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
Andrew Huberman interviews Dr Jared Rutter, one of the world's leading experts on mitochondria and cellular metabolism. 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 them to pathologically grow rather than pump — mirroring what happens in human heart failure. Dr. Rutter also explains the Warburg effect in cancer, arguing that cancer cells are not metabolically broken but are instead highly effective at redirecting resources toward building new cells rather than generating energy, and that future cancer treatment will likely require combination therapies targeting multiple features of a tumor's unique biochemistry simultaneously.
Key Takeaways
FULL TRANSCRIPT
What metabolism really is — the cellular view
Andrew Huberman: 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. 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. Then that cell does whatever it needs to do with the molecules it takes in to fulfill its particular functions. 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, 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 — 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.
Why cells lose energy with age
Andrew 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 — could be a muscle cell, could be a neuron — versus an older version of that cell, why it 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 Jared Rutter: 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 it's expensive in terms of the damage that can come as a side effect of that. The accumulation of that damage over time is certainly correlated strongly 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 — the origin of a scientific passion
Andrew 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 Jared 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 bacterium — a free-living bacterium — was engulfed by another cell and in a way kind of domesticated.
Andrew 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 basically were 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. And so now mitochondria live in us, but they didn't start off living in us.
Dr Jared Rutter: That's right. And we hear that about the gut microbiome — we have these trillions of bacteria that live in us and we can recolonize after antibiotics, eat your yogurt, and so on. But the fact that the mitochondria made it stably into our genome and are transmitted from one generation to the next is remarkable.
Andrew Huberman: We think of them as us, but you're saying there is solid evidence that they came from outside of humans.
Dr Jared 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 — that there was a bacterium and another cell that got together, and together that combination could do things that any one of either of them on their own could not do, and that they worked together to enable the evolution of complex life. Eukaryotes, which are the type of cell that resulted from that combined situation, 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.
Andrew Huberman: Is it synergistic? Forgive me for interrupting, but when I think about viruses, I think they kind of 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. 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 Jared Rutter: This is a bit of a philosophical question. Of course, we don't have a record of what exactly happened when and who benefited in real time, but one thing we do know is all of complex life resulted from cells that underwent that event. 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 could then enable 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
Andrew Huberman: I'd like to ratchet 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 — 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 Jared 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 it's a little bit dangerous for me to talk about neurons with 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.
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 — is a key function of mitochondria. 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.
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 that leading edge of the cell, which is very energetically expensive. Crawling 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. It's a fascinating example of that local demand for energy.
Andrew Huberman: Is there any reason to believe that a given mitochondrion knows what cell it belongs to? Like, 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? But how much identity do they have?
Dr Jared Rutter: I would say this is a topic that is at the frontier of what we know. You're asking some questions that are right at the edge of our current knowledge. 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.
Andrew Huberman: Is there any turnover of those cells? We know neurons don't tend to turn over.
Dr Jared Rutter: Very little. Very little.
Andrew Huberman: Well, that's reassuring.
Dr Jared Rutter: You can imagine that it would be hard to replace that in real time. 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 —
Andrew Huberman: Your whole gut is turning over every five to seven days?
Dr Jared Rutter: The lining of your gut, yes. 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. So we talked about the metabolism of the organism — the metabolism of those cells is very complex because it needs to replicate all the DNA, duplicate it to go into a new cell, duplicate all the proteins, duplicate all the membranes, the lipids, and that needs to happen rapidly. That metabolic wiring is completely different. And 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.
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. This diversification of mitochondria is 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 that there's actually evidence, most prominently published recently by Craig Thompson at Sloan Kettering, that showed that in one cell you can have two different kinds of mitochondria that have two different functions and they're distinct within one cell.
Andrew Huberman: What is each of them doing?
Dr Jared 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 the body allocates energy across cells — insulin, glucagon, and the fed state
Andrew 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 shuttling to important structures like the brain, keeping you alive — breathing, heart — a prioritization of organs. 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 Jared 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. That then 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 they just keep on doing what they were doing. Some cells care a lot.
Adipocytes, for example — these are the fat cells, the cells that make up our fat tissue. They care a great deal about that. When they see insulin, what they do is they turn on a protein — they start making a protein that will cause glucose to be taken up into that adipocyte, that fat cell. And that glucose will then be converted through a series of chemical reactions into a fat molecule. And then that fat molecule will be stored away in a way that is very safe and 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.
Andrew Huberman: The picture you just described leads me to conclude that basically every cell obviously knows its job and is diligently fulfilling that role. And somehow the whole thing is orchestrated so that we work. 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 that can prepare the cell — like, "Oh, I'm going to go to work hard now, be the little squirrel that I am of a fat cell and squirrel away as much as I can," or be a brain cell: "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, right? And 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 not done ever on this podcast — is how you go from ATP to actually the cell being able to perform its roles. I know there's a lot of biochemistry there, but you've worked on some really lynchpin molecules in that pathway that perform very specific 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, but that actually mean something for the cell.
Dr Jared 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.
Andrew Huberman: North and south, which is pretty much the only direction you can go on the subway. I'm not a New Yorker. I realize you can go across too.
Dr Jared Rutter: So glucose comes into a cell, goes through a series of chemical reactions, and you mentioned it gets to pyruvate. That's the end point of glycolysis, this set of chemical reactions. And then 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, which is essentially burning it, combining it with oxygen — and that is a very effective way to extract all the energy that can be extracted from that glucose via pyruvate.
Andrew Huberman: Tell us a little bit about pyruvate. What's the best way to conceptualize pyruvate for somebody like me?
Dr Jared Rutter: It's an intermediate — a midpoint, let's say, from glucose. Glucose is a six-carbon molecule, a complex 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 — and that's very effective for generating ATP, for extracting all the energy that can be extracted — and that's what cardiomyocytes, for example, really love to do: take 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 that 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 molecules — 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 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 antibodies are. 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?
Andrew 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 that you're describing as pyruvate. And pyruvate is either going to say, "Let's make more" — you called it biomass, but stuff of cells — or we're going to use it 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 Jared 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.
Andrew Huberman: Exactly. So we're at this key bifurcation, this key split point. Is it just as metabolically demanding for a cell to use pyruvate to keep itself going — like a cardiomyocyte — versus making biomass? Or is one more costly? Rough percentages — I won't hold you to it.
Dr Jared 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. An 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 — fluorodeoxyglucose — is a labeled version of glucose. So FDG PET is used to diagnose cancer frequently and very effectively. That is one metric for this.
A cancer cell is 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 a cellular resource allocation problem — and the Warburg effect
Andrew Huberman: 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 — 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 viruses have their own quote-unquote intelligence — stay alive but keep the host alive too and transmit. And in the case of rabies, it's the easiest one to conceptualize — impact areas of the brain that trigger aggression, trigger biting. 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, cell turnover gone awry, tumor gets big, it starts to encroach on other tissues, metastasize, boom, you kill the host. That's not a great strategy from the perspective of the tumor. So it obviously isn't thinking about its long-term outcome in any kind of adaptive way. But has anyone ever looked at tumors in the same way that we think about viruses? The logic there is the same, except it seems that their goal is to kill the organism. Is there a potential set of answers about how to deal with tumors and think about cancer that could be borrowed from any of those other examples?
Dr Jared Rutter: Viruses — 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. 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.
Andrew Huberman: 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.
Dr Jared 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. If that virus had a mutation that made it better able to do that, that virus would 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.
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 give it to co-workers — that's viral propagation, which we all sadly know about. There's very little evidence that cancer is infectious.
Andrew 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 these tumors growing at wound sites, and it turns out those are cancer. So somehow fighting and wounds — it might be bacterial, I don't know. But there was this idea that they could transmit cancers to one another through fighting.
Dr Jared 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. It's 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 is the same principles at play in both.
The discovery of MPC1 and MPC2 — the mitochondrial pyruvate carrier
Andrew 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 kind of check out. But I think it's so important that people understand this business of metabolism — whether we're young or old, have a lot of energy or less of it, 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 Jared 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. 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 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, 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.
Andrew Huberman: Way back when I was trained, 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. That's 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 cell assay. Is that kind of how MPC was found? Or 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 Jared Rutter: I think we know. We know all the proteins in a heart cell because they are encoded by our genome, which has been sequenced. We know what that is. But we don't know everything that's expressed in a given cell.
Andrew Huberman: Twenty years ago, could you say what you just said with much less confidence?
Dr Jared Rutter: Now I think we know essentially everything. Again, there are going to be subtle nuances that we don't know, but 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 that 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 these 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 that these are the proteins that do this transport of pyruvate into the mitochondria.
It was a really fun time for me as a scientist to see that happen. And what was maybe even more exciting than the discovery of the mitochondrial pyruvate carrier itself — 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, so to speak, 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.
What happens when the MPC is deleted — lessons from the heart
Andrew 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 Jared 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 — and it will die. 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.
Andrew Huberman: He developed a technology that would allow for organ- and cell-type-specific deletions or additions of genes.
Dr Jared 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 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's a postdoc now running his own lab at Rutgers, was the one who started this, and other people have contributed. What essentially happens to that heart is that it lives, and the animal lives for weeks after that. But eventually the animals die. And when you look at what they die of, they 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've eliminated their ability to make ATP from it at least as effectively, and instead they make biomass. They grow. And when cardiomyocytes grow, that creates structural problems for the heart. Almost every human that succumbs to heart failure will end up with a big dilated heart that's less effective at pumping. And that's what we see in the mouse.
That maybe tells us something about the fundamental importance of this resource allocation decision. And this is obviously just in the context of cardiomyocytes. But again, that resource allocation decision is happening in every cell in our body all the time. 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?
Cell identity, size, and the balance between building and being
Andrew Huberman: Is it fair to say that the allocation of energy, which is made pathological in this mutant mouse but also in people who have these cardiac conditions and die of heart failure — it's almost like the identity of the cells is screwed up? They're still a cardiomyocyte, but they're devoting too much energy to making more of themselves and not enough to doing what they're supposed to do.
I have two analogies I want to throw out there. I love dogs. I have 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 we actually know that's because of dosing of IGF-1, which is a growth pathway thing. So there is this story about larger animals within a given species tending to live much shorter lives than the smaller variety of that same species. There are some exceptions, but there does seem to be a rule that you can either be big and live a short life or you can be small and live a longer life within certain species.
But there's also this thing about heartbeats — this theory that you only get so many heartbeats in your life. The reason I like these higher-level comparisons is that ultimately when I think about life and evolution and the propagation of species and health versus pathology, it's all about energy. How are you devoting energy? It seems like at the cellular level and at the subcellular level, which is what you're describing, the allocation of energy is the difference between life and death. And this decision — you're not telling us there's a fan-out of 50 different options. You're saying make more biomass, more of self, or use energy to be self. And there seems to be a critical balance there.
If you look at the data on longevity in different athletes — the gymnasts, the sprinters seem to live three to six years longer on average than others. The endurance runners are somewhere in the middle. You look at very large athletes like the powerlifters — moving aside all things like use of drugs in sports — 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 build more of oneself and the use of fuel to just be oneself. And that self could be a cell, that self could be an organ, that self could be a whole organism.
Dr Jared Rutter: That's a complex analogy, but I think one thing that is very clear about what you're talking about is this sense of identity in a cell. That's a fundamentally important phenomenon that we've known about for a long time, and there's been some understanding in some cell types about how that identity is established and maintained. But your question is a really interesting one — to what extent is disease associated with loss of that cell identity? Cell identity is a bit of a squishy parameter. How do you measure what a cell thinks it is?
I think what you're talking about is that within an organ, within a cell type, you sort of have a choice of either make more of oneself or just be you. And there's something conceptually sticky about this notion of size versus use. I think we're talking about resource allocation — allocating to energy versus making more stuff, which could mean another cell or a bigger cell. There are 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. There are many examples of that.
Lactate — not a waste product
Andrew 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, who's really one of the pre-eminent public educators in exercise physiology, 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 Jared Rutter: Pyruvate, to a first approximation — and it's a little more complicated than this, but this is a good way to think about it — when pyruvate is made, it simplistically has two fates. It can go into the mitochondria, as we talked about. 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.
Andrew Huberman: Why would it not burn it or make more of itself? Because it's just got it in excess?
Dr Jared 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. That 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. So that really is that resource allocation decision we've 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.
Andrew 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 does seem to be a signal to the brain for brain-derived neurotrophic factor, which 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 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 Jared Rutter: We joke all the time in the mitochondria field about the powerhouse of the cell, right? Which it really is — 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.
Energy prioritization — fatty acids, glucose, and toxicity
Andrew 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 Jared Rutter: 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.
Andrew Huberman: And not just because it clogs arteries.
Dr Jared Rutter: Yeah, in ways that we probably don't need to get into, but they 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. And 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.
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, that individual survived better, and that trait was selected for. And we're now pretty good at it.
The Warburg effect and cancer metabolism
Andrew Huberman: Could you tell us about the Warburg effect and its role in cancer? 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 don't actually believe in cancer or germ theory. I believe cancer exists and I believe that cancers can come about through a variety of mechanisms. It's true, right, that there are a lot of paths to cancer?
Dr Jared 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 ten or fifteen 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's just 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 mention 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 1920s for many years.
Andrew Huberman: Broken meaning they're not making ATP, or they're doing something wacky?
Dr Jared Rutter: 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 be using 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
Andrew 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 or ten years out, that if we could just solve that, we would be in a position to treat and cure many more cancers? Is there some place where you feel like if we could just turn that bolt, we would be in a much better position?
Dr Jared 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 technical term for the molecules, the features that are recognized by the immune system — it doesn't necessarily have antigens 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, they are us — 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 of the things that's 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. Cancer cells — a tumor — is under evolutionary pressure. Let's take an example where we have a tumor and we get a 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 and make a new tumor. 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 or goes away, maybe even becomes invisible by imaging tools — but then it comes back. That's because these cells are under evolutionary pressure. If one cell theoretically 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 now 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, targeting specific proteins that are contributing to the cancer in a completely specific way, not doing anything else in the body to normal cells. 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.
Andrew 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 eleven years now. He runs a lab — serious scientist — but he also has this not-for-profit called Every Cure, which has been successfully using AI and cell assays to take biopsies and try to figure out, in the case of a kid who's dying of a particular cancer, let's just throw a bunch of not random 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. I'm encouraged by things like that and what you're describing — that we're not necessarily going to have the miracle drug, but the miracle cocktail for that individual, that cancer.
Dr Jared 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 the 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.
Andrew Huberman: You're highlighting something really important about the sociology of medicine and science. So much of the way things are in medicine and science can be answered by a phrase that everyone should hate: "Well, we've always done it that way." 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, "Oh, 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 Jared 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 in a way are 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.
There's been a lot of energy in the field over the last ten or fifteen 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 — beyond just the mutations are the metabolic processes that enable those mutations to be manifest in what turns into a tumor.
Metabolic imaging and the future of diagnostics
Andrew Huberman: How far are we from a world where I drink a fluid, I step into a tube, and I get a picture of red and green in every cell — an image of the proportion of my metabolism in different organs, and you could zoom in to a single cell? 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 the population of age-matched 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 Jared 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 be able to have a surrogate of metabolism that we can actually see. Our metabolism has nothing visual that we can see with the naked eye. 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. The key thing is figuring out what to measure — what would be the one metabolic parameter you'd really want to measure to assess whether this cell is healthy or not healthy? And then figuring out a way to measure that non-invasively. These are hard problems, but the technology just keeps getting better. The experimental tools that we can use in mice or in cells in culture are definitely getting better. That's an aspect of studying metabolism that's really exciting — 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. And that is then going to be informative when we think about how it's working in a human.
Smell, breath, and metabolic signatures of disease
Andrew 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 saying, "Oh yeah, I remember this now." There's a whole lot of correlation and just-so story that can emerge from that, but 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, 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 Jared Rutter: I mean, 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. And when a person's doing different metabolism, they're going to be producing different chemicals in different proportions. 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. And 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 mitochondrial overload
Andrew Huberman: We were talking a few moments ago about excess energy toxicity. This is something that Layne 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 Jared 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. These are 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.
Andrew 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 actually think this is fascinating, and for a variety of reasons. First of all, we've never had a serious discussion about what mitochondria actually do besides just help create energy. So first of all, thank you so much for telling us how they actually allocate their resources towards things other than just making more energy for usage, and 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. No, they didn't tell me to say this, but 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, 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.
Dr Jared Rutter: Thanks, Andrew. It's been a lot of fun.
Andrew Huberman: We'll do it again anytime.
Dr Jared Rutter: Cheers.