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

a famous um marinologist 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 were of the engines and if they heard a were of the engine that had the certain cycle of a general mo you know motors engine they wouldn't fire. 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. 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 your body is getting like more complex then that those books you know start to have every possible possibly every possible permutation of every biomolelecule could could could be made by your body at that point and then a virus doesn't necessarily have anything unique about it. >> Welcome to the Huberman Lab podcast where we discuss science [music] and science-based tools for everyday life. >> [music] >> I'm Andrew Huberman and I'm a professor of neurobiology and opthalmology at Stanford School of Medicine. My guest today is Dr. Max Kuml, a professor and 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 sleepd 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 with an 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. Dr. Croml 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's is a truly special and important episode to educate and inform you in actionable ways. I should also mention that Dr. Dr. Crumbl has an incredible zerocost substack. It's called the immune beyond. You can access it by going to the immune beyond all oneword.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 zerocost 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 for my discussion with Dr. Maxruml. Dr. Max Kuml, welcome. >> Thanks. >> Most everybody, including me, has heard of this thing we call the immune system. And most people just think, okay, this is the thing that when I'm rested, 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 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 uh one of the transcription factor biologists, you know, mentor said, uh, you know, why do you want to work in imunology? It's not really a field. And so at the time it was kind of true, you know, everything was about um DNA cloning. We still, you know, it's obviously still a lot about molecular biology, what we do, but uh, 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 a virus or something foreign. Um and otherwise it generally had to be quiet and kind of leave you alone. I think cancer imunotherapy changed that a lot. that that gave us the idea that you could tune its reactivity so that you could get to the point where if you gave an amnotherapy, what it was actually doing was raising the threshold of when a T- cell would activate and allowing tea cells that might be just letting the tumor get by get they'd be able to go and go after that tumor and and and kill it. I think that changed the spectrum a certain degree where we suddenly saw okay this isn't just a just a you know foreign versus self thing because it's a tumor is kind of not exactly self but it's exactly it's also not foreign it's was once you it's a cell that's kind of evolved so I think tumor immunology really changed our perspective on that you know to the point where we now think of it as a as a tunable system but then I think you know a lot has happened in the last 20 years there's been a lot of excitement about cancer imunotherapy because we're curing people with cancer which really wasn't done before. And you're now in this space where um the immune system is showing all these other roles. I mean, you know it in the in the nervous system, the brain, there's microglea that do various functions, cleaning up, etc. 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 kind of like the right quantity. So, it's kind of guarding yourself. It's uh, you know, it sits in your liver regulating how how much you metabolize. there's a collection of cells there. Um, it's in your heart. It's, you know, regulating cardiomyio function. Those are the the muscle cells of your heart. Uh, 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 in the in the heart. So, it has all these additional functions that kind of before were were 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 to help us be who we are, you know, and that's hopefully that's you as a healthy person, you know, and 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 it can actually help perpetuate it because um well it's you know some ways it's trying its best >> but it's applying the wrong program to the wrong situation. Um so yeah it's it's changed a ton and I'll give you another little funny story which is that that um you know when I first came into immunology again we had the story like you know the mentor who says you know this isn't really a field the year was like came to the field in 1989 and that's right at the peak of AIDS and um AIDS was like as as a biologist was really interesting because you know the HIV virus infects tea cells so your body is filled with 10 the 11th or so T- cells like a ton of different kinds of T- cells and um you had a you have a subset of TE- cells that are called CD4 T cells they're kind of a flavor of TE- 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 the manifestations of AIDS for those that weren't around dur 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 would would kill people but so too would you see you saw people with carbosio saroma you saw like a opportunistic vi like where you know a cancer is emerging um and you just saw all these kind of manifestations of where the immune system was important dementias in in people with HIV as well you know it was early 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 that like fueled the discoveries ies that have led to where we are right now. And some of those I, you know, I think it's worth pointing out were just these curiosity questions like what are these cells? Like they were hard to study at in the beginning. You know, they're they don't live, you know, it's sometimes hard to keep cells out of out of a out of a human body alive. So, you know, there's there's issues about how do you keep these things alive in the very first place and then and then what kinds of things, you know, trigger them to do stuff and you got to 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 the cell types and the and the behaviors that they can engage in. And it just gets more comp, you know, more 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 of a of a set of biomolelecules, proteins, and they form a peptides. they can measure that and each one then can say that's out of range or that's in range. So it's like you have like 10 to the 11th little sensors going around you curating you know making sure you're the right thing and if they see something that's out of 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 um perspective on this for a second and then I have a basic health question. Yeah. 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. >> Yeah. And it also is the case that you know as we get older much older in fact uh last quarter of life let's say people tend to get sick more uh what's going on um in terms of immune system function um or is there something more broadly happening at level of just kind of energetics mitochondrial function very curious about this >> if I can take a step even further back I'll ask you a question of like who are you and I don't mean that like in the personal sense, but I can talk about that too if you want. Uh, but the more the question is like at at some point where does your body end and where does the world outside start and one of the things that, you know, you start to realize if you look in a microscope is that we're covered with microbes all over our surface. We're covered with microbes all the way in our gut. In fact, we can't, you know, you can't digest, you've probably heard this before, but you can't digest animal fats if it weren't for the bugs, the bacteria in your gut. They make some of the key components of of bile acids that allow you to digest animal fats. So, you need this system that's around you. So, you aren't just the cell like if you learn biology, you've got the again, we're going to go way back. There's the egg and the sperm and they fertilize and now you got this this this cell that starts to divide and gives rise to every other cell in our body. So you might say that your body is just that collection of cells, [snorts] but in fact it's it's it's it's absorbed a lot of viruses and and bacteria from our environment. And you know, 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 the bacteria in your gut can now help you absorb nutrients that you wouldn't otherwise. If you eat sushi, you know, you've heard this probably, right? You get you get bacteria in your gut that can help you absorb the the the seaweed, you know, nutrients from seaweed. So, so taking this into your question, you know, when you're first born, you've never really seen anything. And so, two things are are I think worth pointing out at 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 six months that's because your body is 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 you're you know your immune system's like oh I see something different and now I need to react. So that's well known and that's 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 you're 6 months or or older. But I think to your point, one of the things that's happening with kids is that they then then as they go into their like until they're 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 cuz they've never seen the body's never that body and kids body has never seen flu before. So every single virus and pathogen that hits it is going to elicit some, you know, some amount of illness. But then they have a very strong immune system. it reacts and you know gets rid of that with the exception of the ones that you know are those those certain viruses and bacteras mumps, measles, rebella that are they're lethal and that's why we immunize as we say and that's those are things that your immune system if they get too much of those kids will die and so it's better to protect them with a vaccine. All right. So that's the front end, right? The front end has this initial, you know, imunosuppression, 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 get a we have to reach a day tant with some of them. You know, 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 and and allow them to live in us 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 know, you can see that both in the form of, you know, kids getting sick a lot, but you'll also see that their guts develop way diverse microbiome. You know, they allow a whole bunch of things that come in from the outside and are acceptable and are quite good for you. That's the front end. In the back end of life, it's a little bit more complicated, but I'll tell you I'll tell you two things that I think are important. On the one hand is the idea that is is the fact that a lot of your cells in general become less functional, including immune cells, and you get less cells produced. And and that might just be because, you know, we were never selected as organisms to live as long as we do right now. That's one idea of aging, right? >> We know that that we just were supposed to be dead by 70. >> Well, no, but we do know that that we can reproduce and and you pass on our genes successfully already when we're 16. So, you know, 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. um you know at some point maybe there's no selection. So we don't know that but it's 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 psychologists would tell us that uh the wisdom of people, you know, 60, 70, 80 and beyond is useful for um groups of humans that live in, you know, you know, villages of 100 or so people because they can give information to younger people that is on the periodicity of like every 5 to 10 years, maybe every 30 years. >> But that's a just so story, right? I mean, it's a nice just so story. >> I like it too. And the I think the genome geneticists will refer to that as like the grandfather effect where genes may be selected for and maybe they're mostly about you know genes that make us social in the in for for for the elderly that do you know they're going to have effects on the fitness of their grandchildren which is their genes. >> And so this yeah I think there's something to be said for that in in conceptual space. I don't know if I can prove it to you that that's >> it's a tough experiment to do. It's a really tough experience to have two villages where the you know the grandparents are eliminated or like kept you know both non-ethical and also non >> but we were talking about the aging immune system and I think I think there's two things that again come to this question that I was asking you like who are you um and I was saying okay well in aging you have this issue that the immune system is is tapering in its efficacy it's many of the cells that you you know you've been holding your whole life start to 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 basic biology ology say that sperm, you know, like uh fertilizes the egg. So, you've got your mom's genes and your dad's genes. You got 23 chromosomes for your mom, 23 chromosomes for your dad. And and and at least in when you're first born, every cell is a clone. It has exactly the same information. But DNA replication and 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 by basic sun exposure. And it's that that's higher than some of the other organs. But the basic idea is that your DNA, you know, it's susceptible to UV radiation. That's one of the reasons we put on sunscreen. [gasps] But what it what it practically means, no matter what number you put in there, whether it's 10,000 mutations per day or remember the the genomes are huge, right? So 10,000 mutations out of terabytes of of of information, still is only a certain number. But do that over every over years. And the main thing is that that means is that every cell in your body is no longer identical to the one next to it because this one got different mutations on day one. This one 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 that 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 some new has to has to form, they might be the fittest to fill that void. [laughter] >> And one of the other clones over here that got a different mutation may not be fit to fill that clone. And so you 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 it okay. You want you want another analogy? I would like another analogy. The only um exception that I can think of to this and I 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, but so you're saying mutations are constantly occurring in the neurons in the DNA. So there it is fascinating by the way that neurons live that long. and you know hair cells that they say that the the proteins in in our hair hair cells of our ear are the same exact molecules atoms as we had when we were born. So there's there's some cells that are along the 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 the we tend to think that one of the reasons that immune stem cells live in our bone marrows 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 like to think that they live in there because it protects them from a reagent they they they they hang out stem cells are You know that the bone actually serves not only a structural purpose in our body, but they it's a cavity in which things can live and >> keep it away from from solar radiation. >> Keep it away from chemical cues in the environment that can mutate. >> Sequester your stem cells >> and um >> don't burn them. >> Yeah. >> That kind of thing. >> Yeah. Likewise, the neurons in the in the uh inside of the skull. >> Yeah. >> And the spinal cord >> are protected. >> They're protected. >> Yeah. >> And that's interesting. >> Yeah. >> Yeah. I would like to take a quick break and acknowledge one of our sponsors, JWVE. JWV makes medical grade red light therapy devices. Now, if 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. Now, in addition to sunlight, which I've talked about a lot on this podcast, red light, near infrared, and infrared light have been specifically shown to have positive effects on improving numerous aspects of cellular and organ health. These include faster muscle recovery, improved skin health, wound healing, improvements in acne, reduce pain and inflammation, improved mitochondrial function, and even improvements in vision. Nowadays, there are a lot of red light devices out there. 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If you'd like to try eight, go to eightsleep.com/huberman to get up to $350 off the new Pod 5. Eight ships to many countries worldwide, including Mexico and the UAE. Again, that's eight.com/huberman to save up to $350. >> Sometimes I tend to think the immune system, you want to defend it like you want to defend a nation and you want to defend it from outsiders. And I've just told you a story that's if you want to take a political statement from it's pro- immigration because all these bacteria that live on us are actually bringing us goods and they they do a lot. >> We just lost half the audience. No, I'm just kidding. I'm I'm totally joking. We we're a bipartisan audience. I'm joking. Take it how you want. But by analogy, it's the argument for, you know, why why certain um you know, influx of of of u in this case organisms onto us, you know, create a more robust, you know, person than we were before. But I want to give you this story that one of a famous um marinologist in the 1970s drew this parallel in wartime and said in you know World War II submarines would be underneath the ocean and they'd be traveling around and they would if they could if they heard another submarine they would scuttle the missiles the torpedoes because that could be the enemy and the enemy could fire at them. [snorts] And so they had two sets of books that they used. Uh, 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. And so they could listen to the were of the engines and if they heard a were of the engine that had the certain cycle of a general mo, you know, motors engine, they wouldn't fire. 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 uh, you know, 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 the aging is this concept that as you get weirder and different your body is getting like more complex then that those books you know start to have every possible possibly every possible permutation of every biomolelecule could could could be made by your body at that point. And then a virus doesn't necessarily have anything unique about it. A virus is also going to make proteins and that's your immune system can see the viral proteins and say oh a new thing has come in and that's you know that's out of range and now I need to mount that a T- cell response against this I need to make the you know bring in the troops but with aging we have this this kind of you know us diverging problem so that this you know this system that's supposed to sense us >> is just you know has a lot of cosmic background has a lot of noise in it and so I think it I think that's one of the reasons why we also have issue when we're aging and it's I I think it's also one of the issu 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 cancerous but also the immune system has been seeing 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 you know, is it's got some differences. >> What about the argument that there's so much cellular turnover that um 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, then they die. Is this is that the way it works? >> Yeah. And I think I think you 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 is little these white spots on your skin. And we we think that those are places where the immune system has sensed a collection of cells that were precancerous, maybe they were even beginning of cancer, and has wiped them out. And and so the you know, a lot of the origin of cancers in skin is is melanin producing cells like melan, you know, melanoma is what we call skin cancer. um those 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 [snorts] of as dark as your as the rest of 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 it looks like there's pretty good evidence for that. >> Um and the question is when does something become dangerous that's that's that's you know that's fundamentally question with cancer and these sorts of things. If you said, "I want to actually have the fittest cells in my skin to uh fill in a gap if I scratch myself. I would like to 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 they're their wound healing. I mean, there's a group out of Stanford that studies this, but essentially, you know, wound healing in in in young is quite quite a bit faster and more efficient and and there's many that there's many levels of that. Yeah. >> But um yeah, remarkably faster. If you're a parent, you've seen this. You know, you cut yourself on the same day as a kid, your kid cut yourself and they're they're 3 days later, they can't even find it on them and you know, like four weeks later, you're still like got, you know, scap or something. But I was just coming to the point that if you do that and you you want this, do you want you maybe want that to fill back in because you certainly out in the wild having an open wound is a bad thing. So, you 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's cells 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. They may be a little bit better at growing. And then again, the 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 and go other places and grow, which is called metastasis in 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 a new immunity. Immunity used to be like a fuel gauge. You'd say it was low for itself and it was really high against viruses and it was like a fuel gauge. You don't know. Now it's really hot. And what we originally thought we were doing with cancer imotherapy 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 are 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. The bacteria as long as they're in the right zone, there's not too many of them, there's not too few of them, immune system can actually help them be there. It can produce things that like either tighters them out of circulation or keeps them there. You know, in all these other settings, like I say, in the heart and the can go to almost any organ and uh and the immune system is consistently present and it's consistently measuring you. And the U again is 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 acred and all the bacteria and 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 a of a illness that we've gone back to our pure state. This may came from religion. You know, that we were born pure and if God made us correctly, then we would be pure at the end of things and you know that would be pure immunity would would purify us of things. But the more we look, the more we find that every virus leaves a little evidence of 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 our cells to get rid of every virus that's infected one of our cells. We need to leave some of those alive. We don't like for example herpes virus infection infects the nerves and when people have uh you know emergence they 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 the the it's imopathology. The immune system is c causing as much of the damage and problem as the virus is. And it's the failure of that day tant. And when certain viruses are just sitting in us, we're perfectly fine. You know, we have new viruses sitting around. As long as they're laying dormant, our immune system can say, "Okay, I'm going to hang out here and if anything bad happens, I'm going to squatchch 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 if the goal of us is to make it to 30, let's say you get a a 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 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's can 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 I like the sound of that. Um as will 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 >> um 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. Right? So that if we are indeed born pure um in the biological sense um [laughter] let's just keep it there for sake of today's discussion and you know by the time we are um you know 32 years old we are a mosaic of mutations >> as it 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 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 y >> right in the same way that you know soldiers you know they might hear a shot whis by but then do they necessarily reveal their location and launch an attack no but but if it's enough of an of an attack they'll uh fight back >> it seems like there should be some way to that the immune system could quantify either bodywide or or local organ or or over some period of time they could integrate over time. I have to imagine that such a mechanism exists. you're coming from neurobiology as 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 aas if you know the names is a 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 striking it really hits you but after being in the town for like an hour >> Mhm. you don't notice it. Yeah. >> And that's neuronal accommodation where your nervous the same kind of thing you're talking about where the you know the sensors in your nose can become they're like okay I've seen it. I'm seeing it now it's not anymore and and so I'm going to tune that out because then your nose has the potential to smell other dangers or other stuff. Right. So that's the nervous system. I I think you're exactly right where you're going with this is and we think this is true that the immune system is it you know for danger it's looking for something you would call like a it's how it's seeing the signal over time. So, a virus may, you know, let's let's say you're a T- cell that recognize 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 replicating 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 an immune [clears throat] response and you learn it and so the next time around you'll be faster to respond to it 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 it your entire life. So that amount of protein, maybe it's a maybe it's insulin, you know, which we think in general, you know, it has a little bit of signal up and down as you have a sugar, but there's a range for that. And so your body gets used to that range. And the tea 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 this peak that you have with virus and so like a a mutant cell and maybe it's just a tiny tiny bit above normal for months and then it makes two copies of your cells and now it's a little bit higher than normal and the immune system is 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 I try to live my life a little bit this way but it's not validated by any you know any experimental stuff is the idea that whatever you are is what the immune system is going to help you be if it if it's if If it's a slow direction this way, it's going to it's going to be okay with that. What it doesn't like is like big spikes and and and 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 and nefarious. It grows over time and it and 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 isn't 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, this commensal is so long as it doesn't accompany. Again, viruses have two features in common. One one is this spike of 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 the additional proteins that come in and then they exchange information just like your brain, you know, uh you can talk about the fact that the brain has this wired, you know, set of cells that are wired in space. They're, you know, across your body from your brain all the way to a muscle. Let's say immune system has this collection of cells that are they're literally crawling around us right now. And 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 can form synapses and one can say to another one, "This is what I saw." And oh, you saw that? Oh, I you know, I'm just being this. and they can, you know, form a cluster of cells that basically get together like a neural 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 not that bad." I realize this perhaps is not your immediate area of uh research, but recently I've been seeing a lot more interest um 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. um because [snorts] we've never covered the thymus on this podcast in any amount of detail. If you could just uh educate us a bit uh what it is, what it does, and why it might be interesting as a as a um therapeutic. I mean, maybe we in a few years we'll all be banking our thymic cells. Um maybe we will be >> I know some people are already injecting non-FDA approved peptides that uh come from the thymus. I'm not recommending anyone do that, but people are already doing it um because that's the the internet in 2026. But what's the thymus? What does it do? Wh why this interest? >> Yeah. Well, I can back up one step and I've 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 had blood taken, you know, if you have blood taken in hospital, whatever, you 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 we for the moment we'll talk about two. One are called B cells and one are called T- cells. And TE- 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 substacks these days and and I'm writing one that's supposed to be released tomorrow about the thymus because it uh it really should have gotten the Nobel Prize. There's a guy who's alive. He's like 97 years old in in Australia who did this saw did this remarkable kind of experiment. There was this time when kids that had heart issues would come in for surgeries and they would discover this enormous white whitish organ as growth near the heart as they were taking the body, you know, this cutting open. And all the autopsies up to that point had 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." they they didn't really know what it did [snorts] and so they would remove it and uh the kids then would go home and it was usually exploratory heart surgery but then kids would go home and uh far from you know dying of heart disease many of them would die from like opportunistic infections they get all these infections they 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 Jo Miller who's this this 97-year-old codger in in Australia at the time he was in in England and he basically took a bunch of mice and then when they were newborn he removed their thymus the same same little whitish organ. And sure enough, those mice were 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 tea cells. And it and it comes from a kind of a convoluted path, but you remember how we talking about how the stem cells of your immune system lives in your bone? Well, there's stem cells that live in your bone and they travel through your bone through your blood to the thymus and become te- cells. And [snorts] the 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 tea cells that come in there, the tea cells are developing and they each have a possible 10 to the 11th different kinds of receptors to smell different things. And you don't want any to come out that are too reactive to you. So you don't want you don't want to produce tea cells that are going to go off and kill your pancreas or, you know, kill your big toe or anything, right? you want to you want to maintain like tolerance. So you want to make sure that you don't make the immune system that's too harsh. So the the thymus has the the role of producing tea 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 to let you be you in that way. Now to [snorts] the point about the 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 this huge output. So as like between [snorts] 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 tea cells and it's because probably what you're talking about you're getting exposed to all kinds of different back 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 the thymus involutes it gets super super small so that in aged people it's like tiny [snorts] and um and so it's not putting out new tea 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 like in cancer for example wouldn't you like to have a whole bunch of new tea cells that could come into into you flood in there with exactly the specificity for the for the tumor the tumor has managed to teach all your normal cell your other diesel cell in 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 you mentioned you talked to Alex Marson not too long ago and I'm sure he would have talked about engineering cells that you can engineer on the outside and give them specificity but [snorts] the sort of like if you will the more natural route to that might be to to let the thymus make use more tea cells and 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, the T- cells in that case. But it does have this like aging hit, you know, sort of aging effect that seems to make us a little bit more susceptible to things later in life. You know, again, we could argue about what whether there was a big evolutionary design behind doing that or whether there just wasn't needed because if you got you got to 30 and you died of an arrow wound, you know, you know, and but you given your genes, you're you're a winner in the evolutionary sense. You know, I love this uh uh this stance on well, if you've already reproduced, I'll just give a brief uh vignette. Uh we were introduced by our uh mutual friend uh David Felheim who's a a phenomenal developmental biologist from UC Santa Cruz and his wife Sophie Salama's also phenomenal biologist a mutual friend and years ago I was in Dave's lab because we are longtime collaborators and published a bunch of papers together and uh he was doing some injections. I'm going to get you in trouble Dave. He doesn't do this any longer. >> Yeah. I'm going to I'm going to join him to get you in trouble cuz we >> he was doing some injections and he might have been using might have been using carocyanide dyes. >> This was kind of conventional tool back. You put a little crystal in a piece of tissue that's fixed tissue so it's not a live 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 um and I walked over and I I saw Dave doing this and he wasn't wearing any gloves. >> And I thought, these are carboyanide dyes >> with cyanide. >> Cyanide being the And I said, um >> Dave, uh don't you want to put on gloves? And he literally looked up from the microscope at me. I'll never forget. And he said, I've already successfully reproduced. And he went back to doing it. And it's his lab. So, and everyone else was following a safety protocol. Don't go after him. doesn't do this any longer, folks. But, um, there's an interesting mindset among you because he comes from cell biology, Randy Sheckchman's lab. You both trained in Nobel Prize winning laboratories as graduate students. So, I I find it remarkable that this this stance of uh, well, if you've already successfully reproduced, we really aren't needed. But, um, his kids are now graduated or in college. So, there is this thing about raising the young, too, and not just creating them and then dying. >> Agreed. I think there's a fitness associated with being older than that. And again when I say that this it is maybe just taking this from a purely like what would have been the source of what we are today. You know what would have been the selective pressures on them and it would have been a little bit like David saying you got to you know the selective pressure is to get your uh you know 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 giraffes where they drop off and they you know drop out and within an hour they're running. Um [clears throat] so that that that period of of raising children I think creates more pressure in in humans to to 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 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 like I think this issue that I that I brought up of our mosaics is is a is a real confounder to everything because that creates something that is >> quite hard to defend against. I think that that that that aging backdrop um and uh 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 in faced with that new reality of a 50-year-old or 70-year-old or whatever it looks quite you know looks quite more complex but you would have you would have definitely wanted in gene space you know gene space 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 that say who are you? And and it's again there's that isn't to 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 some questions that are almost 90% of them are going to be dead ends. You know you can hypothesize it's one thing. Well, you got to do the experiment to like eliminate that. Mhm. >> And this is one of the things that people I don't think always understand about science is that for all the discoveries that you know I made or other people have made, there is hundreds [snorts] and hundreds of like disappointments. You know, and you'll recognize this where you you just go home from the lab at the end of the day and you've you know you've you've done everything right, but the answer isn't the one isn't the right one. >> Yeah. One control experiment can >> nuke your 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 and you know, we can only imagine stuff >> and then try and see if it's true and or or more importantly try to prove that it's not true. So the better experiments, the kind of we call them killer experiments, right? The ones that kill them kill the idea if they're wrong. if the idea is wrong, but it's killer because it if it's turns out the way you hope it will, you know, again, when we get to some of these aging things, there's a lot of in 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 I wish that because of age certain things would happen. That's that's a that's lovely. But it could be super the word was baroque, you know, like [clears throat] 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, I didn't realize that this system that seems like it might be quite as simple is so complicated. The world is so strange." >> Well, when I started in neurobiology, the brain, the actually the entire central nervous system was considered an immuneprivileged organ. Yes. There weren't supposed to be immune cells there. And thanks to the beautiful work of Carla Shatz with the major histo compatibility complex work and um Ben Baris and I'm failing to mention all their scientific offspring but Beth Steven, Shala Ergloo like and on and on. Um it would take the rest of the episode to name all all of Ben's scientific offspring and Carlos too being you one of >> right I didn't work on those issues but um but I was in those labs when it was happening. We now know that the immune system is active and alive in the central nervous system throughout the whole lifespan serving critical roles. >> There are two things that well three really that 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 off infections? Do we know what's happening? Is it like you've got so much adenosine which is the sleeping molecule and and [clears throat] uh like that that adenosine inhibits T- cell function or something? Do we actually know? Because 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 um some some really nice work shows that at night a few wacky thing when you're sleep a few what you might have thought would be wacky things happen and and one of them is that a lot of your immune cells clear back to the bone marrow um and and your tissues become populated with a bunch of neutrfils that come out of the bone marrow and and seem to be you know depositing collagen around your body and and so there's a lot of things that I think are reparative about sleep. But I've thought about this a lot in my own life as probably you have with sleep is to one of the questions of course is why do we bother to have sleep and and I guess I can only imagine this because our you know we've created these these bodies of ours are so capable and they're so energetically and you know you know um consumptive and they make all these byproducts during the day that that at some point you just need a cleanup phase and that's that's one interpretation of sleep. You just need to reset. So the immune system is definitely resetting and and you know there's as I said there's evidence that a lot of the cells go kind of quesuscent into the tissues and they they may leave you alone for those reparative processes and actually allow those >> you know in terms of the data on there there's there's a lot of studies that are being done and and I can't say that I've come to a a conclusion about that. This is this comes in the question of like is it known or do I do I not know it or is it does nobody know it and I'd say this is might be one of these areas where about 10 factions of people know it but they don't agree >> you know so there's variations on things but I I think the data for example that immune cells dive into the bone marrow at night is is pretty solid >> that makes sense >> what they're doing and why that's important in the long sense of like what you're talking about everything from well but I think it's you know things that happen overnight you you're definitely your cognition improves is that immune immune or is that neuronal or both? I think it's both. >> Something in the lymph plumbing immune system. One thing that's just striking like that is undeniable is probably the best way to put it is um everybody has bags under their eyes and looks like when they are sleepd deprived. They sleep for a night or two >> and it goes away. >> That's clearly accumulation of lymph. We we actually know that. That's just lymph fluid that's not being cleared. And it might not even be the brain's uh glimpmphatic clearance system. It's just there's a bunch of lymph pooling under your eyes. That's why you look like >> Yeah. >> And then you sleep for two nights. >> Well, and you look better again. And the eyes get glassy. We know that the eyes get glassy when we're sleepd deprived. >> That's also a a lymphatic clearance issue. This is well established. Like, so there's some things that are just like plumbing works better when we sleep and get up again. There's something literally about lying down and getting up. But but that to me can't explain the the immune thing entirely because like the lymphatic system is like among other things, you know, immune surveillance. But >> I mean, one night lousy sleep and the person coughing across the room gets you sick >> often. >> But when you're well rested, you actually feel this robustness like n like okay, I might wash my hands or just kind of avoid them and you're good. >> Yeah. So it's it's I mean it's an incredible effect one way or the other. >> Again, I don't know the degree to which we can nail down, you know, which which part of things that are happening is which. I always like the story that that the um there's macrofasages, immune cells in your eye that are basically clearing the clearing the lens, >> you know. So there's there's all these like places where it's doing little cleanup that you can imagine that if the the thing it's trying to get rid of is granularity that that you need to have sleep where you just aren't making more granularity so they can you know sort of like when you wash your car windshield you do it completely at that point and but you can't be driving with flying and right [laughter] you'll never clean. >> That's a great analogy >> you So, I think there's certain elements of some of these cleanup processes that happen best when you're not getting things, you know, you know, dirty or again, I think a lot of what we're talking about is byproducts of our energetics that leave, you know, some damage behind it. I I think we just use a lot of ATP and we do a lot of stuff as our bodies in in the sleep time where you can not be, you know, producing more of that and get ahead of the curve on cleaning things up a bit. >> Um, like pulling into a gas station, cleaning 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 HMBB, and zinc carnosine. Each serving has 5 grams of creatine monohydrate to support muscle strength and performance, as well as brain health. calcium HMBB to support muscle recovery and reduce muscle breakdown and zinc carnosine 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 started 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 drinkaga1.com/huberman to get a special offer. AG1 is giving away a free bottle of omega-3 co-enzyme Q10 with your first subscription. Again, go to drinka1.com/huberman to get a free bottle of omega-3 co-enzyme Q10 with your first AG1 subscription. This thymus thing is really intriguing. And uh I know a lot of people who um opted to bank their child's umbilical cord in the hopes that the stem cells from the umbilical cord will someday be useful. >> Yeah. >> How invasive is it? Andor should we be uh banking thyic cells? >> Uh because these seem like incredibly valuable cells for their ability to immune surveil and create kind of the perfect situation using our own indogenous tea cells to battle infections. I mean, I kind of wish I had a little little chunk of my thymus. Yeah. >> Um, in a minus 80 freezer someplace so that when I'm 85 years old, >> you might >> I might be able to exploit that. >> Yeah. >> Well, I'll I'll say that the umbilical cord one is is pretty straightforward. It's, you know, the umbilical cord is being 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 of banking that material and banking just means you put it into a vial small little you know small little vial with right of 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 Are there kids even kids or adults that are alive today because they banked their umbilical courses? >> But certainly companies sell access to that >> somebody has to pay to keep the freezers on backup generators and things like that. So people invest time and money into this idea. Is is there a >> walking talking breathing human who would be otherwise dead would otherwise be dead excuse me because they they paid money to bank their their umbilical cord? >> It's a really good question. I don't know the answer to that question. I guess the parents pay the >> I can tell you and this will be just like this is this is the depth of to which you're you're describing uh Dave Felheim injecting a you know 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 blood cancer and you can do that. I'm sure you can do it in humans too. I have zero doubt that it also works. I don't know whether those companies have done that. That's that's just actually something where I >> this is offered in mass now. >> Yeah. Yeah. Do you want to do you want to keep the umbilical cord? >> Honestly, honestly, I would do it because it's one of those situations where if it's not too Well, I don't know if it you know, it depends on your your how much money you have to spend because the >> it's within within the noise. Yeah. Yeah. It's one of those so it's one of those ones where you particularly 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 if they happen to have a a childhood leukemia this would this would cure it >> which is an 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 >> 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 um not just in the Bay Area. A lot of people uh however are starting to think about oh maybe I make some induced pur potent stem cells from a fiberblast from one of my skin cells put the so-called Yamanaka factors on revert to stemness and then I might be able to grow a new pancreas or study my uh you know whatever organs in these so-called organoids or what however they're referred to. Yep. >> But I learned today from you that if I take that fibroblast now, that fibroblast might not be completely Andrew Huberman as I know him to be [clears throat] genetically. It's actually could have some uh mutations. That seems important to compare against a sort of um a standard cell. >> I don't want to grow organ organoids from a from an IPS environment that um carries mutations. that that seems like a bad idea. >> Yeah, >> 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, a liver [snorts] disease or a heart disease. But if those are mutant cells, that's a lousy experiment. >> Yeah, I wouldn't I wouldn't say they're likely mutant cells for that reason. I think the biggest question would be whether your induction of them to become the organ that you, you know, want was successful, was replicating the actual organ itself. So you're you're referencing these things called organoids which are collections of cells from a body of a human for example that are are induced with various different factors to grow to resemble maybe an organ a particular organ. You know I think all of us have little doubt and this this is the source of the California Institute for Regenerative Medicine that making stem cells that can become particular organs will at some happen. We will figure all these things out. And I 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 is a bigger question. If you take out your fiberblast today, that might only cure you someday in the future. And meanwhile, you may die of that thing that you wish you had the stem cells 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. You get hit by a car, you know, [laughter] it won't help you that you've got those things bang. I think in some of these cases like overemphasizing this might be your point about the storage of of umbilical 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 fates that can be flawless as humans that have nothing to do with you know stem cells from the bone marrow and 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, that's certainly not how I live right now. There's a lot of >> kind of excitement, attention around so-called longevity. And um at at the extremes of never dying or living to be 120, which seems to be the >> perhaps the genetic limit uh currently. Um it's not my fascination. I'm more interested in living in the years I've got as it seems you are too. Exactly. Vital, healthy, you know, being able to move, >> sense, and and think [clears throat] seems like and remember, you know, those seem like the critical ones. You know, you know, a moment ago you mentioned the concept of like removing a bit of thymus and I I think that the issues with for me with that are or 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 I mean in fact you can make thyic that so the thymus is both the cells that come into it from the bone marrow. So it as an organ it has contents but its structure are some thymic epithelial cells a kind of cell that make a matrix that all those cells live in and they get educated in and um 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 [laughter] 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 No, I I I 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 were doing it. You're like, "Oh my god, we've got a cure for cancer. That's great. Okay, let's go and do the next thing." Two things that So you're like, you know, the California Institute for Regenerative Medicine, they 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 learn a lot and that is the risk >> about stem cell biology >> about stem cell about biology and that is the risk we take when we do research. You know we're talking a 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 and then one hour and you understand everything because you know so all of a sudden all those failures make us make make sense. I think when we get into some of this stem cell biology it's it's intuitive and it's almost certainly true that we will have some of these things. Whether we'll have them in time for like you or me I I don't know. I just don't [clears throat] know. And I I think that's true of a lot of these things that say, "Oh, you know, we seem to be right on the cusp right now." For example, in in cancer therapy, we've been on the cusp for 10 or 15 years of these things called cartis. Alex will have told you about these where you engineer your tea 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. They haven't worked. And T- cell the immune system gets turned off. These cells don't make it. They don't fail they 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 it's, you know, that gets frustrating. And I think it gets frustrating for people that are like waiting for it to um on the outside like why can't you solve this? And you're 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. >> This is an important discussion that we haven't spent enough time on in this podcast that I think is very important for people to hear. And I have some thoughts about it, but I I'd love for any disagreements. I'm not looking for um 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 the podcast. [clears throat] So I'm very immersed in like what's happening right at the cutting edge. And um 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. Wouldn't it 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're like wow this would be incredible for amputees and brain regeneration and right >> 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 electroporate liposomes. Uh we're going to use calcium phosphate. Like great research tools. Tons of things happen. It's like we're going to modify genes. Zinc finger nucleus. 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 uh gene alterations with crisper cickle cell anemia treatments as well. More benevolent example. than the person who went rogue and just kind of did this in humans in China. But Crisper just kind of broke through it all. >> This 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. >> Yeah. >> 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 the last example would be, you know, for years it was like the country is getting fatter. The c the country is getting obese. What are we going to do? Do calories matter? Of course calories matter. This kind of thing, you know, laws of thermodynamics still apply. And then all of a sudden, this freaking helila monster biologist. >> Yeah. Yeah. >> Tells people what they already knew because the GLPs were already being used as a drug, just not at significantly high levels. Yeah. >> 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, etc. I'm not 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. >> Yeah. And then and you say, "Well, couldn't we have just gotten Crisper first or the GLP's 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 and I ju just would like your thoughts on I feel like it's necessary, but not sufficient to have lots and lots and lots of failures. >> Yeah. And I think it's necessary and 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 you gave the example clip one. Somebody was just curious as to why Hila monsters. It was the feature was that Hila monsters can go into, you know, dormcancy for like 10 months, not eat, and then uh 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? Crisper, you know, that was people were studying like how do bacteria defend against other bacteria? Well, they use this. It turns out there's this enzyme and it 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 that and like kill it. Well, that same you know that same enzyme then which we now use for all this human engineering came out of a basic like how do bacteria defend themselves. It's not anything about like you know modifying single cell anemia. It was about how does the world work? My career is exactly as long as as the as the lifespan of of this this field we call cancer imotherapy. I did the first imotherapy experiment. I injected a mouse with an antibbody that I had made. It was against molecules on te- cells and I'd shown already in the lab that that molecule caused the tea cells to get more activated when you blocked it and uh and we did a series of like other mouse experiments of like all kinds of diseases and it you know kept jamming up the tea cells and then then you know Jim I said we got some tumors in the fridge and so we set up that experiment and uh you know he injected this antibbody and the tumors melted. Well that was the start of cancer imunotherapy. We're like that's that's this that's the origin. This is the experiment for which let's just be direct here that your your adviser won the Nobel Prize. >> Correct. Correct. >> Did you at least get to attend the ceremony? >> Yeah. Yeah. >> It was a little thing. >> This is how science works folks. Doesn't matter who did the experiment. Doesn't matter what lab you're in. >> Yeah. You got, you know, got to go to the the afterparties were good. Uh but I guess I take you back like we weren't trying to cure cancer when we started this. I the thesis project when I went into Jim my my mentor at that point. The discussion was like, well, there's some molecules on TE- cells and and I said, you know, we knew from AIDS and a few other things that T- cells were important. So, that was the attraction, even though you had people say, why would you do immunology? Well, we they seem to be interested. And there was a molecule. 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 can say, well, if I could dial up, what will happen to vaccination? Well, it got better. What will happen to, you know, multiple scerosis? The disease got worse. You know, what will happen to cancer? Oh, we can start to have an effect on and and and you know the X-ray you know the people were studying physics and then it turns out to be that that they were like oh I can measure I can I can measure bone and that's how we use X-rays now like to to you know so there's all these examples that everything you know 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 the workaround that comes with some orthogonal piece of 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 how do bacteria do it? You know, how do they defend themselves? Oh, they use this enzyme. And I think that's a really important message that that dispels this idea that everything is sort of like basically just easy for us to engineer. Yes, once you have the crisper 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 in the first drags of doing it, this would become an industry. >> You know, this would become a whole thing. And and maybe that's important because you need to foster that. If if everybody always thought they were doing it to build a company and, you know, sell a product or something, then then I don't think we would do the things that get us new. You know, that's that's all that's all kind of what we already know. That's human knowledge. We want to build human knowledge. And to build human knowledge, we got to go off the piece. You can't ski on the slope. You got to be like in the trees. And maybe you'll bunk your head a bunch of times. I I think that's the reality. And it's like you got a lot of people out there that are that have decided to do that for a life because it's a it's a it's a chance to like solve a puzzle. It's like there's there's puzzles about how the world works. And if you've ever done a jigsaw puzzle where you there's always like the oh you get in and especially in the end you're like how you what pieces come together to do it. I think that's what makes this whole science thing really fun. It's that's the that's the reward is that you get the puzzle piece in and you're like oh you know it makes sense that now I know what I've been building. and I've been building this puzzle and and then you go back and you do it again because that's really satisfying at the end of it even though you know you again with a family puzzle the first parts are so hard thousand pieces and you you maybe find the edge but the intervening where there's like all clouds super hard and and I think that's that's that is what science is a lot about is uh is doing that and then realizing what the picture is you know what is that picture of and then then all the you know the brakes are are off I often tell people that if if an if an experiment if experiment you'll do in lab has a 10% chance of yielding anything interesting you got to do at least 10 you know to even meet the fundamental stats you actually have to do quite a few more. So that's where it's not a um it's not a cost-effective thing if you it's it's really difficult to be a scientist because there's no quid proquo. There's nothing there's nothing to say if you put in five hours that you'll get five units of goodness of of knowledge out of it. A lot of times you get zero and and but then sometimes you put five and you get 500, >> right? >> And and those are the jackpot moments where you're like >> it's like life. >> It's like life. It really is. I have to say anyone who's considering a PhD. We had a call in from audience recently and someone said they're finishing undergraduate, they want to go the or finishing graduate school, should they go the research route? They want to do a posttock. 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 a rather niche qu question. But I mean also just in training your reward system to work for 5 years on something >> is so valuable especially in this day and age because everything else feels like it comes at like warp speed. >> Yeah, you know it clicks. >> Yeah. Like and um to just put steady pressure on something with all the failures and all the things and then to finally complete something it's a lot of people think it'll be underwhelming. I think I think quite the opposite. >> Yeah. It's like anyone that's like done a triathlon or, you know, raised raised a kid or done anything, you're like, "Oh my goodness." Like, and that never ends, right? There's nothing better than these long-term investments. >> Yeah. >> Nothing. >> Yeah. When they break through that you're like your analogy, when you break through that dam or when you realize sometimes that you broken through the dam. That's that's one of the funny things about I think science and maybe it's true in triathlons and stuff too where you've realized that you've all of a sudden got somewhere. >> I haven't done a triathlon so I have to be fair. Rob, our producer sitting to our left is he has done many Iron Mans. Um, 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 what to force yourself not to do or think about. >> Yeah. 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. >> Okay? >> And I'm going to pose a question that may or may not fit with um this framework, but either way, I'd like like you to educate us on it. >> I'm fascinated by these old kind of barbaric experiments in medicine. Um wonderful book, by the way, folks, is uh The Prince of Medicine about Galen. If you ever want to learn about how we learned about medicine back when, it was truly barbaric. It was like surgeries done on warriors and without anesthesia. And we've known for a long time that if uh somebody, god forbid, has a finger lpped off or a hand lpped 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. Turns out that's true. >> Is that true? >> Yeah. There's a bunch of juicy stuff in the in the gut that maybe it's the warmth. Maybe it's the immune system. Okay. >> Maybe it's the lack of infection from being inside as opposed to outside the body. Who knows? >> Gut. You mean the intestine or you mean the sto within the stomach? 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 and restoration. Like for instance, I've talked many times on this podcast about the fact that above our the roof of our mouth, we have this small cluster of neurons, the super kaismatic nucleus organizes the circadian rhythms of every cell in our body from the genetic to the transmitter level, peptides, etc. Keeps us >> sleepwake cycles, does all the organization that we need for circadian rhythms. So much so that you can take just one subpopul of these neurons, the calbindon expressing super chaismatic 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." >> Yeah. >> 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. 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. >> Yeah. 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 described 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 for which I'm asking this, but I'm just going to tuck that away uh to peique people's interest and I'll get to it. But this is relevant to how we to decision important decisions that we make I believe. >> Well, the the answer is yes and yes, you know, it's it's both. So although I described the immune system in the earlier part of this discussion as super migratory, it you know hitches 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. It's how you drain the the fluid back out of your tissue. [snorts] So [clears throat] although there's you know these mass migration of cells there's also in like even in just in T- cells there's tea cells that lodge in particular settings and they you know act to protect that tissue and they um and they're resident cells of those tissues. they never leave. And um so both are true that you have, you know, parts of your immune system that are, you know, protective or or like nurturing of particular areas and then there's ones that are circulating and can hit any any spot. You know, going back to your idea of organs and and such being moved. I think there's two components of 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 and lymphatic outflow and maybe even some neuronal activity that you know makes that tissue work. So so that's where like if you take the pancreas you can famously put it underneath a kidney capsule. Kidney has kind of like a skin around it. You can tuck some 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 diabetes for those, you know, type 1 diabetes or 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 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 um 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 some of your immune system that lives spatially in certain areas is going to be very like defensive against whatever it's you know specific against in that area but may not care what's happening elsewhere because those cells just aren't it's not like the brain where like if I I do something here it's sensed in my brain immune system that if it does if the cells don't migrate they don't have really a lot of ways to communicate that they can they can hitch some signals on neurons and that's a really interesting we could talk about the the capacity for your brain and you know the insular cortex there's great set of stories emerging about how your insular cortex can program your immune state into organs and can via via the Vegas can can essentially program >> by levels of of calm or stress or by thoughts themselves. >> Well, the the one the latter one is the one that gets me super excited about the possibility that you could have triggers for thoughts that so the insular cortex as I understand it it's a source of some of our moral decision- making. And it's also the the thought to be the part of our brain where if you cut your hand and and I see a bleeding, I can feel it in my hand, I oh ow. You know, I can sense and you can sense each other's pain. It's a set set that this very nice uh Israeli group did this Royce lab did this very nice study where they induced into the guts of of mice inflammatory bowel disease. They fed them a really kind of weird sugar that causes the the bowel to puncture and then they get they get a really bad, you know, stomach ache. um uh stomach ache, inflammatory bowel disease, diarrhea and um and in that period they used you know you know what dreads are. So they they marked um for the for the crowd it's they used they they used they used a way to to mark all the neurons that were firing during that period in the instrumental cortex and then later they could fire them like after the mouse had recovered and the 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 and the cues for that in that case were a drug but we know that we can you know cue the insular cortex like me watching you do things >> so it's always it's maybe wonder whether you know like some of the things we we smell all cut grass and we can it'll 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 our you know our ability of our thoughts to control that region are are going to be revealed to you know to have potential that you could train >> uh you know train yourself to to you know to bring up an immune state in a particular tissue. >> And just so I'm 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 if like if an animal or or human, let's just keep it at humans, gets um shocked, scared, or traumatized in a given region. Yeah. >> Or even I've had friends visit San Francisco and get their cars broken into and their computers stolen. >> You can develop a context context dependent or and or place dependent memory where you kind of don't like San Francisco as much even though the rest of the trip was awesome. That's a pretty broad interpretation. or um you have a great experience someplace and you actually really love >> San Francisco because you met your future spouse there or you just had a particularly awesome experience there even if it was just in one part you might feel better about your computer getting stolen anyway okay insula 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 The immune system is also part of that contextual memory. And [snorts] so merely by recalling the positive or negative, but in this case positive memory, we can also rec 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 um we've heard for so long that like 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 that the the immune enhancing effects of acute cortisol and stress are are really important and and I think they've been overlooked. But I love this because one of the problems slash um luxuries that I 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 wackiness. >> But more and more we're finding that within the complete nonsense wackiness there are 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 and that's seeming less and less wacky even outside California. Yeah. >> Because of studies like the one you described. One of my friends who's a faculty, Dan Lim at NYU, we were talking about the same study and he was like that may be what meditation is doing because it may be allowing your brain to you know communicate and reset um you know 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 you know the 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 the brain fire again of this mouse you would see you not as profound but you saw this 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 that again you know that the concept of I mean I'm sure you've talked about this before of of meditation where the idea is that you um you know you it's one of the ways that you can control your autonomous nervous system is through is through your breath >> um that happens with meditation I think that >> to me there's something 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 and don't turn out to be true. But the 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 and like a regions of the brain and however those are triggered. Now, maybe, you know, again, I've I've lost 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 there kind of crazy thoughts, but but again, there's an element of that that's intuitive, too, where we say, "Oh, that seems to be the case. My mom makes me a comfort meal." Is it really the meal settling in, or is it just the that the sensations that make me feel like, you know, less, you know, stressed in one sense, >> but maybe also to this point and literally resetting your tissue. 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So there are these [clears throat] 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 you less and less with each year because I do feel I pay more attention to the sleep piece >> um than I certainly than I did when I was a graduate student postto or junior professor but there does seem to be this quote unquote >> positive or let's just call it a reinforced mindset as opposed like [clears throat] an immune rein reinforcement associated with mindset because um some people will say like I I just always get sick and I believe them. They always seem sick. But it could be that um you get sick in in a given environment once and then you you just decide that you're sickly. So then you you know it could be that the immune system is listening to these thoughts but not in the form of words. I think this is where like it gets hokey for people like real biologists and and physicians are like yeah you got to be kidding me like but because immune cells don't listen to thoughts they listen to brain states >> triggers of some sort >> triggers of some sort right um and then there's like as humans we have this obsession with language that makes it seem like you can you know write affirmations and then it's the word content but it's the feeling state associated with that that >> a biological level makes total sense. So we were talking about spatial biology and the fact that you can tuck some pancreas in the kidney and unless they someone has type 1 diabetes >> a lot of the functions of the pancreas can um can persist 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 thyic tissue bank it just later like put it in a slowrelease capsule under our skin of our hand, you know, like. And that might sound crazy, but I have friends, one of whom might be at Neurolink [clears throat] now, who actually embedded a little radio receiver under his hand to be able to open his >> um locks at his home and his car. And his wife might have one also. And like that might sound really like Bay Area like future tech kind of wacky biohacking, but >> if I knew that I could be much healthier >> by taking a few thyic cells and in a you know a sterile capsule and sliding it under the skin, you know, people get their ears pierced with, you know, right >> less less invasive uh 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 were just talking about if I do 10 experiments, one might work. yours isn't a bad idea, but you know, is there it's 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? Um I mean, we know that in a lot of studies of cancer and tumors, I used to see these mice down in the vivarium, >> they would slide tumors under the skin and study them >> and give animals drugs or give animals stuff. >> Very common. Yeah. >> Yeah. Uh tumors are happy to thrive in novel environments. 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 um replacing an organ with one that might be better is that at some point if you come in so one of the the challenges of tissue engineering is if you want to bring in new genes the vector the material the the the surrounding whether you bring in using a virus to and you know to bring it into those cells that you're going to now put into the person whether it's a virus or a small piece of DNA called a plasmid you you effectively are giving that a new bit of identity and when that when you go to transplant that organ back in it's seen as foreign >> and it's it's just like you just put an infected cell in you you know as far as the immune system knows all of a sudden there's a cell with huge number of new things being expressed and some of them viral literally so you know that's a that represents an issue I think when we talk about any kind of you know sort of engineering at the you know the moment is is if you engineer a system to be maybe better the immune system isn't necessarily going want better and and so you have to overcome this issue of tolerance maybe at the same time and and and again that's why 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 going to let it fly. >> I'm not considering doing this. I just 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 and so forth to 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 and it matters for all biological systems. I'll just give you an example. We did a study of of wound healing uh some years ago and if you have a wound in a mouse that's maybe just a like you know 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 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 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 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 so I think one of the tricks that we don't really understand about this is when is something good uh 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 I would say that more so than ever in in 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 and then you have this rise of things on the internet of of anecdotes that become seen as data like I took this thing and this happened. And that's you know I I I could drink this drink and have something great happen to me or something bad happen to me but might have nothing to do with the drink, right? >> You know that that issue is one that I think is really um is really critical in in this in this window of time right now. And honestly I don't know what to think about the idea that people you know do experiments on themselves. I I think we all want to improve ourselves. We all do all all do some kind of experiments on ourselves. you read a book, you're trying to improve yourself, right? Um the physical one gets a bit tricky when uh you know, you're not sure whether something's going to be dangerous or not, but >> Oh, yeah. And I'm not promoting that people do this. I think that of course you would want to see pre-clinical, clinical, and and other um trials for this. I >> think I would personally. I mean, just >> Yeah. I mean, I'm I there are a few areas well where I am um a bit more adventurous, but for the most part, I'm like, you know, based on my training and [clears throat] background, I have to orient toward, you know, I'd like a bunch of Let me put this way. I'd like to a bunch of other people to do it first. >> Yeah. >> Like, who wouldn't? 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 of that right now is and this is, you know, sort of nationwide or even international is vaccine hesitancy. And I know this is a touchy topic, so we can open. Well, I'll just point out that that the one group that's completely no matter whether they're hesitant against childhood vaccines and the number of them we get and the the fact that the government makes you take them and these sort of things, if those people have cancer, they're very interested in vaccines because it's a there there's really good data that you can promote more immune cells against the um 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 a virus or anything in in a childhood vaccine on similar concept um just different peptides. their peptides from the tumor and and in those situations it's context, right? So if if you and I had cancer and we don't have the the conventional cures are not going to work on us. We know there we know statistics really well. Chemo is not very good for a lot of you know cancers and that's the only thing we got. But if you have access to something that's relatively new and particularly vaccines despite what you know some people worry about they're pretty safe. Um, and so the the certain die 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 know you can see where people's their their question about whether they're going to try something or not is very context dependent >> very I think uh 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 um 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. um which is I think there are a very large number of people for whom they are neither antivaccine nor super pro but they are um they're asking about timing and combinations. >> Agreed. >> They're saying okay listen and we had Jay Bachari on here and I've had several others who said maybe there should be an investigation of the spacing of these things how many um how critical it is to do at a given age you know um and on and on. We could 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 immune the young immune system with a lot of vaccines is a very different thing than spacing out the uh delivery of those vaccines. I'm not saying don't give them all. I'm saying >> over what time window does one give them? Yeah. >> I think a lot of people, many more people are asking that question. Yeah. It's just a quieter murmur >> than our um saying, "Listen, we don't want to take any of these things." >> Yeah. >> We don't want our kids to take any of these. >> Well, I've heard that, too. And I I think there's some fair aspect to which most of these vaccines were not studied in the context when they were studied of of what it does, you know, in in in combination and and these sorts of timings. The fact is that, you know, the the evidence that there's that there's bad things happening doesn't look to me, you know, 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 I don't know. >> Just being fair, as long as we're admitting psychology as a factor. >> Yeah. >> Yeah. So, there there's fairness on both sides of that discussion. And I think I think that almost certainly where we are now, there's probably ways to put together vaccines and certainly more convenient ways. It's I I I as a parent I I actually had something very similar where we delayed you know my first daughter's one of her vaccines partly because I know that that as a you know like there's a certain element to which when we designed a protocol like the the protocol for imotherapy of cancer for patients was 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 the 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 also or safest or even one that is less disruptive to the lives of the children and the parents. We we delayed one of our kids vaccines, you know, by just a month or something because uh she had not been feeling well just straight up. And it is true, you know, and I'd say that a couple of the vaccines that have come out that I've had recently, the shingles one is a good example. I had the other has knocked me completely out and it, you know, it's very very heavily advented. So, it's clear that it's, you know, it's having to um does it does it need to be, you know, I actually don't know. I don't know what studies were done. And and there's kind of an aspect to which you I don't know that we're all um 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. >> Um some of them are chosen by competing far pharma companies that each make their own, you know, materials. And you know, again, I think there's a there's a lot in this question. And I don't know how much of it also represents the one problem of science that I could talk about is this um this issue that's a lot of science treat science as a kind of a papacy like we know the language we know the facts and and we probably don't have time to tell you why we think this and where where the holes are. >> Excuse 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 of their own, health challenges of their own, kids of their own, and on and on, and no one was hearing from them. >> Yeah, >> it 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 you're offering perhaps the opportunity for for better understanding and certainly delivery of the information. >> Yeah. >> Yeah. I mean it's it's a huge problem. >> Yeah. Well, I guess it's it's one of those ones that I can only speak about what I did, right, as a as a as 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, you know, vaccinated kids and that was it seemed like it seems even now like a a reasonable no-brainer. But I just told you too that I I asked to go off protocol because at some point I know that these protocols have a little bit of like again they were designed on a one study but it doesn't mean that it doesn't work if you wait another month. In fact if you do if you've done enough mouse experiments 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 and even sometimes for 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 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 um it's like it's like brushing your teeth in the morning, you do it in the morning, the evening, it's 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 in vaccine 2 that relates to the question of like at what point can the government do tell you what to do, which is, you know, it's a it's a surrogate question to the vaccine one where vaccine is, you know, if there's a harm, who gets to choose with 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 wouldn't not immunize my kids. Could there be additional studies about the combination of these into like fewer shots? I think so. I don't see why not. Here's where you get the financial re. What's the benefit to any pharma company of doing that? >> Well, I think this is again I I [clears throat] have to be careful that I don't place myself into an advocacy group that I'm not. I I'm I look at everything on a case- by case basis. I try to do that. >> I really try 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 a lot around SSRIs. But you talk to somebody with clinical grade OCD and they will tell you that SSRI saved their life. >> So then 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 and till recently the GLPs were mostly available through pharma. Now they're sort of it's kind of the wild west. People are micro doing them from all sorts of compoundingies 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 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 one I've seen publicly. Yeah, there 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 kid seemed essentially fine, got a vaccine, and 3 days later started exhibiting symptoms that then set them off on a course that was um really, really tragic. >> Yeah. >> Um and those groups are the ones that have accumulated the most oomph out there. >> And if you think about the 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. But you can understand if your kid is one way, walked out of the doctor's office is is another way. And you can't do anything about it. That's got to be >> I mean beyond maddening >> and and 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 it can't go backward. >> 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 the parents made that choice on the basis of what they thought was the best. So that there's a certain um >> guilt/ anger. I mean there's a whole psychology to it that's completely understandable. >> Yeah. >> 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 in uh medical space and, you know, you guys obviously from time to time talk about peptides and these sorts of things that people are using, you know, off lab, well, not even off label, they're just getting them from from uh who wherever the internet. And you know that 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 straits than before because I think it 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 than the symptoms that we're leaving and and that sort of uh you know again I 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 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 strict scripture and things and than your behavior but somehow [snorts] in here this idea that that um you know we can be told to do things by people that aren't quite in our best interests. I think it opens up the idea well why why can't I choose my best interest? You know who who are these experts that I can't always trust? >> What's more American than that after all? Well, it is it is it is part of the pioneering spirit. Like if the if the government's not going to protect my 40 acres, I got to have a gun and protect it myself. And that's 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 at the moment by the by the fact that there, you know, haven't always been good communication with something you're trying to work out and and and maybe even surface any of these ideas that are hard to talk about like should we trust farm companies? I know a lot of people that work for pharma 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 that's not always true. Not just 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 those things exist. It's not like we have to say that it's right or wrong or whatever but at some point those these kind of perverse incentives exist. I I wonder why, you know, like pharma companies haven't um 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 the responders and who are not. But it's still the case that if you get 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 get if they develop a test that shows who is and who isn't going to respond they'll cut their market into 50 in half. So I don't think any pharma executives out out there going but there's no there's no positive incentive to do that study to study those things and I think it's kind of true in some of these other drugs that we've been you know brought brought forward some of which are better and worse than others we could told that this is going to be good for us and and we should take it and and there's a again you're you're getting to the American kind of like mentality which is to say well some point if you fool me twice or you know I'm not going to believe it and and I might not believe it against the 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 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 as a as a species, should you distrust the entire class of science? Probably not. You just need to maybe make it so that knowledge is is freer and knowledge is better communicated and that >> and that um and you do watch out for those situations where there should be you know uh you know and maybe vaccines are one we you know we just need to do something sensible like what you're describing and just to do a study and say let's do that study and and make that very public that we do it and say we're going to do that and and and obviously people can sign up for you know be you can have this regimen or you the old regimen or the new regimen and you know again I I may speaking. I don't do vaccines. It's not what my lab 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 the answer isn't just say no vaccines and we we think they do. There's good evidence that they're protective. But to the extent that you're coming out, could we make it less let's do it and 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 that nobody's actually describing an experiment. >> What would be the experiment? >> Yeah. Well, the discussions haven't happened and I should say a couple of things. Um, first of all, thank you for being willing 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. If anyone cuts a clip, I will be the first to dive in there and say this is taken out of context. It um 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 uh traditional medicine and vaccines etc. I will say this the idea that you need to push back with a with just a fire hose of do this or else >> did not work. >> The pandemic proved that the 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, you're whatever. You're political this or you're a fascist or whatever." Okay, that is proven to be wrong. >> And the path forward is really this kind of conversation. It's highly educated people like yourself in the educated in the immune system who understand this who have children who've made certain choices saying yes and I can understand why you would be considering the following um questions and we should do a study and and in the meantime you're not preventing anyone from getting vaccines. There's now a hunger for more nuanced conversation around these things. I think it's the right time to have it when we're not in the throws of a pandemic. >> Yeah. >> Yet yet. I mean, there's some things that are on the rise. It is scary. I'll I'll be quite blunt. Um, you know, the 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. >> Not a pretty picture. Yeah. >> So, I think it's great that these conversations are starting >> and it won't be taken out of context. >> Yeah. Well, I mean on the vaccination front, I mean, I just wrote a little a little subsequ um you know, the origins of small vaccination and I think what's lost in those stories is if you look on the internet that the the absolute that that's a terrible disease. I mean that you know the reality of what we're protecting against we haven't it's really hard to to like also have the conversation without doing a little bit of reading into your history >> you know and I I don't think the history books are pulling the wool over our eyes by saying some of these things were really horrendous >> small box was dreadful >> so so there's an element of that though that I think you know that we have to make sure that the conversation focuses on on what are we what are we trying to achieve here and and and sometimes that that question is can get lost. But I think man, if my kid got smallox or got measles or got mouse and and and and you know, as we know like measles is not a a theoretical again, you know, that that concept uh 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 [clears throat] think that's also an important again that's what that's me as a parent saying and I did look at the history of these things and 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 uh you propose experiment that's let's you know I think there's a you know like cutting off you know the concept of human curiosity and science at the legs is probably not the way to figure something out from my experience you you you dive in you think of the experiment they would 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 from my this is me as a parent looking at the numbers of of u you know like the the danger of of 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 caused by a vaccine which I don't by the way can I tell you a little story please maybe you know this already but if you want to induce autism in mice. People do it by injecting a bacterial infection into the mom when she's pregnant. >> Mhm. >> 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 in an aduant situation. Again, I I may regret saying this because it's, you know, it's going to open up a conversation to have this, but to say it's not outside the bounds to say that 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 infection during pregnancy? That's 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 the cells of the brain. >> In fact, one of the one of the best experiments that I love along these lines, it's not about about autism at all, but it's about um when you get a flu, >> you tend to go you you tend to feel like you want to socially isolate yourself. At least I do and most people do. I think they kind of want to crawl in a hole in a hole. There's an experiment that was done that involved injecting gamurfon 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 [snorts] they become uh you know socially isolating from just the molecule that's made by the immune response during infection >> not even 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 the signs of social isolation and >> the lab that did this um also showed that the brain has receptors for these immune molecules. And you know the simple conclusion of that paper and you know there's still always work to be done but simple conclusion was that the brain could sense infection and and it would affect behavior [snorts] um even in mature in us as mature. So, you know, again, there's these these ideas that there is there's something that I mean, scientists use that infection of a mom, you know, to lead to neuronal changes that lead us to be able to under study autism in later mice. So, there there's definitely potential there. I don't know that the vaccines and all of them and or whether there's a circumstance or whether it's, you know, again, the mom actually had a fever before and that vaccine now disgued or didn't or just circumstance because you give vaccines at 2 years of age, which is when autism appears. there's all kinds of options, you know, and that and and the sort of anecdotes of of that. And and um I just think that 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 that's important to know. >> That work is still ongoing by laboratories to understand autism. They want to understand the origins of it and maybe it will not turn out to be vaccines at all. Again, we we need data and and we're in we definitely need data. >> We're almost in a co situation. I describe the co 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 it's not just the publishing problem. It's how we how we synthesize knowledge that under data sparse circumstances to make decisions. I think we're not very good at that society. Um you when we have tons of data and it says absolutely if you have cancer and you take imotherapy then there's a 50% chance you're going to revive great those stats are solid they're very good and I would I would take that drug every time but if it's sort of a case where you're like no there's some things that are happening and there's some other things that happen we don't know you remember at the beginning of co we talked about it amongst ourselves in labels 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 was it could we get it from blood um and 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 was seem seen as confusion that matter of fact it's like do you mask you not mask do you touch do you not touch 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 there you know there are people that will critique people saying okay your experience is anecdata it's correlative but then the the the w with regard to vaccines and autism and other issues, but then the push back is well this vaccine, etc. was directionally guided by sparse information to begin with under times [clears throat] of pressure. There's financial incentives. So, it's just this pingpong 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." >> Um, but you have every right to ask your doctor, >> right? But they're not asking because they're extremists. They're not antivaxers. They're asking because they love their kids 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 re in reality. The data cannot be as polarized as it's been presented. >> Yeah. Certainly certainly in media some of these things get presented quite quite um you know inflammatory and again if if newspapers want to sell a newspaper they show a plane crash you know so it's not happening every day >> but they'll show you an airline ad in the same issue. Well, there's that, too. Yeah. So, >> I think one of the interesting things that we could get into is that in you 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 something orthogonal, crisper, checkpoint blockade, uh, you know, x-rays, you look for that orthogonal use for it, right? And you or that that orthogonal meaning that would sometimes be called extensibility. Like I see that if I 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. You know, it becomes a tool. And and [snorts] I think one of the things that's that that is lost sometimes is that some things are not extensible. So, you know, you can imagine that like if I if I had something that move 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 minus20 degrees to, you know, 110 degrees. We can not eat for a long time. you know, all you know, 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 we lead. And I think a lot of science sometimes doesn't, you know, and and from the outsider, even as an insider, you can read a paper and they they they point to why it might be important, but they're really doing that to to to get garner interest for their story, you know, and then say, "This might be important for this, but I haven't shown it's important for they don't say it's important as it might be important." And they're trying to look for that orthor 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 oneanddone drugs that you you take a pill and it cures everything you know forever. That's sort of found of youthish. And um you know we found a few of those. I'd say check one blockade is one of those that you can take it and you know in 50% of melanomas 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. Uh, you know, that that can cause, you know, 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, you remember I 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 and you push the 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 serious way because resiliency the res the systems like even in chronic disease but even in health we're pretty resilient and like we 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. M >> and this is when whenever somebody he also warned whenever somebody says they understand quantum stuff you have to ask them to demonstrate it for you because because people talk quantum because >> and and we make all these assumptions about quantum they talk about quantum fields so we think they're smart but but that >> theoretical physicists >> and therefore engineers you know develop all sorts of incredible theorems and real experiments and then technologies based on all of that >> because 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 by virtue of the fact that >> there's 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 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 is and I think you know this is back to talking to experts. It's really quite good at at 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 orthopedic 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 mean going answer you know the question you're trying to raise if I get a tumor from a patient and I take apart all the cell and I look at all the genes that are expressed in all the different cell types I can build in silicico 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. [snorts] That that's that's now doable, but it relies on an area of math is not really AI. It's called machine learning. And sometimes these things are conflated, but machine learning is basically looking to say what are some of the relationships that I can discover about, you know, um the relationship between this feature of the cell and this other feature of the cell. So it's it's learning about it and then it's 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 or am I going to study a little bit more and try to understand some some things in a greater detail than maybe the machine learning gave me but it's not clear to me that any anywhere right now we can say the the corpus of knowledge doesn't have a bunch of examples of cures you know across from treatments and say oh all I need to do is match those up which is kind of what AI does when it comes to large language Well, you query it. It looks in statistically and says what are the what are the relationships between what you query and what I give you back as an answer. In a discovery space, we don't have examples of the you know the other end. we have you know sure I can tell you all the things you could do but you know knowing which one is going to be orthogonal big big hit isn't there but what I'm talking about a little bit is is to 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 any one act will do it also the world is pretty sure political systems despite what we think are somehow semi-stable but a series of of 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 in fact we need to do is if we want this tumor to get cured, we need to first let it not look like it's a wound that's healing. So 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 dissemble some of its defenses. And that's that's a way of you know again in this in this kind of deep computational space we end up with a lot of feature the tissue of the of tissue cells and how they're organized and what genes are expressing that start to look like Mellin's map of the of the of the world that you know in its early phase it only had parts and then you know starts as you explore and you add things to it 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 fibroblast certain cells are doing this and epithelial cells are doing this and that's That's a we call them archetypes. They're [snorts] they're like 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 saying, well, they may some 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 fountain of youth the thing that cures a disease and and and it's been forever that we've looked for a 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 too collection of behaviors and foods you eat and sleep you get and all these things create and partners you know your >> loves of your life, the the friends you have, they're all part of I think this this and that's getting a little away from imology obviously, but >> no, but an thing about the insula, you know, not so much a good friend of mine who's a physician in the Bay Area says uh 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, you know, 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 um >> many people are curious about autoimmune >> issues. More and more I hear about, you know, I don't know is 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, uh they it absolutely exists. Um they're tired. I believe them. I know someone who had a myalgia >> uh recently. Um psoriasis is something that I maybe have known to be now >> autoimmune. Um asthma >> these are interesting conditions not all of them life-threatening. Yeah. >> But some of them cause a lot of discomfort. um 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, fundamentally, again, this is I think where um the immune system and you know, 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 with cells in certain ways. And I think if you look at autoimmunities, there's a there's a view of them that they represent a misplaced immune system that's either thinks that it's under attack or it 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 um you know lupus there's a familial mutation in a a receptor that's on a B cell that normally helps turn off the immune system and it's defective. And so those 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 pro, you know, to jazz up for COVID vaccines, you know, those can be overactive and they can be genetically overactive and you know, one wonders why we'd ever have such genes and why they would be propagated except that maybe in some s circumstances you need it when there's a big pandemic or something people might have a particularly good response. So there's definitely genetic origins of some of these things. I think what's uh you know what's interesting to some extent is is something that you'd alluded to with asthma where asthma was one of these things that historically would be called an allergy and it still is an allergy you know where you have you know inciting things that are grass pollen you know these sorts of things but in a lot of these settings the concept that that is is coming in part and parcel with you know the immune system recognizing self you know is is a is a thing and 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 like like 10 years ago we might have just said you know what is if I I might have taken a a lung of a asthmatic patient who died and like cut it and look it in a microscope and say oh yeah I can really see that there's thickening of the airways and that why that's why they couldn't breathe but 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 like seven or eight and they have and that's why some people are, you know, like can take the inhalers and it works and other people can't. Some people they're very like chlorine sensitive. They go to a pool and it and initiates are cold sensitive. So there's there's variations on what sets up that inflammatory focus and I would call it like an archetype. Some of them have lots of cells called eosinaphils. Other ones have lots of cells called neutrfils. So it's asthma isn't just one disease. It's one symptom fail, you know, difficulty breathing, but it has many different sort of configurations and and I guess I'm I would just say that in a lot of this domain, I mean, 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, you know, variations and lupus for sure and inflammatory bowel disease and and and you know this in the clinic because inflammatory bowel disease, you ask about drugs, is a good case where there's a couple different drugs is that for some patients work really well. TNF therapy for example it blocks a cytoine and some people with IBDs is like really bad diarrhea and manifests and very very painful um you know some people they 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. Inflammatory bowel disease and 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 thing then where it doesn't work. >> Sounds like psychiatry. >> It does. Yeah, there's [laughter] a lot. It sounds like a >> no disrespect to the psychiatrist. >> But they have a hard job, right? I mean drugs will work for a while then they don't work. Side effects crop up that never existed before. It's it's a tough one. >> Yeah. Agreed. Agreed. So yeah, autoimmunity is a real thing. It's 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 you just got a different football team out there playing or they running a different play. If somebody has a kind of mild autoimmune condition like let's say mild psoriasis >> does that I've read but that doesn't necessarily mean anything. Um I've read that that might confer because it's autoimmune that might confer them with a bit better uh viral and bacterial infection resistance. So, you know, there's a trade-off there like, okay, so scalp cells are like sloing off and like I think it's like interlucan 17 or something now like the treatment they have some good shampoos for this or but >> anti-influc but but you that individual is um maybe better at fighting out other infections. So, you know, given there's a anti-influcch um and uh 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. And people might wonder like, are we really talking about psoriasis? But I think it's sort of a individ point for why autoimmunity could actually be useful. Yeah. >> Um it's not always the case. It's like there 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 cickle cell gene. This is the one that causes people to have hemoph you know hemophilia and it's a lot of subsaharan African gene people from that origin have this is that it's actually defensive against malaria is you know it seems to be the case that so so having that I think this is true a lot of these situations where the diversity of the human population over time you by having some of these things that make some people hyper sensitive to you know uh to maybe bacter viral infection at the cost of having things like psoriasis pop up or you know various various other autoimmunities is the only way that you know like a a billion strong population has to to to to move forward and I I always give this example that because I think it's a really straightforward one if you take a a flask of bacteria and um and you put them in glucose which is like sugar like you put in your coffee um maybe sucrossse either one you put them in a in a in a simple sugar uh and you watch the colony grow you'll get these cells that grow really really fast the bacteria you know becomes billions, trillions of of individual cells, but there's almost always some just losers that are dividing slowly. And it's for whatever reason, the system always springs us off. You're like, why would you do that? Why would the system why 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 uh crowd uh fitness that comes from diversity of 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 and 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? you know, so I think there's a lot to be said and 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 the differences in urine mine 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 these numbers are averages. Some people may need five times that amount of, you know, vitamin X and other people may need a fifth. And I think this is super critical. The supplement world is kind of like scattershot. Well, I appreciate the rational grounding in all of it. I I think uh thread throughout today's conversation. I think that um I picked up on, you know, I 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 some are beneficial. It's clear some are still experimental. I'm just a big fan of more data and more data collected the right ways and communicated the right ways as the same way with vaccines and all the rest. You have an amazing substack. 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 realize 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 in the ways that you have and uh as somebody who thinks in analogy I and likes to teach in analogy. I really appreciate that 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 uh Substack. 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 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 um how can we make sure that you continue to do it? >> Yeah. Well, thank you for the call out. Um it is it's something I've been trying to work on for about 10 years and it it really started when um a group of us you know were were hanging around after a conference and we were talking about some of the issues with science in society and there were many you know there's many there's there's we've surfaced a few of them today but I think something that you guys are working on is is the capacity for everyone else to think as a scientist like why you can ask yourself you know oh why don't people agree 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 you know that two things two things are important about it I think one of them is you if you present the information in a format that isn't you know familiar you're not going to be able to teach anything anybody anything about what's important but the other thing is that you know we were talking we we spent some time talking about this and we consulted some other folks that are in science comms and we realized you know the other thing is that that 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 like you know there's there's hesitancy among African-American for example to take drugs because of things of history of Tuskegee which is like 80 years ago or however long ago 60 years ago. Wow. It's it's it's it's not in their lifetime in many of these people. And so part of the realization was like maybe part of what we really should be doing as scientists is one of part of our job should be to figure out how we relate to other humans. And it's you know that there's a painting of this and you obviously the media and and things help this happen because it makes it interesting to have a you know kind of a nerdy scientist and and we all you can be a nerdy scientist. I heard you and you know but also you're a human. You're a human being. You have you know there's foibless to you know loves and hates and and um >> certainly foibless. I have plenty of those. [laughter] >> We can get in that off the podcast. But you know that this concept of if we want to relate um you know 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 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 o you know is separate is is this concept that we speak in our our vocabulary that is gets very precise and we forget that you know if you hear a foreign language and you hear one word that you don't recog recognize it. It throws you off for a few sentences and next thing you know you don't know what people are talking about. And I I think that concept that that you know and again this is where I think bringing it down a level and saying let's give it analogy, let's give it that [clears throat] strikes me as really really important to the impact that you can have with with your science and and that science can have in 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 u designs, then then you've lost that that that the potential for it to do good is is gone. So the Substack came about it because I was like, well, I need to write as a person a little bit more and and tell about some of the, you know, the time that you spend on this and why it matters and what it's like to to do this work and and in some respects also what it's like to to lose in this, which happens way more often than the, you know, it's like a casino, right, in science. Science you hear the bells and some cool device comes out and it's but but there's a bunch of people pulling the arm, you know, and they're they're not winning. And so, [laughter] you know, so I feel like that's kind of an important part of this that that again, it's not the glory story always. >> Um, you know, the best some of the bestselling books about science or are the winds, but um, you know, it's might be more relatable at some point to get all of it. So, that's kind of what what I was trying to put together. And 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 it out. been >> working on for a bit. >> Well, I hope you continue to and um >> 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 >> um for your advocacy for science and public education, it's huge. Uh we need more people like you. But you've certainly put your own unique signature on it and the Substack reflects that. It's an incredibly interesting set of reads and um 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 is just really cool. And with all the meaningless dril out there, it's nice to go to a place like your Substack and I'm speaking to the audience now. You you will learn if you read Max's Substack. You will be inspired by certain things. And I promise you, so I'm saying this intentionally, mark my words, at some point some somebody's going to contact you that they decided to study the immune system or they learned something or they explored a a novel treatment with their physician in a in a given unfortunate or maybe even fortunate situation that bettered their lives. It's it's incredible what um Substacks and conversations like the one you've been willing to have today and going forward can can really do. So, thank you so much. should definitely come back again and tell us about cancer and other other things because I I took us off course quite a lot but I 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. Well, same here. Thanks so much. >> Thank you for joining me for today's discussion with Dr. Max Crumbl. To learn more about his work and to find a link to his superb substack, please see the links in the show not caption. 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