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

Dr. Max Krummel:
A famous immunologist in the 1970s drew this parallel in wartime and said in World War II, submarines had two sets of books. One of them was a book that gave them the sound profile of all the US submarines. And so they could listen to the whir of the engines, and if they heard a whir 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 submarines. And if they heard that, then they absolutely would fire. And that's a self versus non-self-discrimination problem, just like the immune system has to do. But what I bring you with it aging is this concept that as you get weirder and different, and your body is getting more complex, than as those books start to have every possible, possibly every possible permutation of every biomolecule could be made by your body at that point. And then a virus doesn't necessarily have anything unique about it.

Andrew Huberman:
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 of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Max Krummel, a professor and leading expert in immunology and cancer biology at the University of California, San Francisco. Today, we discuss your immune system, how it works, what it needs to function at its best, and how things like aging, vaccines, sleep, and even your thoughts and emotions shape immune function. For instance, most everybody knows that being sleep-deprived makes you more prone to getting sick. But why? Meaning mechanistically why? Well, it turns out there's a specific set of cells that need to migrate in a particular way during sleep, and we talk about how you can reinforce that process in ways other than sleep. We also discuss incredible findings that certain brain states and memories can be associated 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. Krummel is incredibly balanced throughout today's conversation, and yet he's also willing to state his views very clearly. So it provides a very rich discussion about vaccines and all the rest. Indeed, thanks to Max's incredible breadth of understanding of immunology and much more, and his ability to break down complex topics and make them accessible, plus his genuine care for public education and science, today's is a truly special and important episode to educate and inform you in actionable ways. I should also mention that Dr. Krummel has an incredible zero-cost Substack. It's called The Immune Beyond. You can access it by going to theimmunebeyond, all one word, .substack.com, and there he teaches about science and more. Again, it's awesome, it's free, so definitely check it out. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Dr. Max Krummel. Dr. Max Krummel, welcome.

Dr. Max Krummel:
Thanks.

Andrew Huberman:
Most everybody, including me, has heard of this thing we call the immune system, and most people just think, "Okay, this is the thing that when I'm rested, 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 funguses and viruses." And I think that's probably what most people understand. And they probably also understand that there are cells and T cells and B cells, but if we want to think about a little bit of the history of our understanding of the immune system and what we understand now, maybe you could orient us, because in reading your work prior to this discussion, I'm realizing that this is a very recent field, and also there's still a lot that we do not understand.

Dr. Max Krummel:
When I started in immunology, sort of 30 years ago, I was rotating in labs at Berkeley, I think you were at Berkeley as well, and one of the transcription factor biologists, mentor said, "Why do you want to work in immunology? It's not really a field." And so at the time, it was true. Everything was about DNAs, cloning. It's obviously still a lot about molecular biology, what we do, but at the time it was pretty simple. We thought of the immune system as something that on the one hand, it had to come into play when you saw a virus or something foreign, and otherwise it generally had to be quiescent and leave you alone. I think cancer immunotherapy changed that a lot, that gave us the idea that you could tune its reactivity so that you could get to the point where if you gave an immunotherapy, what it was actually doing was raising the threshold of when a T cell would activate and allowing T cells that might be just letting the tumor get by, they'd be able to go and go after that tumor and kill it. I think that changed the spectrum a certain degree, where we suddenly thought, "Okay, this isn't just a foreign versus self thing," because a tumor is not exactly self, but it's also not foreign. It was once you. It's a cell that's evolved. So I think tumor immunology really changed our perspective on that, to the point where we now think of it as a tuneable system. But then I think a lot has happened in the last 20 years. There's been a lot of excitement about cancer immunotherapy because, well, 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. You know it in the nervous system, in 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 the right quantity. So it's guarding yourself. It sits in your liver Regulating how much you metabolize. There's a collection of cells there. It's in your heart. It's regulating cardiomyocyte 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 before were lost in the foreign, battle against the foreign. And now we have this perspective of this system that measures us all the time. It measures everything about us, and it exists in some ways, I think it's to help us be who we are. Hopefully that's you as a healthy person. 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, well, in some ways it's trying its best.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
But it's applying the wrong program to the wrong situation. So yeah, it's changed a ton. I'll give you another little funny story, which is that when I first came into immunology, again, we had this story, like a mentor who says, "This isn't really a field." The year was, I came into the field in 1989, and that's right at the peak of AIDS. And AIDS was, as a biologist, was really interesting because the HIV virus infects T cells. So your body is filled with 10 to the 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. They're 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 during it, was just a ton of different opportunistic infections. So soil bacteria that you and I fight off without even thinking about it would kill people. But so too you saw people with carcinosarcoma, you saw a opportunistic virus where a cancer's emerging. And you just saw all these manifestations of where the immune system was important, dementias in people with HIV as well. It was an early accent at the time on how many different things the immune system might be important for. So regardless of whether it was a field or not, it was clearly important. And it was all these things we didn't know about it that fueled the discoveries that have led to where we are right now. And some of those, I think it's worth pointing out, were just these curiosity questions. Like, "What are these cells like?" They were hard to study at the beginning. Sometimes it's hard to keep cells out of a human body alive. So, there's issues about how do you keep these things alive in the very first place? And then, what kinds of things trigger them to do stuff? And you've got to make reagents to test those 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 rich as we understand that they're basically every single T cell in your body is like a free agent, and they're part of a sensory system. Each one can measure the concentration of a set of biomolecules, proteins, in 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 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. The whole thing is magnificent.

Andrew Huberman:
It is magnificent. Do you mind if we take a developmental perspective on this for a second? And then I have a basic health question.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
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.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Maybe you could describe what's going on there.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And it also is the case that as we get older, much older in fact, last quarter of life, let's say, people tend to get sick more. What's going on in terms of immune system function? Or is there something more broadly happening at level of just energetics, mitochondrial function?

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Very curious about this.

Dr. Max Krummel:
If I can take a step even further back, I will ask you a question of who are you? And I don't mean that in a personal sense, but we can talk about that too if you want. But the moral of the question is, at some point, where does your body end and where does the world outside start? And one of the things that you start to realize if you look in a microscope is that we're covered with microbes all over our surface. We're covered with microbes all the way in our gut. In fact, you've probably heard this before, but you can't digest animal fats if it weren't for the bugs, the bacteria in your gut. They make some of the key components of bile acids that allow you to digest animal fats. So you need this system that's around you. So you aren't just the cell, if you learn biology, again, we're going to go way back. There's the egg and the sperm. And they fertilize, and now you got this cell that starts to divide and gives rise to every other cell in our body. So you might say that your body is just that collection of cells. But in fact, it's absorbed a lot of viruses and bacteria from our environment. And to go into that really briefly, that's really important because we only have 20,000 genes in our genome. So there's only so much in a given life that we can do with those genes. And so by absorbing all kinds of other species onto us, we get their genomes. So like I was saying, the bacteria in your gut can now help you absorb nutrients that you wouldn't otherwise. If you eat sushi, you've heard this probably, right? You get bacteria in your gut that can help you absorb the seaweed, nutrients from seaweed. So, taking this into your question, when you're first born, you've never really seen anything. And so two things are 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 we presume that for those six months that's because your body's developing so fast that if you were to have a super active immune system, you might actually find yourself attacking yourself. You might think that you're a foreign, because some genes turn on during development, and then all of a sudden your immune system's like, "Oh, I see something different, and now I need to react." So that's well-known, and that's one of the reasons why some childhood vaccinations that are really important to protect kids 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 it. That body, like kid's body, has never seen flu before. So every single virus and pathogen that hits it is going to elicit some amount of illness. But then they have a very strong immune system. It reacts and gets rid of that, with the exception of the ones that are those certain viruses and bacterias, mumps, measles, rubella, that are lethal. And that's why we immunize, as we say. Well, those are things that your immune system, if they get too much of those, kids will die. And so it's better to protect them with a vaccine. All right. So that's the front end, right? The front end has this initial immunosuppression, then just exposure to all these things that are in our environment, and you and I take on as part of our genomes. But we have to reach a detente with some of them. We have to get to the point where the immune system can kind of like fire back when they show up, if they're bad, and allow them to live in us if they're good with us. And so I think that's what's happening a lot in those first years of life. And you can see that both in the form of kids getting sick a lot, but you'll also see that their guts develop way diverse microbiome. They allow a whole bunch of things that come in from the outside and are acceptable and are quite good for you. So that's the front end. And the back end of life, it's a little bit more complicated, but I'll tell you two things that I think are important. On the one hand is the fact that a lot of your cells in general become less functional, including immune cells. And you get less cells produced, and that might just be because we were never selected as organisms to live as long as we do right now. That's one idea of aging right here.

Andrew Huberman:
Do we know that? That we just were supposed to be dead by 70?

Dr. Max Krummel:
Well, no, but we do know that we can reproduce and pass on our genes successfully already when we're 16. So, the selective pressure to pass on your genes, if you imagine that's how genetic evolution happens, is that you pass on your genes as being successful. You can already do that at 16, and anything after that is just cream on the crop. But, at some point, maybe there's no selection. So we don't know that, but it's a reasonable hypothesis to say there wasn't any real selective pressure for passing on genes that do anything past when you're actually having kids.

Andrew Huberman:
The psychologists would tell us that the wisdom of people 60, 70, 80, and beyond is useful for groups of humans that live in villages of 100 or so people because they can give information to younger-

Dr. Max Krummel:
Right. Agreed

Andrew Huberman:
... people that is on the periodicity of like every five to 10 years, maybe every 30 years. But that's a just so story.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Right? I mean, it's a nice just so story.

Dr. Max Krummel:
I like it, too. And I think the geneticists will refer to that as like the grandfather effect, where genes may be selected for, and maybe they're mostly about genes that make us social for the elderly, that they're going to have effects on the fitness of their grandchildren, which is their genes.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And so, I think there's something to be said for that in conceptual space. I don't know if I can prove it to you that that's-

Andrew Huberman:
It's a tough experiment to do.

Dr. Max Krummel:
It's a really tough experiment to have two villages where the grandparents are eliminated or like kept, both non-ethical and also not useful.

Andrew Huberman:
Right.

Dr. Max Krummel:
But we were 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 this issue that the immune system is tapering in its efficacy, many of the cells that you've been holding your whole life start to literally die off. But there's another thing, which is I think a lot of people don't realize when basic biology will say that sperm fertilizes the egg, so you've got your mom's genes and your dad's genes. So you've got 23 chromosomes from your mom, 23 chromosomes from your dad. And at least when you're first born, every cell is a clone, it has exactly the same information. But DNA replication and DNA sort of like fidelity isn't perfect. Like they say that on your skin, the cells of your skin may have somewhere between 10,000 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 or... Remember, the genomes are huge, right? So 10,000 mutations out of terabytes of information still is only a certain number. But do that over years, and the main thing that that means is that every cell in your body is no longer identical to the one next to it, because this one got different mutations on day one, this one got some mutations on day two, and slowly but surely, you are becoming like a mosaic. And I say mosaic because like the tile that you see in Morocco, very intricate designs, because if you actually start to look into tissue, you'll find that certain clones, certain mutations, do make certain cells more fit. And they're the ones that if you scratch yourself and some new cell has to form, they might be the fittest to fill that void.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And one of the other clones over here that got a different mutation may not be fit to fill that clone in. So you end up with this pastiche of who you are. So now again, I ask you, who are you now? So if I want to defend against something that looks different What if everything looks different? What if every cell is different from every other cell? Okay. You want another analogy?

Andrew Huberman:
I would like another analogy. The only exception that I can think of to this, and I could be wrong, is that our neurons, our central nervous system neurons, our brain and spinal cord, most all of them are the same ones that we were born with.

Dr. Max Krummel:
They're the same cells, but the DNA-

Andrew Huberman:
Same cells, but so you're saying mutations are constantly accruing in the neurons as well.

Dr. Max Krummel:
In the DNA. So it is fascinating, by the way, that neurons live that long, and hair cells, they say that the proteins in the 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 dead, 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 marrows, our long bones are hollow, and in there is the source of the immune system's revitalization. It's the stem cells that make more white blood cells. We'd like to think that they live in there because it protects them from radiation. They hang out, and the bone actually serves not only a structural purpose in our body, but it's a cavity in which things can live. And there's-

Andrew Huberman:
Keep it away from solar radiation

Dr. Max Krummel:
Solar radiation.

Andrew Huberman:
Keep it away from chemical cues in the environment that can mutate.

Dr. Max Krummel:
Exactly. Sequester your stem cells.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And-

Andrew Huberman:
Don't burn them.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
That kind of thing.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Yeah. Likewise, the neurons in the inside of the skull-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... and the spinal cord-

Dr. Max Krummel:
Are protected

Andrew Huberman:
... they're protected.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And that's interesting.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
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Dr. Max Krummel:
Sometimes I tend to think the immune system, you want to defend it like you want to defend a nation, and you want to defend it from outsiders. And I've just told you a story that if you want to take a political statement from it, it's pro-immigration because all these bacteria that live on us are actually bringing us goods, and they do a lot of work for us.

Andrew Huberman:
We just lost half the audience.

Dr. Max Krummel:
I'm sorry.

Andrew Huberman:
No, I'm just kidding. I'm totally joking.

Dr. Max Krummel:
I'm sorry.

Andrew Huberman:
We're a bipartisan audience. I'm totally joking.

Dr. Max Krummel:
Take it how you want, but-

Andrew Huberman:
I'm totally joking

Dr. Max Krummel:
... by analogy-

Andrew Huberman:
I'm joking

Dr. Max Krummel:
... it's the argument for why certain influx of, in this case, organisms onto us create a more robust person than we were before. But I want to give you this story that a famous immunologist in the 1970s drew this parallel in wartime and said in World War II, submarines would be underneath the ocean, and they'd be traveling around, and 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 US, of all the US submarines. And so they could listen to the whir of the engines, and if they heard a whir of the engine that had the certain cycle of a General Motors engine, they wouldn't fire. So that's the sort of self, I know what self is. And then they had another book that was the engine sounds of the known diesel engines of whatever engines of the German submarines. And if they heard that, then they absolutely would fire. And that's a self versus non-self-discrimination problem, just like the immune system has to do. But what I bring you with it aging is this concept that as you get weirder and different and your body is getting more complex, then as those books start to have every possible, possibly every possible permutation of every biomolecule could be made by your body at that point. And then a virus doesn't necessarily have anything unique about it. 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." But with aging, we have this us diverging problem, so that this system that's supposed to sense us-

Andrew Huberman:
Mm-hmm

Dr. Max Krummel:
... it has a lot of cosmic background, it has a lot of noise in it. And so I think that's one of the reasons why we also have issue when we're aging. And I think it's also one of the reasons why cancer is more prevalent in later life. There's two parts to that. One is, of course, you've accumulated mutations in your cells that could be cancerous, but also the immune system has been seeing those and all the various different accumulations of them and ones like them over these years to the point where the weird doesn't look that weird anymore. Something like a cancer that is different than you, it's not that much different than another cell over here that's gone, and it's just happily making skin and isn't cancerous, but it's got some differences.

Andrew Huberman:
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 become different, they produce cells that are also different, then they die.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Is that the way it works?

Dr. Max Krummel:
Yeah, and I think you are bringing something up that's also true, which is that all the time, I think the immune system is defending us against mutations. So one example that everybody sees when they get to be about 40 or 50 is little these white spots in your skin. And we think that those are places where the immune system has sensed a collection of cells that were pre-cancerous, maybe they were even beginning 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, and that's why it's white instead of as dark as the rest of your skin. So to that extent, the idea that the immune system is pruning you all the time, it looks like there's pretty good evidence for that.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And the question is, when does something become dangerous? That's fundamentally the 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 would like to have cells that quickly replicate," just like maybe in kids. Kids heal so ridiculously quickly, right?

Andrew Huberman:
Because they have an abundance of these cells that-

Dr. Max Krummel:
I think their wound healing, there's a group out of Stanford that studies this, but essentially, wound healing in young is quite a bit faster and more efficient, and there's many levels of that.

Andrew Huberman:
It's remarkable.

Dr. Max Krummel:
There's many levels of that.

Andrew Huberman:
Yeah.

Dr. Max Krummel:
Yeah. But, yeah, remarkably faster. And if you're a parent, you've seen this. You cut yourself on the same day as your kid cut yourself, and three days later, you can't even find it on them, and four weeks later, you still got a scab or something. But I was just coming to the point that if you do that, you maybe want that to fill back in because certainly out in the wild, having an open wound is a bad thing, so you'd like to heal quickly. Well, if a mutation has happened that fills that cell in 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, that they may be a little bit better at growing. And then again, the question, it's 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, 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 the new immunity. Immunity used to be like a fuel gauge. You'd say it was low for self, then it was really high against viruses, and it was like a fuel gauge. Now it's really hot. And what we originally thought we were doing with cancer immunotherapy was making it just hotter generally. But now you realize that in between immune system not caring about something at all and going and 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, it can 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, immune system can actually help them be there. It can produce things that either titters them out of circulation or keeps them there. In all these other settings, like you say, in the heart, and you can go to almost any organ, and the immune system is consistently present, and it's consistently measuring you. And the you, again, is this complex you. It's not just what came from the egg, it's the you that's you right now, including all the mutations that you might have accrued and all the bacteria and the viruses. 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 maybe came from religion. We were born pure, and if God made us correctly, then we would be pure at the end of things. And that would be pure immunity, which would purify us of things. But the more we look, the more we find that every virus leaves a little evidence of it, a little bit of itself. And then there's the goal for the immune system to quarantine that, to say, maybe we don't want to kill every one of our cells to get rid of every virus that's infected one of our cells. We need to leave some of those alive. Like for example, herpes virus infection infects the nerves, and when people have 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 virus is, and it's the failure of that detente. And when certain viruses are just sitting in us, we're perfectly fine. We have viruses sitting around, and 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.

Andrew Huberman:
Mm.

Dr. Max Krummel:
That's a reality that's a little bit too bad, but it's also one where you say, again, if the goal of us is to make it to 30, let's say you get an early liver infection of HCV or HPV. If the immune system can just let that be, you're not going to destroy your own liver, and you'll live to produce, and your genes will get passed on. On the other hand, if you mounted a massive immune response, you went all the way in the fuel gauge to the right, your immune system can kill you. It absolutely can. It can kill any cell it wants. So, 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.

Andrew Huberman:
This raises a question for me, and obviously I'm not an immunologist, but it seems like one-

Dr. Max Krummel:
You're going to be one by the end of today.

Andrew Huberman:
Yeah, I hope so.

Dr. Max Krummel:
I'm going to...

Andrew Huberman:
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-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... enough to assess how many cells throughout the body, or even just get a local average of how many cells have similar mutations or just are different.

Dr. Max Krummel:
Right.

Andrew Huberman:
So that if we are indeed born pure-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... in the biological sense.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Let's just keep it there for sake of today's discussion. And by time we are 32 years old, we are a mosaic of mutations-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... as it appears we are. If the immune system could surveil multiple regions in the body-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... maybe compare organs or maybe keep it within organ system and say, the number of mutated cells or not pure me cells-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... 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."

Dr. Max Krummel:
Yep.

Andrew Huberman:
In the same way that soldiers might hear a shot whiz by, but then do they necessarily reveal their location and launch an attack? No.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
But if it's enough of an attack, they'll fight back.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
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.

Dr. Max Krummel:
You're coming from neurobiology, as I know, and so there is that in neurobiology of accommodation, right? I always tell the story of I went to this little village in France called Époisses. If you know the name, Époisses is a kind of a famous cheese that they make in this town, and it's super stinky. And they make it only in that town, and they make a lot of it in that town. And so when you drive into that town, it's like somebody has the worst foot odor. It's striking. It really hits you. But after being in the town for like an hour-

Andrew Huberman:
Mm-hmm

Dr. Max Krummel:
... you don't notice it.

Andrew Huberman:
Yeah.

Dr. Max Krummel:
And that's neuronal accommodation, where your nervous... 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've seen 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 you're going with this is, and we think this is true, that the immune system, for danger, it's looking for something that you would call, it's how it's seeing the signal over time. So let's say you're a T cell that recognized 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, you'll be faster to respond to it and keep you from getting sick. That's one kind of signal. But self can have either one of two signals, I think. One of them is that you've had it your entire life. So that amount of protein, maybe it's insulin, which we think in general 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're going to only be very low reactive to that, and 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. And so, like a mutant cell, and maybe it's just a tiny bit above normal for months, and then it makes two copies of itself, and now it's a little bit higher than normal. And 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 is going to help you be.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
If it's a slow direction this way, it's going to be okay with that. What it doesn't like is big spikes, and that's maybe the signal that you're asking about, could you actually get to the point where you'd be reactive? The problem with cancer is that it is slow and 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-- that's commensal. So as long as it doesn't accompany-- Again, viruses have two features in common. One is the spike of appearance, but they also cause damage in that window. And so you have 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 set of cells that are wired in space. They're across your body from your brain all the way to a muscle, let's say. The immune system has this collection of cells that are literally crawling around us right now. We still do a lot of imaging. If you look in a piece of skin, you can see the cells. The immune system are really, really surveying us. They're crawling around. But they get together like neurons, and they can form synapses, and one can say to another one, "This is what I saw." And the other one says, "Oh, you saw that? Well, I'm just seeing this." And they can 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."

Andrew Huberman:
I realize this perhaps is not your immediate area of research, but recently I've been seeing a lot more interest in the thymus.

Dr. Max Krummel:
Hmm.

Andrew Huberman:
This organ that we have when we're young and it disappears as we get older, and there's-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... a lot of interest in the-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... 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-

Dr. Max Krummel:
For therapeutic?

Andrew Huberman:
Maybe in a few years, we'll all be banking our thymic cells.

Dr. Max Krummel:
Hmm.

Andrew Huberman:
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.

Dr. Max Krummel:
That's the fad, yeah.

Andrew Huberman:
What's the thymus? What does it do? Why this interest?

Dr. Max Krummel:
Yeah. Well, I can back up one step, and I've used the word T cell before.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And T cell originally was thymus cell. So for those that maybe have gone to have blood taken, if you have blood taken in a 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. 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, and it has a funny history. In fact, I'm writing these Substacks these days, and I'm writing one that's supposed to be released tomorrow about the thymus because it really should've gotten the Nobel Prize. There's a guy who's alive, he's 97 years old in Australia, who did this remarkable experiment. There was this time when kids that had heart issues would come in for surgeries, and they would discover this enormous whitish organ as a growth near the heart as they were taking the body, as they were cutting open. And all the autopsies up to that point had been done mostly with adults. And in adults, there's only this small little thing there. And so they were like, "Oh my God, part of the heart thing is this overgrown thing." They didn't really know what it did. And so they 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 opportunistic infections. They would get all these infections. They'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 97-year-old codger in Australia, at the time, he was in England, and he basically took a bunch of mice, and when they were newborn, he'd remove their thymus, the same little whitish organ. And sure enough, those mice, they basically grew up okay, but then they all would succumb to bacterial infections. And in fact, a few of them even got tumors, which was kind of noted at the time but forgot. And the reason why that is, is because the thymus is the place that makes all your T cells. And it comes from a convoluted path, but you remember how we were 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 super special place that is able to present to them, to show them all of the genes in your genome in various different ways. And so the T cells that come in there, the T cells are developing, and they each have a possible 10 to the 11th different kinds of receptors that smell different things. And you don't want any of these to come out that are too reactive to you. So you don't want to produce T cells that are going to go off and kill your pancreas or kill your big toe or anything. You want to maintain tolerance. So you want to make sure that you don't make the immune system that's too harsh. So this thymus has the role of producing T cells, but also of educating them in some ways, of only letting the ones that come out that have sensors that are correctly tuned to let you be you in that way. Now, to the point about the story, and you were asking about aging, is that in kids, those are really big because at that point, we were talking about the developing immune system. It has to go from living under the veil of your mother's immunity, and then it needs to let some development happen, and then it needs to burst out and start to be able to react against whatever bacteria and viruses you're going to see over life. So your thymus has this huge output, so as between really from three to six months old and into your four or five years of age, but tapering, your body makes tons of T cells. And it's because of probably what you're talking about. You're getting exposed to all kinds of different bacteria and viruses, and so you need to make that collection of immune cells that both some of them see self at low levels, but then they also can maybe react against different things in the environment, including the ones you need to defend against. Then what happens is, because again, I think we're not needing that later and maybe we don't even want that, the thymus involutes. It gets super, super small, so that in aged people it's like tiny. And so it's not putting out new T cells. And so the reason why there's interest in like these peptides, but all these other approaches to like revitalize the thymus is that 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 cells in your body that it's normal. Maybe you need a source of new material to come in and do that. And there's really two ways. I think you mentioned you talked to Alex Marson not too long ago, and I'm sure he would've 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 them might be to let the thymus make use of more T cells and make sure that as they come out, you make sure that they can react against this tumor or whatever it is you need to defend against. It's always been a fascinating organ from the sense that it's the origin of all the cell types that we care about, the T cells in that case. But it does have this like aging hit, this sort of aging effect that seems to make us a little bit more susceptible to things later in life. And, 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 to 30 and you died of an arrow wound, you know, but you've given new genes. You're a winner in the evolutionary sense. You know?

Andrew Huberman:
I love this stance on, well, if you've already reproduced. I'll just give a brief vignette. We were introduced by our mutual friend, David Feldheim, who's a phenomenal developmental biologist from-

Dr. Max Krummel:
He is

Andrew Huberman:
... UC Santa Cruz, and his wife, Sophie Salama is also a phenomenal biologist, a mutual friend. And years ago, I was in Dave's lab because we are longtime collaborators and published a bunch of papers together, and, he was doing some injections. I'm going to get you in trouble, Dave. He doesn't do this any longer.

Dr. Max Krummel:
Yeah. I'm going to join him to get you in trouble because we-

Andrew Huberman:
He was doing some injections

Dr. Max Krummel:
... we both love you a lot.

Andrew Huberman:
And he might have been using carbocyanine dyes. This was kind of a conventional tool back. You put a little crystal in a piece of tissue that's fixed tissue, so it's not a live animal or anything. And then you put it in the fridge, and then the fluorescent dye would label a set of neurons in a pathway. And, I walked over and I saw Dave doing this, and he wasn't wearing any gloves. And I thought, "These are carbocyanine dyes."

Dr. Max Krummel:
With cyanide being the-

Andrew Huberman:
Cyanide being the-

Dr. Max Krummel:
Yeah. The key

Andrew Huberman:
And I said, "Dave, don't you want to put on gloves?" And he literally looked up from the microscope at me, I'll never forget, and he said, "I've already successfully reproduced." And he went back to doing it. And it's his lab, so. And everyone else was following a safety protocol. Don't go after him. He doesn't do this any longer, folks. But, there's an interesting mindset-

Dr. Max Krummel:
Hmm

Andrew Huberman:
... among you because he comes from cell biology.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Randy Schekman's lab.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
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, we really aren't needed. But, his kids are now graduated or in college. So there is this thing about raising the young, too.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And not just creating them and then dying.

Dr. Max Krummel:
Agreed. I think there's a fitness associated with being older than that. And again, when I say that this, it is maybe just taking this from a purely like, what would have been the source of what we are today? What would have been the selective pressures on them?

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And it would've been a little bit like Dave is saying, the selective pressure is, 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 drop out and within an hour they're running. So that period of raising children, I think creates more pressure in humans to successfully be healthy longer. But I guess there 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-

Andrew Huberman:
Yeah

Dr. Max Krummel:
... 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.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
That aging backdrop. And some of the immune system that is really going to be important to just be super reactive early on may have some compensatory problems when faced with that new reality of a 50-year-old or 70-year-old or whatever. It looks quite more complex. But you would've definitely wanted, in gene space, what genes you have to select for 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.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And, again, that isn't to say that we can't overcome some of those deficiencies if we understand them, but here's my plug for basic research, is that to understand them, we have to ask some questions that are almost 90% of them are going to be dead ends. You know, you cannot hypothesize it's one thing. Well, you've got to do the experiment to eliminate that.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And this is one of the things that people I don't think always understand about science, is that for all the discoveries that I've made or other people have made, there are hundreds and hundreds of disappointments. And you'll recognize this, where you just go home from the lab at the end of the day and you've done everything right, but the answer isn't the right one.

Andrew Huberman:
Yeah. One control experiment can nuke your whole project.

Dr. Max Krummel:
Well, there's that.

Andrew Huberman:
One good control.

Dr. Max Krummel:
There's obviously that you have to do the experiment well and have it controlled, but the answer just could be not the one you thought. And 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. And so the better experiments, we call them killer experiments, right? The ones that 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 Again, when we get to some of these aging things, there's a lot of intuition that we all can put into this, whether we're 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. That I wish that because of age, certain things would happen. That's lovely, but it could be super, the word was baroque.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
The whole system could be configured in a completely weird way that doesn't really initially make intuitive sense to us. And that's also why some of those discoveries are so big to us. We're like, "Oh my God, I didn't realize that this system that seems like it might be quite simple is so complicated. The world is so strange."

Andrew Huberman:
Well, when I started in neurobiology, the brain, actually the entire central nervous system, was considered an immune privileged organ.

Dr. Max Krummel:
Yes.

Andrew Huberman:
There weren't supposed to be immune cells there.

Dr. Max Krummel:
Mm.

Andrew Huberman:
And thanks to the beautiful work of Carla Schatz-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... with the major histocompatibility complex work-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... and Ben Barres-

Dr. Max Krummel:
And Ben Barres

Andrew Huberman:
... and I'm failing to mention all their scientific offspring, Beth Stevens, Cagla Eroglu-

Dr. Max Krummel:
Sure

Andrew Huberman:
... and on and on.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
It would take the rest of the episode to name all of Ben's scientific offspring.

Dr. Max Krummel:
Sure.

Andrew Huberman:
And Carla's, too.

Dr. Max Krummel:
And being you, one of them.

Andrew Huberman:
Right. 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-

Dr. Max Krummel:
Definitely

Andrew Huberman:
... and alive in the central nervous system throughout the whole lifespan, serving critical roles.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
There are two things that, well, three really, that are somewhat practical questions. I'll start with the most basic one. Why is it, at a mechanistic level, that if you miss a night or two of sleep, that your immune system seems so less effective in fighting off infections? Do we know what's happening? Is it like you've got so much adenosine, which is the sleepy molecule-

Dr. Max Krummel:
Mm

Andrew Huberman:
... and that adenosine inhibits T cell function or something? Do we actually know?

Dr. Max Krummel:
Yes.

Andrew Huberman:
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.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Is there a mechanistic understanding of why that's so?

Dr. Max Krummel:
I think there are bits and pieces of it. I think some really nice work shows that at night, when you're asleep, 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 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 in 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? And I guess I can only imagine it's because we've created these bodies of ours are so capable, and they're so energetically and 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. It just needs a reset. So the immune system is definitely resetting and as I said, there's evidence that a lot of the cells go quiescent into the tissues, and they may leave you alone for those reparative processes and actually allow those. In terms of the data on there, there's a lot of studies that are being done and I can't say that I've come to a conclusion about that. This comes into question of, 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.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
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.

Andrew Huberman:
That makes sense.

Dr. Max Krummel:
What they're doing and why that's important in the long sense of what you're talking about, everything from... Well, but I think it's the things that happen overnight, definitely your cognition improves. Is that immune or is that neuronal or both? I think it's both.

Andrew Huberman:
Yeah. Something in the lymph plumbing, immune system. One thing that's just striking, 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.

Dr. Max Krummel:
Mm.

Andrew Huberman:
They sleep for a night or two and it goes away.

Dr. Max Krummel:
Mm.

Andrew Huberman:
That's clearly accumulation of lymph. We actually know that.

Dr. Max Krummel:
Mm.

Andrew Huberman:
That's just lymph fluid that's not being cleared, and it might not even be the brain's glymphatic clearance system.

Dr. Max Krummel:
Right.

Andrew Huberman:
There's a bunch of lymph pooling under your eyes. That's why you look like shit.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And then you sleep for two nights well, and then you look better again.

Dr. Max Krummel:
Mm.

Andrew Huberman:
And the eyes get glassy. We know that the eyes get glassy when we're sleep deprived.

Dr. Max Krummel:
Mm.

Andrew Huberman:
That's also a lymphatic clearance issue.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
This is well established. So there's some things that are just like plumbing works better when we sleep and get up again. There's something literally about lying down and getting up, but that to me can't explain the immune thing entirely because the lymphatic system is, among other things, immune surveillance. But one night, lousy sleep, and the person coughing across the room-

Dr. Max Krummel:
Mm

Andrew Huberman:
... gets you sick-

Dr. Max Krummel:
Mm

Andrew Huberman:
... often.

Dr. Max Krummel:
Mm.

Andrew Huberman:
But when you're well-rested, you actually feel this robustness like, "Man, okay, I might wash my hands or just avoid them," and you're good.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
It's an incredible effect-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... one way or the other.

Dr. Max Krummel:
Again, I don't know the degree to which we can nail down which part of things that are happening is which. I always like the story that there's macrophages, immune cells in your eye that are basically clearing the lens.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
So there's all these places where it's doing little cleanup that you can imagine that if the thing it's trying to get rid of is granularity, that you need to have sleep where you just aren't making more granularity so that it can, sort of like when you wash your car windshield, you do it completely at that point. But you can't be driving with Fly City or you'll never clear it.

Andrew Huberman:
That's a great analogy.

Dr. Max Krummel:
So I think there's certain elements of some of these cleanup processes that happen best when you're not getting things dirty or, again, I think a lot of what we're talking about is byproducts of our energetics that leave some damage behind it. I think we just use a lot of ATP, and we do a lot of stuff as our bodies in the sleep is this time where you cannot be producing more of that and get ahead of the curve on cleaning things up a bit.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
Like pulling into a gas station, cleaning off your windshield.

Andrew Huberman:
I'd like to take a quick break and acknowledge our sponsor, AG1. I'm excited to share that AG1 has just launched their newest formulation, AG1 Pro. AG1 Pro takes the clinically backed AG1 formula, which is a blend of vitamins, minerals, probiotics, and adaptogens, and adds three important new ingredients, creatine monohydrate, calcium HMB, and zinc carnosine. Each serving has five grams of creatine monohydrate to support muscle strength and performance, as well as brain health, calcium HMB to support muscle recovery and reduce muscle breakdown, and zinc carnosine to support and improve the lining of your gut. All three of these ingredients have compelling science to support them, and therefore I love seeing them added to the existing AG1 formula. As most of you know, I've been taking AG1 every day for nearly 14 years now. I started taking it long before I even knew what a podcast was. It's a great product, and it's now made even better with the new AG1 Pro formula. If you would like to try AG1 Pro, you can go to drinkag1.com/huberman to get a special offer. AG1 is giving away a free bottle of omega-3 coenzyme Q10 with your first subscription. Again, go to drinkag1.com/huberman to get a free bottle of omega-3 coenzyme 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-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... in the hopes that the stem cells from the umbilical cord will someday be useful.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
How invasive is it, and/or should we be banking thymic cells?

Dr. Max Krummel:
Mm.

Andrew Huberman:
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 kind of wish I had a little chunk of my thymus-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... in a minus 80 freezer someplace so that when I'm 85 years old-

Dr. Max Krummel:
You might be able to expand that

Andrew Huberman:
... I might be able to exploit that.

Dr. Max Krummel:
Yeah. Well, I'll say that the umbilical cord one is pretty straightforward. 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 small little vial with the right media, and you set it in a very cold environment for whenever you might need it. Is that if you need to have a bone marrow transplant, so for example, if you have a tumor of the bone marrow system, you can subject yourself to radiation and wipe out all that tumor cells, but you'll wipe out all the stem cells. But if you get this vial here, you've got a little replacement.

Andrew Huberman:
Has that ever been done successfully?

Dr. Max Krummel:
Yeah. You can do-

Andrew Huberman:
So are there-

Dr. Max Krummel:
Autologous-

Andrew Huberman:
Are there kids that-- Are there kids or adults that are alive today because they banked their umbilical cords?

Dr. Max Krummel:
But certainly, companies sell access to that.

Andrew Huberman:
Well, and those have to pay to keep the freezers-

Dr. Max Krummel:
Freezers

Andrew Huberman:
... on backup generators-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... and things like that. So people invest time and money into this idea.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
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 cord?

Dr. Max Krummel:
It's a really good question. I don't know the answer to that question.

Andrew Huberman:
I guess the parents paid.

Dr. Max Krummel:
I can tell you, and this is the depths to which you're describing Dave Falta injecting a mouse, is that in mice, this is true. That if you take bone marrow stem cells, you can reconstitute a mouse with a blood cancer, and you can do that. I'm sure you can do it in humans, 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-

Andrew Huberman:
Because this-

Dr. Max Krummel:
... whole of my knowledge

Andrew Huberman:
... this is offered en masse now.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Do you want to keep the umbilical cord?

Dr. Max Krummel:
Honestly, I would do it because it's one of those situations where if it's not too... Well, I don't know. It depends on how much money you have to spend, because the cost is not-

Andrew Huberman:
Assuming it's within-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... the noise.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Yeah.

Dr. Max Krummel:
Yeah. So it's one of those ones where you, particularly when you have kids, there's this whole aspect of 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.

Andrew Huberman:
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-

Dr. Max Krummel:
No

Andrew Huberman:
... by virtue of a new technology. You said it would cure it.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
That's a big statement.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
You can tell I'm ratcheting up from 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 fibroblast from one of my skin cells, put the so-called Yamanaka factors on, revert that to stemness, and then I might be able to grow a new pancreas or study my whatever organs in the so-called organoids or-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... whatever they're referred to.

Dr. Max Krummel:
Yep.

Andrew Huberman:
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.

Dr. Max Krummel:
Mm.

Andrew Huberman:
It actually could have some mutations. That seems important to compare against a sort of standard cell. I don't want to grow organoids from an IPS environment that carries mutations. That seems like a bad idea.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Because then anything I would... I'm not talking about transplanting in those organoids. I'm talking about studying them, thinking I'm getting information about them. People are doing this.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
And thinking, "Oh, I'm seeing what drugs are effective in treating a liver disease or a heart disease." But if those are mutant cells, that's a lousy experiment.

Dr. Max Krummel:
Yeah. I wouldn't say they're likely 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 want was successful, was replicating the actual organ itself. So you're referencing these things called organoids, which are collections of cells from a body, a human, for example, that are induced with various different factors to grow to resemble maybe an organ, a particular organ. 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 particular organs will at someday happen. We will figure all these things out. And I believe in science. I believe in our ability to sort of test, learn, test, learn, test, learn.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
How soon that becomes useful is a bigger question. If you take out your fibroblasts today, that might only cure you someday in the future. And meanwhile, you may die of that thing that you wish you had the stem cells, I mean, because it's not yet ready, the technology and the understanding isn't yet ready. But the other problem with those is you probably will die of something else, or you'll get hit by a car. It won't help you that you've got those things banked. So I think in some of these cases, over-emphasizing, this might be your point about the storage of umbilical cords, is at what point is that a high odds situation where your kid needs it and you have it stored away, versus all the other things, fates that can befall us as humans that have nothing to do with 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.

Andrew Huberman:
Well, it's certainly not how I live. Right now there's a lot of kind of excitement and attention around so-called longevity and-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... at the extremes of never dying or living to be 120, which seems to be perhaps the genetic limit currently.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
It's not my fascination.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
I'm more interested in living in the years I've got-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... as it seems you are, too.

Dr. Max Krummel:
Healthy living. Yeah, exactly.

Andrew Huberman:
Yeah. Vital, healthy, being able to move, sense, and think-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... it seems like. And remember. Those seem like the critical ones.

Dr. Max Krummel:
And a moment ago you mentioned the concept of removing a bit of thymus, and I think that the issues for me with that are it's an invasive surgery, and if you were to take out thymus, it's not clear to me that it's the thymus that you need. In fact, you can make thymic... So 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 pretty strong work that says that you can create a sort of a thymic epithelium that will do some of this work. But whether a guy at home could hold onto the thymic cells, and we would be in a position to do something important for longevity in our lifetime, I don't know. I just don't know. And I think that's true of a lot of these things. Say, oh, 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-Ts, Alex will have told you about these, where you engineer your T cells and you give them special receptors that can get them to go in to eliminate tumors. But for whatever reason, they haven't worked in patients. They haven't worked. And T cell, the immune system gets turned off. These cells don't make it. They fail to eliminate the tumor. We will figure that out, but we've been thinking we'd figure it out sort of for five or 10 years, and that gets frustrating. And I think it gets frustrating for people that are waiting for it, too, on the outside like, "Why can't you solve this?" And you're like, "Well, because the universe isn't always configured how we think it is." And that's discovery. That's the problem of discovery. If we knew what we needed to do, we would engineer it and it would work. But we don't.

Andrew Huberman:
Yeah. This is an important discussion that we haven't spent enough time on in this podcast that I think is very important for people to hear. And I have some thoughts about it, but I'd love for any disagreements. I'm not looking for just agreements, but-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... so my observation from a couple decades or more doing science and then mainly shifting to podcasting, but this is what I do. I talk with great scientists.

Dr. Max Krummel:
Mm.

Andrew Huberman:
So that's the podcast. So I'm very immersed in what's happening right at the cutting edge and because of great guests like you. My sense is that in every field, there's been this kind of steady pressure, like water on rock pressure, like okay, we're going to understand, like salamanders regenerate. Wouldn't it be great if we could do that, too?

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
Cut off a limb, it could grow back. Okay, amazing. I think it's like Eli Tanaka's work has just shown that. You're like, "Wow, this would be incredible for amputees and brain regeneration and-"

Dr. Max Krummel:
Right.

Andrew Huberman:
But then it never really transfers. So we're 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. Great research tools. Tons of things happen. And it's like we're going to modify genes, zinc-finger nuclease, all this. Okay, CRISPR, boom. And one thing just breaks through and goes so much further.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
And even though the ethics are questionable, there are babies that have deliberately induced gene alterations with CRISPR, sickle cell anemia treatments as well-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... is 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.

Dr. Max Krummel:
Hmm.

Andrew Huberman:
The excitement about stem cells led to even initiatives at the legislative level and all these labs working on things. And then, as you said, it's kind of like run up against the dam.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
But I feel like in 10 years, some or all of that information will be extremely relevant when, boom, one thing will just leap out of bacteria or grasshoppers, no pun intended with the grasshoppers. But the last example would be for years it was like the country's getting fatter. The country's getting obese. What are we going to do? Do calories matter? Of course calories matter, this kind of thing. Laws of thermodynamics still apply. And then all of a sudden This freaking Gila monster biologist-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... tells people what they already knew because the GLPs were already being used as a drug, just not at significantly high levels.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And all of a sudden, we have a imperfect but very important, more or less, dare I say, cure-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... for obesity.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
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.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
It's like steady pressure, steady pressure, steady pressure, frustration, and something comes out of nowhere, and it almost seems prerequisite to have all those years of frustration and failure.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And you say, "Well, couldn't we have just gotten CRISPR first or the GLPs first? Why did we go through all these billions of dollars of expenditures, time, energy?"

Dr. Max Krummel:
Yeah.

Andrew Huberman:
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.

Dr. Max Krummel:
Yeah. And I think it's necessary, absolutely necessary, to study things that are just, at some point, curiosities. And that sounds like science is about trivia, but you gave a good example, clip one. Somebody was just curious as to why Gila monsters, the feature was that Gila monsters can go into dormancy for 10 months, not eat, and then come out. And how do they manage that? And so that was just like, what is that? What causes that? CRISPR. People were studying, how do bacteria defend against other bacteria? Well, they use this. It turns out there's this enzyme, and it remembers the sequence of this one bacteria that has come and invaded you before and then can modify the genome and get rid of it and kill it. Well, that same enzyme then, which we now use for all this human engineering, came out of a basic, how do bacteria defend themselves? It's not anything about modifying sickle cell anemia. It was about how does the world work. My career is exactly as long as the lifespan of this field we call cancer immunotherapy. I did the first immunotherapy experiment. I injected a mouse with an antibody that I had made. It was against molecules on T cells. And I'd shown already in the lab that that molecule caused the T cells to get more activated when you blocked it. And we did a series of other mouse experiments of all kinds of diseases, and it kept jamming up the T cells. And then Jim, my PhD, said, "We got some tumors in the fridge." And so we set up that experiment, and injected this antibody, and the tumors melted. Well, that was the start of cancer immunotherapy. That's the origin-

Andrew Huberman:
This is the experiment for which, let's just be direct here-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... your advisor won the Nobel Prize.

Dr. Max Krummel:
Correct.

Andrew Huberman:
Did you at least get to attend the ceremony?

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Oh, well, that was-

Dr. Max Krummel:
Yeah, so it was a little thing

Andrew Huberman:
... this is how science works, folks.

Dr. Max Krummel:
Got to-

Andrew Huberman:
Doesn't matter who did the experiment.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
It matters what lab you're in.

Dr. Max Krummel:
You got to go to the after-parties were good. But I guess, and I'll take you back. We weren't trying to cure cancer when we started this. The thesis project, when I went into Jim, this was my mentor at that point, the discussion was like, "Well, there's some molecules on T cells." And I said 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 suddenly have an immune system that you could dial up. You could say, "Well, if I could dial up, what will happen to vaccination?" Well, it got better. What will happen to multiple sclerosis? The disease got worse. What will happen to cancer? Ooh, we can start to have an effects on it. And the X-ray. The people were studying physics, and then it turns out to be that they were like, "Oh, I can measure bone." And that's how we use X-rays now. So there's all these examples that everything, the big things often come from these orthogonal directions, and then we realize what it might mean. And I think you have to start there. Otherwise, you'll just plow this direction, and you'll hit those walls because you don't have the workaround that comes with some orthogonal piece of information. Orthogonal meaning at right angles, right? So 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 hadn't been out there sort of saying, "Okay, well, how do bacteria do it? 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 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 it's 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 dregs of doing it, that this would become an industry.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
This would become a whole thing. And maybe that's important because you need to foster that. If everybody always thought they were doing it to build a company and sell a product or something, then I don't think we would do the things that get us new. That's all kind of what we already know. That's human knowledge. We want to build human knowledge, and to build human knowledge, we got to go off-piste. You can't ski on the slope. You got to be in the trees, and maybe you'll bonk your head a bunch of times. I think that's the reality, and it's like you got a lot of people out there that have decided to do that for a life because it's a chance to solve a puzzle. It's like there's puzzles about how the world works. And if you've ever done a jigsaw puzzle with your family, there's always like the, oh, you get in, and especially in the end, you're like, what pieces come together to do it? I think that's what makes this whole science thing really fun. That's the reward is that you get the puzzle piece in, and you're like, "Oh, it makes sense. That now I know what I've been building. I've been building this puzzle." And then you go back, and you do it again because that's really satisfying at the end of it, even though, again, with the family puzzle, the first parts are so hard. Thousand pieces, and maybe you find the edge. But the intervening, where there's all clouds, super hard. And I think that is what science is a lot about, is doing that and then realizing what the picture is. What is that picture of it? And then all the brakes are off. I often tell people that if an experiment you'll do in lab has a 10% chance of yielding anything interesting, you got to do at least 10 to even meet fundamental stats. You actually have to do quite a few more. So that's where it's not a cost-effective thing. It's really difficult to be a scientist because there's no quid pro quo. There's nothing to say if you put in five hours, that you'll get five units of goodness, of knowledge out of it. A lot of times you get zero. But then sometimes you put five and you get 500.

Andrew Huberman:
Right.

Dr. Max Krummel:
And those are the jackpot moments where you're like-

Andrew Huberman:
It's like life.

Dr. Max Krummel:
It's like life. It really is. It's like-

Andrew Huberman:
Yeah. I have to say-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... anyone who's considering a PhD, we had a call in from audience recently, and someone said they're 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-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... because it's a rather niche question. But, also just in training your reward system to work for five years on something-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... is so valuable, especially in this day and age.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Because everything else feels like it comes at warp speed.

Dr. Max Krummel:
Yeah. It clicks.

Andrew Huberman:
Yeah. And to just put steady pressure on something with all the failures and all the things, and then to finally complete something, a lot of people think it'll be underwhelming. I think quite the opposite.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
It's like anyone that's done a triathlon or-

Dr. Max Krummel:
Well, yeah

Andrew Huberman:
... raised a kid or done anything, you're like, "Oh, my goodness."

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And that never ends, right?

Dr. Max Krummel:
Yeah.

Andrew Huberman:
There's nothing better than these long-term investments.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Nothing.

Dr. Max Krummel:
Yeah. When they break through, your analogy, when you break through that dam, or when you realize sometimes that you've broken through the dam. 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. You-

Andrew Huberman:
I haven't done a triathlon, so I have to be fair. Rob, our producer sitting-

Dr. Max Krummel:
Has done

Andrew Huberman:
... to our left, he has done many Ironmans.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And he has that mindset-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... of just steady pressure. 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-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... focusing on what you can impact.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And so a lot of it is about learning energetic control.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Doing science, that is, or anything is about what not to think about, what to force yourself not to do-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... or think about.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
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.

Dr. Max Krummel:
Okay.

Andrew Huberman:
And I'm going to pose a question that may or may not fit with-

Dr. Max Krummel:
No

Andrew Huberman:
... this framework, but either way, I'd like you to educate us on it.

Dr. Max Krummel:
Go.

Andrew Huberman:
I'm fascinated by these old barbaric experiments in medicine. Wonderful book, by the way, folks, is "The Prince of Medicine" about Galen, if you ever want to learn about how we learned about medicine back when it was truly barbaric.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
It was surgeries done on warriors and without anesthesia. And we've known for a long time that if somebody, God forbid, has a finger lopped off or a hand lopped off, that it might actually be a worthwhile investment to make an incision in the gut and stuff that thing in the gut to keep it warm and keep the tissue viable for regeneration once you try and put it back on. Turns out that's true.

Dr. Max Krummel:
Is that true?

Andrew Huberman:
Yeah, there's a bunch of juicy stuff in the gut that maybe it's the warmth, maybe it's the immune system.

Dr. Max Krummel:
Okay.

Andrew Huberman:
Maybe it's the lack of infection from being inside as opposed to outside the body. Who knows?

Dr. Max Krummel:
Gut, you mean the intestine, or you mean the stom-

Andrew Huberman:
Within the stomach

Dr. Max Krummel:
... stomach.

Andrew Huberman:
Yeah.

Dr. Max Krummel:
The stomach itself.

Andrew Huberman:
Yeah. I'm not suggesting anyone do this experiment. As I started reading into this, I discovered that there are a lot of really cool experiments, not just in limb or tissue preservation and restoration. Like for instance, I've talked many times on this podcast about the fact that above the roof of our mouth, we have this small cluster of neurons, a suprachiasmatic nucleus, organizes the circadian rhythms of every cell in our body, from the genetic to the transmitter level, peptides, et cetera. Keeps us sleep-wake cycles, does all the organization that we need-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... for circadian rhythms. So much so that you can take just one subpopulation of these neurons, the calbindin expressing suprachiasmatic 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 arrhythmic animal.

Dr. Max Krummel:
Okay.

Andrew Huberman:
So that tells you a lot of cool things. It says, okay, there's probably something that's secreted or... But these cells are that important, and it doesn't really matter where they are-

Dr. Max Krummel:
Hmm

Andrew Huberman:
... at least in the brain. They can do what they need to do, which is super cool.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And then I started reading about, oh, you could actually take perhaps a little bit of pancreatic tissue and stuff it under the skin-

Dr. Max Krummel:
Into your Encapsules. Yeah

Andrew Huberman:
... and that's not ideal, but-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... you get some function back.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
So I'm fascinated by this because we like to think that the organization of our organs is so critical.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
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-

Dr. Max Krummel:
Hmm

Andrew Huberman:
... 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.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
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-

Dr. Max Krummel:
Okay

Andrew Huberman:
... for which I'm asking this, but I'm just going to tuck that away to pique people's interest, and I'll get to it. But this is relevant to important decisions that we make-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... I believe.

Dr. Max Krummel:
Well, the answer is yes and yes. It's both. So although I described the immune system in the earlier part of this discussion as super migratory and hitches a ride in the blood, gets into tissues, it travels through your lymphatics. There are these things called lymph nodes, down to lymphatic tubing, which for those who don't know, lymphatics are like drainage. It's how you drain the fluid back out of your tissue. So although there's this mass migration of cells, there's also even just in T cells, there's T cells that lodge in particular settings, and they act to protect that tissue, and they're resident cells of those tissues. They never leave. And so both are true, that you have parts of your immune system that are protective or nurturing of particular areas, and then there's ones that are circulating and can hit any spot. Going back to your idea of organs and such being moved, I think there's two components to that that you might be thinking about. One of them is the question of whether the organ can survive in the new space.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
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 if you take the pancreas, you can famously put it underneath the kidney capsule. A kidney 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, the immune system will attack it, just as it did the first. Diabetes, for those who don't know, 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, your immune system can be quite dangerous. So when you talk about this concept of spatial, there's a few things to bring in. One is, 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 some of your immune system that lives spatially in certain areas is going to be very defensive 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 if I do something here, it's sensed in my brain. The immune system, if the cells don't migrate, they don't have really a lot of ways to communicate. They can hitch some signals on neurons, and that's a really interesting thing we could talk about, the capacity for your brain and the insular cortex. There's a great set of stories emerging about how your insular cortex can program your immune state into organs and can, via the vagus, can essentially program immune states.

Andrew Huberman:
By levels of calm or stress, or by thoughts themselves?

Dr. Max Krummel:
Well, the latter one is the one that gets me super excited about the possibility that you could have triggers for thoughts. 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. I go, "Oh, ow." It can sense and it sense each other's pain. It's a set that this very nice Israeli group, Roy's lab, did this very nice study where they induced into the guts of mice inflammatory bowel disease. They fed them a really kind of weird sugar that causes the bowel to puncture, and then they get a really bad stomach ache. Not stomach ache, inflammatory bowel disease, diarrhea. And in that period, they used what threads are, so they marked for the crowds, 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, 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. And the cues for that, in that case, were a drug, but we know that we can cue the insular cortex, like me watching you do things.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
So it's made me wonder whether some of the things we smell cut grass and we can instantly take us back to a whole bunch of thoughts about how we were-

Andrew Huberman:
Mm-hmm

Dr. Max Krummel:
... when we were kids and maybe even make you feel a little like that, whether there's aspects to this to which our-

Andrew Huberman:
Mm

Dr. Max Krummel:
... ability of our thoughts to control that region are going to be revealed to have potential that you could train yourself to bring up an immune state in a particular tissue.

Andrew Huberman:
Mm. And just so we make sure everyone's on board what you just described, because there's a lot there. If I understand correctly, we know that the nervous system can do contextual learning.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
Like if an animal or human-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... let's just keep it to humans-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... gets shocked, scared, or traumatized in a given region.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Or even I've had friends visit San Francisco and get their cars broken into and their computers stolen.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
You can develop a context-dependent or place-dependent memory where you kind of don't like San Francisco as much, even though the rest of the trip was awesome.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
That's a pretty broad interpretation. Or you have a great experience someplace.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And you actually really love San Francisco because you met your future spouse there. You just had a particularly awesome experience there.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Even if it was just in one part, you might feel better about your computer getting stolen anyway. Okay. Insula seems like a, 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-

Dr. Max Krummel:
Certainly with that

Andrew Huberman:
... the immune system is also part of that contextual memory. And so merely by recalling the positive or negative, but in this case, positive memory, we 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.

Dr. Max Krummel:
That's what these studies are starting to emerge in.

Andrew Huberman:
Yeah. That's cool. That's really cool.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Because we've heard for so long that we know that chronic stress impedes immunity.

Dr. Max Krummel:
Mm.

Andrew Huberman:
We also know that acute stress boosts it.

Dr. Max Krummel:
Mm.

Andrew Huberman:
And that's something that, with all due respect to my colleagues who've focused on the ill effects of chronically elevated cortisol, the immune-enhancing effects of acute cortisol and stress are really important.

Dr. Max Krummel:
Mm.

Andrew Huberman:
And I think they've been overlooked. But I love this because one of the problems/luxuries that I have is I sit sort of at the interface between real science and biology and what most people perceive as complete nonsense wackiness.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
But more and more, we're finding that within the complete nonsense wackiness, there are kernels of truth.

Dr. Max Krummel:
Mm.

Andrew Huberman:
Like that you can actually meditate your way into a better state, which helps serve your immune system, and so on and so on. And that's seeming less and less wacky, even outside California-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... because of studies like the one you described.

Dr. Max Krummel:
One of my friends who's a faculty, Dan Levitin 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 communicate and reset less inflammatory states-

Andrew Huberman:
Mm-hmm

Dr. Max Krummel:
... across your body because of this axis. And the study was really, I think there's still work to be done, but the fundamentals of it was in the actual event, there were certain cells that would accumulate in there. And then in the induced event, when you made the brain fire again of this mouse, you would see not as profound, but you saw this evidence of these same sorts of cells accumulating there as if 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

Andrew Huberman:
Again, the concept of, I'm sure you've talked about this before, of meditation, where the idea is that it's one of the ways you can control your autonomous nervous system is through your breath. Mm-hmm. That happens with meditation. I think that to me, there's something intuitive about that. But I just an hour ago warned you about the problem of science being intuitive, that 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 insular 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 again, I've often thought, well, maybe when you're healthy, you should smell like mint. And then when you want to be healthy again, like, there's kind of crazy thoughts. But again, there's an element of that that's intuitive, too, where we say, "Oh, that seems to be the case. My mom makes me a comfort meal." Is it really the meal settling in or is it just the sensations that make me feel like less stressed in one sense- Mm-hmm ... but maybe also to this point in literally resetting your tissue? I'd like to take a quick break and acknowledge our sponsor, Function. Function provides over 160 advanced lab tests to give you a clear snapshot of your bodily health. This snapshot gives you insights into your heart health, your hormone health, autoimmune function, nutrient levels, and much more. They've also recently added access to advanced MRI and CT scans. Function not only provides testing of over 160 biomarkers key to your physical and mental health, it also analyzes these results and provides recommendations for improving your health from top doctors. For example, in a recent test with Function, I learned that some of my blood lipids were slightly out of range. 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To learn more, visit functionhealth.com/huberman and use the code Huberman for a $50 credit towards your membership. Again, that's functionhealth.com/huberman. I'm always struck by extremes of personality, but in both directions. Mm-hmm. So there are these people who just say, like, "I don't get sick." Mm-hmm. And they don't get sick, and it's super frustrating- Mm-hmm ... because I'm not one of these people that's very sickly, but I occasionally get like a sniffle or a cold or something. Less and less with each year because I do feel I pay more attention to the sleep piece- Mm-hmm ... certainly than I did when I was a graduate student, postdoc, or junior professor. Yeah. But there does seem to be this quote unquote "positive," or let's just call it a reinforced mindset- Mm-hmm ... as opposed to like an immune reinforcement associated with the mindset. Because some people will say, like, "I just always get sick," and I believe them. They always seem sick. But it could be that you get sick in a given environment once, and then you just decide that you're sickly. So then it could be that the immune system is listening to these thoughts, but not in the form of words. I think this is where it gets hokey for people. Like real biologists and physicians are like, "Yeah, you got to be kidding me." Because immune cells don't listen to thoughts, they listen to brain states. Triggers of some sort. Triggers of some sort, right? Yeah. And then as humans, we have this obsession with language that makes it seem like you can write affirmations, and then it's the word content. But it's the feeling state associated with that, that- Probably does ... at a biological level, makes total sense. Yeah. So we were talking about spatial biology and the fact that you can tuck some pancreas in the kidney, and unless someone has type 1 diabetes- Mm-hmm ... a lot of the functions of the pancreas can- Can still function ... can persist or transplantation of these clock neurons. And clearly there are limits to this, but in the context of the immune system, I'm wondering, can we take a little bit of thymic tissue, bank it, and then just later put it in a slow-release capsule under our skin of our hand? And that might sound crazy, but I have friends, one of whom might be at Neuralink now, who actually embedded a little radio receiver under his hand to be able to open his locks at his home- Yeah ... and his car, and his wife might have one also. And that might sound really Bay Area, like future tech, kind of wacky biohacking. Yeah. But if I knew that I could be much healthier by taking a few thymic cells in a sterile capsule and sliding it under the skin. People get their ears pierced with- Right. ... less invasive procedures. Why not? Well, the question is is that likely to work? You remember how we were just talking about if I do 10 experiments, one might work. Yours isn't a bad idea, but it's more than likely one of the nine out of 10, I would guess. Sure. But is there a correlate from any studies on animals? We know that in a lot of studies of cancer and tumors, I used to see these mice down in the vivarium. They would slide tumors under the skin- Yep ... and study them. Yeah. And give animals drugs or give animals stuff. Very common, yeah. Yeah. Tumors are happy to thrive in novel environments. Sure. 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's more about replacing an organ with one that might be better is that at some point if you come in... So one of the challenges of tissue engineering is if you want to bring in new genes

Dr. Max Krummel:
The vector, the material, the surrounding, whether you bring it using a virus 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 you go to transplant that organ back in, it's seen as foreign.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And it's just like you just put an infected cell in you. As far as the immune system knows, all of a sudden, there's a cell with a huge number of new things being expressed, and some of them viral, literally. So, that represents an issue, I think, when we talk about any kind of engineering at the moment 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.

Andrew Huberman:
I'm not considering doing this.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
I don't know how old you are, but I can guess based on some mutual friends we have. But I'm guessing that a lot of people who are able to understand speech, they're old enough to understand speech, are thinking that in our lifetime, we are going to be able to use our own cells or peptides or synthetic versions of peptides from our own cells and so forth to overcome a lot of the issues that our parents and grandparents were not able to overcome.

Dr. Max Krummel:
With regards to the peptide side of things, and even the cells, and this is maybe where you're going with space, is that context does matter for the immune system. 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 that's maybe just a... 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. So imagine the wound is like this, and it's open. The cells one layer back are doing certain things, but the other ones behind that are also induced to do so. The wound isn't just this area. It's actually sensed all like a gradient almost-

Andrew Huberman:
Mm-hmm

Dr. Max Krummel:
... like in the neurons. And so these cells need to do different things than these cells. So if you wanted to administer a peptide or even just a cell type, you have to be a little bit conscious of where it's going to do the work you want it to do. And the natural system does that naturally. The cells on the inside actually instruct the cells one layer back. But you don't necessarily want everybody getting the same signal.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
So, development happens that way. You know about gradients.

Andrew Huberman:
Sure.

Dr. Max Krummel:
And we were talking about this earlier that there's gradients. So, I think one of the tricks that we don't really understand about this is when is something good for a process, and when is it only good when it's given in the right dose at the right time?

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And I think that's one of the tricks about some of these things. And again, that's where both in the lab and I would say that more so than ever in our lives, we're seeing people experimenting with things on themselves. And one of the sad parts about this, we don't capture a lot of data therefore, 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 I could drink this drink, and something great happened to me or something bad happened to me, but it might have nothing to do with the drink, right?

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
That issue is one that I think is really critical in this window of time right now. And honestly, I don't know what to think about the idea that people do experiments on themselves. I think we all want to improve ourselves. We all do some kind of experiments on ourselves. You read a book, you're trying to improve yourself, right? The physical one gets a bit tricky when you're not sure whether something's going to be dangerous or not, but-

Andrew Huberman:
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.

Dr. Max Krummel:
I think I would personally.

Andrew Huberman:
Yeah. There are a few areas where I am a bit more adventurous, but for the most part, based on my training and background, I have to orient toward, let me put it this way, I'd like a bunch of other people to do it first.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Like who wouldn't?

Dr. Max Krummel:
Yeah.

Andrew Huberman:
It's fun to be first unless you're doing something really stupid and that can get you killed.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
In which case, let other people go first.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Yeah.

Dr. Max Krummel:
Well, I think a good example of that right now is, and this is nationwide or even international, is vaccine hesitancy. And I know this is a touchy topic, so we can-

Andrew Huberman:
No, but you can feel open.

Dr. Max Krummel:
Well, I'll just point out that one group that's completely, no matter whether they're hesitant against childhood vaccines and the number of them we get and 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 different from you. And you introduce those as if you would introduce a 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 the conventional cures are not going to work on us, there we know statistics really well. Chemo is not very good for a lot of cancers, and so that's the only thing we got. But if you have access to something that's relatively new, and particularly vaccines, despite what some people worry about, they're pretty safe. And so the certain die versus try out a vaccine drives a lot of people to be interested in vaccines. And I would say, yeah, in that case, you can see where people's question about whether they're going to try something or not is very context dependent.

Andrew Huberman:
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-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... I think that the The what you refer to as vaccine hesitancy actually comes back to an earlier issue that maybe you'd be willing to comment on.

Dr. Max Krummel:
Sure.

Andrew Huberman:
Which is I think there are a very large number of people for whom they are neither anti-vaccine nor super pro, but they're asking about timing and combinations.

Dr. Max Krummel:
Agreed.

Andrew Huberman:
They're saying, okay, listen. And we had Jay Bhattacharya on here, and I've had several others who said maybe there should be an investigation of the spacing of these things.

Dr. Max Krummel:
Mm.

Andrew Huberman:
How many.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
How critical it is to do at a given age.

Dr. Max Krummel:
Sure.

Andrew Huberman:
And on and on. We could pick any vaccine for that reason. And as an immunologist, do any of those questions make sense to ask? I could see how bombarding the young immune system with a lot of vaccines is a very different thing than spacing out the delivery of those vaccines.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
I'm not saying don't give them all. I'm saying over what time window does one give them?

Dr. Max Krummel:
Yeah.

Andrew Huberman:
I think a lot of people, many more people are asking that question.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
It's just a quieter murmur-

Dr. Max Krummel:
Mm

Andrew Huberman:
... than are saying, "Listen, we don't want to take any of these things."

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Or we don't want our kids to take any of these things.

Dr. Max Krummel:
Well, I've heard that too, and I think there's some fair aspect to which most of these vaccines were not studied in the context when they were studied of what it does in combination and in these sorts of timings. The fact is that the evidence that there's bad things happening doesn't look to me tremendously strong. It's almost like anecdotal sort of information. So-

Andrew Huberman:
Unless it's your kid.

Dr. Max Krummel:
Unless it's your kid, in which case you're going to look for an explanation. So I-

Andrew Huberman:
Right

Dr. Max Krummel:
... I don't know.

Andrew Huberman:
Just being fair, as long as we're admitting psychology as a factor.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Yeah.

Dr. Max Krummel:
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 we delayed my first daughter's, one of her vaccines, partly because I know that there's a certain element to 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.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And 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 of could there give you at least a more convenient one, and also one that's-

Andrew Huberman:
Or best or safest

Dr. Max Krummel:
... Or safest or even one that is less disruptive to the lives of the children and the parents. We delayed one of our kids' vaccines by just a month or something because she had not been feeling well. Just straight up. And it is true. And I'd say that a couple of the vaccines that have come out that I've had recently, the shingles one is a good example. I had it. It just knocked me completely out and it's very, very heavily adjuvanted, so it's clear that it's having a does it need to be? I actually don't know. I don't know what studies were done. And there's an aspect to which I don't know that we're all being shielded from the information, but I don't know that we all know how to read the information about how these regimens were chosen.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
Some of them were chosen by competing pharma companies that each make their own materials and 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 and where the holes are.

Andrew Huberman:
Excuse me for interrupting, but a huge basis of this podcast is to counter exactly that.

Dr. Max Krummel:
I know. I know.

Andrew Huberman:
I know all these incredibly smart, incredibly well-meaning people who have lives of their own, health lives of their own, health challenges of their own, kids of their own, and on and on, and no one was hearing from them.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And as things get more politicized, there's less incentive to give nuance. I actually really appreciate you providing some nuance on the-- It's clear where you stand on vaccines generally based on what you've said-

Dr. Max Krummel:
Yeah. Yeah

Andrew Huberman:
... but you're offering perhaps the opportunity for better understanding and certainly delivery of the information.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Yeah. It's a huge problem.

Dr. Max Krummel:
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, the percentages of these things. I absolutely vaccinated the kids, and it seems even now like a reasonable no-brainer. But I just told you, too, that I asked to go off protocol because at some point, I know these protocols have a little bit of like, again, they were designed on one study, but it doesn't mean that it doesn't work if you wait another month. In fact, if you've done enough mouse experiments, as I have, you know that when you vaccinate on a slightly different schedule, you can still end up with the same outcome, that is protection, with slightly different schedules. It's not that convenient for doctors and hospitals and even sometimes for patients to get off on weird schedule, and then you forget a dose, and then it isn't as effective, right? So there's efficacy that comes with 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 brushing your teeth in the morning. You do it in the morning, the evening, it's when you do it, and so you'll do it twice a day. So there's a lot in this. There's a lot of politics, I think, involved in vaccine, too, that relates to the question of at what point can the government tell you what to do, which is a surrogate question to the vaccine one, where a vaccine is if there's a harm, who gets to choose what the harm-benefit, and then how resources are given out for schools. 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'd-- Personally, I wouldn't not immunize my kids. Could there be additional studies about the combination of these into fewer shots? I think so. I don't see why not. Here's where you get the financial rise. What's the benefit to any pharma company of doing that?

Andrew Huberman:
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.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
I look at everything-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... on a case-by-case basis.

Dr. Max Krummel:
I try to do the same.

Andrew Huberman:
I really try to do that. And I've tried to be, in recent years, more open to at least understanding what the anti-big pharma stance is really about.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
It comes up a lot around SSRIs, but you talk to somebody with clinical grade OCD, and they will tell you that SSRIs saved their life.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
So then you go, okay, well, so we can say all we want about pharma, are you talking about people taking insulin? Or until recently, the GLPs were mostly available through pharma. Now they're sort of, it's kind of the Wild West. People are microdosing them from all sorts of compounding pharmacies as their own issues, and so on.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
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 you're persona non grata."

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
That kind of people being shunned in both directions, in either direction, rather, that's really the source of the problem. There really hasn't ever been a conversation quite like this.

Dr. Max Krummel:
Yeah. I agree.

Andrew Huberman:
At least not one I've seen publicly. Yeah, there are not a lot of labs that are going to devote themselves to this. People will wage the argument that, and I don't know if this is actually true, but that the pharma companies are protected against lawsuits about vaccine injuries.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
I think that probably is very frustrating 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.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And those groups are the ones that have accumulated the most oomph out there.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
And if you think about those parents, it's totally understandable-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... why they would feel that way. Whether or not the basis of their feelings is exactly right, I can't speak to.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
But you can understand if your kid is one way, walk out of the doctor's office is another way, and you can't do anything about it, that's got to be mad-

Dr. Max Krummel:
Super frustrating

Andrew Huberman:
... beyond maddening.

Dr. Max Krummel:
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 backward."

Andrew Huberman:
And you did that to them.

Dr. Max Krummel:
Well, yeah.

Andrew Huberman:
This is the thing, I think-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... that is not often discussed, is that the parents made that choice on the basis of what they thought-

Dr. Max Krummel:
Recommendation

Andrew Huberman:
... was the best.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
So there's a certain guilt/anger. There's a whole psychology to it that's completely understandable.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
The kid didn't wander into the clinic.

Dr. Max Krummel:
Yeah. Well, on the way over here, I was thinking about some of the things that are happening in medical space. And you guys have obviously from time to time talk about peptides and these sorts of things that people are using off late. Well, not even off label, they're just getting them from wherever, the internet. And I was thinking, there's a funny thing there because the legitimacy of pharma companies has sort of fallen into even worse straits than before because 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 the side effects are worse than the symptoms that we're relieving. And that sort of, again, I may find myself 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. 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, by scripture and things and your behavior. But somehow in here, this idea that 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? Who are these experts that I can't always trust?

Andrew Huberman:
What's more American than that, after all?

Dr. Max Krummel:
Yeah. Well, it is.

Andrew Huberman:
Yeah.

Dr. Max Krummel:
It is part of the pioneering spirit. If the government's not going to protect my 40 acres, I 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 haven't always been good communication with somebody you're trying to work out and maybe even surfacing of these ideas that are hard to talk about, like should we trust pharma companies? I know a lot of people that work for pharma, and they are doing good. 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. Just because a bunch of people do it, and it's not always true that the subtle best interest of a corporation is the same as the best interest of an individual. So we have to surface those things exist. It's not like we have to say that it's right or wrong or whatever, but at some point, these kind of perverse incentives exist. And I wonder why 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 come in with melanoma, even though there's only a 50% chance you're going to be cured, which is great, it used to be zero with these drugs, 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. All they'll get, if they develop a test that shows who is and who isn't going to respond, they'll cut their market in half. So I don't think any pharma executives are out there going, "Eh." But there's no positive incentive to do that study, to study those things. And I think it's kind of true in some of these other drugs that we've brought forward, some of which are better and worse than others. We get told that this is going to be good for us, and we should take it. And again, you're getting to the American kind of mentality, which is to say, well, at some point, if you fool me twice or I'm not going to believe it, and I might not believe it against an entire spectrum of things called science. And the problem is that there's people like you and me that are trying to actually do, and most of us, I'd say 99.9% of us, are working our asses off to figure things out and discover stuff that's important for mankind. And then you have these sort of issues that arise and you're like, well, then should you distrust, as a species, should you distrust the entire class of science? Probably not.

Andrew Huberman:
Right.

Dr. Max Krummel:
You just need to maybe make it so that knowledge is freer and knowledge is better communicated and that you do watch out for those situations where there should be... And maybe vaccines are one, we just need to do something sensible like what you're describing and just to do a study and say, "Let's do that study and 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, via you can have this regimen or the old regimen or the new regimen. And again, I may be speaking out. 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. But to the extent that you're coming out, could we make it less... Let's do it and let's just do it. Let's do that experiment. But I don't see that, that's one of the things that's not happening right now is that nobody's actually describing an experiment.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
What would be the experiment?

Andrew Huberman:
Yeah. Well, the discussions haven't happened, and 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. And if anyone cuts a clip, I will be the first to dive in there and say, "This is taken out of context." But, to any people, colleagues or otherwise, that would say, "Hey, actually, this is the wrong stance. You don't want to be talking about nuance in a time when there's so much threat to traditional medicine and vaccines," et cetera. I will say this, the idea that you need to push back with just a fire hose of do this or else-

Dr. Max Krummel:
Mm.

Andrew Huberman:
... did not work.

Dr. Max Krummel:
Mm.

Andrew Huberman:
The pandemic proved that.

Dr. Max Krummel:
Mm.

Andrew Huberman:
That in fact, I think one of the biggest mistakes was to have one individual as opposed to a panel of people with more nuance communicating public health information at that time.

Dr. Max Krummel:
Mm.

Andrew Huberman:
Any person, scientist, doctor or otherwise, who thinks that the way to convince people to change their behavior around vaccines or anything else is to just ram it down the public's throat and say, "Or else you're whatever, you're political this or you're a fascist," or whatever. Okay? That is proven to be wrong.

Dr. Max Krummel:
Mm.

Andrew Huberman:
And the path forward is really this kind of conversation.

Dr. Max Krummel:
Mm.

Andrew Huberman:
It's highly educated people like yourself, educated in the immune system, who understand this, who have children, who've made certain choices, saying, "Yes, and I can understand why you would be considering the following questions, and we should do a study."

Dr. Max Krummel:
Mm.

Andrew Huberman:
And in the meantime, you're not preventing anyone from getting vaccines. There's now a hunger for more nuanced conversation around these things.

Dr. Max Krummel:
Mm.

Andrew Huberman:
And I think it's the right time to have it when we're not in the throes of a pandemic.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Yet.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Yet. There's some things that are on the rise. It is scary. I'll be quite blunt, the rise in measles is scary. People say, "Well, measles, they used to have measles parties." Talk to somebody who had massive inflammation-

Dr. Max Krummel:
Mm

Andrew Huberman:
... and brain inflammation from measles. Not a pretty picture.

Dr. Max Krummel:
No.

Andrew Huberman:
Not a pretty picture.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
So I think it's great that these conversations are starting, and it won't be taken out of context.

Dr. Max Krummel:
Yeah. Well, on the vaccination front, I just wrote a little sub-cycle so about the origins of small vaccination. And I think what's lost in those stories is if you look on the internet, that's a terrible disease. The reality of what we're protecting against, it's really hard to also have the conversation without doing a little bit of reading into your history.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And I don't think the history books are pulling the wool over our eyes by saying some of these things were really horrendous.

Andrew Huberman:
Well, smallpox was dreadful.

Dr. Max Krummel:
So there's an element of that, though, that I think, that we have to make sure that the conversation focuses on what are we trying to achieve here? And sometimes that question can get lost. But I think, man, if my kid got smallpox or got measles or got mumps, and as we know, measles is not a theoretical. Again, it's certain.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
That concept is enough to say, well, there is a risk of that, and that's one where you... It's like 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, just because we haven't seen these things for a while doesn't mean that they're not still real.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And I think that's also an important, again, that's me as a parent saying, look, I did look at the history of these things, and they really are bad. And so we are defending against something, but, is there a better way to do it? Propose experiment. I think there's a, cutting off 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 will answer the question, and you say, "Well, is that the killer experiment for this thing?" Again, I think you look at the numbers, and the numbers from my, this is me as a parent looking at the numbers of the danger of bad stuff happening versus the odds of an adverse effect. They weren't all that high, but again, if you're one of the people that even if it is that, even if it is caused by a vaccine, which I don't, by the way... Can I tell you a little story?

Andrew Huberman:
Please.

Dr. Max Krummel:
Maybe you know this already, but if you want to induce autism in mice, people do it by injecting a bacterial infection into the mom when she's pregnant.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
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, in an adjuvant 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 insult will have influence on neural development, period. Is it the source of autistic children, or was it in fact that the mom had infection during pregnancy? It's not absolutely wacko to think, and you should think this as a neurobiologist, I think you'll probably agree, to think that inflammation, some of the molecules of inflammation will affect the-

Andrew Huberman:
Sure

Dr. Max Krummel:
... the cells of the brain.

Andrew Huberman:
Yeah.

Dr. Max Krummel:
In fact, one of the best experiments that I looked along these lines, it's not about autism at all, but it's about when you get a flu, you tend to feel like you want to socially isolate yourself. At least I do, and most people do, I think. They kind of want to crawl in a hole.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
It's that crawl in a hole feel. There's an experiment that was done that involved injecting gamma interferon, which is one of the things your immune system makes when it's fighting off an infection, into the bloodstream of a mouse, and then just watching it. And they become socially isolating from just the molecule that's made by the immune response during an infection.

Andrew Huberman:
Not even from being sick.

Dr. Max Krummel:
Not even being sick. They're not sick.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
They 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 the simple conclusion of that paper is, 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 as mature. So again, these ideas that there's something that... Scientists use that infection of a mom to lead to neuronal changes that lead us to be able to study autism in later mice. So there's definitely potential there. I don't know that the vaccines and all of them, or whether there's a circumstance or whether it's, again, the mom actually had a fever before and the vaccine now just triggered or it didn't, or just circumstance because you give vaccines at two years of age, which is when autism appears. There's all kinds of options, and those sort of anecdotes-

Andrew Huberman:
Mm-hmm

Dr. Max Krummel:
... of that. And I just think that that fact that the way that we study autism is by giving a pregnant female mouse an infection is sort of like, okay, that's important to know.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
That work is still ongoing by laboratories to understand autism. They want to understand the origins of it. And maybe it will not turn out to be vaccines at all. Again, we need data. And we're in this-

Andrew Huberman:
We definitely need data

Dr. Max Krummel:
... we're almost in a COVID situation. I describe the COVID situation now in retrospect as one that is data sparse. And this is why I've been trying to work on, I was telling you about this project of trying to work on the publishing problem. But it's not just the publishing problem, it's how we synthesize knowledge. That under data sparse circumstances to make decisions, I think we're not very good at that societally. 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. Those stats are solid, they're very good, and I would take that drug every time. But if it's sort of a case where you're like, "Oh, there's some things that are happening and there's some other things that are happening we don't know." You remember at the beginning of COVID, we were talking about it amongst ourselves in lab roles, and we were coming in to analyze blood, and it was sort of unsafe because we didn't know what was safe. We didn't know how it was transmitted. We didn't know anything about it. Could we get it from blood? And that kind of went on for a while, right? And this was the source of a lot of confusion that came from the medical... It was seen as confusion in that matter of fact. It's like, do you mask, do you not mask? Do you touch, do you not touch? I think that's a data sparse situation. The data that we had was sparse. It wasn't a lot of information. And so, how do you make a decision when you don't have a lot of data?

Andrew Huberman:
Well, I think that's the major argument. When there are people that will critique people saying, "Okay, your experience is anecdata, it's correlative," with regard to vaccines and autism and other issues. But then the pushback is, well, this vaccine, et cetera, was directionally guided by sparse information to begin with-

Dr. Max Krummel:
Mm

Andrew Huberman:
... 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."

Dr. Max Krummel:
Yeah.

Andrew Huberman:
But you have every right to ask your doctor.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Right? But they're not asking because they're extremists. They're not anti-vaxxers. They're asking because they love their kids-

Dr. Max Krummel:
Right

Andrew Huberman:
... 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.

Dr. Max Krummel:
Yeah. Certainly in media, some of these things get presented quite inflammatory. And again, if newspapers want to sell a newspaper, they show a plane crash.

Andrew Huberman:
Right.

Dr. Max Krummel:
So it's not happening every day, but-

Andrew Huberman:
Maybe they'll show you an airline ad in the same issue.

Dr. Max Krummel:
Well, there's that too.

Andrew Huberman:
Yeah.

Dr. Max Krummel:
I think one of the interesting things that we could get into too is that in a lot of these studies, scientists 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 orthogonal, CRISPR, checkpoint blockade, 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 drop coffee cup on the thing, that gravity pulls it down. Well, then I can learn that I can drop all kinds of things. I can make gravity work for me. It becomes a tool. And I think one of the things that is lost sometimes is that some things are not extensible. So you can imagine that if I had something that makes a cell move, that that might screw up the whole system forever. But humans and our bodies turn out to be remarkably resilient. We can go from minus 20 degrees to 110 degrees. We can not eat for a long time. All these things don't cause us to fall apart. So if we didn't have resilience, I think our species wouldn't exist because there's all these pressures and all these varieties of life under which we lead. And I think a lot of science sometimes doesn't, and 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, and then say, "This might be important for this, but I haven't shown that it's important for it." They don't say that it's important, they say it might be important, and they're trying to look for that orthogonal or that extensibility of it. And I think that's kind of important also just to go a little bit off this topic for a moment in how we think about drugging diseases as we go forward. And that is to say, we've looked for these one-and-done drugs that you take a pill, and it cures everything, forever. That's sort of fountain of youth-ish. And we found a few of those. I would say checkpoint blockade is one of those, that you can take it, and in 50% of melanomas, the tumor goes away and everything's great. But most biological systems, if you have one button to push, they're super non-resilient. A virus can exploit that button. That can cause it to collapse. And so most things are wired, like in these really complicated ways. And I think what a few of us are thinking, this is for cancer in particular, where you want to get the immune state from like, remember we had our little concept of a fuel gauge. You want to get it from one position to another position. It may not just be about a push here. You may have to push some cells that way, create some new environment that looks like development. Your cells develop through states. And you push the biological systems to reach this new state in a way that doesn't look like they're linear between low immune reactivity and high reactivity. You might have to push it in a serious way because the resiliency, the systems, even in chronic disease, but even in health, we're pretty resilient. You can stand up to a lot of stuff.

Andrew Huberman:
Can humans do that even in the context of abundant funding for basic research?

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
Can what you just described actually be tested to the point where we can develop things? And the analogy here is, I had my dad on the podcast, he's a theoretical physicist, and he explained to me that one of the most important things you learn in physics is that you can't really understand quantum mechanics using your logical brain.

Dr. Max Krummel:
Okay.

Andrew Huberman:
You need the math to prove it.

Dr. Max Krummel:
Mm.

Andrew Huberman:
He also warned whenever somebody says they understand quantum stuff, you have to ask them to demonstrate it for you.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Because people talk quantum because-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... and we make all these assumptions, they talk about quantum fields, so we think they're smart.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
But the theoretical physicists, and therefore engineers, develop all sorts of incredible theorems and real experiments, and then technologies based on all of that.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
Because the math works, not because we can conceptualize it. And I wonder, given the complexity of biological systems-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... 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.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
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, like pushing the cells this way, nudging them that way, and then drugging the outcome in a way that is beneficial but not detrimental, is this a place where machines are going to be better or at least helpful in doing these experiments?

Dr. Max Krummel:
I take the standpoint that AIs, and I think, this is back to talking to AI experts, it's really quite good at producing stuff that is in the corpus. The corpus is the knowledge that we already have. Almost by definition, when you're coming at that with something discovery, you're discovering something, it doesn't exist in the corpus. You might have hints of it there, but you still have to do experiments at some point. So if I'm going to answer 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, what would be the possible consequence of clipping this molecule's ability to touch that cell? That's now doable, but 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 the relationship between this feature of the cell and this other feature of the cell? So it's learning about it, and then it allows you to propose a bunch of experiments. But you still kind of have to choose and select which ones you're going to do. Some experiments are just really expensive. And that's where you have to have, I think, still human judgment that comes into that and say, "Am I going to spend a year studying this question, or am I going to study a little bit more and try to understand some things in a greater detail than maybe the machine learning gave me?" But it's not clear to me that anywhere right now we can say the corpus of knowledge doesn't have a bunch of examples of cures across from treatments and say, "Oh, all I need to do is match those up," which is kind of what AI does when it comes to a large language model. You query it, it looks statistically and says what are the relationships between what you queried 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 orthogonal big hit is in 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, in anything, this could be if I want to change the world. It's unlikely that any one act will do it. Also, the world is pretty, 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 effect we need to do is if we want this tumor to get cured, we need to first let it not look like it's a wound that's healing, so don't give it the power of the immune system, the positive power, and then get to the point where we can say, well, now we want it to teach the immune system to kill it. But we might not be able to do that until we kind of dissemble some of its defenses. And that's a way of, 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 they're expressing that start to look like Magellan's map of the world. That in its early phase, it only had parts, and then as you explore and you add things to it, I think when we start to think about how tissues are configured, we're starting to be able to see these really complicated states where the immune system is doing this, and fibroblasts, certain cells are doing this, and epithelial cells are doing this, and that's a- We call them archetypes. They're like a way that biology organizes itself. And to get from one to the next, we need to understand how it does it developmentally. That would be a really nice thing to follow. And then we need to give those cues in order.

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
And that's where I was coming back, when you were talking about peptides earlier, I was saying, well, some of these drugs may well work, but I might imagine that they might work best if given in the right sequence, and the time, and the place, and that that's when you really want to hammer to get the system to go to that. But then it might be connected to another one. And we all want to find a one thing that like, the fountain of youth, the thing that cures a disease. And it's been forever that we've looked for single hits, one and done. But it may be a collection. And this is how I live my life for health, too. There's collection of behaviors, and food you eat, and sleep you get, and-

Andrew Huberman:
Mm-hmm

Dr. Max Krummel:
... all these things create, and partners, the loves of your life, the friends you have, they're all part of, I think, this. And that's getting a little away from immunology, obviously, but it-

Andrew Huberman:
No, but not-

Dr. Max Krummel:
This is an analogy

Andrew Huberman:
... when we think about the insula, not so much.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
A good friend of mine who's a physician in the Bay Area says, "Better living through chemistry still requires better living."

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Which I love because it says you should never abandon as much as one can, the foundational stuff of sleep, exercise, nutrition-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... circadian rhythm, light-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... social connection, stress mitigation, and on and on.

Dr. Max Krummel:
Right.

Andrew Huberman:
Could I ask you a couple of additional questions about the immune system?

Dr. Max Krummel:
Yeah, please.

Andrew Huberman:
Before we wrap, because I know many people are curious about autoimmune issues.

Dr. Max Krummel:
Hmm.

Andrew Huberman:
More and more, I hear about, I don't know if it's chronic fatigue considered an autoimmune issue by most. A lot of people seem to have chronic fatigue. There was a debate, does it really exist? For someone who believes they have it, it absolutely exists.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
They're tired. I believe them.

Dr. Max Krummel:
Mm-hmm.

Andrew Huberman:
I know someone who had a myalgia-

Dr. Max Krummel:
Hmm

Andrew Huberman:
... recently. Psoriasis is something that I maybe have known to be now autoimmune.

Dr. Max Krummel:
Hmm.

Andrew Huberman:
Asthma.

Dr. Max Krummel:
Hmm.

Andrew Huberman:
These are interesting conditions, not all of them life-threatening-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... but some of them cause a lot of discomfort.

Dr. Max Krummel:
Hmm.

Andrew Huberman:
What is known about the formation of autoimmune conditions, either inheritance, lifestyle factors? And then what excites you about some of the newer treatments that might be available or are currently available-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... for those and other things? It's a big question, but...

Dr. Max Krummel:
Yeah, it'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. And again, we call those archetypes. The immune system is trying to do a certain kind of thing. It's genetically and through history, it's wired to work with cells in certain ways. And I think if you look at autoimmunities, there's a view of them that they represent a misplaced immune system that 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 in lupus, there's a familial mutation in 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, they're called autoantibodies. That's where the B cells, we've talked a lot about T cells, but B cells are the ones that make antibodies, and they're the ones who you try to jazz up for COVID vaccines. Those can be overactive, and they can be genetically overactive. And 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 interesting, to some extent, is something that you'd alluded to with asthma, where asthma was one of these things that historically would be called an allergy, and it still is an allergy, in where you have inciting things that are grass, pollen, these sorts of things. But in a lot of these settings, the concept that that is coming in part and parcel with the immune system recognizing self 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 actually work to be done in a lot of these areas where you say, "What is the immune system up to?" Like 10 years ago, we might have just said, I might have taken a lung of a asthmatic patient who died and cut it and look at it in a microscope and say, "Oh, yeah, I can really see that there's thickening of the airways and that's why they couldn't breathe." 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? No, there's actually definitely seven or eight.

Andrew Huberman:
Wow.

Dr. Max Krummel:
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. They 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 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, difficulty breathing, but it has many different sort of configurations. And I guess I would just say that in a lot of this domain, we have a study right now that's looking at across a bunch of autoimmunities to figure out whether they have things in common with each other. And psoriasis is one where you start to see variations, and lupus for sure, and inflammatory bowel disease. And you know this in the clinic because inflammatory bowel disease, you asked 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 in some people with IBD, it's just really bad diarrhea. It manifests and very painful. So there starts to be classes of patients that have responses to these things. Those drugs are exciting because they say you can modulate this. But a little bit like the checkpoint drugs, we don't really understand why one works in one patient and one doesn't. And inflammatory bowel disease as an autoimmunity is pretty tricky too, because people will respond to a drug for a while and then they'll stop.

Andrew Huberman:
Mm.

Dr. Max Krummel:
And then the doctors just have to do this like whack-a-mole thing where they try one and it doesn't work, so they try the next and it doesn't work.

Andrew Huberman:
Sounds like psychiatry.

Dr. Max Krummel:
It does. Yeah, there's a lot. It sounds like a-

Andrew Huberman:
No disrespect to the psychiatrist.

Dr. Max Krummel:
Psychiatrist, no. But you're trying-

Andrew Huberman:
They have a hard job, right?

Dr. Max Krummel:
Right.

Andrew Huberman:
I mean, drugs will work for a while, then they don't work.

Dr. Max Krummel:
Don't work.

Andrew Huberman:
Side effects crop up that never existed before. It's a tough one.

Dr. Max Krummel:
Yeah, agreed. So yeah, autoimmunity is a real thing. It has, 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 clear 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 immune systems is going to be different. You just got a different football team out there playing, or they're running a different play.

Andrew Huberman:
If somebody has a mild autoimmune condition, like let's say mild psoriasis-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... does that... I've read, but that doesn't necessarily mean anything.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
I've read that that might confer, because it's autoimmune, that might confer them with a bit better viral and bacterial infection resistance. So, there's a trade-off there. Like okay, so scalps, the cells are like sloughing off and I think it's Interleukin-17 or something now-

Dr. Max Krummel:
Mm-hmm

Andrew Huberman:
... like the treatment. They have some good shampoos for this or-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... but-

Dr. Max Krummel:
And it's anti-Interleukin-17.

Andrew Huberman:
And anti-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... Interleukin-17, but that individual is maybe better at fighting out other infections. So, given there's an anti-Interleukin-17 treatment that works-

Dr. Max Krummel:
Yeah

Andrew Huberman:
... cool. Like no flaky, itchy scalp, and yet you're more resistant to infection.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
So you could see how it's adaptive in the modern context. And now severe psoriasis can be very disruptive for people.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
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.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
It's not always the case that it's there to give us asthma or-

Dr. Max Krummel:
Well, a lot of-

Andrew Huberman:
... flaky scalp.

Dr. Max Krummel:
You know, we could talk about there's a lot of disease states, the argument for why we would ever have a sickle cell gene, this is the one that causes people to have hemophilia, and it's a lot of sub-Saharan African gene, people from that origin have this, is that it's actually defensive against malaria, it seems to be the case. So having that, I think this is 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 maybe a viral infection at the cost of having things like psoriasis pop up or various other autoimmunities, is the only way that 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 sucrose, 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. But there's almost always some just losers that are dividing slowly. And for whatever reason, the system always springs those off. You're like, "Why would you do that? Why wouldn't just the winners win?" But if you take a little bit of that culture and you put it into galactose, which is a milk sugar, often the ones that were winners don't win anymore, and it's from the loser pool that the new ones emerge.

Andrew Huberman:
Mm.

Dr. Max Krummel:
And this is a case of a crowd fitness that comes from diversity of genes. And so some of these things that make some of us susceptible to disease are also, as you're pointing out, in other situations, going to be quite good for you. And that seems unfair at the time, that you have these kind of bad genes, but a different day you would've been happy, right?

Andrew Huberman:
Mm-hmm.

Dr. Max Krummel:
So I think there's a lot to be said. And that's also why a lot of the things that we look at anecdotally, somebody takes a supplement and it works for them. I don't know how much you know about this literature, but the differences in your and mine vitamin requirements is going to be quite profound because the metabolic enzymes we have for the vitamins that we might take in are going to be different between us. And so these FDA limits, these numbers, are averages. Some people may need five times that amount of vitamin X, other people may need a fifth. And that's-

Andrew Huberman:
No, I think this is super critical. The supplement world is kind of like scattershot. While I appreciate the rational grounding in all of it, I think a thread throughout today's conversation, I think that I picked up on the fact that we covered things like peptides and things like that, and I'm not certain about the peptide question across the board. It's clear some are beneficial. It's clear some are still experimental. I'm just a big fan of more data.

Dr. Max Krummel:
Mm.

Andrew Huberman:
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.

Dr. Max Krummel:
Oh, thanks.

Andrew Huberman:
Part of the reason we invited you here today is to learn about the immune system, and we barely talked about cancer, I realize. We're going to have to get you back to talk about that, but you've done an amazing job of educating us on the immune system.

Dr. Max Krummel:
Oh, thanks.

Andrew Huberman:
I really want to thank you-

Dr. Max Krummel:
Thanks

Andrew Huberman:
... and speak on behalf of many, many people for that. Never before has somebody presented in the ways that you have. And, as somebody who thinks in analogy and likes to teach in analogy, I really appreciate that -

Dr. Max Krummel:
Thanks

Andrew Huberman:
... that stance. What inspired you to get into-

Dr. Max Krummel:
Mm

Andrew Huberman:
... 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?

Dr. Max Krummel:
Yeah. Well, thank you for the call-out. It's something I've been trying to work on for about 10 years, and 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 in society. And there were many. There's many. We've surfaced a few of them today. But I think something that you guys are working on is the capacity for everyone else to think as a scientist. You can ask yourself, "Oh, why don't people agree with this data that you show and take the action that seems logical?" But then you present it in such a way that they can't... Two things are important about it. I think one of them is if you present the information in a format that isn't familiar, you're not going to be able to teach anybody anything about what's important. But the other thing is that, we spent some time talking about this, and we consulted some other folks that are in science comms, and we realized the other thing is that if you say you're a scientist, it's not a neutral statement. Science has a history, and history is stronger than science, actually. So the history, there's hesitancy among African American, for example, to take drugs because of things, the history of Tuskegee, which is like 80 years ago. However long ago, 60 years ago. It's not in their lifetime, many of these people. And so part of the realization was maybe part of what we really should be doing as scientists is part of our job should be to figure out how we relate to other humans. And there's a painting of this in obviously the media, and things help this happen because it makes it interesting to have a nerdy scientist. And you can be a nerdy scientist. I heard you. But also, you're a human. You're a human being. There's even foibles to loves and hates and-

Andrew Huberman:
Certainly foibles. I have plenty of those.

Dr. Max Krummel:
We can get in that after this podcast. But this concept of if we want to relate, if we want to have impact of the work you do, if you want it to be relevant, at some point, you have to... Science as a field needs to make sure that it doesn't ostracize itself from people. And I think one of the issues there, I'll just use the word ostracize, is separate, is this concept that we speak in our vocabulary that just gets very precise, and we forget that if you hear a foreign language, and you hear one word that you don't recognize, it throws you off for a few sentences. And next thing you know, you don't know what people are talking about. And I think that concept that, 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 as really, really important to the impact that you can have with your science and that science can have in terms of teaching people what we could do better, which I think we all want to do. But if you end up thinking that science is a distrusted, weird collection of people that have different motivations and designs, then you've lost. The potential for it to do good is gone. So the Substack came about it because I was like, well, I need to write as a person a little bit more and 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 than the... 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, and they're not winning. And so-

Andrew Huberman:
Well put. Yeah.

Dr. Max Krummel:
So I feel like that's an important part of this, that again, it's not the glory story always. Some of the best-selling books about science are the wins. But it might be more relatable at some point to get all of it. So that's 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 scratch the surface today. So anyway, thanks for calling that. I've been-

Andrew Huberman:
Yeah

Dr. Max Krummel:
... working on it for a bit.

Andrew Huberman:
Well, I hope you continue to, and thank you so much for the work you've been doing in your laboratory and all the people in your laboratory doing-

Dr. Max Krummel:
Yes

Andrew Huberman:
... that work.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
Because now you're the one calling the shots while other people do experiments.

Dr. Max Krummel:
Yeah.

Andrew Huberman:
But for your advocacy for science and public education, it's huge. We need more people like you, but you've certainly put your own unique signature on it, and the Substack reflects that. It's an incredibly interesting set of reads, and people will really learn. So that's essential, especially in this day and age, but even not in this day and age, science is just really cool, and with all the meaningless drivel out there, it's nice to go to a place like your 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. It'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.

Dr. Max Krummel:
Yeah. Well, same here. Thanks so much.

Andrew Huberman:
Thank you for joining me for today's discussion with Dr. Max Krummel. 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 questions for me or comments about the podcast or guests or topics that you'd like me to consider for the Huberman Lab podcast, please put those in the comments section on YouTube. I do read all the comments. For those of you that haven't heard, I have a new book coming out. It's my very first book. It's entitled "Protocols: An Operating Manual for the Human Body." This is a book that I've been working on for more than five years, and that's based on more than 30 years of research and experience. And it covers protocols for everything from sleep to exercise to stress control, protocols related to focus and motivation, and of course, I provide the scientific substantiation for the protocols that are included. The book is now available by presale at protocolsbook.com. There you can find links to various vendors. You can pick the one that you like best. Again, the book is called "Protocols: An Operating Manual for the Human Body." And if you're not already following me on social media, I am hubermanlab on all social media platforms. So that's Instagram, X, Threads, Facebook, and LinkedIn. And on all those platforms, I discuss science and science-related tools, some of which overlaps with the content of the Huberman Lab podcast, but much of which is distinct from the information on the Huberman Lab podcast. Again, it's hubermanlab on all social media platforms. And if you haven't already subscribed to our Neural Network Newsletter, the Neural Network Newsletter is a zero-cost monthly newsletter that includes podcast summaries as well as what we call protocols in the form of one to three-page PDFs that cover everything from how to optimize your sleep, how to optimize dopamine, deliberate cold exposure. We have a foundational fitness protocol that covers cardiovascular training and resistance training. All of that is available completely zero cost. You simply go to hubermanlab.com, go to the Menu tab in the top right corner, scroll down to Newsletter, and enter your email. And I should emphasize that we do not share your email with anybody. Thank you once again for joining me for today's discussion with Dr. Max Krummel. And last but certainly not least, thank you for your interest in science.