The Peter Attia Drive - #187 - Sam Apple: The Warburg Effect—Otto Warburg’s cancer metabolism theory

Episode Date: December 13, 2021

Sam Apple is the author of the book Ravenous: Otto Warburg, the Nazis, and the Search for the Cancer-Diet Connection, published in May 2021. In this episode, Sam describes the fascinating life story of Otto Warburg, a Nobel Prize-winning scientist who, despite being both Jewish and gay, survived Nazi Germany because of his valuable research on cellular metabolism and cancer. Sam describes Warburg’s observation that cancer cells consume large amounts of glucose anaerobically – a phenomenon subsequently known as the “Warburg Effect” – and relates how Warburg’s seminal work on this topic was largely forgotten after the discovery of oncogenes, only to regain relevance decades later within the field of cancer biology. Sam sheds light on the current debate around Warburg’s interpretation of the causes of cancer, and Peter gives his personal take on the matter. Finally, Peter and Sam tie it all together with a discussion about cancer prevention, the role of hyperinsulinemia, and the link between dietary sugar and cancer. We discuss: Sam’s interest in Otto Warburg and work as a writer [2:30]; Otto Warburg’s dedication to science and his complicated life in Germany [14:00]; Warburg’s interest in cancer and early discoveries about cellular consumption of oxygen [23:00]; The role models who fueled Warburg’s desire to make a great discovery [34:15]; How Warburg described the primary and secondary causes of cancer [42:15]; Warburg’s Nobel Prize in 1931 [45:45]; Warburg’s life and work during WWII in Nazi Germany [46:30]; Warburg’s research in hydrogen transfers and coenzymes—his best science? [59:45]; Warburg’s decision to stay in Germany after WWII [1:03:30]; Discovery of oncogenes in the 1970s and the decline in interest in Warburg’s ideas [1:07:30]; The renaissance of Warburg’s ideas on cancer metabolism and a new explanation for the Warburg Effect [1:13:45]; The argument against the Warburg Effect as a primary cause of cancer and the potential role hyperinsulinemia [1:21:15]; Identifying primary and secondary causes of cancer for the purpose of prevention [1:27:00]; The link between sugar, fructose, and cancer [1:35:30]; Sam’s reflections on the work that went into Ravenous [1:39:45]; More View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Learn More About Peter Attia Sign Up to Receive Peter’s Weekly Newsletter Connect With Peter on Twitter, Instagram, Facebook & YouTube

Hey everyone, welcome to the drive podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop. And we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn more now, head over to peteratiamd.com forward slash subscribe.

Now, without further delay, here's today's episode. My guest this week is Sam Apple. Sam's a freelance writer and author of several books, including one recently published called Ravenous about Otto Warburg, the Nazis, and the cancer metabolism diet connection, which we discuss in great detail during this show. Sam teaches in both the MA in science writing and MA in Writing programs at Johns Hopkins. Prior to coming to Johns Hopkins, Sam taught creative writing and journalism at the University of Pennsylvania for 10 years. He holds a BA in English and creative writing from the University of Michigan and a master in fine arts in creative nonfiction from Columbia University.

In this episode, we go into great detail about the life story of Otto Warburg. We talk about his early upbringing in Germany, how he was influenced by some of the most influential, if not the most influential scientists in Germany. We talk about his seminal work prior to the Second World War and this odd manner in which he was able to remain in Germany unharmed during the Second World War, despite being both Jewish and gay. The interesting part of the story, of course, is that much of his work would be largely forgotten by the time he died in 1970. And it would only be about 30 years later that some of his observations would come back to be relevant within the field of cancer biology. Of course,

it's still not entirely clear if his hypothesis around that observation is correct. I personally do not think it was, but nevertheless, this makes for an interesting discussion. So without further delay, please enjoy my conversation with Sam Apple. Hey, Sam, how are you doing today? I'm doing good. How are you? Good, good. Congratulations on the publication of your book very recently. Having never done that before, I can still only imagine it's akin to giving birth or something like that. Feels like the weight of the world off your shoulders after how much research you put into that. Yeah. It's a, it's a huge relief just to be done. So I'm trying to think about a future project,

but I feel like I need a few years just to, to relax now. Oh yeah. Yeah. I imagine there's nothing more annoying than when you publish a book, when somebody says, so what's your next book going to be about? It's like, let me, let me bask in this one for a while. Like many books that go really deep into a topic, be it science or otherwise, they often start out as articles. And of course, you wrote a piece, was it 2015? It came out in 2016. And it was the New York Times Magazine piece, correct? Right. 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 the work that went into this book. But more broadly speaking,

what attracted you to this topic of Warburg, cancer, metabolism, the era of Nazi Germany, and science in that era? What gravitated you to that? and science in that era. What gravitated you to that? Like so many people in this world, I was influenced by Taubes at a fairly early stage of my interest in metabolism. I read some of his work and that had led me to other authors and eventually to a lot of your work and your blog. So I had been interested in metabolism for a number of years, but 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 19th 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 I hadn't planned to write about it until I came across a mention of Warburg. I think it was just one sentence, you know, 1923, a German scientist makes an important

discovery about the metabolism of cancer cells. So 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. You know, because I'm 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 central character, then I know how to tell a story. So once I had Warburg, I knew I was going to write about it and I knew I had a way to tell the story. Before we get to that story, I want to kind of understand a little bit about your work as a writer. You're a prolific writer. You actually teach a course in science writing at Johns Hopkins now, don't you? Yes, I do. So when did you realize you were a writer? Well, my father's a writer,

so it helped to have that. For many people who grow up, it seems like an unusual career choice, but for me, it was obviously a potential option just having seen my father do it. But the truth is I didn't try to, at least not consciously, to follow in his footsteps. If anything, I thought that I might need to distinguish myself by choosing a different path. And I like my father mostly writes fiction. I like to half joke that my big rebellion was moving into nonfiction. But it really was in college when I wasn't sure what I was going to do. And I was getting a lot of praise for my writing.

And the praise felt good. And I wasn't killing it necessarily in other areas. So, you know, I saw that it was my strength. I enjoyed doing it and, um, I sort of just continued with it because I was succeeding with it. So do you think a good writer was born or made or how much of your success do you attribute to some inborn gift versus something you'd been cultivating and nurturing and practicing? Tough question. I think about it a lot because I teach science writing and general creative writing at Johns Hopkins now. And I certainly think that everybody can improve a lot as a writer. And I think literally every day about how to get better at teaching it and helping

people improve. But at some level, it's innate. Some people have more natural ability than others with language. But I think it's pretty analogous to 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 I don't think it's correlated that strongly with intelligence. It's a sort of just an ability to use language in a certain way that comes naturally to some people and comes to other people with more practice. But I think everybody can get pretty good with enough practice. So when you're teaching a class, 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 breadth of natural ability or the spectrum of natural ability across the students? How would you ferret that out quickly? Truth is that you can see it in almost any writing sample. I'm on the faculty of Johns Hopkins. I'm also involved in the application and reviewing applications and selecting students for the science writing program. And they submit samples of their writing, but I often look most closely just at the cover letters because I feel like within a paragraph or two, I get the feel, if they have a feel for the language or not. So it really comes across, I think almost in any three or four sentences, I can start to feel, are there extra words in these sentences? Is the logic tight? Does it flow? It really doesn't take very much to figure it out.

That's amazing. And it makes me feel so self-conscious because of how often I write. Every Sunday I'm putting out a newsletter and I enjoy writing a lot, but I don't feel like it comes naturally to me. So I can imagine how many people must read that and go, oh my God, yeah, what he's saying is interesting, but he's such a horrible writer. And of course, I know what it's like to read very good writing. You can sort of spot the extremes, or at least I can spot the extremes. I don't think I could rank a hundred people from one to a hundred, even though obviously there's a lot of subjective stuff in there. But I could certainly say, this is exceptional. I can read Sid Mukherjee and say, wow, this is really, really good. 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. So how much of it is also being able to, in that cover letter, say 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. That's a lot to unnecessary words or they're presumably repeating themselves or this is illogical. That's a lot to pick up in just a paragraph. 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 the writer's meaning. So George Orwell famously wrote about politics and English language

and how much good writing depends on clear, concise thinking. And I think that's true. But such a big part of it, everything that I write comes out pretty poorly in the first draft. Even my emails, if I really care about an email, I spend a lot of time just going over and over and over it because it's the repetition. It's correction after correction after correction where the writing starts to improve. So I think the difference between a good writer and a less good writer is often how many times the good writer goes over the work, whereas the lesser writer will just say, yeah, it doesn't matter that much and

send it off. But there's a price to pay. I waste half my life worrying about sentences and an email. So come to the cost. For the record, I was a big fan of your blog when you were posting more regularly. So I think you're being too hard on yourself. Thanks. Did you go to journalism school or did you do something after undergrad to further hone your writing skills? I graduated and then I took a few years off to work at a magazine. And then I spent two years doing a MFA program at Columbia. It's creative nonfiction program. So it's not journalism. I thought about going to the journalism school, but I chose creative nonfiction because I was interested more in long form and more in storytelling as opposed to rigorous reporting that I do that as well. But I was interested more in long form and more in storytelling as opposed to rigorous reporting that

do that as well. But I was really more interested in book writing and long form nonfiction. And how do they teach at that level? I mean, obviously people who show up to do a two-year MFA at Columbia, which is arguably the best school in the United States, at least to study that subject matter. You're dealing with a bunch of really talented people to begin with, but what are they doing in two years to take you to the next level? It's mostly a writing workshop. So every semester, you have a group of about 15 students and a professor, and you submit three, four times during the semester, you submit your own work and everybody in the class critiques it. And the professor, of course, you know, critiques it and discusses it. And that's really the heart of most writing education. And it's a grueling process at

times. You know, you have 15 people sitting there telling you everything that's wrong with your work and you can't listen to all of them. They they often disagree, and you can go a little crazy, you know, trying to make your work sort of fit everybody's expectations. There are some writers in recent years who have really been pushing back against this workshop approach because they feel it turns every piece into sort of a formulaic story or essay where you meet a certain set of expectations that everybody has, and you don't do more experimental work. So there are a lot of debates about that. But I do think it's really important because even the best writers in the world don't know when their own work is working. You know, you need feedback from other people.

So much of it is trial and error and, you know, writing a short story. I might use the first person, you know, telling it from my own perspective. And then everybody says it's not working. So I try it again. And I write from the third person, not using the I, and then it suddenly works. And you don't really know what works until you get responses. Because when you're writing, you know, if you get on a roll, everything feels good. Everything, you know, if you're in that space for, you know, a few minutes when you're writing, you think, oh, I'm on a roll, this is great. And then you show it to your workshop and nobody likes it. So you need that feedback. And, you know, maybe sometimes you're right and they're wrong, but,

but ultimately you're trying to publish your work for an audience. So the audience has to be right at some level. Does it amaze you when you see people like Atul Gawande and Sid Mukherjee and Azra Raza, people who didn't necessarily formally train in writing, but who seem to write beautifully? I mean, it's beyond amazing. It's actually really annoying and frustrating. I'll admire all three of the people you mentioned. And not only are they exceptional writers, but they're full-time physicians and doing these incredible things. And it just absolutely blows my mind that they have the time to do it.

And when they do it, they do it in a way that's almost unimaginably good. It depressed reading Mukherjee because I think, what's the point of me even trying when he's writing in this way? So I don't know how they do it, but I just have to accept that very few people reach that level. And you can still do good things if you're not reaching that level. Well, that's definitely a good way to think about it. So let's get back to the story here.

And let's assume that the listener here doesn't really know anything about Warburg. That name means nothing to them. Where's the right place to begin this story? He's born into a pretty well-to-do family in the kind of latter third of the 19th century. Tell us where to pick up this story. Sure. Yeah. I do think that his childhood is a really important part of the story. I had a hard time finding a lot of original sources and documents about his childhood, but the basic facts are that his father, Emil Warburg, is a very prominent

physicist. 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. And Einstein really loves his father. He says that he's like his favorite physicist. And Emil Warburg ends up providing some of the experimental proof for some of Einstein's theories. So Einstein was a regular in the house when Warburg was a teenager, 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. revered their scientists. The country was at the top of the scientific world at the time.

So Warburg's vision for himself is he's going to grow up and be a great scientist like the people that hang around in his house. He's going to make a world-changing discovery just as his father and Einstein and Emil Fischer have. And the question is where he's going to focus his energies. And he moves away from physics, which is a little surprising. I think that was his rebellion in a way. And he wanted to outdo his father, Emil Warburg. So he moves into the realm of biology and physiology. But it's always throughout his life through the lens of a physicist and always interested in energy and how 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 that extended to a study of photosynthesis as well. How old was he at the beginning of World War I? That's a good question. At the beginning of World War I, I'd have to go back and do the math. So it was 1914, and he was born in 1883. So he was in his early 30s, I guess. And so what was the impact of World War I on German scientists? It was pretty remarkable that given that, if you look back from a historical perspective, I don't think that Germany's position at the time is particularly defensible. But there was, you know, just this huge surge of nationalism and the scientists for 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, you know, many of them did. And in some cases, many of these scientists were Jewish. And because of the politics at the time, their German patriotism was questioned. So by signing up for the war effort, this was a way to prove they were full Germans. So that was a big part of it. And many of them went to the battlefield and others worked with Fritz Haber, who develops these gas weapons and all these sort of new weapons of war that are coming out of German science. It surprises me that Warburg went to the battlefield rather than working with Fritz Haber, who he knew and ended up working in the same area in Dahlem where Warburg worked. So it's hard to understand why that happened, but I think Warburg 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. Now, Einstein urged him not to go, correct? Well, Warburg went and then Einstein wrote a letter to him in 1918. So the war was nearing its end. And by that point, 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 Warburg's mother put it. And they're desperate for Warburg to come home. His parents are desperate. So they're friends with Einstein and they can't 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 turned to Einstein and they know that Warburg reveres Einstein. And they say, well, you write him a letter. So

Einstein does. And it's really a perfect letter because 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 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 most likely convinced him and, you know, possibly saved his life. And five years later, he makes his great breakthrough about cancer and fermentation. So I like to think that Einstein may have saved his life and therefore deserves credit for this great cancer discovery as well in some indirect way. You wrote about Warburg that he was pathologically dedicated to his science.

What did you mean by that? I mean, I think it's hard to understand unless you grew up in 19th century Germany. But 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, is passionate about science. You know, Warburg used to say, a scientist has to be prepared to die for the truth. You get a sense of his perspective there. And I think my favorite example, and the one that's maybe most revealing, is that at one point, a friend was telling Warburg about 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. But that was, you know, reveals 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. I think that comment about the other person really

reveals that he was covering something up by focusing on science all the time and trying not to look inward. What do you think he was afraid to look at? Well, 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. And he was clearly extremely insecure. You know, whenever he was criticized, he would lash out and start these feuds with other scientists. So 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 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 there are various ways it comes out. He can't do public speaking. 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 have failed him. But he was so brilliant that they just finally decided to move him along. So there were a lot of psychological issues there.

Was he in the closet his entire life or did he eventually come out? 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 didn't fully come out and say, was in the closet. So I actually, you know, he didn't fully come out and say, I'm gay 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 partner, Jacob Heiss, would always come with him. Warburg would, you know, in some instances say, I'm not going to come unless my partner comes. So they would go to the opera together and travel to his vacation house together. So he didn't explicitly say,

I'm a homosexual, but I think he came pretty much as close as anybody of that era. And I really respect him for that. Had he met Hitler? There's no record of them meeting. I think there's a lot of indirect evidence that Hitler was directly involved in his case and his fate. I can go into that detail, or maybe we can build up to that, but there's no record of a direct interaction. Well, yeah, I guess before we get there, I want to come back to that because the intersection of them is so fascinating to me. But let's go back to post-World War I and pick it up where

Warburg moves into his sort of seminal work. So it's 1918, Einstein's convinced him to come back, potentially saving his life. His first choice, I suppose, is where is he going to set up shop, right? Is he going to stay in Berlin or is he going to leave? And he elects to stay. Yeah. He actually, 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 the pinnacle of German science. They create this Kaiser Wilhelm Society, which is now the Max Planck Society. It's supposed to be the Oxford of Germany. The idea is that they're going to get the best scientists in the world and give them everything they need. I 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 right before World War I. He's about to start this position. His lab was under construction. And when he returns, it's a very different world. All the wealthy funders of the Kaiser Wilhelm Society are now bankrupt. So he doesn't even have much money for his work at this point. There's this famous example.

He has to write a grant proposal for one of the only times in his life. And 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 marks, and he actually gets the money. When he comes back from the war, he focuses on photosynthesis rather than cancer first. And it's actually really interesting. I think that 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 going to find new ways to grow food, make photosynthesis more efficient and have more crop yields. And the Germans had been starving throughout much of the war and there were a huge few food shortages. So he came back and really, I think, wanted to solve world hunger.

And that remained an interest of his throughout his life. But he was always interested in cancer as well. 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 he wants to make a world-changing discovery.

And cancer really has become a German obsession by the 1920s. If you look back into the early 19th century, there's not much cancer. And 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 try to document in my book, that cancer did really increase and continue to increase well into the 20s and 30s. And by the 1920s, there's a panic. 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 worshipped Ehrlich and Koch and thought he was going to be the next one to make this great discovery. And so he takes on cancer and pretty quickly finds this remarkable thing, which is, as you well know, and probably a lot of your listeners know, most cancers eat differently than other cells. They ferment glucose rather than breaking it down and burning with oxygen, oxidative phosphorylation. So this cancer cell shift to fermentation is a remarkable discovery and ends up occupying his life, his thoughts, and he ends up focusing on

that for much of his life. 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. The background is that he had been studying actually sea urchin eggs in the first years of the 20th century when he's still a young scientist. And he had seen that these eggs, you know, this is a little complicated and that, you know, he didn't necessarily get all of this right. But what his early studies showed was that when the eggs were about to grow and proliferate, they would immediately begin to increase oxygen consumption. And it made perfect sense because you need energy to grow and using oxygen is the more efficient way to create energy for the cell. So when he turns to cancer in 1923, he expects to see the same thing.

The cell needs to grow. It needs more energy. It's going to use more oxygen and burn more nutrients with oxygen to grow. And so, you know, the experiments that he does is, you know, he takes a slice of a tumor from a rat and he attaches it to a manometer, which is a device, a very simple sort of U-shaped tube, which can just measure changing gas pressures. can just measure changing gas pressures. And he expects that these cells will start to take up more and more oxygen and he'll see the pressure change inside of his U-shaped tube. But he doesn't see it. He doesn't see the oxygen consumption increasing. Instead, he checks the solution that these cells are in and he finds it's full of lactic acid. Lactic acid is what's made from fermentation, you know, what human cells make from fermentation. Of course, yeast and other microorganisms will make alcohol and carbon dioxide. So he sees that they're clearly fermenting, and it's a strange

phenomenon that is happening, and he tries to do other experiments. They end up doing, you know, tests in vivo in people and seeing that they have more, with cancer, have more lactic acid in their blood. And every test he carries out comes to the same conclusion that cancer cells are taking up a lot of glucose and fermenting it to lactic acid and using less oxygen than he would expect. Go a little deeper for folks 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 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? He wasn't the first to see that a human cell can ferment. It was understood going back to previous decades that human cells could do this. You know, it was very surprising when it was discovered because it was thought only microorganisms did it. But, you know, Warburg was very close with another physiologist, Otto Meyerhoff, who made a lot of important discoveries and found that human cells could do much the same thing that microorganisms can do. 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 you move to fermentation if you didn't have enough oxygen or if there was, as Warburg thought, some damage

to the mitochondria where the oxygen is used to burn nutrients. So the really surprising part of it was not just that a cell was fermenting. You know, if you do, as you know, intense exercise and oxygen, you know, your lungs are eating and you don't have enough oxygen to sort of keep up with the needs, then fermentation will, glycolysis 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, you fermentation, what we call aerobic glycolysis. So that was the really surprising part.

Yeah, aerobic meaning in the presence of oxygen but still undergoing this inefficient pathway of glycolysis. 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 aerobic metabolism, which would be 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, and then it would enter the mitochondria where it would go through all of the steps of the electron transport chain. The 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 17 X 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 I said, hey, go for a jog and run your eight minute mile pace, that's great. 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 make somebody run for their life, 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 reduces the pH and that reduction in pH with that hydrogen ion makes it very difficult for the 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 think this was a really interesting discovery. And that's why I think the term aerobic fermentation is a paradox, right? Yeah. I mean, the aerobic glycolysis or aerobic fermentation from Warburg's perspective, it was a paradox. And as we'll maybe talk about more, Not everybody sees it that way, but many scientists continue to see it that way. I think that's the only explanation that if you're choosing to 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, then the only way to explain this paradox is that something is broken or why else would a cell do this? Well, and we'll certainly get to that because today I think we have other explanations, but going back to Warburg, how did he then explain the observation? So if science is a process of making an observation and then coming up with hypothesis, what was his hypothesis in light of that observation? coming up with a hypothesis, what was his hypothesis in light of that observation? His hypothesis was that the mitochondria, you know, he didn't have full understanding of mitochondria at this time, but he felt that there had to be some sort of defect in the mitochondria,

you know, the structure that was burning nutrients with oxygen because it made no sense otherwise. And the only way to really understand it is that Warburg idolized Pasteur and he had his library set up so that he was gazing at a portrait of Pasteur at all times. One side was Robert Koch and the other side, Paul Ehrlich, but Pasteur was in the center. It was Pasteur who had discovered 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. Pasteur himself had explained it by the fact that if cells were fermenting and not using oxygen, it must be because there's some

kind of problem because why wouldn't anybody, any cell use oxygen if it could? 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 studying frogs. And, you know, I mentioned Meyerhoff. So that's how everybody understood this relationship. So that was Warburg's lens. I think a seesaw is a good way to think about it. Respiration goes down, fermentation goes up. In my book, I talk about it as a backup generator, clicking on. And what's interesting about it to me is that both Pasteur and Warburg were sort of aristocratic personalities,

and I think they really thought of fermentation as lower and less noble than respiration. Warburg actually literally used those type of terms when talking about it. So for him, it was just almost shocking, almost unbelievable that a cell could use oxygen and they would do this lowly thing that microorganisms do. It's impossible. How did Warburg attempt to actually test the hypothesis? So if the observation is cancer cells are undergoing aerobic 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. He didn't really have a great way to test it, certainly not at the time in the 1920s. I mean, the test that he did was just to see the effect over and over, but he couldn't prove that it was a problem with defective mitochondria. Did he recognize that, by the way, as a limitation? I don't think he did. The most surprising part really is that in the early 20s, his first test actually showed that respiration was continuing. And then later in his career, he does additional experiments and insists that respiration is

not continuing. Or if it is, it can be explained in various ways that there's uncoupling, which causes the electrons to leak out, et cetera. But his early tests showed that fermentation was increasing while respiration continued to sort of hum along. And he just sort of denied that or came up with various explanations for it. But it was really in the post-war period where he starts to make more and more extreme statements. He finds these cancer cells in the abdominal fluid. I think they're called ascites. He sees that in his test of these cells, he sees very little respiration and just very high fermentation rates. So he becomes more and more convinced.

He called these pure cancer cells. He thought it was the best test of it. So he becomes more and more convinced. He called these pure cancer cells. He thought it was the best test of it. But he never really had any concrete evidence that there was some sort of structural defect in the mitochondria. He felt it was almost tautological that the job of respiration is to keep fermentation repressed. And if that relationship is not working, then it's necessarily broken. At one point when critics were charging him 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. Which really is ironic, right? Based on his observation, there is absolutely no way to

know if his observation is the cause or the effect of cancer. So I was struck by, I think in his case, you could almost use the cause or the effect of cancer. 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, as opposed to acknowledging that, hey, absent additional tools, laboratory tools, it's difficult to know for sure if this is cause or effect, which actually brings to the forefront of this discussion, this overlap between him and Hitler, right? Which is this view of cause and effect that Hitler even writes about, right? Oh, I think you're referring to Warburg's thinking about causation and cancer.

Yeah. Correct. Yeah. One of the interesting things that I found is that Warburg and Hitler, you know, Hitler was, you know, one of history's greatest monsters. I always hesitate to compare anybody to him, let alone Warburg, who's somebody I admire greatly despite his flaws. But I couldn't help, you know, because I was writing about both men, I couldn't help but see some parallels in their story. You know, first and foremost, they grew up in Germany or at the same time,

Warburg's born in 1883, Hitler in 1889. And at the time, the hero of the day is Robert Koch, the German scientist who discovers the causal relationship between microorganisms and infectious diseases. It starts with anthrax, then he has his great breakthrough with tuberculosis. So it's hard to, from our perspective today, it's hard to, I think, appreciate how much Germans revered Kuff. They were like parades and flags with his face on it because he was conquering disease. 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, 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 what conditions you have to have to show that a microorganism actually causes the disease. Which are, let's see if we can rattle these off, right? So one is the healthy individual can never contain the microorganism that is reported to be caught. Another one is the corollary is that anyone with the microorganism must have the disease. And then I think anytime you take a healthy person and insert 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. I think that's the third one. That's the gist of the logic. It's a very rigorous logic that again,

I think we all take for granted today, but at the time it was remarkable and it demonstrated the causal relationship between these various microorganisms and the diseases they caused. Yeah. And a key breakthrough, if I'm remembering correctly, is that they had already known that you could take blood or whatnot from one organism to another and transfer the disease. But Koff understood that he first had to get the microbe and grow it outside the body. So he wasn't transferring anything else. You know, he had to prove that it was the microbe itself by growing it independently and then taking some of those microbes and injecting them. In any case, if you listen to Hitler's speeches, you know, some of his speeches in the 40s

and read some of Warburg's papers, they actually, it's almost like they're quoting Robert Koff. You can hear the same phrases and talking about causality. They both refer to Koch directly. But you know, the most chilling thing I found, I think, is that Hitler on multiple occasions referred to himself as the Robert Koch of politics. And he said that Koch had saved the world through science by eliminating the microbes, the microorganisms that cause disease. And I've done the same thing with the Jew. So he saw his effort in some ways as a scientific project and killing Jews in his twisted mind was like eliminating microbes. Of course, it wasn't

just Warburg and Hitler, but I was just struck that they were both using this language of causality. And so how did Warburg describe that in terms of primary and secondary causality of cancer? How did he really start to sharpen his thinking on that? Warburg says that every disease has a prime cause and a secondary cause. And he uses the analogy of Robert Cuff that the prime cause of the disease is the microbe. And then there are all these secondary causes, the unsanitary the disease is the microbe. And then there are all these secondary causes, the unsanitary conditions that cause the microbe to get onto a person and make them sick,

various plagues and anything that causes a microbe to transfer and get into someone's blood is the 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 primary cause. So Warburg tries to extend this to cancer. He says, the most fundamental thing about cancer is the shift to fermentation. And so that is the primary cause. Although there was never proof of this, he insisted that it existed in 100% of all cancers. I think today people say 70% 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 as they have reduced access to oxygen, if they become advanced cancers. But at the most fundamental level, I don't think you can say 100%, but 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 a dangerous chemical and that injures the mitochondria and therefore you have fermentation. So that's the secondary cause is the chemical or 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 to be damaged and fermentation to increase in a seesaw-like relationship. What did Warburg believe accounted for the significant increase in the prevalence of cancer leading up into the 1920s and 1930s as a secondary cause by his definition? At the time, in the 20s and 30s, he doesn't say much about it, but I think it's clear looking back that he was from an early time, very worried about environmental carcinogens. But in the post-war period, he becomes very outspoken about environmental carcinogens. And I think his influence is much wider than many people realize.

And I think his influence is much wider than many people realize. In Germany, he starts campaigning against smog from automobiles and buses and food dyes used in the German food supply and all sorts of chemicals. He becomes basically an organic farmer, 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 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 ourselves, poisoning the mitochondria and causing the shift to fermentation. But what's really interesting, I think, is that if you read Rachel Carson, Silent Spring, which is a hugely influential book and really changed American environmental policy, Warburg

is actually the first cancer scientist mentioned in the book. And it's clear that that's exactly how she viewed cancer and saw these environmental chemicals as causing cancer via the damage to respiration that Warburg cited. So I think he ended up having a massive influence on American life. Just nobody knows about it. He was awarded the Nobel Prize in 1931. What was the seminal work for which he was awarded? Yeah, a lot of people think that he got the award for cancer, but that's not true. He was nominated in 1926 and should have won for his cancer research, but doesn't win it. And then in 1931, he gets it really for figuring out the final step. He

believes it's the only step at the time, but really the final step of a respiration, understanding how the electron passes down the electron transport chain and is able to react with oxygen. So he sort of elucidates this process and wins the Nobel Prize for that. What happens during World War II? As you point out, obviously he's Jewish, he's gay. I'm guessing that both of those things make him an enormous target for Nazis. Why does he stay in Germany? Yeah, it's one of the most fascinating parts of his story. 1933 comes along, and only two years earlier, 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 flee, his Jewish colleagues. They see what's coming. And Warburg refuses to see it. He's not going to give up his kingdom in Dahlem in southwestern Berlin. He says, I was here before Hitler. And like a lot of Germans, he believed that the Nazi phenomenon would be short-lived. His cousin, Max Warburg, had said, 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 couldn't fathom anybody telling him what to do, let alone, you know, he called them Bavarian noisemakers. These Nazi thugs were going to kick him out of his institute. No way. I mean, that was his perspective. And I think the most shocking thing about his story is 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 stays, but he provokes the Nazis. 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 he really was in a very dangerous situation.

In 1936, you know, the New York Times ran an article saying Warburg may be in jeopardy. You know, he was famous enough at the time that they were writing about him in the Times. And he was also tremendously stubborn. He said to his sister at one point that it's going to be either me or them. I'm not budging. And his sister's understanding of it was that the more pressure he got, the more he insisted on staying because he couldn't stand to think that he would lose that battle. And it's very hard to understand this. 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 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, that was the antithesis of everything Warburg stood for. To do anything that would cause him shame would be unimaginable. So there was really no way he was leaving. He did think about it, but I think he correctly understood that he would never be the same if he left. Did he journal? What type of sources were you able to, if any, get into his head during that period of time? It was honestly one of my most important finds. I didn't find it myself, but it already existed in German. But one of his sisters, Lotte, kept a diary and she was a writer and 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. 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 he was already world famous. But at the very end of the war, he actually did scribble out some notes. A few years ago, a historian, Karin Nicholson in Germany, actually discovered in the back of his notebooks, these notes, which were really fascinating. He was dealing, we haven't really talked about that part of the story, but he was dealing with some guilt that he faced by not protecting certain people who worked for him from being forced into the military. So he started to

scribble out these defenses. And 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 some ways I think he felt as well. How many people did he know that died in concentration camps? I think he felt as well. How many people did he know that died in concentration camps? Fewer than you would think, partially because most of the Jewish people that he associated with left. In the Kaiser Wilhelm Society, I think there were like 2,500 Jews at various institutions, and Warburg was the only one who stayed until the very end. So most of them left. And you know what? A lot of people don't realize that German Jews, in many cases, were more likely to survive the Holocaust than other European Jews. Some of his Warburg cousins actually were murdered in the camps. He wasn't particularly

close with them, but he didn't lose a lot of people who were close to him. But I don't have a good answer to that question, but it would be impossible for him to have not known a lot of people who died. But I don't know that they were the people who were closest to him, but I don't have a good answer to that question. But it would be impossible for him to have not known a lot of people who died, but I don't know that they were the people who were closest to him. He certainly knew hundreds or thousands of people who fled for their lives. In countries like Poland, there was clearly a moment in time when you could no longer leave. Was that true in Germany as well? Was there basically a time beyond which if you had not left, you were not going to leave? Certainly for Warburg there was because he was famous and the Nazis saw sort of propaganda value in having him there. For others, it really changed a lot after the war started. And that was,

you know, by that point, if you hadn't left, you know, you were in great danger if you were Jewish or homosexual or, you know, various other persecuted categories in Nazi Germany. But in the early 30s, you had an opportunity to leave Germany at least. But they also had to, it was extraordinarily difficult because you, they would take all your wealth. You basically had to give up everything and leave with nothing and find a new career. And this is in Germany. The other countries didn't have the advance warning, and the Jews of Eastern Europe were much less wealthy.

These are, in many cases, more people who lived in much less wealth than the German Jews and never really had a real opportunity to escape when the Germans rolled in. So it was very different for Eastern Europe, where the Holocaust really begins. 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 from Hitler or someone else saying, despite the fact that he's everything we despise, there's value in the work he'll do? So by the mid-30s, it's clear that he serves propaganda value for them. The Berlin Olympics in 1936. They're able to show that, you know, this guy has Jewish ancestors, is still here working in Germany. But by the late 30s, that propaganda value sort of drifts away and certainly is useless once the war starts. So he's in increasingly sort of great danger as things progress throughout the late 30s. as things progressed throughout the late 30s. Meyerhoff, a lot of people stayed until 1938.

Meyerhoff, who's also a Nobel Prize winner, escapes in 1938 and flees to France. And from that point on, that's when Germans roll into Austria and all the Austrian Jews who can escape, escape in 38. But the fascinating thing, really, it comes to a head in 1941, where by that point, the war is in full swing. And there's no value to keeping Warburg alive, really, for propaganda means at that point.

So Warburg is called to Nazi headquarters in 1941, June 21st. And he meets with Viktor Barak, who is one of the worst Nazis, the guy who designs the euthanasia killing program that sort of starts the mass killing. And it looks like it's going to be the end for him. He's already received an eviction notice from his institute. 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 how many people hated him and wanted to get rid of him. All the other institutes were full of Nazis. His was the only one that wasn't. So they finally succeed in getting rid of him. And he's called to Nazi headquarters. He sits down with Viktor Brach. And he's told that he's actually going to be allowed to live on one condition, that he focus on cancer research. It's extraordinary in itself, but the part that surprised me most, 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. At dawn the next morning, the German tanks rolled into Soviet territory. It was

the launch of Operation Barbarossa, which is at the time the biggest military invasion in history. It was the most significant moment in the Nazi project in a lot of ways. And that very day, they're sitting around, you know, worrying about Warburg. And it wasn't just Viktor Barak. You see it in Himmler's Daily Planner that he has a meeting about Warburg that day. And then later that night, Goebbels kept a diary and he records in his diary that later that night, just hours before Operation Barbarossa, he and Hitler are talking about cancer research. 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 that Hitler knew what was going on. And Warburg, there's more evidence of Hitler's direct involvement

because Warburg has applied for something that they called a German blood certificate. This just shows you what a twisted, horrific world it was at the time that for a Jew to survive in Nazi Germany at that point, 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. But Hitler would actually review these applications himself. And certainly for a Nobel Prize winner, Hitler would have reviewed this application. So, you know, you had to talk about all your ancestors and submit photos, you know, just sick stuff where, you know, 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 never actually formally Aryanized Warburg. But it's clear that Hitler would have been involved in that review. And that probably decided on that day, June 21st, 1941, to let him continue to focus on cancer. Was Hitler personally obsessed or touched by cancer, or was it simply just the epidemiology of the time?

Yeah, he was very personally touched by it. When he was a teenager, he lost his mother to breast cancer, and his mother was really, historians say, the only person he was capable of loving. And he had already just sort of failed to get into art school and was depressed. He comes back to his hometown in Austria and sees his mother dying of breast cancer and is just distraught. It's actually a Jewish doctor who's caring for his mother. And he left a little reflection on the experience.

He said in his entire life, he's never seen anybody look as dejected as Hitler. reflection on the experience. He said in his entire life, he's never seen anybody look as dejected as Hitler. And 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 as a metaphor, but was also a hypochondriac who constantly had stomach problems and thought it was stomach cancer. And, you know, it became a huge part of the Nazi project is trying to eliminate cancer. And, you know, one of the very uncomfortable things about this is that as monstrous as the Nazis were in every way, they actually did make some advances in cancer prevention, you know, for all the wrong reasons, but they inherited a great scientific establishment

and it makes sense that they would actually make some progress on cancer. It's very interesting to imagine a world without the Nazis, given the prominence of German science going into the Second World War and how much of a shift in power that was scientifically post-World War II, right? How effectively that was the change from Germany being the epicenter of science, not just biological sciences, but physics. And then that shifting. In fact, so many of the journals, right, shifted from being published in German to being published in English post-World War II. Yeah. I mean, in the early 20th century, you had to speak German to be a scientist or be able to read German. Yeah. It's incredible how the extent to which

all the early Nobel Prize winners were Germans, not all, but a shocking percentage. It's rumored, and I've never actually been able to confirm if this is true or not, because I've read various accounts, that Warburg could have won a second Nobel Prize during the Second World War. What was your finding on that? I think that he certainly deserved a Nobel Prize for his cancer work, which he didn't get in 1926. I don't think there's really proof of the, you know, Warburg said that he didn't get the Nobel Prize in the 40s because the Nazis wouldn't allow it. He certainly would have was considered for it. I found evidence that he was considered for it, but I didn't find any evidence that they were going to sort of give him the award, but couldn't because of the Nazi.

And what work was that in the 40s that they would have been potentially considering him for? Warburg, his Nobel prize, as we talked about before, was for understanding the last stage of respiration, this enzyme that we now call cytochrome oxidase. 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 finally accepted that no, respiration is actually a multi-stage process. And you actually need not just to react directly with oxygen, but to rip hydrogen off these nutrients and to pass the electrons down the transport chain. So he became interested in these hydrogen transfers

and understanding how the reaction took place. And a lot of people think this is the best science he ever did. He actually made huge advances in understanding the role of coenzymes and how they react with hydrogen and allow for these transfers. It was really innovative work, kind of set the stage for decades of enzyme research. So that led to the discovery of the components of NAD, among other things. So he did deserve a Nobel Prize for that, but I didn't find any evidence that they were going to give it to him. But I think he fairly deserved three Nobel Prizes. Say a little bit more about his work on NAD. That was actually new to me. I, 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. But it's actually kind of an interesting story, right, about how he made these discoveries. sort of, he would basically find the, you know, what they call the fingerprints of cells by using lights of different wavelengths and getting light patterns to identify enzymes. But by the 1930s, he's trying to actually, you know, isolate the enzymes and to do chemical analysis to find out what the reactive components are. So Warburg's trying to do a chemical analysis to figure out the reactive component of what we now call NAD. He called the in-between ferment. 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 to study it. And he says at one point, to figure this out, I'm going to need

to kill all the horses in Germany. And he was a great lover of horses. So that was not a good option for Warburg. But he knows he has enough of the stuff to figure out the molecular weight and a few basic facts about it. So he has a friend who works in the chemistry industry, in the chemical industry, and it's just a big part of German industry. And he asked him to look it up, see if he can find anything similar. And based on what he looks up, he finds an exact match, which is nicotonic acid. So Warburg is the one that figures out that, you know, this key component that makes this reaction possible is actually a chemical that everybody knew about that was being used in photography for decades. You know, Warburg said, you know, a day ago, I couldn't buy it for all the money in the world. And now I can get it for two marks.

And it actually turned out to be hugely important, not only for understanding respiration, but for understanding the disease pellagra, which was only sort of solved after Warburg made that discovery. And someone thought, 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's one of the ironies of Warburg's story that 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. 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 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. What was his reason for staying? For a few years after the war, I think he was prepared to go elsewhere. I mean, I found letters of him searching for places. And he comes to America in the late 40s. And he stays in one lab for six months and another lab for six months. But it's clear that there's no future for him 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 he had stayed. You know, the truth is he despised the Nazis as much as anyone. But 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 occupation of Berlin. So he gets to go back to his beautiful institute. And he has, again, some propaganda value for the Germans. We 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 if he had gotten the right offer, I think he would have gone to America, but he ended up sort of returning and reestablishing his old life in a lot of ways. In some ways, it's shocking and upsetting. But by 1955, from his perspective, it was like nothing

had happened. He's continuing with all the same stuff. Now, from his perspective, it was like nothing had happened. He's continuing with all the same stuff. Now, forgive my ignorance. Was it an easy choice for him to end up in West Berlin as opposed to East Berlin following the war? And what determined that? Was it simply a function of where he was prior to the war, and therefore it was somewhat fortuitous? Yeah, it is actually interesting and a little bit complicated. His institute ended up in the American sector. But another extraordinary thing about his story is in 1943, bombs are falling near his institute. And he's actually moved to a new institute.

And the Nazis built him. They sort of refurbished this beautiful sea house for Warburg in the middle of the worst part of the war for them. When 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. And that institute was actually ended up in Soviet territory. So he was sort of caught between these two different worlds. And he had a vacation house, which is in Soviet territory. So when the war ends, he is actually under Soviet rule, and he has to escape back to the West. But the Soviets were trying to recruit him, much more so than Americans, interestingly, you know, both a lot

of the great German scientists, you know, unfortunately, a lot of Nazis ended up being smuggled into America for the purposes of American science, but the Soviets were going after them as well. So he is sort of caught between these different worlds, but ends up, because his institute is in West Berlin, is able to stay in the American side ultimately. So interesting to me, because you have to wonder if people in Berlin at that time understood how stark that contrast would be. You could argue that, well, gosh, it's wonderful that the war is over and the Nazis are gone. And you might end up on this American side or what the time was American occupied, or you might end up on this, what will be a Soviet side. But it probably couldn't have been clear just how different those two would end up being over the coming four or

five decades. I don't think it was clear, but it was clear that the Soviets, with good reason, were much more feared. So in the last days of the war, 1945, you had 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 murdered and raped, because the Soviets were, with good reason, furious at the Germans and out for revenge. 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 the following decades. Warburg has a really interesting tit for tat with Sidney Winehouse

in science about a decade later. I actually was able to pull up the article and read it. They both wrote letters. And Winehouse was really kind of a mild-mannered guy, wasn't he? Yeah. Most of the people Warburg had these vicious scientific feuds with, I would look them up and they seemed much more reasonable and calm than Warburg himself. Winehouse, I'm in the Philadelphia suburbs. He actually worked at a hospital just a mile away. Yeah. He died in what, the early 90s, I think. And he was at Penn, wasn't he? Or no, he was at Jefferson, if I recall. He may have been, I think he was at Lankanaugh Hospital, but maybe at Jefferson as well. I'm

not sure, but he was around here. I actually found some people that knew him and talked to them a little bit. But he publicly called Warburg out. He basically said, don't agree with this observation. I mean, agree with the observation, don't agree with the interpretation, is what he said. Yeah. I think if you look at the quotes from him, he was relatively calm about it. But as a journalist, I have to laugh. I'm sure it was the headline writer. The headline under one of the articles was cancer theory overthrown. I don't think that Winehouse would have put it that way, but some editor like me just wanted to make it a little more sensational. Well, and he was deferential to Warburg in the article. I mean, he did say something to the

effect of, I don't remember exactly, but the gist of it was, and we owe a great debt to Warburg for his amazing contributions to the field, et cetera, et cetera. But cellular respiration is basically, he said, look, there's no difference in oxygen consumption between these cells and there's no evidence that the mitochondria are damaged. Warburg's rebuttal was far less kind. You might be thinking of the papers in science in 1956. Yes, exactly. Yep. I believe it's August 1956 where where first, you know, Warburg writes a piece in early 56, and then Winehouse responds, and Warburg responds to his response.

And, you know, Warburg comes off, I mean, it's a really elegant paper that he writes. He's a great writer. And we should have talked about Warburg's writing at the beginning, because, you know, I really admire his writing. But, writing. But he makes much bolder statements and denounces his opponents in a way that Winehouse doesn't. Winehouse is a more humble scientist. I encourage all listeners to look up Warburg's paper from 56. It's pretty remarkable. We'll link to it in the show notes for sure. I love reading that stuff. I mean, I just absolutely fancy reading that stuff, which actually an example of one of my favorite scientific papers to read is the next logical place to go in this

story, which is the paper by Watson and Crick describing the helical structure of DNA. So that's relevant to the story for reasons you will tell us, but it's also a funny paper in that I think it's the last line either in the abstract of the paper makes some very, very, very understated remark that this thing, what they're referring to as DNA, may prove to be of interest at some point or something to that effect. I used to be able to quote it verbatim. But what is it about the discovery of DNA that would ultimately change the course of Warburg's discovery and this entire field of cancer metabolism for decades to come? By the 50s and 60s, Warburg is already fading away for some of the reasons we've talked about.

Winehouse challenges his belief that 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 science and more than anything, the discovery of oncogenes beginning really 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 old world biochemistry stuff. And if you want, if you want to really understand cancer,

you got to look at the DNA and these signal transduction pathways and all the new molecular biology. And, you know, there's literally stories of like, you know, people seeing manometers 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 nobody's interested by the 90s. Students don't know his name. And then- And by the way, he died in what, 1970? But there's all these remarkable examples in the year 2000.

Robert Weinberg, co-authors, the Hallmarks of Cancer paper, which I'm sure you know better than I do, the six fundamental traits of cancer, and doesn't include the Warburg effect or mention Warburg or metabolism. They later do a revised edition and do mention it 10 years later, I believe. So Warburg is just gone from cancer science, gone from textbooks. Weinberg's famous textbook in 2006 doesn't mention him. Mukherjee, who I think his book is absolutely brilliant, but also doesn't mention him. Mukherjee, who I think his book is absolutely brilliant, but also doesn't mention Warburg just because nobody was mentioning it. It's just not something that people were interested in. They talked, the enzymes that Warburg

say were referred to as housekeeping enzymes, seems cancer needs to divide and therefore it needs energy, it needs nutrients, but it's sort of not fundamental to the process, just something that's needed to supply cancer as it progresses. but it's sort of not fundamental to the process, just something that's needed to supply cancer as it progresses. And it's really shocking to me that something so fundamental could just get lost. But to some extent, that's how science works. There's an exciting new thing and it's hard to focus on two things at once. And look, I mean, I think it is a very remarkable discovery in the 1970s that there are oncogenes. And Harold Varmus and Michael Bishop were awarded the Nobel Prize in 1989 for that discovery. It holds a lot of great promise.

Certainly by the time I got to medical school in the late 90s, 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's the only thing that mattered in cancer biology. So what do you think led to the Renaissance? I mean, for me personally, the first thing that came on the radar screen was a science paper in 2009 written by Matthew Vander Heiden and co-authored by Lou Cantley and Craig Thompson. Was that sort of the first 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. So clearly this idea that metabolism mattered was on the

radar of others, even though it was not necessarily on the forefront of the field. Yeah. I think that paper was, you know, the moment is 2009 or 2010 that it sort of reached the mainstream. But, you know, as you mentioned, they had been working on this stuff for some time. So it was really in the late 90s that the revival starts, mid to late 90s. in the late 90s that the revival starts, mid to late 90s. And the two key labs, I think, at the early stages, one is Craig Thompson, who you mentioned, who is now the president and CEO of Memorial Sloan Kettering. And the other lab was Chi Van Dang, who was at the time at Johns Hopkins.

And they both were working on understanding cancer molecular biology and both tracing these signaling pathways to the cell and sort of working their way back to metabolic enzymes. In Chi's case, he found that the transcription factor, MYC, was actually activating lactose dehydrogen, LDH. And he was really quite shocked to find this pathway leading back to this basic fermentation reaction. So he became very curious about Warburg and reading the old papers on enzymes and really helped launch a lot of the metabolism revival. And then Craig Thompson and Vander Heiden was a student in his lab. They had also sort of independently rediscovered

metabolism and ended up focusing on AKT, which was already known as 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 allow glucose into the cell and that Thompson, I think correctly states that this is the most fundamental thing that it does and that the proliferation is downstream of this glucose uptake. Yeah. It's a very pro-growth factor. So 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. And what was that explanation?

So prior to this point, the accepted view or that Warburg's view, which again, some people still support is that all fermentation is a response to defective mitochondria. It's compensatory. The cell can't create energy in one way, so it's using the backup generators. It's revving up fermentation. But what Thompson and Van der Heiden and Cantley argue in that paper is that we actually don't have, as we talked about with Winehouse, we don't actually have the evidence that respiration is completely defective. So the mitochondria still seem to be functional and intact. And 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 new nucleotides and lipids for the daughter cells. So it makes sense that 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 have enough to continue to function. What they really need are the building blocks for growth. And so that is a sort of new way to understand the Warburg effect. And I think that, you know, that's now what most scientists, but not all, sort of view is the main explanation. What's your view? It's tough as a science writer, as a reporter. You know, I'm not trained as a scientist, and I interview one person, you know, famously, Thomas Seyfried, who is very much a Warburgian, who thinks that Warburg got it exactly right,

and that it is a problem of defective mitochondria. And he cites the research of, I believe, Peterson at Johns Hopkins, who also believes this. So there are a lot of very smart, accomplished scientists who think Warburg got it exactly right. And it would have been easier for me to writing this book to conclude that Warburg was right about everything. That's a story that would have been easier to tell and made my narrative tighter. But I interviewed many more people who felt that Warburg was wrong about this, that it was not ultimately a problem of defective mitochondria. And, you know, I look at papers from both sides and don't ultimately feel that, you know, I have a good so with Cantlie and Thompson and Vanderhyde and others like Nav Shandell, who also takes this position. And 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 brilliant.

And it's partially also sort of an intuitive feel for the science. And it's partially also sort of an intuitive feel for the science. I say that because one of the things that really struck me is when Craig Thompson was giving a demonstration for students about 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 in understanding prolific 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, prolific 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. They take up the grain and they grow and they grow and they multiply. 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 is what causes this prolific program to take off.

And I think it's in single-celled organisms, it's the nutrients. And, 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 fundamental program is running and it's the nutrients and the growth factors. the fundamental program is running and it's the nutrients and the growth factors. I mean, I think if you just step back from it and you say, what is cancer? It's a problem of growth. Okay, well, what causes things to grow? Nutrients and hormones, that's where you start the conversation. And I think that if science had progressed in a different way, then that always would have been the focus. But it was only in the late 1960s where we could even measure insulin in the blood. So cancer, all this stuff about the Warburg effect as a response to damaged respiration made sense before

we knew anything about insulin and growth factors. But, you know, the science has progressed and I tend to view it in much more of the way 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, I think everybody agrees that as a cancer progresses, you know, the blood vessels no longer are getting oxygen in the same way. And that's clearly playing a role in terms of revving up fermentation. So it's not necessarily either or, but at the sort of core origin of cancer, I don't see that the respiration damage is being sort of conclusive. And I don't either. I mean, I just think on first principles, it doesn't actually make sense. If you follow the logic of Warburg, 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 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 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 metaplastic and ultimately dysplastic and ultimately becoming metastatic. I think that the hormones and the nutrients are simply the fuel that allow the thing to happen, but they're not the spark. And to me, the spark is what matters. And that's why I don't agree that Warburg was correct. I don't agree that the initial insult is the mitochondrial insult. I think that the event that is driving

this, I think the oncogenic effect is the driver. And I think the metabolism allows the cancer to be even more adaptable to the scenarios that you described. 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. But in the end, it somewhat matters because 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 is 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. And then in the presence of it, what can you do? How did this work impact your thinking on that question? In my mind, that's really the key to my whole story is there's sort of two components to it. One is what's going on inside the cancer cell. And that's all this discussion we've had about the Warburg effect. But there's another part to the story, which is 150 years, 200 years of cancer epidemiology and seeing various environmental causes of cancer or various theories about what causes cancer. And what really struck me, and I don't think, you know,

as a journalist, I can't understand the science sometimes in the same way that probably you can and a lot of the people I interview can, but what I try to do 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 really struck me was that in the late 90s, at the very same time that Thompson's lab and Chi Van Dang's lab are returning to Warburg metabolism, we have these new epidemiology papers coming out showing both that insulin is correlated, you know, elevated insulin, hyperinsulinemia is correlated with cancer and obesity is correlated with cancer. So it happens at the same moment. And that in a lot

of ways, that was my project 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. And I think those two stories are related. And that's why, you know, the last part of my book is really a focus on hyperinsulinemia, because I think it's the piece that puts it all together. It could explain the obesity, it could explain the cancer, and it could explain why cancer was once a rare disease, and then in step with diabetes and obesity and other quote unquote diseases of civilization became much more common. So in my book, insulin is sort of the explanation which ties it all together, which obviously not all cancers are caused by insulin. And insulin's role, according to some scientists, is only indirect.

It causes the obesity and the obesity causes other hormonal changes and inflammation. But one way or another, I think it's a big part of the cancer story and the part that if we're going to really make progress on prevention, we have to focus, I think, on hyperinsulinemia. To me, this is now exactly 50 years since the war on cancer began, and we've made so little progress in many ways, certainly with respect to prevention. There's been remarkable cures and therapies and I revere the scientists who make this work, but certainly in terms of prevention, we're just not making progress. And I think it probably comes back to the hyperinsulinemia. Again, I do kind of like the way Warburg positioned a prime cause and secondary causes. So when you think of the ravenous diarrhea that was ripping through London in the 1800s, the prime cause was cholera,

but the secondary cause was the lack of sanitation. It was that which permitted the cholera to travel so freely from sewage to drinking water. 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, at least in the developed world. foremost is smoking. And second, as you point out, is obesity, 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? Yeah. I mean, it does come down to semantics at some level. You could argue that the prime cause is the mutation in the DNA that's driving the cancer. 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 and the very first step in the process. So I think you can say cigarette smoking is the prime cause. But by Warburg's definition, he would say that if you accept that paradigm, then you would say the mutation is the prime cause,

the chromosomal damage, whatever it is. Another way to think about this is that the accepted paradigm is that all the problems, one way or another, go through the DNA and that the safe read paradigm is that all the problems go through the DNA and that the safe read and paradigm is that all the problems go through the mitochondria. So those are the two sort of causal centers. But I think logically, prime cause should be the very first thing. So smoking in the case of cancer makes sense to me. Yeah. No, I agree with you. I think that makes sense. So now the question is, how do we apply that thinking to the second one? Well, if you pause it first that indeed obesity plays a causal role in cancer, there's no dispute that the correlation is quite strong. I mean, 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. 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. With obesity, it's a little harder because the hazard ratio isn't nearly as large as it is with tobacco. And obesity 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. The list goes on and on and on of other things 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, of which insulin is one? Is it other changes that are prominent with obesity, such as inflammation? How do you then arrive at, for example, insulin being 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 going to then have to go, which is, is it the enabler or is it the primary cause? Sure. My argument is that ultimately, as you said, these are very complicated.

There's many different factors that play out, 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. So I think part of the evidence for that is that there are people who are quote unquote metabolically healthy, obese, that they store more nutrients in their subcutaneous fat and more energy in their subcutaneous fat and not the visceral fat. And they tend to be 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 and people who are thinner, but clearly, I think it's most people actually do have insulin resistance. And when you see that metabolic disruption in people who aren't obese, that also tends to

correlate with cancer. So I think you can, to some extent, dissociate the obesity, but then you still have to, the insulin-cancer correlation isn't as strong 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 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 a mutation that occurs for some other reason and allows the cancer cell to take advantage of that hyperinsulinemia? So. Yeah. Is the model basically that if you take a two by two matrix where you have chromosomal insult, yes or no, hyperinsulinemia, yes, no. So which one gets cancer? Is it only the double positive? I mean, we would agree that the double

negative almost assuredly does not. And we would probably agree that the double positive does. The question is what's happening on the other corners? 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 take clinically, which is 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. 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, at least for me, I don't have a great understanding of those because I think

they exist in both. I think there are examples and counterexamples for both. I don't think anybody has a great answer for it at this point, but I do find, you know, this is speculative, but one hypothesis is sort of that these chromosomal insults occur by chance or for whatever reason. And, you know, eventually you get one in this PI3K pathway and the cell is now able to take advantage of that hyperinsulinemia. But another speculative idea is that if you have hyperinsulinemia and excessive glucose metabolism, that it's actually going to be driving the chromosomal insult through creation of reactive oxygen species in the mitochondria, and that the hypermetabolism, as Craig Thompson puts it,

actually creates a way for the cell to mutagenize. So I think that's probably part of the story. And there's new research coming about how nutrients actually play a huge role in epigenetics as well. So it may be that 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 they say. Maybe the immune system can kill these microscopic tumors, if not for the insulin, keeping the insulin really tells a cell to stay alive. And so I don't think we have great answers to these questions. But I think that if you just step back and look at the epidemiology,

something has to be going on with nutrition, because the cancer was so much more rare prior to the shift to the Western diet. And it could be many different things, but it all points to hyper insulinemia. And, you know, it's a growth factor, you know, and cancer cells are covered in insulin receptors. It just makes a lot of sense that this is really fundamental in one way or another. The counterpoint is maybe that you just have bad luck and get an AKT mutation, then the cell, you know, no longer needs insulin and can just get all the glucose at once. And that, you know, maybe is true in some cancers, but 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 it makes a cell more susceptible. You know, what about non-insulin requiring nutrients such as fructose? Rick Johnson and Lou Cantley have both spoken about this. What, if anything, did you uncover about the potential role of fructose in cancer? That was one of the more surprising parts of the story for me and humbling in a way as well. A reminder to me, I was writing about Warburg who always believed too strongly in his own ideas and couldn't accept that they may be wrong. And it's anytime you're writing a book that has any kind of argument in it, you sort of fall into that trap and have to remember that science

changes and not everything's proven. So I had decided early in my writing process that I thought sugar, sucrose, was a big part of this story. But my assumption was that it was all by way of driving liver fat and insulin resistance and hyperinsulinemia. In recent years, this work out of Cantley's lab and Richard Johnson's has shown that even independent of the effects on insulin, that fructose seems to drive certain cancers that, particularly in the colon, that are able to get the fructose and actually turns on, you know, through sort of an odd metabolism, actually turns on the Warburg effect and allows sort of ATP to go down and then glucose to flow

in. But the surprising part for me was that it could be disassociated with insulin. And I had to step back and say that maybe sugar is even worse than we thought and is sort of causing cancer in two different ways in some cases? Yeah, that to me is the most interesting question. Still somewhat unresolved, frankly, although I think Rick Johnson's work is among the most compelling I've seen to disentangle that relationship of fructose independent of its caloric contribution. And as you said, this is a mechanism that has an indirect effect on insulin. So fructose metabolism, when consumed in excess, does in fact lead to insulin resistance, which by its very definition leads to hyperinsulinemia. But the work you allude to in colonic cancer by Lou Cantley

actually posits that it's the energetic issue in the cell that you've alluded to of the trans and johnson as well it's this lowering of atp in the process of metabolizing fructose and it's that adp atp sort of switch that can drive the hyper influx of glucose and that's not necessarily an insulin driven phenomenon yeah now that um you know it is kind of odd for me. In a way, it supported my hypothesis that sugar is at the center of the story, but it sort of upended my idea of what the mechanism was. So, yeah, there's still clearly a lot to learn. But I found Rick Johnson's whole discussion of this absolutely fascinating. I listened to the podcast, and when he was talking to you, part of it, all the stuff we were talking about, the talking to you, part of it, you know, all this stuff we were talking

about the turn to fermentation, 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 the seesaw like relationship does exist. But his example, which really fascinated me was that these naked mole rats, I don't know if you remember this, but they live in this low oxygen environment. And they run a lot of Warburg metabolism by converting glucose to fructose and then using the fructose to drive the Warburg effect. It was really fascinating to me. What did you learn in this project that you absolutely positively could have never predicted? I mean, 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 challenged what you thought you knew about yourself or this body of work? Yeah, it's a good question. I think one of the things that really struck me, 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 maybe realize it, is, you know, I grew up Jewish and they were, but I never humanized them. And now I had to sort of look at the personal stories of all these Nazis and not think of them as in an abstract, 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 go into the office and, you know, work on documents that lead to, you know, millions of people ultimately getting murdered. You know, just getting into the lives of these people and seeing that progression really was chilling and eye-opening in a way to make me think that this wasn't an anomaly, that this, in theory, it has happened elsewhere in various forms and could happen elsewhere. So it made me much more politically attuned to certain extremist politics. So that was part of it on a political level. And on a personal level, in terms of the writing, it was such a daunting

project for me. How many terms of the writing, it was such a daunting project for me. How many words is the book, Sam? I actually don't even know. I think it's about 120,000 some words. But I didn't have the training in biochemistry. I didn't speak German fluently. And I didn't plan to write the book. The publisher came to me and said, I saw your New York Times article. Do you want to do this? And I hesitated and say yes right away because such a big project. But I think that

over the years, I sort of learned a lot about myself as a writer and sort of was able to gradually trust myself more as a historian. And I feel more confident as a writer having completed this project. We'll see if I still feel that way after somebody trashes the book. But for me, I felt like I was taking a big risk and that I made it to the end of that project. It's very rewarding. It makes me feel confident about taking on other stuff. 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? I go out of my way to avoid reviews. What's fascinating to me is that even positive reviews, which I'm very grateful for, but they also make me uncomfortable. Just the thought of anybody sort of passing judgment

on something that you work on so hard for so many years. It's just too much to get a reaction to it in some ways. 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 I think there's going to be a New York Times review out soon. I'm not even sure I can read it. I have the same thing with my students. I teach and students provide assessments of my teaching at the end of each semester. And I read them because I need to know how to become a better professor, but it makes me deeply uncomfortable. I don't write book reviews anymore because it's just, when somebody works on something so hard for so many years, it's terrible to have to pass

judgment on it. I'm kind of a softie, I guess. But how do you learn then? I mean, I can be totally sympathetic to that, but is there a model where you let somebody else read the reviews and pass on just the objective, this is working, this is not working feedback? I'm asking honestly for personal reasons as I sort of think about how to digest feedback in a forum that is actually very harsh. No, I think it's certainly true that if you don't read your reviews, you're not going to learn as much, but in a way it's too late at that point. You know, what I do is before, before I finished the project, I sent me out first and foremost, my editor who is wonderful, liverite, Dan Gerstle to do a shout out. But you know, I also have a handful of trusted friends who I send the manuscript to and get their feedback on. And certainly, that doesn't make me uncomfortable because it's a different dynamic. It's not in public, it's in private. And they're people that I trust. And I don't feel publicly shamed if they tell me it's awful. And I can't get better unless I get their feedback. And I got tremendously valuable feedback from those early readers. So every writer I know does some form of that and I think everybody should.

So Sam, tell folks again, the name of the book. The book is Ravenous, Otto Warburg, the Nazis and the search for the cancer diet connection. All right. Well, Sam, thank you very much for taking the time, so much time to sit down with me today and talk about this and share these insights with all the folks that are, everybody's interested in cancer. So I think there was a lot here, both in the history of it and also the implication, which is potentially that metabolism plays a very important role in cancer. It might not be entirely clear if it's the trigger, if it's the spark, if it's the oxygen, if it's the fuel, but it's in that mix. So the more we can do to reduce hyperinsulinemia, improve our metabolism, reduce reactive oxygen

species, all these things that you've spoken about, presumably the better odds we have against the disease to which we've made very little progress as you point out in the last few years. So thank you, Sam. Yeah. Thank you so much. It was an honor to be on the show. 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 kick-ass 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.

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