. And what's really interesting to think about when it comes to synesthesia is, again, this is a an example where the natural inclination, I think people have is to, just is to think some people have synesthesia, and in those people, their sensory channels have crosstalk between them, but I don't have it. And that doesn't happen with me, but it's really a matter of degree, because when you think about synesthesia in particular, but also just perception in general, that much of our perception is coming from this intertwined nature of these different sensory channels. So like what I'm watching his talk right now, right? I'm, I'm, my perception is being driven just as much by the visual signal of your lips moving as it is the sound waves going into my ear. Yeah. Then you get things like the McGurk effect. Yeah. So what does it start to tell us about the nature of perception in terms of this sort of cross modality that's always there?

Kevin Mitchell 1:34:56

Yeah. So So I want to push back a little bid on the idea that, you know, synesthesia is a continuum, because actually, it is the case, I think that some people really have it, and some people really don't. And even within individual families, you can see, you can see that kind of segregation. So I think, but it's also absolutely true that we're all doing multi sensory integration all the time, right. And you refer to, you know, lip reading, which is something that we do often, you know, quite subconsciously, but you can manipulate it by, you know, playing these videos where there's a mismatch between the lips moving, and the audio that's played. And then as you said, this McGurk effect, people will hear a kind of a phoneme that sort of in the middle of that interpretation, so. So what's happening is that there's a, there's information from the visual system, about the way the lips are moving, that's giving an expectation of what the auditory systems signal should be interpreted as. And really, that highlights a completely general fact about perception, which is, it's, it's very much driven by a comparison between our top down expectations of what should be in the world, and our incoming information. So we're not just passively driven by incoming signals, we are actively making sense of the world. And we're using all our past experience to do that. And sometimes, the most obvious way is that I have an expectation right now that everything I'm looking at in the scene here is going to continue to exist for the next moment, right. And if something suddenly disappeared, I'd be surprised, and that's good, that's my brain, saying, hey, that's something you should pay attention to, something has changed in the scene, you should be used to be aware of that. So it's setting up an expectation. And that expectation may be sort of violently, you know, disrupted by the incoming information. Or it may be just, you know, I may have an expectation, but other things like the fact that in the world, generally, light tends to come from above. So I kind of have a baseline prior of the way things tend to be illuminated. And that helps me infer what's an object and what isn't. And that can lead to these sorts of optical illusions, and so on. So we're our, you know, our systems are wired in such a way that we, we form these expectations through experience, or some innate ones. And then they can be, they can be tweaked, right, they can be taken advantage of, and we can be fooled into, you know, seeing something as say, brighter than it is, or further away than, or bigger than it actually is. Because our brain is saying it's further away. But you know, it's an image that's been manipulated or something like that. So, so yeah, perception is very much a two way street, it's us actively making sense of our incoming sensory information, in the light of these expectations that we that we have built up, that we're constantly modulating, because what happens with perception is we compare it to the model that we have with the world. And then we update the model. And that's now our expectations for the next moment of perception.

Nick Jikomes 1:38:02

So, you know, we've spent a lot of time talking about, you know, how genes and randomness and environmental factors all come together to influence the developmental trajectories that we take as, as our organism as our bodies are constructed, ultimately, to create who we are and how we behave. We've talked about how people vary in terms of how they see the world, how they perceive the world, how they act in the world, ways that that can go wrong, and just the natural variation that we see from person to person, when you start to think about, you know, and a lot of what we're talking about, right? When we're talking about variation in personalities variation between so called normal cognitive phenotypes, and, you know, comparing those two things like having a psychiatric condition that is problematic, like schizophrenia say, I think before you mentioned something that a lot of this kind of really boils down to differences in decision making, and how the brain is performing that kind of operation. And, you know, the pattern by which you and I differ in how we make decisions is going to account for a lot of how we differ in terms of our personality. When we think about decision making, when we think about personality, and a lot of the stuff that we've been touching on where does a concept like agency come into this? Is there really agency? Or is this just something we're kind of imposing, imposing on the brain?

Kevin Mitchell 1:39:19

Yeah, it's such an interesting question. And something I'm working on at the moment. And, you know, it comes up when we, if you say, you know, say we look at variation in personality traits, like you said, which, which basically are patterns of decision making. And if it's the case, as I've, you know, arguing that there's some genetic contribution to that variance. And there's some developmental contribution to it, which together make up what we would call nature. Well, I didn't choose any of that, you know, I come pre wired a certain way. So, you know, I'm constrained in my choices. So for thinking about agency, and even, you know, the philosophical issue of freewill, then the question is, how free Am I If I'm sort of subject to these prior causes that I didn't choose, and actually, you know, that's the same problem, if it's environment that's causing you to be a certain way, if it was your upbringing, it's no better really, you know, it can be just as deterministic in that in that view. So, the way I think about that is that is to think of, yeah, we're not blank slates, we do come with these innate predispositions, which is good, because they're really adaptive. You know, every species has an innate predisposition. So actually, in the first instance, we have predispositions just by virtue of being human beings. People don't get so hung up about those oddly, even though they vastly constrain our behavior much, much more than the little subtle variations that we call personality. But people tend to be more worried about being constrained to behave like themselves than being constrained in the same way that everybody else is by virtue of being a human. But anyway, so there's a set of constraints that we have just our evolved human nature. And then we have our individual natures, which are variations on that theme. And then, you know, the question is, how does that actually manifest through our lives. And again, it comes back to this idea of a trajectory. So if you think about, you know, personality constructs like extraversion and neuroticism, and so on, you can think about them in a way, like you could say, Okay, I got 10 People in this given situation, and I know this person's profile is like a, and this person's profile is like B and C, and so on. And so this person is going to do that this person is going to do that. And that's just, they're just woeful for predicting actual behavior of actual individuals in actual contexts, right? They're more like, descriptions of climate than predictions of the weather at any given moment. And so it's true, it's raining in Ireland, generally, it was not raining right now. So. So really, what they are is they're they're setting some some baselines for these different kinds of decision making parameters. But those are really low level kinds of things that as we go through life, we actually just adapt to the world, right? We're learning from our experience, what's out in the world? What, what's rewarding for us? What are the experiences I like to do? What am I going to? How am I going to craft my environment and so on, we're agents in that process. And that process feeds back onto our habits, right. So it's not the case that we're just sort of passive in this process, we have our pre wired things, and then experiences happen to us and shape us. And we're just being molded by things out in the world. We're really active agents in that process, we're molding our own habits. And our own character character is just a description of habits really, of ways of behaving, but at a broader level, you know, than being extroverted. They're more specific than that. But so I like to think of character as emerging through time, in a way that is something that is not just antecedent causes that we didn't have any involvement in, we're very much involved in that process. Now, we could be more or less sort of aware of our involvement in that process, and trying to control it in particular ways, right. So this gets into a whole area of moral philosophy, really. And it goes back to people like Aristotle and Cicero. And Cicero in particular had interesting things to say about this. In fact, in some letters, he wrote to his son, which sound remarkably modern these days you read them there were his son was off at basically a university in Greece, studying with some philosophers in Greece. And Cicero, the Roman statesman was was sending him some letters, kind of fatherly advice. On, you know, what, what are good ways to behave, live the good life as it were. And so he talks about how our character emerges. And he identifies four factors, which are very much the factors that I've been talking about. So one is general human nature. The other is our individual nature.

The other is events. And in in that he included chance sort of stuff as well. But experience, and then the fourth is our own decisions, right? The cumulative effect of our own decisions that feedback on to ourselves. And actually, the crafting of ourselves through our cognitive and social development is something that we are doing, right but we're not just passively being shaped by that. So. So that's one angle to the question of agency and freewill that I think can incorporate this idea of genetic genetic variation and innate predispositions without leaving you feeling like you're an automaton that just to a certain way, then you had no hand in that process whatsoever.

Nick Jikomes 1:44:48

Interesting. And you know, when you said, you know, when you when you refer to things like human nature, what I heard you say is that, you know, what is human nature? It's the set of hard constraints that are you universal to all human beings that make us behave like humans rather than some other type of organisms. Within that there's variation from individual to individual absolute, but what are some of those constraints? In other words, what is the essence of human nature? In your view?

Kevin Mitchell 1:45:13

Yeah, well, I mean, so again, when you're asking that question, you typically, what you're really asking is, is kind of a comparison. Right? So what is it for example, that's different about human nature versus chimp nature? That's a different question from what's different between human nature and a fruit fly. So there's lots of things that you would say. So if you were David Attenborough, say, right, and you were doing a nature program on these strange creatures called humans, there's some descriptors that you would use in a kind of zoological sense, right, where you would say, well, they're bipedal, and they're diurnal, they move about during the day, they're gregarious, and they live in these groups, and sorry, I'm slipping into an Attenborough. And they, and they, you know, and they have these sort of dominance, relationships, and they have sex differences in behavior. They, they're, you know, monogamous, more or less, which is, which is actually rare in many animals, and most are not. They they're both in, you know, both parents are involved in parenting. And then there's a whole bunch of other things where you could say, Okay, those are sort of, you know, on the behavioral side, but then on the, there's a bunch of behavioral abilities, or cognitive abilities, which are actually very much linked to what our bodies can do as well. So, you know, the, the evolution of our brains is very much linked to the evolution of our fingers and hands and the the incredible dexterity that we have much more than any other animal, the fact that we can throw that we can run long distance, you know, the all of those are part of our ecology, the niche that we're in, that we that we inhabit, that our cognitive and behavioral traits are adapted to, of course, the difference with human beings, is that we develop this amazing cognitive ability to craft our own environments. You know, through the evolution of culture and language, somehow, we sort of transcended the typical constraints of most species, and that we can craft our environments, much more than any other species can so much that we've shaped the entire world. And so the, there are limits to just a biological description of what human nature is like, because part of that biological description is the capacity for culture and language and cumulative learning, which manifests then obviously, as our as our cultural things, which, which in turn, constrain the behaviors that we have, because we have evolved under the constraints of pro social cooperative behavior. And of course, there's competition within that. But if we hadn't evolved those pro social kind of tendencies, we never would have evolved culture, and civilization, and everything else that goes with it. So there's a yeah, there's a really interesting sort of relationship there between the biological nature that enables the culture that feeds back onto the constraints that, you know, all of us are guided by in our everyday behavior.

Nick Jikomes 1:48:16

Ya know, it's, there's almost an analogy there. With the brain itself, right? You have a lot of these feed forward systems, but then there's these, there's this hierarchy of circuits and networks in the brain with a lot of feedback to each level. Yeah,

Kevin Mitchell 1:48:29

absolutely. And, you know, you can think of our behavior we talked about as decision making. And, you know, the simplest way to think of decision making is, you know, do I want coffee or tea, you should I go left or right, you know, it's just sort of binary things, right. But most of our action is not like that at all, we're in, you know, very complex situations that we have to navigate. So really, it's an optimization problem. And when you're doing an optimization problem, you've got some immediate kind of goals and pressures, and drives and so on. But you may have some longer term goals and drives that these ones might conflict with. So you might be, you know, hungry and want to eat something, but you might also be on a diet. And so because you want to lose weight, so you've got a longer term goal, that under short term goals will then nested within that, right. And so what we think happens is that those goals are kind of a over different timeframes may be mediated by the actions of different parts of the brain, represented by those. So an each part of the brain may be trying to sort of satisfy its constraints at a given moment, but that you can get this top down information where the the bit that has the long term goal of being on a diet, or losing weight is constraining the actions of the bit that controls hunger and eating and appetite behavior and so on. And so that's a simple example. But you can imagine the nested nested nested ones, and how that goes on and it's really, you know, expands of course for him. means the time horizon over which we think is, well, it can be centuries, you know, but in our own lives, it's years or decades for a lot of our decisions, and so we make policy decisions and commitments, that then constrain our behavior on a daily basis. So say we decide to go to college, well, then when you wake up in the morning, on Tuesday morning, you don't have to decide, then what you're going to do that day college is on your go to college. So, yeah, so that that kind of hierarchy of goals over different timeframes, I think, is really important. And like with the perceptual stuff, it illustrates this top down and dodge honestly, active kind of control. That I mean, really, the brain is a part of that control system, to most adaptively meet all of these different goals and drives that we have.

Nick Jikomes 1:50:50

Well, Kevin, I want to thank you for your time. We covered a lot. And I think this is a really fun episode that ties into a lot of other episodes that I've done. This one ties a lot of different things together in a really interesting way. Do you want to take a minute to describe some of the work that you've done books that you've published? And maybe stuff that's upcoming for people? Sure. Yeah.

Kevin Mitchell 1:51:07

So I mean, I have a, you know, published on lots of strangely, lots of different areas over my career from you know, neural development, synesthesia and psychiatric genetics and stuff like that, you know, there's so there's a bunch of academic articles there. The stuff that's more accessible for people would be recent book innate, which is about a lot of the topics that we just discussed, that came out in 2018. I'm working on another one now, which is called agents. And the subtitle is how life evolved the power to choose. So that's really about these questions of, you know, freewill and agency. But But starting very much with a thinking about what what what does it even mean for an organism to call something or do something? How does it How does that even happen and going very much back to the the origin of life to try and understand how it can be that an organism even as simple as a bacterium, can have some causal power in the world be organized in a certain way as a kind of a an instance of this historical trajectory of life. So that should be out next year. And then I also have a blog called the wiring the brain blog, where I discuss and write about a lot of this and I'm on Twitter on admiring the brain.

Nick Jikomes 1:52:20

All right, well, Dr. Kevin Mitchell, thank you for your time. Great. Thanks very much.

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