Speaker 1There's a widely accepted hypothesis that mitochondria with excess energy leads to problems. Many people that are listening have probably heard of reactive oxygen species. This is forms of oxygen that become reactive and end up spinning out and damaging proteins and nucleic acids. And I think it is widely accepted that one of the contributors to that is mitochondria that have too much energy. Basically, the form that energy takes when it's extracted from the food we eat and before it's converted to ATP is powering the mitochondria. And when that mitochondria is overpowered, that leads to a state that is very susceptible to generation of these reactive species that end up damaging our genome, creating mutations and damaging proteins and creating many of the problems that we see. Welcome to the Huberman Lab Podcast, where we discuss science
Speaker 2and 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. Jared Rutter. Dr. Jared Rutter is a professor of biochemistry at University of Utah and an investigator with the Howard Hughes Medical Institute. He is one of the world's top experts in the biology of mitochondria and metabolism. Mitochondria are known as the powerhouse of the cell. But as you'll learn today, they do far more than just power our cells. They also determine how much energy goes into making new cells to making sure that cells stay healthy and to fighting off disease. Today's conversation explains how mitochondria do that and clarifies what your metabolism really is. And in doing so, you will learn that you don't have one metabolism. Your metabolism, as it's called, is actually a reflection of the constellation of all the metabolisms of all the cells in your body. So today's conversation will teach you the real biology of mitochondria, and it will provide a framework for you to make better decisions on the behalf of your health. So what follows is a conversation about mitochondria and metabolism, unlike any that you've heard from one of the world's premier experts in this topic. 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. Jared Rutter. Dr. Jared Rutter, welcome. Thank you. Thanks for having me on. I have many questions about metabolism, mitochondria, and I know many people do as well. Most people hear the word metabolism and they think calories in, calories out. They hear the word mitochondria and they probably think the powerhouse of the cell. And that's all great. People are becoming more educated about cells and their bits and pieces and what they do. You have a very different perspective. That is very important, I believe, for people to understand. Maybe we could start off by talking about how the metabolism of any one cell in our body relates to what we call our metabolism, the collective metabolism of all those cells. And as you go, if you could take any liberties you want to tell us what we probably don't know about the quote-unquote powerhouses of the cell.
Speaker 1You know, when we think about metabolism, as you say, I think all of us think about metabolism in terms of our body's metabolism. Our metabolic rate, as you say, calories in, calories out. What that is really, our body's metabolism is basically the sum total of what we ingest, you know, what we eat, what we drink, what we breathe. That enters our body and gets processed. And the results of that processing are individual molecules, amino acids and sugars and so forth that then distribute throughout the body, go into individual cells. And enter this process that we call metabolism, what we call cellular metabolism. And I think it's reasonable to think of cellular metabolism as almost like a map. There's an entry point, a molecule of glucose, a sugar comes into a cell and that sugar can be chemically modified in a variety of ways to fulfill the needs of that cell. And then that cell does whatever it needs to do with the molecules it takes in to fulfill its particular functions. And then that leads to the release of waste products that we eliminate from our body. And that is sort of the organismal metabolism, the metabolism of our body. And as you allude to, I think something that maybe many people don't understand is that cellular piece of it. The metabolism of our body is really the sum total of the metabolism of each one of our 30 trillion cells or so. That's really where my passions lie, are those individual cells and how they choose to take up certain nutrients, how they choose how to process them, turn them into other things, how they use them to fulfill their particular functions, and how that's regulated. The masterful coordination of each of those cells working together to allow us to be sitting here talking to one another and go out and run. whatever we do. It's a beautiful orchestration, but that happens at the level of individual cells. And I think that's one of the fascinating things that is maybe a little bit less understood.
Speaker 2If we were to just take the single cell view for a moment, and I know that aging is in a, like your specific area of interest, but one thing that's always intrigued me because my postdoc advisor once came down the hall and said, why do I have so much less energy than I used to? And he had a ton of energy. So I wonder what he used to be like. But it's a great question. He used to do this every once in a while. Just ask these very basic questions that no one else on our halls at Stanford could really answer. Why does a kid have so much energy? And when we're older, we don't. People say, well, people are moving less. The tissues are wearing out. But at the level of energy production, are we aware as biologists at this point in history as to why a young cell, it could be muscle cell, it could be neuron, whatever, versus an older version of that cell, why it either produces less energy, I don't know if it does, I'm guessing it might, but why the whole body just seems to have less
Speaker 1get up and go? Do we have an answer for that? I think we have a partial answer for that. I think that's definitely a frontier of science is trying to understand exactly what goes wrong during aging. There's many aspects to it. As you alluded to, one of my passions also is the mitochondria. And I think it's almost... universally the case that mitochondria become less energized, less effective, let's say, as we age. And the reasons for that are to some extent clear, but I think largely unclear. But that is definitely a feature of the aging process. There is this sort of aspect of accumulation of damage. Living in the world we live in, as I alluded to before, this orchestration of metabolism that happens through the aging process, there's a lot of damage that happens through the aging process. That's hard. It's expensive. And it's expensive not only in terms of what we need to eat to fuel it, but it's expensive in terms of the damage that can come as a side effect of that. And the accumulation of that damage over time is certainly correlated strongly with aging. And I think there's some really nice evidence in models where we can do genetics in animal models that suggest that that accumulation of damage is a big part of the aging process. And it's a huge area of interest in the field is trying to understand how you can decrease the onset of damage, how you can reverse damage that comes. One thing that I like about how you ask that question is thinking about that in the context of the cell, which again, I don't think we tend to think of aging as a cellular phenomenon, but I think fundamentally it almost has to be. We are made up of cells and the processes that lead to aging are the accumulation of processes that happen at the level of individual cells. And I think that's a huge area of interest in the field. And I think that's a huge area of interest in the field is trying to understand how you can decrease the onset of damage. And I think that's a huge area of interest in the field is trying to understand how you can decrease the I think in a way we're at the precipice of understanding a lot of this because of the tools that we are starting to have access to that will help us better understand cause and effect and the specific molecular features of the aging process.
Speaker 2Let's talk about mitochondria. Perhaps surprisingly, I'm going to ask you why you study them with the caveat that they are incredibly interesting. They are involved in energy production and metabolism. But what specifically drew you to mitochondria versus all the other things that you studied? What specifically drew you to mitochondria versus all the other pieces of cells or parts of the body or organs that you could have worked on? Why the mitochondria? What's so sticky about those as a place to, I mean, you devote a significant fraction of your life to them.
Speaker 1Yeah, it's an area of cell biology, an area of sort of the details of how life works. One of these things that is, in my view, just a brilliant example of taking chemistry of incredible complexity and making it work. Yeah, it's an area of cell biology, an area of sort of the details of how life works. One of these things that is, in my view, just a brilliant example of taking chemistry of incredible complexity and making it work.
Speaker 2And then that bacterium became part of our stable genome going forward. It went into what we call the germ line and therefore was propagated from parents to kids. And so now mitochondria live in us, but they didn't start off living in us. That's right. And we hear that about the gut microbiome. Like we have these trillions of bacteria that live in us and we colonize and we can recolonize, take antibiotics, then you need to replenish, eat your yogurt and so on. But the fact that the mitochondria made it stably into our genome and are transmitted from one generation to the next, we think of them as us. But you're saying there is solid evidence that they came from outside of humans.
Speaker 1I think that's the only model that I think any of us as scientists have any good reason to believe. And, you know, that's fascinating history, right? That there was a bacteria in another cell that got together and together that combination could do things that any one of either of them on their own could not do. And that they work together in some way. To- Yeah. Enable the evolution of complex life. You know, eukaryotes, which are the type of cell that resulted from that combined situation that we were just talking about. These are all the organisms that we see around us. Plants, animals, fungi even, are all the result of these two cells getting together and making peace, so to speak, and teaming up to make this synergistic cell.
Speaker 2Is it synergistic? Forgive me for interrupting. Yeah. When I think about viruses, I think viruses have their own sort of intelligence. They kind of, they hijack the genomes of cells and they either kill those cells or if they're really smart, they keep them, those cells alive and use those cells to continue to live and then propagate through like the behavior of an animal, like the rabies virus, like, oh, let's get this animal aggressive so that it bites. And then, I mean, viruses don't think, but they have an intelligence. Do we know that the mitochondria were benefiting the cells and the cells were benefiting the mitochondria or would have this been a takeover by the mitochondria?
Speaker 1I mean, this is a bit of a philosophical question. Of course, we don't have a record of what exactly happened when and who benefited in real time. But one thing we do know is all of complex life resulted from cells that underwent that event. One time or multiple times, but all of complex life evolved from that. And I think that tells us that more than likely, complex life could not result from a bacterium on its own. Or the archaea, the cell that became the host for that bacteria. So I think you can make a compelling argument that this was beneficial. And one reason it was beneficial because it enabled a form of metabolism that wasn't possible before and enabled now a more complex cell to be able to do things metabolically, to be more metabolically efficient and diversified, that it could enable, you know, again, complex life to evolve. Totally. Totally fascinating history. But I think, as you alluded to, also has very interesting implications for life today.
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Speaker 1The main genome of the cell, the cellular genome, still... Yeah. DNA contained typically in the nucleus of the cell. Mitochondria exist in the cytosol outside the nucleus. One of the interesting things about mitochondria, which I think is totally fascinating and has really interesting disease implications and worthy of talking about, we may or may not come back to it, is that mitochondria have their own separate genome that is sort of a relic of the bacterium that they are the descendants of. It's in a circle like the bacterial genome, which is the genomes of the microorganisms. Whereas the nuclear genome of a eukaryotic cell is linear chromosomes. And that genome performs very essential functions, encodes very important proteins that enable our mitochondria to function as the powerhouse of the cell, which we know them to be, to enable the extraction of usable energy from the food that we eat. So, as you alluded to, those cytoplasmic mitochondria somehow make it from generation to generation, and one of the interesting features of them being cytoplasmic is they're completely inherited from the mom, from the egg. Because, as you know, when the sperm invades the egg, the genome from the sperm gets into the egg, fertilizes it. The cytoplasm of the sperm does not. So, the mitochondrial genome of you came completely from your mother. Mine came completely from my mother. And, again, that has interesting implications for the inheritance of diseases that are mitochondrial in origin. But that's sort of how we think it works. It basically propagates from the egg upon fertilization, then it gets distributed to all the cells, including the germline that that fertilized embryo will have, and then gets passed on to the next generation in the same way.
Speaker 2Ratcheting toward the actual functioning of mitochondria, you gave a beautiful picture of the mitochondria not, not in the nucleus of the cell, but in the cytoplasm. So, still inside the cell. And most people probably remember from their high school biology, a picture of a cell always looks round. I'm guessing you're going to tell us that the mitochondria can be distributed lots of places in the cell because a lot of cells aren't round. A lot of them look hairy or they have long extensions like neurons. Is it fair to say that you can find mitochondria everywhere in a cell? So, no matter what shape it is, it's got mitochondria everywhere. And if so, what is the importance of having mitochondria distributed? What is the importance of having mitochondria distributed spatially through the cell? So, maybe we go, so that people know where we're going. We'll talk about the spatial distribution, because it turns out that's very important. We'll talk about the functioning, and then I want to talk about time as a factor. And that can be a little bit abstract for people, so we'll come to that.
Speaker 1Yeah, spatially, you know, I, one of my scientist colleagues might call me on this, but to mine all, I can't think of a place that exists in cells where there aren't mitochondria. And I think, as you alluded to, it's a little bit dangerous for me to talk about that. I'm a neuroscientist. I am not a neuroscientist. But one of the brilliant bodies of work that's been done on mitochondria has been done in neurons. It's fascinating, these neurons that have one-meter-long projections. And mitochondria transit from the cell body down those projections. And as best we can tell, those mitochondria play essential roles at the ends of those projections, typically being able to generate, again, usable energy. extracting the energy from the food that we eat empowering the neurotransmission, the functions of those nerve terminals. And I think that's true of virtually every cell in our body. The extraction of energy and turning it into a usable form, typically in the form of ATP, adenosine triphosphate, obviously that is the energy currency that's used by almost every cell in our body. And that is a key function of mitochondria. We'll probably come to functions of mitochondria that are outside of just extracting energy, but that is a critical function of mitochondria. And that ATP is needed in virtually every place of every cell. And by having local production, that makes it more efficient. So I think spatial distribution is a key part of that. It's fascinating. There's been beautiful work that's shown that when a cell is crawling, as cells sometimes do, like an immune cell that sees something it's chasing, there will be a distribution of mitochondria. Towards that leading edge of the cell, which is very energetically expensive to crawl for a cell. It requires a lot of ATP. And mitochondria will congregate at that leading edge where that ATP is being consumed to make ATP right there so it can be used. I think it's a fascinating example of that local demand for energy.
Speaker 2I'm asking some high-level questions, I realize, but is there any reason to believe that a given mitochondria knows what cells are doing? I'm asking some high-level questions, I realize, but is there any reason to believe that a given mitochondria knows what cell it belongs to? I'm asking some high-level questions, I realize, but is there any reason to believe that a given mitochondria knows what cell it belongs to? Are they different? Are the mitochondria in one cell type so very different than the mitochondria in another cell type? And are the mitochondria between, let's say, a neuron of the eye? Let's get out of it, since you're saying you don't want to talk neurons as a per se. We can do it. Two adjacent skin cells. They're both skin cells. They have mitochondria in them. But do they know which cell they belong to? And do your mitochondria, I'm guessing because they came from your mom's genome, they know that they're different? They're different than my mitochondria, but how much identity do they have?
Speaker 1I would say this is a topic that is at the frontier of what we know. You're asking some questions that are right at the edge of our current knowledge. Yeah, mitochondria are different. To a first approximation, you could say that virtually every cell in our body has slightly different mitochondria that are particularly suited to the demands of that cell. A heart muscle cell, a cardiomyocyte. That cell... Kind of has one job, and that's to contract every second of every minute of every hour of every day for our entire life. And when it coordinates that contraction with the other cells in the heart, that enables our heart to beat. That's what its job is.
Speaker 2Is there any turnover of those cells? We know neurons don't tend to turn over. Very little.
Speaker 1Very little.
Speaker 2Well, that's reassuring. Very, very little.
Speaker 1I'm glad to hear that. You can imagine that it would be hard to replace that in real time, right? That's a... I'm a hockey fan, and that's a change-on-the-fly scenario of biblical proportions. So those cardiomyocytes, their mitochondria is wired to consume whatever it has available and make ATP, because that ATP is going to be incredibly important to enable that contraction of that cell and the beating of the heart. Mitochondria in other cells, for example, like cells that line, that are the stem cells that enable our intestinal lining. To be turned over every five to seven days, which is amazing, by the way.
Speaker 2Your whole gut.
Speaker 1Your whole gut is turning over every five to seven days. The lining of that, of your gut. That is wild. It is amazing. Those stem cells, ATP is not the major demand of those cells. They need to completely duplicate themselves constantly, every day or less. So their metabolic process... The metabolic program is very different from a cardiomyocyte, which just needs to make ATP to a first approximation. They need to make a whole new cell. So we talked about the metabolism of the organism. The metabolism of those cells is very complex because it needs to replicate all the DNA, duplicate it to go into a new cell, duplicate all the proteins, duplicate all the membranes, the lipids, and that needs to happen rapidly. And so... That metabolic wiring is completely different. And again, the mitochondria are fundamental to that. So those mitochondria are wired in a way that enable them to produce the biomass that's required to make a new cell, quite different from the mitochondria of a cardiomyocyte. And that distinction plays out in virtually all cells in our body, right? Every one of our cells has some particular purpose, some particular function that it serves for the body. And the demands of the mitochondria, therefore, of that cell, are different depending on the unique functions and demands of that cell. And so it's a fascinating topic, this diversification of mitochondria. I think, again, that's something that we're learning about. One of the developments that's really been happening over the last few years, very much a frontier field, is you might imagine a cell that has a complex set of demands. There's actually evidence. Most prominently... Most prominently published recently by Craig Thompson at Sloan Kettering, that showed that in one cell, you can have two different kinds of mitochondria that have two different functions. And they're distinct in one cell.
Speaker 2What's each of them doing?
Speaker 1Yeah. One of them tends to be more biosynthetic, maybe producing biomass, and one of them tends to be more energy extracting and producing ATP. That's an overly simplified, but generally accurate way of thinking about it. It really emphasizes this unique function. It's a very complex function of mitochondria that can be adapted, again, for the needs of the cell.
Speaker 2Okay. So I eat some food, and that food's absorbed, and I get glucose circulating in my bloodstream. I've got some stored energy in the form of glycogen, et cetera. And I'm curious, how greedy are the different mitochondria? Is the name of the game that every cell is trying to get as much energy as it can to produce as much ATP as possible? Or are they communicating, and is energy being allocated in some way that's a little bit more democratic? Yeah. That's one question. And then framed within that, I could imagine two scenarios. One non-mutually exclusive, where the vasculature just distributes the glucose very well to everything. So every cell gets access to some of this glucose, and then is just greedily trying to make as much ATP as possible, and the whole system works beautifully. I could also imagine a situation where there's some shuttling to important structures like the brain. Right. You know what I mean? Right. There's some prioritization of organs. I'm talking about under non-stressful conditions. So yes, how is energy allocated to cells, and then how are cells divvying up the goods? Yeah.
Speaker 1It's a brilliant question and a fascinating area of physiology. As you allude to, when we eat, our digestive system starts extracting the constituents of what we eat, again, sugars, amino acids, fats from that food, that then triggers signals of different kinds. T1 being one, insulin being another. Those signals then are hormones. They get secreted and they go to many cells throughout the body, and that tells each individual cell we just ate. And the implications of that are different from each cell. Some cells don't care. Some cells don't pay attention to that and they just keep on doing what they were doing. Some cells care a lot. Adipocytes, for example, these are the fat cells, the cells that make up our fat tissue. They care a great deal about that. And when they see insulin, what they do is they turn on a protein, they start making a protein that will cause glucose to be taken up into that adipocyte, that fat cell. And that glucose will then be converted through a series of chemical reactions into a fat molecule. And then that fat molecule will be stored away in a way that is very safe and enabled to be stored for potentially a very long time. And again, it's a beautiful way for the organism to coordinate. I just ate. Our energy status as an organism, as a body, is great. It's very good. So let's squirrel away some of that energy in the form of fat that can be stored in our adipocytes, again, very safely, and can be then used when we go through a period of prolonged fasting. Which doesn't happen for us all that frequently but happened for our ancestors probably much more frequently. And those adipocytes full of fat from when we ate probably kept our ancestors alive when they went through the periods of prolonged fasting. Insulin has other effects on muscle and other cells throughout the body. But again, this is the brilliance of this coordination. The response of different cells to the fed state is different depending on the needs and functions of that cell. Again, some cells don't care at all. They're going to just go about and do their business. And some cells completely rewire their function depending on the metabolic state, the fed fasted state of the organism.
Speaker 2So the picture you just described leads me to conclude that basically every cell obviously knows its job and is not greedily but is diligently fulfilling that role. Yeah. And somehow the whole thing is orchestrated so that like we work. Yeah. Which I know, I think for some people it might be like, duh. just like think about that it's crazy like the liver cell isn't really talking to the brain cell in any kind of direct way about how much glucose it has access to what you describe makes me really understand for the first time the brilliance of having this hormone signal insulin not just as a shuttle because i think most people we think like insulin sensitive most people listen to this podcast or just existed in the world today they're like oh you want to be insulin sensitive you want yourselves to recognize this signal but we've never actually talked on this podcast but what exactly that signal is we think about insulin as a shuttle yeah but the size of that signal is saying what's likely to be there and i realize has all sorts of cool implications that can prepare the cell to like oh i'm going to go to work hard now to be the little squirrel that i am of a fat cell and then scroll away as much as i can or be a brain cells like let's go i'm ready to fire action potentials if i need to yeah and some cells like the photoreceptors in the eye are just doing that yeah eyes closed they're firing eyes open well it's tricky but they're right more or less fire firing it's a not worth going into obviously but in every one of these cells mitochondria are the ones that are essentially going to drive this atp thing yeah right and that seems extremely efficient too to just have essentially one major cellular energy source so if you could walk us through what happens as glucose gets into the cell and and really what we've not done ever on this podcast and i don't think i've heard elsewhere on any podcasts maybe it's out there but is how you go from atp to actually the cell being able to perform its roles and i realize there's a lot of biochemistry there but you've worked on some really linchpin molecules in that pathway that perform very specific roles and so like maybe we could really talk about what basically gets us from atp to pyruvate which might scare some people away but you'll you'll educate us as to why it's not scary it's just super cool and why it's so important to have these signals that that aren't just like chemicals they actually mean something for the cell because for me forgive me for going a little long here but then i'll shut up i think if people can really internalize this idea that yeah like hormones go up hormones go down cortisol goes up with stress it goes down you wake up cortisol goes up melatonin when you're sleepy it's not just that it's there but that the size of the signal says a lot more than just be sleepy it's saying what once happened is different than what's happening now it sets a stage for what happens next and this is really like the verbs of biology that are harder to communicate even in video yeah so take us from glucose to atp and atp to this thing that we call energy yeah there's
Speaker 1obviously a lot to unpack there glucose is the dominant let's say carbohydrate the dominant sugar that most of our cells are consuming and when glucose is brought into a cell it goes through again a series of chemical reactions that we call glycolysis and i'm going to simplify because there's obviously sure this is the subway map of new york there's a lot of branches going all over the place that we're going to
Speaker 2we just need to go north yeah north and south which is pretty much the only direction you can go on the cell i'm not in new york i'm kidding i realize you can go across across the island yeah
Speaker 1don't insult the new yorkers yeah so glucose comes into a cell goes through a series of chemical reactions and you mentioned it gets to pyruvate that's the end point of glycolysis this set of chemical reactions and then pyruvate there's a decision that has to be made by that cell you can either take that pyruvate into the mitochondria and burn it essentially oxidize it which is essentially burning it combining it with oxygen and that is a very effective way to extract all the energy that can be extracted from that glucose via pyruvate tell us a little bit about
Speaker 2pyruvate yeah what's the best way to like conceptualize pyruvate for somebody like me
Speaker 1it's an intermediate it's a midpoint let's say from glucose glucose is a six carbon molecule a complex chemical six carbon chemical that gets again chemically modified down to this pyruvate which is as i alluded to in a way kind of a pivot point in the metabolism of that glucose and the reason why we became really fascinated with pyruvate is because of that bifurcation that happens pyruvate can either be again taken into mitochondria and that's very effective for generating atp for extracting all the energy that can be extracted and that's what cardiomyocytes for example really love to do take that everything they can from the circulation burn it make atp keep our heart pumping and again other cells on the other hand don't do that they don't need as much atp so those intestinal stem cells that i talked about that are the factory in a way that's enabling the repopulation of our gut so that's why i'm so excited to talk to you about that because i'm so excited to be talking to you about that and i'm so excited to talk to you about that and i'm so excited to talk to you about that and i'm so excited to be talking to you about that and i'm so excited to be talking to you about that and i'm so excited to be talking to you about that and i'm so excited to be talking to you about that and i'm so excited to be talking to you about that and i'm so excited to be talking to you about that and i'm so excited to be talking to you about that and i'm so excited to be talking to you about that and i'm so excited to be talking to you about that and i'm so excited to be talking to you about that and i'm so excited to be talking to you about that and i'm so excited to be talking to you about that and i've become totally fascinated with this bifurcation food can either be converted to energy or it can be converted to biomass i think that's maybe a bit overly simplistic but i think a good baseline way to think about the what we get out of the food that we eat energy or building blocks that can be used to make a new cell to repair a cell that's been damaged for a b cell an immune cell that are the ones that make antibodies making a bunch of antibodies which an activated b cell needs to do that's a lot of stuff that needs to be made that requires that b cell to have a lot of amino acids that can be turned into proteins which are antibodies are proteins and and that again that's a very important part of our immune system that keeps us protected from invaders that might otherwise kill us and so that that distinction that lands at the point of pyruvate i think is a is a super fascinating pivot point in metabolism that i think many of us are fascinated by exactly how the cell organizes itself to make the right resource allocation decisions you know every one of our cells is all every second of every day is making resource allocation decisions what does it do with the stuff that it has and and this is one that i think is really fascinating so we are probably like
Speaker 2seven i'm insulting the cell biologists but probably seven steps away from sandwich so sandwich goes in the mouth into the gut gets absorbed right curry we get glucose glucose gets into the cell we've got some important biochemistry that you know is in this uh atp generation pathway and we get to this like key node that you're describing as pyruvate and pyruvate is either going to say let's make more you called it biomass but stuff of cells yeah sort of like you have lumber arriving maybe it might be a decent enough now right you're either going to use it to build more house or you're going to burn it for heat energy great analogy um and let's look make a add a condition where you need to burn some of that lumber for heat energy to keep the construction project going exactly okay so we're at this key bifurcation this key split point is it just as metabolically demanding for a cell to use pyruvate to keep itself going like a cardiomyocyte versus making biomass or is one more costly i'm thinking again as you beautifully pointed out at the beginning about thinking about that our metabolism as a whole body as a person is is the sum total of all these these things is it equivalent in terms of like how much sandwich relatively speaking is going into maintaining us and rebuilding us what you call biomass what i'm calling building you know allocating lumber for the for the house itself versus to uh fuel the fire so to speak that's
Speaker 1hard math to do there's a lot of nuance rough percent yeah yeah i won't hold you to it yeah no i mean one way to think about that many of us are probably unfortunately aware of pet imaging right this is this is something that happens it's often used to diagnose cancer on emission tomography positron emission tomography and fdg pet which is the most common form of pet is basically you're giving cells a form of glucose that can then be visualized with this pet scan that many people are aware of and the reason we do that is because tumors take up a lot of glucose and fdg pet is fluorodeoxyglucose this is a labeled version of glucose so the reason we do fdg pet is to see the cells where in the body is taking up a lot of glucose and tumors take up a lot of glucose so fdg pet is used to diagnose cancer frequently very effectively so that is one metric for this a cancer cell is again a cell that is making a resource allocation decision all the time but in the context of that cell when it transforms into a cancer cell that resource allocation becomes very much about building more cells that's why a tumor is a tumor is because that one cell that was the first bad actor decided instead of doing the thing it was supposed to be doing decided to duplicate itself and duplicate itself again and build a cluster of cells that then become a tumor okay i have a
Speaker 2pseudo-philosophical question but it's really a scientific medical question about tumors bacteria have the opportunity to hijack genomes of cells viruses certainly probably the easiest example for people to understand is like a herpes virus like hsv-1 or something which lives on neurons, doesn't kill the neuron, which is convenient for the virus, right? Because if it killed the neuron, it too would die because the neuron is expressing that virus, it's hijacked the genome. So this earlier I was saying like viruses have their own quote unquote intelligence, like stay alive, but keep the host alive too and transmit. And in the case of rabies, it's like the most easy, it's one to conceptualize like impact areas of the brain that trigger aggression with that trigger biting. And people have speculated like, does the virus know that it's doing this? Like probably not, right? Doesn't, they're not brains, but pretty impressive level of quote unquote adaptive behavior and intelligence. I think of cancer as just a bad thing all around, right? That these cells are greedy, they're taking glucose, they're making more of themselves, it's cell turnover gone awry, tumor gets big, it starts to encroach on other tissues, metastasize, boom, you kill the host. That's not a great strategy from the perspective of the tumor. So it obviously isn't thinking about its long-term outcome in any kind of adaptive way. But has anyone ever looked at tumors in the same way that we think about viruses? Like the logic there is the same, except it seems that their goal is to kill the organism. I'm not trying to anthropomorphize about cells and cellular processes, but I think is there a potential set of answers about how to deal with tumors and think about cancer that could be borrowed from any of those other examples? - Yeah. - Or am I, am I going down the wrong path here?
Speaker 1- Yeah, it's an interesting question. You know, viruses and bacteria, similar to how you were describing viruses, some of the same principles apply to bacteria, parasitic bacteria. Viruses, as you allude to, their goal, if you do want to anthropomorphize them, their goal is to propagate, right? They are under evolutionary pressure. The way that that virus survives is to make more of itself, go infect another organism, and have that other organism make a bunch of additional viruses that will then go and infect another organism, right? That is the evolutionary game. And that's what viruses do, and they're very good at it. And you described some really interesting biology where viruses will actually affect the behavior of the host to make them better at getting into the next host.
Speaker 2- So wild. - It's amazing. - I wish we had a better language for this thing, 'cause intelligence is not really it because it's not of brains, but it's this adaptive logic.
Speaker 1- Yeah, that's a good phrase for it, adaptive logic. - Adaptive logic that enables the survival and propagation of that virus. And this is how evolution works, of course. If that virus had a mutation that made it better able to do that, that virus then would infect better, and it would get into hosts better, propagate better, and it would eventually take over the population of that virus. That is the process of evolution. And I think, again, it makes intuitive sense. You know, you asked about cancer. Cancer is awesome. It's obviously fundamentally different in one key way. If I get a virus and I come in here and we're sitting across the table and I'm hacking and whatever, and I spew across the table at you, you might get the virus, get sick, build a bunch of additional virus, and then you give it to coworkers. And that's viral propagation, which we all sadly know about. There's very little evidence that cancer is infectious.
Speaker 2- What about the Tasmanian devils?
Speaker 1You know about this, right? - No, I don't know about this.
Speaker 2- Okay, I don't know if this held up, but there was this idea for a while, someone will tell us in the comments, this is what's fun about doing this on the internet, that Tasmanian devils fight and that there's wound-induced propagation of cancers. These very disturbing, as an animal lover, very disturbing images of these cute little animals with the little teeth there, they have a viciousness to them, and they have these tumors growing at wound sites, and it turns out those are cancers. So there's somehow like fighting and wounds, and it might be viral, it might be bad, it might be bacterial, I don't know, that's outside my expertise. But there was this idea that they could transmit cancers to one another through fighting. - Interesting. - Which I thought was sad, but fascinating nonetheless. And Australia is a weird place. - Yeah, a lot of stuff happens that it doesn't have. - I mean, the world's upside down down there, so after all, no. But right, you're right. - In general. - Yeah, we don't actually think that people are catching cancers from one another.
Speaker 1- So when you think about the evolution of a cancer, the scope of that evolution is different, right? The scope of that evolution is different, right? That evolution of a cell in me is limited to me. Cancer cells undergo evolution in the exact same way. You know, if one cell in my body starts propagating, it acquires a mutation that enables it to divide and divide faster, and maybe, you know, get out from underneath the limits that are being placed upon it by the immune system and by other systems that control propagation of cells in the body, it can then divide, and divide again, and that's basically the continuous process of cancer development, is the acquisition of mutations that make that cell better able to evade the immune system, to duplicate itself, evade the problems that would come with DNA damage, which many cancers have, and to continue to make cells that survive. And that is, in a way, an evolutionary process playing out at the level of individual cells, but how that interacts with the host, is obviously different, because again, a virus has this sort of evolutionary drive to get from one organism to another, to another, to enable its propagation. Cancer isn't fueled by the same motivations, let's say, because again, as far as we're aware, that very rarely, if almost never, happens to get from one organism to another. And so, the motivations are different, but the evolutionary process is different. And so, the process underlying it, it's the same principles at play in both.
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That means I discovered it and started taking it daily, long before I even knew what a podcast was. I continue to take it and back it, here on the podcast, because it is an excellent formula, and it's now even better with the AG-1 Pro formula. For a limited time, you can get an extra 20% off your first subscription to AG-1 Pro, by going to drinkag1.com/huberman, and using the code BACK2ROUTINE, so that's with the numeral two, back, numeral two, routine. Just go to drinkag1.com/huberman. Today's episode is also brought to us by Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. One of the best ways to ensure you get a great night's sleep is to make sure that the temperature of your sleeping environment is correct. And that's because in order to fall asleep and stay deeply asleep, your body temperature actually has to drop by about one to three degrees. 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Eight Sleep ships to many countries worldwide, including Mexico and the UAE. Again, that's eightsleep.com/huberman to save up to $350. - I'll take us down one more estuary, then we are actually going to talk about mitochondria and pyruvate again, and your contributions to this critical node of where pyruvate puts its efforts, building more stuff of the cell or using energy. Anytime I have a serious cell biologist, which isn't that often on this podcast, or somebody who thinks about the pieces that make up up us, I try and ask this. I'm bothered by this one thing I heard once, which is that like, it's so easy to think about evolution. It's like, okay, we're all adaptively trying to make more of ourselves care for our young and go forward. That's like what every mammalian species does. That all makes sense until I learned about the gut microbiome from my colleague, Justin Sonnenberg. And he said, you know, every time you shake hands, like we exchange a microbiome today, and we're sharing in the air and skin. We shook hands, you see. And like, there is this one model of like all of this that's very purely biological that we are just shuttles for the microbiota and everything that we're doing, like building electric cars and holding debates and protests and sending kids to school. And all of that we think is about us, but the microbiota are just like, they've hijacked this process. And like, they're not sitting there going, this is all about them and we're just trying to spread and make sure that we continue. and maybe long after they're gone, we're just going to keep going. And I can't poke any holes in this. It's like too good a theory. I keep hoping somebody is going to tell me, at least from a purely biological perspective, that like, that's not true. But it kind of scares me. Every once in a while, I think like, maybe I'm just a bunch of microbiota. I'm a shuttle. You're just the vehicle. We're just a shuttle, but we got this brain, which is very convenient for them, right? Because it makes me want to go out and do things. And I think about failures and successes and how I want to do better and what I want to do at different stages. And like, maybe it's just all about them getting as far and wide as they can.
Speaker 1Well, unfortunately, Andrew, I'm not sure I'm going to be able to provide you the concrete proof that that's not true. It's a fascinating hypothesis. And kind of eerie, right? Yeah, very eerie. We definitely don't like to think of ourselves as anything other than the pinnacle of evolution and the reason for everything. But there's no question, to your point, the microbiome are the bacteria that live in our gut and on our skin. They're being driven by the microbiome. They're being driven by the same evolutionary pressures that we've been talking about for viruses and for us. They're trying to propagate themselves and fill the niche that they live in, fill the little chunk of the universe that they live in and do it better than their competing neighbors. And if they can do that, then their genome is going to get passed on again and again. And it's fascinating to think about the role that we play for them and they play for us. This is, I think, a phenomenon that's been known for a long time. But I think the implications of the microbiome is something that really has only been, I think, experimentally dealt with in a really serious way in the recent decade or so. And I think we're still learning about the implications, but there's no question that they're big.
Speaker 2Tell us about MPC1 and 2. I'm asking about biochemical steps in a key process of energy production and allocation. And normally when people hear acronyms, they don't understand. They kind of go, oh my goodness, like, what are we doing here? But like, I think it's so important that people understand, like, this business of us, of this metabolism, having energy, whether we're young or old, have a lot of it or less of it, healthy or dealing with cancer, like, this is a key node. And what I want to know truly is, how do you actually discover something like this? Because, and this is where I think we can really illustrate the scientific process in a way that, like, most people just don't understand. You need cells, first of all. You need to be able to find the mitochondria. You need to be able to know what's ATP and what's pyruvate. And then you know they're going to two different pathways because someone else said that, and you can observe it down a microscope. But then how do you find this thing? And then tell us what it's doing, perhaps. Or tell us what it's doing. But I think it would be very useful for people to get a picture of how this is done. Because we hear this stuff, like, oh, this molecule, and people go, oh, is there a peptide for that? Hold off. Let's think about how we come to understand these essential aspects of ourself. I think it would be so useful.
Speaker 1I appreciate you asking about that. It allows me to reminisce a little bit about the process of discovering that, which was, you know, a fun time in my career and was fueled by the brilliant people in the lab that did it. So MPC, this is a case where the acronym actually makes sense. It's the mitochondrial pyruvate carrier. So you don't have to be a scientist. We did not name it. It was named before. I'll tell you that when I tell you about the story.
Speaker 2Because I don't like acronyms that aren't informative.
Speaker 1MPC named is the carrier that enables pyruvate to get into the mitochondria. Mitochondrial pyruvate carrier. That's what it does. Sits in the mitochondria and basically provides a very specific hole in the membrane to enable pyruvate to get in so that it can then be burned by the mitochondria to, again, extract all the energy to make ATP. That's basically what it does. The history of this is really interesting. It's been known for 60 or 70 years that mitochondria can get into the mitochondria. And it's been known for 60 or 70 years that mitochondria must have a carrier to enable pyruvate to get in. But it was not identified what that protein was, how it worked. And fast forward to 2008 or 2009 or so, and our laboratory had just recently become, again, fascinated with mitochondria. I would say the motivating piece of information that convinced us to start working on mitochondria was the realization, that many of the proteins that make up mitochondria, that do the stuff that mitochondria do, we don't know what their functions are. And that suggested that this organelle, powerhouse of the cell, we kind of, I at least felt like we knew a lot about what mitochondria do. There's mysteries there that we don't have answers for. And so we started just taking some of these proteins that we know are in mitochondria, we don't know what they do, and trying to figure out what they do. And we found that there was a lot of mitochondria that do. And two of those turned out to be MPC1 and MPC2.
Speaker 2Way back when, I observed and was taught, I didn't do a ton of this, that if you want to figure out what proteins are in a cell, you get a bunch of those cells, which you can do, and then you kind of grind them up. And then you run them through a bunch of columns, like literally tubes. And those tubes have filters that either let big, less big, small, or very small things through, what we call fractionation, right? And then you kind of run them through a bunch of columns, like literally kind of test the different stuff that comes through for its ability to do something in some sort of cell or that. It's like, how did you actually find MPC2? Was it done by sort of hardcore, what we call hardcore biochemical purification? That was kind of the old way of doing it. Or, well, let me ask this. Do we know the total number of proteins in a given human heart cell? I think we know, yeah.
Speaker 1I know everything that's in a heart cell. I think we know all the proteins in a heart cell. Again, you can get into the nuances of slightly modified versions, but we know the proteins because they are encoded by our genome, right? We know the human genome. That's been sequenced. We know what that is. But we don't know everything that's expressed in a given cell. That's right. That's true. And there are some very interesting features there.
Speaker 2Can I, sorry, I'm interrupting on purpose. 20 years ago, could you say what you just said?
Speaker 1With much less confidence than I can now.
Speaker 2You'd say heart cell, but we don't actually know all the bits in it. But now we do.
Speaker 1Now I think we... We know essentially everything. Again, there's going to be subtle nuances that we don't know, but I think we know almost everything. That's good. Doesn't mean we know what all those things do. And that's maybe the frontier for the biochemistry frontier for the next generation of scientists to figure out. We don't know what they all do, but we know more or less what they all are. Knowing what they are, but not knowing what they do, motivated us to go take these two proteins that were in the mitochondria. We could make a very strong hypothesis that they were important because they were in every cell that has mitochondria down to a yeast that's a single-celled organism and plants and animals, everything that has a mitochondria has these two MPC-1 and MPC-2 proteins. And it would probably take too long to explain on this podcast the processes that we went through to try to identify the proteins that were in the mitochondria. And it would probably take too long to explain on this podcast the processes that we went through to try to identify the proteins that were in the mitochondria. And I think one of the highlights of my career, different people in my lab and in the lab of my colleague, Carl Thummel, that worked together. Carl was a fly geneticist or is a fly geneticist that used his unique skills and resources. And we were using yeast as a model system as well as human cells and triangulating all that data. And I think one of the highlights of my career, different people in my lab and in the lab of my colleague, Carl Thummel, that worked together. Carl was a fly geneticist or is a fly geneticist that used his unique skills and resources. And we were using yeast as a model system as well as human cells and triangulating all that data. And I think one of the highlights of my career, different people in my lab and in the lab of my colleague, Carl Thummel, that worked together. Carl was a fly geneticist or is a fly geneticist that used his unique skills and resources. And we were using yeast as a model system as well as human cells and triangulating all that data. And I think one of the highlights of my career, different people in my lab and in the lab of my colleague, Carl Thummel, that worked together. And I think one of the highlights of my career, different people in my lab and in the lab of my colleague, Carl Thummel, that worked together. And I think one of the highlights of my career, different people in my lab and in the lab of my colleague, Carl Thummel, that worked together. And I think one of the highlights of my career, different people in my lab and in the lab of my colleague, Carl Thummel, that worked together.
Speaker 2They consistently devote 90% of their ATP to energy utilization. and they just know 10%, like how quantitative are these pathways? Because you can't have the
Speaker 1walls fall down. It doesn't matter how much energy you produce. It's a brilliant question. And it's definitely not programmed. Like there's a spigot with a diverter valve that 90% goes this way and 10% goes that way. What actually happens, and this doesn't just happen in cardiomyocytes, it happens in every cell, is that basically the cell is measuring the outputs. Again, to anthropomorphize, and I have to say there are some scientists that hate us when we anthropomorphize cells. I'm talking about tumors having an intelligence or an adaptive logic, so it's okay. I think you've provided cover for me to do it on for cells then. Cells basically are measuring their resources all the time. I think you could make a compelling argument that every cell, almost all cells, know how much usable energy, ATP, they have all the time. And when it gets low, they will initiate a series of reactions to that, responses to that, to bring it back up. They'll turn off processes that use ATP. They'll start pulling glucose out of the circulation to make more ATP. There's this really profound response to ATP depletion. And I think that's true for many. of the end products of our metabolic map. Again, these are the products of the metabolic map are the amino acids that make proteins and the nucleotides that are required to make DNA
Speaker 2and RNA, our genome. There's a greediness to all these cells. If the fat cells are greedy, you could really see a problem. Like if we're not ingesting enough glucose, let's hold off on ketosis for a second and alternate metabolic pathways, we will touch on it. But if the fat cells are also very self-serving, then at some point are they just forced to liberate the stuff, but like ultimately fat cells just want to get bigger and bigger. But if this cardiomyocyte, it doesn't have enough glucose. And eventually it's like, it could shut down any number of things. Like you can remodel a house down to, you know, just the fireplace and a little bit of structure around it, but eventually you need the resource. So then what happens? The adipocyte liberates the energy and, and cells, everybody gets a little bit and you just hang on. So it's a famine.
Speaker 1Yeah, exactly. I mean, just as insulin tells the body, I just ate, we're good. Take that energy that's available in the form of glucose, squirrel it away, use it. There are hormones that do the opposite. Glucagon is one of them. And glucagon again, has become a little bit more popular recently because it's now being combined in some of the GLP-1, uh, uh, more, more newer GLP-1s. Drugs. Glucagon is called a fasting hormone. So glucagon in many ways does the opposite of insulin. It will go to the fat cell, bind to the fat cell, tell the fat cell to take the fat that it has squirreled away and release it. And now that can go to other cells in the body. The heart, heart is very good at consuming fatty acids that come from adipose tissue. And so, so.
Speaker 2That's good. I'm actually relieved to hear that.
Speaker 1Yeah.
Speaker 2Right. Because if, if God forbid, there's a shortage of food that lasts long enough, like that's definitely an
Speaker 1organ I don't want shutting down. Exactly. And, and most of us have fat in our fat cells and, and you could make an argument that the key destination of that fat is the heart to keep it alive. And, you know, in a normal human, I think it's estimated 70 to 80% of the energy extraction that happens in cardiomyocytes and heart muscle cells is happening from fat. You said under fasted conditions. Especially under fasted conditions, but even in fed conditions, fat is, is, is available for the heart to use and.
Speaker 2Dietary fat or fat from adipocytes?
Speaker 1Both. Whatever fat is in the circulation, the cardiomyocyte is pretty good at taking it up
Speaker 2and burning it, making ATP from it. The brain likes glucose, but it can use, maybe now we, I'm not super versed in, in the ketogenic pathways, but I know that our brain can thrive on ketones. So carbohydrates are not quote unquote essential. You know, all the ketogenic folks love to say that there's no such thing as an essential carbohydrate. That doesn't change the fact that like the preferred fuel source for most every cell is glucose. But anyway, that's a separate issue. You don't want the brain to shut down either. So if the form of energy changes, is it still, once you get to mitochondria, pyruvate, MCP and downstream, is it all the same? Is it essentially like energy is energy at that point? Or is it, or is there, are there multiple pathways depending on the fuel source?
Speaker 1Yeah. The ability of neurons to consume fatty acids is limited. I think it's traditionally been thought that it's very close to zero. I think that's being questioned now, but it's limited. As you allude to, neurons are particularly fond of consuming glucose and use that glucose to make their ATP. And, you know, that obviously puts a very stringent demand on the body to always have glucose available. Glucose is one of these things that's fascinating. The systems that we have in our body to maintain glucose, you know, diabetes is defined as high blood sugar. That is the definition, the clinical definition of diabetes, when basically our body does not adequately limit the circulating glucose. And that is destructive, damaging, but it's damaging on the, in the course of years, right? A person can live with diabetes for years before succumbing to it. If glucose is too low, you die within minutes, not seconds. And that, I think, for a few different reasons, but probably the most important one is the brain requires some amount of glucose to keep it functioning. So, you know, again, I alluded to this before, this very elaborate dance that is happening by these individual cells, taking up different nutrients out of the body. And, you know, I think that's a very important part of the brain. And I think that's a very important part of the brain. And I think that's a very important part of the brain. And neurons, again, are very adept at taking in glucose and burning it and making ATP from it. I think, again, the heart I feel like is really fascinating because it'll eat anything. It's an omnivore. Fats, glucose, lactate, ketones, amino acids, it will make ATP out of just about anything that ATP can be made out of. And again, that's important for us to enable us to live no matter just aid or not. Heart is very good at that. So I think this elaborate dance that we have going on in our body all the time between different cells, cells doing it different way, taking in different fuels and using them for their unique purposes. What is the consequence of eliminating the MCP
Speaker 2shuttle? Like if you take a mouse, you're at the University of Utah. Let's give a shout out to Mario Capecci, whose life story is amazing, who won a Nobel Prize for essentially developing what are called knockout mice. Yeah. Among other things. You can eliminate genes to test the role of a particular protein downstream of that gene. If you make a mouse that lacks these proteins, do you get a dead mouse?
Speaker 1They do not survive to birth. Yeah.
Speaker 2You can get sperm egg and somehow it can become a mouse.
Speaker 1Yeah. It'll start to develop. And then I think if I remember right, it's about 12 or 13 days of development, which is two thirds of the way from fertilization to birth of the mouse. It will start to develop. So what has been done, and obviously you're probably getting there, is because of the technologies that Mario developed and then others following after him, we can now make mice that lack the MPC only in the liver or only in the heart or only in the muscle or only in the brain. And many of these things have been done. Sorry, I should have been given credit. He
Speaker 2developed a technology that would allow for organ and cell type specific deletions or additions of genes. Forgive me, but you reminded me like in all much to him. Yeah. And many people have
Speaker 1been contributing that technology and different ways to use it for decades now. And as you might imagine, given the unique demands of different cells, the effects are different. The heart is again, very focused. Its metabolic program is focused on generating ATP. So what if we eliminate the MPC in the heart? So we have now made ATP generation from glucose less efficient. We've now cut off the ability to... Use mitochondria, at least in the conventional way. So I actually think the results of that experiment are fascinating. And this is work that has been done by a few different labs. Achmed Klunten, who's a postdoc now running his own lab at Rutgers, was the one who started this and other people have contributed. What essentially happens to that heart is that it lives and the animal lives for weeks after that, but eventually the animals die. And when you look at what they die of, they actually die. And so what happens is that they die. And so what happens is that they have a massive heart. They die of heart failure. And what has become clear as we've gone and done more sophisticated analyses of this heart and why they die, it's pretty clear that they don't die from an inability to make ATP. Because they can burn other things to make ATP. We talked about this. They can burn fats. They burn fats just fine. What they appear to die from, and I would say I'm speculating a bit here. We don't have all the answers to all the questions, but we do have the answers to all the questions, but we do have the answers to all the questions. ATP, they start making biomass. That again, we talked about that bifurcation. We've eliminated their ability to make ATP from it, at least as effectively. And instead, they make biomass, they grow. And when cardiomyocytes grow, that creates structural problems for the heart. Almost every human that succumbs to heart failure will end up with a big dilated heart that's less effective at pumping. And that's what we see in the mouse. And that maybe tells us something about the fundamental importance of this resource allocation decision. And this is obviously just in the context of cardiomyocytes. But again, that resource allocation decision is happening in every cell in our body all the time. And that's one reason why I'm fascinated with this field, is we're just starting to understand how those resource allocation decisions are made, what are the implications of making them correctly and incorrectly, and maybe even more excitingly, can we go and fix that? When a cardiomyocyte or when a heart more aptly is making a resource allocation decision that is pathological, can we fix it? Can we find a therapeutic that will go and correct that and rewire it in the appropriate and healthy way? And can that then restore the proper function of the heart? Again, I think we're at the frontier of this field, but it's a really exciting place that our field exists now where we're starting to understand the problems. And we're starting, I would say, early in developing the right agents to act and to manipulate this metabolic map that might be able to fix things.
Speaker 2I'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. As a result, I decided to start supplementing with natokinase, which is a blood lipid supplement that I've been using for a long time. And I've been using it for a long time. I've been using it for a long time. I've been using it for a long time. Which can naturally help reduce LDL cholesterol. And it did. In a follow-up test, I could confirm that this strategy worked. My blood lipids are now back exactly where I want them. Comprehensive lab testing of the sort that Function offers is just so important for health. I mean, how else are you going to know what's going on under the hood? And while I've been doing blood work for years, it used to be time-consuming, complicated, and expensive. In fact, I used to spend thousands of dollars per year trying to get this kind of data. And the data, frankly, were not all that good. But now with Function, it's extremely easy and affordable. A Function membership is only a dollar a day, $365 a year. And if you think about the information it provides and the health challenges it helps you avoid and the proactive things that it can do for you to enhance your health, I truly look at it as a savings. To learn more, visit functionhealth.com slash Huberman and use the code Huberman for a $50 credit towards your membership. Again, that's functionhealth.com slash Huberman. So is it fair to say that the allocation of energy, which is made pathologic in this mutant mouse, but also in people who have these cardiac conditions and die of heart attack, essentially, it's almost like the identity of the cells is screwed up. They're still a cardiomyocyte, but they're devoting too much energy to making more of themselves and not enough to doing what they're supposed to do. I have like two analogies that I want to throw out there, and maybe they're too much of a reach, but I love dogs. I have now a medium-sized dog. I used to have a large dog. The larger breeds, dogs live much shorter lives than the smaller ones. And we actually know that's because of dosing of IGF-1, which is a growth pathway thing. So there is this like story about larger animals within a given species tend to live much shorter lives than the smaller variety of that same species. There's some exceptions to this, but there does seem to be a sort of rule that you can either be big and live a short life, or you can be small and live a longer life within certain species. But there's also this- This thing about heartbeats, right? Like this theory that you only get so many heartbeats in your life. The reason I like these higher level, perhaps appropriate comparisons, a lot of caveats there, is that like ultimately when I think about life and evolution and a propagation of species and health versus pathology, it's all about energy, right? It's like, how are you devoting energy? It can get into the kind of mystical spiritual piece. That's not our purpose. It's not my purpose in bringing this up now, but it seems- It seems like at the cellular level and at the sub-cellular level, which is what you're describing, the allocation of energy, in this case is the difference between life and death, but this decision, you're not telling us like, oh, you know, these pathways I discovered along with others are really like, there's a fan out of like 50 different options. You're saying make more biomass, more of self, or use energy to be self. And there seems to be like a critical balance there. And I have another story I could tell you about this. I have a story I could tell about how like, if you look at the data on longevity in different athletes, like the gymnasts, the sprinters seem to live three to six years longer on average than others. And the endurance runners are somewhere in the middle. And you look at very large athletes, like the power lifters and the moving aside all things of like use of drugs in sports. I mean, you'd go like the sports where there's just a lot more of a somebody, that's not good for longevity. And it really isn't. So there does seem to be this balance between size and the use of fuel to build more of oneself and the use of fuel to just be oneself. And that self could be a cell. That self could be an organ. That self could be a whole organism. And I find that like not incidental, but maybe I'm taking too many liberties here.
Speaker 1Yeah. I mean, that's a complex analogy. But I think one thing that is very clear about what you're talking about is this sense of identity in a cell. I mean, that's a fundamentally important phenomenon. That again, we've known about for a long time, and there's been an understanding in some cell types in some ways about how that identity is established and maintained. But I think your question is a really interesting one. To what extent is disease associated with loss of that cell identity? And cell identity is a bit of a squishy parameter. How do you measure what a cell
Speaker 2thinks it is? There's no way to ask it. Yeah. I'm talking about function, right? So yeah, when we had Max Crummel, on the podcast, he was like, you know, every one of your cells, by the time you reach our age, roughly, you know, in our 30s, 30s, no, I'm kidding, in our 50s, early 50s, is we're a mosaic of like our original genetic makeup, plus all these mutations that have accumulated. Nobody likes that picture. That's true. We're a patchwork of like our former self and our newer self. That's one form of cell identity. What I like here is that you're talking about within an organ, within a cell type, you sort of have a choice of A, make more of oneself, or B, just be you. So there's something like kind of like to me, conceptually sticky about this notion
Speaker 1of size versus use. Yeah. I think, as you say, I think that in a way we're talking again about resource allocation, allocating to energy versus making more stuff that could mean another cell or a bigger cell. There's many examples of where making more stuff instead of making more energy is pathological. We talked about cancer. We talked about the heart getting pathologically bigger. Immune cells becoming hyperactivated can lead to inflammatory diseases. You know, there's many examples of that. So I think this is all playing out at the level of individual cells. And what you're talking about is obviously a bigger conceptual framework in which to think about it. But I think there is that connection. And I don't know, this is a bit non-scientific, but I do think it's fascinating to understand the history of the brain. I think there's a lot of historical philosophical ways that our ancestors thought about the world. And we find relics of that in our science, right? That we can see reflected in the discoveries that are made today.
Speaker 2I don't want to take us off the biology, but if we can go down this pathway a little bit more, you know, I sometimes think about energy in terms of human interactions. And I think most of us can think of the extremes of benevolent versus malevolent energy exchange. Like let's say somebody, like money is just a tool, right? Right. Money is just a tool, right? And I think most of us can think of the extremes of benevolent versus malevolent energy exchange. Like let's say somebody like money is just a tool, right? And I think most of us can think of the extremes of benevolent versus malevolent energy exchange. Like let's say somebody like money is just a tool, right? And I think most of us can think of the extremes of benevolent versus malevolent energy exchange. Like let's say somebody like money is just a tool, right? Like people say money is energy. That sounds very like, you know, like internet-y. But really it can be exchanged for something, right? We've decided that. And if somebody steals from us or they promise something and it turns out they overcharge us or something like that, like we fundamentally understand the math there. You said it was going to cost this much and it cost another. You said it was going to be this. Instead I got that and this isn't what I paid for, right? But if you look at human interaction and behavior, the stuff that we consider, But if you look at human interaction and behavior, the stuff that we consider, But if you look at human interaction and behavior, the stuff that we consider, But if you look at human interaction and behavior, the stuff that we consider, malevolent is usually when something, when someone perceives that the energy has been stolen from them, usually in the form of time, but often in the form of physical energy, because time is physical energy, right? And then benevolent acts are generally ones in which there's either an even or a kind of a, like a net positive exchange of energy. And this is like a lot of what structures human interactions. Like I don't want to take us too far. This is not a psychology podcast, but I think about this all the time. And like, well, I like zooming down at the level. And I think about this all the time. And like, well, I like zooming down at the level. And this is like a lot of what structures human interactions. Like I don't want to take us too far. This is not a psychology podcast, but think about this all the time. And like, well, I like zooming down at the level. of the cell is we can find there isn't going to be a perfect relationship between the cell and human interactions at large, but this notion of no cell, if it wants what's best for itself, and therefore the organ it resides in, and therefore the organism, can afford to really cheat itself. That's right. Like you bring it down to like the individual cell, like the cell can't afford to cheat itself. And if too many cells do that, you end up with a big heart that doesn't pump. Exactly. So it cheated itself. So for me, that's very useful. I don't know if it is for anyone else. So when I think about like really critical biology, all these proteins, like which ones are you going to study? Like it's clear to me now why this set of proteins is very important, very, very important. What I didn't get was how you actually found it. So was it that you knew there was a gene there that coded for this thing of a certain size? So you started making some, what we call recombinant version of that, and like throwing it on cells, seeing what happened. Is that kind of the steps that went through?
Speaker 1We knew the protein was there. What we didn't know is what it was.
Speaker 3What it did.
Speaker 1And I would say the key discoveries of that came from genetics. Basically, Carl's lab made flies that lacked the MPC. Dead fly? They were actually alive. There's an interesting story there that's probably too in the weeds, but they live, but they had specific manifestations that we could analyze using chemistry. And I'll tell you about the results of that. We were studying in other cell types, in yeast cells and in human cells. And studying the results of losing these genes. Again, this is what's enabled by doing genetics. Mario Capecchi figured out how to do this in mice and his colleagues that gave us the ability to do knockout mice. Other people have enabled it in other species. And by doing that and studying the results, we could then deduce, oh, what's happening in these yeast cells? These fruit flies and these human cells grown on a dish, is they aren't able to take their pyruvate into the mitochondria. By analyzing them using sophisticated chemical tools, we could see that they were basically their metabolic pathway from glucose to pyruvate to pyruvate in the mitochondria to ATP. That was being blocked and it was being blocked specifically at that level of the pyruvate. So that then gave us the initial hypothesis. Maybe that's what these proteins are doing and we could then go and validate that hypothesis in multiple experiments and that, like I said, had been validated by many other people over the ensuing decade or so. So those were the experiments that enabled us to figure it out. It was really genetics that enabled us to do it.
Speaker 2Very satisfying when a discovery comes about in yeast flies and mammalian, including human cells. What year span was all of that happening? If you had to really tighten it to...
Speaker 1We published the paper in 2012, it probably was going on from 2008 or 9 to 2012, something like that.
Speaker 2This is actually an important moment, I think, for people to understand when they hear about yeast or flies, they're probably like, "Why are we doing this stuff?" And I'm not here to plug federal funding for research. I think that just happens naturally as a consequence of the podcast, or at least I hope so. But my graduate advisor told me that yeast, they have a very quick turnover, so that's why they're good to use. And she said that... She was a wine drinker. They were much smarter than us because they know how to make their own alcohol. So now we know why biologists use yeast. Fruit flies, it's because of the short generation time. You can get a lot of experiments done.
Speaker 1Yeah. And they have many of the same structures that a human does. Not exactly, obviously, but they have many structures that human does, and there's some things that they're particularly good at. You can look at the whole thing in the microscope and see different cells and different features. And I would say, again, not to plug our specific experiments, but we could not have made that discovery with anyone. We could not have made that discovery with any other type of organism. If we'd just had the yeast data, we wouldn't have figured it out. If we'd just had the fly data, we wouldn't have figured it out. Same with the human cell data. But putting it all together, we could triangulate what we were seeing in one to what we were seeing in the other, and it became obvious that this is the hypothesis we should pursue. And I think that's been, obviously, an effective strategy that's been employed by scientists for a long time, is to take multiple different approaches, multiple different model systems to answer a complex question. A complicated question.
Speaker 2Let's talk about lactate. Every time lactate's come up on this podcast before, it's been in the context of exercise physiology. We had the great Andy Galpin, whose name I don't expect you to recognize, but he's really one of the preeminent public educators. He's a professor of physiology and exercise physiology. And he told us, and he told the world, everyone talks about lactic acid, but we don't actually make lactic acid. We make this thing called lactate. But within the cell, lactate plays a very crucial role in this metabolic pathway. I know you spent some time on it. I know you spent some time with lactate. So when you think about lactate, what do you think about?
Speaker 1I mean, so pyruvate, we talked about pyruvate extensively. To a first approximation, again, it's a little more complicated than this, but I think this is a good way to think about it. When pyruvate is made, simplistically, it has two fates. It can go into the mitochondria we talked about. What we didn't talk about is the other major fate is to be converted to lactate and exported. And that decision, burn it, make lactate, I think you could make a very... It's a very strong argument, is one of the most important metabolic decisions that cells are making all the time. Why would it not burn it or make more of itself? Because it's just got it in excess? Yeah, there's something about that production of lactate that enables ongoing production of biomass. So again, a little more complicated than this. If you burn the pyruvate, that turns into carbon dioxide, we breathe it out. The stuff is gone. We breathe it out. There's no stuff. There's just the energy. If you don't burn it, that stuff doesn't get eliminated as carbon dioxide and can turn into a protein, can contribute to protein production or carbohydrate production or fatty acids that can be used to make new cells. And so that really is that resource allocation decision we talked about many times, building or burning. And lactate is one of the mediators in a way of that building decision. And so lactate, I think, historically has been thought of as a waste product. When our cells can't burn, typically because of lack of oxygen, we haven't talked so much about the role of oxygen in all this. When I talk about burning, what I really mean is taking that pyruvate or fatty acids or other things and oxidizing them using oxygen and by so doing, extracting the energy and doing this unbelievably amazing chemistry that the mitochondria do. To basically very effectively capture all that energy and make it usable in the form of ATP. When oxygen isn't available, that pyruvate cannot be burned and then it essentially has to be converted to lactate. That's why when we exercise and our muscle becomes hypoxic or doesn't have adequate oxygen, we make lactate and that lactate is what causes the burn that we feel. And we've thought about it traditionally as a waste product. There's been beautiful experiments done in the last five or 10 years. Josh Rabinowitz, a friend of mine and professor at Princeton has done some of these that have demonstrated that lactate is a very important fuel on its own. The heart, for example, is quite good at consuming lactate and burning it.
Speaker 2The heart seems like it's consuming a sort of like dog's breakfast of fuels. It likes lipids, it'll take glucose, it likes lactate.
Speaker 1Anything. That's good for us because that keeps it beating no matter what the metabolic status, as long as we're alive. We have something that it can burn. And lactate is just an important mediator of carrying that energy around.
Speaker 2It can be a fuel, it can be a shuttle. In the context of exercise and brain, and I know we're not talking about actionables here, but like I've mentioned before on this podcast, if we do an intense, typically it's aerobic exercise, we get enough lactate generated, that does seem to be a signal to the brain for this brain-derived nootrophic factor, which now kind of makes sense in this context, because the whole purpose of BDNF is to build more stuff, more connections typically, rather than break connections. So it's amazing that we think of these things like a waste product, just like we used to talk about like junk DNA. Nobody does that anymore. But to be very careful with language and biology, I'm realizing. The moment we label something conceptually, you like shut down a field and like a line of discovery that almost always ends up being like super important.
Speaker 1Yeah. We joke all the time in the mitochondria field about the powerhouse of the cell, right? Yeah. Which it really is. I mean, the mitochondria are very good at being a powerhouse and making ATP, but they do so much more. And again, just to illustrate the point that when we categorize something into one thing, this is what it does, we're almost always proven wrong and it turns out to be a bit
Speaker 2more complicated. There's something I can't wrap my head around, because if I have an excess of energy and therefore I'm making lactate, am I going to now prioritize lactate? Is that going to now get burned off the top of the energy priority scale?
Speaker 1Yeah. That's a good question. I don't think we have strict answers to this, but there's definitely prioritization of energy. One of the most important things to burn is fatty acids. And the reason for that is that when fatty acids are in excess, they can be toxic. And they can be toxic in an acute way, quickly. Glucose again is toxic in excess, but chronically. Maybe it's a little bit less dangerous if we have high glucose for some time. High free fatty acids is dangerous now. And not just because it clogs arteries. - Yeah, of course. Yeah, exactly. - Yeah. Yeah, in ways that we probably don't need to get into, but it can be disruptive to cell structures and so forth. And so, you know, most cells, when they have fatty acids, will burn the fatty acids first probably as a response to, hey, this could kill us. Let's take care of this first.
Speaker 2It's also true of the fatty acids we ingest.
Speaker 1This is also true of the fatty acids we ingest, if they get into cells, of course. You know, you could imagine, again, it's a little more complicated than this, but the fatty acids we ingest and the fatty acids we make end up in the same pathways, right? They both get into other cells throughout the body. And when they do, they need to be handled appropriately. Lactate is maybe a little bit more on that side. It has some important effects to the chemistry of cells that are important to deal with. And so, lactate, if it gets too high in the body, it can be toxic. You know, lactic acidosis, which is essentially the... The phenomenon where we have too much lactic acid, lactate in our circulation, that's bad and can be lethal. And so, dealing with that lactate is important. And so, yeah, I think there is a prioritization that probably comes as a result of evolutionary pressure. You know, we had ancestors that maybe didn't deal with fatty acids so well and maybe didn't survive, but we had one individual that figured out how to deal with them more effectively and that individual survived better. And so, I think that's a good thing. And that trait was selected for, and we're now pretty good at it.
Speaker 2We had a colleague of yours on the podcast who studies hypoxia and spleen function, and we were talking about how everyone hears the word mutation, and they think, like, oh, mutations are just always damaging. But, you know, these mutations that afford more life, that are adaptive, essentially, people can't hear that enough. Mutations are the reason we're here. That's right. Yeah. So, the X-Men had it right. Yeah, exactly. That's a good series to watch. On the other side of the coin, the maladaptive situation. Could you talk a little bit about that? Could you tell us about the Warburg effect and its role in cancer? And I do want to frame this properly, because nowadays, we're living in a weird time around this topic of cancer. There are these corners of the internet that, like, don't actually believe in cancer or germ theory. They just, like, don't believe it. And some of that is actually kind of catching on. I believe cancer exists, and I believe that cancers can come about through a variety of mechanisms. So, only if you believe that to be true, that it can come about. So, if you believe that to be true, that it can come about through a variety of mechanisms, would I ask you to, like, agree? If you disagree, please disagree. But it's true, right, that there are a lot of paths to cancer.
Speaker 1Yeah. There's no question that there are some fundamental features of cancer. All cancers, to my knowledge, have mutations in the genome. And those mutations are many, but tend to cause, again, work together to cause that cell to divide, to replicate itself more rapidly. To evade the immune system, which is patrolling, looking for misbehaving cells to eliminate them, and somehow cancer cells can avoid that, critically important. And, you know, one of the most exciting developments in cancer therapy over the last 10 or 15 years has been these checkpoint inhibitors, PD-1, PD-L1 inhibitors, that basically reverse that. You know, cancer cells are very good at cloaking themselves, let's say, from the immune system, and those therapies eliminate that cloak. And, you know, cancer cells are very good at cloaking themselves, let's say, from the immune system, and those therapies eliminate that cloak. And allow them to be seen by the immune system and eliminate it. And there's just been amazing responses to those new therapies. Again, they don't treat every cancer to the same degree, but there's been wonderful examples where they've been effective. So, yeah, cancers can arise through many different pathways. They all are associated with mutations. One of the common features of cancer is changes in metabolism. And this is, when you talk about the Warburg effect, this is really fundamentally what you're talking about. Yeah. The Warburg effect is a phenomenon that was named after Otto Warburg, a scientist, a German scientist, back in the 1920s, that observed that cancer cells consumed less oxygen than would be expected from the cells around them. And that has been named the Warburg effect. What Otto Warburg thought was that that's because the mitochondria are broken. And then concluded that broken mitochondria are probably the cause of cancer. That was the thinking that permeated from the time of Otto Warburg in the 1920s for many years.
Speaker 2Broken meaning they're not making ATP or they're doing something wacky.
Speaker 1Yeah. Well, they're not consuming oxygen. That was the observation. The oxygen consumption was low. And that is, again, mitochondria as the powerhouse of the cell are consuming oxygen. That's how they're doing their powerhouse function. Making ATP. So that was the observation. The interpretation of that observation was that mitochondria are probably broken. We now know, we've talked about this, that mitochondria do more than just make ATP. And it turns out that mitochondria in cancer cells are not broken. In fact, they're very, very good, not necessarily at making ATP, but at making stuff. And again, the stuff is what's so important for a cancer cell because it needs to divide itself. It needs to duplicate itself to a ventilator. So the Warburg effect is a phenomenon, again, in simple terms, that is absolutely the case. That many cancer cells, most tumors, consume less oxygen than you would imagine because they're, instead of burning their fuel. Again, we talked about this bifurcation. Cancer cells tend to not be burning. And by burning, that's consuming oxygen. But they're using their resource allocation to build stuff, to build a new cell. And so I think this dovetails very nicely with what we've been talking about before. The oxygen consumption, the Warburg effect, is basically just a surrogate for that resource allocation question. And cancer cells are very adept at using their resources to duplicate themselves.
Speaker 2Of the modern treatments for cancer, radiation, chemotherapy, and immunotherapies, and what's happening now, I had someone on talking about, you know, CART-T cells. And things of that sort. But is there anything that you kind of sense on the horizon, it might be five, ten years out, or two years out, that, like, if we could just solve that, that we would be in a position to treat and cure many more cancers? Like, what's the kind of linchpin thing here? Is it being able to reallocate the use of pyruvate? Like, if we could do that, if that was a druggable thing, or you could do a gene therapy, or you could use non-invasive tools like ultrasound or light. Like, these are all just forces, right? Chemical or... I would like to simplify things, like, for people, if possible. Like, there are two ways to change things in the body, healthy or unhealthy. You have mechanical choices and chemical choices, right? You can feel more full by having your gut distend. You can feel more full because your hypothalamus says, you're full. And there's a bunch of other stuff involved. But, like, that's all we've got is mechanical and chemical forces. So let's assume you had the tool. Is there some place where, like, you feel like if we could just turn that back, bolt, we would be in a much better position to treat a lot of cancers or cure them?
Speaker 1Let's maybe take a step back from that and then get to that question in a second and talk about cancer, you know, what it is and why it's so difficult. If a bacteria invades us, it's very easy for our immune system to say, hey, that's not us. Let's go kill that thing. If a cancer cell starts hyperproliferating, it's us, right? It's ourselves. It doesn't necessarily have antigens, which are the technical term for the molecules, the features that are recognized by the immune system. It doesn't necessarily have antigens that are recognized as not us, non-self. So that's one of the big challenges of cancer. The challenge for us is to figure out a way to kill those cells, which, again, are our cells. They are us. It's to kill those cells without killing the rest of our cells. Because if we kill the rest of our cells, we kill us. Right? That's the challenge of cancer therapy, in my view. Again, I'm oversimplifying. But that's a big challenge. And many of the features of cancer cells are not completely new things that that cancer just invented. It's using the functions that our normal cells have. For example, one of the things that's common, not universal, but common in cancer cells is to become more like a stem cell. It has many features. So, okay, we can find a way to target a specific stem cell pathway and kill all the cells that have that. Well, then we're killing many of our stem cells, too. And now the lining of our gut doesn't regenerate, which we talked about. That's driven by stem cells. Hair falls and hair falls. Exactly. This is obviously one reason why many of the side effects of chemotherapy is to target those proliferating cells, which share many features with cancer cells. But that's the problem of cancer therapy. And there's a second problem that's worth talking about, too. We've talked about evolution a lot here, which I think is a great rubric by which to think about biology. Cancer cells, a tumor, is under evolutionary pressure, right? So we now, let's take an example where we have a tumor. And we get a drug, we have a great drug, that kills 99.9% of the cells in that tumor. But 0.1%. percent of the cells either through a mutation or some sort of an adaptation, are not killed by it. But that 0.1% can now repopulate, make a new tumor. And this is what happens in cancer therapy. We all know of tragic examples where we, loved ones, had a tumor, got a treatment, and they went into remission. You know, the tumor maybe shrinks, it goes away, maybe even becomes invisible by the imaging tools that we have to image cancers. But then it comes back. And that's because these cells are under evolutionary pressure. If one cell, theoretically, one cell acquires a mutation that makes it resistant to that drug, doesn't get killed by that drug, that one cell can now repopulate, make a new tumor, and be just as damaging. And now it's resistant to the drug. Now the drug doesn't work anymore. And this is the second big problem with cancer therapy. You know, this is not my field of expertise per se, but I feel like, given that situation, this is not dissimilar to what happens with viruses. HIV now can be managed and frequently is managed by a triple combination therapy. And the reason for that is you now give three drugs that are gonna kill that virus or prevent the propagation of that virus. It's now very difficult to acquire resistance to all three simultaneously. I think the analogy applies to cancer. I think the analogy applies to cancer too. I think the future of cancer therapy, again, in my worldview is going to be, we have many safe and effective drugs that hit different features of the cancer cells biochemistry. And by virtue of understanding the specifics of the tumor that I might have, the astute oncologist can say, given that unique biochemistry of that tumor, this drug, and this drug are gonna work together to kill that tumor. And it's going to be very hard for that tumor to become resistant to all of those drugs simultaneously. And as a result of that, that might result in something approximating a cure. I think that's the world that we need to get to. So there's been amazing therapies that have come out. You know, one of the most exciting recently are drugs that target specific oncogenic mutations, specific mutations that cause cancer, KRAS, mutations are one that are really exciting, that target specific proteins that are contributing to the cancer in a completely specific way. Don't do anything else in the body to normal cells, only hit those mutations that are oncogenic. But again, eventually there can be resistance that's acquired to that. So if we can now make multiple examples of that kind of specific safe kind of drug and use them in combinations, our ability to treat cancer is gonna be dramatically improved.
Speaker 2- That's very encouraging. We had a guy on the podcast named David Fagenbaum. He's a medical doctor. Are you familiar with his work? He's at University of Pennsylvania. He had Castleman's disease and he was able to cure his own Castleman's disease 'cause he was basically on his deathbed. And he basically just started taking different combinations of already approved drugs in a kind of desperate attempt to save his life. And he found things that would extend his life. And he's been alive 11 years now and he runs a lab, serious scientist, as we say, but he also has this not for profit, but called EveryCure, which has been successfully using AI and cell assays and things to take tumor biopsies and try and figure out like, okay, in this tragedy of a kid who's dying of a particular cancer, like let's just throw a bunch of not random drugs, but already approved drugs at this tumor in a dish. And if some of them work, like if the parents agree and there's no other hope, do it. And like, in some cases they're curing. And in many cases they're extending life. It matches up well with what you're describing, it requires this AI piece to run iterations. 'Cause there's a huge catalog of drugs that even oncologists might not be aware of. One particular highlight of his work is that we know now that in breast cancers, where they use lidocaine during the surgery, the incidences of recurrence are significantly lower. And it turns out that lidocaine has some effect on the local environment. I'm not, this isn't my area, but you know, David talks about this and I'm encouraged by things like that and what you're describing, that we're not necessarily going to have like the miracle drug, but then the miracle cocktail for that individual, that cancer.
Speaker 1- That's the key thing is that, you know, David's situation is very specific to David and every tumor is a little bit different. And one of, I think the unhelpful results of historically how we talk about tumors is we talk about breast cancer or liver cancer or, you know, colon cancer. There are some breast cancers that are more similar to some liver cancers than they are to other breast cancers, right? This is our historical classification of cancer has just been by where it is. It was defined by the surgeons that would take it out, but the specific mutations that cause that cancer and keep that cancer, again, evading the immune system, propagating, avoiding cell death and so forth are unique to that cancer. So if we understand the unique mutational landscape of that cancer, that gives us then an ability to say, again, in a world that isn't today's world, but hopefully not too far from now, where we have the ability to say this combination of drugs is going to be effective at killing the cells in that tumor.
Speaker 2- You're highlighting something really important that is both about the sociology of medicine and science. - Yeah. - That is just the, the disparaging of it. It's just, it is the way it is because of history. So much of the way things are in medicine and science can be answered by the phrase that everyone should hate, which is, well, we've always done it that way, which is the worst reason to do anything unless it's working spectacularly well, right? But is it a stretch to say that there are some liver cancers that are called liver cancer, but that are actually much closer in terms of their cellular phenotype to, to cancer of a cardiomyocyte, because of the way that say MPC one is changed. In other words, like, should we be classifying cancers as, oh, this is a cancer of the sort that the cells are making too much of themselves, as opposed to they're overusing energy, but there's too much pyruvate. I'm making this up, right? I'm obviously not my field, but rather than think only about address in the body.
Speaker 1- Yeah. No question that we should be thinking about the specific features of cancer. I've been talking about it in terms of, in terms of the mutation, the specific mutations that define a cancer. And I think that's a useful way to do it because those mutations in a way are the instructions for making a new cell, right? The genome of a cell are the instructions for how to make a new cell, the constituents that would make up a new cell. But I think a very important feature that you're touching on that I appreciate you bringing up is on top of that, layered on top of that is the unique, the unique metabolism that makes up that cell, right? That enables those instructions to be executed. You know, a cell can have all the right instructions to make a new cell, but if it doesn't have the building blocks, the lumber and the bricks and the mortar to make a new cell, it can't make a new cell. And so I think that's a really important feature of this that we need to talk about. And there's been a lot of energy in the field over the last 10 or 15 years, maybe even 10 years or less, at trying to specifically block the resource allocation of cancer cells toward building new cells. The challenge there, again, is that it's fairly easy to develop resistance to that. A cancer cell can just make a mutation and rewire its metabolism to build that same thing a different way. But that is a very important feature of the cancer too. Beyond just the mutations are the metabolic processes that enable those mutations to happen. Those mutations to be manifest in what turns into a tumor.
Speaker 2- How far are we from a world where I drink a fluid, and it's a safe fluid, 'cause we do this for like other types of imaging, and I step into a tube, and I do it when I'm like five, and I do it when I'm 50, and I get a picture of red and green in every cell, right? So I get like an image of like the proportion of my metabolism in different organs, and you could zoom in to a single cell. This is not like science fiction at the level, like it couldn't be done, where you say, okay, like this is a healthy cardiomyocyte, and it's using 65% of its energy to just keep pumping. And then it like puts aside a little bit to make sure it can make more of its stuff so it stays around. And a little bit, it's like going to this other pathway. And like, that's a healthy cardiomyocyte. We know this from the population of age match data. And then when I'm, you know, 40, 50, you go, yeah, I don't know, like your heart's looking a little more dry. It's looking a little more green than red or something like that. We can kind of turn the dial back. Like we have druggable, you know, targets inside of cells, and we can like kind of like adjust the energy allocation. Like it's what I'm describing, like so crazy, because I can imagine a mouse experiment or paper will probably come out on that next week if it hasn't already. And like, that's kind of what you want. You want subcellular resolution. 'Cause I feel like we've gone from this place where like, I was around when the first MRI, like functional magnetic resonance imaging, stuff was kind of like, here's a person looking at a banana. Here's a person hearing a joke. And like, now you can see dynamics. dynamics and you can see X on pathways, but if we get down to the cells, cool, it's a lot of salt and pepper. And then you get down to the inner workings of the cells and you can't see everything. If you look at everything, it's going to look like chaos. Someone put on X this morning, actually, a AI rendering of all the proteins in a cell in one tiny patch of cell. And it's just like overwhelming. You're just like, oh my God, like there's so much here. But if you could just say, like, let's just look at metabolism at this key node and we know what healthy should be, here's where you're at. And you're just trying to tilt that balance. I mean, that to me feels like that could be done. Like we've got smart people working on this. We need more money for scientists to work this stuff out and more scientists to do that work. But I feel like that's doable.
Speaker 1Conceptually, pieces of that are doable. I think, you know, when you talk about, can we basically image metabolism with cellular resolution? I should be clear, that's a very difficult problem. The spatial resolution, the ability to see fine enough detail to make out individual cells are even smaller than that. That's a challenge. That's definitely a challenge inside a human body. And it's also a challenge to be able to have a surrogate of metabolism that we can actually see. Of course, our metabolism, there's nothing visual that we can see with the naked eye, right? There's nothing I can see in the metabolism of a cell. So what could we make that would enable us to see the metabolism of a cell? And I think that's a very difficult problem. What could we make that would enable us to visualize that? There's really exciting tools being developed of many different kinds to be able to image various features of metabolism in a cell.
Speaker 2Well, we would, in neuroscience, I mean, again, I was fortunate to be part of this wave of technology. It didn't contribute to building any of it, but it was like, how do you know which brain areas are active? Well, you could drop electrodes in, or you could remove a piece and go, well, it probably did that when it was there because you lost that function. But, you know, a lot of it was just blood flow. It was like oxygenated to deoxygenated blood, reflects light differently. And like you'd get these beautiful maps, but you were just looking at blood flow. Now, then you got to deoxyglucose. You can look at glucose uptake, but it was spatially very crude, or it was the time resolution wasn't very good. I feel like we've come some way. You can look at voltage, you can look at calcium. I feel like the moment that chemists, bioengineers, and physicists, and computers came into biology, things got a lot better. Yeah. I mean, some people say it got a lot better. Yeah. I mean, some people say it got a lot worse, but they retired now. So, like it got a lot better because you could see what's really
Speaker 1happening. Maybe I'm overly optimistic. Yeah, no, I think we need to be able to figure out what to measure. I mean, that's obviously a key thing. What would be the metabolic parameter? What would be the one metabolic parameter you'd really want to measure to assess is this cell healthy or not healthy? And it's hard to know exactly what that one thing would be or collection of things, and then figure out a way to measure that. Non-invasively, so to speak. It's one thing, if I'm going to measure that, do I have to cut off my arm, shave it into slices, and measure it? Nobody wants that. Nobody wants that. Yeah. So, how can I measure it without doing damage to me while I'm measuring it? These are hard problems. But as you say, the technology just keeps getting better in all versions of this. The experimental tools, the tools that we can use in mice or in cells and culture are definitely getting better. And that's an aspect of this field of studying metabolism that's really exciting is our ability to now be able to measure what's happening at individual places in individual cells and looking at specific individual molecules, intermediates and products and substrates of this metabolic map. And that, I think, is teaching us a lot about how metabolism works in individual cells. And that is then going to be informative when we think about how it's working in a human.
Speaker 2I'm intrigued by this really wild thing that you see in the news every once in a while, which I believe to be true, but no one can explain, which is that there are dogs and there are occasionally people who can detect the scent of cancer beyond chance. No one really knows the basis of this. And recently, there's an example. My understanding is it's validated of a woman who was able to smell Parkinson's as a musty scent, a musky, excuse me. And now spouses of people that had Parkinson's and particularly the female, the wives of these men, like, oh yeah, I remember this. Now, of course, there's a whole lot of like placebo correlation, just so story that can emerge from that. But as you're telling me some of this, like, obviously you wouldn't want this to be the one and only frontline detection system, but it kind of makes sense that if cellular metabolism is at the heart of certain cancers or neurodegenerative conditions, it makes sense that we're breathing out the byproducts. Obviously these scents are just correlative, right? And the shifts in movies with infants, parents are remarkably good at being like, something's off because they can't communicate verbally with us yet, right? Like something's off in their stool or something is off in their skin pallor that's not extreme and become remarkably astute at detecting real underlying issues. So do you think that there could be useful information coming from the air we expel in terms of revealing at a systemic level, or maybe even at a cellular level, how well or poorly we're
Speaker 1regulating energy? Yeah. I mean, obviously, as you said, in alluding to this, this is again, at the frontier of science. And I don't think we understand much of the specifics, but I think you could imagine that because again, smells, scents are chemistry, right? These are chemical compounds that are coming from the person. And when a person's doing different metabolism, they're going to be producing different chemicals in different proportions. And I think it is possible can be detected in specific ways. That's not so dissimilar from some of the diagnostics that we do use where we actually measure the blood chemistry. You know, the blood chemistry is different between people that have different diseases and don't. And so, you know, and obviously the breath is some measure of the chemistry that's going on in the person. It's obviously different from the blood, but it's a fascinating topic. And as that gets to chemical specificity, it'll become probably more clear what's going on there and why. Why is Parkinson's specifically susceptible to that different chemistry in a way that can be detected by scent?
Speaker 2We were talking a few moments ago about excess energy toxicity. This is something that Dr. Lane Norton brought up on this podcast. He's a serious biochemist, nutrition, exercise science guy, public educator, loves randomized controlled trials and meta-analyses. That's like his, if it's not there, he's not interested or he's perfectly interested in tossing away everything else. So that's- That's kind of his hallmark. So that should feel good to you and just knowing that. But he talks about this energy toxicity, you know, like excess calories leads to problems, not just because of the presence of excess body fat, but because of just too much energy at the front end creates downstream biochemical issues across the body. How does this relate to some of what we've been
Speaker 1discussing? There's a widely accepted hypothesis that mitochondria with excess energy leads to problems. You know, many people that are listening have probably heard of reactive oxygen species. This is, you know, forms of oxygen that become reactive and end up spinning out and damaging proteins and nucleic acids. And I think it is, again, widely accepted, not universally, but widely accepted that one of the contributors to that is mitochondria that have too much energy. Basically, the form that energy takes, when it's extracted from the food we eat and before it's converted to ATP, is powering the mitochondria. And when that mitochondria is overpowered, that leads to a state that is very susceptible to generation of these reactive species that end up damaging our genome, creating mutations and damaging proteins and creating many of the problems that we see. And I think there's been a number of studies that have suggested they might contribute to various pathologies, including aging. So I think that idea, of excess energy, is one that is really important to consider from the level of the organism down to the level of individual cells and even the mitochondria within those cells.
Speaker 2Once again, I'm thinking about this notion like no individual or collection of individuals or cell or collection of cells can really get away with, what's the saying, like you pay the piper somehow. Like cells really get punished for cheating themselves by taking too much energy or not allocating it correctly. Like you can level up from these like single cell analysis all the way to societies, I actually think. This is fascinating for a variety of reasons. First of all, again, we've never had a serious discussion about what mitochondria actually do besides just help create energy. So first of all, thank you so much for telling us how they actually allocate their resources towards things other than just making more energy for usage to build more of oneself. Also for framing that in the context of disease and health. And also for shining a light on the fact that like, while we might be right here now, that I do think, I'll just say what maybe you were trying to say, but are too humble to say that I think as long as we're looking at things just like, oh, this is a cancer of this tissue and not actually asking what specifically is happening to the cells there that might be common to other cancers elsewhere. And like changing our nomenclature and boundaries of how we classify things, opening up our minds to it, as well as really thinking about the whole body as a like a constellation of these little microfactories that is us, I am certain that people hearing this will no longer think about like metabolism just as them, my metabolism, but this constellation of metabolisms and the health status of all the different cells. So it goes without saying that it's a really unique opportunity for the general public to hear from like a world-class biologist working on these specific issues and related issues for decades now, right? And so, and you're a very busy person. So I'm very grateful to you, to the University of Utah for allowing and encouraging public education to Howard Hughes. No, they didn't tell me to say this, but I think people really need to understand what an amazing opportunity is to learn from people. And there are others in the field, you're so good at attribution, who are really trying to figure out these really hard problems in biology that are crucial to health and to disease and therefore to curing disease and really trying to move things forward in your workshop that you call a laboratory. Yeah. So you don't have to do this sort of thing, but I greatly appreciate it. And I speak on behalf of many, many people who really appreciate it. There's information and then there's superb information. So thank you so much. Thanks, Andrew. It's been a lot of fun. We'll do it again.
Speaker 1Anytime. Cheers. Thank you.
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