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

00:00:00A famous runologist 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 U.S. submarines. And so they could listen to the wear of the engines. And if they heard a wear of the engine that had the certain cycle of a general 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 engines of the German, 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 me with

00:00:39aging is this concept that as you get weirder and different, your body is getting like more complex, then those books, you know, start to have every possible, possibly, every possible permutation of every biomolecule 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 and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor

00:01:07of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Max Cromwell, a professor in leading expert in immunology and cancer biology at the University of California, San Francisco. Today we discuss your immune system, how it works, what it needs to function at its best, and how things like aging, vaccines, sleep,

00:01:28and even your thoughts emotions shape immune function. For instance, most everybody knows that being sleep deprived makes you more prone to getting sick. But why? Meaning mechanistically why? Well, it turns out there's a specific set of cells that need to migrate in a particular way during sleep.

00:01:43And 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. Cromwell is incredibly balanced throughout today's conversation,

00:02:16and 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.

00:02:40I should also mention that Dr. Cromwell has an incredible zero-cost substack. It's called The Immune Beyond. You can access it by going to the immune beyond, all one word, dot substack.com, and there he teaches about science and more. Again, it's awesome, it's free, so definitely check it out. Before we begin, I'd like to emphasize,

00:02:57that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Max Krummel. Dr. Max Krummel, welcome. Thanks. Most everybody, including me, has heard of this thing we call the immune system.

00:03:21And most people just think, okay, this is the thing that when I'm rested, it keeps me from getting sick. and when I'm not as well rested, I tend to get more sick. And there are these airborne things and we can get sick. And there's like funguses and viruses. And I think that's probably what most people understand. And they probably also understand that there are like cells and T cells and B cells. But if we want to think about a little bit of the history of our understanding of the immune system and what we understand now, maybe you could orient us.

00:03:51Because in reading your work prior to this discussion and realizing, that this is a very recent field. And also, there's still a lot that we do not understand. When I started immunology, sort of 30 years ago, I was rotating in labs at Berkeley. I think you were at Berkeley as well. And one of the transcription factor biologists, you know, mentor said, you know, why do you want to work in immunology? It's not really a field. And so the time was kind of true.

00:04:18You know, everything was about DNAs, cloning. We still, you know, it's obviously still a lot about molecular biology of what we do. but at the time it was pretty simple. We thought of the immune system is something that on the one hand it had to come into play when you saw a virus or something foreign and otherwise it generally had to be quiescent and kind of leave you alone. I think cancer immunotherapy changed that a lot

00:04:39that gave us the idea that you could tune its reactivity so that you could get to the point where if you gave an immunotherapy, what it was actually doing was raising the threshold when a T-cell would activate and allowing T-cells that might be just letting the tumor get by, get, they'd be able to go and go after that tumor and kill it. I think that changed the spectrum of a certain degree where we suddenly thought, okay, this isn't just a, just a, you know, foreign versus self thing, because a tumor is kind

00:05:06of not exactly self, but it's also not foreign. It 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 tunable system. But then I think, you know, a lot has happened in the last 20 years. It's been a lot of excitement about cancer immunotherapy because we're curing people with cancer, which really wasn't done before. You're now in the space where the immune system is showing all these other roles.

00:05:34I mean, you know it in the nervous system. The brain, there's microglia that do various functions, cleaning up, et cetera. But it's in your gut. It's allowing microbes to live in you, but it's titrating them. It's keeping them there in kind of like the right quantity. So it's kind of guarding yourself. It sits in your liver. regulating how much you metabolize.

00:05:56There's a collection of cells there. It's in your heart. It's regulating cardiomyosite function. Those are the muscle cells of your heart. They have to be cleaned up from time to time. So there's a set of immune cells that will help get rid of their byproducts in the heart. So it has all these additional functions that kind of before we're lost in the just, you know, the foreign battle against the foreign.

00:06:20And 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 is to help us be who we are. And hopefully that's you as a healthy person. You know, in chronic disease, unfortunately, it can be part of the problem where it becomes part of the things that's letting the chronic thing, whether that's a tumor or kidney disease or what have you. It can actually help perpetuate it because, you know, in some ways it's trying its best. But it's applying the wrong program to the wrong situation. So, yeah, it's changed a ton.

00:06:56I'll give you another little funny story, which is that, you know, when I first came in immunology, again, we had the story like, you know, mentor who says, you know, this isn't really a field. The year was, like, I came to the field in 1989, and that's right at the peak of AIDS. And AIDS was like, as a biologist, was really interesting because, you know, the HIV virus infects T cells. So your body is filled with 10 to 11th or so T cells, like a ton of different kinds of T cells. And you have a subset of T cells that are called CD4 T cells.

00:07:29They're kind of a flavor of T cells. And the virus gets rid of those. So HIV virus will infect the CD4 T cells and then you end up with not having them. And the manifestations of AIDS, for those that weren't around there in, was just a ton of different opportunistic infections. So like soil bacteria that you and I fight off with the, even thinking about it, would kill people. But so too would you see, you saw people with carbustisocci-coma. You saw like a opportunistic, like where, you know, cancer's emerging.

00:08:01And you just saw all these kind of manifestations of where the immune system was important, dementia's in people with HIV as well. You know, it was a really accent at the time on how many different things the immune system might be important for. So regardless of whether, you know, it was a field or not, it was clearly important. And it was all these things we didn't know about it. that like fueled the discoveries that have led to where we are right now. And some of those, you know, I think it's worth pointing out, were just these curiosity questions.

00:08:27Like, what are these cells? Like, they were hard to study it in the beginning. You know, they don't live, you know, it's sometimes hard to keep cells out of a human body alive. So, you know, there's issues about, you know, how do you keep these things alive in the very first place? And then 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 behaviors that they can engage in. And it just gets 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.

00:09:05And they're part of a sensory system. Each one can measure the concentration of a set of biomolecules, proteins, and the form of 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, 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.

00:09:32It is magnificent. Do you mind if we take a developmental 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.

00:09:59Maybe you could describe what's going on there. And it also is the case that, you know, as we get older, much older, in fact, last quarter of life, let's say, people tend to get sick more. what's going on in terms of immune system function or is there something more broadly happening at level of just kind of energetic 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?

00:10:30And I don't mean that in the personal sense, but I can talk about that too if you want. But the more of the question is like 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 of 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 weren't for the bugs, the bacteria in your gut. They make some of the key components of bio acids that allow you to digest animal fats.

00:11:02So 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've got this cell that starts to divide and gives the rise

00:11:14to every other cell in our body. So you might say that your body is just that collection of cells. But in fact, it's absorbed a lot of viruses and bacteria from our environment.

00:11:26And, 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.

00:11:35And so by absorbing all kinds of other species onto us, we get their genome. So like you said, like I was saying, 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 bacteria in your gut that can help you absorb the seaweed, nutrients with seaweed.

00:11:54So taking this into your question, you know, when you're first born, you've never really seen anything. And so two things 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 months, that's because your body's developing so fast that if you were to have a superactive immune system, you might actually find yourself attacking yourself. You might think that you're foreign because some genes turn on during development and then all of a sudden your immune system's like, oh, I see something

00:12:25different and now I need to react. So that's well known and that's one of the reasons why some childhood vaccinations, they're really important to protect kids in long over life, why they aren't given until you're six months or older. But I think to your point, one of the things that's happening with kids is that then as they go into their, 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 because they've never seen the body's never. That body, the kid's 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.

00:13:04It reacts and, you know, gets rid of that. with the exception of the ones that, you know, are those certain viruses and bacteria's mumps, measles, rebella that are lethal, and that's why we immunize. And 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 the vaccine. All right, so that's the front end, right?

00:13:22The front end has this initial, you know, immunosuppression, then just exposure to all these things that are in our environment and you and I take on as part of our genomes, but we have to get a, we have to reach a detente 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 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.

00:13:45And 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. So that's a front end. And in the back end of life, it's a little bit more complicated, but I'll tell you two things that I think are important. And on the one hand is the idea that is the fact that a lot of your cells in general become

00:14:08less functional, including immune cells. And you get less cells produced. And that might just be because, you know, we were never selected as organisms to live as long we do right now. That's the one idea of aging, right? Did you know that? That we just were supposed to be dead by 70? Well, no.

00:14:24But we do know that we can reproduce and, you know, pass on our genes successfully already when we're 16. So, you know, the selective pressure to pass on your genes, if you've imagined. and that's how genetic evolution happens is that you pass on your genes as being successful. You can already do that at 16 and anything after that is just cream on the crop. But at some point, maybe there's no selection.

00:14:46So we don't know that, but it's a reasonable hypothesis to say there wasn't any real selective pressure for passing on genes that do anything past when you're actually having kids. The psychologists would tell us that the wisdom of people, you know, 60, 70, 80 and beyond is useful for groups of human beings. that live in, you know, villages of 100 or so people

00:15:08because they can give information to younger people that is on the periodicity of like every five to 10 years, maybe every 30 years, but that's a just so story. Yeah. Right? I mean, it's a nice just so story. I like it too, and I think the geneticist will refer to that as like the grandfather effect

00:15:24where genes may be selected for, and maybe they're mostly about genes that make a social in the, and for the elderly that do, they're going to have effects on the fitness of their grandchildren, which is their genes. And so, yeah, I think there's somebody to be said for that in conceptual space. I don't know if I can prove it to you that that's a tough experiment to do. It's a really tough experiment to have two villages where the grandparents are eliminated or like kept, you know, both non-ethical and also not enough. Right.

00:15:55But we're talking about the aging immune system. And I think there's two things that, again, come to this question that I was asking, like, who are you? And I was saying, okay, well, in aging, you have that. this issue that the immune system is tapering and it's efficacy, it's many of the cells that you've been holding your whole life, start to literally, they die off. But there's another thing, which is, I think a lot of people don't realize when you say, when the basic biology would say the sperm, you know, like fertilized the egg, so you've got your mom's genes and your dad's genes. You've got 23 chromosomes from your mom, 23 chromosomes your dad. And at least, when you're

00:16:26first 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 basic sun exposure. And that's higher than some of the other organs. But the basic idea is that your DNA is susceptible to UV radiation. That's one of the reasons we put on sunscreen. But what it practically means, no matter what number you put in there, whether it's 10,000 mutations per day. Remember, the genomes are huge, right?

00:17:01So 10,000 mutations out of terabytes of information still is only a certain number. But do that over years. And the main thing is that that means is that every cell in your body is no longer identical than one next to it because this one got different mutations on day one. 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 you see in Morocco, you know, very intricate designs. Because if you actually, you know, start to look into tissue, you know, you all.

00:17:31find that certain clones, certain mutations, do make certain cells more fit, and they're the ones that if you scratch yourself in a cell has to form, some new has to form, they might be the fittest to fill that void. And one of the other clones over here that got a different mutation may not be fit to fill that clone. So you end up with this pastiche of who you are. So now, again, I ask you, like, who are you now? So if I want to defend against something that looks different, what if everything looks different?

00:17:59What if every cell is different from every other cell? It's, it's, okay, you want another analogy? I would like another analogy. The only exception that I can think of to this, and that could be wrong, is that our neurons, our central nervous system neurons, our brain and spinal cord, most all of them are the same ones that we were born with. Same cells, but the DNA. So you're saying mutations are constantly accruing in the neurons as well. So there's just, it is fascinating, by the way, neurons live that long.

00:18:27And, you know, hair cells, they say that the proteins in our hair, hair cells of our ear are the same exact molecules, atoms, as we had when we were born. So there's some cells that are long, 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. We tend to think that one of the reasons that immune stem cells live in our bone marrow, you know, our long bones are hollow. And in there is the source of the immune system's revitalization.

00:18:56It's the stem cells that make more white blood cells. We'd like to think that they live in there because it protects them from a reaction. They hang out, the stem cells are, you know, the bone actually serves not only a structural purpose in our body, but it's a cavity in which things can live. Keep it away from solar radiation. Solar radiation. Keep it away from chemical cues in the environment that can mutate. Sequester your stem cells. Don't burn them.

00:19:20Yeah. That kind of thing. Yeah. Yeah. Likewise, the neurons in the inside of the skull and the spinal cord are protected. They're protected. Yeah. And that's interesting.

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00:21:49across different sleep stages. It will even elevate your head if you're snoring, and it makes other shifts to optimize your sleep. If you'd like to try eight sleep, go to eight sleep.com slash Huberman to get up to $350 off the new pod five. Eight Sleep ships to many countries worldwide, including Mexico and the UAE. Again, that's eight sleep.com slash 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.

00:22:17And 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 do a lot of work. We just lost half the audience. I'm sorry. I'm just kidding. I'm totally joking. We're a bipartisan audience.

00:22:31I'm totally joking. Take it how you want to. But by analogy, it's the argument for, you know, why certain, you know, influx of, in this case, organisms onto us or, 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, orinologist in the 1970s drew this parallel in wartime and said in, you know, war, war, war, two, submarines would be underneath the ocean and they'd be traveling around.

00:22:59And 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. And so they had two sets of books that they used. One of them was a book that gave them the sound profile of all, let's say it's a U.S., of all the U.S. submarines. And so they could listen to the wear of the engines. and if they heard it were of the engine that had a certain cycle

00:23:24of a general 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.

00:23:40And 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 me with it aging is this concept that as you get weirder and different, and your body is getting more complex, then those books start to have every possible, possibly, every possible permutation of every biomolecule

00:24:00could 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 out of range, and now I need to mount that T-cell response against this. I need to bring in the troops.

00:24:19But with aging, we have this kind of, you know, 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 that's one of the reasons why we also have issue when we're aging. And it's, I think it's also one of the reasons why cancer is more prevalent in later life. 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

00:24:48of them and ones like them, you know, over these. years to the point where the weird doesn't look that weird anymore. You know, something like a cancer that is different than you, it's not that much different than like another cell over here that's gone, you know, like, and it's just happily making skin and isn't cancerous, but, you know, it's got some differences. What about the argument that there's so much cellular turnover that the cells that accumulate these mutations are being eliminated? You're saying because they're clonal, they're producing different, they become different, they produce cells that are also different, then they die. Is that the way it works? Yeah. And I think, I think you are bringing some of it that's also true,

00:25:29which 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 little these white spots, you know, your skin. And we think that those are places where the immune system has sensed a collection of cells that were pre-canceres. Maybe they were even, beginning of cancer and has wiped them out. And so a lot of the origin of cancers in skin is melanin producing cells like melanoma, is what we call skin cancer. Those melanocytes, that white area, they've been wiped of a whole collection of melanocytes.

00:26:05And that's why it's white instead of as dark as your rest of your skin. So to that extent, the idea that the immune system is pruning you all the time is, you know, it looks like there's pretty good evidence for that. And the question is, when does somebody become dangerous? That's fundamentally a question with cancer and these sorts of things. If you said, I want to actually have the fittest cells in my skin to fill in a gap if I scratch myself, I really like to have cells that quickly replicate, just like maybe in kids. Kids heal so ridiculously quickly, right?

00:26:37Because they have an abundance of these cells that I think they're wound healing. I mean, there's a group out of Stanford that studies this, but essentially, you know, wound healing in young is quite a bit faster and more efficient. And there's many levels of that. There's many levels of that. Yeah. But, yeah, remarkably faster. And if you're a parent, you've seen this, you know, you cut yourself in the same day as your kid cut yourself.

00:26:58And there, three days later, it came and find it on them. And, you know, like four weeks later, you're still like got that, you know, scat or something. But I was just coming to the point that if you do that and you want to, you maybe want that to fill back in because, you know, certainly out in the wild, having an open wound is a bad thing. So you'd like to yield quickly. Well, if a mutation has happened that fills that cell in, 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.

00:27:38They 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 help you, but at some point you don't want it to basically form a lesion and grow, grow, grow, grow, grow, grow, and go other places and grow, which is called metastasis in cancer, which is how most people die. To me, 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. And then at the same time, the idea of what you can do with that information is also, I call this kind of the new immunity. immunity used to be like a fuel gauge, you'd say it was low for itself, then it was really high against viruses, and it was like a fuel gauge. Now it's really hot.

00:28:20And what we originally thought we were doing with cancer immunotherapy was making it just hotter in general. But now you realize that in between, like the immune system not caring about something at all and going in 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 like quarantine bacteria. it's not going to kill them. It's in that zone. Bacteria, as long as they're in the right zone, there's not too many of them, there's not too few of them.

00:28:46The immune system can actually help them be there. It can produce things that like either titers them out of circulation or keeps them there. You know, in all these other settings, like you say, in the heart and the, you could almost any organ. And the immune system is consistently present and it's consistently measuring you.

00:29:03And the U, again, is this complex view. It's not just what came from the egg. It's the U that's you right now, including all the mutations, that you might have accrued and all the bacteria 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 illness that we've gone back to our pure state. This may come from religion.

00:29:21You know, 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. It 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 ourselves. We need to leave some of those alive.

00:29:47Like, for example, herpes virus infection infects the nerves, and when people have, you know, emergence, they get nerve pain and worse. A lot of that is caused by the immune system reacting to the virus trying to get out and then killing off neurons. So it's immunopathology. The immune system is causing as much of the damage and problem as the viruses. And it's the failure of that detente. And when certain viruses are just sitting in us, we're perfectly fine.

00:30:15You know, we have new viruses sitting around. As long as they're laying dormant, our immune system can say, okay, I'm going to just hang out here. And if anything bad happens, I'm going to squelch that. But it's not like we've been purified. You know, that's a reality that's a little bit too bad. But, you know, it's also one where you say, again, if the goal of us is to make it to 30, let's say you get a papato, an early liver infection of a HV or HBV, if the immune system can just let that be,

00:30:41you'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 matter the massive immune response, you went all the way in the fuel gauge to the right, your immune system can kill you. It absolutely can.

00:30:55It can kill any cell it wants. So 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...

00:31:12You're going to be one by the end of today. I hope so. I like the sound of that, 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 enough to assess how many cells throughout the body or even just. 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 in the biological sense, let's just keep it there for sake of today's discussion.

00:31:50And, you know, by time we are, you know, 32 years old, we are a mosaic of mutations, as it appears we are. If the immune system could surveil multiple regions in the body, maybe compare organs or maybe keep it within organ system and say, you know, the number of mutated cells or not pure me cells would be one way to do it more simply, perhaps, has exceeded a certain threshold measured, I don't know, like enough receptors have something in them that the cell goes, okay, you know what, I'm going to fight. Yeah.

00:32:25In the same way that, you know, soldiers, you know, they might hear a shot was by, but then do they necessarily reveal their location and launch an attack? No. Yeah. But if it's enough of an attack, they'll fight back. It seems like there should be some way that the immune system could quantify either body-wide or local organ or over some period of time. They could integrate over time. I have to imagine that such a mechanism exists.

00:32:53You're coming from neurobiologists, I know. And so there is that in neurobiology of accommodation, right? I always tell the story. I went to a little village in France called Epoise. If you know the name, Opoise is kind of a... famous cheese that they make in this town, and it's super stinky. And they make it only in that town, and they make a lot of it in that town. And so when you drive into that town, it's like somebody has the worst foot odor.

00:33:14It's striking. It really hits you. But after being in the town for like an hour, you don't notice it. And that's neuronal accommodation where you're nervous. There's the same kind of thing you're talking about where 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 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 think you're exactly right where

00:33:38you're going with this, and we think this is true, that the immune system is, you know, for danger, it's looking for something that you would call like a, it's how it's seeing the signal over time. So a virus may, you know, 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 and 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 response and you learn it. And so the next time around, it'll be faster to respond to it and keep you from getting sick.

00:34:12That'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 insulin, you know, which we think in general, you know, it has a little bit of signal up and down as you have a trigger, but there's a range for that. And so your body gets used to that range. and the T cells that see insulin, they are very low, they're going to only be very low reactive to that,

00:34:36and 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 viruses. So like a mutant cell, and maybe it's just a tiny, tiny bit above normal for months, and then it makes two copies of its cells, and now it's a little bit higher than normal.

00:34:57And the immune system 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 experimental stuff, is the idea that whatever you are is what the immune system

00:35:13is going to help you be. If it's a slow direction this way, it's going to be okay with that. What it doesn't like is like big spikes. And that's maybe the signal that you're asking about, like, could you actually get to the point where you be reactive? The problem with cancer is that it is

00:35:29You know, slow and nefarry, it grows over time. And I think we're made to absorb slow change. Because if it's not causing us to be sick yesterday and a little bit more of it 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, that's commensal. It's as long as it doesn't accompany. Again, viruses have two features in common. One is this spike of, you know, appearance.

00:35:54But 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 some cells are going to see the damage and some cells are going to see the additional proteins that come in. And then they exchange information just like your brain. You can talk about the fact that the brain has this wired, you know, a set of cells that are wired in space. 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 literally crawling around us right now. And we used to do, we still do a lot of imaging.

00:36:24If you look in a piece of skin, you can see the cells, the immune system are really, really surveying us that are 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. Oh, you saw that. Well, I'm just seeing 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've 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 research. But recently I've been seeing a lot more interest in the thymus, this organ that we have when we're young and it disappears

00:37:05as we get older and there's a lot of interest in the thymus. Maybe because we've never covered the thymus on this podcast in any amount of detail. If you could just educate us a bit what it is, what it does, and why it might be interesting as a therapeutic. I mean, maybe we in a few years we'll all be banking our thymic cells. Maybe we will be, I know some people are already injecting non-FDA approved peptides that come from the thymus. I'm not recommending anyone do that, but people are already doing it because that's the internet in 2026. What's the thymus? What does it do? Why this interest? Yeah. Well, I can back up one step and I've used the word T-cell before. And T-cell originally was thymus cell. So for those that maybe don't, you know,

00:37:49you've gone to and had blood taken, you know, if you have blood taken in the hospital, whatever, 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 million, well, they come in multiple flavors. But for the moment, we'll talk about two. One are called B cells and one are called T cells. And T cells were named because of the thymus. So the thymus is this funny organ.

00:38:10And it has a funny history. In fact, I'm writing these substaxes. And I'm writing one that's supposed to be released tomorrow by the thymus because it really should have gotten the Nobel Prize. So there's a guy who's alive. He's like 97 years old in Australia who did this. 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-ish organ as growth near the heart as they were taking the body, you know, this they're cutting open.

00:38:42And 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 didn't really know what it did. And so he would remove it. And the kids then go home, and it was usually exploratory heart surgery, but kids would go home. And far from dying of heart disease, many of them would die from like opportunistic infections. They'd get all these infections.

00:39:09They'd get flu and et cetera. And so there was this hint that maybe this removal had taken out a critical part of your immune system, had made it so you were super susceptible to bacteria. And so this guy named Jacques Miller, who's this nice seven-year-old. Kodger in Australia. At the time, he was in England, and he basically took a bunch of mice, and when they were newborn, he removed their thymus, the same little whitish organ. And sure enough, those mice basically grew up, okay, but then they all would succumb to bacterial infections.

00:39:40And in fact, a few of them even got tumors, which was kind of noted at the time, but forgot. And the reason why that is, is because the thymus is the place that makes all your T-cells. And it comes from a kind of a convoluted path, but we know how we're talking about how the stem cells of your immune system lives in your bone. Well, there are stem cells that live in their bone, and they travel through your blood to the thymus and become T cells. And the reason they need to do that is that the thymus is this kind of super special place

00:40:06that is able to present to them, to show them, all of the genes in your genome, in various different ways. And so the T cells that come in there, the T cells are developing, and they each have a possible 10 to the 11th different kinds of receptors to smell different things. and you don't want any ideas to come out that are too reactive to you. So you don't want to produce T cells that are going to go off and kill your pancreas or, you know, kill your big toe or anything. 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 stymus has the role of producing T cells, but also of educating them in some ways, of only letting the ones that come out that have sensors that are correctly tuned to let you be you in that way.

00:40:47Now, to the point about the story, and you were asking about aging, is that in kids, those are really big because at that point, we were talking about the developing immune system, it has to go from, like, you know, living under the veil of your mother's immunity, and then it needs to let some development happen, and then it needs to burst out and start to be able to react against whatever bacteria and viruses you're going to see over life. So your thymus has a huge output. So as it, like, between really from, you know, three to six months old and, you know, into your, into your, into your, into your, four or five years age, but tapering, your body makes tons of T cells. And it's because probably what you're talking about, you're going to expose to all kinds of different bacteria and viruses. And so you need to make that 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

00:41:34environment, 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 invalutes. It gets super, super small. So in aged people, it's like tiny. And so it's not putting out new T cells. And so the reason why there's interest in like these peptides,

00:41:53but 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 T cells that could come into you flood in there with exactly the specificity for the tumor? The tumor has managed to teach all your normal cell, your other T's on your body that it's normal. Maybe you need a source of new material to come in and do that.

00:42:15And there's really two ways. I think you mentioned you talked to Alex Marcia, 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 the sort of like, if you will, the more natural route to that might be to let the thymus make you some more T cells. And make sure that as they come out, you make sure that they can react against this tumor or whatever it is you need to defend against. It's always been a fascinating organ from the sense that it's the origin of all the cell types that we care about,

00:42:43that T cells in that case. But it does have this like aging, you know, sort of aging effect that seems to make us a little bit more susceptible to things later in life. And, you know, again, we could argue about whether there was a big evolutionary design behind doing that or whether it just wasn't needed. Because if you got you had to 30 and you died of an arrow wound, you know, you know. But you're given new genes. You're a winner in the evolutionary sense, you know. I love this stance on, well, if you've already reproduced. I'll just give a brief vignette.

00:43:16We were introduced by our mutual friend, David Feldheim, who's a phenomenal developmental biologist from UC Santa Cruz and his wife, Sophie Salama, is also phenomenal biologist, a mutual friend. Years ago, I was in Dave's lab because we were longtime collaborators and published a bunch of papers together, and he was doing some injections. I'm going to get you in trouble, Dave. He doesn't do this any longer. I'm going to join him to get you in trouble because we was doing some injections,

00:43:43And he might have been using, might have been using carbosionide dyes. This was kind of conventional toolback. 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 I walked over and I saw Dave doing this and he wasn't wearing any gloves. And I thought, these are carbosyanide dyes. With cyanide being the...

00:44:08The key. And I said, Dave, don't. Don't you want to put on gloves? And he literally looked up from the microscope of 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.

00:44:23And everyone else was following a safety protocol. Don't go after him. He doesn't do this any longer, folks. But there's an interesting mindset among you, because he comes from cell biology, Randy Shackman's lab. You both trained in Nobel Prize winning laboratories as graduate students. So I find it remarkable that this stance of, well, if you've already successfully reproduced really aren't needed, but his kids are now graduated or in college. So there is this

00:44:47thing about raising the young, too, and not just creating them and then dying. I agree. 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 Davis and you got to, you know, the selective pressure is to get your, you know, 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 within an hour they're running. So that period of raising children,

00:45:28I think creates more pressure in humans to, you know, to successfully be healthy longer. But I guess just, you know, that it may be a negative viewpoint, but that concept that maybe there isn't as much pressure for you to be healthy. And going with this is the idea that some of the things that we want to be super efficient early on might actually be bad for us as we get. Like I think this issue that I brought up with our mosaics is a real confounder to everything because that creates something that is quite hard to defend against, I think, that aging backdrop. And, you know, some of the immune system that is really going to be important to just be super reactive early on may have some, you know, compensatory problems when faced with that

00:46:14new reality of a 50-year-old or 70-year-old or whatever, it looks quite, you know, it looks quite more complex. But you would have, you would have definitely wanted in gene space, you know, in a 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, let's say, Are you? And it's, again, there's, it 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 questions that are almost 90% of them are going to be dead ends. You know, you cannot hypothesize it's one thing. But you've got to do the experiment to like eliminate that. And this is one of the things that people I don't think always understand about science is that for all the discoveries that, you know, I made or other people have made, there are hundreds and hundreds of like disappointments. you know, and you'll recognize this where you just go home from the lab at the end of day and you've done everything right,

00:47:10but the answer isn't the one isn't the right one. Yeah, one control experiment can nuke your whole project. Well, there's that. One good control. There's obviously that you have to do the experiment well and have it controlled,

00:47:20but the answer just could be not the one you thought. And, you know, we can only imagine stuff and then try and see if it's true or more importantly try to prove that it's not true. This is the better experiments, that kind of way we call them killer experiment. right, the ones that are going to kill the idea if they're wrong, if the idea is wrong, but it's killer because if it turns out the way you hope it will.

00:47:41You know, again, when we get to some of these aging things, and 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 I wish that because of the age certain things would happen, that's a, That's lovely, but it could be super, the word was Baroque, you know, like 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, where like, oh, my God, I didn't realize that this system that seems like it might be quite simple is so complicated. The world is so strange.

00:48:25Well, when I started in neurobiology, the brain, actually the entire central nervous system was considered an immune privileged organ. Yes. There weren't supposed to be immune cells there. And thanks to the beautiful work of Carla Shats with the major historic compatibility complex work and Ben Barris. And I'm failing to mention all their scientific offspring, Beth Stephen, Chala Eriglu, and on and on. They would take the rest of the episode to name all of Ben's scientific offspring. And Carlos, too. And being you.

00:48:55Right. I didn't work on those issues, but I was in those labs when it was happening. We now know that the immune system is active in a lot. living alive in the central nervous system throughout the whole lifespan serving critical roles. There are two things that, well, three really that are somewhat practical questions. I'll start with the most basic one. Why is it at a mechanistic level that if you miss a night or two of sleep that your immune system seems so less effective in fighting off infections, do we know what's happening?

00:49:23Is it like you've got so much adenosine, which is the sleepy molecule and like 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 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 bits and pieces of it.

00:49:43I think some really nice work shows that at night a few wacky things, when you're sleep, a few what you might have thought would be wacky things happen. And one of them is that a lot of your immune cells clear back to the bone marrow. and your tissues become populated with a bunch of neutrophils that come out of the bone marrow and seem to be, you know, depositing collagen around your body. And so there's a lot of things that I think are reparative about sleep. I've thought about this a lot of my own life as probably you have with sleep as to, one of the questions, of course, is why do we bother to have sleep?

00:50:18And I guess I can only imagine it's because our, you know, we've created these bodies of ours are so capable and they're so energetically and, you know, you know, consumptive and they make all these byproducts during the day that at some point you just need a cleanup phase. And that's one interpretation of sleep. You just need to reset. So the immune system is definitely resetting. And, you know, there's, as I say, there's evidence that a lot of the cells go kind of quiescent into the tissues. And they may leave you alone for the reparative processes and actually allow those. You know, in terms of the data on there, there's a lot of studies that are being done. And I can't say that I've come to a conclusion about that. This is, this comes in the

00:50:56question of like, is it known or do I not know it or does nobody know it? And I'd say this might be one of these areas where about 10 factions of people know it, but they don't agree. So there's variations on things. But I think the data, for example, that immune cells dive into the bone marrow at night is pretty solid. That makes sense. What they're doing and why that's important in the long sense of like what you're talking about, everything from, well, but I think it's, you know, things that happen overnight, you're definitely your cognition improves. Is that immune or is that neurone or is that neurone? or both. I think it's both.

00:51:28Something 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 everybody has bags under their eyes and looks like shit when they are sleep deprived. They sleep for a night or two, and it goes away. That's clearly accumulation of lymph. We actually know that. That's just lymph fluid that's not being cleared.

00:51:49And it might not even be the brain's glymphatic clearance system. It's just there's a bunch of lymph pooling under your eyes. That's why you look like. shit. Yeah. And then you sleep for two nights well and then you look better again. And the eyes get glassy. We know that the eyes get glassy when we're sleep deprived.

00:52:06That's also a lymphatic clearance issue. This is well established. So there's something 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 that to me can't explain the immune thing entirely because like the lymphatic system is like, among other things, you know, immune surveillance, but I mean, one night's 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, man, like, okay,

00:52:40I might wash my hands or just kind of avoid them, and you're good. Yeah. So it's, I mean, it's an incredible effect. Yeah. One way or the other. Again, I don't know, the degree to which we can nail down, you know, which part of things that are happening which I always like the story

00:52:54that there's macrophages immune cells in your eye that are basically clearing the lens you know so there's all these like places where it's doing little cleanup that you can imagine that if the thing is trying to get rid of is granularity

00:53:10that you need to have sleep where you just aren't making more granularity so that it can you know it's sort of like when you wash your car windshield you do it completely at that point but you can't be driving with flycitting and everyone right Or you'll never clear. That's a great analogy.

00:53:24You know, so I think there's certain elements of some of these cleanup processes that happen best when you're not getting things, 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 think we just use a lot of ATP and we do a lot of stuff as our bodies in the sleep business time where you cannot be, you know, producing more of that and get ahead of the curve on cleaning things up a bit. 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 it adds three important new ingredients, creatine monohydrate, calcium HMB, and zinc carnacine.

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00:54:44If you would like to try AG1 Pro, you can go to Drinkag1.com, slash 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 drinkag1.com slash Huberman to get a free bottle of omega-3 co-enzyme Q10 with your first AG1 subscription. This thymus thing is really intriguing. And I know a lot of people who opted to bank their child's umbilical cord in the hopes that the stem cells from the umbilical cord will someday be useful.

00:55:16Yeah. How invasive is it and or should we be banking thymic cells? Because these seem like incredibly valuable cells for their ability to immune surveil and create kind of the perfect situation using our own endogenous T cells to battle infections. I mean, I kind of wish I had a little chunk of my thymus in a minus 80 freezer someplace so that when I'm 85 years old, I might be able to exploit that. Yeah. Well, I'll say that the umbilical cord one is pretty straightforward.

00:55:50It'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 the utility of those is a little different than the thymus. The utility of banking that material. And banking just means you put it into a vial, small little, you know, small little vial with the right 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,

00:56:22but 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, yeah, you can do... So are there... Are there kids that are adults that are alive today because they banked their umbilical course? But certainly companies sell access to that.

00:56:37Well, somebody has to pay to keep the freezers on backup generators and things like that. So people invest time and money into this idea. Yeah. Is there a walking, talking, breathing human who would be otherwise dead, would otherwise be dead, excuse me, because they paid money to bank their umbilical court? It's a really good question. I don't know the answer to that question. I guess the parents pay.

00:56:57I can tell you, and this will be just like, this is the depths of which you're describing a default, I'm 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, you're, you're, a mouse with a 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 just actually something where I hold in my knowledge.

00:57:23This is offered in mass now. Yeah. Maybe it's more than 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 depends on your, you're, how much money you have to spend because the cost is not. Assuming it's within the noise. Yeah. Yeah.

00:57:37Yeah. 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 I think this would, if they happen to have a childhood leukemia, 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.

00:58:04Yeah. I mean, that's a big statement. Yeah. You can tell I'm ratcheting up from like sleep to banking thymus and umbilical cord. Now I'm going to go to the sort of next level, which is not just in the Bay Area, a lot of people, however, are starting to think about, oh, maybe I make some induced pluripotent 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, you know, whatever organs in these so-called organoids or whatever they refer 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 genetically. It actually could have some mutations.

00:58:50That seems important to compare against a sort of a standard cell. I don't want to grow organoids from an IPS environment that carries mutations. 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.

00:59:11People are doing this. I'm thinking, oh, seeing what drugs are effective in treating, you know, a liver disease or a heart disease. But if those are mutant cells, that's a lousy experiment.

00:59:21Yeah, I wouldn't, I wouldn't say there would like to be mutant cells for that reason. I think the biggest question would be whether your induction of them to become the organ that you, you know,

00:59:29was successful, was replicating the actual organ itself. So you're referencing these things called organoids, which are collections of cells from a body of a human, for example, that 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 is the source of the California Institute for Regenerative Medicine, that making stem cells that can become pre-tricor organs will it someday happen. We will figure all these things out. And I believe in science. I believe in our ability to sort of like test, learn, test, learn, test, learn. How soon, you know, that becomes useful is a bigger question.

01:00:08If you take out your fibroblast today, that might only cure you someday in the future. And meanwhile, you may die of that thing that you wish you had this 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 can head by a car, you know, it won't help you that you've got those things back. So I think in some of these cases, like, over-emphasizing, and this might be your point about the storage of umbilical cords, is like, at what point is that a high-oddds situation where your kid needs it and you have it stored away

01:00:40versus 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 to me, that's a point where you could spend your life worrying about how you're going to die. And maybe that's not a good way to live. Well, certainly not how I live, right? now there's a lot of kind of excitement and attention around so-called longevity. And at the extremes of never dying or living to be 120, which seems to be the, perhaps the genetic limit currently.

01:01:09It's not my fascination. I'm more interested in living in the years I've got, as it seems you all to. Yeah, vital, healthy, you know, being able to move sense and think seems like, and remember, you know, those seem like the critical ones. You know, a moment ago you mentioned the concept of like removing a bit of thymus. And I think that the issues for me with that are, you know, it's an invasive surgery. And like if you were to take out thymus, it would, it's not clear to me that it's the thymus that you need. You might be able to, I mean, in fact, you can make thymic.

01:01:38So the thymus is both the cells that come into it from the bone marrow. So 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 there's definitely, you know, pretty strong work. It says that you can create sort of a thymic epithelium that will do some of this work. But whether, you know, a guy at home could hold on to the thymic cells and we would be in a position to do something important for longevity in our lifetime. I don't know.

01:02:12I honestly don't know. Some things in my career, I've seen things happen really fast, so fast that almost like you didn't realize that you're doing it. You're like, oh, my God, we've got a cure for cancer. That's great. Okay, let's go on do the next thing. Two things that, so you're like, you know, the California Institute for Regenerative Medicine, we thought that we would have some stem cell therapies, you know, within the seven or eight year window of that bond, first bond, and then there was a second bond.

01:02:35We didn't really get very many out of that. We learned a lot, and that is the risk. About stem cell biology. 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 one hour and you understand everything.

01:02:51because, you know, so all of a sudden, all those failures make sense. I think when we get into some of the stem cell biology, it's intuitive and it's almost certainly true that we will have some of these things. Whether we will have them in time for like you or me, I don't know. I just don't know. And 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 cancer therapy, we've been on the cusp for 10 or 15 years of these things called CAR-T's, Alex will have told you about this,

01:03:17where you engineer your T cells and you give them special receptors that can get them to go into to eliminate tumors. But for whatever reason, they haven't worked in patients. They haven't worked. They haven't worked. They haven't worked. And T-cell, the immune system gets turned off. These cells don't make it.

01:03:30They 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 ten years. And it's, you know, that gets frustrating. And I think it gets frustrating for people that are, like, waiting for it to, on the outside. Like, why can't you solve this? And you're like, well, because the universe isn't always configured how we think it is. And that's discovery.

01:03:49That's the problem of discovery. If we knew what we needed to do, we would engineer it and it would work. Yeah. This is an important discussion that we haven't spent enough time on in this podcast that I think is it very important for people to hear. And I have some thoughts about it, but I'd love for any disagreements. I'm not looking for just agreements. Yeah. So my observation from a couple decades or more doing science and then mainly shifting to podcasting, but this is what I do.

01:04:15I talk with great scientists. So that's a podcast. So I'm very immersed in like what's happening right at the cutting edge. and because of great guests like you. You know, my 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,

01:04:32like salamanders regenerate. Wouldn't 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. It's just shown that. You're like, wow, this would be incredible for amputees and brain regeneration.

01:04:43But 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, We're going to use calcium phosphate at like great research tools. Tons of things happen. And it's like we're going to modify genes. Zing finger nucleus.

01:04:58All this is. Okay, CRISPR, boom. And one thing just breaks through and goes so much further. And even though, you know, the ethics are questionable, there are babies that have deliberately induced gene alterations with CRISPR, a sickle cell anemia treatments as well. It's a more benevolent example. But then the person who went rogue and just kind of did this in humans in China. But CRISPR just kind of broke through it all.

01:05:23The 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 last example would be, you know, for years, it was like the country's getting fatter.

01:05:49the country's getting obese. What are we going to do? Do calories matter? Of course, calories matter, this kind of thing. And, you know, laws of thermodynamics still apply. And then all of a sudden, this freaking heli monster biologist tells people what they already knew because the GLP's were already being used as a drug, just not at significantly high levels. And all of a sudden, we have a imperfect but very important, more or less, dare I say, cure.

01:06:18for obesity. It's got problems. There's muscle wasting. There could be other issues, apathy, et cetera. I'm not trying to discount any of that. But I feel like that's the way science works. It's like steady pressure, steady pressure, steady pressure, frustration. And something comes out of nowhere.

01:06:33And it almost seems prerequisite to have all those years of frustration and failure. And you say, well, couldn't we have just gotten CRISPR first or the JLP's first? Like, why did we go through all these billions of dollars of expenditures, time, energy? Yeah. I don't know. I feel like there's some natural order to this. And I just would like your thoughts on it. I feel like it's necessary but not sufficient to have lots and lots and lots of failures.

01:06:57Yeah. 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 gave an example clip one. Somebody was just curious as to why Gila monsters. It was the feature was that Gila monsters can go into, you know, dormancy for like 10 months,

01:07:17eat 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 and it remembers the sequence of this one bacteria that has come and invaded you before and then can modify the genome and get rid of it 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 to bacteria defend themselves it's not anything about like what you know, modifying single cell anemia.

01:07:50It was about how does the world work? My career is exactly as long as the, as the lifespan of this field we call cancer immunotherapy. I did the first immunotherapy experiment. I injected a mouse with an antibody that I had made. It was against molecules on T cells. And I'd shown already in the lab that that molecule caused the T cells to get more activated when you blocked it. And we did a series of like other mouse experiments of like all kinds of diseases and it, you know, kept jamming up the T cells. And then, you know, Jim, my PI, the other side said, we got some tumors in the fridge.

01:08:19And so we set up that experiment and, you know, injected this antibody and the tumors melted. Well, that was the start of cancer immunotherapy. We're like, that's the, that's the, that's the experiment for which, let's just be director, that your advisor won the Nobel Prize. Correct, correct. Did you at least get to attend the ceremony? Yeah, yeah. That was a little thing.

01:08:36This is how science works, folks. It doesn't matter who did the experiment. It matters what lab you're in. You know, it gets cool. The after parties were good. But I guess I'm now take you back. Like, we weren't trying to cure cancer when we started this. The thesis project, when I went into Jim, this is my mentor at that point, the discussion

01:08:54was like, well, there's some molecules on T cells. And I said, you know, we knew from AIDS and a few other things that T cells were important. So that was the attraction, even though you had people say, why would you do immunology? Well, they seem to be interested. And there was a molecule. And it 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 can dial up.

01:09:13You can say, well, if I could dial up, what will happen to vaccination? Well, it got better. What will happen to, you know, multiple sclerosis? The disease got worse. You know, what will happen to cancer? Ooh, we can start to have an effect on it. And, you know, the X-ray, you know, the people were studying physics, and then it turns out to be that they were like, oh, I can measure bone.

01:09:31And that's how we use x-rays now. Like to, you know. So there's all these examples that everything, you know, is like the big things often come from these orthogonal directions. And then we realize what it might. might mean. And I think you have to start there. Otherwise, you'll just plow this direction and you'll hit those walls because you don't have to work around that comes with some orthogonal piece of information. The orthogonal meaning at right angles, right? So, you know, again, CRISPR came from bacteria, but it's really useful in us as an engineering tool. But we wouldn't have known that if somebody

01:10:01hadn't been out there sort of saying, okay, well, 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 dispels this idea that everything is sort of like basically just easy for us to engineer. Yes, once you have the CRISPR tool, it becomes actually kind of easy to do some really cool things with it and still creative. But the fundamental leap that you're describing, I don't think in many of those cases that people were kind of conceiving when they were in the first drags of doing it. This would become an industry. This would become a whole thing. And maybe that's important because you need to foster that. If everybody always thought they were doing it to build a company and

01:10:38you know, sell a product or something. And then I don't think we would do the things that get us new. You know, 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've got to go off pieced. You can't ski on the slope. You've got to be like in the trees and maybe you'll balk your head a bunch of times.

01:10:56I 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 chance to like solve a puzzle. It's like there's puzzles about how the world works. And if you've ever done a gigas-old puzzle, your family's always like, oh, you're getting, and especially in the end, you're like, you know, what pieces come together to do it.

01:11:14I think that's what makes this whole science thing really fun. It's, 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. I've been building this puzzle. And then you go back and you do it again because that's really satisfying at the end of it, even though, you know, again, with a family puzzle, the first parts are so hard, thousand pieces, and you maybe find the edge.

01:11:37But the intervening where there's like all clouds, super hard. And I think that's, that is what science is a lot about is doing that. And then realizing what the picture is, you know, what is that picture of? And then all the, you know, the brakes are off. I often tell people that if an experiment, if an experiment you'll do in lab has a 10% chance of yield anything interesting, you've 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 cost-effective thing.

01:12:11It's really difficult to be a scientist because there's no quid pro quo. There's nothing to say if you put it in five hours that you'll get five units of goodness of knowledge out of it. A lot of times you get zero. But then sometimes you put five and you got 500. Right. And those are the jackpot moments where you're like. It's like life. It's like life.

01:12:29It really is. I have to say anyone who's considering a PhD, we had a call in from audience recently and so one's They're finishing undergraduate. They want to go the, or finishing graduate school, should they go the research route? They want to do a postdoc. And I'm like, yes, yes, and yes. Rather than answer publicly, I decided to just have a call with this individual because it's a rather niche question. But, I mean, also just in training your reward system to work for five years on something is so valuable,

01:12:57especially in this day and age. Because everything else feels like it comes at like warp speed. Yeah. So it clicks. Yeah. Yeah, like, and 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 quite the opposite.

01:13:14Yeah, yeah. It's like anyone that's like done a triathlon or, you know, raised a kid or done anything, you're like, oh, my goodness. And that never ends, right? Yeah. Yeah. There's nothing better than these long-term investments. Yeah.

01:13:27Nothing. Yeah. When they break through that, like your analogy, when you break through that dam or when you realize sometimes that you broke and through the dam, And 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.

01:13:43Rob, our producer, sitting to our left, as he has done many Iron Man's. And he has that mindset of just steady pressure. I mean, his relationship to work and effort is remarkable because he burns so little energy worrying about things that we refer to as in the left column, like the stuff you can't impact and just focusing on what you can't impact. Yeah. And so a lot of it is about learning energetic control.

01:14:04Like doing science, that is, or anything, is about what not to think about, what to force yourself not to do or think about. If I may, I'd like to shift us to this very interesting area of immunology and biology, which you refer to as spatial biology. Okay. And I'm going to pose a question that may or may not fit with this framework, but either way I'd like you to educate us on it. I'm fascinated by these old kind of barbaric experiments in medicine.

01:14:31Wonderful book, by the way, folks, is The Prince of Medicine about Galen, if you ever want to learn about how we learned about medicine back when it was truly barbaric. It was like surgery is done on warriors and without anesthesia. We've known for a long time that if somebody, God forbid, has a finger lopped off or a hand lopped 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. That's true. Is that true? Yeah, there's a bunch of juicy stuff in the gut that maybe it's the warmth, maybe it's the immune system. Okay.

01:15:09Maybe 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 stomach? Within the stomach. Yeah. Yeah, I'm not suggesting anyone do this experiment. As I started reading into this, I discovered that there are a lot of really cool experiments, not just in limb or tissue preservation and restoration.

01:15:28Like for instance, I've talked many times in this podcast. about the fact that above our, the roof of our mouth, we have this small cluster of neurons, the super-chaismatic nucleus, organizes the circadian rhythms of every cell in our body from the genetic to the transmitter level, peptides, et cetera. Keeps us sleep-awake cycles, does all the organization that we need for circadian rhythms,

01:15:47so much so that you can take just one subpopulation of these neurons, the calbindin 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 a rhythmic animal. Okay.

01:16:12So that tells you a lot of cool things. It says, okay, there's probably something that's secreted. 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. It's not ideal,

01:16:35but 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, which I'm asking this, but I'm just going

01:17:14to tuck that away to peak people's interest and I'll get to it. But this is relevant to how we, to decision, important decisions that we make, I believe. Well, the answer is yes and yes. You know, it's both. So although I've described the immune system in the earlier part of this. discussion as super migratory. And, you know, hitches a ride in the blood, gets into tissues, it travels through your lymphatics.

01:17:37There are these things called lymph nodes down to lymphatic tubing, which for those that don't know, lymphatics are like drainage. That's how you drain the fluid back out of your tissue. So although there's, you know, these mass migration of cells, there's also in, like, even just in T cells, there's T cells that lodge in particular settings. And they, you know, act to protect that tissue. And they're resident cells of those tissues. never leave. And so both are true. You have, you know, parts of your immune system that are,

01:18:05you know, protective or, like, nurturing of particular areas and then there's ones that are circulating and can hit any spot. You know, going back to your idea of organs and such being moved, I think there's two components 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 lymphatic outflow and maybe even some neuronal activity? that makes that tissue work. So that's where, like, if you take the pancreas, you can famously put it underneath the kidney capsule.

01:18:37Kidney has kind of like a skin around it. You can tuck 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,

01:18:54the immune system will attack it just as it did the first diabetes for those. Type 1 diabetes is caused by the, immune system that gets too active against the pancreas, it's autoimmunity, it's where it's now saying the pancreas is not self, it's something foreign, and it wipes it out. And that's the source of what I said earlier, like your immune system can be quite dangerous. So like when you talk about this concept of like spatial, there's a few things to bring in. One is this the organ, can the organ get what it needs? And then does the immune system accept it in some ways in that environment? And that's where like some of your immune system that lives spatially in certain areas is going to be very,

01:19:29defensive against whatever it's 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 you like, if 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. They can, they can hitch some signals on neurons. And that's a really interesting thing. We could talk about the capacity for your brain, you know, the insular cortex. There's a great set of stories emerging about how your an insular cortex can program your immune state into organs and can via the Vegas can essentially program.

01:20:03By levels of calm or stress or by thoughts themselves? Well, the latter one is the one that gets me super excited about the possibility that you 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. It's also thought to be the part of our brain where if you cut your hand and I see it bleeding, I can feel it in my hand. And I can sense and you can sense each other's pain. It's a set that this very nice Israeli group to this, Royce Lab did this very nice study where they induced into the guts of mice, inflammatory bowel disease.

01:20:37They fed them a really kind of weird sugar that causes the bowel to puncture and then they get a really bad, you know, stomachache. stomachache, inflammatory bowel disease, diarrhea. And in that period, they used, you know, you know what dreads are. So they marked for the crowd, they used a way to mark all the neurons that were firing during that period in the insular cortex. And then later they could fire them, like after the mouse had recovered. And they saw evidence that the immune system was resetting up itself in the gut as if it had just been punctured. You know, like with this. And the cues for that, in that case, were a drug.

01:21:15But we know that we can, you know, cue the insular cortex, like me watching you do things. So it's always, it's made me wonder whether, you know, like some of the things we smell. cut grass and we can, you know, instantly take us back to a whole bunch of thoughts about how we were when we were kids and maybe even make you feel a little like that, whether there's aspects to this, to which our, you know, our ability of our thoughts to control that region are going to be revealed to, you know, to have potential that you could train, you know, train yourself to, you know, to bring up an immune state in a particular tissue. And just so we make sure everyone's on board what you just described, because there's a lot there. If I understand,

01:21:54correctly, we know that the nervous system can do contextual learning. Like if an animal or human, just keep it to humans, gets shocked, scared or traumatized in a given region, or even I've had friends visit San Francisco and get their cars broken into and their computers stolen, you can develop a context, context dependent or place dependent memory where you kind of don't like San Francisco as much, even though the rest of the trick was awesome. That's a pretty broad interpretation. Or you have a great experience someplace.

01:22:24And you actually really love San Francisco because you met your future spouse there. 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 with that. The immune system is also part of that contextual memory.

01:22:54And so merely by recalling the positive or negative, but in this case positive memory, we can also 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. That's cool. That's really cool because 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 the immune enhancing effects of acute cortisol and stress are really important. And I think they've been overlooked.

01:23:38But I love this because one of the problems slash luxuries that I have is I sit sort of at the interface between like real science and biology and like what most people perceive as complete nonsense wackiness. But more and more we're finding that's within the complete nonsense wackiness, they're. kernels of truth, like that you can actually meditate your way into a better state, which helps serve your immune system and so on and so. And that's seeming less and less wacky, even outside California, because of studies like the one you described. One of my friends who's faculty, Dan Lippman 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, you know, less inflammatory states across your body because of this axis.

01:24:23And the study was really, I think it was, you know, there's still work to be done it, but the, you know, the fundamentals of it was in the actual event there were certain cells that would accumulate in there. And then in the induced event, when you made the brain fire again of this mouse, you would see, you know, not as profound, but you saw, you know, 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, the concept of, I mean, I'm sure you've talked about this before. of meditation where the idea is that you, you know, it's one of the ways that you can control your autonomous nervous system is through your breath 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,

01:25:11that some things that make, they sort of make a great story in our minds that don't turn out to be true. But the data on this insert cortex thing is starting to look like it's a real thing. Like there's a real connection between some of the peripheral. states and like regions of the brain. And however those are triggered now, maybe, you know, again, 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, it's kind of crazy

01:25:36thoughts. 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 that the sensations that make me feel like, you know, less, you know, stressed in one sense, but maybe also to the meal. this point in literally resetting your tissue. I'd like to take a quick break and acknowledge

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01:27:23or visit functionhealth.com slash Huberman and use the code Huberman for a $50 credit towards your membership. Again, that's functionhealth.com slash Huberman. I'm always struck by extremes of personality, but in both directions. So there are these people who just say, like, I don't get sick.

01:27:43And 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 know, less and less with each year. because I do feel like pay more attention to the sleep piece than I certainly then I did when I was a graduate student postdoc or junior professor.

01:28:01Yeah. But there does seem to be this quote unquote positive or let's just call it a reinforced mindset as opposed like an immune reinforcement associated with mindset because some people will say like I just always get sick and I believe them. They always seem sick. But it could be that you get sick and give an environment once and then you just decide that you're sickly. So then, 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

01:28:34and 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? And then this is 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. But it's the feeling. state associated with that that at a biological level makes total sense. So we were talking about spatial biology and the fact that you can tuck some

01:29:01pancreas in the kidney and unless say someone has type 1 diabetes a lot of the functions of the pancreas 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

01:29:17wondering can we take a little bit of thymic tissue, bank it and then just later, like put it in a slow release capsule under our skin of our hand. You know, like, and that might sound crazy, but I have friends, one of whom might be at neural link now, who actually embedded a little radio receiver under his hand to be able to open his locks at his home and his car and his wife might have one also. And like, that might sound really like Bay Area, like future tech kind of wacky biohacking.

01:29:47But if I knew that I could be much healthier, like taking a few thymic cells, and in a sterile capsule and sliding it under the skin, you know, people get their ears pierced with, you know, less invasive procedures. Why not? Well, I mean, the question is, why would that, you know, is that likely to work? You're basically, remember how we're just talking about if I do 10 experiments, one might work? Yours isn't a bad idea, but, you know, is there, it's more than likely at one of the 9 out of 10, I would guess. Sure. But is there a correlate from any studies on animals?

01:30:20I mean, we know that in a lot of studies of cancer and tumors, I used to see these mice down in the viarium, they would slide tumors under the skin and study them and give animals drugs or give animals stuff. Very common, yeah. Yeah. Tumors are happy to thrive in novel environments. Yeah. So why wouldn't healthy cells? No, I think you can. I think one of the things that comes into play a little bit about that that's more about, you know, replacing an organ with one that might be better is that at some point if you come in.

01:30:49So one of the challenges of tissue engineering is if you want to bring in new genes, the vector, the material, the surrounding, whether you bring in it using a virus to, 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 plasmid, 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 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 a huge number of new things being expressed in some of them viral, literally. So, you know, that represents an issue, I think, when we talk about any kind of, you know, sort of engineering at the moment is, is if you engineer a system to be maybe better, the immune system isn't necessarily going to want better. And so you have to overcome this issue of tolerance maybe at the same time. 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's going to let it fly.

01:31:54I'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. to be able to use our own cells or peptides or synthetic versions of peptides from our own cells and so forth to overcome a lot of the issues that our parents and grandparents were not able to overcome. You know, with regards to like the peptide side of things and even the cells, and this is maybe where you're going to space, is that context does matter for the immune system.

01:32:35So, and it matters for all biological systems. I'll just give you an example. We did a study of wound healing some years ago. And if you have a wound in a mouse, it's maybe just a, like, 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. There's zones within there where certain biology is really important to be happening. And then, so imagine the wound is like this and it's open. The cells, like one layer back are doing certain things.

01:33:07But the other ones behind that are also induced to do something. The wound isn't just this area. it's actually sensed all, like a gradient, almost like in the neurons. And so these cells need to do different things than these cells. So if you wanted to administer some, you know, like a peptide or even just a cell type, you have to be a little bit conscious of like where it's going to do the work you wanted to do. And the natural system does that naturally. Like the cells on the inside actually instruct the cells one layer back.

01:33:32But 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 gradient. So I think one of the tricks that we don't really. understand about this is when is something good for a process and when is it only good when it's given in the right dose at the right time. And I think that's one of the tricks about some of these things. And again, that's where, you know, both in the lab and, you know, like I would say that more so than ever in our lives, you know, we're seeing, you know, people kind of like experimenting

01:34:01with things on themselves. And one of the sad parts about this is we don't capture a lot of data, therefore, you know, because it's not seen as a study and we can't say everybody that took this gets this result. And then you have this rise of things on the internet of anecdotes that become seen as data. Like, I took this thing and this happened. And that's, you know, I could drink this drink and have something great happen to me or something bad happening. It might have nothing to do with the drink, right? You know, that issue is one that I think is really critical 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 think we all want to improve ourselves. We're all,

01:34:38I'll do some kind of experiments on ourselves. You read a book. You read a book. you're trying to improve yourself, right? The physical one gets a bit tricky when, you know, you're not sure whether somebody's going to be dangerous or not. Oh, yeah, and I'm not promoting that people do this. I think that, of course, you would want to see preclinical, clinical, and other trials for this. I think I would personally.

01:34:58I mean, just, yeah, I mean, there are a few areas where I am a bit more adventurous, but for the most part, I'm, like, you know, based on my training and background. I have to orient toward, you know, I'd like a bunch of, let me put this way. I'd like 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,

01:35:20in which case, like, let other people go first. Yeah. Well, I think a good example that right now is, and this is, you know, sort of nationwide or even international, is vaccine hesitancy. I don't know this is a touchy topic. No, but you can feel open. Well, I'll just point out that the one group that's completely, no matter whether they're hesitant against childhood vaccines and the number of them we get

01:35:39and the fact that the government makes you take them and these sorts of things, if those people have cancer, they're very interested in vaccines because there's really good data that you can promote more immune cells against the tumor by making a vaccine that consists of some of the proteins and peptides that are unique to the tumor and not different from you.

01:36:00And you introduce those as if you would introduce the virus or anything in a childhood vaccine, similar concept, just different peptides. They're peptides from the tumor. And in those situations, it's context, right? So if you and I had cancer and we don't have the conventional cures are not going to work on us. There we know statistics really well. Kemos is not very good for a lot of cancers, but 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. And so the certain die versus try out a vaccine

01:36:35drives a lot of people to be interested in vaccines. And I would say, yeah, Yeah, in that case, it's a really, you know, you can see where people's, their question about whether they're going to try something or not is very context dependent. Very. I think I don't want to go too deep into the vaccine debate, and I don't want to be a spokesperson for either side because that's not my role today. But I think that the what you referred to as vaccine hesitancy actually comes back to an earlier issue that maybe you'd be willing to comment on. Sure. Which is, I think there are a very large number of people for whom they are neither anti-vaccincy. nor super pro, but they are, they're asking about timing and combinations.

01:37:15Agreed. They're saying, okay, listen, and we had J. Badachari on here, and I've had several others who said maybe there should be an investigation of the spacing of these things, how many, how critical it is to do at a given age, you know, and on and on. We can pick any vaccine for that reason. And as an immunologist, do any of those questions make sense to ask? I mean, I could see how, you know, bombarding the young immune system with a lot of vaccines is a very different thing than spacing out the delivery of those vaccines.

01:37:47I'm not saying don't give them all. I'm saying over what time window does one give them. I think a lot of people, many more people are asking that question. It's just a quieter murmur than are saying, listen, we don't want to take any of these things. Yeah. We don't want our kids to take any of these things. Well, I heard that too. I think there's some fair aspect to which most of these vaccines were not studied in the context

01:38:11when they were studied of what it does, you know, in combination and in these sorts of times. The fact is that, you know, the evidence that there's bad things happening doesn't look to me, you know, tremendously strong. It's almost like anecdotal sort of information. Unless it's your kid. Unless it's your kid, in which case you're going to look for an explanation. So I don't know. Just being fair. As long as we're admitting psychology as a factor.

01:38:36Yeah. Yeah. Yeah. So there's fairness on both sides of that discussion. And I think that almost certainly where we are now, there's probably ways to put together vaccines and certainly more convenient ways. As a parent, I actually had something very similar where he delayed, you know, my first daughter is one of her vaccines, partly because I know that there's a certain element

01:39:00to which when we design a protocol, like the protocol for immunotherapy of cancer, for patients was actually based a little bit on the mouse work, a lot on the mouse work that I did. You can imagine that mice and humans are quite different. But that is the protocol. Protocol is protocol, and that's how it's done in medicine. And that's because you have a fairly good sense of the safety of it because of statistics. But that isn't to say that it's the only protocol that would work. And I think you're getting at this concept like, could there be at least a more convenient one? And also one that's safest or safest or even one that is less disruptive to the lives of the children and the parents. We delayed one of our kids' vaccines,

01:39:33by just a month or something, because 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 have come out that I've had recently. The shingles one is a good example. I had it just knocked me completely out. And it, you know, it's very, very heavily adjuvanted.

01:39:48So it's clearly, you know, it's having it. Does it need to be? You know, I actually don't know. I don't know what studies were done. And there's kind of an aspect of which, you know, I don't know that we're all being shielded from the information, but I don't know that we all know how to read the information about how these regimens were chosen.

01:40:06Some of them are chosen by competing pharma companies that each make their own materials. Again, I think there's a lot in this question. I don't know how much of it also represents. One problem of science that I could talk about is this issue that a lot of science treat science as a kind of a papacy. Like, we know the language, we know the facts, and we probably don't have time to tell you why we think this

01:40:31and where the holes are. Excuse me for interrupting, but a huge basis of this podcast is to counter exactly that. I know. I know all these incredibly smart, incredibly well-meaning people who have lives of their own,

01:40:47health 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 was, and as things get more politicized,

01:40:57there's less incentive to give nuance. I actually really appreciate you, providing some nuance on the, I mean, it's clear where you stand on vaccines generally based on what you've said, but you're offering perhaps the opportunity for, or better understanding and certainly delivery of the information. Yeah. Yeah. I mean, it's a huge problem. Yeah. Well, I guess it's one of those ones that I can only speak about what I did, right? 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.

01:41:31I absolutely vaccinated kids and that was, it seems like, it seems even now like a reasonable no-brainer. But I just told you too that I asked to go off protocol because at some point I know these protocols have a little bit of like, again, they were designed on one study, but it doesn't mean that it doesn't work if you wait another month. In fact, if you do, if you've done enough mouse experiments as I have,

01:41:51you know that when you vaccinate on a slightly different schedule, you can still end up with the same outcome. You know, that is protection, you know, with slightly different schedules. It's not that convenient for, doctors and hospitals and even 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 like, it's like brushing your teeth in the

01:42:19morning you do it the morning and the evening and 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 vaccine too that relates to the question of like, what point can the government tell you what to do, which is, you know, it's a surrogate question to the vaccine one, where a vaccine is, you know, if there's a harm, who gets to choose with the harm benefit and then 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 bathwater. I don't think you personally, like, I wouldn't not immunize my kids.

01:42:55Could there be additional studies about the combination of these into like fewer shots? I think so. See, why not? Here's where you get the financial rise. What's the benefit to any pharma company of doing that? Well, I think this is, again, I have to be careful that I don't place myself into an advocacy group that I'm not. I look at everything on a case-by-case basis. I try to do that.

01:43:18But I've tried to be in recent years more open to at least understanding what the anti-Big Pharma stance is really about. It comes up 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 taking insulin or, you know, until recently the GLPs were mostly available through pharma. Now they're sort of kind of the Wild West. People are microdosing them from all sorts of compounding pharmacies as their own issues

01:43:53and so on. But my sense is that the frustration around the kind of dictatorial, like you're going to do this at this point because this or else like your persona non grata. That kind of like people not people being shunned in both directions, in either direction, rather. That's, you know, that's really the source of the problem. There really hasn't ever been a conversation quite like this. Yeah, I agree. At least not when I've seen publicly.

01:44:20Yeah, there are not a lot of labs that are going to devote themselves to this. People will wage the argument that, and I don't know if this is actually true, but that the pharma companies are protected against lawsuits about vaccine injuries. Yeah, yeah. I mean, I think that probably is frustrating to, very frustrating, excuse me, to a parent whose kid seemed essentially fine, got a vaccine, and three days later started exhibiting symptoms that then set them off on a course that was really, really tragic.

01:44:46Yeah. And those groups are the ones that have accumulated the most oomph out there. Yeah. And if you think about those parents, it's totally understandable. Yeah. Why they would feel that way, whether or not the, basis of their feelings is exactly right. I can't speak to, but you can understand if your kid is one way, walked out of the doctor's office is another way, and you can't do anything about it,

01:45:09that's got to be maddening. I mean, beyond maddening. And the question is, what could you have done differently, I think, is in those situations, having been in them, not that exact situation, where you said, oh, now it's done, and now I can't go back. 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 there's a certain guilt slash anger. I mean, there's a whole psychology to it that's completely understandable. Yeah.

01:45:39They didn't wander into the clinic. Yeah. Well, I mean, you know, on the way over here, I was thinking about some of the things that, you know, are happening in medical space. And, you know, you guys have obviously from time and time talk about peptides and these sorts of things that people are using, you know, off late. Well, not even off label. or just getting them from wherever, the internet. And, you know, I was thinking, well, you know, there's a funny thing there because the legitimacy of pharma companies has sort of fallen

01:46:05into even worse straits than before because I think I was thinking about this. A lot of it does relate to the fact that we are advertised to take a lot of things that often aren't, you know, the side effects are worse than the symptoms that were relieving. And that sort of, you know, again, I may find myself like having a bunch of colleagues hate me for talking about this with you, but I do think it's kind of important at some point. to surface where all this comes from. You know, and the idea that we can do experiments on ourselves, on our own bodies, again, it's quite different to say read a book, although you can be infected by, we believe,

01:46:36like by, you know, scripture and things in your behavior. But somehow in here this idea that, you know, we can be told to do things by people that aren't quite in our best interests, I think it opens up the idea that, well, why can't I choose my best interest? You know, who are these experts that I can't always trust? What's more American than that after all? Yeah, well, it is, it is. It is part of the pioneering spirit.

01:47:00Like if the government's not going to protect my 40 acres, I've got to have a gun and protect it myself. And that's been a part of our culture for a very long time. And I think this idea of individuality plays into this. But it could be exacerbated at the moment by the fact that there, you know, haven't always been good communication with somebody you're trying to work out and maybe even surfacing these ideas that are hard to talk about. Like, should we trust farm companies? I know a lot of people that work for pharma and they really, They are doing good.

01:47:26They, you know, they're like you and me. They really think, and they are treating disease. They're making really good drugs, and they do really good things. But it's not always true. Not just because, you know, a bunch of people are doing it. And it's not always true that the subtle best interests of a corporation is the same as the best interest of an individual. So, you know, we have to surface those things exist.

01:47:44It's not like we have to say that is right or wrong or whatever, but at some point, those kind of perverse incentives exist. And I wonder why, you know, like pharma companies haven't gotten better tests for who's going to respond to these checkpoint drugs. that we made. 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 it coming 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, again, 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 farmer executives out there going, eh, yeah, yeah. But there's no,

01:48:32there'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 forward, some of which are better and worse than others. We could, told this is going to be good for us and we should take it. And there's a, again, you're getting into the American kind of like mentality, which is to say, well, at 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 an entire spectrum of things called science. And the problem is that there's people like you and me that are trying to actually do, and most of us, I'd say 99.9% of us are working our asses off to like figure things out

01:49:07and discover stuff that's important for mankind. And then you have these sort of issues that arise and you're like, well, then should you distrust as a species, should you distrust the entire class of science? Probably not. You just need to maybe make it so that knowledge is freer. are just better communicated and that, and that you do watch out for those situations where there should be, you know, and maybe vaccines are one. You know, we just need to do something sensible like what you're describing and just

01:49:36do a study and say, let's do that study and make that very public that we do it and say we're going to do that. And obviously, people can sign up for, you know, you can have this regiment or the old regiment or the new regiment. You know, again, I may be 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 think they do, there's good evidence that they're protective.

01:50:05But to the extent that you're coming out, could we make it less? Let's do it. Let's 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 is actually describing an experiment. What would be the experiment? Yeah, well, the discussions haven't happened.

01:50:20And I should say a couple of things. 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. But to any people, colleagues or otherwise, that would say, hey, actually, this is the wrong stance. You don't want to be talking about nuance in a time when there's so much threat to traditional medicine. and vaccines, et cetera. I will say this. The idea that you need to push back with just a fire hose

01:50:57of do this or else did not work. The pandemic proved that. In fact, I think one of the biggest mistakes was to have one individual as opposed to a panel of people with more nuanced communicating public health information at that time. Any person, scientists, doctor or otherwise, who thinks the way to convince people to change their behavior around vaccines or anything else, else is to just ram it down the public's throat and say, or else, you're whatever, your 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,

01:51:45and I can understand why you would be considering the following questions, and we should do a study. 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 throes of a pandemic. Yeah. Yet. Yeah. I mean, there's some things that are on the rise.

01:52:06It is scary. I'll be quite blunt. You know, the rise in measles is scary. People say, well, measles, they used to have measles parties. talk to somebody who had massive inflammation and brain inflammation from measles, not a pretty picture. Yeah. Not a pretty picture. Yeah.

01:52:22So 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 subsection also about, you know, the origins of small vaccination. And I think what's lost in those stories is if you look on the Internet, the absolute, that's a terrible disease. I mean, you know, the reality of what we're protecting against, we haven't. It's really hard to, like, also have that a conversation without doing a little bit of reading into your history. You know, and I don't think the history books are pulling the wool over eyes by saying some of these things were really horrendous. A small box was dreadful.

01:52:59So 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 trying to achieve here? and sometimes that question can get lost, but I think, man, if my kid got smallpox or got measles or got moths, and, you know, as we know, like, measles is not a theoretical. Again, you know, that concept is enough to say, well, there is a risk of that. And that's one where you, it's like you, you're 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. not still real. And I think that's also an important, again, that's what, that's me as a parent.

01:53:43And I did look at the history and 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? You can propose experiment. That's, you know, I think there's a, you know, the cutting off, you know, the concept of human curiosity and science at the legs is probably not the way to figure something out from my experience. You dive in, you think of the experiment that 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 for my, this is me as a parent, looking at the numbers of, you know, like the danger of bad stuff happening versus 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 a vaccine, which I don't, by the way, can I tell you a little story? Maybe you know this already, but if you want to induce autism and mice, people do it by injecting a bacterial infection into the mom when she's pregnant, which tells you that an immune challenge can affect the neurons of a developing pup. So it's not outside the realm to say that in some situations, an adjuance situation, again, I may regret saying this because it's going to open up a conversation to have this, but it's not outside the bounds to say that an immune insolence situation. Again, I may regret saying this because it's going to open up a conversation to have this,

01:55:02but it's not outside the bounds to say that an immune insult will have influence on neurodevelopment, period. Is it the source of autistic children, or was it in fact that the mom had infection during pregnancy? It'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 cells of the cells, the brain. Yeah. In fact, one of the best experiments that I look along these lines, it's not about about autism at all, but it's about when you get a flu, you tend to go, you tend to feel like you want to socially isolate yourself. At least I do, and most people do, I think they kind of

01:55:40want to crawl in a hole. It's that calling a hole feel. There's an experiment that was done that involved injecting gamma-nurferon, which is one of the things your immune system makes when it's fighting off an infection into the bloodstitch of a mouse and then just watching it. And they become 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.

01:56:02They just are given this cue that's part of the systemic immune response. And then they show the signs of social isolation. And the lab that did this also showed that the brain has receptors for these immune molecules. And, you know, the simple conclusion of that paper is, you know, there's still always work to be done. But simple conclusion was that the brain could sense infection and it would affect behavior, even in mature. In us, it's mature. So, you know, again, there's these ideas that there's something that, I mean, scientists use that infection of a mom to lead to neuronal changes that lead us to be able to study autism in later mice. So there's definitely potential there.

01:56:45I don't know that the vaccines and all of them and whether there's a circumstance or whether it's, you know, getting the mom actually had a fever before. and the vaccine now just triggered or didn't, or just circumstance because you give vaccines at two years of age, which is when autism appears. There's all kinds of options, you know, and the sort of anecdotes of that. And I just think that that fact that, you know, the way that we study autism is by giving a pregnant female mouse

01:57:12an infection is sort of like, okay, that's important to know. That work is still ongoing by laboratories to understand autism. and they want to understand the origins of it. And maybe it will not turn out to be vaccines at all. Again, we need data. We definitely need data. We're almost in a COVID situation. I described the COVID situation now in retrospect is one that is data sparse.

01:57:33And this is why I've been trying to work on. I was telling you about this project of trying to work on the publishing problem. But it's not just the publishing problem. It's how we synthesize knowledge that under data sparse circumstances to make decisions, I think we're not very good at that societally. when we have tons of data and it says, absolutely, if you have cancer and you take immunotherapy, then there's a 50% chance you're going to revive. Great.

01:57:59Those stats are solid. They're very good. And I would take that drug every time. But if it's sort of a case where you're like, oh, there's some things that are happening and some other things that are happening. You remember the beginning of COVID, we talked about it amongst ourselves in the labels, and we were coming in to analyze blood. And it was kind of unsafe because we didn't know what was safe.

01:58:16We didn't know how it was transmitted. We didn't know anything about it. Could we get it from blood? And that kind of went on for a while, right? And this was the source of like a lot of confusion that came from the medical. It was seen as confusion. And after fact, it's like, do you mask? You're not masked.

01:58:30Do you touch? Do you not touch? I think 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 anecdotal, it's correlative, but then with regard to vaccines and autism

01:58:56and other issues. But then the pushback is, well, this vaccine, et cetera, was directionally guided by sparse information to begin with under times of pressure. There's financial incentives. So it's just this ping pong that goes back and forth, but many thousands of parents write to me and say, should I wait on certain vaccines? And I'm like, listen, I am not the person to answer that question. Yeah. But you have every right to ask your doctor. Yeah. Right.

01:59:21But they're not asking because they're extremists. They're not anti-vaxxers. They're asking because they love their kids. Right. And they've seen enough things to call into question the incentives. And they just know that the conversation cannot be as polarized as it's presented to them in reality. The data cannot be as polarized as it's been presented. Yeah.

01:59:38Certainly in media, some of these things get presented quite, you know, inflammatory. And again, if newspapers want to sell a newspaper, they show a plane crash. Right. So it's not happening every day. 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 a lot of these studies,

01:59:58scientists are, there's a motivation to make the most of your result. And we've talked about why that's important is that if you find something to orthogonal, CRISPR, checkpoint blockade, you know, x-rays, you look for that orthogonal use for it, right? Or that orthogonal meaning, sometimes we call it extensibility. Like I see that if I, if I draw, you. 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.

02:00:23You know, it becomes a tool. And I think one of the things that's, that it is lost sometimes is that some things are not extensible. So, you know, you can imagine that, like, if I had something that makes a cell move, that that might screw up the whole system forever. But humans and our bodies turn out to be remarkably resilient. I mean, we can go from minus 20 degrees to, you know, 110 degrees. We can not eat for a long time. You know, all these things don't cause us to fall apart.

02:00:51So if we didn't have resilience, I think our species wouldn't exist because there's all these pressures and all these varieties of life under which would lead. And I think a lot of science sometimes doesn't, you know, from the outsider, even as an insider, you can read a paper and they point to why it might be important. But they're really doing that to garner interest for their story. You know, and then say this might be important for this, but I haven't shown that it's important. They don't say that it's important as it might be important. And they're trying to look for that orthogonal or that extensibility of it.

02:01:21And I think that's kind of important. Also, just to go a little bit off this topic for a moment in how we think about drugging diseases as we go forward. And that is to say, we've looked for these one and done drugs that you take a pill and it cures everything. You know, forever. That's sort of found abutish. And, you know, we found a few of those. I would say checkpoint 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.

02:01:46But most biological systems, if you have one button to push, they're super non-resilient. A virus can exploit that button, you know, that can cause, you know, collapse. And so most things are wired, like in these really complicated ways. And I think what a few of us are thinking, and this is for cancer in particular, where you want to get the immune state from, like, 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,

02:02:16that looks like development. Your cells developed through states. And you push the biological systems to reach this new state in a way that doesn't look like the linear between low immune reactivity and high reactivity. You might have to push it in a series of way because resiliency, the systems,

02:02:33like even in chronic disease but even in health, we're pretty resilient. And 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.

02:02:57And he explained to me that one of the most important things you learn in physics is that you can't really understand quantum mechanics using your logical brain. You need the math to prove it. And this is when whenever somebody, he also warned, whenever somebody says they understand quantum stuff, you have to ask them to demonstrate it for you. Because people talk quantum because we make all these assumptions about quantum. They talk about quantum fields so we think they're smart. But theoretical physicists and therefore engineers develop all sorts of incredible theorems

02:03:28and 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 a limited amount of funding, people need to sleep at night and on and on, that doing the kinds of experiments like you described,

02:03:59like pushing the cells this way, nudging them that way, and then drugging the outcome in a way that is beneficial but not detrimental, is this a place where machines are going to be better or at least helpful in doing these experiments. I take the standpoint that AI is, and I think, you know, this is back to talking about the AI experts, it's really quite good at producing stuff that is in the corpus. The corpus is the knowledge that we already have.

02:04:28Almost by definition, when you're coming at that with or something discovery, you're discovering something, it doesn't exist in the corpus. You might have hints of it there, but you still have to do experiments at some point. So if I'm going to answer you, 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 silico a network where I can look at how all those cells are wired together now. And I can ask, you know, what would be the possible consequence of clipping this molecule's ability to touch that cell? That's now doable.

02:05:03But it relies on an area of math that's 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, the relationship between this feature of the cell and this other feature of the cell. So 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

02:05:31into that and say, am I going to spend a year studying this question? Are I going to study a little bit more and try to understand some things in a greater detail than maybe the machine learning gave me? But it's not clear to me that anywhere right now we can say the corpus of knowledge doesn't have a bunch of examples of cures across from treatments and say, oh, all I need to do is match those up, which is kind of what AI does when it comes to Lars Nangertrandefal. You query it. It looks statistically and says, what are the relationships between what you query and what I give you back as an answer. In a discovery space, we don't have examples of the other end. Sure, I can tell you all the things you could do. but knowing which one is going to be

02:06:12orthogonal big hit isn't there but what I'm talking about a little bit is to take a problem apart and say if I have something like I want to change something and anything this could be if I want to change the world it's unlikely that when he one act

02:06:28will do it. Also the world is pretty early political systems despite what we think are somehow semi-stable but a series of these nudges can create the condition where the last one takes you across the border and I think that's what we're going to have to do in disease, where we say, look, nature doesn't necessarily want us banging on it. It'll bang back. What in fact, we need to do is if we want this tumor to get

02:06:50heathen 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 a way of, you know, again, in this kind of deep computational space, we end up with a lot of feature of tissue cells and how they're organized and what genes are expressing that start to look like Magellan's map of the world that, you know, in its early phase, it only had parts. And then, you know, it starts as you explore and you add things to it.

02:07:24I 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 fibroblasts, certain cells are doing this, and epithelial cells are doing this. And that's a, that's a, like we call them archetypes. They're like a way that biology organizes itself. And to get from one to the next, we need to understand how it does it developmentally. That would be a really nice thing to follow. And then we need to give those cues in order.

02:07:49And that's where I was coming back, you know, when you were talking about peptides earlier, I'm saying, well, some of these drugs may well work, but I might imagine that they might work best if given in the right sequence and the time and the place. And that's when you really want to like hammer it to get the system to go to that, but then it might be connected to another one. And we all want to find the one thing that like, you know, the founder of youth, the thing that cures a disease. And it's been forever that we've been looked for a single, you know, single hits, one and done.

02:08:17But it may be a collection of, and you know, this is probably this is how I live my life for health too. There's a collection of behaviors and food you eat and sleep you get and all these things create. And partners, you know, your loves of your life, the friends you have, they're all part of, I think, this. this, and that's getting a little away from immunology, obviously, but it. No, but not, the only thing about the insula, you know, not so much. A good friend of mine who's a physician in the Bay Area says, you know, better living through chemistry still requires better living, which I love because it says you should never abandon as much as one can, the foundational stuff of sleep, exercise, nutrition, circadian rhythm,

02:08:55light, social connection, you know, stress mitigation and on and on. Right. Could I ask you a couple of additional questions about the immune system? Yeah, please. Before we wrap. Because I know many people are curious about autoimmune issues. More and more I hear about, you know, I don't know if it's chronic fatigue considered an autoimmune issue by most. A lot of people seem to have chronic fatigue.

02:09:18There was a debate, does it really exist? For someone who believes they have it, it absolutely exists. They're tired. I believe them. I know someone who had a myalgia recently. psoriasis is something that I maybe have known to be now autoimmune, asthma. These are interesting conditions, not all of them life-threatening, but some of them cause a lot of discomfort.

02:09:44What 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, that's a big question. Well, fundamentally, again, this is, I think, where the immune system and our bodies have, I think they have playbooks, like a football team or something that they can run and they can put players in particular configurations. Again, we call those archetypes. The immune system is trying to do a certain kind of thing.

02:10:16It's genetically and through history it's wired to work with cells in certain ways. And I think if you look at autoimmunities, 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, you know, in lupus, there's a familial mutation and a receptor that's on a B-cell that normally helps turn off the immune system and it's defective. And so those people are susceptible to getting what are called auto-antibodies. That's where the B cells, we've talked a lot about T-cells, but B-cells are the ones that make antibodies

02:10:53and they're the ones that you try to prune 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'd be propagated, except that maybe in some sort of circumstances you need it when there's a big pandemic or something, those people might have a particularly good response. So there's definitely genetic origins of some of these things. I think what's, you know, what's interesting to some extent is something that you alluded to with asthma, where asthma was one of these things that historically would be called an allergy,

02:11:24and it still is an allergy, and 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 coming in part and parcel with, you know, the immune system recognizing self, you know, 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?

02:11:53Like, 10 years ago, we might have just said, you know, what is it? I might have taken a lung of an 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's 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 those seven or eight. And that's why some people can take the inhalers and it works and other people can't. Some people, they're very chlorine sensitive.

02:12:23They go to a pool and it initiates or cold sensitive. So 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 eosinophils. Other ones have lots of cells called neutrophils. So asthma isn't just one disease. It's one symptom, you know, difficulty breathing, but it has many different sort of configurations.

02:12:44And I guess 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 psorias is one where you start to see variations and lupus for sure and inflammatory bowel disease. And you know this in the clinic because inflammatory dialysis you ask about drugs is a good case where there's a couple different drugs that for some patients work really well. TNF therapy, for example, it blocks a cytokine. And some people with IBD is just like really bad diarrhea manifests and very, very painful. You know, some people, so there starts to be classes of patients.

02:13:24that 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. Inflammary bowel disease is an autoimmune disease is pretty tricky too because people will respond to a drug for a while and then they'll stop.

02:13:41And 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 where it doesn't work. Sounds like psychiatry. It does. Yeah, there's a lot. It sounds like a, you know. No disrespect to the psychiatrist.

02:13:54No, but you're trying. They have a hard job, right? I mean, drugs will work for a while, then they don't work. Not effects crop up that never existed before. It's a tough one. Yeah, agreed. Agreed. So, yeah, autoimmunity is a real thing.

02:14:06It 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 the 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. systems is going to be different. You just got a different football team out there playing or they've got running a different play. If somebody has a mild autoimmune condition, like let's say mild psoriasis, does that, I've read, but that doesn't necessarily mean anything, I've read that that might confer, because it's autoimmune, that might confer them with a bit better viral and bacterial infection resistance.

02:14:51So there's a tradeoff there. like, okay, so scalp cells are like sloughing off. And like, I think it's like interleukin 17 or something now, like the treatment. They have some good shampoos for this. But anti-antilukin-17. Anti-interlucin 17. But you, that individual is maybe better at fighting out other infections. So, you know, given there's a anti-interlucin-17 treatment that works cool, like no flaky, itchy scalp.

02:15:20And yet you're more resistant to an. 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 an interesting case point for why autoimmunity could actually be useful. Yeah. It's not always the case. It's like there to give us asthma or flaky scalp. You know, we can talk about there's a lot of disease states, you know, the argument for why we would ever have a sickle cell gene. This is the one that causes people to have hemophilia, you know, hemophilia and it's a lot of sub-Saharan African gene, people from that origin have this,

02:15:57is that it's actually defensive against malaria. It seems to be the case. So having that, I think that's true a lot of these situations where the diversity of the human population over time, by having some of these things that make some people hypersensitive to, you know, to maybe bacterial viral infection at the cost of having things like psoriasis pop up or, you know, various other water immunities is the only way that, you know, like a billion strong population has to move forward. And I always give this example, because I think it's a really straightforward one, if you take a flask of bacteria and you put them in glucose, which is like sugar, like you put in your coffee, maybe synchrosy, either one, you put them in a simple sugar and you watch the colony grow, you'll get these cells that grow really, really fast. the bacteria becomes billions, trillions of individual cells.

02:16:50But there's almost always some just losers that are dividing slowly. And for whatever reason, the system always springs us off. You're like, why would you do that? Why would the system, why wouldn't just the winners win? But if you take a little bit of that culture and you put it into galactos, 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 a crowd fitness that comes from diversions.

02:17:16diversity of genes. And so some of these things that make some of us susceptible to disease are also, as you're pointing out, in other situations, going to be quite good for you. And that seems unfair at the time that you have these kind of bad genes. But like a different day, you would have been happy, right? So I think there's a lot to be said. And that's also why a lot of the things that we look at, you know, anecdotally, somebody takes a supplement and it works for them.

02:17:41I mean, I don't know how much you know about this literature, but the differences in your in mind vitamin requirements is going to be. to be quite profound because the metabolic enzymes we have for the vitamins that we might take in are going to be different between us. And so these FDA limits, these numbers, are averages. Some people may need five times that amount of, you know, vitamin X. 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 and all of it. I think thread throughout today's conversation, I think I picked up on, you know, the fact that we covered things like peptides and things like that.

02:18:15And 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 the 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.

02:18:37And 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 the ways that you have. As somebody who thinks an analogy and likes to teach an analogy, I really appreciate that. Thanks, thanks. That stance.

02:19:02What 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 substack. We'll put a link to it in the show notes. It's so thoughtful, so nuanced, so relevant to all the issues that we're talking about, if not directly, then in the general contour. And in some cases, directly, and I imagine you're going to continue doing this. So what inspired you to do it and how can we make sure that you continue to do it? Yeah.

02:19:32Well, thank you for the call out. It is something I've been trying to work on for about 10 years in it. It really started when a group of us were hanging around. after a conference. And we were talking about some of the issues with science and society. And there were many. You know, there's many. There's, we've surfaced a few of them today.

02:19:55But I think something that you guys are working on is, is the capacity for everyone else to think as a scientist. Like, you can ask yourself, you know, oh, why don't people agree with this data that you show and take the action that seems logical? But then you present it in such a way that they can't, you know, two things, two things are important about it. I think one of them is 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 spent some time talking about this, and we consulted some other folks that are in science comms.

02:20:28And we realized, you know, the other thing is that if you say you're a scientist, it's not a neutral statement. Science has a history, and history is stronger than science, actually. So the history, like, you know, 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 not in their lifetime, many of these people.

02:20:54And 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, there's a painting of this and obviously the media and things to help this happen because it makes it interesting to have a, you know, kind of a nerdy scientist. And we can be a nerdy sciences, I heard you. But also you're a human. You're a human being. You have, you know, there's even foibles to, you know, loves and hates and.

02:21:22So, only foibles. I have plenty of those. We can get in that off the podcast. But, you know, this concept of if we want to relate, 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 is 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 also, you know, is separate, is this concept that we speak in 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 recognize it, it throws you off for a few sentences.

02:21:59And next thing, you know, you don't know what people are talking about. And I think that concept 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 strikes me is really, really important to the impact that you can have with your science and that science can have in terms of teaching people what we could do better, which I think we all want to do. But if you end up thinking that science is a distrusted, weird collection of people that have different motivations and designs, then you've lost. That the potential for it to do good is gone.

02:22:35So the substack came about it because I was like, I need to write as a person to do a little bit more and tell about some of the time that you spend on this and why it matters and what it's like to do this work. And in some respects also what it's like to lose in this, which happens way more often. It's like a casino, right? In science, you hear the bells and some cool device comes out. But there's a bunch of people pulling the arm, you know, and they're not winning. So I feel like that's kind of an important part of this.

02:23:08Again, it's not the glory story always. Some of the best-selling books about science are the winds. But it might be more relatable at some point to get all of it. So that's kind of what I was trying to put together. And at the same time, I think the immune system is also just so relevant and so important. And it's got all these different facets and these archetypes and these sorts of things that it's doing that we kind of scratch the surface today. So anyway, thanks for calling that. I've been working on for a bit.

02:23:35Well, I hope you continue to. And thank you so much for the work you've been doing in your laboratory and all the people in your laboratory doing that work. Because now you're the one calling the shots while other people do experiments. But for your advocacy for science and public education, it's huge. We need more people like you. But you certainly put your own unique signature on it. And the substack reflects that. It's an incredibly interesting set of reads and people will really learn.

02:24:03So that's essential, especially in this day and age. But even not in this day and age, science is just really cool. And with all the meaningless drivel out there, it's nice to go to a place like your substack. And I'm speaking to the audience now, 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, somebody's going to contact you that they decided to study the immune system or they learned something. Or they explored a novel treatment with their physician in a given unfortunate. or maybe even fortunate situation that bettered their lives.

02:24:38It's incredible what substacks and conversations like the one you've been willing to have today and going forward can really do. So thank you so much. Definitely come back again and tell us about cancer and other things because I took us off course quite a lot, but I had a great time talking about all of this. And I'm going to be thinking about a lot of it and really appreciate you. Yeah, well, same here. Thanks so much.

02:25:03Thank you for joining me for today's discussion with Dr. Max Crummel. To learn more about his work and to find a link to his superb substack, please see the links in the show note caption. If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero cost way to support us. In addition, please follow the podcast by clicking the follow button on both Spotify and Apple. And on both Spotify and Apple, you can leave us up to a five-star review. And you can now leave us comments at both Spotify and Apple. Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. If you have

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