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

00:00:00.000 Hey, everyone. Welcome to The Drive Podcast. I'm your host, Peter Atiyah. This podcast,

00:00:15.480 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:28.880 If you enjoy this podcast, we've created a membership program that brings you far more

00:00:33.280 in-depth content if you want to take your knowledge of this space to the next level.

00:00:37.260 At the end of this episode, I'll explain what those benefits are, or if you want to learn more now,

00:00:41.960 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay, here's

00:00:48.080 today's episode. My guest this week is Sam Apple. Sam is a freelance writer and author of several

00:00:55.340 books, including one recently published called Ravenous, about Otto Warburg, the Nazis, and the

00:01:00.360 cancer metabolism diet connection, which we discuss in great detail during this show. Sam teaches in

00:01:05.640 both the MA in science writing and MA in writing programs at Johns Hopkins. Prior to coming to

00:01:10.800 Johns Hopkins, Sam taught creative writing and journalism at the University of Pennsylvania for

00:01:15.400 10 years. He holds a BA in English and creative writing from the University of Michigan and a master

00:01:20.140 in fine arts in creative nonfiction from Columbia University. In this episode, we go into great

00:01:25.740 detail about the life story of Otto Warburg. We talk about his early upbringing in Germany,

00:01:31.440 how he was influenced by some of the most influential, if not the most influential scientists

00:01:35.620 in Germany. We talk about his seminal work prior to the Second World War and this odd manner in which

00:01:43.000 he was able to remain in Germany unharmed during the Second World War, despite being both Jewish and gay.

00:01:49.260 The interesting part of the story, of course, is that much of his work would be largely forgotten

00:01:54.800 by the time he died in 1970, and it would only be about 30 years later that some of his observations

00:02:00.660 would come back to be relevant within the field of cancer biology. Of course, it's still not entirely

00:02:06.580 clear if his hypothesis around that observation is correct. I personally do not think it was,

00:02:12.400 but nevertheless, this makes for an interesting discussion. So without further delay,

00:02:16.460 please enjoy my conversation with Sam Apple.

00:02:19.260 Hey Sam, how are you doing today?

00:02:26.220 I'm doing good. How are you?

00:02:28.020 Good, good. Congratulations on the publication of your book very recently. Having never done that

00:02:34.540 before, I can still only imagine it's akin to giving birth or something like that. Feels like the

00:02:39.840 weight of the world off your shoulders after how much research you've put into that.

00:02:43.500 Yeah, it's a huge relief just to be done. So I'm trying to think about a future project,

00:02:50.880 but I feel like I need a few years just to relax now.

00:02:54.680 Oh, yeah, yeah. I imagine there's nothing more annoying than when you publish a book when somebody

00:02:58.880 says, so what's your next book going to be about? It's like, let me bask in this one for a while.

00:03:03.160 Wow. Like many books that go really deep into a topic, be it science or otherwise, they often start

00:03:10.620 out as articles. And of course, you wrote a piece, was it 2015?

00:03:16.660 It came out in 2016.

00:03:19.400 And it was the New York Times Magazine piece, correct?

00:03:21.560 Right.

00:03:21.860 And I remember that quite well. You and I had spoken quite a bit before then. And I know that

00:03:26.400 that sort of ultimately led to the work that went into this book. But more broadly speaking,

00:03:32.640 what attracted you to this topic of Warburg, cancer, metabolism, the era of Nazi Germany and

00:03:40.160 science in that era? What gravitated you to that?

00:03:43.440 Like so many people in this world, I was influenced by Taubes at a fairly early stage of my interest

00:03:50.180 in metabolism. I read some of his work and that had led me to other authors and eventually to a lot

00:03:56.460 of your work and your blog. So I had been interested in metabolism for a number of years,

00:04:01.420 but I had not really thought of cancer as a metabolic disease or thought about cancer as being

00:04:07.960 lumped with obesity and diabetes and heart disease. And when I started to read more about that and see

00:04:12.720 that they clustered together and that you see the same pattern that begins in the 19th century of

00:04:17.500 all these metabolic conditions growing more common. That's what really sort of sparked my curiosities.

00:04:23.320 You know, cancer isn't supposed to be metabolic like these other diseases. You know, it's bad luck.

00:04:28.360 It's mutations that are caused by environmental carcinogens or whatnot. So it just stayed in my mind.

00:04:34.180 But I hadn't planned to write about it until I came across a mention of Warburg. I think it was just

00:04:39.160 one sentence, you know, 1923. A German scientist makes an important discovery about the metabolism of

00:04:44.500 cancer cells. So I Google Otto Warburg and I start to read about him and, you know, it was kind of a

00:04:49.840 light bulb moment for me. Like, oh my gosh, I have to write about this man. You know, because I'm a

00:04:54.820 journalist, a storyteller by profession. And so I don't write about science usually unless I feel like

00:05:00.240 I know how to tell a story. If I have a central character, then I know how to tell a story. So once I

00:05:05.640 had Warburg, I knew I was going to write about it and I knew I had a way to tell the story.

00:05:10.380 Before we get to that story, I want to kind of understand a little bit about

00:05:13.740 your work as a writer. You're a prolific writer. You actually teach a course in science writing at

00:05:19.180 Johns Hopkins now, don't you? Yes, I do.

00:05:21.660 So when did you realize you were a writer? Well, my father's a writer, so it helped to have that,

00:05:28.140 you know, for many people grow up, it seems like a, you know, an unusual career choice. But for me,

00:05:33.720 it was, you know, obviously potential option just having seen my father do it. But the truth is,

00:05:38.960 I didn't try to, at least non-consciously, to follow in his footsteps. If anything,

00:05:43.580 I thought that, you know, I might need to distinguish myself by choosing a different path.

00:05:48.200 And, you know, I like my father mostly writes fiction. I like to half joke that my big rebellion

00:05:52.580 was moving into nonfiction. But it really was in college when, you know, I wasn't sure what I was

00:05:58.040 going to do. And I was getting a lot of praise for my writing. And, you know, the praise felt good.

00:06:03.420 And I, you know, I wasn't killing it necessarily in other areas. So, you know, I saw that it was my

00:06:08.440 strength. I enjoyed doing it. And I sort of just continued with it because I was succeeding with

00:06:14.760 it. So do you think a good writer is born or made or how much of your success do you attribute to

00:06:20.780 some inborn gift versus something you'd been cultivating and nurturing and practicing?

00:06:28.420 Tough question. I think about it a lot because I, you know, I teach science writing and general

00:06:34.120 creative writing at Johns Hopkins now. And I certainly think that everybody can improve

00:06:39.400 a lot as a writer. And I think literally every day about how to get better at teaching it and

00:06:46.160 helping people improve. But at some level, it's innate. Some people have more natural ability than

00:06:52.900 others with language. But I think it's pretty analogous to musical talent, where some people

00:06:59.300 can very quickly get very good at an instrument, sit down on the piano in a matter of weeks, be good.

00:07:03.900 And others will struggle for months and have to practice again and again, but they eventually get

00:07:09.240 there. So I don't think it's correlated that strongly with intelligence. It's a sort of just an

00:07:15.860 ability to, you know, use language in a certain way that comes naturally to some people and comes to

00:07:20.840 other people with more practice. But I think everybody can get pretty good with enough practice.

00:07:27.100 So when you're teaching a class, let's just say there's a hundred students in the class,

00:07:31.860 what type of an assignment would you give if you wanted to very quickly figure out the breadth of

00:07:37.180 natural ability or the spectrum of natural ability across the students? How would you ferret that out

00:07:42.140 quickly?

00:07:42.980 Truth is that you can see it in almost any writing sample. I'm on the faculty of Johns Hopkins. I'm also

00:07:49.060 involved in the application and reviewing applications and selecting students for the

00:07:54.660 science reading program. And, you know, they submit samples of their writing, but I often look most

00:08:00.100 closely just at the covered letters because I feel like, you know, within a paragraph or two, I get the

00:08:05.540 feel, you know, if they have a feel for the language or not. So it really comes across, I think, almost in

00:08:11.420 any three or four sentences, I can start to feel, are there extra words in these sentences? Is the logic

00:08:17.000 tight? Does it flow? It really doesn't take very much to, to figure it out.

00:08:22.440 That's amazing. And it makes me feel so self-conscious because of how often I write,

00:08:27.540 you know, every Sunday I'm putting out a newsletter and I enjoy writing a lot, but it doesn't, I don't

00:08:33.160 feel like it comes naturally to me. So I can imagine how many people must read that and go, oh my God,

00:08:38.200 like, yeah, what he's saying is interesting, but he's such a horrible writer. And of course I know what

00:08:42.640 it's like to read very good writing. You know, you can sort of spot the extremes or at least I can

00:08:47.880 spot the extremes. I don't think I could rank a hundred people from one to a hundred, even though

00:08:52.680 obviously there's somewhat, you know, there's a lot of subjective stuff in there, but I could

00:08:56.480 certainly say this is exceptional. Like I can read Sid Mukherjee and say, wow, this is really, really

00:09:04.120 good. And similarly, I can read something that is absolutely horrible and say, this is really,

00:09:09.740 really bad. I might not be able to tell you why though. So how much of it is also being able to,

00:09:15.380 in that cover letter, say you gave a couple of examples, right? Like this person is using a lot

00:09:20.880 of unnecessary words or they're presumably repeating themselves, or this is illogical.

00:09:26.820 That's a lot to pick up in just a paragraph. I think it comes down to clarity more than anything.

00:09:32.200 You can read something and grasp it right away because the language is concise and clear and you can

00:09:37.900 read other things where it's just a very simple statement, but you actually have to read it two

00:09:41.800 or three times just to grasp the writer's meaning. And so George Orwell famously wrote about politics

00:09:48.140 and English language and how much good writing depends on clear, concise thinking. And I think

00:09:54.640 that's true, but such a big part of it, everything that I write comes out pretty poorly in the first

00:10:01.900 draft. Even my emails that if I really care about an email, I spend a lot of time just going over and

00:10:06.900 over and over because it's the repetition. It's correction after correction after correction

00:10:11.520 where the writing starts to improve. So I think the difference between a good writer and a less

00:10:16.500 good writer is often how many times the good writer goes over the work, whereas the lesser writer will

00:10:22.000 just say, yeah, it doesn't matter that much and send it off. But there's a price to pay. I waste half

00:10:26.460 my life worrying about sentences and an email. So it comes at a cost. For the record, I was a big fan of

00:10:33.140 your blog when you were posting more regularly. So I think you're being too hard on yourself.

00:10:37.560 Thanks. Did you go to journalism school or did you do something after undergrad to further hone

00:10:42.040 your writing skills? I graduated and then I took a few years off to work at a magazine. And then I

00:10:48.260 spent two years doing a MFA program at Columbia. It's creative nonfiction program. So it's not

00:10:55.240 journalism. I thought about going to the journalism school, but I chose creative nonfiction because I was

00:11:00.220 interested in more in long form and more in storytelling as opposed to rigorous reporting

00:11:07.220 that do that as well. But I was really more interested in book writing and sort of long

00:11:12.500 form nonfiction. And how do they teach at that level? I mean, obviously people who show up to do

00:11:18.480 a two-year MFA at Columbia, which is arguably the best school in the United States, at least to study

00:11:24.060 that subject matter. You're dealing with a bunch of really talented people to begin with, but what are

00:11:28.560 they doing in two years to take you to the next level? It's mostly a writing workshop. So every

00:11:35.220 semester you have a group of about 15 students and a professor and you submit three, four times

00:11:42.640 during the semester, you submit your own work and everybody in the class critiques it. And the

00:11:48.080 professor, of course, critiques it and discusses it. And that's really the heart of most writing

00:11:52.660 education. And it's a grueling process at times. You have 15 people sitting there telling you

00:11:58.180 everything that's wrong with your work. And you can't listen to all of them. And they often

00:12:02.760 disagree. And you can go a little crazy, you know, trying to make your work sort of fit everybody's

00:12:07.980 expectations. There are some writers in recent years who have really been pushing back against

00:12:12.780 this workshop approach because they feel it turns every piece into sort of a formulaic story or essay

00:12:19.460 where you meet a certain set of expectations that everybody has and you don't do more experimental

00:12:23.880 work. So there are a lot of debates about that. But I do think it's really important because

00:12:28.500 even the best writers in the world don't know when their own work is working. You know, you need

00:12:35.260 feedback from other people. So much of it is trial and error and, you know, writing a short story. I might

00:12:40.960 use the first person, you know, telling it from my own perspective. And then everybody says it's not

00:12:46.520 working. So I try it again and I write from the third person not using the I. And then it suddenly

00:12:51.100 works. And you don't really know what works until you get responses. Because when you're writing,

00:12:56.960 you know, if you get on a roll, everything feels good. Everything, you know, if you're in that space

00:13:01.620 for, you know, a few minutes when you're writing, you think, oh, I'm on a roll. This is great. And

00:13:05.720 then you show it to your workshop and nobody likes it. So you need that feedback. And, you know,

00:13:10.440 maybe sometimes you're right and they're wrong, but ultimately you're trying to publish your work for

00:13:14.740 an audience. So the audience has to be right at some level.

00:13:17.820 Does it amaze you when you see people like Atul Gawande and Sid Mukherjee and Azra Raza,

00:13:24.340 people who didn't necessarily formally train in writing, but who seem to write beautifully?

00:13:30.620 I mean, it's beyond amazing. It's actually really annoying and frustrating. I'll admire all three of

00:13:36.900 the people you mentioned. And, you know, not only are they exceptional writers, but, you know,

00:13:42.180 they're full-time physicians and doing these incredible things. And it just absolutely blows my mind that

00:13:47.300 they have the time to do it. And when they do it, they do it in a way that's almost unimaginably

00:13:52.440 good. Like it depressed reading Mukherjee because I think what's the point of me even trying when he's

00:13:57.040 writing in this way. So I don't know how they do it, but I just have to accept that very few people

00:14:03.060 reach that level and you can still do good things if you're not reaching that level.

00:14:06.340 Well, that's definitely a good way to think about it. So let's get back to the story here and let's

00:14:11.820 assume that the listener here doesn't really know anything about Warburg. That name means nothing

00:14:17.600 to them. Where's the right place to begin this story? He's born into a pretty well-to-do family in

00:14:23.440 the kind of latter third of the 19th century. Tell us where to pick up this story.

00:14:30.300 Sure. Yeah. I do think that his childhood is a really important part of the story. I had a hard

00:14:36.840 time finding a lot of original sources and documents about his childhood, but the basic

00:14:42.540 facts are that his father, Emil Warburg, is a very prominent physicist. Despite coming from a famous

00:14:49.060 Jewish family, he rises to the top of German physics. He's at the University of Berlin, which

00:14:53.880 is very unusual for somebody of a Jewish background in the late 19th century. And Einstein really loves

00:15:00.200 his father, you know, says that he's like his favorite physicist. And, you know, Emil Warburg

00:15:05.200 ends up providing some of the experimental proof for some of Einstein's theories. So Einstein was

00:15:11.280 a regular in the house when Warburg was a teenager, Max Planck, Emil Fischer, you know, all these titans

00:15:17.080 of German science. And, you know, the Germans revered their scientists. The country was at the top of the

00:15:23.420 scientific world at the time. So Warburg's vision for himself is, you know, he's going to grow up and be

00:15:30.080 a great scientist like the people that hang around in his house. He's going to make a world-changing

00:15:35.400 discovery just as his father and Einstein and Emil Fischer have. And the question is where he's

00:15:42.040 going to focus his energies. And he moves away from physics, which is a little surprising. I think

00:15:48.460 that was his rebellion in a way. And he wanted to outdo his father, Emil Warburg. So he moves into the

00:15:53.940 realm of biology and physiology. But it's always throughout his life through the lens of a

00:16:00.520 physicist and always interested in energy and how, you know, we can understand biology through

00:16:06.140 an understanding of energy. So he didn't fully move away from his father so much as take the

00:16:11.400 physics into a new realm. And that extended to a study of photosynthesis as well.

00:16:17.220 How old was he at the beginning of World War I?

00:16:18.980 That's a good question. At the beginning of World War I, I'd have to go back and do the math. So it's

00:16:25.400 1914 and he was born in 1883. So he was in his early thirties, I guess.

00:16:32.180 And so what was the impact of World War I on German scientists?

00:16:36.820 It was pretty remarkable that given that if you look back from a historical perspective, I don't think

00:16:44.480 that Germany's position at the time is particularly defensible, but there was, you know, just this

00:16:49.580 huge surge of nationalism and the scientists for, by and large, got, you know, signed on and

00:16:55.600 signed letters in support of the fatherland and were ready to go fight on the front lines. And,

00:17:01.680 you know, many of them did. And in some cases, many of these scientists were Jewish. And because of the

00:17:07.760 politics at the time, they were, you know, their German patriotism was questioned. So by signing up for

00:17:15.020 the war effort, this was a way to prove they were full Germans. So that was a big part of it. And, you

00:17:20.980 know, many of them went to the battlefield and others worked with Fritz Haber, who develops these gas

00:17:26.680 weapons and, you know, all these sort of new weapons of war that are coming out of German science. You

00:17:32.820 know, it surprises me that Warburg went to the battlefield rather than working with Fritz Haber,

00:17:37.840 who, you know, he knew and ended up working in the same area in Dahlem where Warburg worked. So

00:17:43.280 it's hard to understand why that happened. But, you know, I think Warburg was really

00:17:48.020 wanted to prove himself and he loved horses and he joined a cavalry regiment. So I think that was a

00:17:54.160 part of the appeal for him as well.

00:17:56.280 Now, Einstein urged him not to go, correct?

00:17:58.260 Well, Einstein, Warburg went and then Einstein wrote a letter to him in 1918. So the war was

00:18:06.740 nearing its end. And by that point, everybody could see everybody who was rational and paying

00:18:12.540 attention that it was a lost cause. Germans were dying by the tens of thousands. And, you know,

00:18:18.420 it was madness, as Warburg's mother put it. And they're desperate for Warburg to come home. His

00:18:23.740 parents are desperate. So they're friends with Einstein and they can't convince Warburg to come

00:18:27.840 home. So they turned to Einstein and, you know, they know that Warburg reviers Einstein. And they

00:18:32.200 say, you know, will you write him a letter? So Einstein does. And it's really a perfect letter

00:18:36.560 because he knew Warburg well enough to know that he was a narcissist. And so he wrote the letter

00:18:42.340 saying that you're just too important for science. We can't afford to lose you. And we don't have

00:18:47.560 Warburg's response to that letter, but sure enough, he comes home shortly thereafter. So I think it was

00:18:52.500 the letter from Einstein that most likely convinced him and, you know, possibly saved his life.

00:18:57.480 And five years later, he makes his great breakthrough about cancer and fermentation. So

00:19:02.440 I like to think that Einstein may, you know, have saved his life and therefore deserves credit for

00:19:08.260 this great cancer discovery as well in some indirect way.

00:19:12.460 You wrote about Warburg that he was pathologically dedicated to his science. What did you mean by that?

00:19:18.620 I mean, I think it's hard to understand unless you grew up in 19th century Germany. But somebody, a friend

00:19:27.060 who knew him described it as having a religious devotion, like a prophet who has like this fervor who

00:19:33.420 just thinks about nothing but science and is passionate about science. You know, Warburg used to say

00:19:37.880 a scientist has to be prepared to die for the truth to get a sense of his perspective there. And I think my

00:19:44.620 favorite example, the one that's maybe most revealing, that at one point, a friend was telling Warburg

00:19:50.700 about somebody, a mutual friend or somebody she knew who was having mental difficulties, and going through

00:19:59.020 various problems. Warburg's advice for this person was, tell him to think about nothing but science, just think

00:20:04.460 about science all day. And, you know, the person in question wasn't even a scientist. But that was, you know, reveals a

00:20:10.620 lot about Warburg, I think about how he viewed the world. And this devotion to science was partially

00:20:16.540 about narcissism, and wanting to be great. But I think partially, you know, obviously, a genuine love

00:20:23.420 of science and curiosity about the truth, but also a way to avoid looking internally. You know, I think

00:20:28.700 that comment about the other person really reveals that he was covering something up by focusing on

00:20:33.580 science all the time and trying not to look inward. What do you think he was afraid to look at?

00:20:38.780 Well, you know, he was, he was a great narcissist. And, you know, I think, when you see that personality

00:20:46.460 type, it almost always comes sort of hand in hand with deep insecurity. And he was clearly extremely

00:20:54.620 insecure, you know, whenever he was criticized, he would lash out and start these feuds with other

00:20:59.980 scientists. So that's where it ultimately came from. But he also had, you know, all these difficult

00:21:07.020 things to deal with, you know, being Jewish in Germany wasn't easy, even before the Nazis. And

00:21:13.020 then he has this other complicated issue, which is that he's clearly homosexual, he ends up spending

00:21:18.380 his whole life with his male partner, and he couldn't be out at the time in Germany. And his

00:21:24.700 mother was pressuring him to get married and questioning his lifestyle. And there were all sorts of rumors

00:21:29.580 about him. So he had a lot of stress. And there are various ways it comes out. Like he can't do

00:21:36.060 public speaking. He keeps being told, you know, to get your degree, you have to go and give these

00:21:40.940 talks that he just refuses. And if it was anybody else, they probably would have failed him. He was

00:21:45.020 so brilliant that they just finally decided to move him along. So there were a lot of psychological

00:21:50.220 issues there.

00:21:50.940 Was he in the closet his entire life? Or did he eventually come out?

00:21:55.900 I'm not sure I would use the phrase in the closet. I mean, in a sense, almost everybody was in the

00:22:00.540 closet. So I actually, you know, he didn't fully come out and say, I'm gay or talk about it. But

00:22:06.780 I think he was about as out as one could be throughout most of his life. You know, he didn't

00:22:11.420 try to hide the fact that he lived with another man when he was invited to give a talk. His partner,

00:22:16.780 Jacob Heiss would always come with them. Warburg would, you know, in some instances say, I'm not

00:22:21.260 going to come unless, you know, my partner comes. So, you know, they would go to the opera together

00:22:26.060 and travel to his vacation house together. So, you know, he didn't explicitly say, I'm a homosexual,

00:22:33.260 but I think he came pretty much as close as anybody of that era. And, you know, I really respect him for

00:22:39.100 that.

00:22:39.340 Had he met Hitler?

00:22:40.860 There's no record of them meeting. I think there's a lot of

00:22:46.460 indirect evidence that Hitler was directly involved in his case and his fate. I can go

00:22:53.900 into that detail or maybe we can build up to that, but there's no record of a direct interaction.

00:22:59.180 Well, yeah, I guess before we get there, let's, I want to come back to that because it's,

00:23:04.220 the intersection of them is so fascinating to me. But let's go back to post-World War I and pick it up

00:23:10.700 where Warburg moves into his sort of seminal work. So it's 1918. Einstein's convinced him to come back,

00:23:19.260 potentially saving his life. His first choice, I suppose, is where is he going to set up shop,

00:23:24.140 right? Is he going to stay in Berlin or is he going to leave? And he elects to stay.

00:23:28.140 Yeah. He actually, right before he leaves, he's given this incredible position,

00:23:33.820 his own sort of wing in the Kaiser Wilhelm Institute for Biology, which is sort of, you know,

00:23:39.820 the pinnacle of German science. They create this Kaiser Wilhelm Society, which is now the Max Planck

00:23:45.260 Society as, you know, supposed to be the Oxford of Germany. The idea is that they're going to get the

00:23:50.300 best scientists in the world and give them everything they need. I was actually inspired a lot by the

00:23:54.460 Rockefeller model and the Rockefeller Institute in the United States, just find the most brilliant

00:23:58.940 people, give them what they need and let them go. So he returns, you know, right before World War I,

00:24:03.740 he's about to start this position. His lab was under construction. And when he returns, it's a very

00:24:09.420 different world. You know, all the wealthy funders of the Kaiser Wilhelm Society are now bankrupt.

00:24:14.540 So he doesn't even have much money for his work at this point. There's this famous example,

00:24:20.460 he has to write a grant proposal for one of the only times in his life. And, you know,

00:24:24.780 he can't bear to do it because he's so narcissistic. So he finally writes, you know,

00:24:29.340 scribbles on a piece of paper, I need 10,000 marks, and he actually gets the money.

00:24:34.780 When he comes back from the war, he focuses on photosynthesis rather than cancer first. And

00:24:38.860 it's actually really interesting, I think, that when his father was trying to get him out of the war,

00:24:43.020 he was making the case that Warburg was needed for photosynthesis research because he was going to

00:24:48.380 find new ways to grow food, make photosynthesis more efficient, and have more crop yields. And

00:24:53.740 the Germans had been starving throughout much of the war, and there were huge food shortages. So he

00:25:01.020 came back and really, I think, wanted to solve world hunger. And that remained an interest of his

00:25:05.980 throughout his life. But he was always interested in cancer as well. At one point, he asked another

00:25:11.820 famous scientist for advice, should I do photosynthesis or cancer? And the scientist says,

00:25:15.900 do cancer photosynthesis is working pretty well. So he decides to do cancer. And it's because

00:25:22.780 he wants to make a world changing discovery. And cancer really has become a German obsession

00:25:27.500 by the 1920s. If you look back into the early 19th century, there's not much cancer. And obviously,

00:25:34.380 there's all sorts of discussions and things you have to look at in terms of longevity and diagnostic

00:25:39.580 techniques. But I think there's overwhelming evidence, which I try to document in my book,

00:25:43.820 that cancer did really increase and continue to increase well into the 20s and 30s. And

00:25:50.860 by the 1920s, there's a panic. So many people are getting cancer. It still pales in comparison to

00:25:57.180 today's rates, but it's a panic at the time. And the Germans had conquered so many diseases. Robert

00:26:02.700 Koch and Paul Ehrlich had figured out bacteriology and infectious diseases. And it just seemed natural

00:26:08.220 that they were going to do the same thing with cancer. And Warburg worshiped Ehrlich and Koch and

00:26:14.140 thought he was going to be the next one to make this great discovery. And so he takes on cancer and

00:26:19.500 pretty quickly finds this remarkable thing, which is, as you well know, and probably a lot of your

00:26:24.300 listeners know, most cancers eat differently than other cells. They ferment glucose rather than

00:26:31.500 burning, breaking it down and burning with oxygen, oxidative phosphorylation. So this cancer

00:26:37.180 cell shift to fermentation is a remarkable discovery and, you know, ends up occupying his life,

00:26:44.060 his thoughts, and he ends up focusing on that for much of his life.

00:26:48.460 So let's go back to how that discovery was made and what he was actually seeing in the laboratory that

00:26:54.060 led him to this observation.

00:26:56.380 The background is that he had been studying actually sea urchin eggs in the first years of the 20th

00:27:02.700 century, when he's still a young scientist. And he had seen that these eggs, you know,

00:27:08.780 this is a little complicated and that, you know, he didn't necessarily get all this right. But what his

00:27:14.780 early studies showed was that when the eggs were about to grow and proliferate, they would immediately

00:27:22.140 begin to increase oxygen consumption. And it made perfect sense because you need energy to grow and

00:27:28.220 you know, using oxygen is the more efficient way to create energy for the cell. So when he turns to

00:27:35.340 cancer in 1923, he expects to see the same thing. The cell needs to grow, it needs more energy, it's going

00:27:41.260 to use more oxygen and burn more nutrients with oxygen to grow. And so, you know, the experiments that

00:27:48.540 he does is, you know, he takes, you know, a slice of a tumor from a rat, and he attaches it to a

00:27:55.660 manometer, which is a device, really a very simple sort of U shaped tube, which can just measure changing gas

00:28:01.980 pressures. And he expects that the cells, he'll, will start to take up more and more oxygen, and he'll see the

00:28:09.420 pressure change inside of his U shaped tube. But he doesn't see it, he doesn't see the oxygen consumption

00:28:16.140 increasing. Instead, he checks the solution that these cells are in, and he finds it's full of

00:28:21.420 lactic acid. Lactic acid is what's made from fermentation, you know, what human cells make

00:28:27.180 from fermentation. Of course, yeast and other microorganisms will make alcohol and carbon dioxide.

00:28:32.780 So he sees that they're clearly fermenting. And it's a strange phenomenon that is happening. And he

00:28:39.340 tries to do other experiments, they end up doing, you know, tests in vivo and people and seeing that they

00:28:45.580 have more, you know, with cancer have more lactic acid in their blood. And, you know, every test he

00:28:50.540 carries out comes to the same conclusion that cancer cells are taking up a lot of glucose and fermenting

00:28:57.020 it to lactic acid and using less oxygen than he would expect. Go a little deeper for folks

00:29:05.020 into that biochemical pathway. So when a cell is presented with glucose as substrate,

00:29:11.900 and it wants to make ATP, what are the different fates of that glucose molecule? And why is it

00:29:18.700 so absurd that a cell would, in the presence of sufficient oxygen, choose to make lactate? Why

00:29:26.860 is that such an unusual thing to do? Why is he so surprised by this?

00:29:30.460 He wasn't the first to see that a human cell can ferment. It was understood, going back to

00:29:39.740 previous decades, that human cells could do this. You know, it was very surprising when it was

00:29:44.780 discovered because it was thought only microorganisms did it. But, you know, Warburg was very close with

00:29:49.820 another physiologist, Otto Meyerhoff, who made a lot of important discoveries and found that human cells

00:29:57.340 could do much the same thing that microorganisms can do. So Warburg knew a cell could do this,

00:30:03.180 but what he didn't know was that a cell would ever do this if oxygen was available. It was always

00:30:08.540 thought to be a compensatory thing that moved to fermentation if you didn't have enough oxygen or, you

00:30:14.860 know, if there was, you know, as Warburg thought, some damage to the mitochondria where the oxygen is

00:30:20.300 used to burn nutrients. So the really surprising part of it was not just that a cell was fermenting,

00:30:25.740 you know, if you do, as you know, intense exercise and oxygen, you know, your lungs are

00:30:31.420 eating and you don't have enough oxygen to sort of keep up with the needs, then fermentation will,

00:30:37.420 glycolysis will take place in that setting as well. But the surprising thing and what we now call

00:30:41.820 the Warburg effect is that the cancer cells had oxygen and they were still turning to fermentation,

00:30:46.700 you know, what we call aerobic glycolysis. So that was the really surprising part.

00:30:50.220 Yeah. Aerobic meaning in the presence of oxygen, but still undergoing this inefficient pathway of

00:30:55.900 glycolysis. And it's so inefficient, in fact, that from an energetic standpoint, it's hard to

00:31:01.500 understand because the total yield of ATP when you take glucose to lactate, I believe is four units of

00:31:09.820 ATP to going from, and I could be wrong. It could be two. Whereas in normal aerobic metabolism,

00:31:16.780 which would be oxidative phosphorylation, you would take glucose, which has six carbons,

00:31:23.100 you would make two molecules of pyruvate, which each have three carbons. And that pyruvate would

00:31:29.180 be turned into acetyl-CoA into, and then it would enter the mitochondria and where it would go through

00:31:35.020 all of the steps of the electron transport chain. The final emissions would be carbon dioxide and

00:31:40.620 water. And that process would yield either 32 or 34 net molecules of ATP. So the difference is so

00:31:49.660 stark, right? It's like a 17 X difference in energy yield, which as you point out, the only reason you

00:31:59.020 would ever make that sacrifice in favor of lower energy yield is if you have no choice. So if I said,

00:32:06.620 hey, go for a jog and run your eight minute mile pace, that's great. I'm demanding ATP at a slow

00:32:14.220 enough rate and therefore you have enough oxygen that you can do it the efficient way. But if we make

00:32:21.100 somebody run for their life, the fastest quarter mile ever, all of a sudden the need for ATP

00:32:29.340 is so great that it can't be matched by enough oxygen intake. So you take this inefficient pathway,

00:32:36.380 which unfortunately we can't sustain for as long because with lactate comes hydrogen and hydrogen

00:32:43.420 reduces the pH and that reduction in pH with that hydrogen ion makes it very difficult for the

00:32:48.860 actin and myosin filaments in the muscle to release. And that's what people are actually experiencing when

00:32:54.220 they feel that horrible burn that's actually erroneously attributed to lactate. It's really

00:32:59.660 the hydrogen ion. So yeah, it's like we knew about this, but I think this was a really interesting

00:33:06.460 discovery. And that's why I think the term aerobic fermentation is a paradox, right?

00:33:11.340 Yeah. I mean, the aerobic glycolysis or aerobic fermentation from Warburg's perspective,

00:33:18.140 it was a paradox, you know, and you know, as we'll maybe talk about more, not everybody sees it that

00:33:22.860 way, but, um, many scientists continue to see it that way. I think that's the only explanation that,

00:33:29.580 you know, if you're choosing to, you know, use glucose in this way to ferment it rather than

00:33:35.820 to do the much more efficient way of breaking it down and getting much more ATP, then, um,

00:33:41.420 the only way to explain this paradox is that something is broken and why else would a cell do this?

00:33:45.980 Well, and we'll certainly get to that because today I think we have other explanations,

00:33:51.020 but going back to Warburg, how did he then explain the observation? So if science is a process of making

00:33:57.740 an observation and then coming up with hypothesis, what was his hypothesis in light of that observation?

00:34:04.700 The hypothesis was that the mitochondria, you know, he didn't have full understanding of

00:34:09.820 mitochondria at this time, but he felt that there had to be some sort of defect in the mitochondria,

00:34:17.100 you know, the structure that was burning nutrients with oxygen because it made no sense otherwise. And

00:34:24.460 the only way to really understand it is that, you know, Warburg idolized Pasteur and he had his,

00:34:29.900 his library set up so that he was gazing at a portrait of Pasteur at all times. One side was

00:34:35.340 Robert Koch and the other side, Paul Ehrlich, but Pasteur was in the center. It was Pasteur who had

00:34:40.140 discovered that microbes could ferment, that they didn't need oxygen. It was this, you know, shocking

00:34:45.740 thing to him. He called it, you know, life without air. Pasteur himself had explained it by the fact that

00:34:51.740 the cells were fermenting and not using oxygen, it must be because there's some kind of problem

00:34:57.740 because why, why wouldn't anybody, any cell use oxygen if it could? And it's called the Pasteur

00:35:03.820 effect, the seesaw like relationship, you know, respiration with oxygen goes down, fermentation goes

00:35:09.100 up. So that was how, you know, and that's what other scientists had found when they were studying frogs.

00:35:15.100 And, you know, I mentioned Meyerhoff. So that's how everybody understood this relationship. So

00:35:20.300 that was Warburg's lens. I think a seesaw is a good way to think about it. Respiration goes down,

00:35:26.380 fermentation goes up. I think my book, I talk about it as a backup generator clicking on. And what's

00:35:32.380 interesting about it to me is that both Pasteur and Warburg were sort of aristocratic personalities.

00:35:37.740 And I think they really thought of fermentation is lower and less noble than respiration. Warburg actually

00:35:44.380 literally used those, those types of terms when talking about it. So for him, it was just almost

00:35:50.620 shocking, almost unbelievable that a cell could use oxygen and they would do this lowly thing that

00:35:56.540 microorganisms do. It's impossible. How did Warburg attempt to actually test the hypothesis? So if the

00:36:03.100 hypothesis, if the observation is cancer cells are undergoing aerobic glycolysis to fermentation,

00:36:11.100 and the hypothesis is they're doing this because their mitochondria are defective,

00:36:18.140 how would he test that hypothesis to increase the confidence that he would have in that hypothesis?

00:36:24.380 He didn't really have a great way to test it. Certainly not at the time in the 1920s. I mean,

00:36:31.900 the test that he did was just to see the effect over and over, but he couldn't

00:36:36.380 prove that it was a problem with defective mitochondria.

00:36:40.220 Did he recognize that, by the way, as a limitation?

00:36:43.420 I don't think he did. The most surprising part really is that in the early 20s, his first test

00:36:50.140 actually showed that respiration was continuing. And then later in his career, he does additional

00:36:57.580 experiments and insists that respiration is not continuing, or if it is, it can be explained in

00:37:04.060 various ways that there's uncoupling, which causes the electrons to leak out, etc. But his early

00:37:11.980 tests showed that fermentation was increasing while respiration continued to sort of hum along.

00:37:18.220 And he just sort of denied that or came up with various explanations for it. But it was really in

00:37:24.140 the post-war period where he starts to make more and more extreme statements. He finds these cancer

00:37:30.460 cells in the abdominal fluid. I think they're called ascites. You know, he sees that in his test

00:37:36.860 of these cells, he sees very little respiration and just very high fermentation rates. So he becomes

00:37:42.860 more and more convinced. And he called these pure cancer cells. He thought it was the best test of it.

00:37:48.140 But he never really had any concrete evidence that there was some sort of structural defect or

00:37:54.780 in the mitochondria. He felt it was almost tautological that the job of respiration is to

00:38:00.380 keep fermentation repressed. And if that relationship is not working, then it's necessarily broken. At

00:38:06.540 one point, when critics were charging him with asking for more proof, he said it was a semantic

00:38:12.460 debate. It's necessarily true because it's not supposed to work that way. Which really is ironic,

00:38:16.940 right? Based on his observation, there is absolutely no way to know if his observation is the cause or the

00:38:21.900 effect of cancer. So I was struck by, I think in his case, you could almost use the word,

00:38:28.060 the arrogance with which he would treat it as tautological, as opposed to acknowledging that,

00:38:32.940 hey, absent additional tools, right? Laboratory tools, it's difficult to know for sure if this

00:38:39.820 is cause or effect, which actually brings to the forefront of this discussion, this overlap between

00:38:45.340 him and Hitler, right? Which is this view of cause and effect that Hitler even writes about, right?

00:38:50.460 Are you, oh, I think you're referring to Warburg's thinking about causation and cancer? Yeah.

00:38:58.620 Correct. Yeah.

00:38:59.500 One of the interesting things that I found is that Warburg and Hitler, you know, Hitler was,

00:39:05.260 you know, one of history's greatest monsters. I'm always hesitant to compare anybody to him,

00:39:10.860 let alone Warburg, who's somebody I admire greatly, despite his flaws. But I couldn't help,

00:39:16.700 you know, because I was writing about both men, I couldn't help but see some parallels in their

00:39:21.100 story. You know, first and foremost, they grew up in Germany or at the same time, you know,

00:39:25.820 Warburg's born in 1883, Hitler in 1889. And at the time, the hero of the day is Robert Koch,

00:39:34.380 the German scientist who discovers the causal relationship between microorganisms and infectious

00:39:41.420 diseases. You know, it starts with anthrax, then he has his great breakthrough with tuberculosis. So

00:39:46.620 it's hard to, from our perspective today, it's hard to, I think, appreciate how much Germans revered

00:39:53.340 Koch. You know, they were like parades and flags with his face on it, because he was conquering disease.

00:39:58.540 So Hitler and Warburg are both narcissists, both want to be the greatest men of their generation. And

00:40:04.060 the model for that is Robert Koch, first and foremost in their childhood. And what's amazing,

00:40:10.940 I think is that, you know, Koch is most famous in a way for his postulates, which talk about how you

00:40:15.980 can know one thing causes another thing and what conditions you have to have to show that a

00:40:20.700 microorganism actually causes the disease.

00:40:23.420 Which are, let's see if we can rattle these off, right? So one is the healthy individual can never

00:40:30.060 contain the microorganism that is reported to be caught. Another one is the corollary is that anyone

00:40:40.220 with the microorganism must have the disease. And then I think anytime you take a healthy person and

00:40:47.020 insert the microorganism, you must be able to cause the disease is that, I think that's the third one.

00:40:52.700 That's the gist of the logic. It's, it's, it's very, it's a very rigorous logic that again,

00:40:58.060 I think we all take for granted today, but at the time it was remarkable and it demonstrated the

00:41:05.180 causal relationship between these various microorganisms and the diseases they caused.

00:41:11.180 Yeah. And a key breakthrough, if I'm remembering correctly, is that, you know,

00:41:14.780 they had already known that you could take blood or whatnot from one organism to another

00:41:19.020 and transfer the disease. But Cuff understood that he first had to get the

00:41:22.700 microbe and grow it outside the body. So he wasn't transferring anything else.

00:41:26.540 You know, he had to prove that it was the microbe itself by growing it independently and then taking

00:41:30.460 some of those microbes and injecting them. In any case, you, if you listen to Hitler's

00:41:36.460 speeches, you know, some of his speeches in the 40s and read some of Warburg's papers,

00:41:41.420 they actually, it's almost like they're quoting Robert Cuff. You can hear the same phrases and

00:41:46.540 talking about causality. They both refer to Cuff directly, but you know, the most chilling thing

00:41:51.340 I found, I think, is that Hitler on multiple occasions referred to himself as the Robert Cuff

00:41:56.540 of politics. And he said that Cuff had saved the world through science by eliminating the microbes,

00:42:03.020 the microorganisms that cause disease. And I've done the same thing with the Jew.

00:42:06.300 So he saw his effort in some ways as a scientific project and that killing Jews in his twisted mind

00:42:13.900 was like eliminating microbes. Of course, it wasn't just Warburg and Hitler, but I was just struck

00:42:19.820 that they were both using this language of causality. And so how did Warburg describe that

00:42:25.580 in terms of primary and secondary causality of cancer? How did he really start to sharpen his thinking on

00:42:31.660 that? Warburg says that every disease has a prime cause and a secondary cause. And he uses the

00:42:38.220 analogy of Robert Cuff that the prime cause of the disease is the microbe. And then there are

00:42:43.980 all these secondary causes, the unsanitary conditions that cause the microbe to get onto a person and make

00:42:50.860 them sick. Various plagues and anything that causes a microbe to transfer and get into someone's blood is

00:42:58.700 the secondary cause. And the microbe itself is the primary cause. So Warburg tries to extend this to

00:43:04.060 cancer. He says, the most fundamental thing about cancer is the shift to fermentation. And so that

00:43:10.060 is the primary cause. Although there was never proof for this, he insisted that it existed in 100% of all

00:43:15.980 cancers. I think today people say 70% or more, but not 100%, but Warburg thought it was 100% of all

00:43:23.740 cancers. I should modify that by saying probably all cancers at some point start to ferment as they

00:43:30.460 have reduced access to oxygen if they become advanced cancers. But at the most fundamental

00:43:35.820 level, I don't think you can say 100%, but Warburg said it was 100% of all cancers ferment. This is the

00:43:40.620 primary cause and anything that causes the fermentation can be thought of as a secondary cause. So you might have

00:43:47.180 a dangerous chemical and that injures the mitochondria and therefore you have fermentation. So that's the

00:43:54.060 secondary cause is the chemical or anything you can think of. A virus that causes cancer would damage

00:43:59.500 the mitochondria. It's always viewed through the lens of causing the structural problem, which causes

00:44:05.340 respiration to be damaged and fermentation to increase in the seesaw-like relationship.

00:44:10.540 What did Warburg believe accounted for the significant increase in the prevalence of cancer

00:44:17.900 leading up into the 1920s and 1930s as a secondary cause by his definition?

00:44:23.020 At the time, in the 20s and 30s, he doesn't say much about it, but I think it's clear looking back

00:44:29.500 that he was, from an early time, very worried about environmental carcinogens. But in the post-war

00:44:35.500 period, he becomes very outspoken about environmental carcinogens. And I think his influence is much

00:44:41.980 wider than many people realize. In Germany, he starts campaigning against smog from automobiles

00:44:48.860 and buses and food dyes used in the German food supply and all sorts of chemicals. He becomes basically

00:44:56.060 an organic farmer, one of the first organic farmers I've heard about. He has his own garden and he has

00:45:01.180 his partner, Jacob Heiss, is the only person who's allowed to cook for him. And he even has a well

00:45:06.220 where he gets his own water. So his hypothesis was that the chemicals in our food, first and foremost,

00:45:13.020 were poisoning ourselves, poisoning the mitochondria and causing the shift to fermentation. But what's

00:45:20.060 really interesting, I think, is that if you read Rachel Carson, Silent Spring, which is a hugely influential

00:45:26.300 book, really changed American environmental policy. Warburg is actually the first cancer scientist

00:45:32.700 mentioned in the book. And it's clear that that's exactly how she viewed cancer and saw all these

00:45:39.660 environmental chemicals as causing cancer via the damage to respiration that Warburg cited. So

00:45:46.300 I think he ended up having a massive influence on American life, just nobody knows about it.

00:45:50.540 He was awarded the Nobel Prize in 1931. What was the seminal work for which he was awarded?

00:45:57.500 Yeah, a lot of people think that he got the award for cancer, but that's not true. He was nominated

00:46:02.780 in 1926 and should have won for his cancer research, but doesn't win it. And then in 1931,

00:46:09.020 he gets it really for figuring out the final step. He believes it's the only step at the time,

00:46:15.100 but really the final step of a respiration, understanding how the electron passes down

00:46:21.420 the electron transport chain and is able to react with oxygen. So he sort of elucidates this process

00:46:28.060 and wins the Nobel Prize for that. What happens during World War II? As you point out, obviously he's

00:46:33.900 Jewish, he's gay. I'm guessing that both of those things make him an enormous target for Nazis. Why does

00:46:41.260 he stay in Germany? Yeah, it's one of the most fascinating parts of his story. 1933 comes along

00:46:48.060 and only two years earlier, the Rockefeller Foundation has built this beautiful institute

00:46:53.500 for him. He has designed the institute himself after a country manner that he admires. And he's

00:46:59.420 on top of the scientific world. He's just won the Nobel Prize. And all his colleagues start to

00:47:05.980 flee his Jewish colleagues. They see what's coming and Warburg refuses to see it. He's

00:47:11.980 not going to give up his kingdom in Dahlem, in southwestern Berlin. He says,

00:47:15.820 I was here before Hitler. And like a lot of Germans, he believed that the Nazi phenomenon would

00:47:21.020 be short lived. His cousin, Max Warburg had said, we just need to give Hitler enough rope to hang

00:47:26.380 himself. So Warburg had said, maybe six months a year, he thought they'd be gone. But I think that

00:47:32.780 part of it was, you know, he was so arrogant and so narcissistic that he couldn't fathom anybody

00:47:38.780 telling him what to do, let alone, you know, he called them Bavarian noisemakers. These Nazi

00:47:42.540 thugs were going to kick him out of his institute. No way. I mean, that was his perspective. And

00:47:47.500 I think the most shocking thing about his story is he has a famous Jewish name. His father's Jewish,

00:47:52.780 so he's Jewish by the Nazi standards. He lives with his male partner. He should have been as vulnerable

00:47:57.500 as anybody in Nazi Germany. And yet he not only stays, but he provokes the Nazis. You know, he

00:48:04.460 screams at them when they come to his institute, demanding Aryan descent forms. At one point, he says,

00:48:08.540 he'll burn down his institute if they come again. He won't do the Hitler salute. He won't put up the Nazi

00:48:13.100 flag. So he really was in a very dangerous situation. 1936, you know, the New York Times

00:48:18.940 ran an article saying Warburg may be in jeopardy. You know, he was famous enough at the time that

00:48:24.220 they were writing about him in the Times. And he was also tremendously stubborn. You know,

00:48:29.100 he said to his sister at one point that, you know, it's going to be either near them. I'm not budging.

00:48:33.900 And his sister's understanding of it was that the more pressure he got, the more he insisted on staying

00:48:39.420 because he couldn't stand to think that he would lose that battle. And it's very hard to understand

00:48:44.460 this. When we look back, we see these Jewish scientists fleeing and we think, oh, you know, what

00:48:49.580 wise moral people, they saw what was coming and they left. They didn't want to be a part of it.

00:48:54.940 But at the time, it was really considered a shameful thing that to leave was to accept that you were

00:49:01.500 somehow a lesser German. And Warburg, you know, that was the antithesis of everything Warburg stood

00:49:09.260 for. You know, to do anything that would cause him shame would be unimaginable. So there was really

00:49:14.060 no way he was leaving. He didn't think about it, but I think he correctly understood that he would

00:49:20.220 never be the same if he left. Did he journal? What type of sources were you able to, if any,

00:49:26.380 get into his head during that period of time? It was honestly one of my most important finds. I didn't

00:49:31.980 find it myself, but it already existed in German. But one of his sisters, Lotte, kept a diary and

00:49:37.980 she was a writer and she wrote a great deal about him and recorded their conversations.

00:49:43.340 So that ended up being really my key source for a lot of this. Warburg didn't keep a diary,

00:49:49.740 but because he was famous and he wrote a lot of letters, I had a lot of letters that he wrote. And

00:49:55.260 whenever somebody encountered him, they would often write down their impressions because he was such a

00:50:00.220 character and he was already world famous. But at the very end of the war, he actually did scribble out

00:50:07.260 some notes a few years ago. A historian, Karin Nicholson in Germany, actually discovered in the

00:50:13.660 back of his notebooks, these notes, which were really fascinating. He was dealing, we haven't

00:50:19.740 really talked about that part of the story, but he was dealing with some guilt that he faced by not

00:50:24.700 protecting certain people who worked for him from being forced into the military. So he started to

00:50:29.660 scribble out these defenses and just, it's only a few sentences here and there, but it gives you

00:50:34.460 a window into how persecuted he felt at the end and how guilty. And in some ways I think he felt as well.

00:50:40.860 How many people did he know that died in concentration camps?

00:50:44.620 Fewer than you would think, partially because most of the Jewish people that he associated with

00:50:52.300 left in the Kaiser Wilhelm Society. I think there were like 2,500 Jews at various institutions,

00:50:57.900 and Warburg was the only one who stayed until the very end. So most of them left. And you know what

00:51:04.380 a lot of people don't realize, you know, that German Jews in many cases were more likely to survive

00:51:10.460 the Holocaust than other European Jews. Some of his Warburg cousins actually were murdered in the camps.

00:51:16.620 He wasn't particularly close with them, but he didn't lose a lot of people who were close to him,

00:51:21.500 but I don't have a good answer to that question. But it would be impossible for him to have not

00:51:25.820 have known a lot of people who died, but I don't know that they were the people who were closest to

00:51:29.660 him. He certainly knew hundreds of thousands of people who fled for their lives.

00:51:33.260 You know, in countries like Poland, there was clearly a moment in time when you could no longer

00:51:38.380 leave. Was that true in Germany as well? Was there basically a time beyond which if you,

00:51:44.060 if you had not left, you were not going to leave?

00:51:45.980 Certainly for Warburg there was because he was famous and the Nazis saw sort of propaganda value

00:51:53.500 in having him there. For others, it really changed a lot after the war started. And that was, you know,

00:52:02.140 by that point, if you hadn't left, you know, you were in great danger if you were Jewish or homosexual

00:52:08.380 or, you know, various other persecuted categories in Nazi Germany. But in the early 30s, you had an

00:52:16.780 opportunity to leave Germany at least, but they also had to, it was extraordinarily difficult because

00:52:21.500 you, they would take all your wealth. You basically had to give up everything and leave with nothing

00:52:26.220 and find a new career. And, you know, this is in Germany. The other countries didn't have

00:52:31.420 the advance warning and the Jews of Eastern Europe were much less wealthy. You know, these are in many cases

00:52:37.340 more, you know, people who lived in much less wealth than, than the German Jews and never really

00:52:43.260 had a real opportunity to escape when the, when the Germans rolled in. So it was very different

00:52:47.820 for Eastern Europe where's where the Holocaust really begins. So what do you attribute the fact

00:52:52.780 that he survived the war to? Is it simply that the Germans benefited more by him staying there and

00:53:00.460 being alive as a showcase of their scientific prowess? Or do you think there was an explicit directive

00:53:07.340 from Hitler or someone else saying, despite the fact that he's everything we despise,

00:53:13.180 there's value in the work he'll do?

00:53:16.540 So, you know, by the mid 30s, it's clear that he serves propaganda value for them. You know,

00:53:22.220 the Berlin Olympics in 1936, they're able to show that, you know, this guy has Jewish ancestors,

00:53:28.380 is still here working in Germany. But by the late 30s, that propaganda value sort of

00:53:33.100 drifts away and certainly is useless once the war starts. So he's in increasingly sort

00:53:39.100 of great danger as things progressed throughout the late 30s. Meyerhof, a lot of people stayed until

00:53:44.460 1938. Meyerhof is also a Nobel Prize winner, escapes in 1938 and flees to France. And from that point on,

00:53:53.420 that's when Germans roll into Austria and all the Austrian Jews who can escape escape in 38. But

00:53:59.980 the fascinating thing really, it comes to a head in 1941, where by that point, the war is in full swing

00:54:09.020 and there's no value to keeping Warburg alive really for propaganda means at that point. So Warburg is

00:54:15.420 called to Nazi headquarters in 1941, June 21st. And he meets with Victor Brock, who is one of the worst

00:54:23.820 Nazis, the guy who designs the euthanasia killing program that sort of starts the mass killing.

00:54:29.900 And it looks like it's going to be the end for him. He's already received an eviction notice

00:54:33.660 from his institute. He has a lot of enemies in German science. I mean, you have to keep in mind,

00:54:38.140 he had a lot of enemies in German science before all this started. So you can imagine that how many

00:54:42.780 people hated him and wanted to get rid of him. You know, all the other institutes were full of Nazis.

00:54:46.460 His was the only one that wasn't. So, you know, they finally succeed in getting rid of him. And

00:54:52.220 he's called to Nazi headquarters. He sits down with Victor Brock, and he's told that he's actually

00:54:58.060 going to be allowed to live on one condition, that he focus on cancer research. It's extraordinary in

00:55:03.900 itself, but the part that surprised me most, other German historians had recorded this meeting on June

00:55:09.740 21st, 1941. But what I realized, nobody had yet realized that this was an extremely important

00:55:15.580 moment in German history. At dawn the next morning, the German tanks rolled into Soviet territory. It was

00:55:21.260 the launch of Operation Barbarossa, which is, at the time, the biggest military invasion in history.

00:55:26.700 It was the most significant moment in the Nazi project in a lot of ways. And that very day,

00:55:32.060 they're sitting around, you know, worrying about Warburg. And it wasn't just

00:55:35.580 Victor Brock. You see it in Himmler's Daily Planner that he has a meeting about Warburg that day.

00:55:41.340 And then later that night, Goebbels kept a diary, and he records in his diary that later that night,

00:55:48.140 just hours before Operation Barbarossa, he and Hitler are talking about cancer research.

00:55:52.460 The diary, that diary doesn't say Warburg's name, but given that everything else that went on that day,

00:55:56.700 and that Warburg was in the building, it certainly seems that Hitler knew what was going on.

00:56:01.020 And at Warburg, there's more evidence of Hitler's direct involvement because Warburg has applied for

00:56:08.220 something that they called a German blood certificate. This just shows you what a twisted,

00:56:13.740 horrific world it was at the time that, you know, for a Jew to survive in Nazi Germany at that point,

00:56:18.700 if you had managed to stick around that long, you could apply to have yourself upgraded to be more

00:56:23.980 Aryan. So Warburg goes through this application process. At this point, I think it's defensible because,

00:56:29.980 you know, it's really to save his life in a way. But Hitler would actually review these

00:56:34.540 applications himself. And certainly for a Nobel Prize winner, Hitler would have reviewed this

00:56:38.700 application. So, you know, you had to talk about all your ancestors and submit photos, you know,

00:56:45.100 just sick stuff where, you know, Hitler would look at the noses of the people and decide if he would

00:56:50.460 upgrade them or not. So they never actually formally Aryanized Warburg, but it's clear that Hitler would

00:56:57.420 have been involved in that review. And that probably decided on that day, June 21st, 1941,

00:57:02.700 to let him continue to focus on cancer. Was Hitler personally obsessed or touched

00:57:07.580 by cancer? Or was it simply just the epidemiology of the time? Yeah, he was very personally touched

00:57:14.540 by it. When he was a teenager, he lost his mother to breast cancer. And his mother was really, you know,

00:57:21.260 historians say the only person he was capable of loving. And he had already just sort of failed to get

00:57:26.380 into art school and was depressed. He comes back to his hometown in Austria and sees his mother dying

00:57:32.700 of breast cancer and is just distraught. It's actually a Jewish doctor who's caring for his

00:57:37.180 mother. And he left a little, you know, reflection on the experience. He said in his entire life,

00:57:42.620 he's never seen anybody look as dejected as Hitler. And, you know, Hitler sort of okayed these experimental

00:57:48.780 treatments on his mother, which left her writhing in pain. And he was there at the bedside.

00:57:53.580 And for the rest of his life, he was obsessed with cancer and talked about it constantly in

00:57:58.860 his speeches as a metaphor, but was also a hypochondriac who constantly had stomach problems

00:58:03.980 and thought it was stomach cancer. And, you know, it became a huge part of the Nazi project is trying

00:58:09.500 to eliminate cancer. And, you know, one of the very uncomfortable things about this is that as

00:58:15.900 monstrous as the Nazis were in every way, they actually did make some some advances in cancer

00:58:20.620 prevention, you know, for all the wrong reasons, but they inherited a great scientific establishment.

00:58:25.020 And it makes sense that they, they would actually make some progress on cancer.

00:58:28.300 It's very interesting to imagine a world without the Nazis,

00:58:32.140 given the prominence of German science going into the Second World War and how much of a shift in

00:58:37.580 power that was scientifically post-World War II, right? How effectively that was the change from

00:58:43.980 Germany being the epicenter of science, not just biological sciences, but physics. And then that,

00:58:49.660 that shifting. In fact, so many of the journals, right, shifted from being published in German to

00:58:55.420 being published in English post-World War II. Yeah. I mean, the early 20th century,

00:58:59.180 you had to speak German to be a scientist or be able to read German. Yeah. It's incredible how

00:59:04.220 the extent to which, you know, all the early Nobel Prize winners were Germans, not all, but, you know,

00:59:08.380 shocking percentage. It's rumored. I don't, I've never actually been able to confirm if this is

00:59:13.500 true or not, because I've read various accounts that Warburg could have won a second Nobel Prize

00:59:18.700 during the Second World War. What was your finding on that? I think that he certainly deserved a Nobel

00:59:25.740 Prize for his cancer work, which he didn't get in 1926. I don't think there's, there's really proof

00:59:31.420 of the, the, you know, Warburg said that he didn't get the Nobel Prize in the forties because the

00:59:37.340 Nazis wouldn't allow it. He certainly would have, was considered for it. I found evidence that he

00:59:41.580 was considered for it, but I didn't find any evidence that they were going to sort of give

00:59:46.060 him the award, but couldn't because of the Nazi. And what work was that in the forties that they

00:59:51.100 would have been potentially considering him for? Warburg, his Nobel Prize, as we talked about before,

00:59:58.220 was for the understanding of the last stage of respiration, this, you know, enzyme that we now

01:00:03.500 call cytochrome oxidase. The whole time he had been saying in the twenties that this is the only

01:00:08.380 thing you need to know for respiration. It's kind of analogous to what he said about cancer,

01:00:12.620 but then he finally accepted that no respiration is actually a multi-stage process. And you actually

01:00:20.300 need not just to react directly with oxygen, but to rip hydrogen off these nutrients and to pass the

01:00:26.700 electrons down the transport chain. So he became interested in these hydrogen transfers

01:00:31.180 and understanding, you know, how the reaction took place. And he actually, you know, a lot of people

01:00:36.620 think this is the best science he ever did. He actually made huge advances in understanding

01:00:41.660 the role of coenzymes and how they react with hydrogen and allow for these transfers. You know,

01:00:49.180 it was really innovative work, kind of set the stage for decades of enzyme research. So that led to

01:00:56.140 the discovery of the components of NAD among other things. So he did deserve a Nobel prize for that,

01:01:01.660 but I don't, I didn't find any evidence that, uh, they were going to give it to him, but I think he

01:01:06.300 fairly deserved three Nobel prizes. Say a little bit more about his work on NAD. That was actually

01:01:11.340 new to me. I, uh, until recently was not aware of his contributions there. It's not surprising,

01:01:17.180 I suppose, when you consider his involvement with the electron transport chain. And as you point out,

01:01:21.580 the electron transport chain transports its electrons using hydrogen back and forth,

01:01:27.180 transporting between NAD and NADH. But it's actually kind of an interesting story, right?

01:01:31.500 About how he made these discoveries. Yeah, it was pretty surprising. You know,

01:01:35.660 his earlier research had been on sort of all this indirect evidence and sort of, he would basically

01:01:42.220 find the, you know, what they call the fingerprints of cells by, by using lights of different wavelengths and

01:01:48.540 getting light patterns to identify enzymes. But by the 1930s, he's trying to actually, you know,

01:01:54.460 isolate the enzymes and to do a chemical analysis to find out what the reactive components are.

01:02:01.260 So Warburg is trying to do a chemical analysis to figure out the reactive component of what we now

01:02:06.620 call NAD. He called the in-between ferment. And he can isolate a very small amount, but he can't

01:02:13.980 get enough of it to really understand and do the chemical analysis of what it is. And he's using

01:02:19.100 horse blood to study it. And he says at one point, to figure this out, I'm going to need to kill all

01:02:23.820 the horses in Germany. And he was a great lover of horses. So that was not a good option for Warburg.

01:02:29.100 But he knows he has enough of the stuff to figure out the molecular weight and a few basic facts about

01:02:35.340 it. So he has a friend who works in the chemistry industry, in the chemical industry. And, you know,

01:02:40.540 it's just a big part of German industry. And he asked him to look it up, see if he can find anything

01:02:45.340 similar. And based on what he looks up, he finds an exact match, which is nicotonic acid. So Warburg

01:02:52.060 is the one that figures out that, you know, this key component that makes this reaction possible is

01:02:57.420 actually a chemical that everybody knew about that was being used in photography for decades.

01:03:02.780 You know, Warburg said, you know, a day ago, I couldn't buy it for all the money in the world. And now,

01:03:06.380 you know, I can get it for two marks. And it actually turned out to be hugely important,

01:03:11.740 not only for understanding respiration, but for understanding the disease pellagra,

01:03:18.060 which was only sort of solved after Warburg made that discovery. And someone thought,

01:03:22.380 huh, you know, let's give this chemical to people who suffer from this disease and see if it cures them.

01:03:26.780 And sure enough, it did. And it's one of the ironies of Warburg's story that he always wanted

01:03:30.940 to make a great discovery and save lives. And he actually did, but he never even really recognized

01:03:35.740 it or saw it that way. So he stays in Germany after the war ends. He could obviously at this

01:03:42.460 point have gone anywhere. He could have come to the United States, which is what many of his peers

01:03:46.380 had done before the war. What was his reason for staying? For a few years after the war, I think he

01:03:52.300 was prepared to go elsewhere. I mean, I found letters of him, you know, searching for places and

01:03:57.260 he comes to America in the late forties and, you know, he stays in one lab for six months and another

01:04:03.100 lab for six months. But it's clear that there's no future for him in America that, you know,

01:04:09.020 a lot of the Rockefellers no longer want anything to do with them because, you know, it looks suspicious

01:04:13.580 that he had stayed. You know, the truth is he despised the Nazis as much as anyone,

01:04:17.260 but anybody who stayed when they could have left is under suspicion. And, you know, he's making more

01:04:22.540 and more extreme statements about cancer. So he's alienating a lot of people. And meanwhile,

01:04:29.980 in 1950, the Americans give him back his institute. They had taken it over when they had their military

01:04:36.140 occupation of Berlin. So he gets to go back to his beautiful institute and he has, again, some propaganda

01:04:42.460 value for the Germans. We can say, look, we've given this person of Jewish descent his institute

01:04:46.700 back and he's living here and thriving in Germany. So I think, you know, if he had gotten the right offer,

01:04:51.740 I think he would have gone to America, but he ended up sort of returning and reestablishing

01:04:56.860 his old life in a lot of ways. And in some ways it's shocking and upsetting, but, you know, by 1955,

01:05:03.180 from his perspective, it was like nothing had happened. You know, he's continuing with all

01:05:06.700 the same stuff. Now, forgive my ignorance. Was it an easy choice for him to end up in West Berlin

01:05:12.460 as opposed to East Berlin following the war and what determined that? Was it simply a function of where

01:05:17.100 he was prior to the war and therefore it was somewhat fortuitous?

01:05:20.620 Yeah, it is actually interesting and a little bit complicated. His institute ended up in the

01:05:24.940 American sector, but another extraordinary thing about his story is in 1943, bombs are falling near

01:05:31.900 his institute and he's actually moved to a new institute and the Nazis built him, you know,

01:05:38.700 they sort of refurbished this beautiful seahouse for Warburg in the middle of the worst part of the

01:05:43.260 war for them when, you know, there's no gasoline for anything. It's forbidden to build anything if

01:05:47.340 it's not for the war effort and they take time out to build, you know, something for Warburg to

01:05:51.420 continue his cancer research in a safer place. And that institute was actually ended up in Soviet

01:05:56.940 territory. So he was sort of caught between these two different worlds and he had a vacation house,

01:06:02.540 which is in Soviet territory. So when the war ends, he is actually under Soviet rule and he has to

01:06:07.980 escape back to the West. But the Soviets were trying to recruit him much more so than Americans,

01:06:13.580 interestingly, you know, both a lot of the great German scientists, you know, unfortunately,

01:06:18.220 a lot of Nazis ended up being smuggled into America for the purposes of American science,

01:06:23.100 but the Soviets were going after them as well. So he is sort of caught between these different worlds,

01:06:27.980 but ends up because his institute is in West Berlin is able to stay in the American side, ultimately.

01:06:35.180 So interesting to me because you have to wonder if people in Berlin at that time understood how

01:06:40.780 stark that contrast would be. You could argue that, well, gosh, it's just, it's wonderful that

01:06:45.660 the war is over and the Nazis are gone and you might end up on this American side or at the time

01:06:51.820 was American occupied, or you might end up on this, what will be a Soviet side. But it probably

01:06:57.340 couldn't have been clear just how different those two would end up being over the coming four or five

01:07:01.980 decades. I don't think it was clear, but it was clear that the Soviets, you know, with good reason,

01:07:07.660 were much more feared. So, you know, in the last days of the war in 1945, you had a lot of people

01:07:12.380 fleeing westward, not so much because they could imagine what the Cold War was like for decades,

01:07:17.420 but because they were worried about being, you know, murdered and raped, you know, because

01:07:20.940 the Soviets were with good reason, you know, furious at the Germans and out for revenge. And they

01:07:27.260 certainly took that revenge. So it was understood that you had a better chance of surviving if you

01:07:31.100 made it westward. But I don't think anybody could have foreseen what happened in the following decades.

01:07:36.620 Warburg has a really interesting tit for tat with Sidney Winehouse in science about a decade later.

01:07:43.020 I actually was able to pull up the article and read it. They both wrote letters. And Winehouse was

01:07:49.020 really kind of a mild-mannered guy, wasn't he? Yeah, he was, you know, most of the people

01:07:54.780 Warburg had these vicious scientific feuds with. I would look them up and they seemed, you know,

01:07:59.740 much more reasonable and calm than Warburg himself. Winehouse, I'm in the Philadelphia suburbs. He

01:08:05.100 actually worked at a hospital just, you know, a mile away. Yeah, he died in what, the early 90s,

01:08:10.300 I think. And he was at Penn, wasn't he? Or no, he was at Jefferson, if I recall.

01:08:15.260 Yeah, he may have been. I think he was at Lankana Hospital, but maybe at Jefferson as well. I'm not

01:08:20.460 sure. But he was around here. I actually found some people that knew him and talked to them a

01:08:25.580 little bit. But he publicly called Warburg out. He basically said, don't agree with this observation.

01:08:31.340 I mean, agree with the observation, don't agree with the interpretation, is what he said.

01:08:34.540 Yeah, I think if you look at the quotes from him, he was relatively calm about it. But, you know,

01:08:39.500 as a journalist, I have to laugh. Yeah, I'm sure it was the headline writer. You know,

01:08:42.540 the headline under one of the articles was, cancer theory overthrown. I don't think that

01:08:46.940 Winehouse would have put it that way, but some editor like me just wanted to,

01:08:51.100 you know, make it a little more sensational. Well, and he was deferential to Warburg in

01:08:55.500 the article. I mean, he did say something to the effect of, I don't remember exactly,

01:08:59.900 but the gist of it was, and we owe a great debt to Warburg for his amazing contributions to the field,

01:09:04.940 et cetera, et cetera. But cellular respiration is basically, he said, look, there's no difference in

01:09:10.540 oxygen consumption between these cells. And there's no evidence that the mitochondria are

01:09:14.140 damaged. Warburg's rebuttal was far less kind. You might be thinking of the, the papers in science

01:09:20.460 in 1956. Yes, exactly. Yep. I believe it's August, 1956, where first, you know, Warburg writes a piece

01:09:28.380 in early 56, and then Winehouse responds and Warburg responds to his response. And, you know,

01:09:33.260 Warburg comes off, I mean, it's a really elegant paper that he writes. He was a great writer. I mean,

01:09:38.540 we should have talked to Warburg's writing at the beginning because, you know, I really admire his

01:09:42.300 writing and, but, you know, he makes much bolder statements and denounces his opponents in a way

01:09:49.500 that the Winehouse doesn't. Winehouse is a more humble scientist. I encourage all listeners to

01:09:54.620 look up Warburg's paper from 56. It's pretty remarkable. We'll, we'll link to it in the show

01:09:58.620 notes for sure. I love reading that stuff. I mean, I just absolutely fancy reading that stuff,

01:10:04.060 which actually an example of one of my favorite scientific papers to read is the next logical

01:10:09.820 place to go in this story, which is the paper by Watson and Crick describing the helical structure

01:10:16.140 of DNA. So that's relevant to the story for reasons you will tell us, but it's also a funny paper in

01:10:22.380 that I think it's the last line either in the abstract or the paper makes some very, very, very

01:10:28.700 understated remark that this, this thing, what they're referring to as DNA, you know,

01:10:33.900 may prove to be of interest at some point or something to that effect. I used to be able to

01:10:39.020 quote it verbatim, but what is it about the discovery of, of DNA that would ultimately change

01:10:46.140 the course of Warburg's discovery and this entire field of cancer metabolism for decades to come?

01:10:50.940 By the fifties and sixties, Warburg is already fading away for some of the reasons we've talked

01:10:57.340 about. Winehouse challenges his belief that cancer cells have defective mitochondria. He sees

01:11:04.220 respirations running fine. So there's more skepticism of Warburg and people suspect him because of the

01:11:10.540 Nazi years. But I think the single biggest factor was sort of the changing wind in science and more

01:11:17.740 than anything, the discovery of oncogenes beginning really in the mid 1970s when they're first able

01:11:25.820 to identify specific genes that in their mutated, activated form caused cancer. So this unleashes

01:11:33.020 the whole new world of molecular biology and Warburg's study of enzymes and cancer metabolism starts to

01:11:39.820 seem like old world biochemistry stuff. And, you know, if you want to really understand cancer,

01:11:45.180 you've got to look at the DNA and these signal transduction pathways and all the new molecular

01:11:50.860 biology. And, you know, there's literally stories of like, you know, people seeing manometers thrown in

01:11:55.580 the trash, you know, Warburg's signature tool. And it's just amazing to me how quickly Warburg gets relegated

01:12:03.580 to the old world. And, you know, nobody's interested by the nineties, you know, students don't know his name.

01:12:08.940 And by the way, he died in what, 1970? 1970. But, you know, there's all these remarkable examples

01:12:15.420 in the year 2000, Robert Weinberg coauthors, you know, the hallmarks of cancer paper, which I'm sure

01:12:22.060 you know better than I do, the six fundamental traits of cancer and doesn't include the Warburg

01:12:27.660 effect or mention Warburg or metabolism. You later, you know, they later do a revised edition and do

01:12:33.260 mention it 10 years later, I believe. So Warburg is just gone from cancer science, gone from textbooks,

01:12:38.700 you know, Weinberg's famous textbook in 2006 doesn't mention him, you know, Mukherjee, who I think

01:12:44.460 his book is absolutely brilliant, but also doesn't mention Warburg just because nobody was mentioning

01:12:48.940 it. You know, it's just not something that people were interested in. They talked, you know,

01:12:52.620 the enzymes that Warburg say were referred to as housekeeping enzymes, you know, seems, you know,

01:12:57.260 cancer needs to divide and therefore it needs energy, it needs nutrients, but it's sort of not

01:13:02.780 fundamental to the process, just something that's needed to supply cancer as it progresses.

01:13:07.580 And it's really, it's really shocking to me that something so fundamental could just get lost.

01:13:12.460 But to some extent, that's how science works. You know, there's an exciting new thing and it's

01:13:16.460 hard to focus on two things at once. And look, I mean, I think it is a very remarkable discovery

01:13:22.860 in the 1970s that there are oncogenes and Harold Varmus and Michael Bishop awarded the Nobel Prize in 1989

01:13:29.980 for that discovery. It holds a lot of great promise. Certainly by the time I got to medical school in the

01:13:36.780 late nineties, my God, if I could go back and figure out how many oncogenes and tumor suppressor genes I

01:13:42.620 had memorized and all the pathways and such, I mean, that was really what, that's the only thing that

01:13:48.380 mattered in cancer biology. So what do you think led to the Renaissance? I mean, for me personally,

01:13:55.100 the first thing that came on the radar screen was a science paper in 2009 written by Matthew Vander

01:14:02.540 Heiden and coauthored by Lou Cantley and Craig Thompson. Was that sort of the first thing that

01:14:09.100 showed up on the radar? I mean, obviously those three had been doing a lot of work leading up to

01:14:13.660 that. I've had Lou on the podcast and we've talked at great length about his work and the discovery of

01:14:18.380 PI3 kinase. So clearly this idea that metabolism mattered was on the radar of others, even though it was not

01:14:24.700 necessarily on the forefront of the field. Yeah. I think that paper was, you know, the moment

01:14:31.100 it was 2009 or 2010 that it sort of reached the mainstream. But, you know, as you mentioned,

01:14:36.380 they had been working on this stuff for some time. So it was really in the late nineties that the

01:14:42.140 revival starts mid to late nineties. And the two key labs, I think at the early stages, one is Craig Thompson,

01:14:49.820 who you mentioned, who is now the president and CEO of Memorial Sloan Kettering. And the other lab was

01:14:55.340 Chi Van Dang, who was at the time at Johns Hopkins. And they both were working on, you know,

01:15:02.860 understanding cancer molecular biology and both tracing these signaling pathways to the cell and

01:15:09.500 sort of working their way back to metabolic enzymes. In Chi's case, he found that the

01:15:15.500 transcription factor, Mick was actually activating lactose dehydrogen, LDH. And, you know, he was

01:15:21.980 really quite shocked to find this pathway leading back to this basic fermentation reaction. So he

01:15:28.380 became very curious about Warburg and reading the old papers on enzymes and really helped launch a lot

01:15:35.740 of the metabolism revival. And then Craig Thompson and Vander Heiden was a student in his lab. They had

01:15:43.660 also sort of independently rediscovered metabolism and ended up focusing on, on AKT, which was already

01:15:51.260 known as a, an oncogene that caused cells to proliferate. So the surprising part of their work

01:15:57.660 wasn't that they had found an oncogene, but that this oncogene was actually a metabolic gene that what

01:16:02.540 its role was basically to, you know, allow glucose into the cell. And that, you know, Thompson,

01:16:07.980 I think correctly states that this is the most fundamental thing that it does and that, uh,

01:16:12.540 the proliferation, you know, is, is, is downstream of this glucose uptake.

01:16:16.860 Yeah. It's a very pro growth factor. So what I think is most interesting about the 2009 paper in science

01:16:23.900 is that it acknowledges the Warburg effect, but comes up with a different explanation.

01:16:28.460 And what was that explanation?

01:16:29.580 So prior to this point, the accepted view or that Warburg's view, which, you know, again,

01:16:36.380 some, some people still support is that all fermentation is a response to defective

01:16:41.900 mitochondria is compensatory. The cell can't create energy in one way. So it's using the backup

01:16:47.340 generators. It's, it's revving up fermentation, but you know, what Thompson and Vander Heiden and

01:16:52.060 Cantlie argue in that paper is that we actually don't have, as we talked about with Winehouse,

01:16:57.100 we don't actually have the evidence that, that respiration is completely defective.

01:17:01.580 So the mitochondria still seem to be functional and intact. And, uh, there are other reasons that

01:17:06.620 a cell might need to take up a lot of glucose and, you know, first and foremost, they're bioenergetic.

01:17:11.820 They need the building blocks to create new nucleotides and lipids for, for the daughter cells.

01:17:18.140 So it makes sense that glucose uptake would increase rapidly, but the cells,

01:17:22.700 they actually, you know, they're getting some energy, some ATP from respiration,

01:17:26.620 some from fermentation, but they have enough to continue to function. What they really need are

01:17:30.940 the building blocks for growth. And so that is a sort of new way to understand the Warburg effect.

01:17:36.460 And, uh, I think that, you know, that's now what most, most scientists, but not all sort of view

01:17:42.060 is, is the main explanation. What's your view? It's tough as a science writer,

01:17:48.060 as a reporter, you know, I, I'm not trained as a scientist and I interview one person, you know,

01:17:53.660 famously Thomas Seyfried, who is very much, uh, a Warburgian who thinks that Warburg got it exactly

01:18:00.460 right. And that it is a problem of defective mitochondria. And he cites the research of,

01:18:06.220 uh, I believe, uh, Peterson at Johns Hopkins, who, who also believes this. So there are a lot

01:18:10.540 of very smart, accomplished scientists who think Warburg got it exactly right. And, you know,

01:18:15.820 it would have been easier for me to writing this book to conclude that Warburg was right about

01:18:19.580 everything. You know, that's the story that would have been easier to tell and made my narrative

01:18:23.260 tighter. But I interviewed many more people who, who felt that Warburg was wrong about this, that

01:18:29.020 it was not ultimately a problem of, of defective mitochondria. And, uh, you know, I look at papers

01:18:33.820 from both sides and don't ultimately feel that, uh, you know, I have a good way of resolving this debate,

01:18:39.660 but ultimately I, I sided much more so with, um, Cantlie and Thompson and Vanderheide and, and, and

01:18:48.300 others like Nav Shandel, who, who also takes this position. And it's partially just a numbers thing.

01:18:55.180 Like many more people believe this and their evidence is compelling and I can see that they're

01:18:58.780 brilliant. And it's partially also sort of an intuitive feel for the science. I say that because

01:19:06.220 one of the things that really struck me is when Craig Thompson was, uh, giving a, a demonstration

01:19:11.180 for, for students about, uh, what cancer is, he puts up this slide. I don't know if you've ever

01:19:16.780 seen this talk and he shows a mold growing on a piece of bread and he said, everybody's first

01:19:21.980 cancer experiment. And then he shows the mold growing and, you know, it really goes back to

01:19:27.660 Pasteur and an understanding of proliferative metabolism is not something that happens in microorganisms

01:19:33.580 only in response to defective respiration. And that's what Pasteur thought, but he was wrong.

01:19:39.260 You know, proliferative metabolism happens when a cell can get all the nutrients at once. You know,

01:19:44.700 you put, I mean, when I say a cell, I mean the microorganisms and you put the yeast on grain and

01:19:49.420 they don't care how much oxygen is available. They take up the grain and they grow and they grow and

01:19:53.900 they multiply. And, and that I think is a fundamental program that our cells know how to do as well.

01:19:59.340 And I think that's really the key to the story is what causes this proliferative program to take

01:20:07.660 off. And I think it's in single celled organisms, it's the nutrients. And, you know, when you look

01:20:12.300 at advanced organisms, animals, we have to think not just about the nutrients, but the hormonal

01:20:17.020 involvement as well. It's much more complicated, but the fundamental program is running and it's the

01:20:23.500 nutrients and the growth factors. I mean, I think if you just step back from it and you say,

01:20:29.100 what is cancer? It's a problem of growth. Okay. Well, what causes things to grow, you know,

01:20:33.420 nutrients and hormones, that's where you start the conversation. And I think that

01:20:38.380 if science had progressed in a different way, then that always would have been the focus. But,

01:20:43.180 you know, it was only in, you know, the late 1960s where we could even measure insulin in the blood.

01:20:48.220 So, cancer, all this stuff about the Warburg effect as a response to damaged respiration made

01:20:56.460 sense before we knew anything about insulin and growth factors. But, you know, the science has

01:21:01.900 progressed and I tend to view it in much more of the way of Thompson and Cantley. But I do think that

01:21:09.100 Seafree deserves a ton of credit for sort of bringing metabolism back into the conversation. And it is,

01:21:14.780 as I said before, I think everybody agrees that as a cancer progresses, you know, the blood vessels

01:21:21.420 no longer are getting oxygen in the same way. And that's clearly playing a role in terms of revving

01:21:25.820 up fermentation. So, it's not necessarily either or, but at the sort of core origin of cancer,

01:21:32.780 I don't see that the respiration damage is being sort of conclusive. And I don't either. I mean,

01:21:38.860 I just think on first principles, it doesn't actually make sense. If you follow the logic of Warburg,

01:21:44.140 if the primary insult or the prime cause to use his language is damage to the mitochondria,

01:21:52.060 that's an insult to a cell. That's a deficit to a cell. That's an inhibition of a cell's ability

01:21:59.420 to respire and frankly, acquire energy. So, the fact that the cell has the ability to do something

01:22:06.860 outside of the mitochondria in a compensatory fashion is great. But in and of itself, that doesn't

01:22:12.060 explain why it would take up more nutrient. It simply explains why it would metabolize nutrient

01:22:19.100 in a different way. And for me, at least, to focus just on the availability of nutrients

01:22:24.780 and hormones doesn't explain to me why, if we're, let's just talk about colon cancer, right? Or

01:22:31.100 pancreatic cancer. You pick your cancer. You have a normal cell and you have an abnormal cell.

01:22:38.140 The normal cell, presumably then, is the one that is not going to become cancer. The abnormal cell

01:22:43.420 is the one that is going to seed the cancer. They're both exposed to the same amount of nutrient.

01:22:48.860 They're both exposed to the same hormonal milieu. So, why is only one of them going down that cancerous

01:22:55.020 pathway? Why is one turning into a polyp? And why is only that polyp becoming dysplastic and ultimately,

01:23:02.220 you know, or metaplastic and ultimately dysplastic and ultimately becoming metastatic?

01:23:07.660 I think that the hormones and the nutrients are simply the fuel that allow the thing to happen,

01:23:12.300 but they're not the spark. You know, and to me, the spark is what matters. And that's why I don't

01:23:17.580 agree that Warburg was correct. I don't agree that the initial insult is the mitochondrial insult.

01:23:23.500 I think that the event that is driving this, I think the oncogenic effect is the driver.

01:23:28.220 And I think the metabolism allows the cancer to be even more adaptable to the scenarios that you

01:23:35.100 describe. And I've spent, perhaps not as long as you, but I've certainly spent a lot of time

01:23:40.860 talking with people on both sides of this, going to conferences. But in the end, it somewhat matters

01:23:45.900 because it comes down to what's the implication of this from a treatment and prevention standpoint.

01:23:50.300 And I would say in the opposite order, right? What's the implication of this from a prevention

01:23:53.740 standpoint? What's the implication of this from a treatment standpoint? And that's what I think

01:23:58.620 about because in the end, that's the part that I think is a kind of a bedside doctor. That's the

01:24:04.620 part you have control over is what can you do to prevent cancer or reduce the probability of cancer?

01:24:10.540 I don't think one can truly ever prevent it. And then in the presence of it, what can you do?

01:24:15.260 How did this work impact your thinking on that question?

01:24:18.940 In my mind, that's really the key to my whole story is there's sort of two components to it. One

01:24:26.700 is what's going on inside the cancer cell. And that's all this discussion we've had about

01:24:32.620 the Warburg effect. But there's another part to the story, which is 150 years, 200 years of cancer

01:24:39.100 epidemiology and seeing various environmental causes of cancer or various theories about what

01:24:47.020 causes cancer. And what really struck me, and I don't think, you know, as a journalist, I can't

01:24:54.780 understand the science sometimes in the same way that probably you can and a lot of the people I

01:24:59.500 interview can. But what I try to do is connect dots. You know, that's one thing I can do as a journalist,

01:25:04.380 is look at one scientific field and another scientific field that aren't

01:25:07.820 necessarily talking to each other and try to put stories together. And the thing that really struck

01:25:13.020 me was that in the late 90s, at the very same time that Thompson's lab and Chi Van Deng's lab are

01:25:19.660 returning to Warburg metabolism, we have these new epidemiology papers coming out showing both that

01:25:26.300 insulin is correlated, you know, elevated insulin, hyperinsulinemia is correlated with cancer and obesity

01:25:31.340 is correlated with cancer. So it happens at the same moment. And that, in a lot of ways,

01:25:35.580 that was my project for the end of the book is trying to understand, you know, is the obesity

01:25:40.620 story related to the overeating of glucose in the cancer cell? And I think those two stories are

01:25:46.860 related. And that's why, you know, the last part of my book is really a focus on hyperinsulinemia,

01:25:52.780 because I think it's the piece that puts it all together. It could explain the obesity, it could explain

01:25:58.300 the cancer, and it could explain why cancer was once a rare disease. And then in step with diabetes

01:26:05.900 and obesity and other, quote unquote, diseases of civilization became much more common. So

01:26:11.260 in my book, insulin is sort of the explanation which ties it all together, which obviously not

01:26:16.540 all cancers are caused by insulin. And insulin's role, according to some scientists, is only indirect.

01:26:22.460 It causes the obesity and the obesity causes other hormonal changes and inflammation. But one way

01:26:27.500 or another, I think it's a big part of the cancer story and the part that if we're going to really

01:26:31.660 make progress on prevention, we have to focus, I think, on hyperinsulinemia. To me, this is now exactly

01:26:38.620 50 years since the war on cancer begun. And we've made so little progress in many ways, certainly with

01:26:45.580 respect to prevention. And there's been remarkable cures and therapies. And I revere the scientists who make

01:26:51.180 this work. But certainly in terms of prevention, we're just not making progress. And I think it

01:26:55.820 probably comes back to the hyperinsulinemia. Again, I do kind of like the way Warburg positioned

01:27:02.540 a prime cause and secondary causes. So when you think of the ravenous diarrhea that was ripping through

01:27:09.980 London in the 1800s, the prime cause was cholera. But the secondary cause was the lack of sanitation.

01:27:17.580 It was that which permitted the cholera to travel so freely from sewage to drinking water.

01:27:26.300 So now let's think about cancer through the lens of the two most readily identified epidemiologic

01:27:33.420 factors on scale. Not necessarily with the clarity of evidence, but just in terms of breadth of numbers

01:27:39.020 impacted. First and foremost is smoking. And second, as you point out, is obesity, at least in the

01:27:44.140 developed world. So with smoking, would we put it in the prime or secondary cause? I think we'd put

01:27:51.900 it in the prime cause, right? I think we would argue that the evidence for the causal relationship

01:27:58.540 between cigarette smoking and cancer is likely related to the carcinogenic effect of the tobacco

01:28:07.180 on presumably the DNA structure of the cells that leads to mutations that drive unresponsive or

01:28:15.820 unregulated growth. Would you agree with that? Yeah. I mean, it does come down to semantics at

01:28:21.660 some level. You could argue that the prime cause is the mutation in the DNA that's driving the cancer,

01:28:28.780 or you could say that cigarette smoke is the prime cause. I personally find it

01:28:33.180 more sort of logically compelling to talk about the prime cause as the very first thing in the step

01:28:38.700 and the very first step in the process. So I think you can say cigarette smoking is the prime cause.

01:28:44.380 But by Warburg's definition, he would say that if you accept that paradigm, then you would say

01:28:49.580 the mutation is the prime cause, the chromosomal damage, whatever it is.

01:28:54.860 Another way to think about this is that the accepted paradigm is that all the problems,

01:28:59.100 you know, one way or another go through the DNA and that the safe read and paradigm is that all the

01:29:05.500 problems go through the mitochondria. So those are the, you know, the two sort of causal centers.

01:29:09.900 But I think logically prime cause should be the very first thing. So smoking in the case of cancer

01:29:14.780 makes sense to me. Yeah. No, I think that I agree with you. I think that makes sense.

01:29:18.380 So now the question is, how do we apply that thinking to the second one? Well,

01:29:23.340 we pause it first that indeed obesity plays a causal role in cancer. There's no dispute that

01:29:30.780 the correlation is quite strong. That, I mean, you don't need to be an epidemiologist to understand

01:29:36.300 that. The question is, is that correlation causative? Now with tobacco, the correlation is

01:29:42.060 so strong that it's very hard to find somebody who doesn't appreciate that there's a causal relationship

01:29:49.340 there. I did see somebody on Twitter the other day, try to argue that tobacco has no relationship

01:29:55.980 to cancer, but let's put that guy aside for a moment with obesity. It's a little harder because

01:30:02.300 the hazard ratio isn't nearly as large as it is with tobacco and obesity is, is actually harder to

01:30:09.100 disentangle from its other multivariate parameters. It comes with so much else. So the person who is obese

01:30:17.260 obese eats a different way, sleeps a different way, exercises a different way, the list goes on and

01:30:23.900 on and on of other things that could potentially play a role. But again, for the purpose of the

01:30:31.020 discussion, if we posit that obesity is causally related to cancer, then the next step is, is it

01:30:38.540 one of the growth factors associated with obesity of which insulin is one? Is it other changes that are

01:30:44.860 prominent with obesity such as inflammation? How do you then arrive at, you know, for example,

01:30:50.460 insulin being the prime candidate to use the word prime again within the obesity paradigm that's

01:30:58.380 driving this? And that says nothing by the way of where we're going to then have to go, which is,

01:31:03.100 is it the enabler or is it the primary cause? Sure. My argument is that ultimately,

01:31:10.140 as you said, these are very complicated. You know, there's, there's many different factors

01:31:16.300 that play out, but, but my ultimate argument is that the obesity is not causal, that it's

01:31:21.980 actually the hyperinsulinemia that is simultaneously driving the obesity and the cancer cell proliferation.

01:31:29.340 So I think part of the evidence for that is that there are people who are quote unquote,

01:31:34.540 metabolically healthy obese that, you know, they store more nutrients in their, their subcutaneous

01:31:40.540 fat and more energy in their subcutaneous fat and not the visceral fat. And they tend to be

01:31:45.020 metabolically healthy and do not have insulin resistance. And they seem to be no more likely

01:31:49.100 to get cancer. Whereas when you look at the insulin resistance and people who are thinner,

01:31:53.580 but clearly, you know, I think it's most of the people actually do have insulin resistance.

01:31:57.740 And when you see that metabolic disruption in people who aren't obese, they,

01:32:01.340 that also tends to correlate with cancer. So I think you can, to some extent, dissociate the obesity,

01:32:07.100 but then you still have to be insulin cancer correlation isn't as strong as smoking either.

01:32:13.260 So, you know, you still have a lot to work with. And then, you know, there's the question

01:32:17.420 that you brought up is, I think this is what you're referring to is the insulin actually, you know,

01:32:23.980 the first prime step in the process, the hyperinsulinemia, or is it a mutation that occurs for some

01:32:29.340 other reason and allows the cancer cell to take advantage of that hyperinsulinemia?

01:32:34.140 Yeah. Is the model basically that if you take a two by two matrix where you have chromosomal insult,

01:32:43.740 yes or no, hyperinsulinemia, yes, no. So which one gets cancer? Is it only the double positive?

01:32:52.860 I mean, we would agree that the double negative almost assuredly does not.

01:32:57.340 And we would probably agree that the double positive does. The question is what's happening

01:33:01.820 on the other corners? What's happening in the individual who has the chromosomal insult in the

01:33:07.580 absence of hyperinsulinemia? And what's happening to the person without the chromosomal insult who is

01:33:13.820 hyperinsulinemic? To me, those are the questions that matter a lot and they matter a lot for the sake

01:33:19.340 of prevention. Now, the obviously, and this is the approach that I take clinically, which is,

01:33:25.580 let's be overly aggressive and assume that both of those are sufficient. Then you would say,

01:33:32.300 well, you have to put yourself in the double negative box, which is avoid hyperinsulinemia and

01:33:39.900 any sign of metabolic ill health and do every single thing imaginable to reduce the burden of

01:33:47.020 DNA insult. And you try to narrow yourself and confine yourself into this very narrow box. And

01:33:53.500 then you layer on a whole bunch of other things like really aggressive screening and all this other

01:33:57.660 stuff. So that's kind of what you would do if you don't have a choice. If you're absent perfect

01:34:03.020 information, you have to probably act more aggressively. But I still think this question

01:34:07.580 of which of the two positive, negative, negative, positive squares, at least for me, I don't have a

01:34:13.420 great understanding of those because I think they exist in both. I think there are examples and

01:34:17.260 counterexamples for both. I don't think anybody has a great answer for it at this point, but I do find,

01:34:24.380 you know, this is speculative, but one hypothesis is sort of that these chromosomal insults occur by

01:34:29.980 by chance or for whatever reason. And, you know, eventually you get one in this PI3K pathway and

01:34:35.740 cells now able to take advantage of that hyperinsulinemia. But another speculative idea is

01:34:41.180 that if you have hyperinsulinemia and excessive glucose metabolism, that it's actually going to be

01:34:46.460 driving the chromosomal insult through, you know, creation of reactive oxygen species in the mitochondria

01:34:52.780 and that the hypermetabolism, you know, as Craig Thompson puts it, actually creates a way for the cell

01:34:57.740 to mutagenize. So I think that's probably part of the story. And, you know, there's new research

01:35:02.220 coming about how nutrients are actually, you know, play a huge role in epigenetics as well. So

01:35:08.780 it may be that there's just bad luck, a mutation comes along, and then if the insulin is there,

01:35:13.580 a cell takes advantage. And if it's not, maybe that microscopic tumor never takes off. You know,

01:35:17.900 a lot of people die with cancer rather than from cancer, as they say. Maybe the immune system can

01:35:23.500 kill these microscopic tumors if not for the insulin, keeping the, you know, insulin really

01:35:28.860 tells the cell to stay alive. And so I don't think we have great answers to these questions. But I think

01:35:34.140 that, you know, if you just step back and look at the epidemiology, like, you know, something has to

01:35:38.700 be going on with nutrition, you know, because, you know, the cancer was so much more rare prior to the

01:35:43.740 shift to the Western diet. And, you know, it could be many different things, but it all points to

01:35:49.180 hyperinsulinemia. And, you know, it's a growth factor, you know, and cancer cells are covered in

01:35:55.500 insulin receptors. It just makes a lot of sense that this is really fundamental in one way or another.

01:36:01.180 The counterpoint is maybe that you just have bad luck and get an AKT mutation and the cell,

01:36:07.900 you know, no longer needs insulin and can just get all the glucose it wants. And that, you know,

01:36:13.340 may be true in some cancers, but as I understand it, that even when you have these mutations in this,

01:36:19.180 PS3K, KTM to our pathway, that they're still insulin dependent, just less dependent.

01:36:23.260 So you can imagine a scenario at least where keeping insulin really low will help even if

01:36:28.140 that chromosomal insult takes place and it makes the cell more susceptible.

01:36:32.380 You know, what about non-insulin requiring nutrients such as fructose? Rick Johnson and

01:36:39.100 Lou Cantley have both spoken about this. What, if anything, did you uncover about the potential

01:36:44.700 role of fructose in cancer? That was one of the more surprising parts of the story for me

01:36:51.500 and humbling in a way as well. A reminder to me, you know, I was writing about Warburg who

01:36:56.700 always believed too strongly in his own ideas and couldn't accept that they may be wrong. And,

01:37:02.300 you know, it's anytime you're writing a book that has any kind of argument and you sort of fall into

01:37:05.980 that trap and have to remember that science changes and not everything is proven. So I had

01:37:12.060 decided early in my writing process that I thought sugar, sucrose, was a big part of this story.

01:37:18.300 But my assumption was that it was all by way of driving liver fat and insulin resistance and

01:37:25.420 hyperinsulinemia. In recent years, this work out of Cantley's lab and Richard Johnson's has shown that

01:37:31.820 even independent of the effects on insulin that fructose seems to drive certain cancers that

01:37:38.780 particularly in the colon that are able to get the fructose and actually turns on, you know,

01:37:43.900 through sort of a, an odd bit of metabolism actually turns on the Warburg effect and allows

01:37:48.460 sort of ATP to go down and then glucose to flow in. But, um, the surprising part for me was that

01:37:53.580 that could be disassociated with insulin. And I had to step back and say that maybe sugar is even worse

01:37:59.020 than we thought and, uh, is this sort of causing cancer in two different ways in some cases.

01:38:03.980 Yeah. That, that to me is the most interesting question. Still somewhat unresolved, frankly,

01:38:09.820 although I think Rick Johnson's work is among the most compelling I've seen to disentangle that

01:38:15.260 relationship of fructose independent of its caloric contribution. And as you said, this is,

01:38:21.020 this is a mechanism that has an indirect effect on insulin. So fructose metabolism,

01:38:27.100 when consumed in excess does in fact lead to insulin resistance, which by its very definition

01:38:33.340 leads to hyperinsulinemia, but, but the work you allude to in, in colonic cancer by Lou Cantley

01:38:40.220 actually posits that it's the energetic issue in the cell that you've alluded to of the trans and

01:38:46.220 Johnson as well, it's this lowering of ATP in the process of metabolizing fructose. And it's that ADP,

01:38:52.780 ATP sort of switch that can drive the hyperinflux of glucose. And that's not necessarily an insulin

01:39:01.020 driven phenomenon. Yeah, that, you know, it's kind of odd for me in a way it supported my hypothesis

01:39:07.260 that sugar is at the center of the story, but it, it sort of upended my idea of what the mechanism

01:39:11.500 was. Yeah. So, you know, there's still clearly a lot to learn, but I found, you know, Rick Johnson's

01:39:17.420 whole discussion of this absolutely fascinating. I listened to the podcast and when he was talking to

01:39:22.540 you, part of it, you know, all this stuff we were talking about the turn to fermentation,

01:39:27.260 low oxygen environments, which, you know, again, I think you and I agree that that's maybe not the

01:39:31.900 whole story of some people think, but that it, the seesaw like relationship does exist. But

01:39:36.860 his example, which really fascinated me was that these naked mole rats, I don't know if you remember

01:39:41.740 this, but the, you know, they live in this low oxygen environment and they, they run a lot of

01:39:45.820 Warburg metabolism by converting glucose to fructose and then using the fructose to drive the Warburg

01:39:51.820 effect. It was really fascinating to me. What did you learn in this project that

01:39:57.100 you absolutely positively could have never predicted? I mean, you, you sort of alluded to

01:40:01.340 the fructose more than glucose issue here. Was there anything else that either historically or

01:40:06.140 scientifically completely caught you off guard and challenged what you thought you knew about

01:40:10.700 yourself or this body of work? Yeah, it's a good question. I think one of the

01:40:18.620 things that really struck me, I think a lot of people who spend years researching and writing about

01:40:24.940 Nazis end up with a similar insight, but you sort of have to go through it to, to maybe realize it

01:40:31.980 is, you know, I grew up, you know, Jewish and learning about the Holocaust and Nazis and

01:40:38.780 in my mind, you know, they were evil monsters and, and, and they were, but I, I never humanized them. And

01:40:46.140 now I had to sort of look at the personal stories of all these Nazis and, and, and not think of them as

01:40:53.580 in an abstract, evil, monstrous way, but understanding as human beings, how they went down this path and

01:41:01.020 how it happened progressively throughout the thirties and how it could be that somebody who,

01:41:06.300 you know, might in one context, be a nice neighbor and friend, and then go into the office and, you know,

01:41:11.900 work on documents that lead to, you know, millions of people ultimately getting murdered, you know, just

01:41:16.460 getting into the lives of these people and seeing that progression, it really was chilling and eye

01:41:21.500 opening in a way to make me think that this wasn't an anomaly, that this in theory, you know, it has

01:41:28.540 happened elsewhere in various forms and could happen elsewhere. So it made me much more politically

01:41:34.220 attuned to certain extremist politics. So that was part of it on a political level. And on a personal

01:41:41.340 level, in terms of the writing, it was such a daunting project for me. How many words is the

01:41:46.220 book, Sam? I actually don't even know. I think it's about 120,000, some words, but I didn't have

01:41:54.540 the training in biochemistry. I didn't speak German fluently. And I didn't plan to write the book. The

01:42:01.100 publisher came to me and said, I saw your New York Times article. Do you want to do this? And I

01:42:06.460 hesitated. I didn't say yes right away because it's such a big project. But I think that over the

01:42:12.140 years, I sort of learned a lot about myself as a writer and sort of was able to gradually trust myself

01:42:19.740 more as a historian. And I feel more confident as a writer having completed this project. We'll see, you

01:42:27.900 know, if I still feel that way after somebody trashes the book. But for me, I felt like I was taking a big risk

01:42:34.220 and that I made it to the end of that project, you know, it's very rewarding. It makes me feel

01:42:39.340 confident about taking on other stuff. As a writer, do you pay attention to what

01:42:43.900 people say about your work? Or do you go out of your way to avoid reviews and things like that?

01:42:48.460 I go out of my way to avoid reviews. What's fascinating to me is that even positive reviews,

01:42:54.860 which I'm very grateful for, but they also make me uncomfortable. Just the thought of anybody

01:42:59.900 sort of passing judgment, you know, on something that, you know, you work on so hard for so many

01:43:05.020 years, it's just, it's just too much to, to get a reaction to it in some ways. I am incredibly

01:43:10.700 grateful for the positive reviews. And it's been really rewarding to get some nice responses to the

01:43:15.100 book on Twitter. But I think there's gonna be a New York Times review out soon. I'm not even sure I

01:43:19.260 can read it. You know, I just, I have the same thing with my student, you know, I teach and students

01:43:24.380 provide assessments of my teaching at the end of each semester. And I read them because I need to know,

01:43:29.820 how to become a better professor, but it makes me deeply uncomfortable. I don't write book reviews

01:43:34.060 anymore because it's just, you know, when somebody works on something so hard for so many years,

01:43:38.220 it's terrible to have to pass judgment on it. You know, I'm kind of a softy, I guess.

01:43:42.700 But how do you learn then? I mean, I can be totally sympathetic to that, but is there a model

01:43:47.180 where you let somebody else read the reviews and pass on just the objective, this is working,

01:43:52.780 this is not working feedback? I'm asking, honestly, for personal reasons, as I sort of think

01:43:57.580 about how to digest feedback in a forum that is actually very harsh.

01:44:02.220 No, it's certainly, I think it's certainly true that if you don't read your reviews, you're not

01:44:06.220 gonna learn as much. But in a way, it's too late at that point. You know, what I do is,

01:44:12.140 before, before I finished the project, I sent, you know, first and foremost, my editor, who is

01:44:16.300 wonderful liverite, Dan Gerstle, to do a shout out. But, you know, I also have a handful of trusted

01:44:22.540 friends who I send the manuscript to and get their feedback on. And certainly, that doesn't make me

01:44:28.700 uncomfortable, because it's a different dynamic. It's not in public, it's in private. And there are

01:44:32.620 people that I trust. And I don't feel publicly shamed if they tell me it's awful. And I can't get

01:44:38.540 better unless I get their feedback. And, you know, I got tremendously valuable feedback from

01:44:42.700 those early readers. So, every writer I know does some form of that. And I think everybody should.

01:44:48.540 So, Sam, tell folks again, the name of the book.

01:44:50.220 The book is Ravenous, Otto Warburg, The Nazis, and The Search for the Cancer Diet Connection.

01:44:56.220 All right. Well, Sam, thank you very much for taking the time, so much time to sit down with me today

01:45:02.140 and talk about this and share these insights with all the folks that are, everybody's interested in

01:45:07.260 cancer. So, I think there was a lot here, both in the history of it and also the implication,

01:45:11.900 which is potentially that metabolism plays a very important role in cancer. It might not be entirely

01:45:18.780 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

01:45:24.940 mix. So, the more we can do to reduce hyperinsulinemia, improve our metabolism, reduce reactive oxygen

01:45:31.500 species, all these things that you've spoken about, presumably the better odds we have against the

01:45:35.100 disease to which we've made very little progress, as you point out in the last few years. So,

01:45:38.700 thank you, Sam.

01:45:39.180 Yeah. Thank you so much. It was an honor to be on the show.

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01:48:14.320 you

The Peter Attia Drive - December 13, 2021

#187 - Sam Apple： The Warburg Effect—Otto Warburg's cancer metabolism theory

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