#110 – Lew Cantley, Ph.D.: Cancer metabolism, cancer therapies, and the discovery of PI3K

1. 0:00 – 0:17

   Intro

   1. PAPeter Attia0:07

      [intro music]

2. 0:17 – 8:45

   Intro, Disclosures, and Teaching Science Through Discovery

   1. PAPeter Attia0:17

      Hey everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn more now, head over to peterattiamd.com/subscribe. Now, without further delay, here's today's episode. [upbeat music] My guest this week is Lew Cantley. Lew is the Meyer Director and Professor of Cancer Biology at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medical College in New York City. Lew's research has made significant advances in cancer research, stemming primarily from his discovery of the signaling pathway for PI 3-kinase, or PI3K, in the mid-'80s. And his results here have really touched multiple fields, including cancer first and foremost, but also diabetes and autoimmune disease. Lew is a very decorated scientist, to put it mildly. It would take me too long to rattle off all of the awards that he's won, but I'll leave it to the four most prestigious: the Gairdner Award, the Breakthrough Prize in Science, the Wolf Prize, and most recently, the Horwitz Prize. Arguably, the only two prizes that are not on that list would be the Lasker Prize and the Nobel Prize, and I think that many people suspect that Lew will ultimately be awarded at least the Nobel Prize, if not both. This is a podcast that at times gets very technical, but most of the technical stuff falls at the end of the podcast. It's actually what we started with, but much like we did in a previous podcast, we're going to move that to the back end of the podcast so that we can jump right into the more concrete stuff that I think people want to hear about with respect to science, and we'll treat what was the first 45 minutes of this interview as a technical tour de force of the discovery of pre, PI3K, and we'll move that as basically an appendix. So if you're listening to this and you really want to understand science and you really want to understand how discovery is done, stuff that I really like to hear about, by all means, you'll just listen to this as it's laid out. And if you really just want to hear about the implications of Lew's work as it pertains to cancer, then you will probably just listen to the first hour and 45 minutes or so of this and not the remaining 45 minutes. Before we jump into this, there are just two things I want to say. The first is I want to note Lew's disclosures. Lew is the co-founder of two pharmaceutical companies, Agios and Petra, and he is also the co-founder of a company that is just getting off the ground called Faeth. That's F-A-E-T-H. Faeth is a company that hopes to pair nutrition with pharmaceuticals, and that will all make sense during the podcast. These are all really interesting companies, but I think it's important, obviously, to list those disclosures at the outset. Secondly, I want to be sure that everyone understands that we have a discussion here that is very detailed at times and very tactical at times with respect to cancer treatment. And certainly every time I talk with Lew, I come away with a new way of thinking about the care of patients with cancer. Please do not mistake what we are talking about here as medical advice. It is impossible to provide medical advice to someone with whom you do not have a doctor-patient relationship. And so, unfortunately, I hate saying that, but it is an obligatory disclaimer that I must provide. And whatever we talk about here, the combinations of therapies with respect to drugs for diabetes, drugs for cancer, and of course, nutritional therapies, really needs to be had in discussion with your physician. Actually, I lied and I said two things. There's one other thing I want to talk about, which is there is a cancer trial that is about to take off that is a really interesting and exciting prospect through one of Lew's companies. The enrollment for that trial is just kicking off now, and we will list to that should anybody listening to this podcast either have the type of cancer that's being studied or know somebody who does, and it would be great to know that people are able to more readily get enrolled in that clinical trial. So without further delay, please enjoy my conversation with Lew Cantley. [upbeat music] Lew, thank you so much for coming over.

   2. LCLew Cantley4:40

      Oh, it's great to be here, Peter.

   3. PAPeter Attia4:42

      You live, like, 10 feet from me here, and yet this is the first time you've been here, I think, right?

   4. LCLew Cantley4:46

      Yeah. It took me five minutes to walk here.

   5. PAPeter Attia4:47

      [laughs] It's great to see you always. You're definitely one of the most generous people with his insights and with the work you've done, and I consider you an absolute mentor in how I think about these problems in biology. So it's-- we've been trying to get on this podcast together for a year, but it's a testament, I was gonna say to how busy I am, but it's, no, it's to how busy you are. [chuckles] I'm busy, but you are even busier than me.

   6. LCLew Cantley5:10

      I do keep pretty busy.

   7. PAPeter Attia5:11

      [laughs] Well, there are a lot of things I want to talk about today. I think to set my own expectations, we probably won't be able to get through them all, which speaks in some ways to the breadth of your work. We're gonna talk so much about cancer and metabolism and things here, but there's what we know today about PI3K, which I think would be a nice thing to spend a moment on. But I also love this idea, like, I have this idea, Lew, which is we should be teaching kids science not the way you were taught biology as a 16-year-old, which was rote memorization. We should simply teach science through the lens of discovery. So in other words, every biology class, even at the high school level and even younger, should be less about memorizing what it is that you see. Look under this microscope and memorize all the organelles or something like that. It's more of let's tell the stories of science, because, one, if our goal is to train scientists, well They're gonna go and become experts in whatever they're gonna become expert in. We don't have to worry that in high school they're not gonna learn enough content. But if we're trying to screen for people who are interested in science, what you have to be screening for is the process, is the discovery, is the game, is the thinking that went into the experiment. It's the blind luck. It's the bad luck, and that comes out in the story of everything. I've yet to hear a single world-class scientist, and I have the privilege of sitting down with so many of them, tell their story without some element of good luck and bad luck combined.

   8. LCLew Cantley6:45

      Serendipity.

   9. PAPeter Attia6:46

      Yes.

   10. LCLew Cantley6:46

       Serendipity in science is absolutely critical that when you get a result that's unexpected, you should be laser-focused on understanding at the biochemistry, at the chemical level why you got the different result than you expected to get.

   11. PAPeter Attia7:01

       And following these journeys is, to me, a better way to weave the narrative arc of science. I mean, I think frankly, it's not that there's no value in knowing that DNA is a helical structure and it has these base pairs and it has this backbone, but that shouldn't be the focus. To me, actually walking through the fumbling of how those guys got there, that's a very interesting story and that probably will serve a non-scientist better when they're done with science class, 'cause they'll have an appreciation for the process. And now I'm getting on my soapbox about it would be better if policymakers understood that that's how science worked as opposed to trying to remember what they learned in a biochemistry class thirty years earlier. And of course, for the people who are gonna go into science, I still think they're gonna go back and learn the basics anyway, so we don't have to through rote memory get that stuff into them. But it's this process of thinking and collaborating and walking down the hall and seeing the result, as you said, that doesn't quite make sense and saying, "Well, wait a minute. There's something in there. There's a story." I mean, science is basically just one big mystery. It's really about curiosity. That's what I'm hearing in your story is it's less about your innate brilliance and more about your obsessiveness, your ability to make an observation and not let it go.

   12. LCLew Cantley8:19

       Yeah. If I get a result that suddenly doesn't make sense, to me that's more exciting. It means there's something more complicated going on than the simplest explanation for what I'm seeing. If the simple explanation works, then fine, you publish it in some second-rate journal. But if you've broken up a whole new field because your simple explanation doesn't work and you figured out why it didn't work and what was wrong, then that's where most breakthroughs come from.

3. 8:45 – 16:58

   From Pyruvate Kinase to Cancer Metabolism

   1. PAPeter Attia8:45

      When did cancer become such a high focus? So we met, we met in two thousand eleven, two years after you, Matthew Vander Heiden, and Craig Thompson wrote what I thought was sort of one of the most interesting papers I'd read on cancer in the journal Science. It's hard to believe we're ten years away from that paper. What was the lead up to your collaboration in that paper? And, and less about the paper, but more about thinking about cancer metabolism, because today when I think of Lew Cantley, I think of cancer metabolism. When did that transition occur?

   2. LCLew Cantley9:18

      There was a postdoc joined my laboratory, Matt Vander Heiden, who had trained with Craig Thompson. Matt's an M.D. Ph.D. now on the faculty at MIT, but he had been obsessed about glucose metabolism as a graduate student with Craig. And in fact, I'd gotten one of his papers to review, which I was very impressed by. And so he suddenly showed up at my office one day saying that he wanted-- he was interested in doing his postdoctoral work as he finished his clinical training. And at that time, a graduate student, Heather Christof, had been working in my laboratory and she'd made the observation that if she used tyrosine phosphorylated peptides to pull down a degenerate sequence context, and it wasn't a single peptide, it was a whole mixture of billions of peptides all of the same length, biotinylated so you could pull down anything they bound to, and then use mass spec to identify all the things that came down. First of all, she rediscovered all the proteins that were known to bind to-- that have SH2 domains. This is a domain that many proteins, including PI3 kinase, have that allow them to bind to tyrosine phosphorylated proteins. And so in that one experiment, she rediscovered everything that had been published of all the things that bind to tyrosine phosphorylated proteins. But she's discovered the thing that bound better than anything else in the cell, or that was most massively pulled down, was an enzyme in metabolism, pyruvate kinase. And that was shocking and, and I remember her first response to that was, "Well, the only novel thing I found here that wasn't already known was this-"

   3. PAPeter Attia11:05

      This affinity for pyruvate kinase.

   4. LCLew Cantley11:07

      Pyruvate kinase. And, and she said, "Well, that's a metabolic enzyme and they're all boring, so I don't think I really wanna work on that." And I said, "No, no, that's whenever you get the result-"

   5. PAPeter Attia11:16

      You pulled a Lew.

   6. LCLew Cantley11:17

      "... the totally unexpected result, that's the thing you should focus on." And so she did. And at the time that Matt was interviewing with me, I told him about her results and he got very excited about that, and the two of them worked together to show how that was working.

   7. PAPeter Attia11:35

      So this is early two thousands, right?

   8. LCLew Cantley11:37

      This was two thousand and-

   9. PAPeter Attia11:40

      Mid two thousand, like two thousand five?

   10. LCLew Cantley11:41

       Two thousand five maybe.

   11. PAPeter Attia11:43

       Matthew Vander Heiden was a classmate, I believe. I've obviously met Matt since, but I believe he was a medical school classmate of one of my close friends, Ted Shafer, who actually I had on the podcast, and Ted also was an M.D. Ph.D., did his Ph.D. in Harold Varmus' lab, so it all kind of comes full circle. A lot of smart folks came out of the University of Chicago.

   12. LCLew Cantley12:02

       So anyway, so he, Matt and Heather, ended up publishing two back-to-back papers in Nature that both explained structurally How phosphotyrosine peptides or proteins binding to pyruvate kinase could turn off its activity and then also explained why turning off the activity of pyruvate kinase was important to increase anabolic growth. And that is kind of the basis for why we decided to start Agios, that Craig was interested in how metabolism was regulated in cancer cells, and we had made this observation that pyruvate kinase regulation was important in oncogenic regulation, anabolic processes in cells. And so we proposed pyruvate kinase activators rather than inhibitors as a way to reduce tumor growth as one of the targets to go after at Agios as we were starting the company. So that review, which I should say that Matt played a much bigger role in writing that review than Craig or I did. [chuckles]

   13. PAPeter Attia13:03

       He was the first author.

   14. LCLew Cantley13:04

       Yeah.

   15. PAPeter Attia13:04

       So yeah, that was pretty clear. [chuckles]

   16. LCLew Cantley13:05

       Yeah.

   17. PAPeter Attia13:06

       When did the Warburg effect-- When did you start paying attention to it? I mean, obviously, it was around before you were born.

   18. LCLew Cantley13:13

       Yeah, so actually, I mentioned F. Racah earlier. F. Racah was-- knew Warburg quite well, and they overlapped in Germany. He was obsessed by understanding the Warburg effect, the Warburg effect being a result published by Warburg back in the nineteen twenty-oners, almost a hundred years ago, that if you chemically induce cancer in rats, the tumor that evolves takes up glucose and metabolizes it in an anabolic way much, much faster than the tissue of origin prior to transformation. This was chemical induced cancer formations.

   19. PAPeter Attia13:50

       And this also, this observation was that even when there was sufficient cellular oxygen to generate ATP much more efficiently through the mitochondria, it was as though the cancer cell elected to go this faster, less efficient route.

   20. LCLew Cantley14:05

       That's right. The surprising result was, well, there's plenty of oxygen. We've taken the tumor out. We are in an oxygen environment. Why doesn't it make ATP through mitochondrial oxidative phosphorylation instead of through glycolysis?

   21. PAPeter Attia14:16

       Why do you think the Warburg effect was largely forgotten in the forties and fifties and sixties? I mean-

   22. LCLew Cantley14:21

       It wasn't-- It fell out of favor really not until late sixties, early seventies. And what was taking over at that time was evidence for virally induced cancers, v-src, Harold Varmus and Mike Bishop. So once it was shown that viruses could turn on cancers, the idea that it was just an altered metabolism fell out of favor. Of course, the discovery of oncogenes, of which v-src was the first clear oncogene because it told us that we've met the enemy and it is us. [chuckles] It is our own genes that are getting altered in cancer. And so proto-oncogenes were being picked up by retroviruses.

   23. PAPeter Attia15:00

       Did anyone at the time think these two mechanisms aren't mutually exclusive? The expression of or the amplification of or the mechanism by which this viral injury to the genome can perpetrate and can perpetuate could be through this defective metabolism?

   24. LCLew Cantley15:20

       I think people who thought about it deeply and who were trained as biochemists who were doing metabolism, which F. Racah was one of the prime examples, continued to realize you have to alter metabolism to do cancer. You need to switch a cell from a quiescence, not only from a quiescence state to a dividing state, but in order to divide and make a bigger cluster of cells, you have to drive glucose and amino acid uptake and anabolic processes, converting those to proteins and lipids and DNA and RNA. So there was no doubt you had to turn up metabolism. The question was, at what level did metabolism play the role? Was it just a consequence-

   25. PAPeter Attia16:03

       Yes, exactly

   26. LCLew Cantley16:04

       ... of the viral transformation or the oncogenic transformation, or did they work cooperatively in some more complicated way? So our paper on pyruvate kinase suggested, yes, there is some clear cooperation where the active tyrosine phosphorylating proteins was directly regulating the activity of metabolic enzyme rather than just turning up the expression, for example, through a transcriptional cascade. So that's why it shifted the emphasis back to there may be targets in metabolism that could give you an efficacy/toxicity ratio for treating cancer. The truth is, chemotherapy, as you know better than I, is really targeting metabolism. You're blocking DNA synthesis or other steps in metabolism as a way of killing cancer cells. So that's, in a way, targeting metabolism is our first approach to curing cancer, and now we're back to doing it in a more serious way today.

4. 16:58 – 20:24

   Rethinking the Warburg Effect: Carbon for Growth

   1. PAPeter Attia16:58

      What was the point that you guys made that was so novel in that two thousand and nine paper? Because it's a subtle point that I think you can easily miss. You could easily look at that paper and say, "Oh, this is just another paper discussing the Warburg effect." But you came up with a very clear explanation for why the Warburg effect might exist that was different from the explanation that I think I had looked at before, which was the mitochondria are defective. So I think the easy explanation for the Warburg effect is the mitochondria don't work, therefore, the cancer cell has no choice but to undergo anaerobic glycolysis. You guys proposed something different.

   2. LCLew Cantley17:35

      Yeah, we proposed that you could, even with totally functional mitochondria, you could divert intermediates in glycolysis into anabolic processes by regulating steps in glycolysis. And so the biggest question, we know that if you have high ATP in the cell, it will shut off glycolysis, and that's a feedback that there's high citrate and high ATP, either one of those directly bind to phosphofructokinase, shut off its activity, and the remaining glucose that comes in that gets phosphorylated either goes to the pentose phosphate shunt, or it goes to glycogen storage, or it just goes back out of the cell again. So there's a break right there. And so F. Rocker was obsessed by how you relieve that break because how do you get a ten to fifty-fold increase in glycolysis if you're making so much ATP? It should shut-

   3. PAPeter Attia18:30

      It should shut it off

   4. LCLew Cantley18:31

      ... shut it back off again. So the, the idea that it was defective mitochondria was a simple explanation. There's no other way to make ATP, so you have to make it through glycolysis. But the idea that there was something more complicated than that was really what we were discussing in that review, that there was a way to regulate steps in glycolysis that would divert intermediates in glycolysis from making ATP to the carbon atoms of glycolysis would go into lipid synthesis, serine synthesis, glythi- glycine synthesis.

   5. PAPeter Attia19:02

      So it was sort of like a mass balance argument. It was an energetics for construction argument. It was basically saying, "Look, the way to really think about this is cancer's growing like crazy. It's easy to talk about the energy requirement, but just think about the carbon requirement of growth."

   6. LCLew Cantley19:19

      Right. So I-- And one analogy I like to make is imagine you have a river flowing through a valley and you want to flood some fields in order to get enough water to grow plants. So if you put a dam here, then those other little canals that you've generated, the water level will go up to flood into those other canals and allow you to grow plants. That's sort of what happens if you turn off pyruvate kinase, then you slow down ATP production. That means there's less ATP made. That means glycolysis, upper part of glycolysis can continue, but instead of going to make more ATP, it goes off to make serine and glycine and ribose and lipids, and that gives you all the molecules you need to grow.

   7. PAPeter Attia20:03

      Without shutting the system off because you don't let it go all the way to ATP.

   8. LCLew Cantley20:07

      Right.

   9. PAPeter Attia20:07

      Yeah.

   10. LCLew Cantley20:08

       And that allows the mitochondria to make whatever ATP you need, and glycolysis is now used to do anabolic processes instead of make ATP. That still makes some ATP, but you can now rebalance that whole equation so that you can grow better rather than just make ATP.

5. 20:24 – 26:05

   Growing Up in West Virginia and the Rise of Sugar

   1. PAPeter Attia20:24

      Now, this had a profound impact on the way you thought about your life. You're one of the-- I don't want to say the few, but, but there are a lot of people who-- a lot of great scientists, frankly, who their professional work and their personal-- the way they go about conducting themselves and their own choices around food or whatever, there seems to be a disconnect there. Not the case with you. I remember the first time we had a meal in probably two thousand and twelve, you were quite particular about what you ate and what you didn't eat, and the thing that you were most careful about was fructose. So what is it about the work that you were doing in the two thousands, the early two thousands into this decade we're in today, the beginning of the decade we're in today, that had you start to think about nutrition in that way?

   2. LCLew Cantley21:10

      So I have to say that I made my decision about what to eat and not to eat before I knew anything about metabolism, and it came from a simple empirical observation. So I grew up-- I mentioned earlier I grew up-

   3. PAPeter Attia21:23

      West Virginia, right?

   4. LCLew Cantley21:23

      ... Blackwoods of West Virginia. In retrospect, I realized that as I was growing up in the fifties, we were eating incredibly healthy meals. In those days, the most expensive thing to buy at the grocery store was sugar. And my grandparents, who I spent a lot of time with working on their farm, raised everything they ate. They were sustenance farmers. They had essentially no income. They sold some strawberries in the spring. My grandfather would plow fields for people to make additional money, but they had very minor income. But they lived off of everything they grew. The one thing they couldn't grow, for a while they grew some sugar beets, but it was hard to get enough sugar. And so when my grandmother went shopping, essentially the only thing she would buy was flour and sugar, and one five-pound bag of sugar had to last several years. And so [chuckles] when she would make what she called a cake, we would call it a biscuit today. It had essentially no sugar in it [chuckles] because it had to be sprinkled in very small amounts. And so that, as a consequence, we were all very healthy. Nobody in my family... In fact, I didn't know anyone who was overweight in West Virginia because most people lived like my grandparents, and that was in the fifties. What happened in the sixties was really what was tragic, and it was all triggered by Castro, as you know the story. And Castro's taking over Cuba and us boycotting sugar from Cuba and the anticipation the cost of sugar would go up even higher, a German scientist had worked out a way to convert corn starch into high fructose corn syrup, which could be made much, much more cheaply than raising cane.

   5. PAPeter Attia23:03

      It's funny. I always thought it was a Japanese scientist. I didn't realize it was a German scientist.

   6. LCLew Cantley23:07

      I could be wrong on that.

   7. PAPeter Attia23:08

      I would take your word over mine, but-

   8. LCLew Cantley23:09

      We'll blame somebody from World War II. [laughs]

   9. PAPeter Attia23:11

      The irony of it is it's always someone that got hurt in World War II, and the joke is this was their payback.

   10. LCLew Cantley23:17

       Exactly. And then Castro's payback. So Castro-

   11. PAPeter Attia23:20

       Yeah

   12. LCLew Cantley23:20

       ... did this to us. We did it to ourselves is the truth, and we're still doing it. And as long as Iowa is where the primaries are held, first primaries, and where nobody's going to cut off taxpayer support for corn starch or growing corn.

   13. PAPeter Attia23:36

       But you had this profound belief. I mean, it's-- I guess you got to experience something very few people do, which is a natural experiment.

   14. LCLew Cantley23:43

       Yeah. So I watched West Virginia go from what I would argue in the fifties was the skinniest state in America. I never saw anyone overweight. None of the kids in my school, none of my relatives, none of them were overweight in the fifties. Most of them were very thin. And then along came high fructose corn syrup, and suddenly the cheapest thing you could buy were sodas that normally at a six ounce Coke would be my total allowance for a week to buy one six ounce Coke, and now suddenly you find ten times as much for that cost. And so people advent of very sugary drinks. People had started consuming 10, 20, 50 times as much sugar as they were consuming before. And over from the mid-'60s to mid-'70s, I watched when I went back, I was at that time at Cornell getting my graduate degree, and didn't, didn't go back to Western Union that often. But when I did go back, I every time noticed a dramatic change in that all my friends and relatives were suddenly becoming obese. And I just watched what they ate, and I realized they were consuming massive amounts of sugar. Many of them were consuming diet drinks, but then at the end of the day, because of their addiction to sweets, would eat like a gallon of ice cream per person. When I asked them, "How can you eat a gallon of ice cream?" They would tell me, "If I don't eat a gallon of ice cream, I'll wake up two hours later and go raid the refrigerator, so I can't sleep through the night without eating a massive amount of sweets." So at that point, I realized this is a real addiction, and I cut out drinking anything that was sweet, and I cut out eating dessert. So that was 1975. Didn't know anything about the metabolism of fructose or glucose. Just empirically, I saw the change in diet and the consequent massive change in obesity.

   15. PAPeter Attia25:38

       So you basically have these two sort of separate stories, which is this is this observational journey of your life, and then you have the work of your career that is bringing you closer and closer to cancer metabolism. When did you finally realize in the laboratory that this observation of yours had mechanisms to it that could go far beyond obesity, but also play a role in metabolic diseases inclusive of cancer?

6. 26:05 – 32:28

   Insulin, PI3K, and Cancer Risk Beyond Obesity

   1. LCLew Cantley26:05

      What really brought it all together, and this is why I keep emphasizing insulin, as a postdoc and ultimately starting my own lab, I kept coming back to how does insulin work? And whenever we managed to see this PI kinase activity co-precipitating with Src and insulin receptor, I realized that the same enzyme was mediating the effects of the oncogenes and also effect of normal insulin signaling. And so that by 1990, it was very clear in my mind that insulin was triggering cell growth in exactly the same way that oncogenes were. They were both activating PI3 kinase. And that suggested then a correlation between the two, and particularly as we began to notice that the mutations, so many years later, mutations in PI3 kinase were identified. It was more than 15 years after we discovered the enzyme, the mutations were picked up from Bert Vogelstein's laboratory. And as we began to explore what those mutations did, we realized they increased the ability of insulin to activate the enzyme. So this whole connection between everything that insulin does goes through PI3 kinase and most oncogenes manage to activate PI3 kinase by either directly binding or indirectly activating it, not necessarily through insulin, but they were bypassing the need for insulin.

   2. PAPeter Attia27:31

      We're going to come back to that very important observation in a moment, right?

   3. LCLew Cantley27:35

      Yes.

   4. PAPeter Attia27:36

      [laughs] You know exactly where I'm going with the next line of questioning, okay.

   5. LCLew Cantley27:39

      Right.

   6. PAPeter Attia27:40

      Yep.

   7. LCLew Cantley27:40

      But it also raised the possibility that being insulin resistant, which results in elevated serum insulin because the pancreas has to generate more insulin if your liver and muscle and fat cells are failing to respond to insulin, then more insulin has to be made in order to bring glucose back down. So insulin resistance is pretty much a silent disease because you don't really know it if you go for an overnight fasting glucose measurement in the urine, your glucose is okay. But if you do a glucose tolerance test, which very few people do, you realize that the glucose has to-- goes up much higher, takes longer to come back down, and the insulin level is much, much higher than normal during that process of adapting. So that's how insulin resistance is defined. But I realized that high level of insulin, if we add it to our cells in culture, cancer cells in culture, it makes them grow better. And we've known that since the 1960s and '70s. We use fetal calf serum to make our cancer cells grow in culture. And if fetal calf serum doesn't work, we either order another batch, you know, another lot from the company, or we just add insulin. And adding insulin always makes it work again. [laughs] And so we've known for a long time that if you have high levels of insulin, you can make almost any cancer cell grow better than just pure fetal calf serum, which already has some insulin in it, and it's variable from batch to batch. So in a way, it's been staring us in the face for years that insulin will drive the growth of cancer cells. And cancer cells tend to have more insulin receptor than the tissue from which they emerged. So in the process of tumors growing out, evolving, they turn up the expression of the insulin receptor, and that allows them to respond to insulin better. So as I kept seeing more and more data on this over the last 15 years or so, I became convinced that the act of being insulin resistant or the state of being insulin resistant in humans sets them up to accelerate tumor growth.

   8. PAPeter Attia29:47

      When I interviewed Sid, gosh, I don't know how long it's been, probably six, eight, nine months ago, he shared something with the listeners that I think for many people is still hard to believe, which is smoking is the leading environmental cause of cancer. Obesity is second. In fact, I think he even mentioned that in the documentary that was made after his book. You were in that documentary as well. Great documentary. It was not named after the book, was it? Was the documentary also called The Emperor of All Maladies?

   9. LCLew Cantley30:15

      Yes, it was.

   10. PAPeter Attia30:16

       Oh, okay. Okay. Phenomenal. We'll link to it in the show notes because it's a real gem. I mean, it's worth every penny you gotta pay to download on Apple and watch that PBS special. Ken Burns, of course, is a master. But Sid made the point there as well. And Hearing you say what you're saying makes you think it's really less the obesity and more the hyperinsulinemia that accompanies obesity in 80% of cases, which is high enough that you could easily, just from an epidemiologic standpoint, identify obesity per se as the trigger, meaning excess adiposity. But my belief, and I think yours, is that no, it's probably the hyperinsulinemia, which means if you're lean and hyperinsulinemic, you're worse off, and I think those data are becoming abundantly clear.

   11. LCLew Cantley31:00

       There was a paper published a few years ago out of Montessori Albert Einstein showing that, in fact, if you take breast cancer patients and separate them into overweight/obese insulin sensitive, 'cause a lot of people can, if you put on peripheral fat but don't have visceral fat-

   12. PAPeter Attia31:17

       Don't have visceral fat, yeah

   13. LCLew Cantley31:18

       ... you don't necessarily become insulin resistant with overweight. So body mass index is not-

   14. PAPeter Attia31:23

       Yeah, it's not enough. It's a first order term

   15. LCLew Cantley31:24

       ... that subset of overweight women who were insulin sensitive did not have an increased risk of breast cancer, but the ones that were insulin resistant did. So that says a lot. And that paper also had data on lean women who got breast cancer, and that correlated with insulin-resistant lean women. And in, in many nationalities, particularly Asians, they may look very lean but still have a lot of visceral fat. And so that, I think we... Our current mechanism of using body mass index as our correlation is not a good one.

   16. PAPeter Attia31:58

       Yeah, it's just not good enough. And Mitch Lazar in 2013, I believe, published a paper showing basically the two by two of lean and not lean, metabolically healthy and not, as a proxy for hyperinsulinemic, and it turned out that it wasn't the body mass that was the thing that tracked with health. Now, a moment ago, you gave this very eloquent explanation of the role of insulin in cancer. Now, four months ago in "Science," you published a really interesting paper. What did that paper show?

7. 32:28 – 37:55

   The Sugar-Water Colorectal Cancer Study in Mice

   1. LCLew Cantley32:28

      So this is a paper in which was inspired by Mayor Bloomberg's attempt to ban the 40-ounce Coke. So Ji-A Yun, a postdoc in my laboratory who migrated with me from Harvard to Weill Cornell 2012, '13, decided that she was inspired by Mayor Bloomberg, and she would try to test the possibility that high sugar consumption would increase colorectal cancer. She had worked with Bert Vogelstein as a graduate student, so she knew a lot about colorectal cancer and was working on mouse models of colorectal cancer as she migrated into my lab. And so we decided that we would design an experiment to test whether there was higher risk for colorectal cancer with high sugar consumption. And so it was really two questions there, and my hypothesis going into this was the insulin level, that if you go on a high sugar diet, that you'll eventually become insulin resistant, and that will drive high levels of insulin, which may accelerate the growth of colorectal cancer. And in fact, we had data that said that what I just said was true, that in fact, yes, if we allow the mice to have sugar in their drinking water so they could ad lib feed as much sugar as they wanted on top of their normal chow diet.

   2. PAPeter Attia33:47

      How much sugar was in the chow?

   3. LCLew Cantley33:49

      So the normal chow diet, I don't remember exactly, but there-

   4. PAPeter Attia33:52

      Normal chow might be 10%, but you can buy these really high sugar standard American chows that are-

   5. LCLew Cantley33:57

      Yeah. So we just gave them the normal-

   6. PAPeter Attia33:58

      Okay

   7. LCLew Cantley33:59

      ... chow diet. And so because they were consuming massive amounts, they could drink as much of the sugary water as they want, and they drank five... three to four times as much water, sugary water, as if they just had the water-

   8. PAPeter Attia34:10

      As the controls, yeah

   9. LCLew Cantley34:11

      ... without the sugar. And a consequence, they became massively obese, and they had accelerated polyp formation in the context of having knockout of the APC gene. So APC is the first gene in human cancer that gets lost to initiate the process of colorectal cancer development, as Bert Vogelstein-

   10. PAPeter Attia34:31

       So, so the controls drinking normal water versus the sugar drinking waters, both had the APC knockout?

   11. LCLew Cantley34:39

       They both had the APC knockout.

   12. PAPeter Attia34:40

       And what was the difference in polyp formation?

   13. LCLew Cantley34:42

       So in that, three or more fold size of polyps. They were much more aggressive.

   14. PAPeter Attia34:47

       And what about the cancerous transformation?

   15. LCLew Cantley34:50

       Well, these mice, the polyps became so big that we had to sacrifice the mice because they literally could not digest food anymore.

   16. PAPeter Attia34:57

       Wow.

   17. LCLew Cantley34:57

       They didn't go into metastatic disease, so we couldn't call it a progressive, other than the fact that they were massive and it was beginning to occlude the polyps.

   18. PAPeter Attia35:06

       Now, in this experiment, you also tried to figure out what was playing the role in this, and you looked at glucose. So you could do this experiment with glucose water and fructose water, correct?

   19. LCLew Cantley35:15

       That's right. But let me get to the next step first.

   20. PAPeter Attia35:18

       Okay, okay.

   21. LCLew Cantley35:18

       So the next-- So that was nice and fine and, you know, was consistent with my idea. But Ji-A wanted to challenge me on the idea that maybe the sugar was directly feeding the growth rather than just making the mouse insulin resistant and obese.

   22. PAPeter Attia35:34

       Oh, I'm sorry, because at this point, your hypothesis was all still through the insulin. This was all being mediated through insulin.

   23. LCLew Cantley35:40

       Yeah. That was my hypothesis.

   24. PAPeter Attia35:42

       Yeah.

   25. LCLew Cantley35:42

       So in order to try to always challenge people in my lab to prove me wrong rather than prove me right, and because it's always learned more if my simplest idea is wrong.

   26. PAPeter Attia35:53

       Another great tenet of science.

   27. LCLew Cantley35:55

       So she challenged me on this, and Marcos Goncalves is the other postdoc in my lab that worked with her, and the two of them worked together, and they designed a diet that would not allow the mice to become obese. In other words, they were taking... The total amount of sugar they were consuming was the equivalent of a 12-ounce cola sugary drink. And so on that diet, at least over the six months or so that they were on the diet, they really didn't gain weight, maybe 5% increase in total calories consumed. So they did not gain weight. They did not become insulin resistant. We didn't see elevation in C-peptide, glycosylated hemoglobin. So by all characteristics, those mice were normal. They were not insulin resistant. And yet they still had increased polyps by two to threefold size. So at that point, that raised the possibility that the sugar might be directly feeding the growth of the polyp. And so we characterized that by using either radioactive glucose or radioactive fructose or carbon-13 labeled, a non-radioactive but traceable form of carbon atoms in fructose or in glucose. And we also tried feeding them only glucose, the same number of calories of glucose or the same number of calories of fructose versus the mixture of glucose plus fructose. And they had to have both sugars, fructose and glucose, before the polyps would grow faster. So that was really surprising.

   28. PAPeter Attia37:23

       And do you think that that could be because the glucose provides the insulin and the fructose is... What do you think the fructose is doing in there? 'Cause based on everything you said earlier, a glucose water alone, just a pure dextrose solution should have been sufficient, right?

   29. LCLew Cantley37:37

       That's right. So that turned out not to be the case, and the way to figure it out is, again, using carbon tracing, either by radioactivity or heavy atom. So we did both, and first of all, does the fructose or glucose get all the way to the colon? Question number one.

   30. PAPeter Attia37:53

       It would seem highly improbable.

8. 37:55 – 47:34

   How Fructose Fuels Tumors Through Glucose

   1. LCLew Cantley37:55

      But it turns out if you add-- if you have glucose plus fructose, the glucose competes for the fructose for entry into the small intestine, and as a consequence, the glucose is not as efficiently taken up, and it makes its way all the way to the colon if you give it in a sugary drink.

   2. PAPeter Attia38:12

      I was just about to say, Lew, does this have something to do with it being in a liquid so the transit speed is quicker?

   3. LCLew Cantley38:18

      That's right. So if you gave the same amount in a solid food, it would never make it to the colon. But because it was in a watery mixture, it would transit the intestine fast enough that there was still fructose left.

   4. PAPeter Attia38:32

      Your experiment was elegant because you didn't have to do what my next experiment would've been, which is why I'm not a postdoc in your lab, is I would've done colonic lavage. I would've gone retrograde and seen if I could bathe the polyps and not even deal with the absorption, but I would've missed this detail.

   5. LCLew Cantley38:48

      We wanted to replicate what humans-

   6. PAPeter Attia38:50

      What's physiologic, of course, yeah

   7. LCLew Cantley38:52

      ... the condition in which hu- humans do it. And other labs had already shown that, again, giving a fructose glucose mixture as a liquid at a certain volume, the fructose would make it all the way to the colon. So what we found, the fructose made it to the colon, the glucose got absorbed in the small intestine, but there was some local increase in glucose level in the bloodstream that's full, uh, that is-

   8. PAPeter Attia39:15

      This is the first time I've ever seen this elegant a demonstration of how you could miss in blood sugar a problem, because by definition, the faster it's going through you, the faster the glucose and fructose are getting through and bypassing the small intestine, the more likely you'll get actual colonic content of them and the less likely you'll see glucose in the blood sugar, which is why the group that in the second experiment who were not being given ad libitum access to it didn't get obese and didn't develop hyperinsulinemia but still developed the polyp phenotype.

   9. LCLew Cantley39:57

      Yeah. As a side issue along the lines you're saying, we actually found in the case where we had the water fe- fed rather than a fixed amount, the 12-ounce soda equivalent, that the subset of mice that had the APC mutation actually had... were protected from insulin resistance. [chuckles] Those polyps were eating so much of the sugar that it was protecting the mouse-

   10. PAPeter Attia40:19

       [laughs]

   11. LCLew Cantley40:19

       ... from becoming insulin resistant.

   12. PAPeter Attia40:20

       That is unbelievable, and at some point you'll blow through that, and they'll become quite insulin resistant and get hypertrophic polyps.

   13. LCLew Cantley40:27

       Yeah. Yeah, but in this case, we weren't allowing that to happen. It was a very small amount of sugar, equivalent of a single drink a day, 12-ounce sweetened drink. The real surprise was when we got to the molecular mechanism, and that was that you had to have fructose and glucose because the actual carbon atoms that were being used to grow the tumor were coming from the glucose and not from the fructose. And what the fructose was doing-

   14. PAPeter Attia40:58

       Yeah

   15. LCLew Cantley40:58

       ... is when it went into the polyp, it was converted to fructose one phosphate by an enzyme called ketohexokinase, also called fructokinase. That enzyme's only found in three tissues in, in any significant concentration, the liver, the kidney, and the gut. And so these polyps, like the normal gut cells, have that enzyme. That has been something of a mystery of why that enzyme exists in that, at that location. But in any event, it does. What happens is the fructose goes in and it gets phosphorylated by that enzyme, and it happens very rapidly. It's a very active enzyme, and that drops the ATP level in the cell because you're consuming ATP to phosphorylate that fructose that's coming in. Now, I mentioned earlier that the thing with the Warburg hypothesis is that in order to get glucose to flux at a high rate into a cell, you have to drop the ATP level. Well, this is a way to drop the ATP level. Instead of consuming it in some other way, you're consuming it by phosphorylating the fructose. There's an additional complication, or not complication, but intervention that is also important, which is once you start doing glycolysis at a higher rate, process of doing glycolysis incorporates an inorganic phosphate to make the doubly phosphorylated glycerol and 1,6-bisphosphate. And so that additional consumption of inorganic phosphate drops a negative regulator of inosine deaminase, and that drops the ability to keep ATP synthesis going on in the cell. So the combination too drops the ATP level dramatically. And now the glucose that's coming in is flooding through glycolysis, but it's going into all these anabolic processes. It's being used to make lipids. We see all the label from glucose going into fatty acid synthesis and serine synthesis and nucleotide synthesis going up five or tenfold. It's really quite dramatic what happens. But if you leave the fructose out, even though the glucose gets into the cell, it can't go through glycolysis at a high rate, and so you don't get growth. You have to have both molecules. The carbon atoms are coming from the glucose. The fructose is-

   16. PAPeter Attia43:12

       The fructose is basically driving the kinetics.

   17. LCLew Cantley43:14

       Exactly.

   18. PAPeter Attia43:15

       When you describe it this way, you sound crazy. I mean, you're the guy that nobody wants to talk to at the party. Your wife must be annoyed senseless by her crazy husband who's got this hypothesis that now has so much emerging data behind it that says if you wanted to create a molecule to kill people, it's not just glucose, it's not even just fructose. It's put the two together. And guess what? Nature did that. Nature came up with a 50/50 mixture of this thing, and if that weren't enough, she made it taste so good.

   19. LCLew Cantley43:50

       Right.

   20. PAPeter Attia43:51

       How do we reconcile this?

   21. LCLew Cantley43:53

       Yeah, so that's the part I like best, because I think about everything in regard to evolution. Why do things evolve? Why do we evolve to be addicted?

   22. PAPeter Attia43:59

       'Cause you're ruining the party right now.

   23. LCLew Cantley44:01

       Exactly. So I think this allows... If you think about humans 100,000 years ago, our metabolism hasn't changed in the last 100,000 years. So 100,000 years ago, how often during a typical year in a temperate climate would you have available high amounts of fructose and glucose?

   24. PAPeter Attia44:25

       I mean, maybe in the fall.

   25. LCLew Cantley44:26

       A month. A month or so. So you would get berries ripe and apples ripe. And keep in mind, these are very small berries, very small apples. This is before domestication of plants. And so as a consequence, what that means is at the end of the growing season is when most of the sugary producing fruits are being produced. If you could eat enough of those and you could keep your appetite up enough to just keep consuming anything in place, anything available, you could put on weight.

   26. PAPeter Attia44:56

       As you go into the cold season.

   27. LCLew Cantley44:57

       As you go into the cold season. And if you put on enough weight, then you might actually survive to the next spring period when there's actually some roots to dig up to eat and keep going. And anyone who probably, almost anyone 50,000 years ago who didn't put on 50 pounds or so in the fall would not be alive for the next spring. So a very strong requirement to gain weight in order to survive a period of time when no food is available.

   28. PAPeter Attia45:27

       Yeah. Rick Johnson has written so eloquently about this, and I'm blanking on the name of his collaborator, who's an anthropologist, and they even trace it back to which primates probably developed this first, and they were primates that had left Africa, gone to Northern Europe, and most of them die off. It was only the primates that could develop this mutation, and I believe it was a mutation in both uricase and fructokinase. I could be wrong on that. And I've interviewed Rick, and so we can go back and listen to that. But you had to develop this mutation or else you wouldn't survive the winter. And then what happened was tens of thousands, if not longer, of years of strengthening that is what allowed those primates to then come back to Africa to basically become our descendants. So we as humans, as a species, have these mutations that would have served us well when glucose and fructose combined were provided just at the right level.

   29. LCLew Cantley46:22

       Yeah. So if you didn't anticipate that you needed to gain weight, your body would tell you to do it, basically how it came about. And so makes perfect sense. The extreme example is the hibernating bear. We call it the honey bear often, right? [chuckles] Because in the fall, not only do they eat every berry they can find in the woods, but they also climb up the trees and get to the honey from the bees, and they put on 150, maybe even 200 pounds within a period of two or three months. And then they go into extreme insulin resistance, and they hibernate. They fall asleep. But because of being insulin resistant and having metabolic syndrome, their ability to break down fats is impaired, and that keeps them from quickly burning up all the-

   30. PAPeter Attia47:12

       Their metabolism slows greatly. They preserve the little bit of glucose they have for their brain, and they feed their body off ketones and fats, I assume.
9. 47:34 – 53:37

   Public Policy, Sucrose vs. HFCS, and Whole Fruit vs. Juice

   1. PAPeter Attia47:34

      you've touched on this briefly from a public health perspective. I know you're not a policymaker. You're a scientist. Many would say it's impossible, like we're just never going to see the day when sugary beverages go away. But the data are becoming harder and harder to ignore that there is something uniquely toxic, chronically toxic. People don't like the word toxic because they think it only has an acute implication, like ethanol can be acutely toxic, but I'm talking about the chronic toxicity. But the chronic toxicity associated with sugar-sweetened beverages, inclusive of juices and things like that, right? It's not just a Coke. These data are becoming almost impossible to ignore, yet they still proliferate. I believe their consumption is down. I don't believe people consume nearly the amount of sugar-sweetened beverages that they consumed 20 years ago. I believe we peaked at around the turn of the century. But we're nowhere near what you consumed growing up in West Virginia. Is it possible to get back to that? Is there a solution, or is it simply something that each person must be accountable for? Do you have a view on that even?

   2. LCLew Cantley48:42

      How you reverse the policy? I think- Changing cigarette smoking, there's a lesson to be learned there. What was the incentive? How did the government make this happen? Reducing advertisement is one way to do it. I mean, if you look at TV commercials, almost every commercial about food is about sugary food, and there are many of them tailored to young children to get them to buy the sugary cereals, to get them addicted as young children. You've got them for life, just like cigarette smokers. You get them addicted at 15, 14, they're addicted for life, and there's a market for you. So I think that's the appeal we have to make, and the question is, how do you do this? One way, taxing also helps. If sugar suddenly becomes like it was in the '50s, the most expensive thing that you bought at the grocery store, then maybe you would quit buying it. But of course, most people don't buy sugar anymore. They buy processed foods that have sugar already added to them.

   3. PAPeter Attia49:35

      By the way, looking at your experiments, was there any distinction between if you used sugar as the substrate versus high fructose corn syrup?

   4. LCLew Cantley49:43

      No. Sugar, sucrose, by sugar we typically mean sucrose from cane sugar, which can be crystallized because it's a pure molecule, while high fructose corn syrup is a mixture of fructose and glucose that's 60/40 rather than 50/50. But in our experiments, the difference between those two doesn't make a whole lot.

   5. PAPeter Attia50:02

      The fact that you need to-- if it's sucrose, you have to hydrolyze the bond is irrelevant to the kinetics that you describe.

   6. LCLew Cantley50:08

      Yeah. That happens very quickly.

   7. PAPeter Attia50:10

      So you don't buy the argument that some-- I don't buy it either, by the way, but that you should eat your sugar in natural form, which is it should say cane sugar or beet sugar or something on the ingredient. And there's this whole group of folks who believe that high fructose corn syrup is horrible, but, quote-unquote, "naturally occurring sugar is not." There's so much confusion around this, but I just want to know if experimentally you see any difference.

   8. LCLew Cantley50:33

      No, I think whether sucrose... What shows the difference is whether the sugar is embedded in a fibrous fruit as opposed to being pure in a water.

   9. PAPeter Attia50:43

      There's something about that liquid that is devastating.

   10. LCLew Cantley50:45

       And there are two things. One, for colorectal cancer, it is, as I said before, the fact that having it in a sugary water drink gets it all the way to the colon. If you had the exact same amount of sugar, but it was embedded in a fibrous fruit like an apple, then none of that fructose would make it to the colon. The transit through this intestine would be so slow that the sugar would get absorbed.

   11. PAPeter Attia51:11

       But does that increase the risk of cancer in other organs?

   12. LCLew Cantley51:14

       No, I think this is absolutely unique to colorectal cancer. But I would argue, on the other hand, the difference between eating an apple and eating apple juice not only is whether the fructose makes it all the way to the colon, but whether or not your glucose levels spike after consuming an apple, a whole apple, eating it, as opposed to apple juice. And the answer is, with apple juice, you're going to get a glucose spike for sure. Eating an apple, you may get hardly any change in your glucose because it takes so long to break it down that the absorbance is slow.

   13. PAPeter Attia51:50

       Well, and you might-- you know what I've observed, I don't drink apple juice. I don't drink beverages that have sugar in them. But what I notice is nothing has ever spiked my blood sugar more than a raisin on a per mass basis. You took a fixed mass of raisins and you contrast it with a fixed mass of anything else, it's pretty stark because it doesn't have the water, doesn't have the fiber, doesn't have anything else. And even if you ate, say, call it, compare apple to apple juice, if you did equal grams of glucose, you might even get a similar area under the curve. But where it's going to look different is the apple juice, which will have... You'll get a big spike. In the apple, you'll get a gradual. You're going to have different insulins in response to those. So the glucose AUC could be the same, but the insulin response could be quite different.

   14. LCLew Cantley52:39

       That's the point. And it's, in my opinion, it's all about insulin. Most endocrinologists worry about the glucose. I worry about the insulin.

   15. PAPeter Attia52:47

       So really, there's three things you're worried about. You're worried about glucose, fructose, and insulin, but in how they coexist.

   16. LCLew Cantley52:54

       Right. So colorectal cancer is unique.

   17. PAPeter Attia52:55

       Yep.

   18. LCLew Cantley52:55

       And it can feed directly off the fructose if you get it all the way to the colon through-

   19. PAPeter Attia53:01

       But it has to be in liquid form. Yeah

   20. LCLew Cantley53:02

       ... a water in a liquid form. But the difference between a liquid form apple and apple juice is, as you say, the area under curve is the same, but the fact that the glucose isn't going up as high means you don't get as much insulin released. And of course, it's digested very slowly. The rate at which you're ambiently burning glucose in your brain and muscle may be almost equal to the rate at which it gets absorbed in the bloodstream, in which case you hardly see any increase at all. And that means no spike in insulin whatsoever. So that's the ideal situation, is to never allow that insulin to get high.

10. 53:37 – 58:18

    PI3K Inhibitors, Hyperglycemia, and the Insulin Problem

    1. PAPeter Attia53:37

       Now, before we go into the why, I want to go back to some experiments, some drugs, and something you said earlier. Let's go back to PI3 kinase. Everything you said about PI3 kinase would make someone listening to this think, "If you could block it with a drug, could you block cancer?" Well, obviously, you've thought of that. So tell us about drugs that block PI3K inhibitors when given to cancer patients.

    2. LCLew Cantley54:08

       Okay, so by 1990, I was quite sure that everything insulin did went through PI3 kinase, and it was also quite clear to me that many cancers have emerged because of activation of PI3 kinase. Some pharmaceutical companies came to me and said, "Should we develop a PI3 kinase inhibitor?" And I said, "Well, I can't imagine how you would be able to thread that needle of being able to inhibit PI3 kinase-"

    3. PAPeter Attia54:38

       Without causing diabetes

    4. LCLew Cantley54:39

       ... without causing severe diabetes. And unless insulin went up high enough to offset the inhibition of PI3 kinase- You would have to go off the drug because of the hyperglycemia. If you raise the insulin level, it could override the PI3 kinase. It was also going to activate the tumor to grow more, so.

    5. PAPeter Attia54:56

       It could be worse.

    6. LCLew Cantley54:57

       Yeah. So I was skeptical and, and never, in spite of all of our data saying that PI3 kinase was driving a lot of cancers, I never pulled the trigger in starting a company or even encouraging anyone else to start a company to make inhibitors of PI3 kinase. The fact that mutations in PI3 kinase were picked up in Bert Vogelstein's laboratory in colorectal cancer and ultimately shown to be in many types of cancers led the charge to actually develop an inhibitor. Because by then it was clear that other mutant tyrosine kinases, when they were hypermutated or hyperproduced in cells, could be drugged and those would be effective ways to block cancer growth. So with those observations, numerous companies, probably fifteen companies, went after projects developing PI3 kinase inhibitors. I was still skeptical that you would be able to manage the insulin problem, but agreed, in fact, applied for and got funding from Stand Up to Cancer, American Association for Cancer Research, to put a team together to try to figure out how to most effectively use those inhibitors as they went into the clinic. And I remember after we received that money, several pharmaceutical companies, uh, contacted me and said, "Will you work with us? We have a PI3 kinase inhibitor in human phase one trials." And they said, "What's more, it doesn't cause hyperglycemia, so it's going to be a safe drug." And I said, "Well, if it doesn't-

    7. PAPeter Attia56:23

       How does that work?

    8. LCLew Cantley56:23

       ... if it doesn't cause hyperglycemia, it's not hitting PI3 kinase, so no, I'm not interested [laughs]

    9. PAPeter Attia56:29

       [laughs]

    10. LCLew Cantley56:29

        ... in working with a drug that doesn't cause hyperglycemia." Ultimately, we decided to work primarily with Novartis that had a drug that we-- several drugs actually that clearly caused hyperglycemia. So I was convinced they were hitting PI3 kinase and that that was an on-target effect. And the question then is, can you thread that needle? Can you manage the glucose level without getting insulin levels so high that they would reactivate PI3 kinase in the tumor? And that had been the challenge. So we suspected-- I should say that in working with Novartis, we got them to agree that if when the patients got hyperglycemia that the endocrinologist would judge was not tolerable, that they would ensure that if the patient could not be managed on metformin, that they would have to go off the trial. In other words, I didn't want this-

    11. PAPeter Attia57:22

        You didn't want them being given insulin, does it?

    12. LCLew Cantley57:24

        I didn't want them to be given insulin or an insulin secretagogue, which also raises serum insulin. And I should say that the endocrinologists who were called in and consult for these patients who were hyperglycemic on the trial disagreed with me. They said, "Insulin is totally safe. They should be able to get insulin, and we should do it that way." But I was quite adamant. I said, "Well, I won't work with you on, on these trials unless you exclude patients who have to be managed on insulin or insulin secretagogues." So Novartis kind of reluctantly agreed to do that and went all the way through their approval trial with that as their requirement. Anyone who couldn't be managed, who would need an insulin or insulin secretagogue would be off the trial. And their drug got approved just in May this year. It took a long time because roughly half the patients who tried to enroll could not be managed on metformin.

11. 58:18 – 1:08:05

    Ketogenic Diet and SGLT2 Inhibitors with PI3K Inhibitors

    1. PAPeter Attia58:18

       Could you also use SGLT2 inhibitors?

    2. LCLew Cantley58:20

       So at that time, the SGL2 inhibitors had not yet been approved.

    3. PAPeter Attia58:24

       Mm-hmm.

    4. LCLew Cantley58:25

       So we're talking about ten years ago when the phase 1B trials that were the lead in to the approval trial were being-- where we worked with Novartis on that. But Novartis stuck with the initial requirement through their approval trial that everything had to be managed on metformin, otherwise they would go off the trial. And that's why it took them a long time to enroll enough patients to complete the trial. Now, the SGL2 inhibitors are approved sodium glucose co-transporter inhibitors that reabsorb glucose from the ultrafiltrate in the kidney. If you block that, then the glucose ends up in the urine, and so that's a good way to lower glucose and thereby lower insulin. Uh, so that tool wasn't available at that time. It's now available today. So we did a study over the last four years. It took a long time to do this. Lots and lots of mice and lots of experiments to test whether in a mouse model for cancers, a variety of cancers, twelve different types of cancers, if you give a PI3 kinase inhibitor and use either a sodium glucose co-transporter inhibitor or put the patients on a ketogenic diet, which means that they only have about eight percent of their total diet as, as carbohydrate, and even that is slow release carbohydrate. The rest, eighty percent is fat and twelve percent is protein. And we ask now comparing metformin versus insulin versus sodium glucose co-transporter inhibitor versus a ketogenic diet, what works best in getting the PI3 kinase inhibitors to shrink the tumor?

    5. PAPeter Attia1:00:02

       And I want to just pause for a moment. This is something you alluded to in passing thirty minutes ago, which was very important, which was insulin can go around the PI3K inhibitor when you block it. And that's why just blocking PI3K alone wasn't going to be enough. Is that correct?

    6. LCLew Cantley1:00:20

       More accurately, we know that if you take a tumor that has PI3 kinase mutations, for example, ex vivo. So we did a lot of this work in organoids from our human patients at Weill Cornell, and we would take an organoid endometrial tumor, for example, and give it a PI3 kinase inhibitor at the therapeutic dose, and we could kill every cell in that organoid. But if we now added back the level of insulin that would be in the bloodstream

    7. PAPeter Attia1:00:51

       at the level of glucose that they would've experienced

    8. LCLew Cantley1:00:54

       and the level of insulin that we actually measure in the blood of the patient 30 minutes after giving them the inhibitor.

    9. PAPeter Attia1:00:59

       How high is an insulin level typically in that patient?

    10. LCLew Cantley1:01:01

        So 10 nanograms per mil is roughly what we see within 15 to 30 minutes, and by 90 minutes it's up to twice that, 10 to 20 to 30 nanograms per mil of insulin. And by two hours, the insulin level is high enough that the glucose now in the bloodstream starts to drop. So that tells us that that massive amount of insulin is enough to reactivate PI3 kinase in liver and muscle. And so it's not going around PI3 kinase, it's just reactivated in spite of the presence of the drug.

    11. PAPeter Attia1:01:34

        Because you can't develop a complete inhibitor for physiologic reasons.

    12. LCLew Cantley1:01:37

        That's right. At the dose that you can tolerate-

    13. PAPeter Attia1:01:39

        Yeah, yeah

    14. LCLew Cantley1:01:40

        ... fighting this battle.

    15. PAPeter Attia1:01:41

        I see, I see.

    16. LCLew Cantley1:01:41

        If you completely turn off PI3K-

    17. PAPeter Attia1:01:43

        So if insulin still has to go through PI3K no matter what, you're putting up a porous dam because a complete dam would kill the patient.

    18. LCLew Cantley1:01:51

        Exactly.

    19. PAPeter Attia1:01:52

        And insulin is tougher, and in the end it's gonna win.

    20. LCLew Cantley1:01:55

        So let's suppose you're giving an estrogen receptor antagonist and you start getting toxic effects of losing estrogen. Would you decide that you would now give estrogen-

    21. PAPeter Attia1:02:08

        Yeah. [laughs]

    22. LCLew Cantley1:02:09

        ... to correct that problem? And so that's what the endocrinologist are saying. We want to give them insulin to bring their glucose down.

    23. PAPeter Attia1:02:16

        [laughs] You're like, "That's the whole thing we're trying to stop here."

    24. LCLew Cantley1:02:18

        That's what we're trying to stop, is insulin, 'cause insulin's what's driving the activation. Those mutations in PI3 kinase will not activate PI3 kinase unless insulin is added to the tumor.

    25. PAPeter Attia1:02:29

        And I recall, I think I even told this story, I may have told this story when I was talking with Sid on the podcast, but we were having dinner one night and I talked about a friend of mine with breast cancer who was in a trial, and she was in an arm in one of the Boston hospitals, and she was on a PI3K inhibitor, and I think it was a phase two. She was the only woman who survived. She's still alive today. The only woman with metastatic breast cancer that survived, who on her own went on a ketogenic diet. And I remember telling you this out of curiosity, like, "Lew, what do you think of this? Do you think this is just an odd coincidence?" And that was the time that you and Sid were starting these experiments. As Sid described it, that was sort of maybe the final clinical, the little pearl that sort of made you guys go off and do this, and that paper was published a year ago, right? That was published, it was last summer. Last July?

    26. LCLew Cantley1:03:24

        Last July, yep.

    27. PAPeter Attia1:03:25

        So what was the efficacy of a ketogenic diet versus an SGLT2 inhibitor and metformin? Were they equal?

    28. LCLew Cantley1:03:33

        So if you did a run in to the ketogenic diet, so they have an entire week on the diet and then they're given the inhibitor, it's incredibly effective because by then you've depleted all the glycogen, all the relevant tissues. If you just start on a ketogenic diet a day before you give the first PI3 kinase inhibitor, it's still pretty effective, but not as effective as the whole week run in to deplete glycogen.

    29. PAPeter Attia1:03:59

        Is there any reason not to combine these, ketogenic diet, metformin, SGLT2 inhibitor, PI3K inhibitor as a F you to cancer? For cancers dependent on this pathway, of course.

    30. LCLew Cantley1:04:09

        Yeah. Well, let me address the sodium glucose co-transporter inhibitor first, because that is almost as effective as a ketogenic diet in our mouse models. It keeps the glucose level not quite as low as a ketogenic diet, but pretty damn low. And the importance, of course, is in both cases it brings the insulin, ambient insulin in the serum drops dramatically. But the important thing is that every single 12 different types of cancers, some of them had PI3 kinase mutations, others didn't. Some were RAS mutant tumors. Didn't matter. Some were-- One was AML from Sid's study.
12. 1:08:05 – 1:16:27

    Petra and Faeth: New Trial and Diet-Drug Pairing

    1. LCLew Cantley1:08:05

       To reveal my conflicts here, I do have a company I've started, Petra Pharmaceuticals, that is beginning a PI3K inhibitor trial. It will be combined with sodium glucose co-transporter inhibitor.

    2. PAPeter Attia1:08:17

       Oh, I didn't even realize. I'm bringing up all this stuff. I'm teeing it up for you here.

    3. LCLew Cantley1:08:20

       Yeah, right.

    4. PAPeter Attia1:08:21

       Yeah.

    5. LCLew Cantley1:08:22

       That trial will be starting any day now.

    6. PAPeter Attia1:08:24

       What type of cancers, Lew? Are you looking for enrollment?

    7. LCLew Cantley1:08:27

       So in phase one here, it's going to be a combination of a sodium glucose co-transporter inhibitor plus PI3K alpha inhibitor. Initially, we'll be looking at solid tumors, breast, endometrial, where you see high rates of mutations, but we won't-

    8. PAPeter Attia1:08:40

       So breast, endometrial, in what stage of disease? Is this stage four?

    9. LCLew Cantley1:08:43

       Yes, in stage four disease.

    10. PAPeter Attia1:08:45

        So have you fully enrolled or?

    11. LCLew Cantley1:08:47

        No, no, we're just, you know, trial is just, hasn't enrolled-

    12. PAPeter Attia1:08:49

        So in other words, if someone's listening to this that either has or knows someone with breast or endometrial cancer who is stage four, how can they best find out information on this trial?

    13. LCLew Cantley1:08:59

        So Petra Pharmaceuticals, so of course, this will be registered at clinicaltrials.gov, where you can find every single trial. So if you just go to clinicaltrials.gov and type in Petra, P-E-T-R-A, that will-

    14. PAPeter Attia1:09:11

        We'll link to that for sure. How many patients will you take into phase one?

    15. LCLew Cantley1:09:15

        I've forgotten the exact number, but there, it depends on how many responses we see and so forth.

    16. PAPeter Attia1:09:20

        But the dose escalation-

    17. LCLew Cantley1:09:21

        The dose escalation is going to be pretty quick because we already have, we know what the dose is without a key-

    18. PAPeter Attia1:09:28

        Each of these drugs, you sort of know what they do.

    19. LCLew Cantley1:09:30

        We know. We don't anticipate any toxicity from the combat.

    20. PAPeter Attia1:09:31

        So the hope is to get to phase two quickly.

    21. LCLew Cantley1:09:33

        Yeah. We should get to phase two very quickly, and the person, patients on phase one could transition into phase two.

    22. PAPeter Attia1:09:39

        This is really exciting, Lew.

    23. LCLew Cantley1:09:41

        So in that case, we will recommend that they have for breakfast, because all these drugs, most of these drugs require that you eat breakfast before you take the pill, 'cause that limits some of the toxicities you get from, and increases the absorbance. But I think it makes a hell of a lot of difference what you have for breakfast.

    24. PAPeter Attia1:09:57

        So you'll recommend scrambled eggs and-

    25. LCLew Cantley1:10:00

        Yep

    26. PAPeter Attia1:10:00

        ... avocado and-

    27. LCLew Cantley1:10:01

        Whole milk yogurt, not yogurt with sugar or-

    28. PAPeter Attia1:10:04

        Yep, yep

    29. LCLew Cantley1:10:05

        ... berries in it.

    30. PAPeter Attia1:10:05

        Or a high-fat yogurt and-
13. 1:16:27 – 1:22:29

    Approved PI3K Inhibitors and Bridging Oncology and Endocrinology

    1. PAPeter Attia1:16:27

       How many PI3K inhibitors are currently approved by the FDA?

    2. LCLew Cantley1:16:31

       So there's the alpelisib, Novartis drug just approved in May, that hits specifically only the alpha isoform. Now, that's the isoform that insulin activates and mediates everything insulin does, and that's the one that's caused all the problems with hyperglycemia. But there is also a delta isoform of PI3 kinase that's seldom mutated, but it's actually required for B cell growth. And we discovered that back when we started knocking out PI3 kinase in a hematopoietic lineage cells in mice back in the late 1990s. Uh, David Fruman, a postdoc in my laboratory, was doing those mouse knockouts and found that B cell lineage cells failed to thrive if you knocked out PI3 kinase. T cells, on the other hand, were fine if you knocked out PI3 kinase, and ultimately it turned out to be the delta isoform that was critical for the growth of B cells. So when delta inhibitors were developed, they went into B cell lymphomas as the first possible place to work since that enzyme was already known to be critical in B cells. And they turned out to be effective. Idelalisib was approved about five years ago. It's a delta specific PI3 kinase inhibitor.

    3. PAPeter Attia1:17:50

       Who made that?

    4. LCLew Cantley1:17:51

       That was made by Gilead.

    5. PAPeter Attia1:17:53

       Oh, Gilead. Okay. Yeah.

    6. LCLew Cantley1:17:55

       And then more recently, a, a drug called copanlisib was approved about three years ago by Bayer. This is a drug developed by Bayer.

    7. PAPeter Attia1:18:06

       And which isoform is that?

    8. LCLew Cantley1:18:08

       Again, it also hits delta, but it also hits alpha.

    9. PAPeter Attia1:18:11

       So the alpha one is the only one that causes the hyperglycemia. Yeah. That's the one that my friend was on, by the way.

    10. LCLew Cantley1:18:17

        Right.

    11. PAPeter Attia1:18:17

        But that was approved in May, and that seems to have the most ubiquitous application, doesn't it?

    12. LCLew Cantley1:18:23

        It's certainly where you see the most mutations, and of course, breast cancer is far more numerous than lymphoma.

    13. PAPeter Attia1:18:30

        Yeah. But that's the one that's gonna need the most management of the hyperglycemia and the hyperinsulinemia. Is that message reaching the oncologists?

    14. LCLew Cantley1:18:38

        Slowly, I think they're beginning to understand what we're saying, why it's important to keep the insulin down. The problem you-- as you know better than I, that we're so specialized today in medicine, that people commit to go into either oncology or endocrinology, and from there on, their studies are completely-- they're studying completely different things. And if you have an endocrine problem as an oncologist, you don't try to solve it yourself, you call in an endocrine consult. So your brain isn't really even focusing on how to solve a problem because you have an expert who can do it for you. And the problem is the endocrinologists are not really that alert about what's going on with cancer. Their job is to make sure the glucose is in line.

    15. PAPeter Attia1:19:22

        Yeah, sort of I think it's time that we either-- I mean, there's really two ways around this I see. One is you sort of create a new specialty, which is metabolic oncology. So just today, if someone wants to study oncology, they choose between surgical oncology, medical oncology, radiation oncology. Of course, the challenge is you have to differentiate very early. You don't do oncology first, then surgery, then medicine, then radiology. It's you do radiology or medicine or surgery and then sub-specialize. So therein lies a problem. How would you become a metabolic oncologist? So the other option is basically oncologists learning more about the metabolism of cancer so that when it comes to managing understood and predictable complications of these medications, which are actually desired features, as you point out, if you're using this drug correctly, you should see hyperinsulinemia and hyperglycemia, and you should treat it accordingly. Which reminds me, by the way, how often with the alpha isoform does that drug need to be administered or in your trial?

    16. LCLew Cantley1:20:22

        Decision of how frequently to dose is based on PK/PD, how fast the drug level goes into the bloodstream and how long it stays high and following how quickly it declines. And so most of these drugs that make it in the clinic can stay at their therapeutic dose for three or four hours. So a lot of the companies want to do by two drugs a day, one in the morning, one in the evening.

    17. PAPeter Attia1:20:46

        And what's the total cycle? How long are you being given drug? How long are you given a rest from the drug?

    18. LCLew Cantley1:20:51

        And so, for example, the Novartis drug is daily. It's once a day daily after breakfast on a full meal.

    19. PAPeter Attia1:20:57

        And why does it need a full stomach?

    20. LCLew Cantley1:20:59

        Because otherwise absorption problems, you don't get as good a PK/PD if you eat it on an empty stomach and you get more side effects, diarrhea or nausea or whatever if you try to do it on an empty stomach. But there's no recommendation in the approval trial as to what you're supposed to eat for breakfast before you take the drug or whether you take it with Ensure or apple juice or water, so.

    21. PAPeter Attia1:21:22

        Hence the importance of a company like Phaeth that could start to standardize that. Because look, everybody wants to do the right thing here. And wouldn't it be great if as a doctor you could write a prescription that's not just covering the drug, but covering the food?

    22. LCLew Cantley1:21:34

        Yeah. So that's what we're anticipating at Phaeth at some point, if you can prove in a clinical trial setting that you need this particular food for the drug to be effective.

    23. PAPeter Attia1:21:42

        To maximize absorption, minimize symptom side effects, and most importantly, maximize efficacy.

    24. LCLew Cantley1:21:47

        You should be able to get that food paid for, the delivery of the exact food that matches what your need is.

    25. PAPeter Attia1:21:54

        And think about it, what a trivial cost it is compared to the drug. I mean, you could send people caviar spread all day long at one one-hundredth the cost of a drug.

    26. LCLew Cantley1:22:04

        Exactly. But you have to prove it. You've got to prove it in a phase three clinical trial.

    27. PAPeter Attia1:22:08

        Well, don't get me started on that. I mean, think of how many drugs have been approved that haven't proved jack. I mean, it's Ambien should have been approved. Anyway, don't get me started on the drug approval process here, but I'm completely with you on that. Lew, I want to be kind of mindful of your time. There's kind of one last theme I want to explore. So you're going to be 70 this year, right? Which is kind of hard to believe because I need-

    28. LCLew Cantley1:22:29

        I already passed it.

14. 1:22:29 – 1:27:38

    Cantley's Curiosity and Goals for the Next Decade

    1. PAPeter Attia1:22:29

       You already passed it. So you don't look a day over, I don't know, 56. You've got this ageless phenotype to you. So I don't want to for a moment suggest your career is anything other than continuing to go up in terms of the work you have to do. So as you think about the next chapter of your career, what is the question that you are most obsessed with? What is the question you want to spend as much time as you can trying to answer that currently we really don't have an answer to?

    2. LCLew Cantley1:23:00

       That's hard for me because I'm the most unfocused-- In some ways, I'm compulsive about getting the answer of every question that I get curious about. And as you can tell from this interview, I have an opinion on how everything works. And having never taken any biology courses, I have no prejudice about how it should work. So for me, everything that I run into biology is here's a mystery. I don't bother reading the textbooks because I know they will prejudice me to the wrong answer. And so I'd like to get to the bottom of what's really going on. But the bottom line is that I get absolutely brilliant postdocs and graduate students come to my laboratory. I allow them to do anything they want to do. And if it obviously gives them advice and help interpret the experiments. But this has kept me in so many different fields for 40 some years as I've run my own laboratory. It keeps my mind continually alert about every possible thing. So yes, epileptic seizures. Turns out probably most of the people who have epileptic seizure fits have PIK3CA mutations as a mosaicism in neurons in the brain. Ketogenic diet was developed to minimize that. It makes perfect sense. Keep insulin down. If a PIK3CA mutant neuronal cell, you're going to get less firing of that neuron that's going to solve the problem. But that wasn't how the ketogenic diet was developed. So my curiosity, if just studying everything which PI3 kinase is involved at some level could keep me busy for several years. But that's not the only thing I'm interested in. I'm interested in whatever curious observation that comes up from experiments in my lab that can't be easily explained by current knowledge. To me, that means there's an opportunity to break open some new explanation for some disease. So I'm willing to work in almost any disease that's not yet solved and there's an opportunity to figure it out. I'm a chemist. So to me, unless I understand something at the molecular level, I don't really understand it. But I think with PI3 kinase, I really understand it at the molecular level.

    3. PAPeter Attia1:25:09

       I think that's an understatement.

    4. LCLew Cantley1:25:10

       Very few. There's still some mysteries there, I should say, that we're About to publish a couple of papers, hopefully over the next six to nine months, that are going to completely change how everybody thinks about PI 3-kinase regulation. So there's still some major things to learn about this enzyme.

    5. PAPeter Attia1:25:27

       Well, there's so many other things I'd love to speak with you about, Lew, but I know that some of them are still work that you're doing, and therefore I know you would prefer to wait until things are a little further along to talk about them. But we'll have to come back in a year or so and do this again, 'cause there's so much other stuff that I know we've talked about informally about cancer that is-- I want to believe it's where the field is going to start to go. I want to believe that... Because I get so many emails from people who say, "You know, my mother has cancer," or, "My husband has cancer and they're being offered this therapy," and it's a very standard therapy. The patient is progressing through it. What metabolic options are there? And people like you are, people like Sid, people like all your colleagues and Matt and Ben and all these guys, I mean, you guys are the guys that are kind of driving that forward. And you've made a lot of progress in a decade. It doesn't feel like it sometimes. Like, sometimes I feel like it's not going fast enough. But I think having a discussion like we did today makes me realize how much has happened in a decade, and it's actually quite a bit. I have no doubt that you're going to be here a decade from now working just as hard.

    6. LCLew Cantley1:26:38

       Well, my real motivation, of course, is to convert every observation we make in the laboratory to actually change in practice for whether it's diabetes or cancer or what other disease that we begin to understand a molecular mechanism. If we don't convert those observations into actual change in behavior or change in practice or change in drug metabolism and diet, then in the end we've failed. And so that's my goal. And as being a cancer center director, people sometimes listen to me now when I suggest this is the way, this is the trial we should do, and this is the way it should be designed to test the idea. For me, it's spectacular being here in New York City at Weill Cornell and NewYork-Presbyterian, where we really can translate these breakthroughs into new therapies. That's what my goal will be over the next 10 years.

    7. PAPeter Attia1:27:32

       [outro jingle]

15. 1:27:38 – 1:46:58

    Appendix: Origins in Chemistry, Mitochondria, and Insulin Signaling

    1. PAPeter Attia1:27:38

       I hope you enjoyed that discussion with Lew Cantley, and I hope you found it half as interesting as you can probably tell I did. As you may recall, at the outset of this podcast, I said that the first 45 minutes, which was a much more detailed technical description of Lew's initial work in the '70s and '80s that led to the discovery of PI 3-kinase, that content would be bumped as almost an appendix to the end of the podcast, and that's what you're about to hear now. So I hope you enjoy what was originally the first part of my discussion, but ultimately the appendix to this fun discussion with Lew Cantley. [outro jingle] There are a lot of things I want to talk about today, but I do want to start with the discovery that you led that probably most people would associate with you. If they go to your Wikipedia page, that's probably the first thing they're going to see, although I haven't been to your Wikipedia page in a while, so I don't recall. But let's talk about PI 3-kinase. How do we define it, by the way? Tell people what it-- Yeah, we'll-

    2. LCLew Cantley1:28:39

       So PI 3-kinase stands for phosphoinositide 3-kinase, and the three means that it phosphorylates the 3′ position on the inositol ring, which is the head group of this lipid. And so in the mid, early mid-1980s, phosphatidylinositol phosphorylation, which was known to occur from 1949, the purpose of it was totally ambiguous. Why did this lipid get phosphorylated? And in early 1982, '83, there was a breakthrough with the discovery that the phosphorylated form, phosphatidylinositol with phosphate at the four and the five positions of the inositol ring... By the way, inositol is hexahydroxycyclohexane, so there's six hydroxys. One of them connects to the glycerol backbone, and then the others are potentially available to be phosphorylated. Anyway, the four position and the four plus five position were both identified the year I was born, 1949, and the purpose of that was not known. It was called the futile cycle, maybe a way of just getting rid of-

    3. PAPeter Attia1:29:52

       Getting rid of phosphates or something.

    4. LCLew Cantley1:29:54

       Or getting rid of ATP.

    5. PAPeter Attia1:29:55

       Yeah, yeah.

    6. LCLew Cantley1:29:55

       You just phosphorylate it and dephosphorylate it and-

    7. PAPeter Attia1:29:58

       Sort of like an ATP sink.

    8. LCLew Cantley1:29:59

       And then the idea, the observation that this phosphorylation could be stimulated by various GPCR pathways and growth factor pathways got people thinking about what it might be doing, and it tended to correlate with calcium elevation. And so the breakthrough paper showed that in fact, when cells are stimulated with certain growth factors like EGF or a certain subset of GPCR activators-

    9. PAPeter Attia1:30:26

       And those stand for?

    10. LCLew Cantley1:30:27

        G protein-coupled receptors.

    11. PAPeter Attia1:30:29

        Mm-hmm. And EGF, just for folks?

    12. LCLew Cantley1:30:31

        Epidermal growth factor.

    13. PAPeter Attia1:30:32

        Okay, so all growth.

    14. LCLew Cantley1:30:34

        And so these signaling pathways would activate the hydrolysis of that lipid, that the inositol 1,4,5-trisphosphate that comes off when you hydrolyze it away from the lipid turned out to regulate calcium release from cells. And that was a huge breakthrough, 'cause no one knew how calcium got elevated, and that explained it. So I, in the meantime, was not working on that particular pathway.

    15. PAPeter Attia1:31:01

        And let's pause for a moment and remind everybody, you trained-- You were interested in science from a young age, but you were sort of deciding, I think, a little bit, if I recall, between chemistry and biology. You were very interested in both, correct?

    16. LCLew Cantley1:31:13

        I was a pure chemist. The last biology course I took was in 1964 when I was a sophomore in high school.

    17. PAPeter Attia1:31:20

        So you very quickly declared chemistry your obsession.

    18. LCLew Cantley1:31:23

        I hated biology because at that time, at least in the backwoods of West Virginia where I was growing up, biology was just a bunch of descriptive memorization. And so I was bored with that and decided I would never take another biology course, and I stuck to that. I was pure chemistry, mainly organic chemistry, and then I switched into physical chemistry, but was totally uninterested in biology at all until I took one semester of biochemistry and realized maybe there's something interesting going on in biology. So I went to Cornell in Ithaca to get my Ph.D., and there I focused on biophysical chemistry. It was a chance to apply chemistry to questions like how do you get molecules across membranes? And that's what I worked on. How do you synthesize ATP in the mitochondria or chloroplasts? So that kind of the slippery slope of going into biological questions that could be addressed by simple chemical questions or physics questions.

    19. PAPeter Attia1:32:26

        Now, what got you interested in the mitochondria so early?

    20. LCLew Cantley1:32:28

        I read a paper when I was an undergraduate that was an idea that Peter Mitchell had proposed, that the way you make ATP in the mitochondria and or chloroplasts was using a proton gradient. And his idea was that that gradient would allow you to pull the protons in one direction, the hydroxy ions in the other direction, and remove water from phosphate plus ADP and condense that into ATP. That was just very simple physical property that if you could move those two ions in different directions, it would produce ATP. In effect, the idea was not correct. It was correct that ATP was made from the proton gradient, but the actual mechanism was turned out to be different. There are actually three Nobel Prizes given for how ATP is synthesized in the mitochondria.

    21. PAPeter Attia1:33:19

        I wasn't aware that there were three separate Nobel Prizes. Do you recall who won all of them?

    22. LCLew Cantley1:33:24

        So Mitchell.

    23. PAPeter Attia1:33:24

        Mitchell, obviously, yeah.

    24. LCLew Cantley1:33:25

        Peter Mitchell got one. Then there was a second one by Boyer on the figuring out the actual mechanism by which this occurs, and then a third one from Peter Walker, who figured out structural basis for how this all worked. He-

    25. PAPeter Attia1:33:37

        Oh, I didn't know the Walker one. Okay.

    26. LCLew Cantley1:33:39

        He was a crystal structure and did crystal structures. And I met all of them when I was a young man before becoming a professor, and so it's... I was very invested in that, and that's what I worked on.

    27. PAPeter Attia1:33:51

        For the person who's listening to this, whose world is not necessarily wrapped up in this, which is most people, it's worth pausing for a moment on how much is involved for the Nobel committee to recognize one body of work. That says something that three times they would recognize a different angle of the same body of work probably speaks to why there is so much to this day complete interest and fascination with the mitochondria beyond just the obvious, the energetics, which is what was initially how we would think about it.

    28. LCLew Cantley1:34:23

        Well, it was a fascinating question. Uh, in the 1960s, this was the biggest mystery because you, we knew how you made ATP from glycolysis, but how you made it in the mitochondria and how could the mitochondria do it so much more efficiently than glycolysis? That was the big question when I was a graduate student.

    29. PAPeter Attia1:34:40

        I think this podcast may represent the point at which mitochondrial topics exceed all others. [laughs] It also speaks to that nature. So Mitchell the Great, tell me about how you interacted with Mitchell. How did you come across him?

    30. LCLew Cantley1:34:53

        So he came to give a talk at Cornell.
16. 1:46:58 – 2:11:27

    Appendix: Discovering PI3 Kinase and the 3-Phosphate Lipids

    1. LCLew Cantley1:46:58

       So I saw a paper by Ray Erickson's laboratory in which he found an activity associated with Src that would phosphorylate glycerol. And he published it in JBC. It co-purified with the protein through numerous steps of purification. And so in addition to having the ability to phosphorylate tyrosine antibodies that got phosphorylated on tyrosine on the purified protein, there was also an activity there that phosphorylated glycerol. And I looked at that and thought, "Now, glycerol looks like half of an inositol." So inositol is six carbons, glycerol is three. In both cases-

    2. PAPeter Attia1:47:40

       But in the pure glycerol case, it has OH on each of the carbons?

    3. LCLew Cantley1:47:44

       Yeah, three carbons with an OH on it.

    4. PAPeter Attia1:47:45

       Yeah.

    5. LCLew Cantley1:47:46

       And inositol has six carbons with an OH on all. So if you took two-

    6. PAPeter Attia1:47:50

       Yeah, if you took the two rings and shoved them together, yeah.

    7. LCLew Cantley1:47:52

       Glued them together, you would get inositol. And then what the paper showed was the KM, in other words, the fifty percent concentration of glycerol you needed for it to be phosphorylated, was something like a hundred millimolar.

    8. PAPeter Attia1:48:08

       Enormous concentration.

    9. LCLew Cantley1:48:09

       Huge, like, uh, hundred to thousand fold higher unit ever found in a cell.

    10. PAPeter Attia1:48:13

        Yeah.

    11. LCLew Cantley1:48:14

        So they weren't claiming this was a physiologically relevant-

    12. PAPeter Attia1:48:18

        I see. They were just saying, "Here's a chemical reaction that can take place."

    13. LCLew Cantley1:48:22

        And they just noticed it because they saw this molecule running on their thin layer that ran faster than proteins when they isolated. It turned out to be phosphorylated glycerol. It was sort of out there. Here's, we saw this other activity. What might it be? And so I went to Ray Erickson and said, "Well, that looks a lot like inositol, so why don't we-"

    14. PAPeter Attia1:48:41

        Was Ray at Harvard at the time?

    15. LCLew Cantley1:48:43

        Yeah, one floor below me at Harvard. So my graduate student, Malcolm Whitman, who knew how to do kinase assays on small molecules, collaborated with Ray Erickson's postdoc to see whether phosphatidylinositol might be a better substrate than glycerol. And he tried it, and sure enough, he got this KM now of, like, five micromolar.

    16. PAPeter Attia1:49:06

        Wait, wait, wait, wait. How is this even possible? Let me make sure I understand what you just said. You take glycerol, and you need a KM of a hundred millimolar to get it phosphorylated. You simply take the same structure, but now it's basically two of them stuck together in a ring, and you get down to five micromolar?

    17. LCLew Cantley1:49:26

        And it's also on a membrane component. So the inositol is in a membrane bilayer. So you sonicate the lipid and it, instead of free molecule floating around-

    18. PAPeter Attia1:49:35

        Oh, so it's not a free inositol. It's the inositol and the phospholipid or in the lipid.

    19. LCLew Cantley1:49:38

        In the lipid. Yeah.

    20. PAPeter Attia1:49:39

        Tell me from a chemistry standpoint, and I apologize, I know that for some of you listening right now, you're thinking, wow, you guys are really in the weeds. I promise we're gonna get out of the weeds in a minute. But I also think this is just an interesting example of the specificity of biology too. What is it about that lipid holding that... Is it the position with which it holds the ring in place that enables that phosphorylation?

    21. LCLew Cantley1:49:59

        Well, now that we know the structure of PI3 kinase and how it works and its mechanism, it's easy to explain in retrospect. But at that time, we didn't know that there was anything there other than Src. So it was hard to explain why the Src tyrosine kinase itself was carrying out this reaction.

    22. PAPeter Attia1:50:18

        What did the editors even say of that? I mean, that's one of those things where people are like, is there a mistake here? 'Cause that's like a five log difference.

    23. LCLew Cantley1:50:26

        Physicists had no problem understanding what I just said. If you confine things to two dimensions, they can come together much more readily than if you do it, do it in three dimensions.

    24. PAPeter Attia1:50:35

        And that would account for the difference?

    25. LCLew Cantley1:50:36

        Yeah. Easily. Try closing your eyes, bringing your two fingers together in space, in three-dimensional space, and then do it again on the table.

    26. PAPeter Attia1:50:44

        When they're on the table, yeah.

    27. LCLew Cantley1:50:45

        And you'll find [laughs]

    28. PAPeter Attia1:50:46

        Yeah, yeah.

    29. LCLew Cantley1:50:46

        You'll find each other.

    30. PAPeter Attia1:50:47

        Yeah.

Episode duration: 2:11:27