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Show Notes
This is a ~1 hour conversation with Frank Putnam (https://scholar.google.com/citations?user=KLGgJg4AAAAJ&hl=en) and Alexey Tolchinsky (https://scholar.google.com/citations?user=tiBKmrsAAAAJ&hl=en) about dissociative disorders, clinical psychology, and their applications to the cell biology of regenerative medicine and cancer.
CHAPTERS:
(00:02) Frank's background and research
(07:26) Aging, cancer, and minds
(12:56) Temporal depth and hope
(19:36) Dissociative states and aging
(27:30) Alter abilities and integration
(33:50) Bioelectric integration and conflict
(43:55) Safety, attachment, predictability
(52:17) Stress, plasticity, and aging
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Transcript
This transcript is automatically generated; we strive for accuracy, but errors in wording or speaker identification may occur. Please verify key details when needed.
[00:02] Frank Putnam: Nice to meet you. What a library behind you?
[00:06] Alexey Tolchinsky: Very nice to meet you.
[00:07] Michael Levin: Hey, Alexi, good to see you.
[00:09] Alexey Tolchinsky: Hi, Mike.
[00:10] Frank Putnam: Good to meet you. We were talking about how to carry this on and make connections. Alexey had some ideas.
[00:22] Michael Levin: Please, yeah.
[00:24] Alexey Tolchinsky: Should we say a few words, Frank, about who you are? I'm so grateful that the two of you are talking. You're highly influential in each of your respective fields. You're both poly-scientists. Frank is one of the few renowned psychologists who is brave enough to use nonlinear dynamical systems and computer modeling. You can speak the same language, which I'm very excited about.
[00:52] Frank Putnam: So I'm actually a psychiatrist, but I also had a degree in what would be called neuroscience today. It was more neuroanatomy, neurophysiology, working on invertebrates. I love those creatures. Ended up with cockroaches, which horrifies some people, but they're fantastic critters. There's really a couple of pathways I've been going down, which I see the connections, most people don't. One of them is looking at a particular disorder called dissociative disorders, the multiple personality disorders, but really generalizing that to a set of disorders characterized by rapid transitions in mental state. Bipolar disorder is in there, panic attacks are in there, catatonia is in there, flashbacks are in. There's a whole series of psychiatric disorders in which one of the primary issues is a very rapid transition from one state of mind into another state of mind. I'm interested in what constitutes states, particularly in the process of transitioning from one state to another. I'm interested in the disorder. I'm interested in the larger set of dynamics that are applicable to other disorders and probably represent a place of clinical leverage. If we could control switching, we could switch people out of depression. We could switch people out of mania. We could block panic attacks. We could do a lot of these things much more readily. Based on that work, I transitioned a lot to children. My work with adults told me that they had been this way since children, and that it wasn't possible to retrospectively figure out how they developed into what I would call an us rather than an I, that is the degree of unification in the personality. In that context, I saw a lot of what I felt were biological changes in these children. I created a study that started officially in 1987 and still goes on. It encompassed three generations, looking at the biological effects of very serious child abuse. We chose incest, which hits at the relationship level. Typically, there's a huge number of episodes. It's not simply a molestation by a stranger, but by a family member who's living there. So it's a real hit, and we've been following a sample all these years and looking at them biologically and looking at the HPG axis, HPA axis, looking at cognitive development in the sample, looking at a number of different things. I came to the conclusion that we were looking at an accelerated aging process. With the epigenetic work, looking at epigenetic age acceleration, we really nailed that. Plus now other people, using data we had prospectively and longitudinally, could see that their cognitive development peaked much earlier than our control sample.
[04:09] Frank Putnam: They had lower attainment levels. Their HPA axis went through this transition much faster. Their HPG axis was accelerated. They came into puberty about a year earlier than our matched controls, which is a big thing developmentally. These were a group of incestuously abused girls. We've seen their children and we also followed prospectively their mothers, with retrospective histories on their mothers and prospective follow-up. So we had three generations. I'm also interested in intergenerational transmission of risk. You see that these families have trains of abuse going back generation after generation. That's something I'm trying to take on with computer modeling because you can't do that experiment, if you think about it. We have about 20 things that we can identify as factors for intergenerational transmission. Using agent-based modeling techniques, I'm interested in seeing if I can figure out what the real pivotal issues are and what are essentially the tipping points that lead to transmission across generations, or at least increase risk. It's a crazy problem, but I don't see another way to approach it. In between, I also ran for about 12 years a forensic center that evaluated children. I followed them and their families. The forensic evaluations involved testifying in court and dealing with legal issues. I had a fairly large-scale prevention program in the city of Cincinnati, where I did a maternal intervention aimed at helping the children. So that's a sweep of the different issues. For me, they're all part of the same problem, but people ask, "What do states have to do with prevention of child abuse?" So that's a short story, I guess.
[07:26] Michael Levin: Because you brought it up, I wanted to say one interesting thing that is brand new out of our lab that you may not have seen yet regarding what you said about aging. So it turns out that in normal human patients, if you look at the gene expression in young versus older individuals, one of the things that we find is during aging there is a dissociation of the phylogenetic age of the genes that they are expressing. What I mean by that is younger tissues, all of the different organs are in pretty tight agreement about where on the tree of life most of your genes should be. There's this technique called phylostratigraphy, which tells you for any given gene roughly how old it is across the tree of life. If you look at young tissues, all of the tissues in the body are basically concordant with respect to the age of the genes that they're expressing. During aging, the different organs start to float away from each other. They start to dissociate, and they start to express differently across the tree of life, including some of them traverse the evolutionary history backwards towards more primitive genes. But what you find, which I think is quite interesting with respect to what you study, is the loss of concordance. They are no longer in agreement. There's not just one story about where we are on the tree of life, but there are multiple stories. How much of the aging phenotype is actually a consequence of the fact that you now have different regions in the body that are no longer in agreement about what the age of their gene should be. For years, we've been studying the spatial dissociation of cancer. Cancer in many ways is a disease of spatial dissociation. I call it a somatic dissociative disorder because what happens literally is that cells disconnect from the electrical network that keeps all of the cells focused on building and maintaining specific things. They have this large-scale pattern memory, whether it be a heart or a liver or whatever they're working on. Individual cells disconnect from that, and they can no longer remember that goal. Now they're just amoebas in the environment, and they do what single-celled organisms do. We've developed an integration approach where we don't kill the cells, we don't fix the genetic mutations if they have them. What we do is forcibly reconnect them to the electrical network, and they rejoin and they start doing normal things, behaving normally, and they stop making tumors. Whereas cancer is a dissociation in space, human aging is a dissociation in time, specifically in evolutionary time. I think this is why Alexei brought us together: this issue of dissociation and re-association and switching has profound consequences across scales, not just cognitively, but somatically and biomedically as well.
[10:53] Frank Putnam: That's one of the places I felt there was a connection. They were on very different scales.
[11:02] Michael Levin: Yeah.
[11:03] Frank Putnam: I think the disciplinary versus people.
[11:08] Michael Levin: So overall, that's what I study. I want to understand how very diverse kinds of minds come to be, how they scale up, how parts become integrated — cognitive glue mechanisms: how parts, which might be cells or neurons, form collectives that are dominated by specific thought patterns that make them more than the sum of their parts. We see this. What I like to do is steal tools from the cognitive behavioral science community and the neuroscientists and apply them widely. First, in other kinds of cells that's almost trivial because that is where the mechanisms are all homologous. That is where the brain evolved all of its cool mental tricks, by pivoting them from anatomical spaces that have been navigated since the beginning of multicellularity and even bacterial biofilms. But we also apply them to some other really weird things that are not cells. That's what I'm interested in: learning to detect unfamiliar minds and weird embodiments and trying to understand the scaling process by which they dissociate and associate in the first place.
[12:32] Frank Putnam: I thought your papers were very interesting.
[12:35] Michael Levin: Oh, thank you.
[12:36] Frank Putnam: "The Cognitive Glue" paper. I read that several times. I had a little more trouble with the thoughts and the thinkers, but I really liked "The Cognitive Glue". I thought that was extraordinary. The experiments were just amazing to me.
[12:56] Alexey Tolchinsky: Would it be okay if I try to share a very brief attempt to integrate your work, Michael? So I was thinking, Michael, to start with your hypothesis that if we take development first, development is active. There is a morphogenic goal set up. During development, it's a very active phase. There's a lot of work to do, a lot of construction to make. In that sense, the system is hopeful, optimistic. It's hopeful to reach the goal. You have this measure in your paper with Leo, active information storage, which simply means that during development, there's much data transfer from the past to the present. We use our memories quite a bit, and we use them to move toward the goal in the future. What that means is the temporal depth is significant. Your light cone is present during development. When the goal is accomplished, let's say adulthood or a certain organ is built, then from that point forward, there's not much future. The future is predicted to be the same. There's no need to use the memory systems much. There's no construction going on. So the temporal depth collapses. The temporal light cone is shrinking at that point. Conversely, this could be seen as the onset of aging. The word you used, it's a morphogenic dissociation in that sense, that the temporal depth collapses when the aging starts because the goal is reached. If you do your cure of regenerative work, let's say regeneration of a limb, the new goal shows up. There's again planning for the future, and there's again the use of the past. The system is again hopeful. I want to put the time parameter there explicitly. To go to Frank's work now with complex PTSD. The scale is different. Your work is cells, tissues, organs. Frank's work is the entire person, and perhaps over longer time scales, like several generations. If we take complex PTSD, which is prolonged unbearable stress in circumstances when there's no escape and repeated trauma, then sometimes the person becomes resigned, saying there's nothing to do, which we call helplessness, and nobody's coming in to help. There are no more goals because there's nothing to do; it's helpless. There's also no future. The person is extremely pessimistic, if not depressed and dysphoric. The only prediction is that the pain and suffering will continue, but nothing good is predicted. In that sense, there are no goals in the future. There's just perpetuation of suffering. The extreme form of that is suicidality, saying that the only way to resolve it is destructive. What I'm saying is that state of resignation is also the collapse of the temporal goal. There is no future, and there's no need to use the past. The only prediction is that. There's some similarity in that sense. In therapy, many things happen, and Frank helped us with Bethany Brand's work and Ruth Lenius in finding common ground. One of the small components of therapy at some point in the middle is installation of hope. The hope comes back. There's something to live for, as Nietzsche said. The third perspective is the free energy principle, which I think complements your work nicely because FEP is about maintenance. After you've reached the goal, morphostasis, the maintenance of the shape, is FEP. FEP has optimism bias. The FEP system predicts to remain, and it does certain things to do so. It perceives the world, builds the model of the world, and it acts upon the world to continue persisting. In that sense, it's optimistic. There are forces of nature that are trying to decay the FEP system for different reasons. There's stress on the boundary, on the Markov blanket. Nature wants the system to stop. We need energy to maintain the system. Morphostasis takes energy. As Chris Fields succinctly says, it takes energy to reduce uncertainty. In fact, it takes energy to reduce uncertainty about whether I'll live or I'll die.
[17:16] Frank Putnam: Glare here, I'll just mask out here.
[17:19] Alexey Tolchinsky: Yeah.
[17:20] Frank Putnam: The sun coming in our upper window here.
[17:24] Alexey Tolchinsky: Aging can be seen as a gradual withdrawal of energy from this force of maintenance. Under FEP, we have two forces. The dissipative force, the decay, is called gradient flow, and the one that maintains life is called the solenoidal flow. When aging starts and the energy is gradually decreased from the force that maintains the system structure, it starts decaying. And that can be a description of aging from the FEP standpoint. I don't know if that's how that sounds to both of you.
[18:01] Frank Putnam: As I say, I keep feeling there are places where we crisscross, but it's at such different scales. As when we talked on the phone, I was very interested in this idea of your temporal collapse, and particularly what aspects of dissociation you felt emerged from that process. I had a sense that you felt that temporal collapse brought on dissociation. Is that correct? That the dissociation, as we understand it clinically — out-of-body experiences, the sense of multiple separate selves, and the amnesias — those symptoms emerge out of the temporal collapse?
[18:49] Alexey Tolchinsky: Our hypothesis. But the idea there, Frank, was that the continuation of self in time requires a temporal depth, meaning I am the same as I have been, and I predict to be the same, Alexei, in the future. Now, when that collapses — I live in the here and now of a few seconds or a few minutes — and there's no temporal depth, then there is no continuity of self; it's discontinuous. So the only thing we're saying is that temporal depth is a prerequisite for coherence of the self, and without it it's pretty impossible to maintain the coherence.
[19:36] Frank Putnam: It is really different than what I'm thinking about. One of the striking features of dissociation is amnesia. These are usually autobiographical amnesias, that is, people cannot remember parts of their personal history. They don't feel connected to that flow of history that provides continuity in a sense of self across time. You reach back and feel like you're the same person you were yesterday because you have a continuity of memory, not because your DNA or fingerprints have changed. That ability to reach past memories and to some extent future aspirations is state dependent. In different mental states, a manic person will tell you very different things about their past, future, and present. The same person when depressed has very different associations, even though the history is common across them. One of the things you see in different states is that, in a disorder characterized by many different states, when you're dealing with somebody who has multiple personality, they have half a dozen or more fairly discrete states. They're discrete not only psychologically but actually biologically. That's not surprising given that if you look at somebody who's the same person depressed and the same person manic, they're physiologically different. If you look at the same person having a panic attack versus a euthymic state, they're physiologically different. States have physiological differences. Somebody who is switching states a lot, as these people do, has a lot of discrete physiological differences, but also cognitive differences, particularly in terms of ability to access past knowledge and history. You'll find some who are completely past-focused; they are living in the past. They have a different body image of themselves and they think they're a child or they think they're at a different age. Others think they're at another age. You have this kind of temporal series of compartmentalizations in these people. That shows up as amnesias for past experiences so that they don't remember doing things they were witnessed doing. That is a function of the different dissociative states. We can go in and give cognitive measures and see those differences in the individual in terms of their cognitive attainment — what they can do, what information they can retrieve. We can give one personality a list of words and another personality a list of words that are very similar but different, e.g., sofa and couch or lamp and light, and look at crossover, how much interference there is across. Some of them are very able to keep this information separate, whereas in our control subjects the information gets all confused and they can't pick out which list the word came from. They can't give you words on list A versus list B.
[23:32] Frank Putnam: So there is this state compartmentalization cognitively. There's a physiology that's pretty replicable across different states. We would measure most of our subjects multiple times across multiple days and saw that the different states or personality states were pretty coherent within themselves, but across time, across states, there was a lot of difference. But there were certain places where there were connections. One, at what I'd call the autonomic nervous system level, was things like habituation to startle. If you habituated one personality, that habituation carried across the other personalities if you had two startles. So there was certainly connectivity. They were not entirely separate. There were levels of connectivity, even though their subjective experience is very much as if they were separate people. They're adamant about that. I had this experience of talking to a subject I saw in 1981. He's now about 90 years old and he hunted me down and wanted to talk about the study he was in with me. He was remarkably consistent. I'd seen him 30, 40 years ago. When I met him again, his personalities — Philip, Luther, one called Legion, who's his angry personality — were just the same as they were 40 years ago. He's remarkable because he's still alive at 90. Most of these people don't make it past about 65 or so. I think what we're seeing with this accelerated aging is that they make it to about 60, 65, and then there's just this massive die off. That's because they're developing all these common causes of death, but at much earlier ages. This is one of the consequences of the earlier accelerated aging in them, and you see that in epidemiological studies of people who have these histories: there's a big dropout in the population at around 60–65. Some studies show that these very serious early childhood experiences take about 20 years off your life. So they really are examples of this accelerated aging and its consequences. We're just beginning to tap that, but I'm very excited about these epigenetic tools that are coming out in terms of providing us with biomarkers to look at the effects of trauma. What we see in the very limited data we have is that traumatic experiences happening in childhood seem to be much more associated with subsequent accelerated aging than traumatic experiences that happen in adulthood. In that developmental period that seems to be the case: all the children looked at so far have this epigenetic aging acceleration effect, whereas not all the adults have that. But the adults who have it are more likely to have had trauma in childhood.
[27:30] Michael Levin: Super interesting. I have a question, and then I want to comment on what Alexia had said. My question is this. In these patients, are the different personalities—do they have similar cognitive power? And what I mean by that is, do you get the sense that the sum total of cognitive performance that a given volume of the human brain can put forth: is there an issue about how you support multiple such things on the same hardware? In other words, you would think that, and I know there are other reasons to not think this, but the naive assumption is that there is some degree of cognitive performance that a given volume of substrate can manage, and you're running multiple humans in the same amount. Is that an issue, or do you feel that each one of them is then diminished so that the sum total is basically preserved?
[28:34] Frank Putnam: Really an essential question. What you do see is compartmentalization of certain functions. I've had a number of extraordinary performers come through. In certain personality states, they were capable of really extraordinary cognitive functions. In other personality states, that was not available to them. One of them was a student at Harvard who I had completely independent verification from a professor about her. He came and asked me about her. She was in law school, and she was also getting a degree in philosophy. She could write with both her hands in her legal statement. He said it was driving the other students nuts because she was taking two streams of independent thoughts off lectures. But that was confined to a particular altered state. She also had really remarkable photographic memory. I took it down to the stacks of law, the National Library of Medicine, and I would pull a book off the shelves, open it to a page. She could look at it for a minute and she could read it back verbatim. It was extraordinary. I have certainly seen certain alters having idiot savant level functions that were very narrowly associated with these different states. The same one woman had a child state called Missy. Missy was a little child curled up in a ball and would speak in a tiny whisper and really couldn't participate in many of our studies. It's not as if they all necessarily add up to one single unified sense of self. There are a series of preserved abilities that are very compartmentalized in them. They adapt to the world by developing personalities that handle functions that they can't handle in other states. It gets to be highly refined in some of these people, where there'll be one who puts gas in the car. That's the mechanic. That's all that state comes out for: it's triggered by the need to fill up the car. The capacity is in there somewhere, but it isn't generalizable. It's very compartmentalized. One of the consequences for them behaviorally is they can't learn well from experience, because the experience and the consequences are often quite separate. They end up being very perseverative and making the same mistakes over and over again. They can't use what they know. It's a metacognitive deal for them.
[32:26] Michael Levin: Do the individual personalities ever express a resistance to any integration? Do they have a self-preservation quality where they don't want to disappear into a larger integrated personality?
[32:43] Frank Putnam: That's probably the new norm, that they're interested in preserving the individuality intact. And so clinically, you're not trying to integrate them. You're trying to develop more harmony, more internal communication, and sometimes that needs to pass through some sort of outside process. So I had a technique I called the bulletin board where they left each other notes on the refrigerator, for example. And that's how they began to break down some of those cognitive barriers. And they'll talk about how we meet together in which different ones participate and contribute. And that's where you want to go clinically: increased internal harmony, not so much force them to be one, but they're very afraid that you're going to get rid of the others, which you can't do. But that's their perception that you're going to get rid of some and keep others.
[33:50] Michael Levin: It's interesting: both that and the thing that Alexi was talking about has, potentially, very direct suggestions, I think, for therapeutics both on the cancer side in this case and on the regenerative side for the things that Alexi was talking about. Because the thing about the bulletin board: this is a stigmergy that the cells and patterns in the body use to leave messages for each other. I wonder if the cancer therapeutics that we were using, where we do actually forcibly integrate them, whether that's too much of a sledgehammer and, listening to what you just said, the limitation of that is going to be the resistance. Instead of that, what we should be going for is to augment the stigmergy between them so that they can communicate but reduce the threat that they're going to be wiped out. We, as the clinician, want to wipe it out in that case, but maybe you don't go in there with a therapeutic that is super obvious about it. Maybe we got to do it slightly differently. What Alexi said about the future, hope and the collapse of the future is also very interesting in terms of both aging and regeneration. I think there's a lot to be said for the fact that in some organisms like us, the vast majority of our cells do not believe that they're going to be able to regenerate and thus they don't. I've thought about different ways to affect that prior. One of the things we found that helps is for the leg regeneration work: after amputating the limb, you put on this wearable bioreactor. It's this thing that provides an enclosed aqueous environment for the wound, and then you can put in various payloads like ion channel drugs and things that try to induce specific morphogenetic events. Even an empty biodome helps. An empty biodome that has nothing in it, no payload at all, is already somewhat inductive of regeneration because it provides the cells evidence that they can impact their environment. If you're out in dry air as a mammal or in a giant bucket of water as a frog, you do not have the ability to establish properties of your microenvironment. You have no control over your microenvironment in those scenarios. But if you have a protected aqueous small-volume environment, you can. By putting autocrine signals out there, you can say, I did increase the pH of the medium, or I did increase the amount of sodium or BMP or whatever it's going to be. Even that, by giving them a little bit of control over their microenvironment, helps, because that's a major puzzle: why does the empty biodome work? That shouldn't be. I actually think that's maybe one of the key parts of this: to convince the cells that there actually is a future here, that they're not just waving out in the wind as an animal would be in the wild that gets their leg bitten off. You're going to be trying to step on it, grinding it into the forest floor. You're not going to regenerate anything under those circumstances. It's not safe. It is in fact foolish to put energy into trying because whatever you try to grow is not going to work. That biodome — I've also been thinking about plastogens, psychedelics that try to increase the plasticity of and reduce the certainty of your priors. As a mammalian limb, you have very strong priors that you're never going to be able to regenerate. Your liver doesn't share those priors for some reason, but your limbs do. Deer antlers don't share them either. So bone: there you've got bone, vasculature, innervation, skin. Every year you make a centimeter of new bone per day when they're regenerating these things. It's insane.
[38:01] Frank Putnam: That's an amazing process and the nerve innervation and that is just extraordinary. Well, let me react to that. Because here's where I do see, first of all, where you do see integration is spontaneous. That is, you've broken down the barriers in some way between these different states or personalities. The language there is always a little tricky. And they're better able to share information and particularly retroactive, retrospective memories. And that's where the trauma comes in. Often that trauma is very encapsulated. And so what you often are faced with as a clinician is they come in and they say, Tanya and Tom have joined in their tamia or something like that. Rather than trying to force this, which is what happened in the field very early on, when people were using these hypnotic ceremonies and rituals, trying to fuse these things together, it's more likely to happen spontaneously. Now, that bio compartment that you're talking about, what the patients do is they create that for themselves and that for the different personalities. If you go to their house, you'll see that house is not set up in some continuous linear way for an adult to live. It's set up in little areas and this is Tanya's area and Tom's area and this sort of thing. So it's very compartmentalized. When those states come out, and they often come out in some very regular way in the spontaneous world, we've done things like put beepers on them and beeped them at different times and said what's going on and what personality is out. And we find that they're very different than they are in the office. So what you see in your office is not necessarily what that person is living in the world in terms of the frequency of the altered personalities. But they create different spaces for themselves where they can go off and be by themselves. And that enlarges. And part of that integration process is that Tom and Tanya will merge their spaces, and they feel comfortable that way also. So you see this process going on and to some extent being acted out in their environment.
[40:45] Michael Levin: Amazing. yeah, sorry, please go ahead.
[40:49] Frank Putnam: Sorry, what?
[40:53] Michael Levin: No, please, finish your thought.
[40:54] Frank Putnam: I'm looking at my reflection off the sun; the angle is wiping me out.
[41:03] Michael Levin: It looks like you're about to be kidnapped by aliens. The beam, the beam is coming. It's very interesting about these areas and merging the areas. We see this kind of thing where these dynamic patterns battle for real estate in the body, they compete, sometimes they merge, sometimes they integrate, sometimes they don't, and they set up boundaries between them. If we induce using ion channel expression a specific bioelectric state in a region, and that specific bioelectric state is the thing that generates eye formation, it's what triggers eye formation in our face. You can make ectopic eyes anywhere in the body, but what often happens is there's this battle between the pattern that you've induced that says, to all the cells, even the ones you didn't touch, it's a group effect. So if I manipulate 30 cells, they will get hundreds of their neighbors to help build this eye. But the neighbors are resisting at the same time because there's a different pattern that says, no, we should be gut or we should be skin. Those two patterns have to fight it out. Sometimes they establish a border: I'm going to be this, you're going to be that. They settle down. Sometimes they integrate and they make other things that are neither of those two things, sort of a combination. Sometimes one wins or the other one wins. For example, you often see we have these transgenic animals that light up with the early eye gene, RIX1. We can inject our thing. We see this thing's going to have eight different eyes because there are eight different spots of RIX1 coming on. It comes on and it starts making the eye. Then the other cells around it, as I think it's part of the cancer suppression mechanism, they convince the cells, you don't want to do this. We're going to be skin. This is mediated by electrical synapses, by gap junctions, that enable the local voltage to take over, and they just acquire a skin pattern, and they go away. Or sometimes the eye is strong enough to establish, we're going to be an eye, and here's the limits of it, and you can be skin outside of that. That's it. You can see this, and you can potentiate one way or the other by manipulating the voltage, by manipulating the communication through gap junctions. It's a battle of morphogenetic worldviews about how are we going to go into the future? Are we going to go as an eye or a skin or what are we going to do?
[43:42] Alexey Tolchinsky: I had a reaction, Michael. Go ahead, Frank.
[43:47] Frank Putnam: I thought those eye experiments were extraordinary and that they were functional. It was amazing to me.
[43:55] Michael Levin: Yeah.
[43:58] Alexey Tolchinsky: What you said about the empty container that promotes regeneration, we have a direct analog of that in psychotherapy. In fact, the word "container" is used. If we take the developmental analogy, the three-year-old starts exploring, or even a younger child crawling to different corners, when there's a safe base, mom's lap. When the child doesn't have a safe base, they explore less. So one of the components of therapeutic alliance is to create the safe space to which the patient grows, as opposed to forcing them or telling them, nudging. That is very resonant to what you said. When it's perceived that this space in the relationship, the dyadic space, is safe, the growth starts.
[44:51] Frank Putnam: I would agree with that. Creating a therapeutic space is really a critical piece. Safety is probably the central piece of that. If you can establish they feel safe, then you can deal with a lot of other issues. I think that the thing that I would stress about the trauma here is I'm very much struck by the data that we and others have about attachment and a particular form of attachment called Type D attachment, which is a very disruptive—people call it disorder dissociative attachment—is highly correlated with later developing high levels of dissociation, pathological levels, usually, of dissociation. There are two or three longitudinal studies that have started out classifying infants, and then ended up looking at adults. Those have basically all found that infants and toddlers classified as highly Type D attachment end up as adults with higher levels of dissociation. What we know is that parenting practices are harsh, abusive kinds, and you see some studies, as much as 80% of really maltreated children will have a Type D attachment or attachment disturbance. They're very different, clearly, from the ABC type classifications that came before. So how does that trauma impact these kids? A lot of it has to do with safety and creating a safe sense and internalizing someplace I can go where I feel safe. It also has to do with the fact that the parents aren't teaching the generalization of information across states. Good parenting very much involves helping the child understand that a lot of principles cross when you're in different states. Also having to address the idea that certain states are appropriate in certain situations and not appropriate in others. You have one state in a religious situation and another state when you're in a football stadium. These are different ways of being and different senses of self that go along with it and identification with different sorts of processes, whether it's your religion or your favorite team. When is it appropriate to go this, go that versus what we see is that that's not going on with these kids. They're left on their own to develop. They develop a set of states and nobody's attempting to integrate across those states to say, remember what we learned here, where you can apply that there. This is part of that cause and effect, and there's a tendency, in general, for kids to play a lot with personality. You think about doll play or super figure play or dress up or pretend play; it has a lot to do with identity and personality and role kinds of things. You can be a cowboy or you can be an astronaut or you can be a rock star or whatever, but you develop these sorts of states. I think that's a normal process that gets recruited by these kids under these circumstances to help them cope with this. They don't have stable senses of self that generalize very well.
[48:57] Michael Levin: I think going forward, it would be very helpful to just ideate back and forth later about mapping all of the things you guys know about how to provide that kind of evidence: evidence of being a safe space, evidence that you have control over your environment, and how to remap it into things that we can do for cells. Cell collectives don't have the same level or the same kind of intelligence as these kids do, but I think the basic principles are there. It's the same message that we're trying to get across. It would be interesting. The most obvious thing we've done, which is to put an empty biodome on and say, look, here's your confined environment where you have more control over the chemical milieu and you're protected. Think about what else could happen. What else could we do? For example, here's something we could do. The basic active inference thing, that predictable patterns are less stressful than random patterns, one could imagine within that biodome providing some kind of a predictable stimulus that's completely non-specific. It by itself does nothing for regeneration, but it has the feature that it is predictable and reliable. We found in our recent work that even algae like this. Algae can tell the difference. They get stressed out by unpredictability and they don't like it. They move away. They want a predictable light source, even if it's not any more light than the random one. Maybe even something like that.
[50:37] Frank Putnam: I agree with that. This is for me one of the big issues trying to treat these kids. So many of the kids I see are in residential treatment. You're in this big group space where you've got three shifts of staff and they're reacting to these kids in different ways. The same behavior on the kid can elicit very different responses from the staff. You're creating a very unpredictable environment for these kids, which is very hard for them to make sense of or get better. Much of the work has to do with working with the staff and saying, yes, I know the kid, you've gone over these rules five times with this kid, but I want you to do it again and continually be constant in terms of responses and predictable and be willing to go back over these things. The kids don't have this good cause-and-effect learning because the consequences and behavior are often separated, state-dependent for them. Creating predictability is a major, major deal in treating these kids. That's one of the things — it's easier to do with foster parents or adoptive parents, but even they screw up all the time and just react. I've told you 10 times to do this or whatever. But that's very important in terms of creating safety for these kids. I think that's kind of a biodome in a way. It's a psychodome.
[52:17] Alexey Tolchinsky: To add to what Frank just said, Michael, when Frank mentioned type D attachment, it's called disorganized, meaning the child has no idea what's coming. They cannot rely on a parent's predictable state of behavior. When the parent leaves, they don't know if they need to cry, and that reliably brings the parent down. They don't have a style of how to deal with that separation, which is a huge stress. I wanted to ask you both on a different scale of things: Frank, your paper and your work, Michael, chronic stress early on in childhood — Frank, you wrote that in these DID cases there's hypercortisol initially, but then it balances out to hypocortisol in adulthood. If we look at the period of chronic stress in childhood, there's chronic inflammation, immunosuppression, microglial dystrophy perhaps. Will it bring reduction in plasticity? Because if chronic stress results in reduction in plasticity, this could be a very concrete level for the onset of aging or acceleration of aging.
[53:20] Frank Putnam: The data we have come out of abused kids, of which some subset are fairly dissociative, but it's not exactly specific for dissociation. But we do see this, what we call an attenuation curve, where they start out higher than our controls, and then they, over adolescence, drop down. That is associated with certain biological consequences, one of which is morbid obesity. We see them take off at age 18. They're heavier as a group than 75% of their peers. Their curve was going like this, and our controls are tracking the 50th percentile. It's also showing up in some of the epigenetic stuff. Now I've seen other studies that have to do with cortisol, hypocortisolism, and accelerated aging. So it looks like there is a mechanism there that can be teased out. Certainly, cortisol, we know from a lot of studies, damages the brain. We know that in abused kids we typically see a lot of areas of the brain that, in animal studies, are damaged by hypercortisolemia, are smaller. We have reason to believe that cortisol has those kinds of effects.
[55:04] Michael Levin: Amazing. Super interesting. I've taken a bunch of notes. I learned a lot. This has been great. Thank you. Let me ponder some more. I'll come back with some much more specific questions. But we should really think about this. There's some really good stuff here for aspects of regenerative medicine that are basically stuck. This is the missing piece.
[55:34] Frank Putnam: I've enjoyed it very much. I really liked your papers. It really opened my eyes in a number of areas. I really haven't thought about morphogenesis as being this powerful process in the same way. And you really make a strong argument for it. I thought the experiments were really remarkable. I love the kidney tubules and how they maintain the same diameter down to a single cell.
[56:03] Michael Levin: I think the whole thing now, if I had to define development, I would say it's sense-making. You get some prompts from your genome and that's great, but the fundamental of the process is it's creative sense-making in real time, most of the time it looks like it has the same outcome, but it really doesn't have to. And I think we can learn a lot from the things that you guys are studying.
