Andrew Huberman interviews biochemist Dr Jared Rutter on mitochondria, metabolism, and cellular energy allocation
Andrew Huberman speaks with Dr Jared Rutter, professor of biochemistry at the University of Utah and Howard Hughes Medical Institute investigator.
Summary
Dr. Jared Rutter, one of the world's leading experts on mitochondria and cellular metabolism, joins Andrew Huberman to challenge conventional thinking about what metabolism actually is. Dr. Rutter argues that what we commonly call "our metabolism" is actually the sum total of the individual metabolisms of all 30 trillion cells in the body — each making constant resource allocation decisions about whether to burn fuel for energy or use it to build new cellular material.
A central focus of the conversation is Dr. Rutter's co-discovery of the mitochondrial pyruvate carrier (MPC1 and MPC2), the proteins that transport pyruvate into the mitochondria, and how disrupting this pathway in heart cells causes pathological growth and heart failure.
Dr. Rutter also explains the Warburg effect in cancer — the observation that cancer cells consume less oxygen not because their mitochondria are broken, but because they are redirecting resources toward building new cells rather than generating ATP.
The conversation also covers how excess energy at the mitochondrial level generates reactive oxygen species, contributing to aging and disease, and closes with a discussion of whether metabolic byproducts exhaled in breath — illustrated by the documented case of a woman able to smell Parkinson's disease — could serve as useful disease diagnostics.
Key Takeaways
FULL TRANSCRIPT
What metabolism really means at the cellular level
Andrew Huberman: 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 so-called powerhouses of the cell.
Dr Jared Rutter: When we think about metabolism, as you say, I think all of us think about it in terms of our body's metabolism, our metabolic rate — calories in, calories out. What that really is, our body's metabolism, is basically the sum total of what we ingest: 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, sugars, and so forth — that then distribute throughout the body, go into individual cells, and enter this process that we call cellular metabolism.
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. That cell does whatever it needs to do with the molecules it takes in to fulfill its particular functions, and then that leads to the release of waste products that we eliminate from our body. That is the organismal metabolism — the metabolism of our body.
As you allude to, 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 — those individual cells and how they choose to take up certain nutrients, how they choose 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 it happens at the level of individual cells. I think that's one of the fascinating things that is maybe a little bit less understood.
Huberman: If we were to just take the single cell view for a moment — and I know that aging isn't your specific area of interest — but one thing that's always intrigued me is that my postdoc 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 I wonder what he used to be like. But it's a great question. He used to do this every once in a while — just ask these very basic questions that no one else on our halls at Stanford could really answer. Why does a kid have so much energy, and when we're older we don't? People say, well, people are moving less, the tissues are wearing out. But at the level of energy production, are we aware as biologists at this point in history as to why a young cell — it could be a muscle cell, it could be a neuron — versus an older version of that cell either produces less energy or why the whole body just seems to have less get-up-and-go? Do we have an answer for that?
Dr. Rutter: Yeah, I think we have a partial answer for that. That's definitely a frontier of science — trying to understand exactly what goes wrong during aging. There are many aspects to it. As you alluded to, one of my passions is the mitochondria. And I think it's almost universally the case that mitochondria become less energized, less effective, as we age. The reasons for that are to some extent clear but I think largely unclear, but that is definitely a feature of the aging process.
There is this aspect of accumulation of damage. Living in the world we live in, 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 in terms of the damage that can come as a side effect of that. The accumulation of that damage over time is certainly strongly correlated with aging. There's some really nice evidence in models where we can do genetics — in animal models — that suggests that accumulation of damage is a big part of the aging process. It's a huge area of interest in the field: 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. I don't think we tend to think of aging as a cellular phenomenon, but I think fundamentally it almost has to be. We are made up of cells, and the processes that lead to aging are the accumulation of processes that happen at the level of individual cells. I think in a way we're at the precipice of understanding a lot of this because of the tools that we are starting to have access to that will help us better understand cause and effect and the specific molecular features of the aging process.
Why mitochondria — and their bacterial origins
Huberman: 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 specifically drew you to mitochondria versus all the other pieces of cells or parts of the body or organs that you could have worked on? Why the mitochondria? What's so sticky about those as a place to devote a significant fraction of your life?
Dr. Rutter: It's an area of cell biology, an area of the details of how life works — one of these things that is, in my view, just a brilliant example of taking chemistry of incredible complexity and making it work effectively inside of a living cell. Mitochondria are believed to have been the result of an endosymbiotic event where a free-living bacterium was engulfed by another cell and in a way kind of domesticated.
Huberman: Wild to think about. I'm sure people are following, but in case somebody isn't — what Jared is saying is that our cells were basically invaded by a bacterium, and then that bacterium became part of our stable genome going forward. It went into what we call the germ line and therefore was propagated from parents to kids. So now mitochondria live in us, but they didn't start off living in us.
Dr. Rutter: That's right. And we hear that about the gut microbiome — we have these trillions of bacteria that live in us, we colonize, we can recolonize, take antibiotics and then replenish. 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 there is solid evidence that they came from outside of humans.
Huberman: Is there solid evidence for that?
Dr. Rutter: I think that's the only model that any of us as scientists have any good reason to believe. And that's fascinating history, right? There was a bacterium and another cell that got together, and together that combination could do things that neither one of them on their own could do. They worked together in some way to enable the evolution of complex life. Eukaryotes — the type of cell that resulted from that combined situation — these are all the organisms that we see around us. Plants, animals, fungi — all are the result of these two cells getting together and making peace, so to speak, and teaming up to make this synergistic cell.
Huberman: Is it synergistic? Forgive me for interrupting, but when I think about viruses, I think viruses have their own sort of intelligence. They hijack the genomes of cells and they either kill those cells or, if they're really smart, they keep those cells alive and use them to continue to live and propagate through the behavior of an animal — like the rabies virus. Let's get this animal aggressive so that it bites and then transmits. 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 this have been a takeover by the mitochondria?
Dr. Rutter: This is a bit of a philosophical question. Of course, we don't have a record of exactly what 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. And I think that tells us that more than likely complex life could not result from a bacterium on its own or the archaeon — the cell that became the host for that bacterium. So I think you can make a compelling argument that this was beneficial. One reason it was beneficial is because it enabled a form of metabolism that wasn't possible before, and enabled a more complex cell to be more metabolically efficient and diversified — which in turn enabled complex life to evolve. Totally fascinating history, but I think it also has very interesting implications for life today.
How mitochondria are distributed in cells and why it matters
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? If any of our cells have something put into them — let's say a physical object like a splinter — and then you procreate with somebody, you don't expect that child will have that little bit of splinter in their cells. But if the germ line — the eggs or the sperm — has something incorporated into it, then potentially it could propagate. That's why they call it the germ line as opposed to somatic cells. Most people aren't aware of that distinction. It makes perfect sense once you hear it. But you're talking about many, many years ago a cell having this bacterium go into it and then somehow stably representing itself in the genome so that it propagated forward. How do we think that might have happened?
Dr. Rutter: The main genome of the cell — the cellular genome, DNA contained typically in the nucleus — mitochondria exist in the cytoplasm outside the nucleus. One of the interesting things about mitochondria, which I think is totally fascinating and has really interesting disease implications, is that mitochondria have their own separate genome that is a relic of the bacterium that they are the descendants of. It's in a circle, like bacterial genomes, whereas the nuclear genome of a eukaryotic 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 — to enable the extraction of usable energy from the food that we eat.
As you alluded to, those cytoplasmic mitochondria somehow make it from generation to generation. One of the interesting features of them being cytoplasmic is they're completely inherited from the mom, from the egg. As you know, when the sperm invades the egg, the genome from the sperm gets into the egg and fertilizes it, but the cytoplasm of the sperm does not. So the mitochondrial genome of you came completely from your mother. Mine came completely from my mother. And again, that has interesting implications for the inheritance of diseases that are mitochondrial in origin. That's sort of how we think it works — it basically propagates from the egg upon fertilization, then gets distributed to all the cells including the germ line that that fertilized embryo will have, and then gets passed on to the next generation in the same way.
Huberman: Ratcheting toward the actual functioning of mitochondria — you've given a beautiful picture of the mitochondria not in the nucleus of the cell but in the cytoplasm. So still inside the cell. Most people probably remember from their high school biology a picture of a cell that always looks round. I'm guessing you're going to tell us that mitochondria can be distributed lots of places in a cell, because a lot of cells aren't round. A lot of them look hairy or they have long extensions like neurons. Is it fair to say that you can find mitochondria everywhere in a cell? And if so, what is the importance of having mitochondria distributed spatially through the cell?
Dr. Rutter: Spatially — one of my scientist colleagues might call me on this, but to my knowledge I can't think of a place that exists in cells where there aren't mitochondria. And as you alluded to — 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 neurons that have one-meter-long projections, and mitochondria transit from the cell body down those projections. As best we can tell, those mitochondria play essential roles at the ends of those projections, typically being able to generate usable energy. They're extracting the energy from the food that we eat and powering the neurotransmission, the functions of those nerve terminals.
And I think that's true of virtually every cell in our body. The extraction of energy and turning it into a usable form — typically in the form of ATP, adenosine triphosphate — that is the energy currency 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, and that ATP is needed in virtually every place of every cell. Having local production makes it more efficient.
There's been beautiful work showing that when a cell is crawling — as cells sometimes do, like an immune cell that sees something it's chasing — there will be a distribution of mitochondria towards the leading edge of the cell, which is very energetically expensive. Crawling 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 a fascinating example of that local demand for energy.
Huberman: I'm asking some high-level questions, I realize, but is there any reason to believe that a given mitochondrion knows what cell it belongs to? Are the mitochondria in one cell type very different from the mitochondria in another cell type? And do your mitochondria — I'm guessing because they came from your mom's genome — know that they're different from my mitochondria? How much identity do they have?
Dr. Rutter: I would say this is a topic that is at the frontier of what we know. You're asking questions that are right at the edge of our current knowledge. Yes, mitochondria are different. To a first approximation, you could say that virtually every cell in our body has slightly different mitochondria that are particularly suited to the demands of that cell.
A heart muscle cell — a cardiomyocyte — that cell kind of has one job, and that's to contract every second of every minute of every hour of every day for our entire life. And when it coordinates that contraction with the other cells in the heart, that enables our heart to beat. That's what its job is.
Huberman: Is there any turnover of those cells? We know neurons don't tend to turn over.
Dr. Rutter: Very little. Very little.
Huberman: Well, that's reassuring.
Dr. Rutter: You can imagine that it would be hard to replace that in real time. That's a — I'm a hockey fan — that's a change on the fly scenario of biblical proportions. So those cardiomyocytes, their mitochondria are wired to consume whatever is available and make ATP, because that ATP is going to be incredibly important to enable the contraction of that cell and the beating of the heart.
Mitochondria in other cells — for example, the stem cells that enable our intestinal lining to be turned over every five to seven days, which is amazing. Your whole gut lining is turning over every five to seven days. It is amazing. Those stem cells — ATP is not the major demand of those cells. They need to completely duplicate themselves constantly, every day or less. So their metabolic program is very different from a cardiomyocyte, which just needs to make ATP to a first approximation. They need to make a whole new cell. 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 and lipids, and that needs to happen rapidly. So that metabolic wiring is completely different.
Again, the mitochondria are fundamental to that. Those mitochondria are wired in a way that enables them to produce the biomass required to make a new cell — quite different from the mitochondria of a cardiomyocyte. And that distinction plays out in virtually all cells in our body. Every one of our cells has some particular purpose, some particular function that it serves for the body, and the demands of the mitochondria of that cell are different depending on the unique functions and demands of that cell.
One of the developments that's really been happening over the last few years — very much a frontier field — is that in one cell you can actually have two different kinds of mitochondria that have two different functions and are distinct within that one cell. This was most prominently published recently by Craig Thompson at Sloan Kettering.
Huberman: What is each of them doing?
Dr. Rutter: One of them tends to be more biosynthetic — maybe producing biomass — and one of them tends to be more energy-extracting and producing ATP. That's an overly simplified but generally accurate way of thinking about it. It really emphasizes this unique function of mitochondria that can be adapted for the needs of the cell.
How cells allocate energy — insulin, glucagon, and the fed/fasted state
Huberman: Okay. So I eat some food, that food is absorbed, I get glucose circulating in my bloodstream, I've got some stored energy in the form of glycogen, and so on. How greedy are the different mitochondria? Is the name of the game that every cell is trying to get as much energy as it can to produce as much ATP as possible, or are they communicating and is energy being allocated in some more democratic way? I could imagine two scenarios — one where the vasculature just distributes glucose very well to everything, so every cell gets access to some glucose and is just diligently trying to make as much ATP as possible and the whole system works beautifully. I could also imagine a situation where there's some prioritization of important structures like the brain, keeping you alive, breathing, heart. I'm talking about under non-stressful conditions. So how is energy allocated to cells, and then how are cells divvying up the goods?
Dr. Rutter: It's a brilliant question and a fascinating area of physiology. When we eat, our digestive system starts extracting the constituents of what we eat — again, sugars, amino acids, fats from that food — and that triggers signals of different kinds. GLP-1 being one, insulin being another. Those signals are hormones. They get secreted and they go to many cells throughout the body, and that tells each individual cell: we just ate. The implications of that are different for each cell. Some cells don't care. Some cells don't pay attention to that and just keep on doing what they were doing. Some cells care a great deal.
Adipocytes, for example — these are the fat cells, the cells that make up our fat tissue. They care a great deal about that. When they see insulin, what they do is they turn on a protein — they start making a protein that will cause glucose to be taken up into that adipocyte, that fat cell. And that glucose will then be converted through a series of chemical reactions into a fat molecule, and that fat molecule will be stored away in a way that is very safe and can be stored for potentially a very long time.
It's a beautiful way for the organism to coordinate. I just ate. Our energy status as an organism is great. So let's squirrel away some of that energy in the form of fat that can be stored in our adipocytes very safely and can then be 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. Those adipocytes full of fat from when we ate probably kept our ancestors alive when they went through periods of prolonged fasting.
Insulin has other effects on muscle and other cells throughout the body. The response of different cells to the fed state is different depending on the needs and functions of that cell. Again, some cells don't care at all. They're going to just go about and do their business. And some cells completely rewire their function depending on the metabolic state — the fed/fasted state — of the organism.
Huberman: The picture you just described leads me to conclude that basically every cell knows its job and is diligently fulfilling that role. And somehow the whole thing is orchestrated so that we work — which I know for some people might be like "duh," but just think about that. A liver cell isn't really talking to a 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. Most people think about insulin sensitivity, 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 that has all sorts of cool implications — it can prepare the cell to go to work hard now, to be the little squirrel of a fat cell and squirrel away as much as it can, or be a brain cell going, "Let's go, I'm ready to fire action potentials if I need to."
And in every one of these cells, mitochondria are the ones that are essentially going to drive this ATP thing. That seems extremely efficient — 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 really what we've never done on this podcast and I don't think I've heard elsewhere — how you go from glucose to ATP to the cell actually being able to perform its roles. Maybe we could really talk about what gets us from glucose to pyruvate, which might scare some people away, but 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 aren't just chemicals — they actually mean something for the cell.
Dr. Rutter: Glucose is the dominant carbohydrate, the dominant sugar that most of our cells are consuming. When glucose is brought into a cell, it goes through a series of chemical reactions that we call glycolysis. I'm going to simplify because this is obviously the subway map of New York — there are a lot of branches going all over the place.
So glucose comes into a cell, goes through a series of chemical reactions, and you mentioned it gets to pyruvate. That's the end point of glycolysis. And then at pyruvate, there's a decision that has to be made by that cell. It can either take that pyruvate into the mitochondria and burn it — essentially oxidize it, combining it with oxygen — and that is a very effective way to extract all the energy that can be extracted from that glucose via pyruvate.
Huberman: Tell us a little bit about pyruvate. What's the best way to conceptualize pyruvate for somebody like me?
Dr. Rutter: It's an intermediate. It's a midpoint from glucose. Glucose is a six-carbon molecule — a complex six-carbon chemical — that gets chemically modified down to this pyruvate, which is in a way a pivot point in the metabolism of that glucose. And the reason why we became really fascinated with pyruvate is because of that bifurcation that happens. Pyruvate can either be taken into mitochondria and burned — which is very effective for generating ATP, for extracting all the energy that can be extracted — and that's what cardiomyocytes, for example, really love to do: take everything they can from the circulation, burn it, make ATP, keep our heart pumping.
Other cells, on the other hand, don't do that. They don't need as much ATP. Those intestinal stem cells I talked about — the factory that enables the repopulation of our gut lining every week — they do something different with that pyruvate. Instead of burning it, they turn that pyruvate and other intermediates in glycolysis into biomass — into the stuff that will enable that one cell to duplicate itself.
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 a good baseline way to think about what we get out of the food that we eat. Energy, or building blocks that can be used to make a new cell, to repair a cell that's been damaged, for a B cell — an immune cell that makes 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, because antibodies are proteins. And that's a very important part of our immune system that keeps us protected from invaders that might otherwise kill us.
So that distinction that lands at the point of pyruvate is a super fascinating pivot point in metabolism. Many of us are fascinated by exactly how the cell organizes itself to make the right resource allocation decisions. Every one of our cells, every second of every day, is making resource allocation decisions — what does it do with the stuff that it has?
Huberman: So we are probably about seven steps away from sandwich. Sandwich goes in the mouth, into the gut, gets absorbed, we get glucose. Glucose gets into the cell. We've got some important biochemistry in this ATP generation pathway and we get to this key node — pyruvate — and pyruvate is either going to say, "Let's make more stuff of cells," or it's going to be burned for energy. Like you have lumber arriving — you're either going to use it to build more house or you're going to burn it for heat energy.
Dr. Rutter: Great analogy. And let's add a condition where you need to burn some of that lumber for heat energy to keep the construction project going.
Huberman: Exactly. So we're at this key bifurcation. Is it just as metabolically demanding for a cell to use pyruvate to keep itself going — like a cardiomyocyte — versus making biomass? Or is one more costly? Rough percentages — I won't hold you to it.
Dr. Rutter: One way to think about that — many of us are probably unfortunately aware of PET imaging, right? This is something that's often used to diagnose cancer. FDG PET, which is the most common form of PET, is basically giving cells a form of glucose that can then be visualized with this PET scan. The reason we do that is because tumors take up a lot of glucose. FDG PET is fluorodeoxyglucose — a labeled version of glucose. So the reason we do FDG PET is to see where in the body cells are taking up a lot of glucose, and tumors take up a lot of glucose. So FDG PET is used to diagnose cancer frequently and very effectively.
That is one metric for this. A cancer cell is again a cell that is making a resource allocation decision all the time. But in the context of that cell, when it transforms into a cancer cell, that resource allocation becomes very much about building more cells. That's why a tumor is a tumor — because that one cell that was the first bad actor decided, instead of doing the thing it was supposed to be doing, to duplicate itself and duplicate itself again and build a cluster of cells that then become a tumor.
Cancer as an evolutionary and metabolic phenomenon
Huberman: I have a pseudo-philosophical question but it's really a scientific and medical question about tumors. Bacteria have the opportunity to hijack genomes of cells. Viruses — the easiest example for people to understand is like HSV-1, which lives on neurons, doesn't kill the neuron, which is convenient for the virus, because if it killed the neuron it too would die. So this earlier idea I was raising about viruses having their own quote-unquote intelligence — stay alive but keep the host alive too, and transmit. In the case of rabies, it's the easiest one to conceptualize: impact areas of the brain that trigger aggression, which triggers biting, and people have speculated whether the virus "knows" that it's doing this — probably not, they're not brains, but it's a pretty impressive level of adaptive behavior.
I think of cancer as just a bad thing all around — these cells are greedy, they're taking glucose, they're making more of themselves, it's cell turnover gone awry, the tumor gets big, it starts to encroach on other tissues, metastasize, and 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? Is there a potential set of answers about how to deal with tumors that could be borrowed from any of those other examples?
Dr. Rutter: It's an interesting question. Viruses, as you allude to — their goal, if you do want to anthropomorphize them, is to propagate. They are under evolutionary pressure. The way 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. That is the evolutionary game, 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.
Huberman: I wish we had a better language for this thing, because "intelligence" is not really it — it's not of brains — but it's this adaptive logic.
Dr. Rutter: That's a good phrase for it — adaptive logic that enables the survival and propagation of that virus. And this is how evolution works, of course. If that virus had a mutation that made it better able to do that, that virus would then infect better, get into hosts better, propagate better, and it would eventually take over the population of that virus. That is the process of evolution.
You asked about cancer. Cancer is obviously fundamentally different in one key way. If I get a virus and I come in here and I'm hacking 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 — that's viral propagation, which we all sadly know about. There's very little evidence that cancer is infectious.
Huberman: What about Tasmanian devils? There was this idea for a while — someone will tell us in the comments — that Tasmanian devils fight and that there's wound-induced propagation of cancers. These very disturbing images of these cute little animals with tumors growing at wound sites, and it turns out those are cancer. So there's somehow fighting and wounds and transmission — it might be bacterial, I don't know. But there was this idea that they could transmit cancers to one another through fighting.
Dr. Rutter: Interesting. But right — in general, we don't actually think that people are catching cancers from one another. So when you think about the evolution of a cancer, the scope of that evolution is different. The scope of the evolution of a cell in me is limited to me.
Cancer cells undergo evolution in the exact same way. If one cell in my body starts propagating, it acquires a mutation that enables it to divide faster, maybe gets out from underneath the limits 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. That's basically the continuous process of cancer development — the acquisition of mutations that make that cell better able to evade the immune system, to duplicate itself, evade the problems that would come with DNA damage, and to continue to make cells that survive. 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 a virus has this evolutionary drive to get from one organism to another to enable its propagation. Cancer isn't fueled by the same motivations, because as far as we're aware, that very rarely if almost never happens — getting from one organism to another. So the motivations are different, but the evolutionary process underlying it — it's the same principles at play in both.
Discovering MPC1 and MPC2 — the mitochondrial pyruvate carrier
Huberman: Tell us about MPC1 and MPC2. I'm asking about biochemical steps and a key process of energy production and allocation. And normally when people hear acronyms they don't understand, they go, "Oh my goodness, what are we doing here?" But I think it's so important that people understand this business of metabolism — having energy, whether we're young or old, healthy or dealing with cancer — this is a key node. And what I want to know truly is how do you actually discover something like this? Because I think it would be very useful for people to get a picture of how this is done. We hear about molecules like MPC 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 essential aspects of ourselves.
Dr. Rutter: I appreciate you asking about that. It allows me to reminisce a little bit about the process of discovering that, which was a fun time in my career and was fueled by the brilliant people in the lab that did it. So MPC — this is a case where the acronym actually makes sense. It's the mitochondrial pyruvate carrier. You don't have to be a scientist. MPC, aptly named, is the carrier that enables pyruvate to get into the mitochondria. Mitochondrial pyruvate carrier — that's what it does. It sits in the mitochondria and basically provides a very specific hole in the membrane to enable pyruvate to get in so that it can then be burned by the mitochondria to extract all the energy and make ATP.
The history of this is really interesting. It's been known for 60 or 70 years that mitochondria must have a carrier to enable pyruvate to get in, but it was not identified what that protein was or how it worked. Fast forward to 2008 or 2009 or so, and our laboratory had just recently become fascinated with mitochondria. I would say the motivating piece of information that convinced us to start working on mitochondria was the realization that many of the proteins that make up mitochondria — that do the stuff that mitochondria do — we don't know what their functions are. And that suggested that this organelle, the powerhouse of the cell, had mysteries that we don't have answers for. So we started just taking some of these proteins that we know are in mitochondria but 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.
Huberman: Way back when I was trained, I observed that if you want to figure out what proteins are in a cell, you get a bunch of those cells, you kind of grind them up, and then you run them through a bunch of columns — literally tubes — and those tubes have filters that either let big, less big, small, or very small things through. What we call fractionation. And then you kind of test the different stuff that comes through for its ability to do something in some sort of assay. Is that kind of how MPC2 was found? Was it done by hardcore biochemical purification — the old way of doing it? And do we know the total number of proteins in a given human heart cell?
Dr. Rutter: I think we know. Yeah, I think we know everything that's in a heart cell. 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. We know the human genome — it's been sequenced. We know what that is.
Huberman: But we don't know everything that's expressed in a given cell.
Dr. Rutter: That's true. And there are some very interesting features there.
Huberman: Twenty years ago, could you say what you just said with much less confidence — that we know what's in a heart cell?
Dr. Rutter: Now I think we know essentially everything. Again, there are going to be subtle nuances that we don't know, but I think we know almost everything. That doesn't mean we know what all those things do. And that's maybe the frontier for the next generation of scientists to figure out. We don't know what they all do, but we know more or less what they all are.
Knowing what they are but not knowing what they do motivated us to go take these two proteins that were in the mitochondria. We could make a very strong hypothesis that they were important because they were in every cell that has mitochondria — down to a yeast that's a single-celled organism, and plants and animals. Everything that has a mitochondrion has these two MPC1 and MPC2 proteins.
It would probably take too long to explain all the processes we went through to try to identify the function of MPC1 and 2, but this was a brilliant collaboration and one of the highlights of my career. Different people in my lab and in the lab of my colleague Carl Thummel — who was a fly geneticist and used his unique skills and resources — and we were using yeast as a model system as well as human cells, and triangulating all that data. We came up with data that suggested that this might be the mitochondrial pyruvate carrier. These two unknown proteins that happened to be sitting in the mitochondria — and that has now been validated many times over.
What was maybe even more exciting than the discovery of the mitochondrial pyruvate carrier — which Carl and I did, and we published a paper, and the lab of Jean-Claude Martin in 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 to understand what role this protein plays in the allocation of that pyruvate that we've been talking about. Because now the MPC is the first step towards one destination of that pyruvate. It kind of pulls it into the mitochondria, and once that pyruvate 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 cytoplasm.
We've done a lot of work since on what the implications of that are. And I think it's been exciting to see in different cell types what that means. Cardiomyocytes, for example — again, these are cells that want to make ATP to allow the heart to continue to contract. They need to extract every bit of energy they can and make as much ATP as they can. They use this MPC extensively.
Huberman: How do they ensure that they make just enough to maintain themselves — so they're not so busy burning up all the lumber that the house falls apart?
Dr. Rutter: It's a brilliant question, and it's definitely not programmed like there's a spigot with a diverter valve where 90% goes this way and 10% goes that way. What actually happens — and this doesn't just happen in cardiomyocytes, it happens in every cell — is that basically the cell is measuring the outputs all the time. I think you could make a compelling argument that almost all cells know how much usable energy — ATP — they have at all times. And when it gets low, they will initiate a series of responses to bring it back up. They'll turn off processes that use ATP. They'll start pulling glucose out of the circulation to make more ATP. There's this really profound response to ATP depletion.
And I think that's true for many of the end products of our metabolic map. These are the products of the metabolic map — the amino acids that make proteins, and the nucleotides that are required to make DNA and RNA, our genome.
Huberman: There's a greediness to all these cells. If the fat cells are greedy, you could really see a problem if we're not ingesting enough glucose. But ultimately, fat cells just want to get bigger and bigger — but if the cardiomyocyte doesn't have enough glucose, eventually it could shut down any number of things. Like you can remodel the house down to just the fireplace and a little bit of structure around it, but eventually you need the resource. So then what happens — the adipocyte liberates the energy?
Dr. Rutter: Exactly. 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 has become a little bit more popular recently because it's now being combined in some of the newer GLP-1 drugs. Glucagon is called a fasting hormone. In many ways it does the opposite of insulin. It will go to the fat cell, bind to the fat cell, tell the fat cell to take the fat that it has squirreled away and release it. And now that can go to other cells in the body — the heart. The heart is very good at consuming fatty acids that come from adipose tissue.
Huberman: I'm actually relieved to hear that. Because if, God forbid, there's a shortage of food that lasts long enough, that's definitely an organ I don't want shutting down.
Dr. Rutter: Exactly. And most of us have fat in our fat cells. You could make an argument that the key destination of that fat is the heart to keep it alive. In a normal human, I think it's estimated that 70 to 80% of the energy extraction that happens in cardiomyocytes — in heart muscle cells — is happening from fat.
Huberman: Under fasted conditions?
Dr. Rutter: Especially under fasted conditions, but even in fed conditions fat is available for the heart to use. Dietary fat or fat from adipocytes — both. Whatever fat is in the circulation, the cardiomyocyte is pretty good at taking it up and burning it, making ATP from it.
Huberman: The brain likes glucose, but it can use ketones. So carbohydrates are not quote-unquote essential — the ketogenic folks love to say there's no such thing as an essential carbohydrate. That doesn't change the fact that the preferred fuel source for most every cell is glucose. But anyway, that's a separate issue. If the form of energy changes, is it still the same once you get to mitochondria, pyruvate, MPC, and downstream? Is energy just energy at that point, or are there multiple pathways depending on the fuel source?
Dr. Rutter: The ability of neurons to consume fatty acids is limited. I think it's traditionally been thought that it's very close to zero — I think that's being questioned now, but it's limited. As you allude to, neurons are particularly fond of consuming glucose and use that glucose to make their ATP. And that obviously puts a very stringent demand on the body to always have glucose available.
Glucose is one of these things that's fascinating — the systems that we have in our body to maintain glucose. Diabetes is defined as high blood sugar. That is the clinical definition of diabetes: when basically our body does not adequately limit the circulating glucose, and that is destructive and damaging. But it's damaging in the course of years — 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 I think for a few different reasons, but probably the most important one is that the brain requires some amount of glucose to keep it functioning.
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. Neurons are very adept at taking in glucose and burning it and making ATP from it.
I think the heart is really fascinating because it'll eat anything. It's an omnivore. Fats, glucose, lactate, ketones, amino acids — it will make ATP out of just about anything that ATP can be made out of. And again, that's important to enable us to live no matter whether we just ate or not.
What happens when the MPC is knocked out — and what it reveals about heart failure
Huberman: What is the consequence of eliminating the MPC? If you make a mouse that lacks these proteins, do you get a dead mouse?
Dr. Rutter: They do not survive to birth. It'll start to develop and then, if I remember right, it's about 12 or 13 days of development — about two-thirds of the way from fertilization to birth of the mouse — it will die and you won't get a live mouse. But because of the technologies that Mario Capecchi 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.
Huberman: He developed a technology that would allow for organ- and cell-type-specific deletions or additions of genes.
Dr. Rutter: Yes, and many people have been contributing to that technology and different ways to use it for decades now. 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? We've now made ATP generation from glucose less efficient. We've cut off the ability to use mitochondria at least in the conventional way.
The results of that experiment are fascinating, and this is work that has been done by a few different labs. Ahmed Cluntun, who is a postdoc now running his own lab at Rutgers, was the one who started this, and other people have contributed. What essentially happens to that heart is that it lives, and the animal lives for weeks after that. But eventually the animals die. And when you look at what they die of, they have a massive heart. They die of heart failure.
What has become clear as we've 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, and 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 — is they have made a resource allocation decision that turns out to be pathological for them. Instead of using the glucose that they take in to burn it and make ATP, they start making biomass. We talked about that bifurcation. We've eliminated their ability to make ATP from glucose at least as effectively, and instead they make biomass. They grow. And when cardiomyocytes grow, that creates structural problems for the heart. Almost every human that succumbs to heart failure will end up with a big dilated heart that's less effective at pumping. And that's what we see in the mouse.
And that maybe tells us something about the fundamental importance of this resource allocation decision. This is obviously just in the context of cardiomyocytes, but again, that resource allocation decision is happening in every cell in our body all the time. That's one reason why I'm fascinated with this field — 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 heart is making a resource allocation decision that is pathological, can we find a therapeutic that will go and correct that and rewire it in the appropriate and healthy way, and can that then restore the proper function of the heart?
I think we're at the frontier of this field, but it's a really exciting place. We're starting to understand the problems and we're starting — early — in developing the right agents to manipulate this metabolic map that might be able to fix things.
Lactate — from waste product to important fuel and metabolic signal
Huberman: Let's talk about lactate. Every time lactate has come up on this podcast before, it's been in the context of exercise physiology. We had Andy Galpin on, and he told us — 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. When you think about lactate, what do you think about?
Dr. Rutter: Pyruvate — we talked about pyruvate extensively. To a first approximation, when pyruvate is made, it has two fates. It can go into the mitochondria — we talked about that. What we didn't talk about is the other major fate, which is to be converted to lactate and exported. And that decision — burn it or 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.
Huberman: Why would it not burn it or make more of itself — because it's just got it in excess?
Dr. Rutter: There's something about that production of lactate that enables ongoing production of biomass. If you burn the pyruvate, that turns into carbon dioxide — we breathe it out. The stuff is gone. There's no stuff, there's just the energy. If you don't burn it, that stuff doesn't get eliminated as carbon dioxide and can turn into a protein, can contribute to protein production or carbohydrate production or fatty acids that can be used to make new cells. And so that really is that resource allocation decision we talked about many times — building or burning. And lactate is one of the mediators in a way of that building decision.
Lactate historically has been thought of as a waste product when our cells can't burn — typically because of lack of oxygen. When I talk about burning, what I really mean is taking that pyruvate or fatty acids or other things and oxidizing them using oxygen, and by so doing extracting the energy and doing this unbelievably amazing chemistry that the mitochondria do to very effectively capture all that energy and make it usable in the form of ATP. When oxygen isn't available, that pyruvate cannot be burned and then it essentially has to be converted to lactate. That's why when we exercise and our muscle becomes hypoxic or doesn't have adequate oxygen, we make lactate — and that lactate is what causes the burn that we feel.
We've thought about it traditionally as a waste product. There's been beautiful experiments done in the last five or ten years — Joshua Rabinowitz, 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.
Huberman: The heart seems like it's got a dog's breakfast of fuels. It likes lipids, it'll take glucose, it likes lactate — anything that's good for us, because that keeps it beating no matter what the metabolic status. And lactate is just an important mediator of carrying that energy around — it can be a fuel, it can be a shuttle.
In the context of exercise and the brain — I've mentioned before on this podcast that if we do intense aerobic exercise, we get enough lactate generated that it does seem to be a signal to the brain for brain-derived neurotrophic factor. And it 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 as waste products. Just like we used to talk about junk DNA — nobody does that anymore. We have to be very careful with language in biology. The moment we label something conceptually, you shut down a line of discovery that almost always ends up being super important.
Dr. Rutter: We joke all the time in the mitochondria field about "the powerhouse of the cell," right? Which it really is — 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 — 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.
Huberman: There's something I can't wrap my head around. If I have an excess of energy and therefore I'm making lactate, am I going to now prioritize lactate? Is that going to get burned off the top of the energy priority scale?
Dr. Rutter: That's a good question, and I don't think we have strict answers to this, but there's definitely prioritization of energy. One of the most important things to burn is fatty acids. And the reason for that is that when fatty acids are in excess, they can be toxic — and they can be toxic in an acute way, quickly. Glucose again is toxic in excess, but chronically maybe it's a little bit less dangerous if we have high glucose for some time. High free fatty acids is dangerous now.
Huberman: Not just because it clogs arteries.
Dr. Rutter: Yeah, in ways that we probably don't need to get into, but it can be disruptive to cell structures and so forth. So most cells, when they have fatty acids, will burn the fatty acids first — probably as a response to, "Hey, this could kill us. Let's take care of this first."
Lactate is maybe a little bit more on that side too. It has some important effects on the chemistry of cells that are important to deal with. So lactate, if it gets too high in the body, it can be toxic. Lactic acidosis — essentially the phenomenon where we have too much lactate in our circulation — that's bad and can be lethal. 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. 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 that trait was selected for, and we're now pretty good at it.
The Warburg effect and cancer metabolism
Huberman: Could you tell us about the Warburg effect and its role in cancer?
Dr. Rutter: 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 tend to cause that cell to divide, to replicate itself more rapidly, and to evade the immune system — which is patrolling looking for misbehaving cells to eliminate them. Somehow cancer cells can avoid that. That's critically important, and one of the most exciting developments in cancer therapy over the last 10 or 15 years has been these checkpoint inhibitors — PD-1, PD-L1 inhibitors — that basically reverse that. Cancer cells are very good at cloaking themselves from the immune system, and those therapies eliminate that cloak and allow them to be seen by the immune system and eliminated. There have been amazing responses to those new therapies — they don't treat every cancer to the same degree, but there have been wonderful examples where they've been effective.
So yes, cancers can arise through many different pathways. They're all associated with mutations. One of the common features of cancer is changes in metabolism. And this is what you're talking about when you talk about the Warburg effect. The Warburg effect is a phenomenon named after Otto Warburg, a German scientist back in the 1920s, who observed that cancer cells consumed less oxygen than would be expected from the cells around them. What Otto Warburg thought was that that's because the mitochondria are broken, and he concluded that broken mitochondria are probably the cause of cancer. That thinking permeated from the time of Otto Warburg in the 1920s for many years.
Huberman: Broken meaning they're not making ATP, or they're doing something wacky?
Dr. Rutter: Well, they're not consuming oxygen — that was the observation. The oxygen consumption was low, and 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 was that mitochondria are probably broken.
We now know that mitochondria do more than just make ATP, and it turns out that mitochondria in cancer cells are not broken. In fact, they're very, very good — not necessarily at making ATP, but at making stuff. And again, the stuff is what's so important for a cancer cell, because it needs to divide itself, it needs to duplicate itself to eventually make a tumor. So the Warburg effect, in simple terms, is absolutely the case — many cancer cells, most tumors, consume less oxygen than you would imagine, because instead of burning their fuel, cancer cells tend to use their resource allocation to build stuff, to build a new cell. The oxygen consumption — the Warburg effect — is basically just a surrogate for that resource allocation question. And cancer cells are very adept at using their resources to duplicate themselves.
The future of cancer treatment — combination therapies and tumor-specific targeting
Huberman: Of the modern treatments for cancer — radiation, chemotherapy, immunotherapies, CAR-T cells and things of that sort — is there anything that you sense on the horizon, maybe five to ten years out, that if we could just solve that, we would be in a much better position to treat and cure many more cancers? Is there some lynchpin thing here?
Dr. Rutter: Let's maybe take a step back and talk about cancer — what it is and why it's so difficult. If a bacterium invades us, it's very easy for our immune system to say, "Hey, that's not us. Let's go kill that thing." If a cancer cell starts hyperproliferating, it's us. It's our cells. It doesn't necessarily have antigens — the molecules, the features that are recognized by the immune system — that are recognized as non-self. So that's one of the big challenges of cancer. The challenge for us is to figure out a way to kill those cells — which again are our cells — without killing the rest of our cells. Because if we kill the rest of our cells, we kill us. That's the challenge of cancer therapy.
Many of the features of cancer cells are not completely new things that cancer just invented. It's using the functions that our normal cells have. For example, one thing that's common — not universal, but common — in cancer cells is to become more like a stem cell. So if 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. This is obviously one reason why many of the side effects of chemotherapy involve targeting those proliferating cells, which share many features with cancer cells.
There's a second problem worth talking about too. We've talked about evolution a lot here. A tumor is under evolutionary pressure. Let's take an example where we have a tumor and we get a drug — a great drug that kills 99.9% of the cells in that tumor. But 0.1% of the cells, either through a mutation or some sort of adaptation, are not killed by it. That 0.1% can now repopulate, make a new tumor. And this is what happens in cancer therapy. We all know of tragic examples where loved ones had a tumor, got a treatment, went into remission — the tumor maybe shrinks, it goes away, maybe even becomes invisible by imaging — but then it comes back. That's because these cells are under evolutionary pressure. If one cell acquires a mutation that makes it resistant to 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.
This is not dissimilar to what happens with viruses. HIV can now be managed frequently by a triple combination therapy. The reason for that is you give three drugs that are going to kill that virus or prevent its propagation. 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 is going to be: we have many safe and effective drugs that hit different features of the cancer cell's 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. As a result of that, that might result in something approximating a cure.
There have been amazing therapies that have come out. One of the most exciting recently are drugs that target specific oncogenic mutations — specific mutations that cause cancer. KRAS mutations are one that are really exciting. These target specific proteins that are contributing to the cancer in a completely specific way — don't do anything else in the body to normal cells, only hit those mutations that are oncogenic. But again, eventually resistance can be acquired to that. So if we can make multiple examples of that kind of specific, safe drug and use them in combinations, our ability to treat cancer is going to be dramatically improved.
Huberman: That's very encouraging. We had a guy on the podcast named David Fajgenbaum. He's a medical doctor at the University of Pennsylvania. He had Castleman's disease and was able to cure his own Castleman's disease because he was basically on his deathbed. He started taking different combinations of already approved drugs in a kind of desperate attempt to save his life, and he found things that would extend his life. He's been alive 11 years now, and he runs a lab. He also has a not-for-profit called Every Cure, which has been successfully using AI and cell assays and things to take biopsies and try to figure out — okay, in this tragedy of a kid who's dying of a particular cancer, 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, and if the parents agree and there's no other hope, do it. In some cases they're curing and in many cases they're extending life. It matches up well with what you're describing.
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. It turns out that lidocaine has some effect on the local environment.
Dr. Rutter: That's the key thing — David's situation is very specific to David, and every tumor is a little bit different. One of the unhelpful results of historically how we talk about tumors is we talk about breast cancer or liver cancer or colon cancer. There are some breast cancers that are more similar to some liver cancers than they are to other breast cancers. Our historical classification of cancer has just been by where it is — it was defined by the surgeons that would take it out. But the specific mutations that cause that cancer and keep that cancer 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 an ability to say — in a world that isn't today's world but hopefully not too far from now — this combination of drugs is going to be effective at killing the cells in that tumor.
Huberman: 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 cardiomyocyte — because of the way that, say, MPC1 is changed? In other words, should we be classifying cancers as "this is a cancer of the sort where the cells are making too much of themselves" as opposed to "they're overusing energy" — rather than thinking only about the address in the body?
Dr. Rutter: No question that we should be thinking about the specific features of cancer. I've been talking about it in terms of the specific mutations that define a cancer, and I think that's a useful way to do it because those mutations are in a way the instructions for making a new cell. But I think a very important feature that you're touching on is that on top of that, layered on top of that, is the unique metabolism that makes up that cell — that enables those instructions to be executed. 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. So that's a really important feature of this that we need to talk about.
There's been a lot of energy in the field over the last 10 or 15 years at trying to specifically block the resource allocation of cancer cells toward building new cells. The challenge there again is that it's fairly easy to develop resistance to that. A cancer cell can just make a mutation and rewire its metabolism to build that same thing a different way. But that is a very important feature of the cancer cell — beyond just the mutations are the metabolic processes that enable those mutations to be manifest in what turns into a tumor.
Imaging metabolism at the cellular level — the frontier
Huberman: How far are we from a world where I drink a fluid, step into a tube, and get a picture of the proportion of metabolism in different organs — where you could zoom in to a single cell? This is not science fiction at the level that it couldn't be done. Where you say, "Okay, this is a healthy cardiomyocyte and it's using 65% of its energy to just keep pumping, and then it puts aside a little bit to make sure it can make more of its stuff so it stays around." We know this from population data. And then when I'm 40 or 50, you go, "I don't know — your heart's looking a little more green than red." And we can kind of turn the dial back because we have druggable targets inside of cells and we can adjust the energy allocation. Is what I'm describing so crazy?
Dr. Rutter: Pieces of that are doable. When you talk about imaging metabolism with cellular resolution — I should be clear, that's a very difficult problem. The spatial resolution, the ability to see fine enough detail to make out individual cells or even smaller than that — that's a challenge inside a human body. It's also a challenge 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. 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 are really exciting tools being developed of many different kinds to be able to image various features of metabolism in a cell. And the experimental tools — the tools that we can use in mice or in cells in culture — are definitely getting better. Our ability to now measure what's happening at individual places in individual cells, looking at specific individual molecules — intermediates and products and substrates of this metabolic map — is teaching us a lot about how metabolism works in individual cells, and that is then going to be informative when we think about how it's working in a human.
Huberman: What would be the one metabolic parameter you'd really want to measure to assess whether a cell is healthy or not healthy?
Dr. Rutter: 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. It's one thing if I'm going to measure that — do I have to cut off my arm, shave it into slices, and measure it? Nobody wants that. So how can I measure it without doing damage to me while I'm measuring it? These are hard problems, but the technology just keeps getting better in all versions of this.
Detecting disease through scent — and what exhaled chemistry might reveal
Huberman: 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 occasionally people, who can detect the scent of cancer beyond chance. And recently there's an example — my understanding is it's validated — of a woman who was able to smell Parkinson's as a musky scent. And now spouses of people that had Parkinson's — in particular the wives of these men — are like, "Oh yeah, I remember this now." As you're telling me some of this, it kind of makes sense that if cellular metabolism is at the heart of certain cancers or neurodegenerative conditions, it makes sense that we're breathing out the byproducts. Do you think that there could be useful information coming from the air we expel in terms of revealing how well or poorly we're regulating energy?
Dr. Rutter: Obviously 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 smells and scents are chemistry — these are chemical compounds that are coming from the person — 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. The blood chemistry is different between people that have different diseases and don't. And obviously the breath is some measure of the chemistry that's going on in the person. It's obviously different from the blood, but it's a fascinating topic. As that gets to chemical specificity, it'll become probably more clear what's going on there and why Parkinson's specifically is susceptible to that different chemistry in a way that can be detected by scent.
Excess energy, reactive oxygen species, and the cellular cost of overeating
Huberman: We were talking a few moments ago about excess energy toxicity. This is something that Lane Norton brought up on this podcast — he's a serious biochemist, nutrition and exercise science guy, public educator. He talks about this energy toxicity: excess calories leads to problems, not just because of the presence of excess body fat, but because 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?
Dr. Rutter: There's a widely accepted hypothesis that mitochondria with excess energy leads to problems. Many people listening have probably heard of reactive oxygen species — forms of oxygen that become reactive and end up spinning out and damaging proteins and nucleic acids. And I think it is 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. There have 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.
Huberman: Once again, I'm thinking about this notion that no individual or collection of individuals, or cell or collection of cells, can really get away with taking too much energy or not allocating it correctly. You can level up from this single-cell analysis all the way to societies.
I want to say — we've never had a serious discussion on this podcast about what mitochondria actually do besides just help create energy. So first of all, thank you so much for telling us how they actually allocate their resources towards things other than just making more energy for usage, and for building more of oneself. Also for framing that in the context of disease and health, and also for shining a light on the fact that while we might be right here now, I think as long as we're looking at things 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 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 constellation of these little microfactories that is us — I am certain that people hearing this will no longer think about metabolism just as "my metabolism," but as this constellation of metabolisms and the health status of all the different cells.
It goes without saying that it's a really unique opportunity for the general public to hear from a world-class biologist working on these specific issues and related issues for decades now. And you're a very busy person. So I'm very grateful to you, to the University of Utah for allowing and encouraging public education, and to Howard Hughes. I think people really need to understand what an amazing opportunity it is to learn from the people 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. So thank you so much.
Dr. Rutter: Thanks, Andrew. It's been a lot of fun.
Huberman: We'll do it again anytime.
Dr. Rutter: Cheers.