#187 - The Warburg Effect: Otto Warburg’s Cancer Metabolism Theory with Sam Apple

1. 0:00 – 0:10

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Attia. [upbeat music]

2. 0:10 – 13:35

   Sam’s interest in Otto Warburg and work as a writer [2:30];

   1. PAPeter Attia0:10

      Hey, Sam. How are you doing today?

   2. SASam Apple0:12

      I'm doing good. How are you?

   3. PAPeter Attia0:14

      Good. Good. Um, congratulations on the, uh, the publication of your book, uh, very recently. Uh, I, I-- Having never done that before, I can still only imagine it's, uh, a-akin to giving birth or something like that. Um, feels like the weight of the world off your shoulders after, um, how much research you've put into that.

   4. SASam Apple0:34

      Yeah. It's, uh, it's a huge relief just to be done, so I'm, uh, trying to think about a, a future project, but I feel like I, I need a few years just to, to relax now. [chuckles]

   5. PAPeter Attia0:45

      Oh, yeah, yeah. I, uh, I, I imagine there's nothing more annoying than when you publish a book when somebody says, "So, what's your next book gonna be about?" It's like-

   6. SASam Apple0:53

      Yeah

   7. PAPeter Attia0:53

      ... let me bask in this-

   8. SASam Apple0:54

      Yeah, I've gotten that-

   9. PAPeter Attia0:54

      ... for a little bit

   10. SASam Apple0:55

       ... a few times.

   11. PAPeter Attia0:56

       Like many, uh, books that go really deep into a topic, be it science or otherwise, they often start out as articles. Um, and of course, you wrote a piece, uh, was it two thousand fifteen? When, when was that piece?

   12. SASam Apple1:10

       Came out in two thousand sixteen.

   13. PAPeter Attia1:12

       Yeah. Um, and it was the New York Times magazine piece, correct?

   14. SASam Apple1:16

       Right.

   15. PAPeter Attia1:17

       Um, and I remember that quite well. You and I had spoken quite a bit before then, and I know that that sort of ultimately led to, um, the work that went into this book. But more broadly speaking, what attract you-- attracted you to this topic of, of Warburg cancer metabolism, the, the era of, of Nazi Germany and science in, um, in that era? What, what, uh, what gravitated you to that?

   16. SASam Apple1:43

       Yeah. I mean, like so many people in this world, um, I was influenced by Taubes at, uh, a fairly early stage of my interest in metabolism. I, you know, read some of his work, and that had led me to other authors and, and eventually to, to a lot of your work and, and your blog, uh, which I learned a lot from. So I, I had been interested in metabolism for a number of years, uh, but I, I had not really thought of cancer as a metabolic disease or thought about cancer as being lumped with obesity and diabetes and heart disease. And when I started to read more about that and see that, you know, they clustered together and that you see the same pattern that begins in the nineteenth century of all these metabolic conditions growing more common, that's what really sort of sparked my curiosity is, you know, cancer isn't supposed to be metabolic like these other diseases. You know, it's bad luck. It's mutations that are caused by environmental carcinogens or whatnot. So it just stayed in my mind, but, um, I hadn't planned to write about it until I, I came across a mention of Warburg. I think it was just one sentence, you know, "Nineteen twenty-three, a German scientist makes an important discovery about the metabolism of cancer cells." And, um, you know, so I, I google Otto Warburg, and I start to read about him and, you know, it was kind of a light bulb moment for me, like, "Oh my gosh, I have to write about this man." Uh, you know, because I, I'm a, a, a journalist, a storyteller by profession, and so I don't write about science usually unless I feel like I know how to tell a story. If I have a, a central character, then I know how to tell a story. So once I, I had Warburg, I knew I was gonna write about it and, um, I knew I had a, a way to tell the story.

   17. PAPeter Attia3:21

       Before we get to that story, I wanna kinda understand a little bit about your, your, your work as a writer. Um, you're a prolific writer. You, you actually teach a course in science writing at Johns Hopkins now, don't you?

   18. SASam Apple3:32

       Uh, yes, I do.

   19. PAPeter Attia3:33

       So when did you realize you were a writer?

   20. SASam Apple3:37

       Um, well, my father is a writer, so [chuckles] it helped to, to have that. You know, for many people grow up, it seems like a, you know, an unusual career choice. But for me, it was, you know, obviously, you know, a potential option just having seen my father do it. But, um, truth is, I didn't try to, at least not consciously, to follow in his footsteps. If anything, I thought that, uh, you know, I might need to distinguish myself by choosing a different path. And, um, you know, I, I like my father mostly writes fiction. I like to half-joke that my big rebellion was moving into nonfiction.

   21. PAPeter Attia4:10

       [chuckles]

   22. SASam Apple4:12

       Um, but it really was in college when, um, you know, I wasn't sure what I was going to do, and I was getting a lot of praise for my writing. And, you know, the praise felt good, and I, you know, I wasn't, you know, killing it necessarily in, in other areas. So, you know, I saw that it was my strength. I enjoyed doing it, and, um, I sort of, you know, just continued with it because, uh, I was succeeding with it.

   23. PAPeter Attia4:35

       So do you think a, a, a good writer is born or made, or, uh, how much of your success do you attribute to some inborn, um, gift versus something you'd been cultivating and, and nurturing and practicing?

   24. SASam Apple4:50

       Yeah. It's a tough question. I, I think about it a lot because I-

   25. PAPeter Attia4:54

       Yeah

   26. SASam Apple4:54

       ... you know, I teach science writing and, and, um, general creative writing at Johns Hopkins now. And, you know, I, I certainly think that everybody can improve a lot as a writer and, you know, I think clearly every day about how to get better at, uh, teaching it and, and helping people improve. But, you know, at, at some level, it's innate. Uh, you know, some people have more natural ability than others with language. Uh, but, uh, I think it's pretty analogous to, you know, musical talent, where some people can very quickly get very good at an instrument, sit down on the piano in a matter of weeks, be good, and others will struggle for months and have to practice again and again, but they eventually get there. So, um, you know, it's not-- I don't think it's correlated that strongly with intelligence. It's a sort of just, uh, an ability to, you know, use language in a certain way that, um, comes naturally to some people and comes to other people with more practice. But I think everybody can get pretty good with, with enough practice.

   27. PAPeter Attia5:57

       So when you're teaching a class, um- Let's just say there's 100 students in the class. What type of an assignment would you give if you wanted to very quickly figure out the, the, the breadth of natural ability or the spectrum of natural ability across the students? How, how would you ferret that out quickly?

   28. SASam Apple6:17

       Um, truth is that, um, you can see it in almost any writing sample. You know, I, I'm on the faculty of Johns Hopkins, so I'm also involved in the application, uh, in reviewing applications and, and selecting, um, students for the science writing program and, you know, they submit samples of their writing, but I often look most closely just at the, the cover letters because I feel like, you know, within a paragraph or two I get the feel, you know, if they have a feel for the language or not. Uh, so it really comes across, you know, I think almost in any three or four sentences I can start to feel is, you know, are there extra words in these sentences? Is the logic tight? Does it flow? Um, it, it really doesn't take very much to, to figure it out.

   29. PAPeter Attia7:04

       That's amazing, and it makes me feel so self-conscious because of how often I write. You know, every Sunday I'm putting out a newsletter and, um, I enjoy writing a lot, but it doesn't, I don't feel like it comes naturally to me, so I can imagine, um, w- you know, how many people must read that and go, "Oh my God," like, yeah, what he's saying is interesting, but he's such a horrible writer. Um, and of course I know what it's like to read very good writing. You know, you can sort of spot the extremes, or at least I can spot the extremes. I don't think I could rank 100 people from one to 100 even though obviously there's somewhat, you know, there's a lot of subjective stuff in there. But, you know, I could certainly say this is exceptional. Like, I can read Sid Mukherjee and say, "Wow, this is really, really good." Um, and similarly I can read something that is absolutely horrible and say, "This is really, really bad." I might not be able to tell you why though. Um, so how much of it is also being able to in that cover letter say, um, you gave a couple of examples, right? Like, this person is using a lot of unnecessary words or they're presumably repeating themselves or this is illogical. Um, that's a lot to pick up in just a paragraph.

   30. SASam Apple8:19

       Yeah. I mean, I think it comes down to clarity more than anything. You can read something and grasp it right away because the language is concise and clear, and you can read other things where it's just a very simple statement, but you actually have to read it two or three times just to grasp, uh, the writer's meaning. So, um, you know, George Orwell famously wrote about, uh, politics and English language and, you know, how much good writing depends on clear, concise thinking and, and I, and I think that's true. Um, but such a big part of it, you know, everything that, that I write comes out pretty poorly in the first draft. Even my emails that if I really care about an email [laughs] I spend a lot of time just going over and over and over it because it, it's the repetition, it's correction after correction after correction where the writing starts to improve. So, you know, I think the difference between a good writer and a, and a less good writer is often, you know, how many times the good writer goes over the work whereas the lesser writer will just say, "Yeah, doesn't matter that much," and send it off. But there's a price to pay. You know, I waste half my life worrying about sentences in an email, so, you know, it comes, comes at a cost. Um, and, uh, you know, for the record I, uh, I was a big fan of your blog when you were posting more regularly, so I think you're being too hard on yourself. [laughs]
3. 13:35 – 23:27

   Otto Warburg’s dedication to science and his complicated life in Germany

   1. PAPeter Attia13:36

      So let's get back to the, to the story here. Um, and let's assume that the, the listener here doesn't really know anything about Warburg. That name means nothing to them. Um, what's the... Where's the right place to begin this story? We've, we've... You know, he, he, he's, he's born into a pretty well-to-do family in the, uh, kind of latter third of the 19th century. Um, tell, tell us, uh, where to pick up this story.

   2. SASam Apple14:04

      Sure. Yeah, I, I do think that his childhood is a really important part of the story. Um, you know, I had a hard time finding a lot of original sources and documents about his childhood, but the, the basic facts are that, you know, his father, Emil Warburg, is a very prominent physicist. Uh, despite coming from a famous Jewish family, he rises to the top of German physics. He's at the University of Berlin, which is very unusual for somebody of a Jewish background in the late 19th century. A- and Einstein really loves his father, you know, says that he's like his favorite physicist, and you know, Emil Warburg ends up providing some of the experimental proof for some of Einstein's theories. So, uh, Einstein was a regular in the house when Warburg was a teenager. Uh, Max Planck, Emil Fischer, you know, all these titans of German science. And, you know, the Germans revered their scientists. The country was at the top of the scientific world at the time. Uh, so Warburg's, you know, vision for himself is, you know, he's gonna grow up and be a great scientist like the people that hang around in his house. He's gonna make a world-changing discovery, uh, just as his father and Einstein and Emil Fischer have. Uh, and the question is where he's gonna, you know, focus his energies, and he moves away from, from physics, which is a little surprising. Um, I think that was his, his rebellion in a way, and he wanted to outdo his father, Emil Warburg. And uh, so he moves into the realm of, of biology and physiology, but it's always throughout his life, uh, through the lens of a physicist and always interested in, in energy and how, you know, we can understand biology through an understanding of energy. So he didn't fully move away from his father so much as take the physics into a new realm and, and that extended to a study of photosynthesis as well.

   3. PAPeter Attia15:58

      So how old was he at the beginning of World War I?

   4. SASam Apple16:03

      Uh, that's a good question. At the beginning of World War I, he, um... I'd have to go back and do the math. So it's 1914, and he was born in, in 1883. Uh, so he was in his early 30s, I guess.

   5. PAPeter Attia16:16

      And so what was the impact of World War I on German scientists?

   6. SASam Apple16:22

      Um, it was, you know, pretty remarkable that, um, you know, given that if you look back from a historical perspective, I don't think that, uh, Germany's position at the time is particularly defensible. But there was, you know, just this huge surge of nationalism and, and the scientists were, by and large, got, you know, signed on and signed letters in support of the fatherland and were ready to go fight on the front lines and, uh, you know, many of them did. In, in some cases, you know, many of these scientists were Jewish, and because of the politics at the time, they were, you know, con- Their German patriotism was questioned, so by signing up for the war effort, this was a way to prove they were full Germans. Uh, so that was a big part of it. And, and, you know, many of them went to the battlefield and others, uh, you know, worked with Fritz Haber, who develops these gas weapons and, and, you know, all these sort of new weapons of war that, uh, are coming out of German science. Uh, it, you know, it surprises me that, that Warburg went to the battlefield rather than working with Fritz Haber, who, you know, he knew and, you know, was in, you know, ended up working in the same area in Dahlem where Warburg worked. So it's hard to understand why that happened. But, um, you know, I think Warburg was really... wanted to prove himself and he loved horses and he joined a cavalry regiment. So I think that was a part of the appeal for him as well.

   7. PAPeter Attia17:50

      Um, now Einstein urged him not to go, correct?

   8. SASam Apple17:53

      Um, well, Einstein... Warburg went and then Einstein wrote a letter to him, uh, in 1918, so the war was nearing its end and, and by that point, you know, everybody could see, everybody who was rational and paying attention, that it was a lost cause. Germans were dying by the tens of thousands and, you know, it was madness, as, as Warburg's mother put it, and they want-- They're desperate, you know, for Warburg to come home. His parents are desperate, so they're friends with Einstein and- They can't convince Warburg to come home, so they turn to Einstein and, you know, they know that Warburg reveres Einstein and they say, you know, "Will you write him a letter?" So, so Einstein does, and it's really a perfect letter because it, you know, he knew Warburg well enough to know that he was a narcissist, and so he wrote the letter saying that, "You're just too important for science. We can't afford to lose you." And, um, uh, we don't have Warburg's response to that letter, but sure enough, he comes home shortly thereafter. So I think it was the letter from Einstein that, that most likely convinced him and, you know, possibly saved his life. And, um, you know, five years later, he makes his great breakthrough about cancer and fermentation. So I like to think that, you know, that Einstein may, you know, have saved his life and therefore deserves credit for s- this great cancer discovery as well in, in some indirect way.

   9. PAPeter Attia19:14

      Y- you wrote about Warburg that he was, uh, pathologically dedicated to his science. What, what did you mean by that?

   10. SASam Apple19:21

       Yeah. I mean, I think it's hard to understand unless you grew up in, [chuckles] in 19th century Germany. But, um, you know, somebody, a friend who knew him described it as having a religious devotion, like a prophet who has, like, this fervor, who just thinks about nothing but science and is passionate about science. You know, Warburg used to say, uh, "A scientist has to be prepared to die for the truth." You get a sense of his perspective there. And, um, I think my favorite example, and the one that's maybe most revealing, is that at one point a friend was telling Warburg about, uh, somebody, a mutual friend or somebody she knew who was having mental difficulties and going through various problems. Warburg's advice for this person was, "Tell him to think about nothing but science. Just think about science all day." And, you know, the person in question wasn't even a scientist.

   11. PAPeter Attia20:14

       [laughs]

   12. SASam Apple20:14

       But that was, [chuckles] you know, reveals, you know, a lot about Warburg, I think, about how he viewed the world. And this devotion to science was partially about narcissism and wanting to be great, but I think partially, you know, obviously a genuine love of science and curiosity about the truth, but also a way to avoid looking internally. You know, I think that comment about the other person really reveals that he was covering something up by focusing on science all the time and, you know, trying not to, to look inward.

   13. PAPeter Attia20:44

       What do you think he was afraid to look at?

   14. SASam Apple20:47

       Well, you know, he was, he was a great narcissist and, you know, I think when you see that personality type, it almost always comes sort of hand in hand with deep insecurity. Um, and he, he was clearly, you know, extremely insecure. He would lash... You know, whenever he was criticized, he would lash out and start these feuds with other scientists. So, you know, I think that, um, you know, that, that's where it ultimately came from. But he also had, you know, all these difficult things to deal with. You know, being Jewish in Germany wasn't easy even before the Nazis, and then he has this other complicated issue, which is that he's clearly homosexual. He ends up spending his whole life, uh, with his male partner, and he couldn't be out at the time in Germany, and his mother was pressuring him to get married and questioning his lifestyle, and there were all sorts of rumors about him. So he had a lot of stress and, you know, there are various ways it comes out. Like, he, he can't do public speaking. You know, he keeps being told, you know, "To get your degree, you have to go and give these talks," and he just refuses. And if it was anybody else, they probably would've failed him, but he was so brilliant that they just finally decided to move him along. So, you know, there were, there were a lot of psychological issues there.

   15. PAPeter Attia22:08

       Did he, in, for his... I mean, w- was he in the closet his entire life, or did he eventually come out?

   16. SASam Apple22:14

       Well, yeah. I, I'm not sure I would use the phrase in the closet. I mean, in a sense, almost everybody was in the closet. So I actually... You know, he, he didn't fully come out and say, "I'm gay," or, or talk about it, but I think he was about as out as one could be throughout most of his life. You know, he didn't try to hide the fact that he lived with another man. When he was invited to give a talk, his, his partner, Jacob Heise, uh, would always come with him. Warburg would s- you know, in some instances say, "I'm not gonna come unless, you know, my partner comes." So, you know, they would go to the opera together and travel to his vacation house together. So, you know, he didn't explicitly say, um, you know, "I'm a homosexual," but, uh, I think he came pretty much a- as close as anybody of that era and, you know, I really respect him for that.

   17. PAPeter Attia23:02

       Had he met Hitler?

   18. SASam Apple23:05

       Uh, there's no record of them meeting. Uh, I think there's a lot of indirect evidence that, that Hitler was directly involved in, in his, his case and his fate. Um, I can go into that detail or maybe we can build up to that. But, um, there's no record of, of a direct interaction.

4. 23:27 – 35:57

   Warburg’s interest in cancer and early discoveries about cellular consumption of oxygen

   1. PAPeter Attia23:27

      Well, yeah. I guess before we get there, let's... W- I wanna come back to that 'cause it's, it's the, the, the intersection of them is, is so fascinating to me. Um, but let's go back to post-World War I and pick it up where, um, Warburg moves into his sort of seminal work. So [clears throat] it's 1918. Um, Einstein's convinced him to come back, um, potentially saving his life. Uh, his first choice, I suppose, is where is he gonna set up shop, right? Is he gonna stay in Berlin or is he going to leave? And he elects to stay.

   2. SASam Apple24:02

      Yeah. Yeah. He, um, he actually, you know, right before he leaves, he's given this incredible position, his own sort of wing in the Kaiser Wilhelm Institute for Biology, which is sort of, you know, the pinnacle of, of German science. They create this Kaiser Wilhelm society, which is now the Max Planck Society. Uh, s- you know, it's supposed to be the Oxford of Germany. The idea is that they're gonna get the best scientists in the world and give them everything they need. Uh, it was actually inspired a lot by the Rockefeller model, the Rockefeller institutes in the United States. Just find the most brilliant people, give them what they need, and let them go. So He returns, you know, right before World War I. He's about to start this position. His lab was under construction, and, uh, when he returns, it's a very different world. You know, all the wealthy funders of the Kaiser Wilhelm Society are now bankrupt. Um, so he, he doesn't even have, you know, much money for his, his work at this point. There's this famous example. Uh, he has to write a grant proposal for one of the only times in his life and, you know, he can't bear to do it because he's so narcissistic. So he finally writes, you know, scribbles on a piece of paper, "I need $10,000 or 10,000 marks," and, uh, he actually gets the money. Um, but, uh, he actually focuses on... When he comes back from the war, he focuses on photosynthesis rather than cancer first, and it's actually really interesting, I think, that, um, when his father was trying to get him out of the war, he was making the case that Warburg was needed for photosynthesis research because he was gonna find new ways to grow food, make photosynthesis more efficient, and have more crop yields. And, you know, the Germans had been starving throughout much of the war, and there were huge few- food shortages. So, you know, he, he, um, you know, came back and, and really, I think, wanted to solve world hunger, and that remained an interest of his throughout his life. Um, but he was always interested in cancer as well. Um, at one point he asked another famous scientist for advice, "Should I do photosynthesis or cancer?" And the scientist says, "Do cancer. Photosynthesis is working pretty well." So he decides to do cancer, and it's because, you know, he wants to make a world-changing discovery, and cancer really has become a German obsession by the 1920s. Um, you know, if you look back into, you know, the early 19th century, you know, there's not much cancer around. Obviously, there's all sorts of discussions and things you have to look at in terms of longevity and diagnostic techniques, but I think there's overwhelming evidence, which I, I try to document in my book, that cancer did really increase and, and continued to increase, uh, well into the, the '20s and '30s. And by the 1920s there's, there's a panic. Uh, so many people are getting cancer. You know, it still pales in comparison to today's rates, but it's a panic at the time. And, you know, the Germans had conquered so many diseases. Robert Koch and Paul Ehrlich had figured out bacteriology and infectious diseases, and it just seemed natural that they were going to do the same thing with cancer. And Warburg worshiped Ehrlich and Koch and, uh, you know, thought he was gonna be the next one to make this great discovery. And, uh, so he takes on cancer and, and pretty quickly finds this remarkable thing, which is, you know, a- as you well know, and probably a lot of your listeners know, that, uh, you know, most cancers, uh, eat differently than other cells. They ferment glucose rather than, you know, burning, you know, breaking it down and, and burning with oxygen, oxidative phosphorylation. So this cancer cell shift to, to fermentation is a, a remarkable discovery and, you know, ends up occupying his life, uh, his thoughts, and he ends up focusing on that for much of his life.

   3. PAPeter Attia27:44

      So let's go back to how that discovery was made and what he was actually seeing in the laboratory that led him to this observation.

   4. SASam Apple27:52

      Sure. Yeah. So he... You know, the background is that, um, he had been studying, um, actually sea urchin eggs, uh, in the first years of the 20th century, uh, when he's still a young scientist. And, uh, he had seen that these eggs... You know, this is a little complicated in that, um, you know, he didn't necessarily get all of this right, but what his early studies showed was that, um, when the eggs were about to grow and, uh, proliferate, they would immediately begin to increase oxygen consumption. And it made perfect sense because, you know, you need energy to grow, and, you know, using oxygen is the more efficient way to create energy for the cell. Uh, so when he turns to cancer in 1923, he expects to see the same thing. You know, cell needs to grow. It needs more energy. It's gonna use more oxygen and burn more nutrients with oxygen to grow. And so, um, you know, the experiments that he does is, you know, he takes s- you know, a slice of a tumor from a, a rat and, um, you know, he attaches it to a manometer, which is a device, you know, a very simple sort of U-shaped tube which can just measure changing gas pressures. And, um, you know, he expects that, uh, these cells, he'll-- will start to take up more and more oxygen, and he'll see the pressure change inside of his U-shaped tube. Uh, but he doesn't see it. He doesn't see the oxygen consumption increasing. Instead, um, you know, he checks the solution that these cells are in, and he finds it's full of lactic acid. You know, lactic acid is, is what's made from fermentation, you know, what, what human cells make from fermentation. Of course, you know, yeast and other microorganisms will make alcohol and, and carbon dioxide. But, um, uh, so he sees that they're clearly fermenting and, um, you know, it's, it's a strange phenomenon that, uh, it's happening, and he, you know, tries to do other experiments. They end up doing, you know, tests, uh, in vivo in, in, in people and seeing that they have more, you know, with cancer, have more lactic acid in their blood. And, you know, every, every test he sort of carries out comes to the same conclusion, that cancer cells are, are taking up a lot of glucose and fermenting it to lactic acid and using less oxygen than he would expect.

   5. PAPeter Attia30:18

      Go a little deeper for folks, um, into that biochemical pathway. So when a cell is presented with glucose as substrate and it wants to make ATP, what are the different fates of that glucose molecule? And, and why is it so absurd that a cell would, in the presence of sufficient oxygen, choose to make lactate? Why is that such an unusual thing to do? Why is he so surprised by this?

   6. SASam Apple30:47

      Sure. Um, you know, he wasn't the first to understand or, or to see that a human cell can, um, ferment. It was understood, you know, going back to, uh, you know, the previous decades that human cells, uh, could do this. You know, it was very surprising when it was discovered because it was thought s- only microorganisms did it. But, um, you know, Warburg was very close with another physiologist, uh, Otto Meyerhof, who, you know, made a lot of important discoveries and found that, uh, human cells could do much the same thing that, that microorganisms can do. Uh, so Warburg knew a cell could do this, but what he didn't know was that a cell would ever do this if oxygen was available. It was always thought to be a compensatory thing that, uh, you move to fermentation if you didn't have enough oxygen or, you know, if there was, you know, as Warburg thought, some damage to the mitochondria where the, you know, oxygen is used to burn nutrients. So the, the really surprising part of it was not just that a cell was fermenting. You know, if you do as, as you know, intense exercise and oxygen, you know, your lungs are heaving and you don't have enough oxygen to sort of keep up with the needs, then, you know, fermentation will, you know... Or glycolysis will, will take place in that setting as well. But the surprising thing, and what we now call the Warburg effect, is that the cancer cells had oxygen and they were still turning to fermentation in what we call aerobic glycolysis. So that, that was the really surprising part.

   7. PAPeter Attia32:19

      Yeah. Aerobic meaning in the presence of oxygen, but still undergoing this inefficient pathway of glycolysis. And it's so inefficient, in fact, that from an energetic standpoint, it's hard to understand because the total yield of ATP when you take glucose to lactate, I believe is four units of ATP, two going-- And I could be wrong, it could be two. Whereas in normal, uh, um, aerobic, um, metabolism where-- which would be, um, oxidative phosphorylation, you would take glucose, which has six carbons. You would make two molecules of pyruvate, which each have three carbons, and that pyruvate would be turned into acetyl-CoA into-- and then it would enter the mitochondria and where it would go through all of the steps of the electron transport chain. The f- final emissions would be carbon dioxide and water, and that process would yield either 32 or 34 net molecules of ATP. So the difference is so stark, right? It's like a 17X difference in energy yield, which as you point out, the only reason you would ever make that sacrifice in favor of lower energy yield is if you have no choice. So if, you know, if I said, "Hey, go for a jog and, you know, run your, your eight-minute mile pace," that's great. You have-- I'm demanding ATP at a slow enough rate, and therefore you have enough oxygen that you can do it the efficient way. But if we, you know, make somebody run for their life, you know, the fastest quarter mile ever, all of a sudden the need for ATP is so great that it can't be matched by enough oxygen intake. So you take this inefficient pathway, which unfortunately we can't sustain for as long because with lactate comes hydrogen, and hydrogen, um, reduces the pH and that reduction in pH with that hydrogen ion makes it very difficult for the, um, actin and myosin filaments in the muscle to release, and that's what people are actually experiencing when they feel that horrible burn that's actually erroneously attributed to lactate. It's really the hydrogen ion. So yeah, it's like we knew about this, but I, I think this was, this was a really interesting discovery and that's why I think the term aero- aerobic, uh, for- fermentation, um, is, is a paradox, right?

   8. SASam Apple34:48

      Um, yeah. I mean, uh, the aerobic, you know, glycolysis or aerobic fermentation, you know, from Warburg's perspective it was a paradox, you know. And, you know, as we'll maybe talk about more, not everybody sees it that way. But, um, you know, many, many scientists, um, continue to, to see it that way. I think that's the only explanation that, you know, if you're choosing to, you know, use glucose in this way to ferment it, rather than to do the much more efficient way of breaking it down and getting much more ATP than, um, the only way to explain this paradox is that something is broken or else why else would a cell do this?

   9. PAPeter Attia35:28

      Well, and, and we'll certainly get to that because today I think we have other explanations. Uh, uh, but, but going back to Warburg, how did he then explain the observation? So if, if, if science is a process of making an observation and then coming up with a hypothesis, what was his hypothesis in light of that observation?

   10. SASam Apple35:48

       His hypothesis was that, um, you know, the mitochondria, you know, he didn't have full understanding of mitochondria at this time, but he

5. 35:57 – 45:28

   The role models who fueled Warburg’s desire to make a great discovery

   1. SASam Apple35:57

      felt that there had to be some sort of defect in the mitochondria, you know, the structure that was burning, uh, nutrients with oxygen because it made no sense otherwise. And the only way to really understand it is that, you know, Warburg idolized Pasteur and, um, you know, he had his, his library set up so that he was gazing at a portrait of Pasteur at all times. You know, one side was Robert Koch and the other side Paul Ehrlich, but Pasteur was in the center. And, um, you know, it was Pasteur who had discovered that, um, that microbes could ferment, that they didn't need oxygen. It was this, you know, shocking thing to him. He called it, you know, life without air. And, um, Pasteur himself had, uh, explained it by the fact that, uh, if they were-- if cells were, you know, fermenting and not using oxygen, it must be because there's some kind of problem because why, why wouldn't anybody, uh, any cell use oxygen if it could? Um- And it's called the Pasteur effect, the seesaw-like relationship. You know, respiration with oxygen goes down, fermentation goes up. So that was how... You know, and that's what other scientists had found when they were, you know, studying frogs and, you know, I mentioned Meyerhof. So that's how everybody understood this relationship. So that was Warburg's lens. You know, I think a seesaw is, is a good way to think about it. Respiration goes down, fermentation goes up. I, in my book, I talk about it as a backup generator clicking on. Um, and you know, what's interesting about it to me is that, you know, both Pasteur and Warburg were sort of aristocratic personalities, and I think they really thought of fermentation as, as lower and less noble [chuckles] than respiration. Uh, Warburg actually literally used those, those type of terms when talking about it. So for him, it, it was just almost shocking, almost un- unbelievable that a cell could use oxygen and they would do this lowly thing that, uh, microorganisms do. It's impossible.

   2. PAPeter Attia37:55

      So how did Warburg attempt to actually test the hypothesis? So if the hypothesis, if the observation is cancer cells are undergoing aerobic, uh, glycolysis to fermentation, and the hypothesis is they're doing this because their mitochondria are defective, how would he test that hypothesis to increase the confidence that he would have in that hypothesis?

   3. SASam Apple38:24

      He didn't, he didn't really have a great way to test it. Um, certainly not at the time in the 1920s. I mean, the test that he did was just to see the, the effect over and over, but he couldn't prove that it was a problem with defective mitochondria. Um-

   4. PAPeter Attia38:42

      Did he recognize that, by the way, as a limitation?

   5. SASam Apple38:45

      Um, I don't think he did. You know, and even the most [chuckles] the most surprising part really is that in the early '20s, his first test actually showed that respiration was continuing. Um, and then later in, in his career, you know, he, he does additional experiments and, and insists that, you know, respiration is not continuing, or if it is, it's, you know, can be explained in various ways that the... There's uncoupling which causes the electrons to leak out, et cetera. So, uh, but, but his early tests showed that, um, fermentation was increasing while respiration, you know, continued to, to sort of hum along, and he just sort of denied that or, or, you know, came up with various explanations for it. But, um, you know, it was really in the post-war period where he starts to make more and more extreme statements. He, uh, finds these cancer cells, uh, in the abdominal f- fluid. Um, I think they're called ascites. Um, is that correct?

   6. PAPeter Attia39:47

      Mm-hmm.

   7. SASam Apple39:48

      And, um, you know, he sees that in his test of these cells, he sees, you know, very little respiration and just very high fermentation rates. Uh, so he becomes more and more convinced. Uh, and he called these pure cancer cells. He thought it was the best test of it. But, um, he never really had any concrete evidence that, um, there was some sort of structural defect or in the mitochondria. He felt it was almost tautological that, you know, the job of respiration is to, you know, to keep fermentation repressed, and if that relationship is not working, then it's necessarily broken. At one point, when critics were charging him, you know, with asking for more proof, he said it was a semantic debate. It's necessarily true because it's not supposed to work that way.

   8. PAPeter Attia40:35

      Which really is ironic, right? Um, based on his observation, there is absolutely no way to know if his observation is the cause or the effect of cancer. Um, so I was struck by, I think in his case you could almost use the word the arrogance with which he would treat it as tautological. Um, as opposed to acknowledging that, you know, hey, absent additional tools, right, laboratory tools, it's difficult to know for sure if this is cause or effect. Which actually brings to, um, uh, it brings to the forefront of this discussion this, um, this overlap with between him and Hitler, right? Which is this, this view of cause and effect that, that Hitler even writes about, right?

   9. SASam Apple41:21

      Um, are you... Oh, I think you're referring to Warburg's thinking about causation in, in cancer.

   10. PAPeter Attia41:30

       Correct. Yeah.

   11. SASam Apple41:30

       Yeah. Yeah, one, one of the interesting things that I found is that, um, you know, Warburg and Hitler, you know, I... Hitler was, you know, one of history's greatest monsters. I'm always hesitant to, to compare anybody to him, let alone Warburg, who's somebody I, you know, admire greatly despite his flaws. But, um, I couldn't help... You know, because I was writing about both men, I couldn't help but see some parallels in their story. Um, you know, first and foremost, they grew up, uh, in Germany or at the same time. You know, Warburg's born in 1883, Hitler in 1889. And, um, at the time, the hero of the day is Robert Koch, the German scientist who makes, you know, discovers the causal relationship between microorganisms and infectious diseases. You know, it starts with anthrax, then he has his, his great breakthrough with tuberculosis. So it's hard to... You know, from our perspective today, it's hard to, I think, appreciate how, how much Germans revered Koch. You know, there were like parades and flags with his face on it, uh, because he was conquering disease. And, um, so Hitler and Warburg are both narcissists, both want to be the greatest men of their generation, and the model for that is Robert Koch, first and foremost, uh, in their childhood. And what's amazing, I think, is that, you know, Koch is most famous in a way for his postulates, which talk about how you can know one thing causes another thing and, you know, what conditions you have to have to show that a microorganism actually causes the disease.

   12. PAPeter Attia43:03

       Which are, let's see if we can r- rattle these off, right? So one is-

   13. SASam Apple43:06

       I can't. Maybe you can

   14. PAPeter Attia43:07

       ... the healthy individual can never contain the microorganism that is reported to be caused, right?

   15. SASam Apple43:16

       Right.

   16. PAPeter Attia43:16

       I think that another one is the corollary is that the, uh, a- anyone with the microorganism must have the disease. And then I think anytime you take a healthy person and insert the microorganism, you must be able to cause the disease. Is that... I think that's the third one. What's the fourth?

   17. SASam Apple43:37

       It's been y- it's been years since I-

   18. PAPeter Attia43:39

       But, but that, that's the gist of the logic. It's, it's, it's very... It's a very rigorous logic that, again, I think we all take for granted today.

   19. SASam Apple43:47

       Yeah.

   20. PAPeter Attia43:47

       Um, but at the time, it was remarkable, um, and it demonstrated the causal relationship between these various microorganisms and the diseases they caused.

   21. SASam Apple44:00

       Yeah. And a, a key breakthrough, if I'm remembering correctly, is that, you know, they had already known that you could, you know, take blood or whatnot from one organism to another and transfer the disease. But Koch understood that he first had to get the microbe and grow it outside the body, so, you know, he wasn't transferring anything else. You know, he had to prove that, um, it was, it was the microbe itself by growing it independently and then taking some of those microbes and injecting them. Um, but, um, in any case, you... If you listen to, um, Hitler's speeches, you know, some of his speeches in the '40s a- and read some of Warburg's papers, they actually, you know, it's almost like they're quoting Robert Koch. Uh, you can hear the same phrases and talking about causality. And, um, one of the most chilling things that I, that I... You know, and they both refer to Koch directly, but, you know, the most chilling thing I found, I think, is that, um, Hitler, you know, multiple occasions referred to himself as the Robert Koch of, of politics. And he said that, you know, Koch had, um, saved the world through science by eliminating the microbes, the microorganisms that cause disease, and I've done the same thing with the Jew. Uh, so he, he saw his effort in some ways as a scientific project and, you know, that, that killing Jews in, in his, you know, twisted mind was, was like eliminating microbes. Um, and of, of course, it wasn't just Warburg and, and Hitler, but I, I was just struck that, uh, they were both using this language of causality.

6. 45:28 – 49:15

   How Warburg described the primary and secondary causes of cancer

   1. PAPeter Attia45:28

      And so how did, um, Warburg describe that in terms of primary and secondary causality of cancer? How, how did he really start to sharpen, uh, his thinking on that?

   2. SASam Apple45:39

      So Warburg says that, um, you know, every disease has a prime cause and a secondary cause, and he uses the analogy of Robert Koch that the prime cause of the disease is the microbe, and then there are all these secondary causes, the unsanitary conditions that cause the microbe, you know, to, to get onto a person and make them sick. Um, you know, various plagues and, and, and anything that, you know, causes a microbe to, to transfer and get into someone's blood is a secondary cause, and the microbe itself is the primary cause. So Warburg tries to extend this to cancer. He says the most fundamental thing about cancer is the shift to fermentation. Um, and so that is the primary cause. He-- Although there was never proof for this, he insisted that it existed in 100% of all cancers. I think today people say, you know, 70% or, or more, but not 100%. But Warburg thought it was 100% of all cancers. I should modify that by saying probably all cancers at some point start to ferment a- as they have reduced access to oxygen if they become advanced cancers. But, um, at the most fundamental level, I don't think you can say 100%, but, uh, Warburg said it was 100% of all cancers ferment. This is the primary cause, and anything that causes the fermentation can be thought of as a secondary cause. So you might have, you know, a dangerous chemical and that injures the mitochondria, and therefore you have fermentation. So that's the secondary cause is, is the chemical or, you know, a- anything you can think of. A virus that causes cancer would damage the mitochondria. It's always viewed through the lens of causing a structural problem which causes respiration, um, to be damaged and fermentation to increase in the CSAL-like relationship.

   3. PAPeter Attia47:23

      What did W- Warburg believe, um, accounted for the, um, significant increase in the prevalence of cancer, um, leading up into the 1920s and 1930s?

   4. SASam Apple47:34

      Um-

   5. PAPeter Attia47:34

      As, as a secondary cause by his definition.

   6. SASam Apple47:37

      Yeah. At the time, he doesn't... In the '20s and '30s, he doesn't say much about it. But, um, you know, I, I think it's clear looking back that he was from, from an early time very worried about environmental carcinogens. But in the post-war period, uh, he becomes very outspoken about environmental carcinogens. And I, I think his influence is much wider than, than many people realize. Uh, you know, in Germany, he starts campaigning against smog from automobiles and buses and, uh, food dyes, you know, used in, in the German food supply and, and all sorts of chemicals. He becomes basically an organic farmer, you know, one of the first organic farmers I've heard about. He has his own garden, and he has his partner, Jacob Heiss, is the only person who's allowed to cook for him, and he even has a well where he gets his own water. So his hypothesis was that the chemicals in our food first and foremost were poisoning our cells, poisoning the mitochondria and, and causing the shift to, uh, fermentation. But what's, what's really interesting, I think, is that, um, if you read, um, Rachel Carson, Silent Spring, which is, you know, a hugely influential book and really changed American environmental policy, um, Warburg is actually the first cancer scientist mentioned in the book. And it's clear that, um, that's exactly how, how she viewed, um, you know, cancer and, and saw all these environmental chemicals, uh, as causing cancer via, you know, the damage to respiration that Warburg cited. So You know, I think he ended up having a, a massive influence on American life, just nobody knows about

7. 49:15 – 50:05

   Warburg’s Nobel Prize in 1931

   1. SASam Apple49:15

      it.

   2. PAPeter Attia49:16

      He was awarded the Nobel Prize in 1931. What was the, what was the seminal work for which he was awarded?

   3. SASam Apple49:22

      Sure. Um, yeah, a lot of people think that he got the award for cancer, but that's not true. He, he was nominated in 1926 and should have won for his cancer research, but, uh, and it was apparently a tie, and they gave it to, to the other guy, and no one really knows why Warburg didn't get it in '26. But in 1931, he gets it really for figuring out the, the final step. He believes it's the only step at the time, but really the final step of, of respiration, understanding how the electron passes down the electron transport chain and, you know, is, is able to react with oxygen. Um, so he, he sort of elucidates this process and wins the Nobel Prize for that.

8. 50:05 – 1:05:09

   Warburg’s life and work during WWII in Nazi Germany

   1. PAPeter Attia50:06

      So w- what happens during World War II? Um, as you point out, obviously he's Jewish, he's gay. Um, I'm guessing that both of those things make him an enormous target for Nazis. Um, why does he stay in Germany?

   2. SASam Apple50:23

      Yeah, it's one of the most fascinating parts of his story. You know, 1933 comes along, and only two years earlier, uh, the Rockefeller Foundation has built this beautiful institute for him. He has designed the institute himself after a country manor that he admires, and he's on top of the scientific world. He's just won the Nobel Prize, and all his colleagues start to, you know, flee, his Jewish colleagues. They see what's coming, and, and Warburg refuses to see it. You know, he's not gonna give up his kingdom, uh, in Dahlem in, in southwestern Berlin. He says, "I was here before Hitler." And like a lot of Germans, he, he believed that the Nazi phenomenon would be short-lived. Uh, his cousin, Max Warburg, had said, you know, "We just need to give Hitler enough rope to hang himself." So Warburg had said, you know, maybe six months, a year, he thought they'd be gone. But I think that part of it was, you know, he was so arrogant and so narcissistic that he, he couldn't fathom, you know, anybody telling him what to do, let alone... You know, he called them Bavarian noisemakers. These Nazi thugs were gonna kick him out of his institute? No way. I mean, that, that was his perspective, and I think the most shocking thing about his story is, you know, he, he has a famous Jewish name. His father's Jewish, so he's Jewish by the Nazi standards. He lives with his male partner. He should have been as vulnerable as anybody in Nazi Germany, and yet he not only, you know, stays, but he provokes the Nazis. Uh, you know, he screams at them when they come to his institute demanding Aryan descent forms. At one point he says he'll burn down his institute if they come again. He won't do the Hitler salute. He won't put up the Nazi flag. So, you know, he, he really was in a very dangerous situation. 1936, you know, The New York Times ran an article saying Warburg, uh, may be in jeopardy. Uh, you know, he was famous enough at the time that, um, they were writing about him in The Times, and, you know, he was also tremendously stubborn. You know, he said to his sister at one point that, you know, "It's gonna be either me or them. I'm not budging." And his sister's understanding of it was that, you know, the more, the more pressure he got, the more he insisted on staying because he couldn't, you know, stand to think that, that he would lose that battle. And it's very hard to understand this. You know, when we look back, we see these Jewish scientists fleeing, and we think, oh, you know, what wise, moral people. They saw what was coming a- and they left. They didn't want to be a part of it. But at the time, it was really considered a shameful thing, that to leave was to accept that you were somehow a lesser German. And Warburg, you know, that was the antithesis of, of everything Warburg stood for. You know, to, to do anything that would cause him shame w- would be unimaginable. So there was really no way he was leaving. Um, he did think about it, but, uh, I think he correctly understood that, uh, he would never be the same if he left.

   3. PAPeter Attia53:14

      Did he journal? I mean, how, what, what, what, what type of sources were you able to, if any, um, get into his head during that period of time?

   4. SASam Apple53:23

      Um, it was honestly one of my most important find- I didn't find it myself, but, um, it was, it already existed in, in German. But hi- his, one of his sisters, Lotte, kept a diary and, and she was a writer and, um, she wrote a great deal about him and recorded their conversations. So that ended up being really my key source for a lot of this. Uh, Warburg didn't keep a diary, but because he was famous and he wrote a lot of letters, I had a lot of letters that he wrote, and whenever somebody encountered him, they would often write down their impressions because he was such a character and, and he was already world famous. But at the very end of the war, uh, he actually did scribble out some notes. Uh, a few years ago, uh, a historian, Karin Nicholson in Germany, actually discovered in the back of his notebooks, uh, these notes, which, uh, were really fascinating. Uh, he was feeling, you know, we haven't really talked about that part of the story, but he was feeling with some guilt that, that he faced by not protecting certain people who worked for him from being forced into the military. So he, he started to scribble out these defenses, and it just, you know, it's only a few sentences here and there, but it gives you a window into how persecuted he felt at the end and how guilty in, in some ways I think he felt as well.

   5. PAPeter Attia54:41

      How many people did he know that died in concentration camps?

   6. SASam Apple54:45

      Fewer than you would think. Um, partially because, you know, most of the Jewish people that he associated with left. You know, in the Kaiser Wilhelm Society, I think there were, like, you know, 2,500 Jews at various institutions, and Warburg was the only one who stayed until the very end. So, um, most of them left. And you know what a lot of people don't realize, you know, that, that German Jews- in many cases were more likely to survive the Holocaust than, than other European Jews. Uh, so he didn't... Uh, some of his Warburg cousins actually were murdered in the camps. He wasn't, uh, particularly close with them, but, um, he didn't, um, he didn't lose a lot of people who were close to him. But, um, he certainly, you know, he certainly knew people. You know, I, I, I don't have a good answer to that question, but, uh, it would be impossible for him to have not have known a lot of people who died, but I don't know that they were the, the people who were closest to him. He certainly knew hundreds of thousands of people who fled for their lives.

   7. PAPeter Attia55:47

      Y- you know, in countries like Poland, there was clearly a moment in time when you could no longer leave. Um, was that true in Germany as well? Was there basically a time beyond which if you, if you had not left, you were not going to leave?

   8. SASam Apple56:02

      Yeah. I mean, certainly for Warburg there was, because he was famous, and the Nazis saw sort of propaganda value in having him there. Uh, for others, you know, it really changed a lot, um, after the, you know, the war started, and that was... You know, by that point, if you hadn't left, uh, you know, you were in grave danger if you were Jewish or homosexual or, uh, you know, various other persecuted categories i- in, in Nazi Germany. Um, so but i- in the early '30s, you had an opportunity to leave Germany at least. But, um, you know, they also had to... It was extraordinarily difficult because you... They would take all your wealth. You basically had to give up everything a- and leave with nothing and, and find a new career. And, you know, this is in Germany. The other countries didn't have the advanced warning, and the, the Jews of, of Eastern Europe were much less wealthy. You know, these are in many cases more, you know, people who lived in much, uh, sort of less wealth than, than the German Jews and, and never really had a real opportunity to escape when the, when the Germans rolled in. So it's, it was very different for Eastern Europe, where's, where the Holocaust really begins.

   9. PAPeter Attia57:17

      So, so what do you attribute the fact that he survived the war to? Is it simply that the Germans benefited more by him staying there and being alive as a showcase of their scientific prowess? Or do you think there was an explicit directive, uh, from Hitler or someone else saying, you know, "Despite the fact that, you know, he's everything we despise, there's value in the work he'll do"?

   10. SASam Apple57:44

       Yeah. So, you know, by the mid-'30s, you know, it's clear that he serves propaganda value for them. You have the Berlin Olympics in 1936. They're able to show that, you know, this guy who, you know, has, has Jewish descent, um, Jewish ancestors is still here working in Germany. But, um, by the late '30s, you know, that propaganda value sort of drifts away and certainly is useless once the war starts. Uh, so he's, he's in increasingly sort of grave danger a- as, as things progress throughout the late '30s. Meyerhof, a lot of people stayed until 1938. Uh, Meyerhof is also a Nobel Prize winner, escapes in 1938, and flees to France. And, um, you know, from that point on, you know, that's when Germans roll into Austria, and all the, the Austrian Jews who can escape, escape in, in '38. Um, but the fascinating thing really it comes to a head in 1941, where, you know, by that point, you know, the war is in full swing, and, um, you know, there's no value to keeping Warburg alive really, you know, for propaganda means at that point. Uh, so Warburg is called to Nazi headquarters in, uh, 1941, June 21st, and he meets with Victor Brack, who is one of the worst Nazis, a guy who designs the euthanasia killing program that sort of starts the mass killing, and it looks like it's gonna be the end for him. He's already received an eviction notice from his institute. Uh, he has a lot of enemies in German science. I mean, you have to keep in mind, he had a lot of enemies in German science before all this started. So you can imagine that, uh, how many people hated him and wanted to get rid of him. You know, all the other institutes were full of Nazis. His was the only one that wasn't. So, you know, they finally succeed in, you know, getting rid of him, and he's called to Nazi headquarters. And, um, you know, he sits down with Victor Brack, and he's told that he's actually gonna be allowed to live on one condition: that he focus on cancer research. And, um, it... You know, it's, it's extraordinary in itself, but the part that surprised me most, um, you know, and other German historians had recorded this meeting on June 21st, 1941. But what I realized, nobody had yet realized that this was an extremely important moment in German history. Uh, the very... At dawn the next morning, the German tanks rolled into Soviet territory. It was the launch of Operation Barbarossa, which is, you know, the bigge- at the time, the biggest military invasion in history. It was, you know, the most significant moment in, in the Nazi project in a lot of ways. And, and that very day, they're sitting around, you know, worrying about Warburg. And it wasn't just Victor Brack. You see it in Himmler's daily planner that he has a meeting about Warburg that day. And then later that night, uh, Goebbels kept a diary, and, uh, he records in his diary that later that night, just hours before Operation Barbarossa, he and Hitler are talking about cancer research. The diary, that diary doesn't say Warburg's name, but given that everything else that went on that day and that Warburg was in the building, it certainly seems, you know, that Hitler knew what was going on. And Warburg, there's more evidence of Hitler's direct involvement because Warburg has applied for, uh, something that they called a German blood certificate. This just shows you what a, you know, twisted, horrific world it was at the time that, you know, for a Jew to survive in Nazi Germany at that point, if, if you had managed to stick around that long, you could apply to have yourself upgraded to be more Aryan. So Warburg goes through this application process. At this point, I think it's defensible because, you know, it's really to save his life in a way. Uh, but Hitler would actually review these applications himself, and certainly for a Nobel Prize winner, Hitler would've reviewed this application. Uh, so, you know, it was, you had to talk about all your ancestors and submit photos, you know, just sick stuff where, you know, that Hitler would, you know, look at the noses of the people and decide if he would upgrade them or not so that they, they never actually formally Aryanized Warburg. But, uh, it's clear that, that Hitler would've been involved in, in that review and that probably decided on that day, June 21st, 1941, to let him continue to focus on cancer.

   11. PAPeter Attia1:01:58

       W- was Hitler personally o- obsessed or touched by cancer? What, what was this, um... I mean, or was it simply just the epidemiology of the time?

   12. SASam Apple1:02:07

       Yeah, he, um, you know, was very personally touched by it. Um, when he was, uh, a teenager, uh, he lost his mother to breast cancer, and, uh, his mother was really the, you know, historians say the only person he was capable of loving. And, uh, he had already just sort of failed to get into art school and was depressed. He comes back to Austria, uh, or comes back to his hometown in Austria and, um, sees his mother dying of breast cancer and, um, is just distraught. It's actually a Jewish doctor who's caring for his mother, and he left a, a little, you know, reflection on the experience. He said in his entire life, he's never seen anybody look as dejected as Hitler. Uh, and, you know, Hitler sort of okayed these experimental treatments on his mother, which left her writhing in pain, and he was there at the bedside. And for the rest of his life, he was obsessed with cancer and talked about it constantly in his speeches a- as a metaphor, but was also a hypochondriac who constantly had stomach problems and thought it was stomach cancer. And, um, you know, it became a huge part of the Nazi project, is trying to eliminate cancer. And, um, you know, one of the very uncomfortable things about this is that, you know, as monstrous as the Nazis were in every way, they actually did make some, some advances in, in cancer prevention. You know, for all the wrong reasons, but, um, you know, they, they inherited, you know, a great scientific establishment, and it makes sense that they, they would actually make some progress on cancer.

   13. PAPeter Attia1:03:38

       It's very interesting to imagine a world without the Nazis, given the prominence of German science, uh, into, into going into, you know, the Second World War, and how much of a, a balance in, in, um, how much of a shift in power that was scientifically post-World War II, right? How effectively that was the change from, um, Germany being the epicenter of, uh, science, not just biological sciences, but, but physics. Um, and then that, that shifting. Uh, in fact, so many of the journals, right, shifted from being-

   14. SASam Apple1:04:11

       Yeah

   15. PAPeter Attia1:04:11

       ... published in German to being published in English post-World War II.

   16. SASam Apple1:04:15

       Yeah. Yeah, I mean, the early 20th century, you had to speak German to be a scientist or be able to read German. You know, it, it's incredible how the extent to which, you know, all the early Nobel Prize winners were Germans. Not all, but you know, a shocking percentage.

   17. PAPeter Attia1:04:27

       It's rumored, I don't... I, I, I've never actually been able to confirm if this is, is true or not, 'cause I've read various accounts, um, that, that Warburg could have won a second Nobel Prize during the, the Second World War. Um, what, what was your finding on that?

   18. SASam Apple1:04:43

       Yeah. I, I think that he, you know, certainly deserved a Nobel Prize for his cancer work, which he didn't get in 1926. I don't think there's, there, there's really proof of the, the, you know, Warburg said that he didn't get the Nobel Prize in the '40s because the Nazis wouldn't allow it. Um, he certainly would've, was considered for it. I found evidence that he was considered for it, but I didn't find any evidence that they were gonna sort of give him the award

9. 1:05:09 – 1:09:02

   Warburg’s research in hydrogen transfers and coenzymes—his best science?

   1. SASam Apple1:05:09

      but couldn't because of the Nazis.

   2. PAPeter Attia1:05:10

      And what work was that in the '40s that, um, um, that, that they would've, uh, been potentially considering him for?

   3. SASam Apple1:05:19

      Yeah. Warburg, you know, hi- his Nobel Prize, as, as we talked about before, was, um, you know, for the understanding the last stage of respiration, this, you know, enzyme that we now call cytochrome oxidase. Um, but um, you know, at the whole time, he had been saying in the '20s that this is the only thing you need to know for respiration. It's kind of analogous to what he said about cancer. But then he, he finally accepted that no respiration's actually a multi-stage process, and you actually need, you know, not just to react directly with oxygen but to rip hydrogen off these nutrients and, and to pass the electrons down the, the transport chain. So he became interested in these hydrogen transfers and understanding, you know, how the reaction took place, and he actually... You know, a lot of people think this is the best science he ever did. Uh, he actually made huge advances in, in understanding the role of, of coenzymes and how they react, uh, with hydrogen and allow for these transfers. Um, you know, it was really innovative work. Uh, really kind of set the stage for decades of enzyme research. Um, so you know, and, you know, that, that led to the discovery of the components of, of NAD, among other things. Uh, so he, he did deserve a Nobel Prize for that, but I don't [laughs] I didn't find any evidence, uh, that, uh, they were gonna give it to him. But I, I think he fairly deserved three Nobel Prizes.

   4. PAPeter Attia1:06:43

      W- what, um... S- say a little bit more about his work on NAD. That was actually new to me. I, uh, until recently, was not aware of his contributions there. It's not surprising, I suppose, when you consider his involvement with the electron transport chain. And as you point out, the electron transport chain transports its electrons using hydrogen back and forth, transporting between NAD and NADH. Um, but um, it's actually kind of an interesting story, right, about how he, uh, made these discoveries.

   5. SASam Apple1:07:12

      Yeah. So Warburg, uh, is trying to do a chemical analysis to figure out the reactive component of what we now call NAD, um, he called the in-between ferment. Uh, and he can isolate a very small amount, but he can't get enough of it to really understand and do the chemical analysis of what it is, and he's using horse blood, um- To, to study it. And he says at one point, "If to figure this out, I'm gonna need to kill all the horses in Germany." Uh, and, and he was a great lover of horses, so that was not a good option for Warburg. Uh, but he knows he has enough, uh, of the stuff to figure out the molecular weight and, and a few basic facts about it. So, um, he has a friend who works in the chemistry industry and, uh, in the chemical industry, you know, it's just a big part of, of German industry, and he asked him to look it up, see if he can find anything similar. And, you know, based on what he looks up, he finds an exact match, which is, uh, nicotinic acid. And, um, you know, so Warburg is the one that, that figures out that, you know, this key component that makes this reaction possible is actually a chemical that, you know, that everybody knew about that was being used in photography for decades. Um, you know, Warburg said, you know, "A day ago I couldn't buy it for all the money in the world, and now, you know, I can get it for two marks." Um, and it actually, you know, turned out to be hugely important, um, not only for understanding respiration, but, uh, for understanding, uh, the disease pellagra, uh, which, um, you know, was only sort of solved after Warburg made that discovery and someone thought, "Huh, you know, let's give this chemical to people who suffer from this disease and see if it cures them." And sure enough, it did. And it, it's one of the ironies of Warburg's story that, um, you know, he always wanted to make a great discovery and save lives, and he actually did, but he never even really recognized it or saw it that way.

10. 1:09:02 – 1:13:34

    Warburg’s decision to stay in Germany after WWII

    1. PAPeter Attia1:09:02

       So he stays in Germany after the war ends. He could obviously at this point have gone anywhere. He could have come to the United States, which is what many of his peers had done before the war. Um, what was his reason for staying?

    2. SASam Apple1:09:16

       In terms of staying af- in, in the years after the war?

    3. PAPeter Attia1:09:19

       Correct. Yeah.

    4. SASam Apple1:09:20

       Yeah. I, I think that, um, you know, for a few years after the war, I think he was prepared to go elsewhere. I mean, I found letters of him, you know, searching for places and, and he comes to America in the late '40s and, you know, he stays in one lab for six months and another lab for six months. But, um, it's clear that, um, you know, there's no future for him i- in America that, you know, a lot of the Rockefellers no longer want anything to do with him because, you know, it looks suspicious that, that he had stayed. You know, the truth is he despised the Nazis as much as anyone, but, you know, anybody who stayed when they could have left is under suspicion and, you know, he's making more and more extreme statements about cancer, so he's alienating a lot of people. And meanwhile, in 1950, the Americans give him back his institute. They had taken it over when they had their military, uh, occupation of, of Berlin. So he gets to go back to his beautiful institute, and he has, again, some propa- propaganda value for the Germans who can say, "Look, we've given this person of Jewish descent his institute back, and he's living here and thriving in Germany." So I think, you know, if he had gotten the right offer, I think he would've gone to America, but he ended up sort of returning and, and reestablishing hi- his old life in a, in a lot of ways. In some ways it's shocking and upsetting, but, you know, by 1955, you know, from, from his perspective, it was like nothing had happened. You know, he's continuing with all the same stuff.

    5. PAPeter Attia1:10:45

       Now forgive my ignorance. Um, w- uh, how is it that, um, w- was it a, is, is it, was it an easy choice for him to end up in West Berlin as opposed to East Berlin following the war? And what determined, um, that? Was it simply a function of where he was prior to the war and therefore it was somewhat fortuitous?

    6. SASam Apple1:11:04

       Yeah. It, um, it is actually interesting and, and a little bit complicated. His institute ended up in the American sector, but, um, another extraordinary thing about his story is in, in, you know, 1943, bombs are falling near his institute and he's actually moved to a new institute and the Nazis built him, you know, sort of, they sort of refurbished this beautiful sea house for Warburg in the middle of the worst part of the war for them when, you know, there's no gasoline for anything. It's forbidden to build anything if it's not for the war effort, and they take time out to build, you know, something for Warburg to continue his cancer research in a safer place. But, um, and that, that institute was actually en- ended up in Soviet territory. Uh, so he was sort of caught between these two different worlds and, uh, he had a vacation house which is in Soviet territory. So when the war ends, he is actually, uh, under Soviet rule and, uh, he has to escape back to the West. Um, but the, the Soviets were trying to recruit him much more so than Americans, interestingly. You know, both a lot of the great German scientists and, you know, unfortunately a lot of Nazis ended up, you know, being smuggled into America, uh, you know, for the purpose of, of American science. But the, uh, the Germans, I mean the, the Soviets were going after them as well. So, um, he is sort of caught between these different worlds, uh, but ends up, you know, because his institute is in West Berlin, uh, is able to, uh, stay in the, the American side ultimately.

    7. PAPeter Attia1:12:29

       So interesting to me because you, you have to wonder if people in Berlin at that time understood how stark that contrast would be. You know, you, you could argue that, well, gosh, it's just, it's wonderful that the war is over and the Nazis are gone and, you know, you might end up on this American side or, you know, what, what the time was American occupied or you might end up on this what will be a Soviet side, but it, it, it probably couldn't have been clear just how different those two would end up being over the coming, you know, four or five decades.

    8. SASam Apple1:12:59

       Yeah. I, I don't think it was clear, but it was clear that the Soviets, you know, with good reason, were much more feared. So, you know, in, in the last days of the war in 1945, you have a lot of people fleeing westward, not so much because they could imagine what the Cold War was like for decades, but because they were worried about being, you know, murdered and raped, you know, because the Soviets were, you know, with, with good reason, you know, furious, uh, at the Germans and, and out for revenge and, and they certainly took that revenge. So it was understood that you had a better chance of surviving if you made it westward, but I don't think anybody could have foreseen what happened in, in the following decades.

11. 1:13:34 – 1:20:52

    Discovery of oncogenes in the 1970s and the decline in interest in Warburg’s ideas

    1. PAPeter Attia1:13:35

       Um, Warburg has a really interesting tit for tat with, um, with, with Sidney Weinhaus in, in Science, uh, about a decade later. Um, I actually was able to pull up the article and, and, and read it. They both wrote, uh, letters. Um, and, and Weinhaus was really kind of a mild-mannered guy, wasn't he?

    2. SASam Apple1:13:56

       Yeah, he was... [laughs] You know, most of the people Warburg had these, you know, vicious, you know, scientific feuds with, I would look them up, and they seem, you know, much more reasonable and calm than, uh, than Warburg himself. Uh, Weinhaus, um, in the Philadelphia suburbs, he actually worked at a hospital just a mile away.

    3. PAPeter Attia1:14:13

       Yeah. He, he, he died in, what? The early '90s, I think, and he, he was at-

    4. SASam Apple1:14:19

       Yeah

    5. PAPeter Attia1:14:19

       ... he was at Penn, wasn't he? Or no, he was at Jefferson, if I recall.

    6. SASam Apple1:14:22

       Uh, he may have been. I think he was at L- Lankenau Hospital, but maybe, maybe at Jefferson as well.

    7. PAPeter Attia1:14:27

       Okay.

    8. SASam Apple1:14:27

       I'm not sure. But he w- he was, he was around here. I actually found some people that, that knew him and, and talked to them a little bit. Um-

    9. PAPeter Attia1:14:34

       But he, but he publicly called Warburg out. He basically said, "Don't agree with this observation." Um, I mean, "Agree with the observation. Don't agree with the interpretation," is, is what he said.

    10. SASam Apple1:14:44

        Yeah. I think it-- if you look at the quotes from him, he was relatively calm about it, but, uh, you know, as a journalist, I have to laugh. Yeah, I'm sure it was the headline writer. You know, the headline under one of the articles was "Cancer Theory Overthrown." You know, I don't think that W- uh, Weinhaus would've put it that way, but, um, you know, some editor like me just wanted to, [laughs] you know, make it a little more sensational, so.

    11. PAPeter Attia1:15:05

        Well, and he was deferential to Warburg in the article. I mean, he did say something to the effect of, um, oh, I don't remember exactly, but, you know, the gist of it was, "And we owe a great debt to, to Warburg for his amazing contributions to the field," et cetera, et cetera.

    12. SASam Apple1:15:18

        Yeah.

    13. PAPeter Attia1:15:19

        Um, but, you know, cellular respiration is basically... There, there-- he said, "Look, there's no difference in oxygen consumption between these cells, and there's no evidence that the mitochondria are damaged." Uh, Warburg's rebuttal was far less, uh, kind. Uh, ag-

    14. SASam Apple1:15:33

        Yeah

    15. PAPeter Attia1:15:33

        ... he was-

    16. SASam Apple1:15:34

        Yeah. You might be thinking of the, the papers in Science in 1956.

    17. PAPeter Attia1:15:38

        Yes, exactly. Yep.

    18. SASam Apple1:15:39

        Um, yeah, they had a back and forth, uh, I believe it's August 1956, uh, where first, you know, Warburg writes a piece in early '56, and then Weinhaus responds, and Warburg-

    19. PAPeter Attia1:15:48

        That's right

    20. SASam Apple1:15:48

        ... responds to his response. And, you know, Warburg, you know, comes off... I mean, it's a really elegant paper that he writes. He was a great writer. You know, we should've talked [laughs] about Warburg's writing at the beginning 'cause, you know, I really admire his writing and... But, um, you know, he makes much bolder statements and denounces his opponents in a way that, that Weinhaus doesn't. Weinhaus is a, is a more humble scientist. Um, but, um, that is, yeah, I, I encourage all listeners to look up Warburg's paper from '56. It's pretty remarkable.

    21. PAPeter Attia1:16:18

        We'll, we'll link to it in the show notes for sure. It-- I love reading that stuff. I mean, I just absolutely fancy reading that stuff, which actually, uh, th- an example of one of my favorite scientific papers to read is the next logical place to go in this story, which is the, um, the paper by Watson and Crick describing the helical structure of DNA. Um, so that's relevant to the story for reasons you will tell us, but it's also a funny paper in that the, i- i- I think it's the last line either in the abstract or the paper, um, makes some very, very, very understated remark that this, this thing, what they're referring to as DNA, you know, may prove to be of interest at some point or [laughs] something to that effect. Um, I, I used to be able to quote it verbatim. Um, but, uh, what is it about the discovery of, of DNA that, um, would ultimately put a, uh, change the course of Warburg's discovery and, um, and this entire field of cancer metabolism for decades to come?

    22. SASam Apple1:17:23

        Yeah. So, you know, by the '50s and '60s, Warburg i- is already fading away for some of the reasons we've talked about. You know, Weinhaus challenges his belief that, you know, cancer cells have defective mitochondria. He sees respirations running fine. So there's more skepticism of Warburg, and people suspect him because of the Nazi years. But I think the single biggest factor was sort of the changing wind in, in science and, you know, more than anything, you know, the discovery of oncogenes, uh, you know, beginning really in, you know, in the mid-1970s when they're first able to identify specific genes that in their mutated activated form cause cancer. So this unleashes the whole new world of molecular biology, and Warburg's study of enzymes and cancer metabolism starts to seem like, you know, old world biochemistry stuff. And, you know, if you want to really understand cancer, you gotta look at the DNA and the signal transduction pathways and all the new molecular biology, and, you know, there's literally stories of, like, you know, people seeing manometers [laughs] thrown in the trash, you know, Warburg's signature tool. And it's just amazing to me how quickly Warburg gets relegated to the old world, and, you know, nobody's interested in, um, you know, by, you know, by the '90s, you know, students don't know his name. And then-

    23. PAPeter Attia1:18:50

        And by the way, he died in, what, 1970?

    24. SASam Apple1:18:52

        1970. Um, but, you know, there's all these remarkable examples. Uh, in the year 2000, uh, Robert Weinberg, um, co-authors, you know, the, the Hallmarks of Cancer paper, which sort of, you know, is I'm sure you know better than I do the, the six, uh, uh, you know, fundamental traits of, of cancer and doesn't include the Warburg effect or mention Warburg, uh, or metabolism. He later, you know, they later do a revised edition and do mention it 10 years later, I believe. Um, so Warburg is, is just gone from cancer science, gone from textbooks. You know, Weinberg's famous textbook in 2006 doesn't mention him. Uh, you know, Mukherjee, who, you know, I think his book is absolutely brilliant, but also doesn't mention Warburg just because nobody was mentioning it. You know, it's just- not something that people were interested in. They talked, you know, the enzymes that Warburg studied were referred to as housekeeping enzymes. You know, seemed, you know, cancer needs to divide, and therefore it needs energy, it needs nutrients, but it's sort of, you know, just, um, not fundamental to the process, just something that's needed to, to supply cancer as it progresses. Uh, and it's really, it's really shocking to me that something so fundamental could just get lost. But, uh, I think, you know, to some extent, that's how science works. You know, there's an exciting new thing, and it's, it's hard to focus on two things at once.

    25. PAPeter Attia1:20:10

        And, and, and look, I mean, I think it is a very, um, remarkable discovery in the 1970s that there are oncogenes. Um, and, and, uh, Harold Varmus and Michael Bishop are awarded the Nobel Prize in 1989 for that discovery. Um, it holds a lot of great promise. Uh, certainly by the time I got to medical school in the late '90s, that was, I mean, my God, if I could go back and figure out how many oncogenes and tumor suppressor genes I had memorized and all the pathways and such, I mean, that was really what-- That, that's the only thing that mattered in cancer biology. Um,

12. 1:20:52 – 1:28:59

    The renaissance of Warburg’s ideas on cancer metabolism and a new explanation for the Warburg Effect

    1. PAPeter Attia1:20:52

       so what, what do you think led to the renaissance? I mean, for me personally, um, the first thing that came on the radar screen was a science paper in 2009 written by, um, Matthew Vander Heiden, um, and, and co-authored by Lou Cantley and Craig Thompson. Um, was that sort of the first, uh, thing that showed up on the radar? I mean, obviously, those three had been doing a lot of work leading up to that. I've had Lou on the podcast, and we've talked at great length about his work and the discovery of PI3 kinase. Uh, so clearly this, um, this idea that metabolism mattered, um, was, was, was on the radar of others, even though it was not necessarily on the forefront of the field.

    2. SASam Apple1:21:37

       I think that that paper was, you know, the moment, it was 2009 or 2010, that, um, it sort of reached the mainstream. Uh, but, you know, as you mentioned, they had been working on this stuff, uh, for some time. So it was really in the, in the late '90s, uh, that, uh, the revival starts, uh, mid to late '90s. Uh, and the, the two key labs, I think, at the early stages, um, one is Craig Thompson, who you mentioned, who is now, uh, the president CEO of Memorial Sloan Kettering, and the, and the other lab was, uh, Chi Van Dang, who was at the time at Johns Hopkins. And they both, you know, were sort of, you know, working on, uh, you know, understanding cancer molecular biology and, and both sort of tracing, you know, these signal, signaling pathways to the cell and, and sort of working their way back to metabolic enzymes. Uh, in Chi's case, uh, he found that the transcription factor c-Myc, uh, was actually activating, uh, lac- um, lactose dehydrogenase, LDH. Uh, and, you know, he was really quite, quite shocked to find that, um, you know, this pathway leading back to this basic fermentation reaction. Uh, so he became very curious about Warburg and, and reading the old papers on enzymes and, um, you know, really helped launch a lot of the, uh, metabolism revival. Uh, and then Craig Thompson and, and Vander Heiden was a student in his lab. Uh, they had also sort of independently, uh, rediscovered metabolism and ended up focusing on, on AKT, which is, um, you know, was already known as a, an oncogene that caused cells to proliferate. So the surprising part of their work wasn't that they had found an oncogene, but that this oncogene was actually a metabolic gene, that what its role was basically to, you know, allow glucose into the cell and that, you know, Thompson, I think, correctly states that this is the most fundamental thing that it does and that, uh, the proliferation, you know, is, is, is downstream of this glucose uptake.

    3. PAPeter Attia1:23:46

       Oh, it's, um, it's a very pro-growth, um, uh, uh, factor. So, um, what I think is most interesting about the 2009 paper in Science is that it acknowledges the Warburg effect but comes up with a different explanation.

    4. SASam Apple1:23:59

       Right.

    5. PAPeter Attia1:24:00

       And what was that explanation?

    6. SASam Apple1:24:02

       So, you know, prior to this point, you know, the accepted view or, or the Warburg's view, which, you know, again, some, some people still support, is that, um, all fermentation i- is a response to defective mitochondria. It's compensatory. You know, cell can't create energy in one way, so it's using the backup generator. It's, it's revving up fermentation. But, um, you know, what, uh, Thompson and, and Vander Heiden and Cantley argue in that paper is that, um, you know, we actually don't have, you know, as we talked about with Weinhus, we don't actually have the evidence that, that respiration is completely defective, so the mitochondria still seem to be functional and intact. And, uh, there are other reasons that a cell might need to take up a lot of glucose and, you know, first and foremost, they're bioenergetic. They need the building blocks to create, uh, you know, new nucleotides and lipids for, for the daughter cells. Um, so it makes sense that, um, you know, glucose uptake would increase rapidly. But the cells, they actually, you know, they're getting some energy, some ATP from respiration, some from fermentation, but they, they have enough to continue to function. What they really need are, are the building blocks for growth. And so that is a sort of new way to understand the Warburg effect, and, uh, I think that, you know, that's now what most, most scientists, but not all, sort of view as, as the main explanation.

    7. PAPeter Attia1:25:25

       What's your view?

    8. SASam Apple1:25:27

       Um, you know, it's, it's tough as a, uh, as a science writer, uh, and a reporter. You know, I, I'm not trained as a scientist, and I interview one person, you know, famously, Thomas Seyfried, who is very much a, a Warburgian, uh, who thinks that Warburg got it exactly right and that it is a problem of defective mitochondria, and he cites the research of, uh, believe, uh, Peterson at Johns Hopkins, who, who also believes this. So there are a lot of very smart, accomplished scientists who think Warburg got it exactly right. And [chuckles] you know, I-- it would've been easier for me to writing this book to conclude that Warburg was right about everything. You know, that's a story that would've been easier to tell and made my narrative tighter. But, um, you know, I interviewed many more people who, who felt that Warburg was wrong about this, that, um, it was not ultimately a problem of, of defective mitochondria. And, uh, you know, I look at papers from both sides and, and don't ultimately feel that, uh, you know, I have a good way of, of resolving this debate. But, um, ultimately, I, I sided m-much more so with, um, Cantley and, and, and Thompson and Vander Heiden and, and others like Nav Shandel, who, who also takes this position. Um, and, you know, it's, it's partially just a numbers thing, like many more people believe this, and their evidence is compelling, and I can see that they're, they're brilliant. And it's partially also sort of an intuitive feel for the science. And, uh, I say that because, you know, one of the, one of the things that really struck me is when Craig Thompson was, uh, giving a, a demonstration for, for students about, uh, what cancer is. He puts up this slide, I don't know if you've ever seen this talk, and he shows a mold growing on a piece of bread, and he said, "Everybody's first cancer experiment," and then he shows the mold growing. And, you know, it really goes back to Pasteur and, and understanding proliferative metabolism is not something that happens in microorganisms only in response to defective respiration. That's what Pasteur thought, but he was wrong. You know, proliferative metabolism happens when a cell can get all the nutrients it wants. You know, you put... I mean, when I say a cell, I mean the microorganisms. You know, you put the yeast on grain, and they don't care how much oxygen is available. [chuckles] They, they take up the grain and they grow, and they grow and they multiply. And, and that I think is a fundamental program that our cells know how to do as well. And I think that's really the key to the story. It's what causes, you know, this proliferative program to, you know, to take off. And I, I think it's, you know, in single-celled organisms, it's the nutrients. And I think in, uh, you know, when you look at advanced organisms and animals, we have to think not just about the nutrients, but the hormonal involvement as well. It's much more complicated, but the, the fundamental, you know, program is running, and, uh, it's, it's the nutrients and the growth factors. I mean, I think if you just step back from it and you say, you know, "What is cancer? It's a problem of growth." Okay, well, what causes things to grow? You know, nutrients and, and, and hormones. That's where you, you start the conversation. And I think that if science had progressed in a different way, then that always would've been the focus. But, you know, it was only in, you know, the late 1960s where we could even measure insulin in the blood. You know, so cancer, all this stuff about the Warburg Effect as a response to, you know, damaged respiration made sense before we knew anything about, you know, insulin and growth factors.

13. 1:28:59 – 1:35:33

    The argument against the Warburg Effect as a primary cause of cancer and the potential role hyperinsulinemia

    1. SASam Apple1:28:59

       But, you know, the science has progressed and, and I, I tend to, to view it in much more of the way of, of, of Thompson and Cantley. But I do think that Seyfried deserves a ton of credit for sort of bringing metabolism back into the conversation. And it is, as I said before, you know, I think everybody agrees that as, as a cancer progresses, you know, the, the blood vessels no longer are getting oxygen in the same way, and that's, that's clearly playing a role in terms of revving up fermentation. Uh, so it's not necessarily either/or, but at the, at the sort of core origin of cancer, I don't see that the respiration damage is, is being sort of conclusive.

    2. PAPeter Attia1:29:38

       Yeah. A-and I, and I don't either. I, I mean, I just think on first principles it doesn't actually make sense, right? So if, if you, if you follow the logic of Warburg, um, if the primary insult or the prime cause, to use his language, is damage to the mitochondria, that's an insult to a cell. That's a deficit to a cell. That's an inhibition of a cell's ability to respire and frankly acquire energy. So the fact that the cell has the ability to do something outside of the mitochondria in a compensatory fashion is great, but in and of itself, that doesn't explain why it would take up more nutrient. It simply explains why it would metabolize nutrient in a different way. And to, for me at least, to focus just on the availability of nutrients and hormones doesn't explain to me why if we're-- let's just talk about colon cancer, right? Or pancreatic cancer. You, you pick your, you pick your cancer. You have a normal cell and you have an abnormal cell. The normal cell presumably then is the one that is not going to become cancer. The abnormal cell is the one that is going to seed the cancer. They're both exposed to the same amount of nutrient. They're both exposed to the same hormonal milieu. So why is only one of them going down that cancerous pathway? Why is one turning into a polyp, and why is only that polyp becoming dysplastic and ultimately, you know, or metap- metaplastic and ultimately dysplastic and ultimately becoming metastatic? Um, it-- I, I, I think that the, that the, that the hormones and the nutrients are simply the fuel that allow the thing to happen, but they're not the spark, you know? And to me, the spark is what matters. Um, and, and that's why I, I, I, I, I don't agree that Warburg was correct. Um, I don't agree that, that, that the initial insult is the mitochondrial insult. Um, I, I think that the-- I think that the event that is driving this, I think that the, the-- I think the oncogenic effect is the, is the driver, and I think the metabolism allows the cancer to be even more adaptable to the scenarios that you describe. Um, and I've spent Perhaps not as long as you, but I've certainly spent a lot of time talking with people on both sides of this, going to conferences. Um, um, but in the end, it, it somewhat matters because it, it, it, it comes down to what's the implication of this from a treatment and prevention standpoint, and I would say in the opposite order, right? What's the implication of this from a prevention standpoint? What's the implication of this from a treatment standpoint? And that's what I think about because in the end, that's the part that I think as a kind of a bedside doctor, that's the part you have control over is what can you do to prevent cancer or reduce the probability of cancer. I don't think one can truly ever prevent it. Um, and then in the presence of it, what can you do? Um, so how, how did this work impact your thinking on that question?

    3. SASam Apple1:32:42

       Um, sure. Yeah. In my mind, you know, that, that's really the key to my, my whole story is, you know, there, there's sort of two components to it. One is what's going on inside the cancer cell, and, you know, that's all this discussion we've had about the Warburg effect. But there's another part to the story which is, you know, 150 years, 200 years of cancer epidemiology and seeing, you know, various environmental causes of cancer or various, various theories about what, what causes cancer. And what really struck me, and, and I don't think... You know, as a, as a journalist, I can't understand the science sometimes in the same way that probably you can and, and a lot of the people I interview can, but what I try to do is, is connect dots. You know, that's one thing I can do as a journalist is look at one scientific field and another scientific field that aren't necessarily talking to each other and try to put stories together. And the thing that, that really struck me, uh, was that in the late '90s, at the very same time that, uh, you know, Thomson's lab and Chihab and Deng's lab are returning to Warburg metabolism, we have these new epidemiology papers coming out showing both that insulin is correl- you know, elevated insulin, hyperinsulinemia is correlated with cancer and obesity is correlated with cancer. So it, it happens at the same moment, and that-- in a lot of ways, that was my project, uh, for the end of the book is trying to understand, you know, is the obesity story related to the overeating of glucose in the cancer cell. Um, and, and I think those two stories are related and, and that's why, you know, the last part of my book i- is really a focus on hyperinsulinemia because I think it's the piece that, that puts it all together. It could explain the obesity, it could explain, uh, the cancer, and it could explain why cancer was once a rare disease and then in step with diabetes and obesity and other, you know, quote unquote, "diseases of civilization" became much more common. So in, in my book, insulin is, is sort of the explanation which ties it all together and which, you know, obviously not all cancers are caused by insulin. Uh, and, you know, insulin's role, according to some scientists, is only indirect. It causes the obesity, and the obesity causes other hormonal changes and inflammation. But, but one way or another, I think it's a big part of the cancer story and, and the part that, you know, if we're gonna really make progress on prevention, we have to focus, I think, on hyperinsulinemia. Uh, to me, you know, this is now exactly 50 years since the war on cancer begun, and, you know, we've made so little progress in, in many ways, and certainly with respect to prevention. You know, there's been remarkable cures and therapies and, um, you know, I, I revere the scientists who make this work, but certainly in terms of prevention, you know, we're just not making progress and, and I think it probably comes back to the hyperinsulinemia.

14. 1:35:33 – 1:45:00

    Identifying primary and secondary causes of cancer for the purpose of cancer prevention

    1. PAPeter Attia1:35:33

       A- and, um, again, I, I do kind of like the way Warburg positioned a prime cause and secondary causes. So, um, when you think of the ravenous diarrhea that was ripping through London in the 1800s, the prime cause was cholera. Uh, but the secondary cause was the lack of sanitation, right? It was the-- It was that which permitted the cholera to, um, travel so freely from sewage to drinking water. Um, so now let's think about cancer through the lens of the two most readily identified epidemiologic factors on scale, not necessarily with the clarity of evidence, but just in terms of breadth of numbers impacted. First and foremost is smoking, and second, as you point out, is obesity, uh, at least in the developed world. So with smoking, would we put it in the prime or secondary cause? I think we'd put it in the prime cause, right? I think we would argue that the evidence for the causal relationship between cigarette smoking and cancer is likely related to the carcinogenic effect of the tobacco on presumably the DNA structure of the cells that leads to mutations that drive unresponsive or unregulated growth. Would you agree with that?

    2. SASam Apple1:36:58

       Yeah, I mean, it, it does come down to, you know, semantics at some level. You could argue that the prime cause is the mutation, you know, in the DNA that, that's caused-- that's driving the cancer, uh, or you could say that cigarette smoke is the prime cause. I personally find it more sort of logically compelling to talk about the prime cause as the very first thing in the step-- in the very first step in the process. So I, I, I think you can say cigarette smoking is the prime cause, but, uh, by Warburg's definition, he would say that if you accept that paradigm, then you would say the mutation is the prime cause, the, you know, chromosomal damage, whatever it is. Um, you know, another way to think about this is that the accepted paradigm is that all the problems, you know, one way or another go through the DNA, and that the Seyfried and paradigm is that all the problems go through the mitochondria. So those are the, you know, the two sort of causal centers. But I think logically prime cause should be the very first thing. So smoking in, in the case of cancer makes sense to me.

    3. PAPeter Attia1:37:59

       Yeah. No, I, I think that-- I, I agree with you. I think that makes sense. So now the question is how do we apply that, that thinking to the second one? So if we posit that indeed obesity plays a causal role in cancer. There's no dispute that the correlation is quite strong. That... I, I mean, I... You, you don't need to be an epidemiologist to understand that. The question is, is that correlation causative? Now, with tobacco, the correlation is so strong that it's very hard to find somebody who doesn't appreciate that there's a causal relationship there. [lip smacks] I did see somebody on Twitter the other day try to argue that tobacco has no relationship to cancer, but let's put that guy aside for a moment. Um, with obesity, it's a little harder because the hazard ratio isn't nearly as large as it is with tobacco, and obesity is, is actually harder to disentangle from its other multivariate parameters. It comes with so much else. So the person who is obese eats a different way, sleeps a different way, exercises a different way. Uh, y- the list goes on and on and on of other things that could, that could potentially play a role. But again, for the purpose of the discussion, if we posit that obesity is causally related to cancer, then the next step is, is it one of the growth factors associated with obesity, of which insulin is one? Is it other changes that are prominent with obesity, such as inflammation? Um, how do you then arrive at, you know, for example, insulin being, um, the, you know, the prime candidate, to use the word prime again, within the obesity paradigm that's driving this? And that says nothing, by the way, of where we're gonna then have to go, which is, is it the enabler or is it the primary cause?

    4. SASam Apple1:39:59

       I mean, my argument is that, um, you know, ultimately, uh, you know, as you said, these are very complicated. [chuckles] You know, there's, there, there's many different factors that play out, but, but my ultimate argument is that the obesity is not causal, that it's actually the hyperinsulinemia that is simultaneously driving the obesity and the cancer cell proliferation. Uh, so I think part of the evidence for that is that, um, you know, there are people who are, quote-unquote, "metabolically healthy obese" that, um, you know, they store more nutrients in their, their subcutaneous fat, the more energy in their subcutaneous fat and not the visceral fat, a- and they tend to be metabolic- metabolically healthy and do not have insulin resistance, and they seem to be no more likely to get cancer. Whereas when you look at the insulin resistance in, in people who are thinner, but clearly, you know, I think it's most in- people actually do have insulin resistance, and when you see that metabolic disruption in people who aren't obese, they... that also tends to correlate with cancer. So I think you can, to some extent, dissociate the obesity. Uh, but then you still have to... You know, the insulin-cancer correlation isn't as strong as, as smoking either, so, you know, you still have a lot to work with. And then, you know, there's the question that you brought up is, I, I think this is what you're referring to, is the insulin actually, you know, the first prime step in the process, the hyperinsulinemia, or is it, you know, a mutation that occurs for some other reason and, and allows the cancer cell to, to take advantage of that hyperinsulinemia? So-

    5. PAPeter Attia1:41:34

       Yeah. Is the model basically that if you take, um, you know, a two-by-two matrix where you have, um, chromosomal insult, yes or no, hyperinsulinemia, yes, no. So which one gets cancer? Is it only the double positive? Right?

    6. SASam Apple1:41:59

       Um-

    7. PAPeter Attia1:41:59

       I mean, we would agree that the double negative almost assuredly does not, but the-

    8. SASam Apple1:42:04

       Yeah

    9. PAPeter Attia1:42:04

       ... and we would probably agree that the double positive does. The question is, what's happening in the other corners, right?

    10. SASam Apple1:42:10

        Yeah.

    11. PAPeter Attia1:42:10

        What's happening in the individual who has the chromosomal insult in the absence of hyperinsulinemia, and what's happening to the person without the chromosomal insult who is hyperinsulinemic? To me, those are the questions that matter a lot, and they matter a lot for, for the sake of prevention. Now, the, the, the, the obviously, um... And this is the approach that I take clinically, right? Which is, um, let's be overly aggressive and assume that both of those are sufficient. Then you would say, "Well, you have to put yourself in the double negative box," which is avoid hyperinsulinemia and any sign of metabolic ill health, and do every single thing imaginable to reduce the burden of DNA insult. And you try to narrow yourself and confine yourself into this very narrow box, and then you layer on a whole bunch of other things like really aggressive screening and all this other stuff. Um, but, but... So, so that's kind of what you would do if you don't have a choice. If you're absent perfect information, you have to probably act more aggressively. But I still think this question of which of the two positive-negative, negative-positive squares, uh, you know, until we... Uh, at least for me, I don't have a great understanding of those. And y- 'cause I think they exist in both. I think there are examples and counter examples for both.

    12. SASam Apple1:43:32

        Yeah. No, I mean, uh, I don't think anybody has a great answer for it at this point, but, um, I do find, you know, this is speculative, but, uh, you know, one, one hypothesis is sort of that these chromosomal insults occur by, by chance or for whatever reason, and, you know, eventually you get one in this PI3K pathway and the cell's now able to take advantage of that hyperinsulinemia. But another speculative idea is that, um, if you have, you know, hyperinsulinemia and, um, sort of excessive glucose metabolism, that it's actually gonna be driving the chromosomal insult, uh, through, you know, creation of reactive oxygen species in the mitochondria, and that the hypermetabolism, you know, as Craig Thompson puts it, actually creates a way for the cell-

    13. PAPeter Attia1:44:18

        Mm-hmm

    14. SASam Apple1:44:18

        ... to mutagenize. Um, so, you know, I, I think that's probably part of the story, and there, you know, there's new research coming about how nutrients ... are actually, you know, play a huge role in epigenetics as well. So, you know, it may be that, um, you know, there's just bad luck, a mutation comes along, and then if the insulin is there, a cell takes advantage, and if it's not, maybe that microscopic tumor never takes off. You know, a lot of people die with cancer rather than from cancer as, as they say. Um, you know, maybe the immune system can, can kill these microscopic tumors if not for the insulin keeping the... You know, insulin really tells a cell to stay alive. And so, you know, I don't think we have great answers to these questions, but, um,

15. 1:45:00 – 1:50:00

    The link between sugar, fructose, and cancer

    1. SASam Apple1:45:01

       I think that, you know, if you just step back and look at the epidemiology, like, you know, something has to be going on with, with nutrition, you know, because, you know, the cancer was so much more rare prior to the shift to the Western diet. And, you know, could, it could be many different things, but, you know, the... It all points to hyperinsulinemia and, you know, it's, it's, it's a growth factor, you know, and cancer cells are covered in insulin receptors. It just, you know, makes a lot of sense that, that this is really fundamental in one way or another. I'll just say that the counterpoint is, you know, maybe that you just have bad luck and get a- an AKT mutation, then the cell, you know, no longer needs insulin and can just get all the glucose it wants. And, and that, um, you know, may be true in some cancers, but, but from as I understand it, that even when you have these mutations in this PI3K/AKT/mTOR pathway, that they're still insulin dependent, just less dependent. So you can imagine a scenario at least where keeping insulin really low will help, even if that chromosomal insult takes place and makes a cell more susceptible.

    2. PAPeter Attia1:46:05

       You know, what about non-insulin requiring nutrients such as fructose? Um, Rick Johnson and Lou Cantley have, um, both spoken about this. What, um, what, if anything, did you uncover about the potential role of fructose in cancer?

    3. SASam Apple1:46:22

       Yeah. Um, that was one of the more s- surprising parts of the story for me, uh, and, and, and humbling in a, in a way as well. Uh, you know, a remind- reminder to me. You know, I was writing about Warburg, who always believed too strongly in his own ideas and couldn't, you know, accept that they may be wrong. And, you know, it's anytime you're writing a book that has any kind of argument in it, you sort of fall into that trap and, and have to remember that, you know, science changes and not everything's proven. So I had decided, you know, early in my writing process that, uh, I thought sugar, sucrose was a big part of this story. Uh, but my assumption was that it was all by way of driving, you know, liver fat and insulin resistance and hyperinsulinemia. And then, um, in recent years, this work out of Cantley's lab and Richard Johnson's and, uh, has shown that, uh, you know, even independent of the, the effects on insulin, that fructose seems to drive, you know, certain cancers that, that, you know, particularly in the colon, that are able to get the fructose, uh, and, uh, a- actually, you know, turns on, you know, through sort of a- an on metabolism [laughs] actually turns on the Warburg effect and allows sort of ATP to go down and then glucose to flow in. But, um, the surprising part for me was that, um, you know, that could be disassociated with insulin. I had to, to step back and say that, um, you know, maybe, maybe sugar is, is even worse than we thought [laughs] and, uh, is sort of causing cancer in two different ways in some cases.

    4. PAPeter Attia1:47:55

       Yeah. That, that to me is the most interesting question. Um, still somewhat unresolved, frankly, although I think Rick Johnson's work is among the most compelling I've seen to, um, to disentangle that relationship of fructose, um, independent of its caloric contribution. Um, and as you said, this is, this is a mechanism that's, that has an indirect effect on insulin, right? So, so fructose metabolism, when consumed in excess, does in fact lead to insulin resistance, which by its very definition leads to hyperinsulinemia. But, but the work you allude to in, in colonic cancer by Lou Cantley, uh, actually posits that, you know, that it's the energetic issue in the cell that you alluded to of the trans... And, and Johnson as well. It's this lowering of, um, of ATP in the process of metabolizing fructose, and it's that, um, that ADP/ATP, um, sort of switch that, that can drive the hyper influx of, of glucose, and that's not necessarily an insulin driven phenomenon.

    5. SASam Apple1:49:05

       Yeah. Yeah. Now that, um, you know, it's kind of odd for me in a way it supported my hypothesis that sugar is at the center of the story, but it, it sort of upended my idea of what the mechanism was. You know, so, um, you know, there's still clearly a lot to learn, but, uh, I found, you know, Rick Johnson's whole discussion of this absolutely fascinating. I listened to the podcast and, and when he was talking to you. Um, you know, part of it, you know, all this stuff we were talking about, uh, you know, the turn to fermentation in low oxygen environments, which, you know, again, I think you and I agree that that's maybe not the whole story as some people think, but that it... the seesaw-like relationship does exist. But his example, which really fascinated me, was that, uh, these naked mole rats, uh, I don't know if you remember this [laughs] , but you know, they live in this low oxygen environment, and they, they run a lot of Warburg metabolism by converting glucose to fructose and then using the fructose to, to drive the Warburg effect. It was really fascinating to

16. 1:50:00 – 1:59:05

    Sam’s reflections on the work that went into Ravenous

    1. SASam Apple1:50:00

       me.

    2. PAPeter Attia1:50:01

       W- what did you learn in this project that you absolutely, positively could have never predicted? I mean, you, you sort of alluded to the fructose more than glucose issue here. Was there anything else that either historically or scientifically completely caught you off guard and, and, um, challenged what you thought you knew [laughs] about yourself or, or this body of work?

    3. SASam Apple1:50:22

       Yeah. It's, it's a good question. I think one of- One of the things that really struck me, and I think a lot of people who spend years researching and writing about Nazis end up with a similar insight, but you sort of have to go through it to, to maybe realize it, is, you know, I grew up, you know, Jewish and, and learning about the Holocaust and Nazis, and in my mind, you know, they were evil monsters and [laughs] and, and they were, but I, I never humanized them. And now I had to sort of look at the personal stories of all these Nazis and, and, and not think of them as, uh, in an abstract, you know, evil, monstrous way, but understanding as human beings how they went down this path and how it happened progressively throughout the '30s and how it could be that somebody who, you know, might in one context be a nice neighbor and friend and then, you know, go into the office and, you know, work on documents that, you know, that, uh, lead to, you know, millions of people ultimately getting murdered. You know, just getting into the lives of these people and, and seeing that progression, it really was chilling and, and eye-opening in a way to make me think that this wasn't an anomaly, that this, in theory, you know, it has happened elsewhere and in various forms and, and could happen elsewhere. So it made me sort of much more politically attuned to certain extremist politics. So, so, so that was part of it on, on a political level. And, you know, on, on a personal level, i-in terms of the writing, it was such a daunting project for me. Um, you know-

    4. PAPeter Attia1:52:02

       How many, how many words is the book, Sam?

    5. SASam Apple1:52:04

       [laughs] I actually don't even know. Uh, I think it's about 120,000 some words. Uh, but, you know, I didn't have the training in biochemistry. I didn't speak German fluently, and I really... You know, I didn't plan to write the book. The publisher came to me and said, "I saw your New York Times article. Do you wanna do this?" And, and, uh, I hesitated, didn't say yes right away because such a big project. But, um, you know, I think that over the years, I sort of learned a lot about myself as, as a writer and sort of was able to gradually, you know, trust myself more as a historian. And, you know, I, I think that, um... You know, I feel more confident a-as a writer having completed this project. [laughs] We'll see, uh, you know, if I still feel that way after somebody trashes the book. But, uh, for me, I felt like I was taking a big risk, and that, that I made it to the end of that project, uh, you know, is very rewarding and makes me feel confident about taking on other stuff.

    6. PAPeter Attia1:53:10

       As a writer, do you pay attention to what people say about your work, or do you go out of your way to avoid reviews and things like that?

    7. SASam Apple1:53:18

       Um, I go out of my way [laughs] to, to avoid reviews. Uh, what's fascinating to me is that even positive reviews, which, you know, I'm very grateful for, grateful for, but they also make me uncomfortable, just the thought of anybody sort of passing judgment, you know, on something that, you know, you work on so hard for so many years. It's just, it's just too much to, to get a reaction to it in some ways. And I'm incredibly grateful for the positive reviews, and it's been really rewarding to get some nice responses to the book on Twitter. But, um, you know, I think there's gonna be a New York Times review out soon. I'm not even sure I can read it. [laughs] You know, just... I, I have the same thing with my student... You know, I, I teach, and students pro- provide, um, you know, assessments of my teaching at the end of each semester, and, and I read them because I need to know how to become a better professor, but it makes me deeply uncomfortable. [laughs] Um, you know, it's... I, I don't write book reviews anymore because it's just... You know, when somebody works on something so hard for so many years, it's, it's terrible to have to pass judgment on it. [laughs] Uh, you know, I'm kind of a softie, I guess. But, um-

    8. PAPeter Attia1:54:20

       But how do you learn then? I mean, I can be totally sympathetic to that, but is there, um, is there a model where you let somebody else read the reviews and pass on just the objective, you know, this is working, this is not working feedback? I'm asking honestly for personal reasons, um, as I sort of think about how to digest feedback in a forum that is actually very harsh.

    9. SASam Apple1:54:44

       No, I mean... No, it's certainly-- I think it's certainly true that if you don't read your reviews, you're not gonna learn as much. But in a way, it's too late at that point. You know, what I do is before, uh, you know, before I finish the project, I send, you know, first and foremost my editor, who is wonderful at Liveright, uh, Dan Gerstel, to give a shout-out. Uh, but you know, I also have a handful of trusted friends who, uh, I send the manuscript to and get their feedback on. And, you know, I, I certainly... That doesn't make me uncomfortable because it's, it's a different dynamic. It's not in public. It's in private, and they're people that I trust.

    10. PAPeter Attia1:55:18

        Mm-hmm.

    11. SASam Apple1:55:19

        And I don't feel, you know, publicly shamed if they, uh, tell me it's awful. And, um, [lip smack] you know, I, I can't get better unless I get their feedback. And, um, you know, I got tremendously valuable feedback from those early readers, so you know, I, I don't think there's a writer... I mean, every writer I know does some form of that, and I think everybody should.

    12. PAPeter Attia1:55:39

        So Sam, tell folks again the name of the book.

    13. SASam Apple1:55:42

        Uh, the book is Ravenous: Otto Warburg, the Nazis, and the Search for the Cancer-Diet Connection.

    14. PAPeter Attia1:55:48

        All right. Well, Sam, thank you very much for taking the time, uh, so much time to sit down with, uh, me today and talk about this and share these insights with all, uh, all the folks that are... Everybody's interested in cancer, so, um, I think there was a lot here both in the history of it and also the, um, the implication, which is potentially that metabolism plays a very important role in cancer. Uh, it might not be entirely clear if it's, uh, the, the trigger, the, you know, the... If it's the spark, if it's the oxygen, if it's the fuel, but it's in that mix. So, um, the more we can do to reduce hyperinsulinemia, improve cancer metab- uh, improve our metabolism, reduce reactive oxygen species, all these things that you've spoken about, um, presumably the better odds we have against the disease to which we've made very little progress, as you point out, in the last fifty years, so. Thank you, Sam

    15. SASam Apple1:56:38

        Yeah. Thank you so much. It was an honor to be on the show.

    16. PAPeter Attia1:56:42

        Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription. Now to that end, membership benefits include a bunch of things. One, totally kickass comprehensive podcast show notes that detail every topic, paper, person, thing we discuss on each episode. The word on the street is nobody's show notes rival these. Monthly AMA episodes or ask me anything episodes, hearing these episodes completely. Access to our private podcast feed that allows you to hear everything without having to listen to spiels like this. The Qualies, which are a super short podcast that we release every Tuesday through Friday highlighting the best questions, topics, and tactics discussed on previous episodes of The Drive. This is a great way to catch up on previous episodes without having to go back and necessarily listen to every one. Steep discounts on products that I believe in, but for which I'm not getting paid to endorse, and a whole bunch of other benefits that we continue to trickle in as time goes on. If you want to learn more and access these member-only benefits, you can head over to peterattiamd.com/subscribe. You can find me on Twitter, Instagram, and Facebook, all with the ID Peter Attia MD. You can also leave us a review on Apple Podcasts or whatever podcast player you listen on. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about where I keep an up-to-date and active list of such companies. [outro music]

Episode duration: 1:59:05