My guest today is Dr. Steve Cole PhD, professor of Medicine, Psychiatry and Behavioral Science in the UCLA School of Medicine.
What are signal transduction pathways? It's a way of basically perceiving, at the cellular level, what's going on outside and changing cellular behavior by increasing or decreasing rates of RNA transcription from the DNA genome at specific sites in the genome. A standard signal transduction cascade would have some kind of a receptor on the surface of the cell that detects let's say, a neurotransmitter, or a bacteria or something like that. It relays information from outside the cell, through the cell membrane into the interior of the cell, where it can then kick off a chain reaction of different chemical events, that ultimately leads to turning on or turning off a gene in our DNA genome inside the nucleus of the cell.
We discuss one of Steve’s recent papers, Black mothers in racially segregated neighborhoods embodying structural violence: PTSD and depressive symptoms on the South Side of Chicago. In this study, Steve and his team conceptualize the environment as social phenomena and examine its consequences on the body. They asked themselves: Why do these women have heart attacks more often? Why do they get neurodegenerative diseases more often? Why do they get cancer more often? They found that feeling trapped, significantly predicted increased mental distress in the form of PTSD, depressive symptoms, and glucocorticoid receptor gene regulation that's involved in producing inflammation.
The reason we pay a lot of attention to that is that in addition to healing wounds,
when inflammatory activity is persistent, even at a low level for a long period of time, that kind of molecular scenario acts as a fertilizer for the development of most chronic diseases such as heart disease, neurodegenerative diseases, metastatic cancers, all of the diseases that are the major causes of death in the West.
Moving onto a new subject: cytokines. Initially cytokines were discovered to increase communication between immune cells, to enable them to talk to each other. recently it was learned that brain cells could also hear the signal sent by the cytokines. That opened up this really fascinating area of science, trying to understand how changes in immune biology changed people's neurobiology, and perhaps, as a consequence of that change their psychological experience and their, their behavior in the real world.
One area where this is known to happen, is what we call sickness behaviors. When people get sick, and they feel tired and fatigued and achy, and they have fevers, it turns out, none of that is actually caused by the pathogen. All of that is caused by the cytokines that go to the brain, and they say, ‘Hey, brain, I want you to activate the behavioral package that we call sickness.’
And so the brain, which has essentially learned to do this over millions of years of evolution says, ‘Great, you're sick. So I'm going to stop you from expending a lot of energy by immobilizing you. I'm not going to let you run around, I'm going to make you tired. I especially don't want you to run around infecting other people or getting into fights with other people. So I'm going to make you antisocial and irritable as well.’
In the course of our meeting, we spoke about many other subjects and ended by
talking about the surprising power of pro social behavior for writing many of the wrongs that arise from stress and threat. If I'm anxious, and th
If you liked this podcast
https://www.psychologytoday.com/intl/contributors/thomas-r-verny-md
My guest today is Dr. Steve Cole PhD, professor of Medicine, Psychiatry and Behavioral Science in the UCLA School of Medicine.
What are signal transduction pathways? It's a way of basically perceiving, at the cellular level, what's going on outside and changing cellular behavior by increasing or decreasing rates of RNA transcription from the DNA genome at specific sites in the genome. A standard signal transduction cascade would have some kind of a receptor on the surface of the cell that detects let's say, a neurotransmitter, or a bacteria or something like that. It relays information from outside the cell, through the cell membrane into the interior of the cell, where it can then kick off a chain reaction of different chemical events, that ultimately leads to turning on or turning off a gene in our DNA genome inside the nucleus of the cell.
We discuss one of Steve’s recent papers, Black mothers in racially segregated neighborhoods embodying structural violence: PTSD and depressive symptoms on the South Side of Chicago. In this study, Steve and his team conceptualize the environment as social phenomena and examine its consequences on the body. They asked themselves: Why do these women have heart attacks more often? Why do they get neurodegenerative diseases more often? Why do they get cancer more often? They found that feeling trapped, significantly predicted increased mental distress in the form of PTSD, depressive symptoms, and glucocorticoid receptor gene regulation that's involved in producing inflammation.
The reason we pay a lot of attention to that is that in addition to healing wounds,
when inflammatory activity is persistent, even at a low level for a long period of time, that kind of molecular scenario acts as a fertilizer for the development of most chronic diseases such as heart disease, neurodegenerative diseases, metastatic cancers, all of the diseases that are the major causes of death in the West.
Moving onto a new subject: cytokines. Initially cytokines were discovered to increase communication between immune cells, to enable them to talk to each other. recently it was learned that brain cells could also hear the signal sent by the cytokines. That opened up this really fascinating area of science, trying to understand how changes in immune biology changed people's neurobiology, and perhaps, as a consequence of that change their psychological experience and their, their behavior in the real world.
One area where this is known to happen, is what we call sickness behaviors. When people get sick, and they feel tired and fatigued and achy, and they have fevers, it turns out, none of that is actually caused by the pathogen. All of that is caused by the cytokines that go to the brain, and they say, ‘Hey, brain, I want you to activate the behavioral package that we call sickness.’
And so the brain, which has essentially learned to do this over millions of years of evolution says, ‘Great, you're sick. So I'm going to stop you from expending a lot of energy by immobilizing you. I'm not going to let you run around, I'm going to make you tired. I especially don't want you to run around infecting other people or getting into fights with other people. So I'm going to make you antisocial and irritable as well.’
In the course of our meeting, we spoke about many other subjects and ended by
talking about the surprising power of pro social behavior for writing many of the wrongs that arise from stress and threat. If I'm anxious, and th
If you liked this podcast
https://www.psychologytoday.com/intl/contributors/thomas-r-verny-md
SUMMARY KEYWORDS
people, immune system, transcription factors, stress, cytokines, inflammation, brain, life, sick, biology, signal, glucocorticoid receptor, reward, disease, system, cell, DNA.
0:02
This is Pushing Boundaries, a podcast about pioneering research, breakthrough discoveries and unconventional ideas. I'm your host, Dr. Thomas R. Verny. My guest today is Dr. Steve Cole PhD, professor of Medicine, Psychiatry and Behavioral Science in the UCLA School of Medicine.
0:36
Dr. Cole is also a member of the Jonsson Comprehensive Cancer Center, the Norman Cousins Center, the UCLA AIDS Institute, and the UCLA Molecular Biology Institute. He is a Fellow of the American Association for the Advancement of Science and the Academy of Behavioral Medicine Research. Dr. Cole serves as Director of the UCLA Social Genomics Core Laboratory, and provides consulting support on social regulation of gene expression to the Institute of Medicine, the National Cancer Institute, the National Institute on Aging, the Santa Fe Institute for Complex Systems, and the MacArthur Foundation, among others.
1:40
Welcome, Steve.
1:43
Thank you.
So there are a few things in your research, certain verbiage that may require a little bit of clarification. I understand that your research has pioneered the use of functional genomics in social and behavioral research. So could you just briefly tell us what is meant by functional genomics?
Yeah, sure. So this field really which, you know, we generally call now social genomics is an effort to take tools that were developed for basic research on the human genome and apply them into everyday human life. In other words, getting human biology out of the laboratory, where we analyze it in experimental forms, and just looking at the human genome, as it operates and real living breathing human beings in the world. And when we say functional genomics, what we're really doing is we're distinguishing what we're doing from the more traditional field of structural genomics. Structural genomics is really about DNA sequences, which remain stable from birth, basically, right. Whereas functional genomics is really how that structural DNA actually realizes human life, which is basically by guiding the production of proteins via RNA as an intermediate. And unlike the human genome, at the DNA level, the functional genome that is the effectively active portion of the genome is really, usually quite a bit less in any given cell than the total genomic menu that exists. So what we're really trying to answer is like, for any given individual, which genes are being expressed at high levels, there's lots of RNA and lots of protein being productive, produced as a response to that, versus which genes are, are active at low levels, or completely inactive. And especially why those patterns might differ across people based on the differences in the lives that they lead and the circumstances that they inhabit their perceptions and experiences of those circumstances, the social community around them, their personal life history, as well as their genetic characteristics in the more traditional deep GNA DNA polymorphism sense. So we're really trying to take RNA as sort of a final common pathway for understanding how our bodies arise from this sort of array of different influences that can potentially influence who we are.
Right. Okay, so essentially, we are talking epigenetics. Yeah, broadly speaking, yeah. We get cranky about this, because epigenetics really is a portion of this. But as the general public has come to know the term, they have taken it in a much more expansive way than we actually in molecular biology, would you use the term so I'm going to work with your version and you can call it epigenetics, which is basically stuff that happens around the genome to make us right, we are at any moment in time, right? Because that means it's constantly right. So you can think of actually technically speaking epigenetics as the general public understands that is what we mean in in molecular science by functional genomics. Wonderful, good so far.
5:00
so clear. So you have mapped the signal transit transduction pathways. So what is meant by that? What is signal transduction pathways?
Well, originally for cell biologists a signal transduction pathway was sort of a sequence a cascading sequence a chain of events that would lead a stimulus outside a cell, like let's say a chemical or a microbe or something like that, to change the molecular biology inside the cell. So as a kind of a standard signal transduction cascade would have some kind of a receptor on the surface of the cell that detects let's say, a neurotransmitter, or a bacteria or something like that. And then it as it's sitting in the cell membrane, it relays information from outside the cell, through the cell membrane into the interior of the cell, where it can then kick off a chain reaction of different chemical events, that ultimately leads to turning on or turning off a gene in our DNA genome inside the nucleus of the cell. So it's a way of basically perceiving if you will, at the cellular level, what's going on outside and changing cellular behavior by increasing or decreasing rates of RNA transcription from the DNA genome at specific sites in the genome. So what we did to generalize this is we sort of said, well, if we want to understand human beings and how they're living, what we need to do is stretch that, that concept a little bit farther
6:40
up into the world and talk about how the signals that impinge on these receptors are in turn, structured by the lives that we live by the places we are by the perceptions and experiences we have by the life histories we've experienced. So in social signal transduction, what we're really trying to do is figure out how information flows from the world around us, typically, through our senses, and through our interpretive brains and into our nervous systems, or our endocrine systems, the hormones that circulate in our blood, which then become kind of biochemical representations of our experience of life. And those biochemical representations then interact with these receptors on the surface of the cell to kick off these gene regulation pathways within the cell. So it's really an attempt to take a classical cell biology term, and hook it up to the bigger world of human experience that we know is important for health outcomes and an effort to figure out what role the genome plays in connecting life as we experience it to health or disease. So
7:46
correct me if I'm wrong. But so when you speak of transcription factors, are you talking about the methyl and acetyl groups? Not exactly but close. So what transcription factors are, and thanks for giving me an opportunity to explain it. Transcription factors are actually protein switches, or you can think of them basically as like flags that get activated by these receptors in these biochemical signaling cascades within a cell. And then they go into the nucleus of the cell where the DNA is, and they bind on to the DNA at specific DNA sequences that are scattered throughout the genome, and shaped by evolution. In other words, when evolution wants to build some kind of a stimulus response coupling, and, of course, evolution is a selective force. So it's not designing anything. But basically, as random configurations of stimulus response couplings are created. Some of them work really well, others don't work so well. And the ones that work really well have children basically and base, those end up propagating and shaping this wiring diagram that connects what's going on outside the cell and those receptors to the proximal determinants of RNA transcription.
The dominant switch that turns RNA transcription on or off, are these transcription factors, these proteins that get activated by the receptors, and then land on the DNA. And they flag this particular site of DNA for copying by a big generic RNA copying factory called RNA polymerase, which is floating around and it will basically make an RNA copy of any stretch of DNA genome, as long as two conditions hold one there's a transcription factor there, licensing the the, you know, sort of production of RNA transcripts from this locus into the DNA has to be open to binding of that transcription factor. So in many cases, it turns out our DNA is coiled up into these basically these big time tangled knots, which we call condensed chromatin, these big tangled knots, you can't actually get the transcription factors switch into that tangled knot to land on the DNA.
So the first thing you need to do is in a particular region of the genome, you need to untangle that knot so that the DNA is stretched out in a nice line, that the transcription factors can then land on one of the biochemical factors that determines whether the DNA is stretched out nice and open, in which case the transcription factors can interact with it is the methylation of the DNA, which in turn, allows the DNA to either be be open to this kind of signaling or tangled up and closed. So you can think of it as a second layer of switch that opens up the possibility of gene transcription. And the transcription factor itself is actually the affirmative signal that says yes, do it make a copy of this?
10:59
Not easy.
11:01
yes, a lot of complicated words, but visually, it's very appealing, right? I mean, signal at the surface of the cell transcription factor comes down to the DNA lands on the DNA and you know, copies get made, right.
11:20
Yeah. Well, let's have a look at some of your papers. Because how many papers have you actually written or co- written? Oh, a lot?
You know, I haven't checked this year, but as of last year, it was at least a couple 100. Yeah, at least Yes.
Here is one that really appealed to me. This is a recent one. And it's called black mothers in racially segregated neighborhoods, embodying structural violence, PTSD and depressive symptoms on the south side of Chicago. Do you remember that paper? Yep, absolutely. Okay. So, in it, you write
12:07
the regression models revealed that feeling trapped, significantly predicted increased mental distress in the form of PTSD, depressive symptoms, and glucocorticoid receptor gene regulation? Can you tell us a little bit about that? What is meant by glucocorticoid receptor gene regulation? And how is that important? Yeah, why would we care about that at all. So the glucocorticoid receptor, it turns out, is one of the key regulatory switches in one part of the human immune system that's involved in producing inflammation. So inflammation is a great thing, when you're wounded, because that actually helps catalyze the elimination of bacteria from the wound and the reconstruction of the wounded tissues.
But inflammation can get out of control. And when it does, it causes sepsis and you can die of excessive inflammation within your body, right. So our bodies need some kind of internal brake on inflammation. And the glucocorticoid receptor is the strongest single anti inflammatory signal that travels systemically through our blood, it's a very potent endogenous break on inflammation. So usually, what happens when our bodies are working right is we stage an inflammatory response to a wound and then when it gets bigger and bigger and bigger, the glucocorticoid hormones, which in humans are cortisol predominantly, interacts with the glucocorticoid receptor to basically stomped down the production of further inflammatory molecules.
13:51
So the reason we pay a lot of attention to that is that in addition to healing wounds, when, when inflammatory activity is persistent, and continues, at an even at a low level for a long period of time, that kind of molecular sort of scenario acts as a fertilizer for the development of most chronic diseases, heart disease, neurodegenerative diseases, metastatic cancers, all of the diseases that are the major causes of death and sort of clean, you know, Western Development kind of contexts, what we call modern mortality to distinguish it from infectious disease mortality, which is kind of historically how, how humans had died. And lifespans were limited, but now it's really things like heart attacks and cancers that are the big drivers of death. We know it turns out that inflammation is kind of a generic fertilizer for the production of those diseases. So if, let's say we're in a scenario where we're asking why are these women living in the South
15:00
Black women in Chicago, why are they getting sick and dying? Sooner than everybody else? Why do they have heart attacks more often? Why do they get neurodegenerative diseases more often? Why do they get cancer more often? So one question we might have is, well, let's go to the biology of these diseases and ask whether it's operating differently in their bodies, right? So that's what we were doing in this paper is looking at the expression of this one particular gene product called the glucocorticoid receptor, that should be in the business of shutting down inflammation. But if it gets out of that business, which is what seems to be happening in this scenario, then those inflammatory processes, you know, accelerate the production of disease. So then the next question is like, why did the glucocorticoid receptor go out of, you know, out of task? Why did it stop doing its anti inflammatory activity. And that comes, in part from the fact that we know that so called glucocorticoid, hormones, things like cortisol aren't there just to inhibit inflammation, they also carry out a wide variety of other tasks in the body, effectively as stress hormone. So when people get stressed, these hormones get produced, and they exert a wide variety of effects on our metabolism on, you know, sort of our growth on reproductive biology, all kinds of things that that are regulated by the stress hormones, but they also have these impacts on the immune system. So it seems to be the case that what's happening is living in these chronically stressful environments where there's violence around all the time, you really can't take things for granted, you never know what bad thing is going to happen later today, or two people that you care about. This constant exposure to chaos and threat and uncertainty runs this stress hormone system more or less constantly. And what happens is, a lot of physiological systems stopped listening to that stress hormone, like the immune system, because it's just it's, it's basically it's not saying you're crying wolf, so to speak, but it gets desensitized when this stress biology is constantly signaling through the glucocorticoid receptor. So at some point, the immune system just stops listening to that it sort of lightens up, it becomes partially deaf to this kind of anti inflammatory signal, because that signal was going all the time in response to this chronic stress. So that seemed to be what happened in this this particular study. So does that mean just following up what you just said, that you have an inhibition of the immune system?
17:44
Well, in its in an odd sense, you have the reverse of that actually a dis inhibition of one part of the immune system, but it's the part that actually contributes positively to the production of disease. So remember, these inflammatory molecules are coming from immune cells. But what should happen is the immune cells should, you know, find a damaged piece of tissue produce a short term spiky inflammatory response, and then it should shut it down. Because that inflammation, right otherwise will promote, you know, essentially diseased tissue. And what's happening here is the immune system isn't getting the shutdown signal. And so it keeps making these inflammatory molecules that fertilize the development of those diseases. Oh, I see. So, I mean, we all know that when we are stressed, we are more likely to develop colds and flus and all kinds of diseases. So why would that be? Well, that's probably due in large part to a variety of other effects that these glucocorticoid hormones have. So remember, that, you know, when we're stressed, is for most people sort of a transient experience. So as long as your life style is broadly, not constantly stressed, then when you are stressed, your physiological system will hear that signal and respond to it. And in this case, when when you are occasionally stressed, one of the things that will happen is we will inhibit both the inflammatory system, but also, for instance, the anti viral system. So the classic story is, you know, students at school who work really hard all all semester long, and then at the very end, they're studying and don't get enough sleep and really stressed out, and then they go on their spring break or whatever, and suddenly they get sick, and they're like, no, why did I have to get sick during my vacation? And the answer was, you know, you probably have been sick for weeks and just didn't know it because your immune system was so kind of tamped it down by this transient stress. But now that the stress is gone, your immune system wakes back up and starts to battle this viral infection and produces all these symptoms that you experienced as being sick. So that's
20:00
That's what happens when that stress system actually works is it will peer, you know, periodically suppress the immune system. And then when your stress releases, it will release the immune system and things will kind of bounce back. What happens in people exposed to constant stress, though, is again, the immune system just stops listening to that stress biology. And it basically comes along at a relatively high level of activity, which is great at protecting you against viral infections. But it's bad in the sense that it allows this inflammation to go on catalyzing the development of disease.
20:35
Thank you. Thank you. Okay, so looking at another, another one of your papers, the role of inflammation in acute psychosocial stress induced modulation of reward processing in healthy female adults. And so you write about Anhedonia in that paper,
20:56
or loss of interest and pleasure. And you say, it is a pernicious symptom of depression that involves deficits in reward processing, stressing us inflammation is a plausible bio psychosocial mechanism of reward deficits, but little is known whether stress induced inflammation alters reward behavior. So I guess you have looked looked into behavior? Yep. Quite a lot. So what did you find? Well, so you know, in the first maybe decade or two, Mind Body biology and sort of, you know, kind of interface between the brain and the immune system, we really thought about it in terms of what we were just discussing, the brain experiencing stress causes some change in the immune system. And that as a consequence, you know, produces disease or stuff like that. But a few years into this, this scientific enterprise, we began to realize that it wasn't just a one way street, and and that, in fact, the immune system can also talk back to the brain. And the way that happens is the immune system produces these soluble signaling molecules that allow one immune cell to essentially communicate with another immune cell, these circulating
22:17
proteins often are called cytokines because they float around in the blood.
22:22
And they're signals that move from one cell to another Saito, meaning cell. So although we initially discovered cytokines as signals that allow one immune cell to talk to another immune cell, after a while, we discovered that brain cells could also hear the signal sent by the cytokines Oh, and so that opened up this really fascinating area of science, trying to understand how changes in immune biology changed people's neurobiology, and perhaps, as a consequence of that change their psychological experience and their, their behavior in the real world. So one area where this is known to happen, I think the classic example of this is what we call sickness behaviors. When
23:07
people get sick, and they feel tired and fatigued and achy, and they have fevers, it turns out, none of that is actually caused by the pathogen. All of that is caused by the cytokines that get produced in our body as our immune system is responding to these pathogens. But the cytokines go to the brain, and they say, Hey, brain, I want you to activate the behavioral package that we call sickness. And so the brain, which has kind of essentially learned to do this over millions of years of evolution says, Great, you're sick. So I'm going to stop you from expending a lot of energy by immobilizing, you so I'm not going to, I'm not going to let you run around, I'm going to make you tired. I especially don't want you to run around infecting other people or getting into fights with other people. So I'm going to make you antisocial and irritable as well. And
24:03
another way to keep you from interacting with lots of other people or running around, is to shut down the part of your brain that is excited by new stuff. Because if we're not excited by new stuff, then we're just going to kind of sit in our house. So the reward system is the part of your brain that governs being excited by new stuff. The reward system basically is what gets you, you know, sort of all motivated to go out and make the world a better place or earn some money or get some tasty food or something like that. These are all experiences that healthy people have with relatively high intensity, but when we get sick, this kind of stuff shuts down. And this is all part of this package that evolved to immobilize sick individuals so that they wouldn't waste a lot of energy running around to the world. They would conserve their energy for immune responses. And they wouldn't run around in the world and get in front of a predator. They would basically stay inside their cave and you
25:00
To sort of reduce the risk profile in their life. So this signal that started off in the immune system goes to the brain, and changes these kinds of what we call reward processes, which, you know, I'm not going to bother you guys with the kind of the neurobiological details, but just suffice it to say, when we feel sick, that's actually what's happening is our immune system is sort of paying our brain to be sick to feel sick. And as a result, you know, not only when we're acutely ill like with a cold or a flu, but even if we have like a chronic low grade, you know, sort of immune activation from an autoimmune disease or something like that, that can create a persistent sense of fatigue, and malaise and sort of lack of reward in life. And that's what they mean by Anhedonia. Anhedonia is a term that describes the lack of pleasure, not necessarily the presence of pain, but the lack of pleasure. And so we now in neuroscience think that in many cases of anhedonia, are actually related to the immune system, telling the brain not to feel pleasure, for some aberrant reason the immune system is kind of locked on in a way that it shouldn't be. And it's producing this constant loss of pleasure in life that we call Anhedonia. Sometimes try to treatise depression. So when you speak of,
26:35
of the site of cytokines site, yep, right, okay. Cytokines speaking to neurons in the brain, it's specifically only the reward system, the neurons in the reward system, or are there other neurons involved. Also, there are other neurons involved also. But interestingly, it's closer to only only, you know, a few than to the whole brain. So most of our brains still works perfectly fine. When we're sick. We can do math, when we're sick, we don't want to do math, when we're sick, we feel cranky, and irritable and tired and want to sleep. But we can do it. So the neurotransmitter systems that structure, thought and logic and information processing and all that kind of stuff, they still work just fine. But there are sort of a select few types of neurotransmitter systems or brain structures that are most sensitive to these effects. So the reward system is one of them. Another one that gets deactivated, is kind of a learning and memory system, pretty heavily associated with the hippocampus. So we're terrible at learning stuff when we're sick. And if we learn it, when we're sick, we often can't remember it when we're well. So there are a few specific types of neurons in the brain, another set of neurons in the brain that's sensitive to the cytokines are the ones that govern the temperature of our body. So that's when we get a fever is actually when your brain turns up the basal, you know, sort of temperature production machinery in your body,
28:09
you know, ostensibly to help kill microbes, but that creates this this kind of, you know,
28:15
fever state that many of us find so unpleasant when sick. So is it the, I mean, I would imagine that cytokines are around all the time, but I guess it would be their concentration that makes the difference, right? Exactly. There's a very, very low level of cytokine production most of the time, and it's usually produced, you know, someplace in our body. And so by the time it's diluted into blood, and circulates up to our brain, there's very, very low concentrations of these. But when we get sick, that concentration can go up by 100 to 10,000 fold. So the immune system is really quite remarkable. And it's sort of dynamic range. And that's important because, you know, the immune system is great for dealing with injury and, and infection. But it really hobbles us behaviorally, so we wouldn't be able to get much done in life if our immune system was running at full pitch all the time. So that's that's exactly right. The immune system is kind of locked down under normal, healthy circumstances. And then it's basically released or triggered by microbes when you know we get sick. You have you have few papers, also unstressed during pregnancy.
29:30
And so I was wondering whether stress during pregnancy would also affect the reward center
29:40
in the baby and the unborn child's brain as it is developing. Great question.
29:47
We don't know very well about humans because we can't really run this experiment. The same way I'm about to describe to you but certainly, in in rats, if we
30:00
Make animals sick while they're pregnant, their offspring show usually subtle, you know, they're not dramatic differences in behavior, but subtle differences in behavior. But what's interesting is that those subtle differences in behavior under normal circumstances can turn into big differences in behavior when the animals are stressed or challenged themselves. So what seems to happen is inflammation during pregnancy, essentially conditions, the brain development processes that are taking place in utero, to sort of sensitize the young developing child in utero to stress in the future. So this is actually one of the the long standing theories for major mental disease things like schizophrenia and depression, is that you know, there's a there's a kind of an interesting epidemiological correlation between the year the time of the year when a baby is conceived and carried, determined born. And the incidence of these diseases, which may well have to do with higher rates of acute infectious diseases, like colds and flus and other things like that taking place. And the babies that are in utero during that period, do seem to be a little bit more sensitive to then insults that come later on in their own lives, they're less resilient to the impact of those. So based on that, what, what advice would you give to people about when should they get pregnant, when should a woman get pregnant? You know, now, it's not a bad idea to you know, do it in the the sort of this spring to fall range, right, that's the lowest kind of, you know, environmental disease burden in general. But there's, you know, there's always exceptions to this in the southern hemisphere, I might give you, you know, different advice in terms of time. And then there's some areas of the world where, you know, we normally think of infectious diseases as respiratory infections, classic example being, you know, SARS, to which we just, you know, dealt with in the pandemic, but in many parts of the world around the equator, actually, these kinds of respiratory infections are relatively minor contributions to the overall infectious disease burden, which is much more carried by insects or in water or things like that. Right. So in those domains, you know, they, it probably the time of the year probably doesn't make as much difference as some of these other things. So if you're, you know, mosquitoes tend to be most prevalent, for example, during the summer months. So, you know, in that scenario, you might actually potentially want to avoid the summer mosquito season. If that's a bigger concern. Right. Well, that's very helpful. We'll jump we'll jump to optimism. You have one paper from 2018, which is called optimism and the conserved transcriptional response to adversity. And you talked about this positional optimism. Frankly, I've never heard that term before. What is what what is this bus is this positional optimism?
33:15
I think in general, psychologists use that term to describe a stable and general optimistic stance. And the reason they use that term is to distinguish it from what you might call a selective optimism. So many of the the people who studied optimism, you know, some of them, you know, they recognize that some people are optimistic about everything all the time, basically, crazy optimists, I guess you could kind of think of it whereas other people are optimistic about certain things that they control and not optimistic or maybe even pessimistic about other things, right. So, in this particular scenario, we were using one of the measures,
34:01
which the psychologist had developed to measure this generalized optimum, optimistic disposition, this stable belief about the world generally that you know, good stuff is probably going to happen basically. So, the way they measure that is like I expect good things to happen. I think everything will be all right, that kind of stuff. So people that have that experience of the world as likely to be okay. tend not to be as threatened by life in general and by any particular bad thing that might happen, because they believe it will get better and that other things will compensate or something like that. So the, the kind of the sunny disposition optimists
34:45
tend not to feel as threatened and insecure and overwhelmed, as many of the rest of us do. And that experience of feeling threatened and insecure and overwhelmed doesn't just stay in our head. It
35:00
sends neural signals into our body and basically prepares us for fight and flight and, you know, damage in the context of the immune system. So fight or flight stress physiology, which gets kicked off by this perception of threat or insecurity has, you know, very significant biochemical effects on the immune cells sort of, you can think of it as is thermostatic setting of how much inflammatory molecules it will make. So, one of the things that leads to elevated inflammatory biology as a kind of a background lifestyle life circumstance is high levels and frequent activity of fight or flight stress responses. So, in this particular study, we were speculating that if the, the dispositional, optimists don't feel that sense of threat on a regular basis, they should, in theory have lower levels of inflammatory biology and lower levels of expression of inflammatory genes, right. And that's, in fact, exactly what we found. That's what the conserved transcriptional response to adversity is, is like a long winded clunky term for a signature molecular change that happens when people are confronted by threat or adversity, which involves more inflammation and complementary reduction in antiviral biology. So that's what we saw happening at lower pitch in optimists or at a higher pitch in pessimists.
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So, I guess here is a difficult question. Which comes first, is a person optimistic sort of from boosts on? Or is he optimistic? Because he has got a lower level of the cytokines? Great question. Probably, this is the proverbial snake eating its own tail where both are happening. In other words, you can have more, let's say dispositional, optimism from birth or a more stable, predictable life circumstances early in life, which also leads to this belief that good stuff will generally happen, people care about me, they'll take care of me if I need it, you know, that kind of thing. And that just as you know, would generally predispose lower levels of inflammatory biology. And then you have lower levels of the cytokines going to the brain, right, creating a cranky, pessimistic, you know, threat, hyper vigilant brain that then picks up on ambiguous signals, thinks of them as you know, worrisome anxiety provoking problems in life and perpetuates this fight or flight cycle, basically. Yeah, one of the things that's interesting about that is that allows us to think in different ways about intervening. So you know, you could be there's lots of people now that are thinking about, Hey, can I change people's psychology by giving them anti inflammatory medications? And then other people thinking about? Can I change inflammation related diseases that are chronic, like, let's say, autoimmune diseases by helping people with stress reduction and reframing their life and kind of D catastrophizing, their experience of heavy pay existence?
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Yeah. Well, there's so many other things we would love to talk about. You wrote one paper on the gut microbiome, and how that is influenced? I think that was yeah, that was an optimism too, I think.
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But, you know, I talking about social relations. I read another paper, not by you some time ago, which showed that people who have lots of social relations, particularly particularly older people, have a much more diverse gut microbiome than people who are more sort of
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withdrawn and secluded. Do you agree with that? Yeah, I do agree with that. I think that's likely I mean, I don't have less you pointed out, I don't have the literal data to say, this is the truth based on our own research. But it's quite plausible for two reasons, actually, that we know to be true about the gut microbiome. The first reason is that the more social contact you have, what we do know from the world of research that I do and RNA is that that leads to a more sort of stabilized balanced and well behaved immune system, which tends to produce more diverse kinds of gut microbiomes. Because, essentially, because guess the best way to put it is
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diversity, diversified portfolios of biology are stable, in the same way as diversified financial portfolios are, they're they're less sort of prone to catastrophic failure if one thing goes wrong. In general, in microbial life, you know, diversity is a good thing and getting too much of any one thing, generally, you know, sort of risks for disease. So that's part of it is like social contact and social support and a good sense of communal, social
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existence tends to produce healthier immune system function, and therefore, they've more diverse gut microbiomes. The other thing that's interesting, though, is that one of the most important influences of my gut microbiome is who I spend time with, especially who I spend time in close proximity to sharing food, kissing people, all that kind of stuff. Yeah. So the more people and but also even, you know, just inhaling their exhalation, you know, as we again, were reminded by by COVID, you know, microbes floating around in the air is so people that spend more time with a larger number of other people tend to have more, you can think of them as minor inoculations of these diverse types of microbes that live within all of us. So they're, in some sense, you know, sort of sharing and stabilizing one another through this process. So both through social microbiome mix, we could call it as well as through this, this more socially stabilized immune biology, both of those would tend to promote exactly the connection you described there. And you just mentioned COVID. And we all know that during COVID, there was more isolated behavior, right? A lot of people just stayed in their own apartments didn't even go out. I know some people who, you know, didn't leave their apartment for weeks on end. So then that would then necessarily decrease the diversity of their gut microbiome, which then would affect their brain, and would probably lead to more depression and anxiety. Very possible. Yes. I mean, it's certainly plausible. We have not directly studied that. So I can't say 100%. That's for sure. We confirmed it. But yes, that's exactly the concern that many of us in this line of work had when they said, Oh, yeah, everybody needs to lock down, we're like, wait a minute, that's, you know, robbing the body of some of its most crucial resources for health. So you know, at the very least, we need to balance the costs and benefits of, you know, seclusion and hiding out. And then there's this big question of, you know, if this isn't going to be sustainable for the indefinite future, are we actually undermining are normally well equipped, well equipped, well equip related, now skipping on this word? Well, they
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are normally stable immune responses, by, you know, sort of doing this unusual social, you know, maneuver on ourselves, are we possibly worse off that way? In the long run, even if we're, you know, sort of delaying our encounter with this particular pathogen? So, definitely COVID reminded us that, you know, nothing comes for free in biology. And, you know, even the simplest reactions often have these kinds of hidden costs that we don't realize until later. So
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what is it? No, at this time, in your life, at this moment?
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That really turns you on? What is it that you feel very strongly about?
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Well, scientifically, I think the thing that we're most excited about is the surprising power of pro social behavior for writing many of the wrongs that arise from stress and threat. So the natural reaction that I think most of us have just as as empathic human beings, and certainly as as clinicians, to people who are suffering is to try and reduce that suffering. So if I'm anxious, and threatened and pessimistic, you know, you might say to me, Hey, Steve, you know, cheer up, everything is going to be better, it's not that bad, so on so forth, we know though, that's a hard thing to persuade people of. And it often doesn't lead to very durable changes in my experience. And as a consequence, it may not end up changing my biology very much. One of the things we've been surprised by is, how powerful it is for my physiological health, if I start trying to help other people. So it turns out that this, these actually, these two brain systems that we've discussed, in the context of this conversation is one brain system that is involved in stress and threat detection and fight or flight stress responses. This system is the one that's driving a lot of this sort of chronic dysregulation of the immune system that leads to more inflammation, less protection against viral infections, greater risk of chronic diseases, that kind of stuff. Yes. Just trying to reduce the amount of stress in my life usually doesn't have a big, big effect on those things. It has small detectable effects. But what actually does have the biggest effects we've discovered is if I go trying to make the world a better place somehow, because what that does is it activates that reward system that we talked about earlier. That reward system is intensely curious about other
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people excited about helping other people excited about discovering things, making the world a better place creating things. So the activation of the reward system, it turns out in the brain exerts a very powerful lateral veto over the activity of the threat system that runs these fight or flight stress responses. So we've now started to wonder, you know, whether we can, in addition to reducing stress, how can we promote pro social helping behavior? How can we promote engagement with things that are important and meaningful in life? How can we promote the activity of this reward system in ways that would help us suppress the threat system and reduce the immune dysregulation that results from this kind of constant low grade drizzle of stress, threatened uncertainty that we feel in modern life?
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That is amazing. That is so interesting, really, what we thought, yeah, we're not not anything we ever, you know, could have planned ahead of time, but we bumped into it very much by accident. And now we think of it as like a little recipe, what are the various ways that we can implement this recipe. So you know, as one example, you started off talking about these, these sort of, you know, women living on the south side of Chicago, and this chronically stressed, threatening environment. So
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one of the most interesting projects we have involves is sort of an analogue of that here in Los Angeles, where we have women living in South Central LA, again, a relatively economically deprived area, higher crime, not as crazy high as in Chicago, but still pretty, pretty, pretty, you know, sort of challenging environment. And in this project, what we do is we get these older women who generally stay in the house, most of the day, they, you know, whatever, watch TV, do all that kind of thing. And we get them out of their house for a few hours a day to come into the local school systems to serve as teachers aides, to help kids kind of make their way through the grade school curriculum. And usually, it's only a couple kids per class that really need a lot of extra attention. So having the so called grandmas in helps the teacher you know, sort of move the class along and deal with disruptions and stuff like that. But when you look at the biology of the grandmas who are helping out as teachers aides, they look great, they're antiviral biology is way way up, their inflammatory biology is clicked down. It's because they are engaged in one of the most rewarding pro social activities that exists, which is helping younger people grow and thrive and you know, sort of mature This isn't it's something that is just deeply programmed into all human beings. And when people do this, even though it takes effort, they got to get out of their house, they put on their clothes, no more judge duty right now I gotta go, you know, sort of go to school and help these kids out. But it's tremendously rewarding. People know, they're making a difference. And that feels good in the brain that drives that reward system that we talked about earlier. So this, this project, is a great example of how you can take people, even people living in highly adverse, you know, environments, and still have them connect with others in some kind of pro social way, and as a consequence, improve their physiological well being.
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Do you have a paper on that? Or are you weird? Yeah, yeah, there's a paper on this, written with my collaborator, collaborator, Teressa, Seaman S E M, a n. And let me see if I can find the title of this thing. But
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it
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it is called
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intergenerational mentoring eudaimonic well being and gene regulation in older adults, a pilot study. So eudaimonic well being is the type of well being that comes from basically striving after something that you value. It's the type of well being that comes from essentially from leading a life of virtue, identifying something that's important and good and working to make that happen. As opposed to the version of
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well being that we call hedonic well being which is the kind of happiness that comes from consuming stuff, you know, sort of tasting food, beautiful shots, that kind of thing. So philosophers have distinguished between eudaimonic well being and he Donek well being for you know, 1000s of years. behavioral scientists have now begun to be really interested in it in part because it turns out there's different happiness circuits in our brain. The eudaimonic well being circuit is the reward processing system that we were talking about earlier, which is actually it turns out run on a different set of neurotransmitters and involves different brain structure.
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And then does the hedonic well being machinery, which is more, you know, sort of
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characterized by being satisfied that you've got something that you want. So, self gratifying things, things that just make me feel good directly, typically are described as he donec, whereas self transcendent things where I'm trying to make others feel good, basically, or make the world a better place is what's more activating this reward system. And that's what gets shut down when we're sick. Actually.
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Wonderful. Oh, that is so amazing. Really. I'm very, very, very impressed by this week, really? And it's, I find it fascinating. You must find it interesting, too, I would imagine. Yeah, you know, I do as a matter of fact, it's a, you know, like any profession, it you know, the daily experience can be, you know, sort of a little bit of a grind and overwhelming and that kind of thing. But it is nice to be able to, especially in conversations like this kind of reflect on Yeah, not only kind of what what we're doing and what we're discovering, but especially when there's a non obvious new Urich like this, like, hey, maybe in addition to try to make the bad stuff go away, you can make the good stuff come back. And that might also have the same kind of effect both of those at the same time better than then either by themselves. Well, thank you. I know you're a very, very busy man, I know I need to let you go. I just really want to thank you for an amazing discussion. I'm most grateful.
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I look forward to more important discoveries from your labs, and your
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and your reward center in the brain. That's right.
Thank you, Steve. Your studies of the molecular pathways by which social and environmental factors influence the activity of human, viral, and tumor genomes are truly groundbreaking. I look forward to more important discoveries from your labs in the future. Next week, my guest will be Dr. Helané Wahbeh who is the Director of Research at the Institute of Noetic Sciences, and adjunct
assistant professor in the Department of Neurology at Oregon Health & Science University, and president of the Parapsychological Association. She has published on and spoken internationally about her studies on complementary and alternative medicine, mind-body medicine, extended human capacities, stress, posttraumatic stress disorder and their relationships to physiology, health, and healing.