How Mitochondria Control Your Metabolism | Dr. Jared Rutter

There's a widely accepted hypothesis that mitochondria with excess energy leads to problems. Many people that 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 Hubberman Lab podcast, where we discuss science and science-based [music] tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and opthalmology at Stanford School of Medicine. My guest today is Dr. Jared Ruer. Dr. Jared Ruer 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 Ruer. Dr. Jared Ruer, 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. >> Yeah. You 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 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 and 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 or 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 um 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 or whatever we do. It's a beautiful orchestration, but that happens at the level of of individual cells. And I think that's one of the fascinating things that is maybe a little bit less understood. if we were to just take the single cell view for a moment and I know that aging isn't a like your specific area of interest but one thing that's always intrigued me because my postto adviser 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 that I like I wonder what he used to be like but it's a great question he used to do this every once in a while like 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 what 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 could be muscle cell it could be neuron whatever versus an older version of that cell why it 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 get up and go do we have an answer for Yeah, I think we have a partial answer for that. I think that's a 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 for that are to some extent clear but I think largely unclear but that is definitely a feature of the aging process. You know there there is this sort of aspect of accumulation of damage. You know living in the world we live in as I alluded to before this orchestration of metabolism that happens throughout the body. 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, you know, in in animal models that suggests 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 t 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 in a way we're at the precipice of understanding a lot of this because of the tools that we are um starting to have access to that will help us better understand cause and effect and the specific molecular features of of the aging process. Let'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 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 what's so sticky about those as a place to I mean you devote a significant fraction of your life to them? 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 in chemistry of incredible complexity and making it work effectively inside of a a living cell. Mitochondria are believed to have been the result of an endo symbiotic event where a bacterium a free-living bacterium was engulfed by another cell and in a way kind of domesticated. So wild to think about totally wild. I'm sure people are following, but in case there's somebody who's not, >> what Jared is saying is that our cells basically were invaded by a bacterium and then that bacterium became part of our stable genome going forward. It went into the 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 I 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 and then you need to replenish eat your yogurt and so on. But 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. >> I 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 and another cell that got together and and together that combination could do things that that any one of either of them on their own could not do and that they work together in in some way to enable the evolution of complex life. you know ukarotes which are the 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 uh teaming up to make this synergistic cell. >> Is it synergistic? for forgive me for interrupting, but 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 could have this been a takeover by the by the mitochondria? >> I mean, this is a a bit of a philosophical question. Of course, we don't have a record of 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 bacteria on its own or the archa the the 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 and and diversified that it could enable you know again complex life to evolve and totally fascinating history but I think as you alluded to also has very interesting implications for life today. I would like to take a quick break and acknowledge one of our sponsors, JWVE. JWVE makes medical grade red light therapy devices. Now, if there's one thing that I have consistently emphasized on this podcast, is the incredible impact that light can have on our biology and our health. 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Again, that's betterhelp.com/huberman. Could we explore a little bit of how mitochondria getting into these cells were able to make it stably into their genome and propagate? This isn't going to be a conversation about genetics per se, but I maybe as a just two points of background for people like if any of our cells have something put into them, but let's say a physical object like a splinter, little tiny piece of splinter stays in the cell and then you procreate with somebody, you don't expect that child will have that little bits of splinter in their cells. But if the germ line, right, so the the eggs or the sperm have something incorporated into them, then potentially it could propagate is why they call germline as opposed to sematic cells. I think most people aren't aware of that. It makes perfect sense once you hear it, but you're talking about many, many, many years ago >> a cell having this bacterium go into it and then it was somehow able to stably represent itself in the genome. So that that propagated forward and eventually >> it has to be in the germ line of whatever you know primordial homo sapiens were there otherwise >> your kids I you wouldn't have mitochondria in us how do we think that might have happened >> the main genome of the cell the cellular genome DNA contained typically in the nucleus of the cell mitochondria exists in the cytool 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 genomes. Whereas the nuclear genome of a ukareotic cell is linear chromosomes. And that genome performs very essential functions and codes very important proteins that enable our mitochondria to function as the powerhouse of the cell which we uh 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, cuz as you know, when the sperm invades the egg, the the genome from the sperm gets into the 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 uh diseases that are mitochondrial on 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 the germ line that that fertilized embryo will have and then gets passed on to the next generation in [snorts] the same way >> ratcheting toward the actual functioning of mitochondria. Maybe um you give a beautiful picture of the mitochondria not uh 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. Mhm. >> I'm guessing you're going to tell us that the mitochondria can be distributed lots of places in a cell cuz 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 spatially through the cell? So maybe we go so people know where we're going. We 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. >> Yeah. Spatially, you know, I I one of my scientist colleagues might call me on this but to my know I can't think of a place that exists in cells where there aren't mitochondria. And I think as you alluded to I it's a little bit dangerous for me to talk about neurons with 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 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. They're extracting the energy from the food that we eat and powering the neurotransmission the the functions of those nerve nerve terminals. And I think that's true of virtually every cell in our body. The extraction of energy and turning it into use 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 you know 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 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 fascinating example of that local uh demand for energy. >> I'm asking some highle questions I realize, but is there any reason to believe that a a given mitochondria knows what cell it belongs to? >> Like the like are they different? Is is are the mitochondria in one cell type so very different than the mitochondria in another cell type? or the mitochondria between like let's say a neuron of the eye versus let's get out and since you're saying you don't want to talk neurons as a per se like is 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 than my mitochondria but how much identity do they have >> yeah I would say this is a topic that is at the frontier of what we No, you're 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 cardiammyioite, 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. >> Is there any turnover of those cells? We know neurons don't tend to turn over. >> Very little. Very little. >> Well, that's reassuring. >> Very very little. I'm glad you >> 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 that those cardiammyioytes, >> their mitochondria is wired >> to consume whatever it has available and make ATP because that ATP is is going to be incredibly important to enable that contraction of that cell and the beating of the heart. mitochondria and other cells. For example, like cells that line that that are the stem cells that that enable our intestinal lining to be turned over every 5 to seven days, which is amazing. By the way, >> your whole gut >> your whole gut is turning over every 5 to seven days. The the lining of that of your gut, it is it is amazing. Those stem cells, ATP is not the major demand of those of those cells. They need to completely duplicate themselves constantly every day or less. So their metabolic program is very different from a cardiammyasite which just needs to make ATP to a first approximation. They need to make a whole new cell. So we talked about you know the metabolism of 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 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 cardiammyioite. And that diff 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 uh 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 published recently by Craig Thompson at at Sloan Ketering 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. >> What what's each of them doing? >> Yeah. 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 a an overly simplified but generally accurate way of thinking about it. It really emphasizes this unique function of of mitochondria that can be adapted again for the needs of the cell. >> Okay. So, I eat some food and uh that food's absorbed and I get glucose circulating in my bloodstream. I've got some stored energy in the form of glycogen etc. 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 it energy being allocated in some way that's a little bit more um democratic that's one question then framed within that um I could imagine two scenarios one non mutually exclusive where like the vasculature just distributes the glucose very well to everything so everybody every cell gets gets access to some of this glucose and and then is just greed needy 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, you know, like keeping you alive like breathing, heart that there's a prioritization of of organs. I'm talking about under non-stressful conditions. >> So, yes. So, how is energy allocated to cells and then how are cells divvying up the the goods? Yeah, it'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, GLP-1 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. Aipocites 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 adiposite, 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 adiposytes 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 atyposites 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 and other cells throughout the body that again this is the brilliance of this coordination. The response of different cells to the fed state is different depending on the the the needs and 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 the metabolic state the fed fasted state of the organism. So the picture you just described leads me to conclude that basically every cell obviously knows its job and is not greedily but is um diligently fulfilling that role. >> Yeah. And somehow the whole thing is orchestrated so that like we work which I know I think for some people it might be like duh but like just like think about that crazy >> like a 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 sensit 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 your cells to recognize this signal but we've never actually talked on this podcast about what exactly that signal is we think about insulin as a shuttle >> 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 like squirrel 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 and some cells like the photo receptors in the eye are just doing that >> eyes closed they're firing eyes open well it's tricky but they're more or less 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 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 and really what we've not done ever on this podcast and I 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. Yeah. >> And I realize there's a lot of biochemistry there, but you've worked on some really lynchpin molecules in that pathway that perform very specific roles. And so like maybe we could really talk about basically gets us from ATP to pyuvate, 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. Cuz 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 a obviously a lot to unpack there. Glucose is the dominant, let's say, carbohydrate, the dominant sugar that most 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 I'm going to simplify because there's obviously this is the subway map of New York. There's a lot of branches going all over the place that we're going to >> go north or south. >> North and south, >> which is pretty much the only direction you can go on the cell. I'm I'm not a New Yorker. I'm kidding. I realize you can go across across the aisle. >> Yeah. Don't insult the New Yorkers anymore. Yeah. >> So glucose comes into a cell, goes through a series of chemical reactions, and you mentioned it gets to pyrovate. That's the end point of glycolysis, this set of chemical reactions. And then pyrovate there's a decision that has to be made by that cell. It can either take that pyrovate 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 pyrovate. >> Tell us a little bit about pyrovate. Yeah. What's the best way to like conceptualize pyuvate for for somebody like me? >> It's an intermediate. It's a midpoint let's say from glucose. Glucose is a sixcarbon molecule complex chemical sixcarbon chemical that gets again chemically modified down to this pyrovate 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 pyrovate is because of that bifurcation that happens. Pyrovate can either be again taken into mitochondria and burned and that's very effective for generating ATP for extracting all the energy that can be extracted and that's what cardiammyioytes 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 Okay, that's enabling the repopulation of our gut lining every week. They do something different with that pyrovate. They instead of burning it turn that pyrovate and other molecules intermediates in glycolysis into biomass into the stuff that will enable that one cell to duplicate itself. 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 and 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 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 pyrovate 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 seven 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 we get glucose. Glucose gets into the cell. We 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 pyuvate and pyuvate is either going to say let's make more you called it biomass but stuff of cells. >> Yeah. >> So we're like you have lumber arriving maybe might be a decent enough analogy. 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 pyuvate to keep itself going like a cardomyioite 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 hard math to do there's a lot of nuance rough percentages. 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 that's often used to diagnose cancer emission tomography. >> An 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 fluoroxy glucose. This is a 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 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 pseudo 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 the easiest example for people to understand is like a herpes virus like HSV1 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 if 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 the most easiest one to conceptualize like impact areas of the brain that trigger aggression would that trigger >> right >> biting and 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 >> uh 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 arry 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. >> Yeah. >> Except it 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 a potential set of answers about how to deal with tumors and and think about cancer that could be borrowed from any of those other examples or am I or am I going down the wrong path? >> Yeah, it's an 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 in you know, parasitic bacteria. Viruses, as you allude to, their goal that, you know, 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. It's amazing. >> I wish we had a better language for this thing because intelligence is not really it because it's not of brains, >> but it's this adaptive logic. >> Yeah, that's a good uh phrase for it, adaptive logic that enables the survival and propagation of that virus. And 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 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 co-workers and that's viral propagation, which we all sadly know about. There's very little evidence that cancer is infectious. >> What about Tasmanian devils? >> You know about this, right? >> No, I don't know about this. >> 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, you know, very disturbing images of these cute little animals with these little teeth. They're they have a viciousness to them and they have these like tumors growing at the at wound sites and it turns out those are cancer. So there's somehow like >> fighting and wounds and viral, it might it might be bacterial. I don't know. That's outside my expertise, >> but there was this idea that you 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, you know. >> A lot of stuff happens. >> I mean, the world's upside down there, so after all. No. Um but but right, you're right. In general, yeah, we don't actually think that um people are catching cancers from one another. >> So when you think about the evolution of a cancer, the scope of that evolution is different, right? The scope of that evolution of a 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 it, 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 um the the problems that would come with DNA damage, which many cancers have, and to continue to make it 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 to another to another to enable its propagation. Cancer you 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 underlying it, it's the same principles at play in both. >> I'd like to take a quick break and acknowledge our sponsor, AG1. AG1 just launched their newest formulation called AG1 Pro. And right now, you can get an extra 20% off your first subscription. AG1 takes the clinically backed AG1 formula, which is a blend of vitamins, minerals, probiotics, and adaptogens, and adds three important new ingredients. Creatine monohydrate, calcium HMBB, and zinc carnosine. 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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 spe every you know, mamalian 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 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 uh holding uh debates and protests and um 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 these [laughter] humans they think 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 but I keep hoping somebody's 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 Maybe I'm just a bunch of micro biota shuttle 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. >> Well, 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 it's a fascinating >> kind of eerie, right? >> Yeah, very eerie. We definitely don't like to see think of ourselves as anything other than the pinnacle of evolution and the reason for everything, >> right? >> But there's no question to to your point, the microbiome are the bacteria that live in our gut and on our skin, 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 of the universe that they live in and do it better than their com their competing neighbors. And if they can do that, then their genome is going to get passed on and again and again. And it's fascinating to think about the role that we play for them and they play for us. This is 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. Tell us about MPC 1 and 2. I'm asking about biochemical steps and a key process of energy production and and allocation. And normally when people hear acronyms, they don't understand. and they kind 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 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 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 mic mitochondria. You need to be able to know what's ATP and what's pyuvate. And then you know they're going to two different pathways cuz someone else said that and you can observe it down a microscope. >> Yeah. >> 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 MC and people go oh is there a peptide for that? It's like hold off. Let's think about how we come to understand these these essential aspects of oursel I think would be so useful. >> I 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 pyrovate carrier. So you don't have to be a scientist. >> Uh we did not name it. that was it was named before. I'll I'll tell you that one story cuz I don't like acronyms that aren't informative. >> MPC, >> aptly named >> is the carrier >> that enables pyrovate to get into the mitochondria. Mitochondrial pyrovate carrier. That's what it does. Sits in the mitochondria and basically provides a very specific hole in the membrane to enable pyrovate to get in so that it can then be burned by the mitochondria to again extract all the energy to make ATP. That's that's basically what it does. The history of this is really interesting. It's been known for 60 or 70 years that mitochondria must have a carrier to enable pyrovate to get in. But it was not identified what that protein was, how it worked. And fast forward to 2008 or nine or so, and our laboratory had just recently become again fascinated with mitochondria. I would say the motivating piece of 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 organel 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 two of those turned out to be MPC1 and MPC2. Way back when I I observed and was taught, I didn't do a ton of this, that like 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 >> you kind of grind them up and then you run them through a bunch of columns and like literally tubes. >> Yeah. >> 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 test the the different stuff that comes through for its ability to do something in some sort of cell. It's like how did you actually find MPC2? Was it done by like >> 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 the in a given human heart cell? >> I think we know. Yeah, I think >> we 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 that everything that's expressed in a given cell. That's right. >> That that's true. And there there are some very interesting features there. >> Can I sorry, I'm interrupting on purpose. 20 years ago, could you say what you just said >> with much less confidence that I than I can now? say heart cell, but we don't actually know all the all the bits in it. But now we do. >> Now 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 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-sellled organism and plants and animals. Everything that has a mitochondria has these two NPC1 and NPC2 proteins. And it would probably uh take too long to explain on this podcast this the processes that we went through to try to identify the function of this MPC 1 and 2, but this was a a brilliant collaboration and I think one of the the highlights of my career. different people in my lab and in the lab of my colleague Carl Thumbl that worked together. Carl was a fly geneticist or is a fly geneticist that used his unique skills and and resources and we were using yeast as a model system as well as human cells and triangulating all that data. We came up with data that suggested that this might be the mitochondrial pyrovate carrier. these two unknown proteins that happened to be sitting in the mitochondria and that was now been validated many times over that these are the proteins that do this transport of pyrovate into the mitochondria. It was a really fun time for me as a scientist to to see that happen. And you know, you kind of alluded to this when you asked the question, what was maybe even more exciting than the discovery of the mitochondrial pyrovate carrier, which Carl and I did, and we published a paper and the lab of JeanClaude Martin and Geneva published a paper at the same time showing the same discovery. What's been really fun since then is to see the implications of that and starting again to understand what role this protein plays in the allocation of that pyrovate that we've been talking about because now the MPC is the first step towards one destination of that pyrovate. So it kind of pulls it into the mitochondria so to speak and once that pyrovate is in the mitochondria it's going to be used for something in the mitochondria instead of maybe being used for something else in the cytool. And so that's been work that that we've done a lot of since is what are the implications of that. And I think it's been exciting to see in different cell types what that means. And so cardiamyiotes for example again these are cells that want to make ATP to to allow cardiumes to continue to contract. They need to extract every bit of energy they can make as much ATP as they can. They use this MPC extensively. How do they ensure that that these cardiammyioites make sure that they make just enough to maintain themselves so they they're not so busy burning up all the lumber that they end up going, "Oh my goodness," and the house fell apart. >> Yeah. >> Do they consistently devote 90% of of their ATP to energy utilization and that they just know 10%. Like how quantitative are these these these pathways? >> Because you can't you can't have the walls fall down. It doesn't matter how much energy you produce, right? It's a brilliant question and and it's definitely not programmed like like there's a 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 cardiammyioytes 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 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 endroducts of our metabolic map. Again, these are the the the products of the metabolic map are the amino acids that make proteins. And the nucleotides that are required to make DNA and 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 let's hold off on ketosis for a second and alternate metabolic pathways. But we will touch on it. But if the fat cells are also very self- serving then you know at some point are they just forced to liberate this stuff. But like ultimately fat cells just want to get bigger and bigger and that but if this cardomyite it doesn't have enough glucose eventually it's like it could shut down any number of things like you can remodel the 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 that atyposite liberates the energy. Yeah. >> And and cells everybody gets a little bit and you just hang on. So it's a famine type situation. >> 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 more newer GLP-1 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 vat 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 atapost tissue. And so so that's good. >> I'm actually relieved to hear that. >> Yeah. >> Right. Because if if god forbid there's a shortage of food that lasts long enough, like that's definitely an organ 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 cardiammyioytes and heart muscle cells is happening from fat. You said under fasted conditions is that >> especially under fasted conditions but even in fed conditions fat is is uh is available for the heart to use and and >> dietary fat or fat from adapocytes >> both whatever fat is in the circulation the cardiammyioite is pretty good at taking it up and burning it making ATP from it >> yeah 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. >> Yeah. >> So, if the form of energy changes, is it still once you get to mitochondria, pyuvate, MCP, and downstream, is it all the same? is essentially like energy is energy at that point or is or is there are there multiple pathways depending on the fuel source? >> Yeah, the ability of neurons to consume fatty acids is limited. I 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 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 if not seconds and that I think for a few different reasons but probably the most important one is the brain requires some amount of uh glucose to keep it functioning. So you know again I I alluded to this before this very elaborate dance that is happening by these individual cells taking up different nutrients out of the circulation using them for their own unique purposes and and neurons again are are very adept at taking in glucose and burning it and making ATP from it. I think again the heart I I feel like is really fascinating because it'll 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 whether we just ate 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 uh using them for their unique purposes. >> What is the consequence of eliminating the M MCP a shuttle like you get like if you take a mouse you're at the University of Utah let's give a shout out to Mario Kapi whose life story is amazing who won a Nobel Prize for essentially developing what are called knockout mice among other things. um 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? So >> they do not survive to birth. Yeah, >> you can get sperm egg and a and that somehow the >> it can become a a mouse. >> Yeah, it'll start to develop and then I think if I remember right, it's about 12 or 13 days of development, which is >> you know 2/ird of the way from fertilization [clears throat] to birth of the mouse, it will die and and you won't get a live mouse. But what has been done and and obviously you were 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 developed 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 so >> yeah and many people have been 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 P generation from glucose less efficient. We've 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. Akmed Clinton who's a postoc now running his own lab at Rutgers was the one who started this and uh 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 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, is they have made a resource allocation decision that turns out to be pathological for them. And instead of using the glucose that they take in to burn it and make ATP, they start making biomass. That that again we talked about that 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 cardiamyioytes 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 in the mouse really. And that maybe tells us something about the fundamental importance of this resource allocation decision. And this is obviously just in the context of cardiammyioytes. 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 cardiamyioite or when a heart more aptly is making a resource allocation decision that is pathological, can we fix it? Can we find a 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 at the frontier of this field, but it's a really exciting place that 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. I'd like to take a quick break and acknowledge our sponsor, Function. Function provides over 160 advanced lab tests to give you a clear snapshot of your bodily health. This snapshot gives you insights into your heart health, your hormone health, autoimmune function, nutrient levels, and much more. They've also recently added access to advanced MRI and CT scans. 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But now with Function, it's extremely easy and affordable. A Function membership is only a dollar a day, $365 a year. And if you think about the information it provides and the health challenges it helps you avoid and the proactive things that it can do for you to enhance your health, I truly look at it as a savings. To learn more, visit functionhealth.com/huberman and use the code hubberman for a $50 credit towards your membership. Again, that's functionhealth.com/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 uh cardiac conditions and die of heart attack essentially. It's almost like the the identity of the cells is screwed up. They're still a cardommyioite, >> but they're devoting too much energy to making more of themselves and not enough to to doing what they're supposed to do. I have like two analogies that I want to throw out there and maybe they they're too much of a reach, but I love dogs. I have a now a medium-sized dog. I used to have a large dog. The larger breeds of dogs live much shorter lives than the smaller ones. And 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 like 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 thing about heartbeats, right? Like this theory that you only get so many heartbeats in your life. The reason I 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. There's not my purpose in in bringing this up now, but >> it seems like at the cellular level and at the subcellular level, which is what you're describing, >> the allocation of energy in this case is the difference between life and death, but but this this decision, you're not telling us like, oh, you know, these pathways I discovered along with others are really like there's a a fan out of like 50 different options. You're saying make more >> biomass, more of self, [snorts] or use energy to be self. Mh. >> And there seems to be like a critical balance there. And I have another 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 3 to six years longer on average than than others. And the endurance runners are somewhere in the middle. You look at very large athletes like the powerlters and the um moving aside all things of like use of drugs in sports, you go like >> the the sports where there's just a lot more of 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 to build more of oneself and the use of fuel to just be oneself. And that self could be a cell. >> Yeah. >> 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. >> Yeah. I mean that's a that's a complex analogy. and and but I think one thing that is very clear about about what you're talking about is this sense of of of identity in a cell. I that's a fundamentally important phenomenon that again we've known about for a long time and there's been under 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 and cell identity is a bit of a squishy parameter. You know, how do you measure what a cell thinks it is? You know, there's no function, right? So, yeah, like when we had Max Crumbl 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, 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. >> Yeah. So there's something like kind of like to me conceptually sticky about this notion of size versus use. >> Yeah. I think I as you say I 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 uh conceptual framework in which to think about it. But I think there is that uh connection and I don't know this is a bit non-scientific but I I do think it's fascinating to understand the historical philosophical ways that our ancestors thought about the world >> and we [snorts] find relics of that in our science right that we can see reflected in the discoveries that are made today. I 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 and I think most of us can think of the extremes of benevolent versus malevolent energy exchange like 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 internety, but really it it can be exchanged for something, right? We've decided that. And if somebody steals from us or they 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 us this much cost. You said it was going to be this and 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 malevolent is usually when something when someone perceives 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 a either an even or a kind of a um 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 think about this all the time and like why I like zooming down at the level of the cell is we can find there 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 best for itself and therefore the organ it resides in and therefore the organism. >> Yeah. >> Can afford to really cheat itself. >> That's right. like bring it down to like the individual cell. You can't like the cell can't afford to cheat itself, >> right? >> And if too many cells do that, you end up with a big heart that doesn't pump. >> Exactly. >> So, it cheated itself. >> Yeah. >> 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. Yeah. >> 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 recominant version of that and like throwing it on cells seeing what happened. Is that kind of the the steps that went through? >> We knew the protein was there. What we didn't know is what it did. >> Mhm. >> And I would say the key discoveries of that came from genetics. Basically Carl's lab made flies that lacked the MPC and we could then >> they were actually alive. There's an interesting story there that's probably too in the weeds, but they live, [snorts] >> but they had specific manifestations that we could analyze using >> chemistry. [snorts] And I'll tell you about the results of that. We were studying it in other in other cell types in yeast cells and in human cells and studying the results of losing these genes. You know, again, this is what's enabled by doing genetics. You know, Mario Capeki 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 pyrovate into the mitochondria. You know by analyzing them using sophisticated chemical tools we could see that they were basically their metabolic pathway from glucose to pyrovate to pyrovate in the mitochondria to ATP that was being blocked and it was being blocked specifically at that level of the pyrovate. 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 been validated by many other people over the ensuing decade or so. So those were the experiments that enabled us to to figure it out. It was really um genetics that enabled us to do it. >> Very satisfying when a discovery comes about in yeast flies and mamalon including human cells. What year span was all of that happening if you had to really tighten it? >> Yeah, we published the paper in 2012. It probably was going on from 2008 or 9 to 2012, something something like that. >> This is actually an important moment, I think, for people to understand like when they hear about yeast or flies. They're probably like like why why are we doing this stuff? And I'm not here to like 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 adviser told me that yeast like they have a very quick turnover. So that's why they're good to use. And and she said that um she was a wine drinker. She said and they were much smarter than us because they know how to make their own alcohol. [laughter] 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. And they they have many of the the same structures that a human does. You know, 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 any one type of organism. If we just had the yeast data, we wouldn't have figured it out. If we just had the flight data, we wouldn't have figured it out. >> Same with the 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 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 complicated question. >> Let's talk about lactate. >> Every time lactate's come up on this podcast before, it's been the in the context of exercise physiology. We had the the great Andy Galpin, whose name I don't expect you to recognize, but he's he's really one of the like pre-minent public educator. He's a professor of physiology and exercise physiology. And he told us and he told the world like everyone talks about lactic acid. 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 with lactate. So when you think about lactate what do you think about? >> I mean so pyrovate we talked about pyrovate 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 pyrovate is made simplistically 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 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 pyrovate, that turns into carbon dioxide. We breathe it out. That 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 you know fatty acids that can be used to make make new cells. And so that really is the that resource allocation decision as 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 and all this. When I talk about burning, what I really mean is taking that pyrovate or fatty acids or other things and oxidizing them using oxygen and ex 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 pyrovate 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 5 or 10 years. Joshua Benowitz, a friend of mine, a 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. >> The heart can it seems like it's kind of like a it's got it's consuming a sort of like dog's breakfast of fuels. It likes lipids. It'll take glucose. It likes lactate. anything that's good for us cuz that that keeps it beating no matter what the metabolic status of you know as long as we're alive we have something that it can burn and lactate is just an important mediator of carrying th that energy around >> it can be a fuel it can be a shuttle >> in the context of exercise in brain and I know this is we're not talking about actionables here but like I've mentioned before on this podcast like if we do like an intense typically it's aerobic exercise we get like enough lactate generated that does seem to be a signal to the brain for this brain derived neutrophic 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 [clears throat] anymore we have to be very careful with language in biology I'm realizing >> like the moment we we label something conceptually >> you like shut down a field like line of discovery that almost always ends up being like super important. >> Yeah, we joke all the time in the mitochondria field about the powerhouse of the cell, right? Which it really is. I mean, the cell 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 more 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 uh priority scale? >> That's a good question. And and you know, I 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 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 for some time. High free fatty acids is dangerous now >> and not just because it clogs arteries >> that of course. Yeah, exactly. >> Yeah, >> it Yeah, in reason in ways that we probably don't need to get into, but 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 let's take care of this first. >> Is also true the fatty acids we ingest. >> This is also true. The fatty acids we ingest if they get into cells, of course, you know, um 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 they both get into other cells. uh throughout the body and when they do they need to be handled appropriately. Lactate is maybe a little bit more on that on that side. It has some important effects to the chemistry of cells that are important to deal with. And so lactate if it if it gets too high in the body it can be toxic. you know, uh, lactic acidosis, which is essentially the the the phenomenon where we have too much lactic acid, lactate in our 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 and that trait was selected for and we're now pretty good at it. We had a colleague of yours on the podcast who studies hypoxia and spleen function and and we're 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. Like that's a that's a good series to watch. on the other side of the coin, the maladaptive um situation. Could you tell us about the Warberg effect and its role in cancer? And 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 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 through a variety of mechanisms. Would I ask you to like >> agree uh if you disagree please disagree but >> it's true right that there are a lot of paths to cancer. >> Yeah 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 um exciting developments in cancer therapy over the last 10 or 15 years has been these checkpoint inhibitors PD1 PDL1 that uh 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 and allow them to be seen by the immune system and eliminated 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 Warberg effect, this is really fundamentally what you're talking about. So the Warberg effect is a phenomenon that was named after Otto Warberg, 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 Warberg effect. What Otto Warberg 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 Warberg in the 1920s for for many years. >> Broken meaning they're not making ATP or or they're they're doing something wacky. >> Yeah, they're 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 and 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 eventually make a tumor so the Warberg effect is a phenomenon again in simple terms that is absolutely the case that mo 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 dubtales very nicely with what we've been talking about before. The oxygen consumption, the Warberg effect, is basically just a surrogate for that resource allocation question. And cancer cells are are very adept at using their resources to duplicate themselves. >> Of the uh modern treatments for cancer, radiation, chemotherapy and amunotherapies and what's of happening now had someone on talking about you know cart cells and um things of that sort. But is there anything that um you kind of sense on the horizon? it might be 5 10 years out or two years out that like if if we could just solve that that we would be in a position to treat and cure many more cancers like like what's the >> what's the kind of lynchpin thing here? Is it being able to reallocate the use of pyuvate like if we could do that if that was a druggable thing or you could do a gene therapy but or you could use non-invasive tools like ultrasound or light these are all just forces right chemical or I would I would like to simplify things like for people if possible like there 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 bolt? >> Yeah. >> We would be in a much better position to treat a lot of cancers or cure them. >> Let'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 hyperp proliferating, it's us, right? It's our cells. It doesn't 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 nonself. 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 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 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. Has many features of stem cells. 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 hair. Exactly. This is obviously one reason why many of the the side effects of chemotherapy is to target those proliferating cells which share many features with cancer cells. So 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 it's a great rubric by which to think about biology. Cancer cells a a tumor is under evolutionary pressure. Right? So we know 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.1% of the cells either through a mutation or some sort of an adaptation are not killed by it. But that.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 uh cancers, but then it comes back. And that's because these cells are under evolutionary pressure. If 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 I 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 going to 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 too. I think the future of cancer therapy again in my 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 this drug and this drug are going to 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 encogenic mutations, specific mutations that cause cancer. Krass mutations are one that 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 onenic. 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 [snorts] drug and use them in combinations, our ability to treat cancer is going to be dramatically improved. >> That's very encouraging. We had a guy on the podcast named David Fagenbomb. 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 because 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 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 uh not for profofit called Every Cure, which has been successfully using AI and cell assays and things to take 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 cuz 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. >> That's the key thing is that, you know, >> David's situation is very specific to David and and every tumor is a little bit different. >> Yeah. 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. 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 in a world that isn't today's world but hopefully not too long uh 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. You're highlighting something really important that is both about the sociology of medicine and science that it's just the it's not disparaging of 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 a 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 cancer of a cardiammyioite 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. >> Yeah. >> As opposed to they're overusing energy. There's too much pyuvate. I'm making this up, right? I'm not obviously not my field. But rather than think only about address in the body. >> Yeah, no question that we should be thinking about the specific features of cancer. I've been talking about it 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 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 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 in the field over the last 10 or 15 years and maybe even 10 years or less at trying to specifically block the resource allocation of cancer cells toward building new 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 and rewire its metabolism to build that same thing a different way. But that is a very important feature of the cancer tube. Beyond just the mutations are the are the the metabolic processes that enable those mutations to be manifest in in in what turns into a tumor. How far are we from a a world where um I drink a fluid and it's a safe fluid because we do this for like other types of imaging. I step into a tube and I do it when I'm like five >> and I do it when I'm 50. >> Mhm. And I get a picture of red and green in every cell, right? So you 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 this is a healthy cardommyioite 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 cardio. We know this from the population of of age match data and then when I'm you know 40 50 you go yeah I don't know like the your heart's looking a little more green than red or something like that. we can kind of turn the dial back like like we have druggable, you know, targets inside of cells and we can like kind of like adjust the the energy allocation like is 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 cuz I feel like we've gone from this place where like >> I was around when the first MR 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 and you can see acts on pathways but if we get down to the cells cool >> it's a lot of salt and pepper >> then you get down to the inner workings of the cells 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 I 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 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 a >> that could be done. >> Yeah. >> Like we've got smart people working on this. We need more money >> to for scientists to work this stuff out and more scientists to do that work. But I feel like that's doable >> conceptually. Pieces of that are doable. I think you know when you talk about can we basically image metabolism with cellular resolution I [clears throat] should be clear that's a very difficult problem. The spatial resolution the ability to see fine enough detail to make out individual cells or even uh 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? That there's nothing I can see in the metabolism of a cell. So, 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. >> Well, we would in neuroscience. I mean, again, I was fortunate to be part of this wave of technology. 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 cuz you lost that function. But, you know, a lot of it was just blood flow. It was like oxygenated to deoxxygenated blood >> reflects light differently. And like you'd get these beautiful maps, but you were just looking at blood flow. Now, then you got >> 2D deoxy glucose. You can look at glucose uptake, but it was spatially very crude or it was the the time resolution wasn't very good. But 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 worse, >> but they retired now. So, like, it got a lot better because you could see what's really happening. >> Maybe I'm overly optimistic. No, I I think that 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 would be or collection of things and then figure out a way to measure that >> non-invasively, so to speak. You know, it's one thing if if I'm going to measure that, do I have to cut off my arm, >> shave it into slices, and you know, measure it? Nobody wants that. >> So, how can I measure it without, >> you know, 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. And the experimental tools, the tools that we can use in mice or in cells and culture are definitely getting better. And that that's that's an aspect of this field of 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 you know intermediates and products and substrates of these 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 I'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 like this is like 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 that a musky excuse me and now spouses of people that had Parkinson's in particular the female um 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 if cellar metabolism is at the heart of certain cancers or neurodeenerative conditions makes sense that we're breathing out yeah >> the byproducts obviously these sense are just correlative right and the shifts in when we 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's off in their skin power that's not extreme and and become remarkably astute detecting real underlying issues. Yeah. 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 um how well or poorly we're regulating >> energy? Yeah. I mean, obviously, as you said in your in 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 that those 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 um different from the blood, but it's a fascinating topic and and as that gets to chemical specificity, it'll become probably more clear what's going on there and why why is Parkinson specifically susceptible to that different chemistry in a way that can be detected by scent. We 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 random ice control trials and metaanalysis. That's like his if it's not there, he's not interested or he's perfectly interested in in tossing away everything else. So that's kind of his hallmark. So that should feel good to you 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 discussing? >> There's a a widely accepted hypothesis that mitochondria with excess energy leads to problems. You know, many people that 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 uh 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. Once again, it I'm thinking about the this notion like no individual or collection of individuals or cell or collection of cells can really get away with or 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 this like single cell analysis all the way to to societies. I actually think >> this is fascinating. I for a variety of reasons. First of all, again, we've never had a serious discussion about what mitochondria actually do besides just create 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 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 microactories that is us. I am certain that people hearing this will no longer think about like metabolism just as them my metabolism but this um constellation of metabolisms and and the health status of 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 like a worldclass 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 to you to the University of Utah for allowing uh 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 the people and there are others in the field. you're so good at attribution who are 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. 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 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. >> Uh we'll do it again >> anytime. >> Cheers. >> Thank you. Thank you for joining me for today's discussion with Dr. Jared Ruer. To learn more about his work, please see the links in the show notes caption. 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