How Your Immune System Works & How to Improve It | Dr. Max Krummel

a famous song, I mean, "All Just in the 1970s, drew this parallel in wartime," and said in World War II. Submarines had two sets of books. One of them was a book that gave them the sound profile of all the US submarines. And so they could listen to the word of the engines. And if they heard a word of the engine, then had the certain cycle of a general motor's engine, they wouldn't fire. So that's the sort of like, "self, I know it self is." And then they had another book that was the engine sounds of the known diesel engines of whatever engines of the German submarines. And if they heard that, then they absolutely would fire. And that's a self versus non-self discrimination problem, just like the immune system has to do. But what I bring you with it, aging, is this concept that as you get weirder and different, and your body is getting more complex, then those books, you know, start to have every possible-- possibly every possible permutation of every biomolecule could be made by your body at that point. And then a virus doesn't necessarily have anything unique about it. Welcome to the Hubertman Lab podcast, where we discuss science and science-based tools for everyday life. [MUSIC PLAYING] I'm Andrew Hubertman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Max Kromel, a professor in leading expert in immunology and cancer biology at the University of California, San Francisco. Today we discuss your immune system, how it works, what it needs to function at its best, and how things like aging vaccines sleep, and even your thoughts and emotions shape immune function. For instance, most everybody knows that being sleep deprived makes you more prone to getting sick. But why? Meaning mechanistically why? Well, it turns out there's a specific set of cells that need to migrate in a particular way during sleep, and we talk about how you can reinforce that process in ways other than sleep. We also discuss incredible findings that certain brain states and memories can be associated within immune system status you had when those memories formed, and evidence that just recalling those memories, thinking about where you were, what you were feeling at those times when the memories formed, can activate your immune system in the same way, which is remarkable. We also have a very candid discussion about vaccines and medications more broadly. You'll notice that Dr. Kromel is incredibly balanced throughout today's conversation, and yet he's also willing to state his views very clearly. So it provides a very rich discussion about vaccines and all the rest. Indeed, thanks to Max's incredible breadth of understanding of immunology and much more, and his ability to break down complex topics and make them accessible, plus his genuine care for public education and science, today is a truly special and important episode to educate and inform you in actionable ways. I should also mention that Dr. Kromel has an incredible zero-cost sub-stack. It's called the Immune Beyond. You can access it by going to the Immune Beyond, all one word, dot substack.com, and there he teaches about science and more. Again, it's awesome, it's free, so definitely check it out. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now, from my discussion with Dr. Max Kromel. Dr. Max Kromel. Welcome. Thanks. Most everybody, including me, has heard of this thing we call the Immune System, and most people just think, OK, this is the thing that, when I'm rested, it keeps me from getting sick. And when I'm not as well-rested, I tend to get more sick. And there are these airborne things, and we can get sick. And there's like funguses and viruses. And I think that's probably what most people understand. And they probably also understand that there are like cells and T cells and B cells. But if we want to think about a little bit of the history of our understanding of the immune system, and what we understand now, maybe you could orient us because in reading your work prior to this discussion, I'm realizing that this is a very recent field. And also, there's still a lot that we do not understand. When I started immunology, sort of 30 years ago, I was rotating in labs at Berkeley. I think you were at Berkeley as well. And one of the transcription factor biologists, mentor said, why do you want to work in immunologists not really a field? And so the time was kind of true. So everything was about DNAs, cloning. We still, you know, it's obviously still a lot about molecular biology, what we do. But, you know, at the time, it was pretty simple. We thought of the immune system as something that, on the one hand, it had to come into play when you saw virus or something foreign. And otherwise, it generally had to be quiescent and kind of leave you alone. I think cancer immunotherapy changed that a lot. That gave us the idea that you could tune its reactivity so that you could get to the point where if you gave an immunotherapy, what it was actually doing was raising the threshold if when a T cell would activate. And allowing T cells that might be just letting the tumor get by, they'd be able to go after that tumor and kill it. I think that changed the spectrum of certain degree where we suddenly saw, okay, this isn't just a, just a foreign versus self thing because a tumor is kind of not exactly self, but it's actually, it's also not foreign. It's once you to sell this kind of evolved. So I think tumor immunology really changed our perspective on that to the point where we now think of it as a tunable system. But then I think a lot has happened in the last 20 years. There's been a lot of excitement about cancer immunotherapy because we're curing people with cancer, which really wasn't done before. You're now in the space where the immune system is showing all these other roles. I mean, you know it in the nervous system, in the brain, there's microglio that do various functions, cleaning up, et cetera. But it's in your gut, it's allowing microbes to live in you. But it's titrating them. It's keeping them there in the kind of like the right quantity. So it's kind of guarding yourself. It's, you know, it sits in your liver, regulating, how much you metabolize. There's a collection of cells there. It's in your heart. It's, you know, regulating cardiomyosite function. How does the muscle cells of your heart, they have to be cleaned up from time to time. So there's a set of immune cells that will help get rid of their byproducts in the heart. So it has all these additional functions that kind of before we're lost in the, in the just, you know, the foreign battle against the foreign. And now we have this kind of perspective of this system that measures us all the time. It measures everything about us and it exists in some ways. I think it's to help us be who we are. You know, that's, and that's, hopefully that's you as a healthy person. You know, in chronic disease, unfortunately, can be part of the problem where it becomes part of the things that's letting the chronic thing, whether that's a tumor or kidney disease or what have you, it can actually help perpetuate it. Because, well, it's, you know, some ways it's trying its best, but it's applying the wrong program to the wrong situation. So yeah, it's changed a ton. I'll give you another little funny story, which is that, you know, when I first came into immunology, giving me the story, like, you know, mentor who says, you know, this isn't really a field. The year was, like, came into the field in 1989. And that's right at the peak of eights. And AIDS was like as a biologist was really interesting because, you know, the HIV virus infects T cells. So your body is filled with 10 to 11th or so T cells, like a ton of different kinds of T cells. And you had a, you have a subset of T cells that are called CD4 T cells, kind of a flavor of T cells. And the virus gets rid of those. So HIV virus will infect the CD4 T cells and then, then you end up with not having them. And the manifestations of AIDS, for those that weren't around her, was it was just a ton of different opportunistic infections. So like soil bacteria that you and I, you know, fight off without even thinking about it would kill people. But so too, would you see, you saw people with curbosysocoma, you saw like a opportunistic, like, where, you know, a cancer is emerging. And you just saw all these kind of manifestations of where the immune system was important to mentors in people with HIV as well. You know, there was a really accent at the time on how many different things the immune system might be important for. So regardless of whether, you know, it was a field or not, it was clearly important. And it was all these things we didn't know about it. They're like fuel, the discoveries that have led to where we are right now. And some of those, you know, I think it's worth pointing out, we're just these curiosity questions. Like, what are these cells? Like, they were hard to study it in the beginning. You know, they're, they don't live, you know, it's sometimes hard to keep cells out of a, out of a human body alive. So, you know, there's issues about, you know, how do you keep these things alive in the very first place? And then, and then what kinds of things, you trigger them to do stuff. And, you know, make reagents to test those, you know, ideas you might have about what they might do. It was a long haul, I think, to get ourselves together where we now have a pretty good understanding of all the molecules and cell types and the behaviors that they can engage in. And it just gets more complex, you know, more complex and more like rich, as we understand that they're basically every single T cell in your body is like a free agent. And they're part of a sensory system. Each one can measure the concentration of a set of biomolecules proteins. And they form a peptide, they can measure that. And each one then can say that's at a range or that's in range. So it's like you have like 10 to the 11th little sensors going around you, curating you. You know, making sure you're the right thing. And if they see something that's at a range, they can do something about it. You know, like the whole thing is magnificent. It is magnificent. Do you mind if we take a developmental, perspective on this for a second? And then I have a basic health question. The developmental perspective is, I think most of us either remember or have observed that when humans are young, they get sick a lot more. Presumably that's because their immune system isn't as well developed. But kids tend to get sick and then get over being sick pretty quickly. Yeah. maybe you could describe what's going on there. And it also is the case that, as we get older, much older, in fact, last quarter of life, let's say, people tend to get sick more. What's going on in terms of immune system function or is there something more broadly happening at level of just kind of energetics might of contrile function? Very curious about this. - If I can take a step even further back, I'll ask you a question of, who are you? And I don't mean that in the personal sense, but I can talk about that too if you want. But the more the question is, at some point, where does your body end and where does the world outside start? And one of the things that you start to realize if you look in a microscope is they were covered with microbes all over our surface. We're covered with microbes all the way in our gut. In fact, you can't digest, you've probably heard this before, but you can't digest animal fats if we're in for the bugs, the bacteria in your gut. They make some of the key components of bio acids to allow you to digest animal fats. So you need this system that's around you. So you aren't just the cell, if you learn biology, we're gonna go way back. There's the egg in this worm, fertilizing now you got this cell that starts to divide and gives the rise to every other cell in our body. So you might say that your body is just that collection of cells, but in fact, it's absorbed a lot of viruses and bacteria from our environment. And to go into that really briefly, that's really important because we only have 20,000 genes in our genome. So there's only so much in a given life that we can do with those genes. And so by absorbing all kinds of other species onto us, we get their genomes. So like you said, like I was saying, the bacteria in your gut can now help you absorb nutrients so you wouldn't otherwise. If you eat sushi, you know, you've heard this probably right, you get bacteria in your gut that can help you absorb the seaweed, nutrients from seaweed. So taking this into your question, when you're first born, you've never really seen anything. And so two things are think worth funny out the early phase of life. One of them is for the first six months or so, your immune system is pretty poor at being trained on things. And it's presumably, we presume that for those six months, that's because your body's developing so fast that if you were to have a super active immune system, you might actually find yourself attacking yourself. You might think that you're foreign because some genes turn on during development and then all of a sudden your immune system is like, "Oh, I see something different and now I need to react." So that's well known and that's one of the reasons why some childhood vaccinations, they're really important to protect kids in long-over life, why they aren't given until your six months or older. But I think to your point, one of the things that's happening with kids is that then as they go into their 10 and you're talking about they get sick a lot, they just haven't seen a lot of these bugs before. So they don't have an immune system that knows what flu is 'cause the body's never that body, like kids' body has never seen flu before. So every single virus and pathogen that hits it is gonna elicit some amount of illness. But then they have a very strong immune system that reacts and gets rid of that. With the exception of the ones that are, those certain viruses in bacteria is mumps, measles, rebella that are lethal and that's why we immunize. As we say, "Oh, and those are things that you're immune system "if they get too much of those, kids will die." And so it's better to protect them with the vaccine. All right, so that's the front end. The front end has this initial immunosuppression then just exposure to all these things that are in our environment and you and I take on as part of our genomes, but we have to reach a detente with some of them. We have to get to the point where the immune system can kind of like fire back when they show up if they're bad and allow them to live enough if they're good with us. And so I think that's what's happening a lot in those first years of life. And you can see that both in the form of, kid can you sick a lot, but you'll also see that their guts develop way diverse microbiome. They allow a whole bunch of things that come in from the outside and are acceptable and are quite good for you. That's a front end. And in the back end of life, it's a little bit more complicated, but I'll tell you two things that I think are important. On the one hand is the idea that is a fact that a lot of yourselves in general become less functional including immune cells. And you get less cells produced. And that might just be because we were never selected as organisms to live as long as we do right now. That's one idea of aging, right? - Aging. - Aging. - That we're just supposed to be dead by 70. - Well, no, but we do know that we can reproduce and you have passed on our genes successfully already when we're 16. So the selective pressure to pass on your genes, if you imagine that's how genetic evolution happens is that you pass on your genes as being successful. You can already do that at 16. And anything after that is just cream on the crop. But at some point, maybe there's no selection. So we don't know that, but it's a reasonable hypothesis to say there wasn't any real selective pressure for passing on genes that do anything past when you're actually having kids. - The psychologist would tell us that the wisdom of people 60, 70, 80 and beyond is useful for groups of humans that live in villages of 100 or so people 'cause they can give information to younger people that is on the periodicity of like every five to 10 years, maybe every 30 years, but that's just so story. - Yeah. - Right, that means it's a nice just so story. - I like it too. And I think that geneticists were for that's like the grandfather effect where genes may be selected for, and maybe they're mostly about, genes that make us social for the elderly that do, they're gonna have effects on the fitness of their grandchildren, which is their genes. And so I think there's something to be said for that in conceptual space. I don't know if I can prove it to you that that's a tough experiment to do. - It's a really tough experiment to have two villages where the grandparents are eliminated or like kept, you know, both nonethical and also nonethical. But we're talking about the aging immune system. And I think there's two things that again come to this question that I was asking, like who are you? And I was saying, okay, well aging you have this issue that the immune system is tapering and it's efficacy. It's many of the cells that you know that you've been holding your whole life start to, literally they die off. But there's another thing, which is I think a lot of people don't realize when you say, when the basic biology would say the sperm, you know, like fertilized at the eggs so you've got your moms, genes and your dad's genes so you've got 23 chromosomes from your mom, 23 chromosomes from your dad. And at least when you're first born, every cell is a clone, it has exactly the same information. But DNA replication and DNA sort of like fidelity isn't perfect. Like they say that on your skin, the cells of your skin may have somewhere between 10 and 30,000 mutations per cell per day, just from like basic sonic exposure. And that's higher than some of the other organs. But the basic idea is that your DNA is susceptible to UV radiation as one of the reasons we put on sunscreen. But what it practically means, no matter what number you put in there, whether it's 10,000 mutations per day or remember the genomes are huge, right? So 10,000 mutations out of terabytes of information still is only a certain number. But do that over years. And the main thing is that that means is that every cell in your body is no longer identical than one next to it. Because this one got different mutations on day one, it's going to got some mutations on day two. And slowly but surely you are becoming like a mosaic. And I say mosaic, you know, because like the tile you see in Morocco, you know, very intricate designs. Because if you actually, you know, start to look into tissue, you know, you'll find that certain clones, certain mutations do make certain cells more fit. And they're the ones that if you scratch yourself and a cell has to like some new has to, so lost to form, they might be the fittest to fill that void. And one of the other clones over here that it got a different mutation may not be fit to fill that clone. And so you end up with this pastiche of who you are. So now, again, I ask you like, who are you now? So if I want to defend against something that looks different, what if everything looks different? What if every cell is different from every other cell? It's, it's, okay, you want to be one another now, G? I would like another analogy. The only exception that I can think of to this and that could be wrong is that our neurons, our central nervous system neurons, our brain and spinal cord, most all of them are the same ones that we were born with. - Same cells, but same cells. So your mutations are constantly accruing in the neurons as well. - In the DNA. So there's just, it is fascinating by the way that neurons live that long and, you know, hair cells, they say that the proteins in our hair cells are the same exact molecules, atoms, as we have when we were born. So there's, there's some cells that are long that, but in their nuclei, the DNA that's encoding who they are, who those cells are, is subject to mutation ongoing. And it depends on how deep they are. Like, we tend to think that one of the reasons that immune stem cells live in our bone marrow, you know, our long bones are hollow. And in there is the source of the immune systems, you know, revitalization, it's the stem cells that make more white blood cells. We'd like to think that they live in there because it protects them from a reagent. They hang out, and stem cells are, you know, the bone actually serve not only a structural purpose in our body, but it's a cavity in which things can live. And there's, you've been away from, from your radiation. - From your radiation. - You've been away from chemical cues in the environment that you take. - It's a quest for your stem cells. And, don't burn them. - Yeah. - That kind of thing. Likewise, the neurons in the inside of the skull and the spinal cord, they're protected. - Yeah. - And that's interesting. - Yeah. - Yeah. - I would like to take a quick break at an acknowledged one of our sponsors, Juve. Juve makes medical grade red light therapy devices. Now, there's one thing that I have consistently emphasized on this podcast is the incredible impact that light can have on our biology and our health. 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We just lost half the audience. I'm just kidding. I'm totally joking. I'm just kidding. We're a bipartisan. I'm totally joking. You know, I'm taking how you want to be an intelligent, but by analogy to you, it's the argument for why certain influx of, in this case, organisms, organisms, are more robust person than we were before. But I want to give you this story that one of a famous novelist in the 1970s drew this parallel in wartime and said in World War II, submarines would be underneath the ocean, and they'd be traveling around. And they would, if they could, if they've heard another submarine, they would scuttle the missiles, the torpedoes because that could be the enemy and the enemy could fire at them. And so they had two sets of books that they used. One of them was a book that gave them the sound profile of all, let's say, it's a US, of all the US submarines. So that's the sort of like self, I know what self is. And then they had another book that was the engine sounds of the known diesel engines of whatever engines of the German submarines. But what I bring you with it, aging is this concept that as you get weirder and different, your body is getting more complex, then those books start to have every possible, every possible permutation of every biomolecule could be made by your body at that point. A virus is also going to make proteins, and that's your immune system can see the viral proteins, let's say a new thing has come in and that's out of range. And now I need to mount that T-cell response against this, I need to make the, you know, bring in the troops. But with aging, we have this kind of us diverging problem, so that this system that's supposed to sense us, has a lot of cosmic background, has a lot of noise in it. And so I think that's one of the reasons why we also have issue when we're aging. And I think it's also one of the reasons why cancer is more prevalent in later life. For, I mean, there's two parts of that. One is of course you've accumulated mutations in your cells that could be cancers, but also the immune system has been seen, those and all the various different accumulations of them and ones like them, you know, over these years to the point where the weird doesn't look that weird anymore, you know, something like a cancer that is different than you. It's not that much different than like another cell over here that's gone, you know, like, and it's just happily making skin and isn't cancerous, but, you know, it's got some differences. What about the argument that there's so much cellular turnover that the cells that accumulate these mutations are being eliminated? You're saying because they're clonal, they're producing different, they become different, they produce cells that are also different than they die. Is that the way it works? Yeah. And I think, I think you are bringing something up that's also true, which is that all the time I think the immune system is defending us against, you know, mutations. So one example that everybody sees when they get to be about 40 or 50 is the level of these white spots on your skin. And we think that those are places where the immune system has sensed a collection of cells that were pre-cancerous, maybe they were even beginning up cancer and has wiped them out. And so, you know, a lot of the origin of cancers in skin is melanin producing cells like melanoma, you know, melanoma is what we call skin cancer. And there's melanocytes that that white area, they've been wiped of a whole collection of melanocytes. And that's why it's, you know, it's white instead of as dark as your, as your rest your skin. So, you know, to that extent, the idea that the immune system is, is pruning you all the time is, you know, there's, it looks like there's pretty good evidence for that. And the question is when does something become dangerous? That's, that's, you know, that's fundamentally a question with cancer and these sorts of things. I want to actually have the fittest cells in my skin, to fill in a gap if I scratch myself I really have cells that quickly replicate just like maybe in kids kids heal so ridiculously quickly, right? Because they have an abundance of these cells that I think I think they're there wound healing I mean there's a group out of Stanford studies this but essentially you know wound healing and in young is quite quite a bit faster and more efficient and there's many levels of that yeah, yeah, but yeah remarkably faster. And if you're parent you've seen this you know you cut yourself on the same days of your kid cut yourself and they're there three days later it came and find it on them and you know like four weeks later you're still like you know it's got worse than me. But I was just coming to the point that if you do that and you want to do you want you maybe want that to fill back in because you know certainly out in the wild having an open wound is a bad thing so you'd like to heal quickly. Well if a mutation has happened that fills that cell in quick more quickly that is almost by definition a mutation that's let that cell divide faster well what is cancer? It sells that divide faster so in some sense all these events in your life where winners win by filling in the space left by cells that die is selecting for cells that get a little out of range with growth and they may be a little bit better at growing and then again the quick question is like well how much better do you want that? You want it to like help you but at some point you don't want it to basically form a lesion and grow grow grow grow grow grow and go other places and grow which is called metastasis and cancer which is how most people die. To me that the issue of self and non-self is one of the ones that's been with immunology for a very long time and again it's way richer than we thought about I think in the 1990s or 2000s you know and then at the same time the idea of what you can do with that information is also I call this kind of the new immunity immunity used to be like a fuel gauge you'd say was low for self and it was really high against viruses and it was like a fuel gauge you know now it's really hot and what we originally thought we were doing with cancer in therapy was making it just hotter generally but now you realize that in between like the immune system not caring about something at all and and going and you know like releasing all its fury on something or all these other things it can do with the information it gathers in there and that's where I was saying you know it can it can like quarantine bacteria it's not going to kill them it's it's in that zone bacteria as long as they're in the right zone there's not too many of them there's not too few of them the system can actually help them be there it can produce things that like either titers them out of circulation or keeps them there you know and all these other settings like you say in the heart and the we could almost any organ and and you know immune system is consistently present and it's consistently measuring you and that you again as this complex you it's not just what came from the egg it's the you that's you right now including all the mutations that you might have accrued and all the bacteria and and the viruses you know we have a lot of viruses in our bodies that we tend to think that at the end of of a illness that we've gone back to our pure state this became from religion you know that we were born pure and if God had been made us correctly then we would be pure at the end of the things and you know that would be pure immunity would you would purify us if things but the more we look the more we find that every virus leaves a little evidence of it a little bit of itself and then there's a then there's the goal for the immune system to kind of quarantine that to say this you know maybe we don't want to kill every one of ourselves to get rid of every virus that's infected one of ourselves we need to leave some of those alive we don't like for example herpes virus infection infects the nerves and when people have you know emergence they get nerve pain and worse a lot of that is caused by the immune system reacting to the virus trying to get out and then killing off neurons. So the it's immunopathology. The immune system is causing as much of the damage and problem as the viruses and it's the failure of that day taught. When certain viruses are just sitting in us, we're perfectly fine. You know, we have new viruses in your area. As long as they're laying in the dormant, our immune system can say, okay, I'm just hang out here and if anything bad happens, I'm going to squelch that. But it's not like we've been purified. You know, that's a reality that's a little bit too bad. But you know, it's also one where you say again, if the goal of us is to make it to 30, let's say you get a pad, an early liver infection of a HCV or HPV. If the immune system can just let that be, you're not going to destroy your own liver and you'll live to produce and your genes will get passed on. On the other hand, if you may have mounted a massive immune response, you know, you went all the way in the fuel gauge to the right, your immune system can kill you. It absolutely can, you know, it can kill any cell it wants. So so that that that again, that idea that the space in between is the one that we actually are starting to understand that it has all these specialized roles that are not always about getting rid of things at all cost. This raises a question for me and obviously I'm not an immunologist, but it seems like one you're going to be one by the end of time. I hope so. I like the sound of that. As well the audience, one potentially useful strategy the immune system could have perhaps would be rather than to decide to launch an attack on a particular cell because it's mutated and different enough to assess how many cells throughout the body or even just get a local average of how many cells have similar mutations or just are different. So that if we are indeed born pure in the biological sense, let's just keep it there for today's discussion. And you know, by time we are, you know, 32 years old, we are a mosaic of mutations. As it appears we are, if the immune system could surveil multiple regions in the body, maybe compare organs or maybe keep it within organ system and say, you know, the number of mutated cells or not pure me cells would be one way to do it more simply perhaps has exceeded a certain threshold measured. I don't know. Like enough receptors have something in them that the cell goes, okay, you know what? I'm going to fight. In the same way that, you know, soldiers, you know, they might hear a shot was by, but then do they necessarily reveal their location and launch an attack? No, but if it's enough of an attack, they'll fight back. Yeah. It seems like there should be some way that the immune system could quantify either body wide or or local organ or over some period of time they could integrate over time. I have to imagine that such a mechanism exists. You're coming from neurobiologists, I know. And so there is that in neurobiology of accommodation, right? If I always tell the story of, I went to this little village in in France called a poise. If you know the name of the poise is kind of a famous cheese that they make in this town and it's super stinky. And they make it only in that town and they make a lot of it in that town. And so when you drive into that town, it's like somebody has the worst foot odor. It's striking. It really hits you. But after being in the town for like an hour, you don't notice it. Yeah. And that's neuronal accommodation where you're nervous. The same kind of thing you're talking about, whether the sensors in your nose can become, they're like, okay, I've seen that. I've seen it. Now it's not anymore. And so I'm going to tune that out because then your nose has the potential of small other dangers or other stuff, right? So that's the nervous system. I think you're exactly right where you're going with this is and we think this is true that the immune system is, you know, for danger. It's looking for something that you would call like a, it's how it's seen the signal over time. So a virus may, you know, let's say you're a T cell that recognizes a virus. Well, you're looking for something that you've had nothing of before. And then all of a sudden, the virus comes in. It starts replicated and you have a lot of it. And then at some point, if you get rid of it, it'll come back down to next to nothing. And in that period, you mount a unresponse and you learn it. And so the next time around, it'll be faster responsive and keep you from getting sick. That's one kind of signal. But self can have either one of two signals, I think. One of them is that you've had your entire life. So that amount of protein, maybe it's insulin, you know, we think in general, you know, it has a little bit of signal up and down as you have a trigger, but there's a range for that. And so your body gets to use to that range. And the T cells that see insulin, they are very low, they're going to only be very, very low reactive to that. And there's there's a whole story behind that. But basically, they're going to see that level. But you can also have things that the immune system is going to want to treat like self that maybe do a slow rise. They don't have the peak that you have with virus. And so like a mutant cell, and maybe it's just a tiny, tiny bit above normal for months. And then it makes two copies of the cells. And now it's a little bit higher than normal. And the immune system has, you know, has, I think one of the deficits with cancer is exactly that, that things that you do. And this is sort of like a trend of my life a little bit this way. But it's not validated by any, you know, any experimental stuff. And the idea that whatever you are is what the immune system is going to help you be. If it's a slow direction this way, it's going to be okay with that. What it doesn't like is like big spikes. And that's maybe the signal that you're asking about, like, could you actually get to the point where you be reactive? The problem with cancer is that it is, you know, slow in the fair, it grows over time. And I think we're made to absorb slow change. Because if it's not causing us to be sick yesterday and a little bit more of it is causing us to be sick today, then it's probably just a developmental change. Maybe it's a new bacteria. Maybe it's a new, you know, that it's commensal ease. It's, along with it, it doesn't accompany. Again, viruses have two features in common. One is the spike of, you know, appearance. But they also cause damage in that window. And so you have like these cues that I think the immune system, and I say the immune system because it's some cells are going to see the damage and some cells are going to see the additional proteins that come in. And then they exchange information just like your brain. You know, you can talk about the fact that the brain has this wired, you know, set of cells that are wired in space, they're across your body from your brain all the way to a muscle, let's say. The immune system has this collection of cells that are literally crawling around us right now. And if we used to do, we still do a lot of imaging. If you look in a piece of skin, you can see the cells, the immune system are really, really surveying us. They're crawling around. But they get together like neurons and they conform synapses. And one can say to another one, this is what I saw. And he says, Oh, you saw that. Well, I said, you know, I'm just seeing this. And they can, you know, form a cluster of cells that basically get together like a neural, a little mini brain in our tissue. And they can say, this is bad. We got to do something about that. But I think the slow burn doesn't do that. The slow burn is one of the ones where the cells are like, yeah, it's on that band. I realized this perhaps is not your immediate area of research. But recently, I've been seeing a lot more interest in the thymus. This organ that we have when we're young and it disappears as we get older. And there's a lot of interest in the thymus. Maybe because we've never covered the thymus on this podcast in any amount of detail. If you could just educate us a bit what it is, what it does, and why it might be interesting as a, as a therapeutic, I mean, maybe in a few years we'll all be banking our thymic cells. Maybe we will be, I know some people are already injecting non FDA approved peptides that come from the thymus. I'm not recommending anyone do that, but people are already doing it. Because that's the internet in 2026. What's the thymus? What does it do? Why this interest? Yeah. Well, I can back up one step and I've used the word T cell before. And T cell originally was thymus cell. So for those that maybe don't, you know, have gone to have blood taken, you know, if you have blood taken in the hospital, whatever you'll, you'll get red blood cells. And those are the cells that carry oxygen around your body. And then you have white blood cells that come in two flavors, two me, well, they come in multiple flavors. But for the moment, we'll talk about two, one one we're called B cells and we're called T cells. And T cells were named because of the thymus. So the thymus is this funny organ. And it has a funny history. In fact, I'm writing these substaxies and I'm writing one that's supposed to be released tomorrow by the thymus because it really should have gotten the Nobel Prize. So as a guy who's alive, he's like 97 years old in Australia who did this, saw that did this remarkable kind of experiment. There was a time when kids that had heart issues would come in for surgeries. And they would discover this enormous white, whiteish organ as growth near the heart as they were taking the body, you know, this they're cutting open. And all the autopsies up to that point, you've been done mostly with adults and in adults, there's only this small little thing there. And so they were like, oh my god, part of the heart thing is this overgrown thing. I mean, they didn't really know what it did. And so he would remove it. And the kids then go home and it was usually exploratory heart surgery, but the kids would go home. And far from dying of heart disease, many of them would die from like opportunistic infections. They'd get all these infections. They'd get flu and etc. And so there was this hint that maybe this removal had taken out a critical part of your immune system, had made it so you were super susceptible to bacteria. And so this guy named Jacques Miller, who's this nice, seven year old cager in Australia, at the time he was in England and he basically took a bunch of mice and when they're newborn, he removed their thymus, the same little whiteish organ. And sure enough, those mice, they basically grew up, okay, but then they all would succumb to bacterial infections. And in fact, a few of them even got tumors, which was kind of noted at the time, but forgot. And the reason why that is is because the thymus is the place that makes all your T cells. And it comes from a kind of convoluted path, but we know how we're talking about how the stem cells of your immune system lives in your bone. Well, there's stem cells that live in their bone and they travel through your bone, your blood to the thymus. And become T cells. And the reason they need to do that is that the thymus is this kind of super special place that is able to present to them to show them all of the genes in your genome in various different ways. And so the T cells that come in there, the T cells are developing, and they each have a possible 10 to the 11th different kinds of receptors, it's just male different things. And you don't want any is to come out that are too reactive to you. So you don't want to produce T cells that are going to go off and kill your pancreas or kill your big toe or anything. You want to maintain tolerance. So you want to make sure that you don't make the immune system that's too harsh. So the thymus has the role of producing T cells, but also of educating them in some ways, of only letting the ones that come out that have sensors that are correctly tuned to let you be you in that way. Now to the point about the story and you were asking about aging is that is that in kids, those are really big because at that point we were talking about the developing immune system. It has to go from like, you know, living under the veil of your mother's immunity. And then it needs to let some development happen. And then it needs to burst out and start to be able to react against whatever bacteria and viruses you're going to see over life. So your thymus has a huge output. So as a like between really from, you know, three to six months old and, you know, into your into your four or five years age, but tapering your body makes tons of T cells. And it's because it's probably what you're talking about. You're going to expose to all kinds of different bacteria and viruses. And so you need to make that make that collection of immune cells that both some of them, you know, see self at low levels, but then they also can maybe react against different things in the environment, including the ones you need to defend against. Then what happens is because again, I think we're not needing that later. And maybe we don't even want that. But the thymus invulutes, it gets super, super small so that in aged people, it's like tiny. And so it's not putting out new T cells. And so the reason why there's interest in like these peptides, but all these other approaches to like revitalize the thymus is that I can cancer, for example, wouldn't you like to have a whole bunch of new T cells that could come into into you, flood in there with exactly the specificity for the tumor. The tumor has managed to teach all your normal cell, your other T cells, your body that it's normal. Maybe you need a source of new material to come in and do that. And there's really two ways. I think you mentioned you talked to Alex Marcin, as you were going to go, and he I'm sure he would have talked about engineering cells that you can engineer on the outside and give them specificity. But the sort of like if you will, the more natural route to that might be to to let the thymus make use of more T cells and make sure that as they come out, you make sure that they can react against this tumor or whatever it is you need to defend against. It's always been a fascinating organ from the sense that it's the origin of all the cell types that we care about, that T cells in that case. But it does have this like aging, you know, sort of aging effect that seems to make us a little bit more susceptible to things later in life. And you know, again, we could argue about whether there was a big evolutionary design behind doing that or whether it just wasn't needed because if you got you got to 30 and you died of an arrow wound, you know, you know, but you've given a genes. You're a winner in the evolutionary sense, you know. I love this stance on well if you've already reproduced out. I'll just give a brief vignette. We were introduced by our mutual friend David Feldheim who's a phenomenal developmental biologist from UC Santa Cruz and his wife Sophie Salamas, also phenomenal biologist, a mutual friend. Years ago, I was in Dave's lab because we're longtime collaborators and published bunch of papers together and he was doing some injections. I'm going to get you in trouble, Dave. He doesn't do this any longer. I'm going to join him to get you in trouble because he was doing some injection and he might have been using might have been using carbosyonide dyes. So it's kind of conventional toolback. You put a little crystal and a piece of tissue that's fixed tissue. So it's not alive animal or anything. And then you put it in the fridge and then the fluorescent dye would label a set of neurons in a pathway. And I walked over and I saw Dave doing this and he wasn't wearing any gloves. And I thought these are carbosyonide dyes. And I said, Dave, don't you want to put on gloves? And he literally looked up from the microscope and he'll never forget. And he said, I've already successfully reproduced. Anyone back to doing it. And it's his lab. So and everyone else who was following a safety protocol don't go after him. He doesn't do this any longer folks. But there's an interesting mindset among you because he comes from cell biology. Yeah. Randy checkman's lab. You know, trained in Nobel Prize winning laboratories as graduate students. So I find it remarkable that this stance of well, you've already successfully reproduced really aren't needed. But his kids are now graduated or in college. So there is this thing about raising the young too. Yeah. And not just creating them in the dying. I agree. I think there's a fitness associated with being older than that. And again, why say that this it is maybe just taking us from a purely like what would have been the source of what we are today? What would have been the selective pressures on them? And it would have been a little bit like Davis. And you got to, you know, the selective pressure is to get your, you know, for it for for my genes to be passed on, my offspring have to be born. And then have to get to some age because most humans are born pretty incapable for a period. It's not like drass where they drop off and they drop out within an hour they're running. So that that period of raising children, I think, creates more pressure in humans to, you know, to successfully be healthy longer. But I guess just, you know, that there may be a negative viewpoint. There may, but that concept that maybe there isn't as much pressure for you to be healthy. And going with this is the idea that some of the things that we want to be super efficient early on might actually be bad for us as we get like I'm like I think this issue that I brought up with our mosaics is a is a real confounder of everything because that creates something that is quite hard to defend against, I think, that that aging backdrop. And, you know, some of the immune system that is really going to be important to just be super reactive early on may have some, you know, compensatory problems when faced with that new reality of a 50 year old or 70 year old or whatever it looks quite, you know, like quite more complex. But you would have, you would have definitely wanted in gene space, you know, in a gene space that what genes you have to select for, you know, an immune system, let's say, or even just your body system that makes sure that you get to 30. Let's say, are you? And it's, again, there's, there's, I didn't say that we can't overcome some of those deficiencies if we understand them. But here's my plug for basic research is that to understand them, we have to ask some questions. There are almost 90% of them are going to be dead ends. You know, you cannot hypothesize it's one thing. Well, you got to do the experiment to like eliminate that. And this is one of the things that people I don't think always understand about science is that for all discoveries that, you know, I made or other people have made, there are hundreds and hundreds of like disappointments, you know, and you'll recognize this when you just go home from the lab at the end of the day and you've, you know, you've done everything right. But the answer isn't the one you isn't the right one. One control experiment can well you cure whole project. Well, there's that. There's obviously that you have to do the experiment well and have it controlled. But, but the answer just could be not the one you thought. And, you know, we can only imagine stuff and then try and see if it's true and or more importantly try to prove that it's not true. This is the better experiments that kind of we call them killer experiments. Try the one say, and kill the kill the idea if they're wrong. If the idea is wrong, but it's killer because it if it turns out the way you hope it will. You know, again, when we get to some of these aging things, and there's a lot of there's a lot of intuition that we all can put into this, whether we're like professional scientists or at home scientists. But it's really hard to say that intuition, like your idea about how the way the world should work is in fact the way the world does work. You know, that that I wish that because of the age certain things would happen. That's a that's lovely. But it could be super when the word was baroque, you know, like a. It should the whole system could be, you know, configured in a completely weird way that doesn't really initially make intuitive sense to us. And that's also why some of those discoveries are so big to us. We're like, oh my god, it didn't realize that this system that seemed like it might be quite as simple is so complicated that the world is so strange. When I started in neurobiology, the brain, the actually the entire central nervous system was considered an immune privileged organ. Yes, there weren't supposed to be immune cells there. And thanks to the beautiful work of Carla Schatz with the major histic compatibility complex work and Ben Beres. Ben Beres. And I'm failing to mention all their scientific officer, but that's Steven, Charlotte Erglue, like, hang on and on. They'll take the rest of the episode to name all of Ben's scientific offspring and Carlos too. And you're being you. Right. I didn't work on those issues, but, but I was in those labs when it was happening. We now know that the immune system is actually in a live in the central nervous system throughout the whole lifespan, serving critical roles. Yeah. There are two things that, well, three really that are somewhat practical questions. I'll start with the most basic one. Why is it at a mechanistic level that if you miss a night or two of sleep that your immune system seems so less effective in fighting off infections? Do we know what's happening? Is it like you've got so much adenosine, which is the sleepy molecule and adenosine inhibits T cell function or something? Do we actually know? I think all of us are familiar with the fact that if we we don't sleep well or enough for a couple of nights, we're much more susceptible to getting sick. Yeah. Is there a mechanistic understanding of why that's so? I think there are bits and pieces of it. I think some really nice work shows that at night, a few wacky thing, when you sleep, a few what you might have thought would be wacky things happen. And one of them is that a lot of your immune cells clear back to the bone marrow and your tissues be We come populated with a bunch of neutrophils that come out of the bone marrow and seem to be depositing collagen around your body. There's a lot of things that I think are repressive about sleep. I've thought about this a lot of my own life as probably you have with sleep as to. One of the questions, of course, is why do we bother to have sleep? I guess I can only imagine this because we've created these bodies of ours are so capable and they're so energetically and consumptive. They make all these byproducts during the day that at some point you just need a clean up face and that's one interpretation of sleep. It just needs a reset. The immune system is definitely resetting and as I said, there's evidence that a lot of cells go kind of quiescent into the tissues and they may leave you alone for the repetitive processes and actually allow those. In terms of the data on there, there's a lot of studies that are being done and I can't say that I've come to a conclusion about that. This comes in the question, is it known or do I not know it or is it, does nobody know it? I'd say this might be one of these areas where about 10 factions of people know it but they don't agree. There's variations on things. I think the data, for example, that immune cells dive into the bone marrow at night is pretty solid. That makes sense. What they're doing and why that's important in the long sense of what you're talking about and everything from well, but I think it's things that happen overnight. Your cognition improves, is that immune or is that neuronal or both? Something in the lymph plumbing and immune system. One thing that's just striking like that is undeniable as probably the best way to put it is everybody has bags under their eyes and looks like shit when they are sleep deprived. They sleep for a night or two and it goes away. That's clearly accumulation of lymph. We actually know that. That's just lymph fluid that's not being cleared and it might not even be the brain's glimphatic clearance system. There's a bunch of lymph pooling under your eyes. That's why you look like shit. Then you sleep for two nights, well, and you look better again. The eyes get glassy. We know that the eyes get glassy when we're sleep deprived. That's also a lymphatic clearance issue. This is well established. There's something that's plumbing works better when we sleep and get up. There's something literally lying down and getting up. That to me can't explain the immune thing entirely because the lymphatic system is among other things immune surveillance. One night, it's lousy sleep and the person coughing across the room gets you sick often. When you're well rested, you actually feel this robustness. It's like, "Man, okay, I might wash my hands or just kind of avoid them and you're good." It's an incredible effect. One way or the other. Again, I don't know the degree to which we can nail down, which part of things that are happening is which I always like the story that the macrophages and immune cells in your eye that are basically clearing the lens. There's all these places where it's doing little cleanup that you can imagine that if the thing is trying to get rid of is granularity that you need to have sleep or you just aren't making more granularity so it can, it's sort of like when you wash your car windshield, do it completely at that point. You can't be driving with fly city and that we wouldn't, right? Or you'll never car. That's a great analogy. I think there's certain elements of some of these cleanup processes that happen best when you're not getting things dirty. Again, I think a lot of what we're talking about is byproducts of our energetics that leave some damage behind it. I think we just use a lot of ATP and we do a lot of stuff as our bodies in the sleep is time where you cannot be producing more of that and get ahead of the curve on cleaning things up a bit. I'm pulling into a gas station clean off your windshield. I'd like to take a quick break and acknowledge our sponsor, AG1. I'm excited to share that AG1 has just launched their newest formulation, AG1 Pro. AG1 Pro takes the clinically backed AG1 formula, which is a blend of vitamins, minerals, probiotics and adaptogens and adds three important new ingredients, creatine monohydrate, calcium, HMB and zinc carnocene. Each serving has 5 grams of creatine monohydrate to support muscle strength and performance as well as brain health. Calcium, HMB to support muscle recovery and reduce muscle breakdown and zinc carnocene to support and improve the lining of your gut. All three of these ingredients have compelling science to support them and therefore I love seeing them added to the existing AG1 formula. As most of you know, I've been taking AG1 every day for nearly 14 years now. I start taking it long before I even knew what a podcast was. It's a great product and it's now made even better with the new AG1 Pro formula. If you would like to try AG1 Pro, you can go to drinkag1.com/huberman to get a special offer. AG1 is giving away a free bottle of Omega 3 Coins on Q10 with your first subscription. Again, go to drinkag1.com/huberman to get a free bottle of Omega 3 Coins on Q10 with your first AG1 subscription. This thymus thing is really intriguing and I know a lot of people who opted to bank their child's umbilical cord in the hopes that the stem cells from the umbilical cord will someday be useful. How invasive is it and/or should we be banking thymic cells because these seem like incredibly valuable cells for their ability to immune surveil and create kind of the perfect situation using our own endogenous T cells to battle infections? I mean, I kind of wish I had a little chunk of my thymus in a -80 freezer someplace so that when I'm 85 years old, I might be able to exploit that. Yeah. Well, I'll say that the umbilical cord one is pretty straightforward. It's, you know, the umbilical cord is essentially discarded anyway and it contains a lot of, as you know, bone marrow stem cells that um, the utility of those is a little different than the thymus. The utility of banking that material and banking just means you put it into a vial, small little, you know, small little vial with the right media and you set it in a very, very cold environment for whenever you might need it, is that if you need to have a bone marrow transplant. So for example, if you have a tumor of the bone marrow system, you can subject yourself to radiation and wipe out all that tumor cells, but you'll wipe out all the stem cells. But if you get this vial here, you've got a little replacement. Has that ever been done successfully? Yeah, you can do. So are there other. Autologous. Autologous. You can do kids are adults that are alive today because they banked their umbilical course, but certainly company so access to that. Well, somebody has to pay to keep the freezer back up generators and things like that. So people invest time and money into this idea. Yeah. Is there a walking, talking, breathing human who would be otherwise dead? Would otherwise be dead? Excuse me. Because they paid money to bank their umbilical course. It's a really good question. I don't know the answer to that question. I guess the parents paid. I can tell you, and this will be just like this is this is the depth of to which you're describing uh, day, fall time injecting a you know like mouse is that in mice, this is true. That if you take you know bone marrow stem cells, you can reconstitute a mouse with a blood cancer and you can do that. I'm sure you can do it in humans. So I have zero doubt that it also works. I don't know whether those companies have done that. That's just actually something where I pull my mouse. This is offered in mass now. Yeah. Do you want to keep the umbilical cord? Honestly, I would do it because it's one of those situations where if it's not too exposed, I don't know if it depends on your how much money you have to spend because it's not within the noise. Yeah. Yeah. So it's one of those ones where you particularly even when you have kids, there's this whole aspect of like I would like to protect them from anything that could come their way. And then I think this would if they happen to have a childhood leukemia, this would cure it. A incredible statement if you think about it, even if it hasn't been done successfully yet. You didn't say it might be able to lead to a cure by virtue of a new technology. You said it would cure it. Yeah. I mean, that's a big statement. You can tell I'm ratcheting up from like sleep to banking, thymus and umbilical cord. Now I'm going to go to the sort of next level, which is not just in the Bay Area. A lot of people, however, start anything about, oh, maybe I make some induced pluripotent stem cells from a fiber blast from one of my skin cells, put the so called young manaka factors on revert to stem this. And then I might be able to grow a new pancreas or study my, uh, you know, whatever organs in the so called organoids or whatever they refer to. But I learned today from you that if I take that fiber blast now, that fiber blast might not be completely Andrew Huberman as I know him to be genetically. That actually could have some mutations. That seems important to compare against a sort of standard cell. I don't want to grow organ organoids from, uh, from an IPS environment that carries mutations that that seems like a bad idea. Because then anything I would, I'm not talking about transplanting in those organoids. I'm talking about studying them, thinking I'm getting information about them. People are doing this. And thinking, oh, I'm seeing what drugs are effective in treating, uh, you know, liver disease or heart disease. But if those are mutant cells, that's a lousy experiment. Yeah. And when I wouldn't say they're like to be mutant cells for that reason, I think the biggest question would be whether your induction of them to become the organ that you, uh, you know, once was successful was replicating the actual organ itself. So you're referencing these things called organoids, which are collections of cells from a body, a human, for example, that are reduced with various different factors to grow to resemble maybe an organ, a particular organ. You know, I think all of us have a little doubt in this. This is the source of the California Institute for regenerative medicine that making stem cells that can become particular organs will, at some day, happen. We will figure all these things out. And I believe in science, I believe in our ability to sort of like test, learn, test, learn, test, learn. How soon, you know, that becomes useful as a bigger question. If you take out your fiberglass today, that might only cure you someday in the future. And meanwhile, you may die of that thing that you wish you had this sense of, I mean, because it's not yet ready, the technology and the understanding isn't yet ready. But the other problem about those is you probably will die of something else, head by car, you know, it's won't help you that you've got those things back. So I think in some of these cases, like overemphasizing, this might be your point about the storage of, of, um, um, build code cords is like, at what point is that a high odds situation where you, your kid needs it and you have it stored away versus all the other things faith that can be fall as humans that have nothing to do with them, you know, stem cells from the bone marrow. And to me, that's, that's a point where you could spend your life worrying about how you're going to die. And, and maybe that's not a good way to live. Well, certainly not how I live. Right now there's a lot of kind of excitement, attention around so-called longevity and, um, yeah, at, at the extremes of never dying or living to be 120, which seems to be the, perhaps the genetic limit currently. Yeah. It's not my fascination. I'm more interested in living in the years I've got as it seems you have to. Healthy, vital, healthy, you know, being able to move sense and, and think seems like, and remember, you know, those seem like the critical ones. You know, you know, you know, you, I won't be able to go, you mentioned the concept of like, removing a bit of thymus. And I think that the issues with, for me, without our, you know, it's an invasive surgery. And like if you were to take out thymus, it would, it's not clear to me that it's the thymus that you need. You might be able to, I mean, in fact, you can make thymic, the, the, the thymus is both the cells that come into it from the bone marrow. So it's as an organ, it has contents, but its structure are some thymic epithelial cells that kind of sell that make a matrix that all those cells live in. They get educated in. And there's definitely, you know, pretty strong work that says that you can create sort of a thymic epithelium that will do some of this work. But whether, you know, a guy at home could hold on to the thymic cells and we would be in a position to do something important for longevity in our lifetime. I don't know. I honestly don't know. Some things in my career, I've seen things happen really fast, so fast that almost like you didn't realize that you're doing it. Like, oh, my God, we've got a cure for cancer. It's great. Okay, let's go on to the next thing. Two things that, so you're like, you know, the California Institute for Regenerative Medicine, we thought that we would have some stem cell therapies, you know, within the seven or eight year window of that bond, first bond, and then there's a second bond. We didn't really get very many out of that. We learned a lot. And that is the risk about stem cell biology. About stem cell biology. Yeah. And that is the risk we take when we do research. Even when we're talking moment ago about how many times you might be in a lab spending hundreds of hours and not getting anything that you understand. And then one hour and you understand everything because, you know, so all of a sudden all of these failures make a make sense. I think when we get into some of the stem cell biology, it's intuitive and it's almost certainly true that we will have some of these things. Whether we will have them in time for like you or me, I don't know. I just don't know. I think that's true of a lot of these things. I say, oh, you know, we seem to be right on the cusp right now. For example, in cancer therapy, we've been on the cusp for 10 or 15 years of these things called CARTs. Alex will have told you about these. Are you engineer your T cells and you give them special receptors that can get them to go into to eliminate tumors? But for whatever reason, they haven't worked in patients. They haven't worked. They haven't worked. And T cell, the immune system gets turned off. These cells don't make it. They don't fail to eliminate the tumor. We will figure that out. But we've been thinking we've figured out, you know, sort of for five or 10 years. And it's, you know, that gets frustrating. And I think it gets frustrating for people that are like waiting for it to, on the outside like, why can't you solve this? And you're like, well, because the universe isn't always configured how we think it is. And that's discovery. That's the problem of discovery. If we knew what we needed to do, we would engineer it and it would work. Yeah. This is an important discussion that we haven't spent enough time on in this podcast that I think is it very important for people to hear. And I have some thoughts about it, but I'd love for any disagreements. I'm not looking for just agreements, but yeah. So my observation from a couple decades or more doing science and then mainly shifting to podcasting, but this is what I do. I talk with great scientists. So that's a podcast. So I'm very immersed in like what's happening right at the cutting edge and because of great guests like you, you know, my, my sense is that in every field, there's been like this kind of steady pressure like water on rock pressure. Like, okay, we're going to understand like salamanders regenerate when to be great if we could do that too. Cut off a limb. It could grow back. Okay. Amazing. I think it's like Ellie Tanaka's work has just shown that you like, wow, this would be incredible for amputees and brain regeneration and, but then it never really transfers or like, oh, we're going to figure out ways to get genes into cells. We're going to electropore liposomes. We're going to use calcium phosphate at like great research tools. Tons of things happen. And it's like, we're going to modify genes. They can finger nuclei. All this, okay, crisper. Boom. And one thing just breaks through and goes so much further. And even though, you know, the ethics are questionable, there are babies that have deliberately induced gene alterations with crisper, a sickle cell anemia treatments as well as more benevolent example, but then the person who went rogue and just kind of did this in humans in China. But crisper just kind of broke through it all. The excitement about stem cells led to like, yeah, I mean, even initiatives at the legislative level and like all these labs working on things. And then as you said, it's kind of like run up against the dam. But I feel like in 10 years, some or all of that information will be extremely relevant when boom, one thing will just like leap out of bacteria or like grasshoppers, no pun intended with the grasshoppers. But the last example would be, you know, for years it was like the country's getting fatter, the country's getting obese. What are we going to do? Do calories matter? Of course, calories matter. This kind of thing. And you know, laws of thermodynamics still apply. And then all of a sudden, this freaking heel monster biologists tells people what they already knew because the GLPs were already being used as a drug, just not at significantly high levels. And all of a sudden, we have a imperfect but very important, more or less, dare I say, cure for obesity. It's got problems. There's muscle wasting. You know, there could be other issues, apathy, et cetera. I'm not trying to discount any of that. But I feel like that's the way science works. It's like steady pressure, steady pressure, steady pressure, frustration. And something comes out of nowhere and it almost seems prerequisite to have all those years of frustration and failure. And then you say, well, couldn't we have just gotten CRISPR first or the GLPs first? Like, why did we go through all these, you know, billions of dollars of expenditures, time, energy? Yeah. I don't know. I feel like there's some natural order to this. And I just would like your thoughts on it. I feel like it's necessary but not sufficient to have lots and lots and lots of failures. Yeah. It's necessary, absolutely necessary to study things that are just at some point curiosities. And that sounds like science is about trivia. But you know, you give an example clip one. Somebody was just curious as to why Helomasters. It was the feature was that Helomasters can go into, you know, dormancy for like 10 months, not eat, and then come out. And like, how do they manage that? And so that's, that was just like, what is that? What is it? What causes that? CRISPR. People are studying like how do bacteria defend against other bacteria? Well, they use this, it turns out there's this enzyme. And it remembers the sequence of this one bacteria that has come and invaded you before and then can like modify the genome and get rid of it and like kill it. Well, that same, you know, that same enzyme that would be which we now use for all this human engineering came out of a basic like how to bacteria defend themselves. It's not anything about like, you know, modifying sickle cell in the end. It was about how does the world work? My career is exactly as long as the lifespan of this field we call cancer immunotherapy. I did the first immunotherapy experiment. I injected a mouse with an antibody that I had made it was against molecules on T cells. And I'd shown already in the lab that that molecule caused the T cells to get more activated when you blocked it. And we did a series of like other mouse experiments of like all kinds of diseases and I kept jamming up the T cells and then, you know, Jim, my parents said, we got some tumors in the fridge and so we set up that experiment. And you know, you injected this antibody and the tumors melted. Well, that was the start of cancer immunotherapy. That's the, that's the, that's the origin of the experiment for which let's just be directed at your, your advisor won the Nobel Prize. Correct. Correct. Did you at least get to attend the ceremony? Yeah. Yeah. I was a little think this is how science works. Doesn't matter who did the experiment. Yeah. It matters what lab you're in. You know, it gets colder. The, the after parties were good. But I guess I'm not taking you back. Like we weren't trying to cure cancer when we started this. I, the thesis project when I went into Jim, this is my mentor at that point, the discussion was like, well, there's some molecules on T cells and I said, you know, we knew from AIDS and a few other things that T cells were important. So that was the attraction. And even though you had people say, why would you do immunology? Well, they seem to be interested. And there was a molecule and I was like, well, yeah, let's just see what it does. And once you saw you could turn things off, then everything became possible. Right. Now you set an immune system. You could dial up. You could say, well, if I could dial up, well, we'll happen to vaccination. Well, got better. It will happen to multiple sclerosis that disease got worse. You know, well, we'll have to cancer. Ooh, we can start to have an effect on it. And, and, and, you know, the x-ray, you know, the people were studying physics and then it turns out to be that they were like, oh, I can, I can, I can measure bone. And that's how we use x-rays now. Like to, you know, so there's all these examples that everything, you know, is it like the big things often come from these orthogonal directions and then we realize what it might mean. And I think you have to start there. Otherwise, you'll just plow this direction and you'll hit those walls because you don't have to work around. It comes with some orthogonal piece of information, the orthogonal meaning at right angles, right? So, you know, again, the crisper came from bacteria, but it's really useful in us as an engineering tool. But we wouldn't have known that if somebody hadn't been out there sort of saying, "Okay, well, how do bacteria do it? How do they defend themselves?" Oh, they used this answer. And I think that's a really important message that dispels this idea that everything is sort of like basically just easy for us to engineer. Yes, once you have the CRISPR tool, it becomes actually kind of easy to do some really cool things with it and still creative. But the fundamental leap that you're describing, I don't think in many of those cases that people were kind of conceiving when they were in the first drags of doing it, this would become an industry. This would become a whole thing. And maybe that's important because you need to foster that. If everybody always thought they were doing it to build a company and sell a product or something, then I don't think we would do the things that get us new. That's what we already know. That's human knowledge. We want to build human knowledge. And to build a human knowledge, we got to go off the piece. You can't ski on the slope. You got to be in the trees and maybe you'll block your head a bunch of times. I think that's the reality. And it's like, you got a lot of people out there that have decided to do that for a life because it's a chance to solve a puzzle. There's puzzles about how the world works. And if you've ever done a jigsaw puzzle with your family, there's always like, "Oh, you're getting in, especially in the end," you're like, "What pieces come together to do it?" I think that's what makes this whole science thing really fun. That's the reward is that you get the puzzle piece in. And you're like, "Oh, it makes sense that now I know what I've been building. I've been building this puzzle." Then you go back and you do it again because that's really satisfying at the end of it, even though, you know, again, with the family puzzle, the first parts are so hard. Thousand pieces. And you can maybe find the edge, but the intervening where there's like all clouds. Super hard. And I think that's what science is a lot about, is doing that. And then realizing what the picture is, what is that picture of it? And then all the breaks are off. I often tell people that if an experiment, experiment you'll do in lab has a 10% chance of yielding anything interesting. You've got to do at least 10 to even meet the fundamental stats. You actually have to do quite a few more. So that's where it's not a cost-effective thing. It's really difficult to be a scientist because there's no quid pro quo. There's nothing to say if you put in five hours that you'll get five units of goodness, of knowledge out of it. A lot of times you get zero. But then sometimes you put five, you got 500. And those are the jackpot moments where you're like life. It's like life. It really is. It is. I have to say, anyone who's considering a PhD, we had a call in from audience recently and so and said they're finishing undergraduate. They want to go to the, or finishing graduate school. Should they go the research route? They want to do a post-doc. And I'm like, yes, yes, and yes, I, rather than answer publicly, I decided to just have a call with this individual because it's rather niche-quatch question. But I mean, also just in training your reward system to work for five years on something is so valuable, especially in this day and age, because everything else feels like it comes at like warp speed. Yeah. And to just put steady pressure on something with all the failures and all the things and then to finally complete something, a lot of people think it'll be underwhelming. I think quite the opposite. It's like anyone that's like Donna triathlon or raised a kid or done anything you're like, oh my goodness. And that never ends. There's nothing better than these long-term investments. Nothing. When they break through that, you're an analogy. When you break through that dam or when you realize sometimes that you break into the dam, that's one of the funny things about I think science. And maybe it's true in triathlons, it's tough to where you realize that you've all the sudden got somewhere. I haven't done a triathlon, so I have to be fair. Rob or producer, Sidney. To our left is he has done many iron man's and he has that mindset of just steady pressure. I mean, his relationship to work and effort is remarkable because he burns so little energy worrying about things that we refer to as in the left column, like the stuff you can't impact and just focusing on what you can impact. And so a lot of it is about learning energetic control. Like doing science that is or anything is about what not to think about, what not to force yourself not to do or think about. If I may, I'd like to shift us to this very interesting area of immunology and biology, which you refer to as spatial biology. And I'm going to pose a question that may or may not fit with this framework, but either way, I'd like you to educate us on it. I'm fascinated by these old kind of barbaric experiments in medicine. Wonderful book, by the way, folks, is the Prince of Medicine about Galen. If you ever want to learn about how we learned about medicine back when it was truly barbaric and it was like surgeries done on warriors and without anesthesia. We've known for a long time that if somebody got forbid has a finger locked off or a hand locked off that might actually be a worthwhile investment to make an incision in the gut and stuff that thing in the gut to keep it warm and keep the tissue viable for regeneration. Once you try and put it back on, it turns out that's true. Is that true? Yeah, there's a bunch of juicy stuff in the gut that maybe it's the warmth, maybe it's the immune system. Maybe it's the lack of infection from being inside as opposed to outside the body. Who knows? Got you mean the intestine or you mean the stomach? Within the stomach itself. Yeah, I'm not suggesting anyone do this experiment. As I started reading into this, I discovered that there are a lot of really cool experiments, not just in limb or tissue preservation and restoration. Like for instance, I've talked many times on this podcast about the fact that above the roof of our mouth, we have the small cluster of neurons, the superchiasmatic nucleus, the circadian rhythms of every cell in our body from the genetic to the transmitter level, peptides, et cetera. Keeps us sleep-way cycles. Does all the organization that we need for circadian rhythms so much so that you can take just one subpopulation of these neurons, the cowbinden expressing superchiasmatic nucleus neurons. It's like 5% of the total neurons in this already tiny cluster of neurons and you can transplant them pretty much anywhere. And certainly in the brain and you'll restore the circadian rhythm of an arythmic animal. Okay. So that tells you a lot of cool things. It says, okay, there's probably something that's secreted or but like these cells are that important and it doesn't really matter where they are at least in the brain. They can do what they need to do, which is super cool. And then I started reading about, oh, like you could actually take perhaps like a little bit of pancreatic tissue and like stuff it in the, you know, under the skin. And that's not- It's not ideal, but you get some function back. So I'm fascinated by this because we like to think that the organization of our organs is so critical. But maybe they just need to be there. Now no one should test this hypothesis unless they have to. But when we think about the immune system, you describe the function of the thymus beautifully. You talked about the bone marrow, but you also talked about the massive migration of these cells that are working in this network. How important is spatial compartmentalization of these cells or is the rule eliminate spatial compartmentalization in order to make the immune system function at its best. And there's a very specific practical question. Okay. What I'm asking this, but I'm just going to tuck that away to peak people's interest and I'll get to it. But this is relevant to how we to decision important decisions that we make. Yeah, I believe. Well, the answer is yes and yes, you know, it's both. So although I described the immune system in the earlier part of this discussion as super migratory and you know, HHS is a ride in the blood, gets into tissues, it travels through your lymphatics. There are these things called lymph nodes down the lymphatic tubing, which for those that don't know lymphatics are like drainage and so you train the fluid back out of your tissue. So although there's these mass migration of cells, there's also in, like even in just in T cells, there's T cells that lodge in particular settings and they act to protect that tissue and they're resident cells of those tissues they never leave. And so both are true. You have parts of your immune system that are protective or nurturing of particular areas and others ones that are circulating and can hit any spot. You know, going back to your idea of organs and such being moved, I think there's two components to that that you might be thinking about. One of them is the question of whether the organ can survive in the new space. Like does it have the growth factors and the blood flow and the lymphatic outflow and maybe even some neuronal activity that makes that tissue work? So that's why you're like if you take the pancreas, you can famously put it underneath the kidney capsule. Kidney has kind of like a skin around it. You can tuck some some pancreatic cells in there and they're super happy. They love that. They get all the blood flow they need and it seems to be just right for them. But if you've got somebody with diabetes, for example, and you try to put new pancreatic cells in anywhere in their body, the immune system will attack it just as it did the first that diabetes for those type one diabetes or it is caused by the immune system. It gets too active against the pancreas. It's autoimmunity. It's where it's now saying the pancreas is not self. It's something foreign and it wipes it out and that's the source of what I said earlier. Like your immune system can be quite dangerous. So like when you talk about this concept of like spatial, there's a few things to bring in. One is does the organ can the organ get what it needs? And then does the immune system accept it in some ways in that environment? And that's where like some of your immune system that lives spatial in certain areas is going to be very defensive against whatever it's you know, specifically in that area. But may not care what's happening elsewhere because those cells just aren't, it's not like the brain where you like if I do something here, it's sensed in my brain. It means system that if it does, if the cells don't migrate, they don't have really a lot of ways to communicate. They can they can hitch some signals on neurons. And that's a really interesting thing we can talk about the capacity for your brain and the, you know, the insulin cortex. There's a great set of stories emerging about how your insulin cortex can program your immune state into organs and can move. via the Vegas can essentially program in the levels of calm or stress or by thoughts themselves. - Well, the latter one is the one that gets me super excited about the possibility that you can have triggers for thoughts that, so the insert cortex, as I understand it, it's a source of some of our moral decision making. It's also thought to be the part of the word brain where if you cut your hand and I see it bleeding, I can feel it in my hand. I can sense it in the sense of each other's pain. It's a set that this very nice, Israeli group to this, Roy Slab to this very nice study where they dozed into the guts of mice in inflammatory bowel disease. They fed them a really kind of weird sugar that causes them the bowel to puncture and then they get a really bad stomach ache. Some of the pain in inflammatory bowel disease, diarrhea. And in that period they used, you know what dreads are, so they marked for the crowd. They used to wait up to mark all the neurons that were firing during that period in the insert cortex. And then later they could fire them like after the mouse had recovered and they saw evidence that the immune system was resetting up itself in the gut as if it had just been punctured, you know, like with this. And the cues for that, in that case, were a drug. But we know that we can, you know, cue the insert cortex like me watching you do things. So it's always, it's maybe wonder whether, you know, like some of the things we smell, cut grass and we can, you know, instantly take us back to a whole bunch of thoughts about how we were when we were kids and maybe even make you feel a little like that. Whether there's aspects to this, to which are, you know, our ability of our thoughts to control that region are going to be revealed to, you know, to have potential that you could train, you know, train yourself to, you know, to bring up an immune state in a particular tissue. And just so we make sure everyone's on board what you just described, because there's a lot there. If I understand correctly, we know that the nervous system can do contextual learning, like a, like an animal or human. Yeah, just keep it a humans gets shocked, scared, or traumatized in a given region. Or even I've had friends visit San Francisco and get their cars broken into and their computer stolen. You can develop a context dependent or end or place dependent memory where you kind of don't like San Francisco as much, even though the rest of the trick was awesome. That's a pretty broad interpretation. Or you have a great experience in some place. And you actually really love San Francisco because you met your future spouse there or you just had a particularly awesome experience there. And if it was just in one part, you might feel better about your computer getting stolen anyway. Okay, insolesce seems like a, you know, let's take the positive example. Let's keep it positive for a moment. I think what you're describing is that if we remember the positive thing, if there was a positive immune status associated with that, the immune system is also part of that contextual memory. And so merely by recalling the positive or negative, but in this case positive memory, we can also recall, we recall not just the memory, but also the body state and the body state includes the immune status that accompanied the positive or negative event. That's what these studies are starting to emerge. And that's cool. That's really cool because we've heard for so long that we know that chronic stress impedes immunity. We also know that acute stress boosts it. And that's something that, you know, with all due respect to my colleagues who've focused on the ill effects of chronically elevated cortisol, like the immune enhancing effects of acute cortisol and stress are really important. And I think they've been overlooked. But I love this because one of the problems slash luxuries that I have is I sit sort of at the interface between like real science and biology and like what most people perceive as complete nonsense whackiness. But more and more we're finding that's within the complete nonsense whackiness, they're kernels of truth. Like that you can actually meditate your way into a better state, which helps serve your immune system and so on and so on. And that's seeming less and less whacking even outside California because of studies like the one you described. - One of my friends who's a faculty at the end of the minute at NYU, we were talking about the same study and he was like, that may be what meditation is doing. Is it maybe allowing your brain to communicate and reset less inflammatory states across your body because of this axis? And the study was really, I think it was, you know, there's still work to be done it. But the fundamentals of it was in the actual event there were certain cells that would accumulate in there. And then in the induced event when you made the brain fire again of this mouse, you would see, you're not as profound, but you saw this evidence of these same sorts of cells accumulating there as if they, you know, they're ready for that inflammation. And I think what we're talking about is the idea that you could have that go both directions. And again, you know, the concept of, I mean, I'm sure you've talked about this before of meditation where the idea is that you, you know, it's one of the ways that you can control your autonomous nervous system through your breath that happens with meditation. I think that, to me, there's something to intuitive about that. But, you know, I just an hour ago, warned you about the problem of science being intuitive that some things that make, that they sort of make a great story in our minds that don't turn out to be true. But the data on this insert cortex thing is starting to look like it's a real thing. Like there's a real connection between some of the peripheral states and like a regions of the brain. And however those are triggered now, maybe, you know, again, I thought that well, maybe when you're healthy, you should smell like mint. And then when you want to be healthy again, like, you know, there's, it's kind of crazy thoughts, but but again, there's an element of that that's intuitive too. So that seems to be the case. My mom makes me a comfort meal. Is it really the meal settling in? Or is it just that that the sensations that make me feel like, you know, less, you know, stress in one sense? But maybe also to this point, and literally resetting your tissue. I'd like to take a quick break and acknowledge our sponsor function. Function provides over 160 advanced lab tests to give you a clear snapshot of your bodily health. This snapshot gives you insights into your heart health, your hormone health, autoimmune function, nutrient levels, and much more. They've also recently added access to advanced MRI and CT scans. 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But now with function, it's extremely easy and affordable. A function membership is only a dollar a day, $365 a year. And if you think about the information it provides, and the health challenges it helps you avoid, and the proactive things that it can do for you to enhance your health, I truly look at it as a savings. To learn more, visit functionhealth.com/huberman and use the code "Huberman" for a $50 credit towards your membership. Again, that's functionhealth.com/huberman. I'm always struck by extreme personality, but in both directions. So there are these people who just say, like, I don't get sick. And they don't get sick, and it's super frustrating. Because I'm not one of these people that's very sickly, but I occasionally get like a sniffle or a cold or something, less and less with each year, because I do feel like pay more attention to the sleep piece. Then I certainly then I did when I was a graduate student post-alcohol junior professor. But there does seem to be this quote unquote positive or let's just call it a reinforced mindset, as opposed like an immune reinforcement associate with mindset, because some people will say, like, I just always get sick, and I believe them, they always seem sick. But it could be that you get sick in a given environment once, and then you just decide that you're sickly. So then it could be that the immune system is listening to these thoughts, but not in the form of words. I think this is where it gets hokey for people, like real biologists and physicians like, yeah, you gotta be kidding me. But because the immune cells don't listen to thoughts, they listen to brain states. - Tregers of some sort. - Tregers of some sort, right? And then there's like as humans, we have this obsession with language that makes it seem like you can write affirmations and then it's the word content, but it's the feeling state associated with that, that at a biological level makes total sense. So we were talking about spatial biology, and the fact that you can talk some pancreas in the kidney, and unless someone has type one diabetes, a lot of the functions of the pancreas can still exist. Or transplantation of these clock neurons, and clearly there are limits to this, but in the context of the immune system, I'm wondering can we take a little bit of thymic tissue, bank it, and then just later, like put it in a slow release capsule under our skin of our hand. And that might sound crazy, but I have friends, one of whom might be at Duralink now, who actually embedded a little radio receiver under his hand to be able to open his locks at his home and his car and his wife might have one also. And that might sound really like Bay Area, like future tech kind of wacky biohacking. But if I knew that I could be much healthier, like taking a few thymic cells and sterile capsule and sliding it under the skin, people get their ears pierced with, you know, - Right, less invasive procedures, why not? - Well, I mean, the question is, why would that, you know, is that likely to work? You're basically, remember how we're just talking about if I do 10 experiments, one might work. Yours isn't a bad idea, but, you know, is there, it's more than likely at one of the nine out of 10, I would guess. - Sure, but is there a correlate from any studies on animals? Well, we know that in a lot of studies of cancer and tumors, I used to see these mice down in the vibrarium, they would slide tumors under the skin. - Yeah, yeah, study them. - Yeah, I think give animals drugs or give animals stars. - Very common, yeah. Tumors are happy to thrive in non-environments. - Sure. - So why wouldn't healthy cells? - No, I think you can. I think one of the things that comes into play a little bit about that, that's more about, you know, replacing an organ with one that might be better is that at some point, if you come in, so one of the challenges of tissue engineering is if you wanna bring in new genes, the vector, the material, the surrounding, whether you're using a virus to bring it into those cells that you're gonna now put into the person, whether it's a virus or a small piece of DNA called plasma, you effectively are giving that a new bit of identity. And when you go to transplant that organ back in, it's seen as foreign. And it's just like you just put an infected cell in you, as far as the immune system knows, all of a sudden, there's a cell with a huge number of new things being expressed in some of them viral, literally. So, you know, that represents an issue, I think when we talk about any kind of, you know, sort of engineering at the point, you know, the moment is, is if you engineer a system to be maybe better, the immune system isn't necessarily gonna want better. And so you have to overcome this issue of tolerance, maybe at the same time. And again, that's what that particular experiment, depending on what you're putting under the kidney capsule or whatever, it matters, what the immune state is and what that thing is, as to whether your immune system is gonna let it fly. I'm not considering doing this. I just say, I think we are, I don't know how old you are, but I can guess based on some mutual friends we have, but I'm guessing that a lot of people who are able to understand speech, they're old enough to understand speech, are thinking that in our lifetime, we are going to be able to use our own cells or peptides or synthetic versions of peptides from our own cells and so forth to overcome a lot of the issues that our parents and grandparents were not able to overcome. You know, with regards to like the peptide side of things and even the cells, and this is maybe where you're going with space, is that context does matter for the immune system. So, and it matters for all biological systems. I'll just give you an example. We did a study of wound healing some years ago. And if you have a wound in a mouse, it's maybe just a, like, if you ever have a melanoma removed, they do a punch biopsy, it's a little circle. So you can do that in the back of a mouse and then you can watch the wound healing happen. The, there's zones within there where certain biology is really important to be happening. And then, so, so imagine the wound is like this, and it's open. The cells, like one layer back are doing certain things, but the other ones behind that are also induced to do so. The wound isn't just this area. It's actually sensed all, like, a gradient, almost like in the neurons. And so these cells need to do different things than these cells. So if you wanted to administer some, you know, like a peptide or even just a cell type, you have to be a little bit conscious of like, where it's going to do the work you want it to do. And the natural system does that naturally. Like the cells on the inside actually instruct the cells one layer back. But you don't necessarily want everybody getting the same signal. So like development happens that way you know about gradients and we were talking about this earlier, that there's gradients. So I think one of the tricks that we don't really understand about this is when is something good for a process? And when is it only good when it's given in the right dose at the right time? And I think that's one of the tricks about some of these things. And again, that's where, you know, both in the lab and, you know, like I would say that more so than ever in our lives, you know, we're seeing, you know, people kind of like experimenting with things on themselves. And one of the sad parts about this, we don't capture a lot of data therefore, you know, because it's not seen as a study. And we can't say everybody that took this gets this result. And then you have this rise of things on the internet of anecdotes that become seen as data. Like I took this thing and this happened. And that's, you know, I could drink this drink in. I mean, great happen to me or something bad happen to me. It might have nothing to do with the drink, right? You know, that issue is one that I think is really critical in this window of time right now. And I don't know what to think about the idea that people do experiments on themselves. I think we all want to improve ourselves. We all do some kind of experiments ourselves. I really read a book. You're trying to improve yourself, right? The physical one gets a bit tricky when you're not sure whether something's going to be dangerous or not. And I'm not promoting that people do this. I think that, of course, you would want to see preclinical, clinical and other trials for this. I think I would personally. I mean, just, yeah, I mean, I, there are a few areas where I am a bit more adventurous, but for the most part, I'm like, you know, based on my training and background. I have to orient toward, you know, I'd like a bunch of, but let me put this way. I'd like a bunch of other people to do it first. Yeah. Like who would? It's fun to be first unless you're doing something really stupid and that can get you killed. In which case, like let other people go first. Yeah. Well, I think a good example that right now is, in this is, you know, sort of nationwide or even international, is vaccine hesitancy? I know this is a touchy topic. So we can know that you can feel open. Well, I'll just point out that the one group that's completely, no matter whether there has it in against childhood vaccines and the number of one we get and the fact that the government makes you take them in these first things, if those people have cancer, they're very interested in vaccines. Because there's really good data that you can promote more immune cells against the tumor by making a vaccine that consists of some of the proteins and peptides that are unique to the tumor and not different from you. And you introduce those as if you would introduce the virus or anything in a childhood vaccine, similar concept, just different peptides, their peptides from the tumor. And in those situations, it's context, right? So if you and I had cancer and we don't have the conventional curers are not going to work on us, we know there we know statistics really well. Kimo is not very good for a lot of cancer, but the only thing we got. But if you have access to something that's relatively new and particularly vaccines despite what some people worry about, they're pretty safe. And so the certain dive versus try out a vaccine drives a lot of people to be interested in vaccines. And I would say, yeah, in that case, it's a really, you can see where people's, their question about whether they're going to try something or not is very context dependent. Very, I think I don't want to go too deep into the vaccine debate. And I don't want to be a spokesperson for either side because that's not my role today. But I think that the, the what you refer to as vaccine hesitancy actually comes back to an earlier issue that maybe you'd be willing to comment on. Sure. Which is, I think there are a very large number of people for whom they are neither anti vaccine nor super pro, but they are, they're asking about timing and combinations. They're saying, OK, listen, and we had Jay Bhattacharyon here. And I've had several others who said, maybe there should be an investigation of the spacing of these things. How many? How critical it is to do it a given age, you know? And on and on, we can pick any vaccine for that reason. And as an immunologist, do any of those questions make sense to ask? I mean, I could see how, you know, bombarding the young immune system with a lot of vaccines is a very different thing than spacing out the delivery of those vaccines. I'm not saying don't give them all. I'm saying over what time window does one give them? I think a lot of people, many more people are asking that question. It's just a quieter murmur than are saying, listen, we don't want to take any of these things. Yeah. We don't want our kids to take anything. What is that to? And I think there's some fair aspect to which most of these vaccines were not studied in the context when they were studied of what it does in combination and in these sorts of timings. The fact is that the evidence that there's bad things happening doesn't look to me tremendously strong. It's almost like anecdotal sort of information. So unless it's your kid. Unless it's your kid, in which case, you're going to look for an explanation. So I don't know. Just being fair as long as we're admitting psychology as a factor. Yeah. Yeah. So there's fairness on both sides of that discussion. And I think that almost certainly where we are now, there's probably ways to put together vaccines and certainly more convenient ways. It's as a parent, I actually had something very similar where you delayed my first daughters for vaccines, partly because I know that there's a certain element to which when we design a protocol, the protocol for immunotherapy of cancer for patients was actually based a little bit on the mouse work, a lot on the mouse work that I did. You can imagine that mice and humans are quite different. But that is the protocol. Protocol is protocol. And that's how it's done in medicine. And that's because you have a fairly good sense of the safety of it because of statistics. But that isn't to say that it's the only protocol that would work. And I think you're getting at this concept like could there be at least a more convenient one? And that's the one that's the safest. Or safest or even one that is less disruptive to the lives of the children and the parents. We delayed one of our kids' vaccines by just a month or something because she had not been feeling well. Just straight up. And it is true. And I'd say that a couple of vaccines have come out that I've had recently. The shingles wanted a good example. I had it that is knock me completely out. And it's very, very heavily adjuvanted. So it's clear that it's having it. Does it need to be? I actually don't know. I don't know what studies were done. And there's kind of an aspect to which I don't know that we're all being-- shielded from the information, but I don't know that we all know how to read the information about how these regimens were chosen. Some of them were chosen by competing pharma companies that each make their own materials. And, you know, again, I think there's a there's a lot in this question. I don't know how much of it also represents one problem of science that I could talk about is this this issue that's a lot of science-street science is a kind of a papacy like we know the language we know the facts and we probably don't have time to tell you why we think this and where the holes are. It's easy for me for interrupting, but you know a huge basis of this podcast is to counter exactly that. I know. I mean, I know all these incredibly smart, incredibly well-meaning people who have lives of their own health lives that don't help challenges of their own kids of their own and on and on and no one was hearing from them. It was and as things get more politicized, there's less incentive to give nuance. I actually really appreciate you providing some nuance on the I mean, it's clear where you stand on vaccines generally based on what you've said, but you're offering perhaps the opportunity for better understanding and certainly delivery of the information. Yeah, I mean, it's a huge problem. Yeah. Well, I guess it's one of those ones that I can only speak about what I did, right? It's a human. When I had kids and I looked at the data and I have probably better capacity than some anyways to read it and look at risk versus harm, you know, the percentages of these things. I absolutely as you know, vaccines, kids and that was it seemed like it seems even now like a reasonable no-brainer, but I just told you too that I asked to go off protocol because at some point I know these protocols have a little bit of like, again, they were designed on one study, but it doesn't mean that it doesn't work if you wait another month. In fact, if you've done enough mouse experience as I have, you know, that when you vaccinate on a slightly different schedule, you can still end up with the same outcome. You know, that is protection, you know, with slightly different schedules. It's not that convenient for doctors and hospitals and even some of patients to get off on, you know, like weird schedule and then you forget a dose and then it isn't as effective, right? So there's efficacy that comes with, you know, trying to follow the protocol and because the protocol has some convenience built into it, that means you're going to do it. It's like it's like brushing your teeth in the morning, you do it the morning, the evenings, so when you do it, and so you'll do it twice a day. So there's a lot in this. I mean, you know, there's a lot of politics I think involved in vaccine two that relates to the question of like, what point can the government do tell you what to do, which is, you know, it's a surrogate question to the vaccine one. Where a vaccine is, you know, if there's a harm, who gets to choose what the harm benefit and then how resources are given out for like schools and you know, we know all these, we know all these sort of nuances. From the science standpoint, I don't think you want to wipe out the baby with the bath water. I don't think you personally, like I would not immunize my kids. Could there be additional studies about the combination of these into like fewer shots? I think so. See why not. Here's where you get the financial rise. What's the benefit to any form of company of doing that? Well, I think this is again, I have to be careful that I don't place myself into an advocacy group that I'm not. I'm, I look at everything on a case by case basis. I really tried to do that. But the, you know, and I've tried to be in recent years more open to the, to at least understanding what the anti-big pharma stance is really about. You know, it comes up around SSRIs, but you talk to somebody with clinical grade OCD and they will tell you that SSRIs saved their life. So you go, okay, well, you know, so we can say all we want about pharma. Are you talking about people getting in, taking insulin or, you know, until recently the GLPs were mostly available through pharma now. They're sort of, it's kind of wild west. People are micro-dosing them from all sorts of compounding pharmacies as their own issues and so on. But my sense is that the frustration around the kind of dictatorial, like you're going to do this at this point because this or else, like your persona non-grata, that kind of like people not, people being shunned in both directions, in either direction rather. That's, you know, that's really the source of the problem. There, there really hasn't ever been a conversation quite like this. Yeah, I agree. At least not when I've seen publicly, yeah, there are not a lot of labs that are going to devote themselves to this. People will wage the argument that, and I don't know if this is actually true, but that the pharma companies are protected against lawsuits about vaccine injuries. Yeah, yeah. I mean, I think that probably is frustrating to very frustrating. Excuse me, to a parent whose kids seemed essentially fine, got a vaccine, and three days later started exhibiting symptoms that then set them off on a course that was really, really tragic. Yeah. And those groups are the ones that have accumulated the most umph out there. Yeah. And if you think about those parents, it's totally understandable. Yeah. Why they would feel that way, whether or not the basis of their feelings is exactly right. I can't speak to what you can understand if your kid is one way out of the doctor's office is another way, and you can't do anything about it. That's got to be super frustrating. I mean, beyond madness. And the question is, what could you have done differently, I think, is in those situations, having been in them, not that exact situation where you said, oh, now it's done and now I can't go back where you're in. And you did that to them. This is the thing that, well, this is the thing I think that is not often discussed is that the parents made that choice on the basis of what they thought was the best. So that there's a certain guilt/anger. I mean, there's a whole psychology to it that's completely understandable. Yeah. You didn't wander into the clinic. Yeah. Well, I mean, you know, on the way over here, I was thinking about some of the things that, you know, are happening in medical space. And you know, you guys have obviously from time to time, talk about peptides and these sorts of things that people are using, you know, off-late, well, not even off-label, just getting them from from wherever the internet. And you know, I was thinking, well, you know, there's a funny thing there because the legitimacy of pharma companies has sort of fallen into even worse streets than before, because I think I was thinking about this a lot of it does relate to the fact that we are advertised to take a lot of things that often aren't, you know, the side effects are worse than the symptoms that we're leaving. And that sort of, you know, again, I may find myself like having a bunch of colleagues hate me for talking about this with you, but I do think it's kind of important at some point to surface where all this comes from, you know, and the idea that we can do experiments on ourselves on our own bodies, again, it's quite different to say read a book, although you can be infected by, we believe, like, by, you know, scripture and scripture and things in your behavior. But somehow I'm here this idea that, that, you know, we can be told to do things by people that aren't quite in our best interests. I think it opens up ideally, well, why can't I choose my best interest? You know, who are these experts that I can't always trust? What's more American than that? Yeah, well, it is, it is. It is part of the pioneer in spirit. Like if the government's not going to protect my 40 acres, I got to have a gun and protect myself. And that's been a part of our culture for a very long time. And I think this idea of individuality plays into this, but it could be exacerbated in a moment by the fact that there, you know, haven't always been good communication with somebody you're trying to work out and maybe even surfacing these ideas that are hard to talk about. Like, should we trust farm comes? I know a lot of people that work for farm and they really, they are doing good. They, they, you know, they're like you and me. They, they really think and they are treating disease. They're making really good drugs and they do really good things. But it's not always true. Not just because, you know, a bunch of people, and it's not always true that the subtle best interest of a corporation is the same as the best interest of an individual. So, you know, we have to surface as those things exist. It's not like we have to say that it's right or wrong or whatever, but at some point those kind of perverse incentives exist. I wonder why, you know, like, farmer companies haven't gotten better tests for who's going to respond to these checkpoint drugs that we made. We've had, we've had a few papers that show who are their spawners and who are not. But it's still a case that if you get to come in with melanoma, even though there's only a 50% chance you're going to be cured, which is great. You used to be zero with these drugs. You still take 100% of the market, takes that drug. Well, because the 50% that aren't going to respond, they don't know who they are. And so everybody takes it. So, the companies that sell those have no incentive to develop a test. Although, if they develop a test that shows who is and who isn't going to respond, they'll cut their market into 50 and an half. So, I don't think any farmer executive exactly out there are going, "Eh, eh, eh." But if there's no positive incentive to do that study, to study those things, then I think it's kind of true in some of these other drugs that we've been, you know, brought forward some of which are better and worse than others. We could tell them this is going to be good for us and we should take it. And there's a, again, you're getting to the American kind of mentality, which is to say, well, some point if you fool me twice, or, you know, I'm not going to believe it. And I might not believe it against an entire spectrum of things called science. And the problem is that there's people like you and me that are trying to actually do, and most of us, I'd say 99.9% of us are working our asses off to like, you figure things out and discover stuff that's important for mankind. And then you have these sort of issues that arise, and you're like, well, then should you distrust as a species, should you distrust the entire class of science? Probably not. You just need to maybe make it so that knowledge is freer and knowledge is better communicated and that, and that, and then you do watch out for those situations where there should be, you know, and maybe vaccines are one we, we, you know, we just need to do some insensible like what you're describing and just do a study and say, let's do that study and make that very public that we do it. And say you're going to do that. And obviously people can sign up for, you know, you can have this regiment or you old regiment or the new regiment. And we, you know, again, I may be speaking, I don't do vaccines. It's not what my life studies, but there could be some sense to saying, well, maybe science as a whole could take this on and say, What would be maybe maybe? the answer isn't just say no vaccines and we think they do, they're just good evidence that they're protective. But to the extent that you're coming out, could we make it less? Let's do it. Let's just do it. Let's do that experiment. But I don't see that. That's one of the things that's not happening right now. Is it nobody's actually just describing an experiment? What would be the experiment? Yeah. Well, the discussions haven't happened. And I should say a couple of things. First of all, thank you for going to venture into this area. I seriously doubt that any of your colleagues are going to be upset that you're having this conversation. I will make sure that anything we put out is in context. And if anyone cuts a clip, I will be the first to dive in there and say this is taken out of context. But to any people, colleagues or otherwise that would say, hey, actually, this is the wrong stance. You don't want to be talking about nuance in a time when there's so much threat to traditional medicine and vaccines, et cetera. I will say this, the idea that you need to push back with just a fire hose of do this or else did not work. The pandemic proved to that. In fact, I think one of the biggest mistakes was to have one individual as opposed to a panel of people with more nuance, communicating public health information at that time. Any person, scientist, doctor or otherwise who thinks that the way to convince people to change their behavior around vaccines or anything else is to just ram it down the public's throat and say, or else, whatever, your political day. So you're a fascist or whatever. That is proven to be wrong. And the path forward is really this kind of conversation. It's highly educated people like yourself, educated in the immune system who understand this, who have children, who made certain choices saying, yes, and I can understand why you would be considering the following questions. We should do a study. And in the meantime, you're not preventing anyone from getting vaccines. There's now hunger for more nuanced conversation around these things. I think it's the right time to have it when we're not in the throes of a pandemic. Yet, I mean, there's some things that are on the rise. It is scary. I'll be quite blunt. You know, the rise in measles is scary. People say, well, measles, they used to have measles parties. Talk to somebody who had massive inflammation and brain inflammation from measles. Not a pretty picture. So I think it's great that these conversations are starting and it won't be taken out of context. Yeah. Well, I mean, the vaccination front, I mean, I just wrote a little, a little sub-sec also about, you know, the origins of small vaccinations. And I think what's lost in those stories is if you look on the internet, the absolute, that's a terrible disease. I mean, the reality of what we're protecting against, we haven't, it's really hard to like also have the conversation without doing a little bit of reading into your history. And I don't think the history books are pulling the wool over our eyes by saying some of these things were really horrendous. That's what box was dreadful. So there's an element of that though that I think, you know, that we have to make sure that the conversation focuses on what are we trying to achieve here. And sometimes that question can get lost. But I think, man, if my kid got smallpox or got measles or got moths, and you know, as we know, like measles is not a theoretical. Again, you know, that concept is enough to say, well, there is a risk of that. And that's one where you, it's like you, you know, not teaching your kid how to cross the street properly if you didn't do that. And then the kid got hit by a car, you'd just be decimated. So, you know, just because we haven't seen these things for a while doesn't mean that they're not still real. And I think that's also an important, I think that's what, that's me as a parent. And like, I did look at the history and if these things, they really are bad. And so we are, you know, we are defending against something, but, you know, is there a better way to do it? I mean, propose experiment. That's, that's, you know, I think there's a, you know, the cutting off, you know, the concept of human curiosity and science at the legs is probably not the way to figure out something out from my experience. You, you, you dive in, you think of the experiment, you will answer the question and you say, well, that, is that the killer experiment for this thing? Again, I think you look at the numbers and the numbers for my, this is me as a parent. Looking at the numbers of, of, you know, like the, the danger of, of bad stuff happening versus the, the odds of an adverse effect, they were all that high. But, you know, again, if you're one of the people that, even if it is that, even if it is, don't cause bad effects. I mean, which I don't, by the way, can I tell you a little story? I'm pleased. Maybe you know this already. But if you want to induce autism and mice, people do it by injecting a bacterial infection into the mom when she's pregnant. Which tells you that an immune challenge can affect the neurons of the, of a developing pup. So it's not outside the realm to say that in some situations and an adjuvant situation, again, I get, I may regret saying this because it's, you know, it's, it's going to open up a conversation to have this, but it's a, it's not outside the bounds to say that a, a, immune insult will have influence on neural development. Period. Is it the source of autistic children or was it in fact that the mom had, and infection during pregnancy? Yes. Not absolutely wacko to think. And you should think this is a neurobiologist. I think you'll probably agree to think that inflammation, some of the molecules of inflammation, will affect the, the cells of the brain. Yeah. In fact, one of the, one of the best experiments that I look along these lines, it's not about, about autism at all, but it's about, when you get a flu, you tend to go, you tend to feel like you want to social isolate yourself. At least I do. And most people do, I think they kind of want to crawl in a hole. They call it a hole field. There's an experiment that was done that involved injecting gaminer fear on, which is one of the things your immune system makes when it's fighting off an infection into the bloodstream of a mouse, and then just watching it. And they become, you know, social isolating from just the molecule that's made by the immune response during infection and from being sick. Not even being sick. They're not sick. They just are given this, this cue that's part of the systemic immune response. And then they, they show signs of social isolation. And the lab that did this also showed that the brain has receptors for these immune molecules. And you know, the simple conclusion of that paper is, you know, there's still always work to be done. But simple conclusion was that the brain could sense infection and it would affect behavior. Even in mature, you know, in us as mature. So you know, again, there's these, these ideas that there's, there's something that, I mean, the scientists use that infection of a mom to lead to neuronal changes that lead us to be able to study autism in later mice. So there's definitely potential there. I don't know that the vaccines and all of them, or whether there's a circumstance or whether it's, you know, getting the mom actually had a fever before in the vaccine now just trigger or it didn't, or just circumstance because you give vaccines at two years of age, which is when autism appears. There's all kinds of options, you know, and the sort of anecdotes of that. I just think that that fact that, you know, the way that we study autism is by giving a pregnant female mouse an infection is sort of like, okay, that's important to know. That work is still ongoing by laboratories to understand autism. I want to understand the origins of it. And maybe we'll not turn out to be vaccines at all. Again, we need data. And we're definitely need data. We're almost in a COVID situation. I just grabbed the COVID situation now in retrospect as one that is data sparse. And this is why I've been trying to work on. I was telling you about this project of trying to work on the publishing problem, but it's not just the publishing problem. It's how we synthesize knowledge that under data sparse circumstances to make decisions, I think we're not very good at that societally. And when we have tons of data and it says, absolutely, if you have cancer and you take therapy, then there's a 50% chance you're going to revive. Great. Those stats are solid. They're very good. And I would take that drug every time. But if it's sort of a case where you're like, you know, there's some things that are happening and some other things that are happening. You remember the beginning of COVID, we talked about it amongst ourselves in the levels. And we were coming in to analyze blood. And it was kind of unsafe because we didn't know what was safe. We didn't know how it was transmitted. We didn't know anything about it. It was, could we get it from blood? And that kind of went on for a while, right? And this was the source of like a lot of confusion that came from the medical, it seemed to seem disconfusioned. That natural factor like, do you mask, you're not masked, you're touching, not touching. I think that's a, that's a data sparse situation. You know, the data that we had was sparse. It wasn't a lot of information. And so, you know, how do you make a decision when you don't have a lot of data? Well, I think that's the major argument. When they're, you know, there are people that will critique people saying, okay, your experience is anecdot, it's correlative. But then the, the, with regard to vaccines and autism and other issues. But then the pushback is, well, this vaccine, et cetera, was directionally guided by sparse information to begin with. Under times of pressure, there's financial incentive. So it's just this ping pong that goes back and forth. But many thousands of parents write to me and say, should I wait on certain vaccines? And I'm like, listen, I am not the person to answer that question. But you have every right to ask your doctor, right? But they're not asking because they're extremists. They're not anti-vaxxers. They're asking because they love their kids. Right. And they've seen enough things to call into question the incentives. And they just know that the conversation cannot be as polarized as it's presented to them. In reality, that the data cannot be as polarized as it's been presented to them. Yeah, certainly. Certainly, in media, some of these things get presented quite, quite, you know, inflammatory. And again, if newspapers want to sell a newspaper, they show a plane crash, right? So it's not happening every day. But they'll show you an airline ad in the same issue. Oh, is that true? Yeah. I think one of the interesting things that we could get into is that in a lot of these studies, scientists are, there's a motivation to. to make the most of your result. And we've talked about why that's important, is that if you find somebody to orthogonal, CRISPR, checkpoint blockade, X-rays, you look for that orthogonal use for it, right? And that orthogonal meaning, sometimes we call it extensibility. Like I see that if I drop coffee cup on the thing that gravity pulls it down, well then I can learn that I can drop all kinds of things. I can make gravity work for me, it becomes a tool. And I think one of the things that is lost sometimes is that some things are not extensible. So you can imagine that if I had something that makes a cell move, that that might screw up the whole system forever. But humans and our bodies turn out to be remarkably resilient. I mean we can go from minus 20 degrees to 110 degrees. We cannot eat for a long time. All these things don't cause us to fall apart. So if we didn't have resilience, I think our species wouldn't exist because there's all these pressures and all these varieties of life under which would lead. And I think a lot of science sometimes doesn't, you know, from the outside or even as an insider, you can read a paper and they point to why it might be important. But they're really doing that to get garnering interest for their story. And I then say this might be important for this, but I haven't shown this important for them. They don't say this important as it might be important. And they're trying to look for that orthogonal or that extensibility of it. And I think that's kind of important also just to go a little bit off this topic for a moment in how we think about drugging diseases as we go forward. And that is to say, we've looked for these one-in-done drugs that you take a pill and it cures everything, you know, forever, that's sort of found a butish. And you know, we found a few of those. I just say, check one blockade is one of those that you can take it and, you know, in 50% of melanoma is everything. The tumor goes away and everything's great. But most biological systems, if you have one button to push, they're super non-resilient. A virus can exploit that button, you know, that can cause, you know, in the collapse. And so most things are wired, like in these really complicated ways. And I think what a few of us are thinking, this is for cancer in particular, where you want to get the immune state from like, remember we had a little concept of a fuel gauge, you want to get it from one position to another position, it may not just be about a push here. You may have to push some cells that way, create some new environment that looks like development, you know, your cells develop through states. And you push the biological systems to reach this new state in a way that doesn't look like the linear between like low immune reactivity and high reactivity, you might have to push it in a series of ways because the resiliency, the systems like even in chronic disease, but even in health, we're pretty resilient. And I agree, you can stand up to a lot of stuff. Can humans do that even in the context of abundant funding for basic research? Can what you just described actually be tested to the point where we can develop things? And the analogy here is, I had my dad on the podcast, he's a theoretical physicist and he explained to me that one of the most important things you learn in physics is that you can't really understand quantum mechanics using your logical brain. You need the math to prove it. And this is when, whenever somebody, he also warn, whenever somebody says they understand quantum stuff, you have to ask them to demonstrate it for you. Because these people talk quantum because, and we make all these assumptions about quantum, they talk about quantum fields, so we think they're smart, theoretical physicists, and therefore engineers develop all sorts of incredible theorems and real experiments and then technologies based on all of that because of the math works, not because we can conceptualize it. And I wonder, given the complexity of biological systems, perhaps in 2026, we're running up against this barrier where, by virtue of the sociology of science, that papers need to have one, maybe two take home messages. I've heard you with the fact that there's a limited amount of funding, people need to sleep at night and on and on that doing the kinds of experiments, like you described, like pushing the cells this way, nudging them that way, and then drugging the outcome in a way that is beneficial, but not detrimental, is this a place where machines are going to be better or at least helpful in doing these experiments? I take the standpoint that AI's, and I think, you know, this is back to talking about AI experts, it's really quite good at producing stuff that is in the corpus. The corpus is the knowledge that we already have. Almost by definition, when you're coming at that with something discovery, you're discovering something, it doesn't exist in the corpus. You might have hints of it there, but you still have to do experiments at some point. So if I'm going to get answer the question, you're trying to raise, if I get a tumor from a patient and I take apart all of a cell, and I look at all the genes that are expressed in all the different cell types, I can build in silico a network where I can look at how all those cells are wired together now. And I can ask, you know, what would be the possible consequence of clipping this molecule's ability to touch that cell? That's now doable, but it relies on a area of math that's not really AI, it's called machine learning, and sometimes these things are conflated. A machine learning is basically looking to say, what are some of the relationships that I can discover about, you know, the relationship between this feature of the cell and this other feature of the cell. So it's learning about it, and then it allows you to propose a bunch of experiments, but you still kind of have to choose and select which ones you're going to do. Some experiments are just really expensive. And that's where you have to have, I think, still human judgment that comes into that and say, am I going to spend a year studying this question? Am I going to study a little bit more and try to understand some things in a greater detail than maybe the machine learning gave me? But it's not clear to me that anywhere right now we can say the corpus of knowledge doesn't have a bunch of examples of cures across from treatments and say, oh, all I need to do is mash those up, which is kind of what AI does when it comes to large things. You query it, it looks statistically and says what are the relationships between what you query and what I give you back as an answer. And in discovery space, we don't have examples of the other end. We have, you know, sure, I can tell you all the things you could do, but knowing which one is going to be orthogonal big hit isn't there. But what I'm talking about a little bit is to take a problem apart and say, if I have something like I want to change something and anything, this could be how if I want to change the world, it's unlikely that when you one act, we'll do it. The world is pretty early, political systems despite what we think are somehow semi-stable. But a series of these nudges can create the condition where the last one takes you across the border and I think that's what we're going to have to do in disease where we say, look, nature doesn't necessarily want us banging on it, it'll bang back. What in fact we need to do is if we want this tumor to get you and get a new leader first, let it not look like it's a wound at ceilings. I don't give it the power of the immune system, the positive power, and then get to the point where we can say, well, now we want it to teach the immune system to kill it. But we might not be able to do that until we kind of disemble some of its defenses. And that's a way of, you know, again, in this kind of deep computational space, we end up with a lot of feature of tissue cells and how they're organized and what genes are expressing. That start to look like Magellan's map of the world that, you know, in its early phase, it only had parts. And then, you know, it starts as you explore and you add things to it. I think when we start to think about how tissues are configured, we're starting to be able to see these really complicated states where the immune system is doing this and fiberglass, certain cells are doing this and epithelous cells are doing this. And that's a, that's a, we call them archetypes. They're like a way that biology organizes itself. And to get from one to the next, we need to understand how it does it developmentally. That would be a really nice thing to follow. And then we need to give those cues in order. And that's where I was coming back, you know, when you were talking about peptides earlier, and I was saying, well, some of these drugs may well work. But I might imagine that they might work best if given in the right sequence and the time and the place and that that's when you really want to like, hammer it to get the system to go to that. But then it might be connected to another one. And we all want to find the one thing that like, you know, the founder of youth, the thing that cures it as ease. And it's been forever that we've been looked for single, you know, single hits one and done. But it may be a collection of, and you know, this is probably this is how I live my life for health is. There's a collection of behaviors and food you eat and sleep you get and all these things create partners, you know, your loves of your life, the friends you have, they're all part of I think this, this, and that's getting a little away from you, I mean, I'll obviously about it. - No, but not knowledge. - This isn't an analogy. - You think about the insula, you know, not so much a good friend of mine who's a physician in the Bay area says, you know, better living through chemistry still requires better living. Which I love because it says you should never abandon as much as one can. The foundational stuff of sleep, exercise, nutrition, circadian rhythm, light, social connection, stress mitigation and on and on. Could I ask you a couple of additional questions about the immune system? - Yeah, please. - Before we wrap, because I know many people are curious about autoimmune issues. More and more, I hear about, you know, I don't know if chronic fatigue considered an autoimmune issue by most. A lot of people seem to have chronic fatigue, there was a debate, does it really exist? For someone who believes they have it, they it absolutely exists. They're tired, I believe them. I know someone who had myalgia recently, psoriasis is something that I maybe have known to be now autoimmune asthma. These are interesting conditions, not all of them life threatening, but some of them cause a lot of discomfort. What is known about the formation of autoimmune conditions, either inheritance, lifestyle factors? And then what excites you about some of the newer treatments that might be available or currently available for those and other things? It's a big question, but. - Yeah, it's a big question. Well, I think that's a big question. So fundamentally, again, this is I think where the immune system and our bodies have, I think they have playbooks, like a football team or something that they can run and they can put players in particular configurations. Again, we call those archetypes. The immune system is trying to do a certain kind of thing. It's genetically and through history, it's wired to work with cells in certain ways. And I think if you look at autoimmunity, there's a view of them that they represent a misplaced immune system that's easier, thinks that it's under attack or thinks that it's meant to be doing something that it really isn't. And so the origins of some of those are genetic for sure. There's a lupus, there's a familial mutation and a receptor that's on a B cell that normally helps turn off the immune system and it's defective. And so those people are susceptible to getting what are called auto antibodies. That's where the B cells, we talked a lot about T cells, but B cells are the ones that make antibodies and they're the ones that you try to prune to jazz up for COVID vaccines. Those can be overactive and they can be genetically overactive. One wonders why we'd ever have such genes and why they'd be propagated except that maybe in some circumstances you need it when there's a big pandemic or something that those people might have a particularly good response. So there's definitely genetic origins of some of these things. I think what's interesting to some extent is something that you alluded to with asthma, asthma was one of these things that historically would be called an allergy and it still is an allergy and where you have inciting things that are grass, pollen, these sorts of things. But in a lot of these settings, the concept that is coming in part in parcel with the immune system recognizing itself is a thing. To the degree that we don't understand some of the diseases as well as we should given the tools we have today, there's a lot, there's actually work to be done in a lot of these areas where you say, what is the immune system up to? Ten years ago we might have just said, well, if I might have taken a lung of an asmatic patient who died and cut it and look at it on a microscope and say, oh yeah, I can really see that there's thickening of the airways and that's why they couldn't breathe. Like I'm saying, now we can go into those and we can look at every single cell and ask, how those are wired together. Is there only one form of asthma? That's no. There's actually definitely those seven or eight. And that's why some people can take the inhalers and it works and other people can't. Some people are very chlorine sensitive. They go to a pool and it initiates their cold sensitive. So there's variations on what sets up that inflammatory focus and I would call it like an architect. Some of them have lots of cells called ESynophils. Other ones have lots of cells called neutrophils. So it's asthma isn't just one disease. It's one symptom, difficulty breathing, but it has many different configurations. And I guess I would just say that in a lot of this domain, we have a study right now that's looking at across a bunch of autoimmunities to figure out whether they have things in common with each other. And psoriasis is one where you start to see variations and lupus for sure and inflammatory bowel disease. And you know this in the clinic because inflammatory dialysis, you ask about drugs is a good case where there's a couple different drugs that for some patients work really well. TNF therapy for example, as a block of cytokine. And some people with IBDs is like really bad diarrhea and it's in manifests and very very painful. You know some people they this so there starts to be classes of patients that have responses to these things. Those drugs are exciting because they say you can modulate this. But a little bit like the checkpoint drugs, we don't really understand why one works in one patient and one doesn't. In inflammatory bowel disease is an autoimmunity is pretty tricky too because people will respond to a drug for a while and then they'll stop. And then the doctors just have to do this like whack-a-mole thing where they try one and it doesn't work. They try the next and where it doesn't work. It sounds like psychiatry. It does. Yeah, there's a lot. It sounds like a no disrespect to the psychiatrist. No, but you're trying to have a hard job right? I mean drugs will work for a while then they don't work. Don't work. Side effects crop up. They never existed before. It's a tough one. Yeah, agreed. Agreed. So yeah autoimmunity is a real thing. It has, you know, I think it's similar to cancer where we're just with cancer starting to understand the fact that it comes in these different immune flavors. And so the drugs that you try to use, it's clearly immune system can do a lot of good work for us. But what you need to do to it in these different sort of archetypal immune systems is going to be different. You know, you just go to different football team out there playing or they're running a different play. If somebody has a mild autoimmune condition like let's say mild psoriasis, does that, I've read, but that doesn't necessarily mean anything. I've read that that might confer because it's autoimmune that might confer them with a bit better viral and bacterial infection resistance. So there's a trade off there like, okay, so scalps, you know, cells are like sloughing off and like I think it's like an interleukin 17 or something now like the treatment. They have some good shampoos for the cancer. But anti-antirleukin 17. Yeah, yeah, interleukin 17, but you that individual is maybe better at fighting out other infections. So you know, given there's a anti-interleukin 17 treatment that works well like no flaky itchy scalp and yet you're more resistant to infection. So you could see how it's adaptive in the modern context. And now severe psoriasis can be very disruptive for people. Yeah. And people might wonder like are we really talking about psoriasis? But I think it's sort of an interesting case point for why autoimmunity could actually be useful. Yeah. It's not always the case. It's like they're to give us asthma or flaky scalp. You know, we could talk about there's a lot of disease states, you know, the argument for why we would ever have a sickle cell gene. This is the one that causes people to have hemophilia. And it's a lot of sub-Saharan African gene people from that origin have this is that it's actually defensive against malaria. It seems to be the case. So having that, I think that's true. A lot of these situations where the diversity of the human population over time by having some of these things that make some people hypersensitive to, you know, to maybe bacterial viral infection at the cost of having things like psoriasis pop up or various other other immunities is the only way that a billion strong population has to move forward. I always give this example to, because I think it's a really straightforward one. If you take a flask of bacteria and you put them in glucose, which is like sugar, like you put in your coffee, maybe sweet crusty, either one, you put them in a, in a simple sugar and you watch the colony grow, you'll get these cells that grow really, really fast. The bacteria, you know, becomes billions, trillions of individual cells, but there's almost always some just losers that are dividing slowly. And it's for whatever reason the system always brings us off. You know, like, why would you do that? Why would the system, why wouldn't just the winners win? But if you take a little bit of that culture and you put it into galactose, which is a milk sugar, often the ones that were winners don't win anymore. And it's from the loser pool that the new ones emerge. And this is a case of like, you know, like a crowd fitness that comes from diversity of genes. And so some of these things that make some of us susceptible to disease are also, as you're pointing out, in other situations, going to be quite good for you. And that seems unfair at the time that you have these kind of bad genes. But like, a different day you would have been happy, right? So I think there's a lot to be said. And that's also why a lot of the things that we look at, you know, anecdotally, somebody takes a supplement and it works for them. I mean, I don't know how much you know about this literature, but the differences in your and mind vitamin requirements is going to be quite profound because the metabolic enzymes we have for the vitamins that we might take in are going to be different between us. And so these FDA limits, these numbers are averages. Some people may need five times that amount of, you know, vitamin X as people may need a fifth. And I think this is super critical. The supplement world is kind of like scatter shot. Well, I appreciate the rational grounding and all of it. I think, uh, the red throughout today's conversation, I think that, um, I picked up on, you know, the fact that we covered things like peptides and things like that. And I'm not certain about the peptide question across the board. It's clear summer beneficial. It's clear summer still experimental. I'm just a big fan of more data and more data collected the right ways and communicate the right ways as the same way with be vaccines and all the rest. You have an amazing sub stack. I know that because I've spent time there. No, thanks. Part of the reason we invited you here today is to learn about the immune system and we barely talked about cancer. I realized we're going to have to get you back to talk about that. But you've done an amazing job of educating us on the immune system. I really want to thank you and speak on behalf of many, many people for that. Never before has somebody presented in the ways that you have. And as somebody who thinks in analogy, I, and likes to teach an analogy, I really appreciate that. That's actually that, uh, that stance. What inspired you to get into public education about science and health before coming on this podcast? And by the way, everyone should check out Max's sub stack. We'll put a link to it in the, in the show notes. It's, it's so thoughtful. So nuanced, so relevant to all the issues that we're talking about. If not directly, then in the, in the general contour. And in some cases directly, and I, I imagine you're going to continue doing this. So what inspired you to do it? And how can we make sure that you continue to do it? Yeah. Well, thank you for the call out. It is. It's something I've been trying to work on for about 10 years in it. It really started when a group of us, you know, were, were hanging around after a conference. And we were talking about some of the issues with science and society. And there were many, you know, there's many, there's, there's, there's, we've surfaced a few of them today. But I think some of you guys are working on it. Is the capacity for everyone else to think of? is a scientist like, "You can ask yourself, oh, why don't people agree with this data that you show and take the action that seems logical?" But then you present it in such a way that they can't, two things are important about it. I think one of them is if you present the information in a format that isn't familiar, you're not going to be able to teach anybody anything about what's important. But the other thing is that we spend some time talking about this and we consulted some other folks there in science comps and we realized the other thing is that if you say you're a scientist, it's not a neutral statement. Science has a history and history is stronger than science actually. So the history, there's hesitancy among African-American, for example, to take drugs because of things of history of Tuskegee, which was like 80 years ago, whatever long ago, 60 years ago. It's not in their lifetime in many of these people. So part of the realization was like maybe part of what we really should be doing as scientists is part of our job should be to figure out how we relate to other humans. And there's a painting of this and obviously the media and things to help this happen because it makes it interesting to have a nerdy scientist. And you can be a nerdy scientist, I heard you. But also you're a human. You're a human being. You have there's even foibles to loves and hates and only foibles. I believe those. We can get in that office podcast. But this concept of if we want to relate, if we want to have impact of the work you do, if you want it to be relevant, at some point you have to, the science as a field needs to make sure that it doesn't ostracize itself from people. And I think one of the issues there, I just use the word ostrac, is separate, is this concept that we speak in our vocabulary that is gets very precise. And we forget that if you hear a foreign language and you hear one word that you don't recognize it, it throws you off for a few sentences. And next thing, you don't know what people are talking about. And I think that concept that, again, this is where I think bringing it down a level and saying, let's give it analogy. Let's give it, that strikes me as really, really important to the impact that you can have with your science. And that science can have in terms of teaching people what we could do better, which I think we all want to do. But if you end up thinking that science is a distrusted, weird collection of people that have different motivations and designs, then you've lost. That potential for it to do good is gone. So the subset came about it because I was like, well, I need to write as a person a little bit more and tell about some of the time that you've spent on this and why it matters and what it's like to do this work. And some respects also what it's like to lose in this, which happens way more often than the, it's like a casino, right? And science, if science you hear the bells and some cool device comes out of this, but there's a bunch of people pulling the arm, you know, and there's not winning. And so, well, yeah. So I feel like that's kind of an important part of this that, again, it's not the glory story always. You know, the best, some of the best-selling books about science are the wins. But, you know, it might be more relatable at some point to get all of it. So that's kind of what I was trying to put together. And at the same time, I think the immune system is also just so relevant and so important and it's got all these different facets and these archetypes and these sorts of things that it's doing that we kind of scratch the surface today. So anyway, thanks for calling that up and working on it for a bit. Well, I hope you continue to and thank you so much for the work you've been doing in your laboratory and all the people in your laboratory doing that work. Because now you're the one calling the shots while other people do experiments. But for your advocacy for science and public education, it's huge. We need more people like you, but you certainly put your own unique signature on it and the sub-stack reflects that. It's an incredibly interesting set of reads and people will really learn. So that's essential, especially in this day and age, but even not in this day and age. Science is just really cool. And with all the meaningless drivel out there, it's nice to go to a place like your sub-stack and I'm speaking to the audience now. You will learn if you read Max's sub-stack. You will be inspired by certain things and I promise you. So I'm saying this intentionally, Mark, my words. At some point, somebody's going to contact you that they decided to study the immune system or they learned something or they explored a novel treatment with their physician in a given unfortunate or maybe even fortunate situation that better their lives. It's incredible what sub-stacks and conversations like the one you've been willing to have today and going forward can really do. So thank you so much. Definitely come back again and tell us about cancer and other things because I took us off course quite a lot, but I had a great time talking about all of this and I'm going to be thinking about a lot of it and really appreciate you. Yeah, we'll see you here. Thanks so much. Thank you for joining me for today's discussion with Dr. Max Krumel to learn more about his work and to find a link to his superb sub-stack, please see the links in the show note caption. If you're learning from Endor and enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero cost way to support us. In addition, please follow the podcast by clicking the follow button on both Spotify and Apple and on both Spotify and Apple, you can leave us up to a five star review and you can now leave us comments at both Spotify and Apple. Please also check out the sponsors mentioned at the beginning and throughout today's episode that's the best way to support this podcast. If you have questions for me or comments about the podcasts or guests or topics that you like me to consider for the Hubertman Lab podcast, please put those in the comments section on YouTube. I do read all the comments. For those of you that haven't heard, I have a new book coming out. 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Thank you once again for joining me for today's discussion with Dr. Max Cromwell. And last but certainly not least, thank you for your interest in science.