The Peter Attia Drive - #32 - Siddhartha Mukherjee, M.D., Ph.D.: new frontiers in cancer therapy, medicine, and the writing process

Episode Date: December 10, 2018

In this episode, Siddhartha Mukherjee, oncologist, researcher, and author of the Pulitzer Prize-winning book “The Emperor of All Maladies: A Biography of Cancer,” discusses his writing process, his thoughts about medicine, cancer, immunotherapy, and his recent collaboration on a study combining a ketogenic diet with a drug in mice that provided remarkable and encouraging results. We discuss: Sid’s background [5:00]; How Sid and Peter met [6:00]; Sid’s Pulitzer Prize-winning book: The Emperor of All Maladies [8:00]; Sid’s writing process: the tenets of writing [12:30]; Our struggle to find preventable, human, chemical carcinogens of substantial impact [23:30]; The three laws of medicine — Law #1: A strong intuition is much more powerful than a weak test [26:30]; Law #2 of medicine: “Normals” teach us rules; “outliers” teach us laws [32:00]; Law #3 of medicine: For every perfect medical experiment, there is a perfect human bias [35:00]; The excitement around immunotherapy [38:15]; The story of Gleevec [46:00]; How does the body's metabolic state affect cancer? [49:30]; Can a nutritional state be exploited and/or a drug sensitivity be exploited through a nutritional intervention? [52:00]; How does Sid balance his family, writing, research, laboratory, and patients? [1:00:30]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peteratia-md.com.

Hey everybody, welcome to this week's episode of The Drive. I guess this week is Sid Mukherjee, who is a remarkable writer. In fact, a Pulitzer Prize winning writer, and a remarkable physician and scientist. In fact, probably there's nobody I know that combines those three things as efficaciously as Sid does. His biography reads like I'm making it up. He studied biology at Stanford. He then became a Rhodes scholar, went to Oxford, earned his PhD in immunology, returned to the United States to earn his MD at Harvard, etc, etc, etc. Fast forward to today. He is an associate

professor of medicine in the Division of hematology and oncology at Columbia University, which is where we met to do this interview. He has published also and continues to publish consistently in both the New Yorker and the New York Times, which in and of itself is quite a distinction, as I would learn, typically one is on either side of those, but not both. And of course, he's published in the New England Journal of Medicine, Nature, in addition to a whole host of other medical journals. I met Sid by five years ago at a dinner that was set up

by Lou Cantley, someone I'll be interviewing very shortly, who will be a guest obviously soon. And while I remember that dinner very well, I was surprised to learn that it left such an impression on Sid and he described it as something to the effect of one of the most interesting and perhaps important scientific collaborations in his life that stemmed from it. As we kind of jotted out a napkin experiment that went on to become a paper that was

published by a group led by Lou and Sid. And that paper was published this past summer, and we talk about that in detail. That paper involved the use of ketogenic diets in combination with a class of drugs called PI3 kinase inhibitors. We're going to go into great detail on that, so I obviously don't want to repeat any of that stuff here. But I think for those of you that are interested in cancer, you're obviously going to find this episode very interesting.

But the other thing we'd said is, it doesn't matter if you have no interesting cancer. I think you'll find this discussion interesting because Sid has a way of making everything interesting. And that, to me, is part of Sid's gift. When I got his book, The Gene, in the summer of 2016, when it came out, it's one of probably only six books in my life that I was not able to stop reading from the moment I started.

So it was one of those things where everything else I was doing had to be put aside for a few days until I could finish that book. That's just the way Sid writes. And that's also the way he speaks. He is a unique human being and I think that will come across in this interview. The other thing that was a total pleasant surprise to me was in doing the research for this podcast was coming across a book that I was ashamed to admit. I didn't even know he'd written called the laws of medicine or that's what it's called the three laws of medicine.

to admit I didn't even know he'd written called the laws of medicine. That's what it's called the three laws of medicine. And we talk about these three laws. And rather than even stating them now, I just think it's worth this podcast is worth the price of admission just on the basis of understanding those three laws. So with that, I hope you will welcome Sid to the show. And I do want to just remind folks to please sign up for the email list. I've been putting a lot of effort into those emails every Sunday morning. They go out and I hope that they're at least worth some value. I think they are and I like to be able to kind of share things with folks that I'm reading or seeing along the way and they don't always have to do with longevity.

Keep in mind, one of the things that I think takes up more actual time than anything else with respect to this podcast is putting together the show notes. So Bob and Travis work really hard on those. The feedback we've been getting is incredible. People keep saying, my God, how do you make these things? The short answer is, I don't. I don't do any of it. But Bob and Travis do, especially Travis.

I think that if you spend a few minutes looking at that stuff, especially if you find some of the content challenging. When we get into technical terms, which we do on some of the podcasts, you're pretty much going to find everything in the show notes. Lastly, if you're enjoying this, it would be an honor if you would head on over to Apple Podcast Reviews and leave us a review, especially if it's a positive one. But we'll take a negative one too, as long as you can be constructive in your feedback. So without further delay, here is my guest today, Sid Mukherjee.

Hey, Sid.herjee. Hey, Sid. Thanks for making time. My pleasure. Thanks for being here. Yeah, I don't get up to this part of the city very often. It's a bit of a hike. Well, it's a massive medical school and it's hard to imagine it anywhere else except for uptown in this way. You know, we go right all the way to the river. It's amazing and the last time I was up here was to see another one of your colleagues on the other side of the street, Rudy Libel, who's a good friend. And I used to be up here

a lot more often. So it was nice to come back. Most of our podcasts go really, really long. This one, I don't think we have that luxury of time. So I kind of want to get right into things. But before we do, I certainly think for the listener who doesn't know you well, your background, which I'll allude to a lot in the introductions. We don't spend too much time on it, but you grew up in India, came to the US. Did you do college here? I went to college at Stanford, yeah.

Oh, that's right. You went to undergrad at Stanford, okay. Then medical school at Harvard. Actually, then in the middle, I was away for three years. I did a... You did a Rhodes scholarship. Yeah. Or you a Rhodes scholarship.

I was a Rhodes scholarship, and that's where I got my PhD and my PhDs in immunology Which is a subject that I left behind Went to medical school at Harvard medical school Then did my fellowship my internship my residency at mass general hospital Fellowship at the day and if I were cancer institute and then started my own lab and clinical practice at Columbia University and Have come back to immunology, in a strange widening circle of a way. Yeah, the first time we met was a dinner

that Lou Cantley had planned for us this about three or four years ago. And I remember at the time, the topic that Lou was passionate about that I'm passionate about was sort of metabolism of cancer. And at the time, it wasn't something that seemed as interesting to you as it is today. And I know today I wanna talk so much more about that I'm passionate about was sort of metabolism of cancer. And at the time, it wasn't something that seemed as interesting to you as it is today. And I know today I want to talk so much more about that

because the work you guys have done in the last few years is in many ways what I think is the most interesting stuff to talk about. It was also a tough dinner because you don't eat most things. It's hard to cook. I have dinner with someone when you, when half the menu is off the menu. So anyway, we somehow managed to scrape by

and it was a wonderful evening. And actually, led to, what was that five years ago? Yeah. led to one of the most interesting and perhaps important scientific collaborations in my life with Lou. But it was that dinner which kind of hammered. It was in a Japanese restaurant on the upper east side in a tiny little place. You remember? I that's exactly. I know exactly what exactly was. Well, because we wrote on it, you know, it was a little bit like one of these napkin experiments

where you write on a napkin an idea, and that idea takes five years to come alive. This thing that was sketched on a napkin that evening, and is now leading to actually kind of a massive clinical trial across multiple sites, very energetic teams coming into all of this out of that little napkin Japanese restaurant. Yeah, that was a really fun night. Prior to that, I had read the Emperor of All Malities. I don't think the gene was out yet. The gene was not out yet.

I want to spend just a couple minutes on the Emperor of All Malities because if there's anybody listening to this who hasn't read it, you won the Pulitzer Prize for that book, I believe. I did, yes. Yeah, so it's a must read having myself studied in oncology, there was so much that I learned. I trained at Hopkins, which is, you know, so we're in the Hallstead School of where the

mastectomy was created, where many of these things were created. But to really understand the history of Bernard Fisher's role in the mastectomy, it's just an unbelievable story. My only criticism was at the time quite a depressing story. You know, I mean, I'm not saying that to be critical. I mean, it's less a criticism of you than the field. No, no, to me, actually, interestingly, people often bring this up idea up. For me, it was actually, it's far from a depressing story.

It's just the opposite. In fact, if we don't contend with the question of how, I mean, the emperor of all maladies is just for people who don't know is a history of cancer starting from its first description in Egypt right down to my own patients. Thousands of years of a journey against a disease that seems to morph and change over time. Every time we look at it, it has a new form. It reflects our own diversity to some extent, our own wildness, our own imagination as humans. So to me, not a depressing book, because it is a way to look directly at the face of the enemy, and I don't find that depressing, I find that clarifying. And there are many, many high points in this journey. There's the invention of the great surgeries that save

tens of thousands, hundreds of thousands of lives around the world, the dramatic advances against breast cancer, and most importantly, against some variants of leukemia, whether mortality was 100% in 1950 and is 5% or 10% now, 95% change in mortality is a huge difference in must-rank as one of the great medical inventions of our time. So for me, far from a depressing book, but to me, a clarifying book that tries to clarify why we're here today, where we're going, what happens next, why we're not doing certain things, why we are doing certain things. So that's my impression of what happened at the end of that book. When did the idea to write as it's really referred to the biography of cancer?

When did that idea come to you? Was it in your fellowship and your training at some point? Yeah, I was training and it was a very simple moment. Actually, I remember a woman who I was treating for cancer came to me and I was giving her yet another trial of targeted therapy and new kind of therapy. And she finally sat down one afternoon and she said, where are we going with all of this? Why are we here?

How do we get here? And she was, of course, asking me in a very personal level, but you could take that question and make it a much, much larger question, where are we going in this battle against cancer? Why are we here today? What happens next? Why aren't we elsewhere?

How much of this is the wildness of this family of diseases? How much of this is the capacity to use are the greatest skills of our imagination against this illness. In the 1930s, 1940s, 1950s, when you asked a child what the outer limit of their scientific imagination was, they would say, I want to be a rocket scientist and I want to send a rocket to the moon by the 1950s, 60s, 70s. If you asked that same child what the outer limits of their scientific imagination would bring to the world,

they would say, I want to cure cancer. It began to define the limits of our scientific prowess, or the limits of our imagination, a world without cancer. So there is a sense in which this is such an elemental illness. So much of our culture is now defined through the lens of cancer. And what was shocking as a fellow, when I started encountering cancer in the clinical sense, was shocking was that there was no such history, that it was all ad hoc. And we knew little bits and pieces of it was like looking at the enemy through a patch

work quilt with little holes in it. And the attempt here was to say, well, what is the full story? What does the story look like? When did this start? Why did we end up here? What happens tomorrow? What happens way into the future a hundred years? What will cancer look like? And a lot of thought experiments going to the book. So that's sort of the genesis of the book and that's how it came about. The research is also remarkable for a book like that. Anyone who's read it will appreciate it. And again, I think what's nice is this is one of those books where you can be an oncologist and read it and find it staggering, and you can be someone who has lost a level of cancer

but wouldn't know the difference between a sarcoma and a lyomyosarcoma. Doesn't matter, the book resonates, which I always he speaks to your ability to tell a story and then that's sort of to me what's mind boggling about that book is the way and it's the same in the gene by the way is that you weave in and out of a personal story and then something that's very dense scientifically and on a personal level this is challenging because I'm in the processes you know of writing a book and doing a pretty lousy job of it I think but it's this challenge of you want to be able to do the science justice but you want to be able to do the science justice, but you need to be able to tell a story. So how does the the scientist

Sid Mukherjee get along with the writer Sid Mukherjee? Well, I don't think there are two separate people. I think they're integrated into one person, and that's very important. There are many people in my world. They wrote as a process of thinking. Stephen Jay Gould comes to mind, not to draw a ludicrous comparison. Charles Darwin wrote to think, Oliver Sachs wrote to think, I would suspect that a sugar one day writes to think, I mean, I know a tool. So the two people are fundamentally not different people in my brain in order to do the scientific work that I do, I need to think it through, often through the essays that I work on, and they inspire, in a kind of Yin Yang or roundabout way, circular way, ways to find new ways of thinking about the

world, the cancer world. So there isn't a conflict, I don't feel a conflict. The process is probably of interest. I mean, the process is that when I started writing Emperor, I sort of made a personal vow or a strategy in writing that this was my first book. I'd never written a book before. I wrote down some principles or tenets that I would follow, and I've kept them in every book since. The first one was that there will be no scientific abstraction, but no place or point. So you go through five pages or three pages without there being a human being in the middle of this. I'm a translational researcher, I'm a human scientist. And that meant that I've made a personal promise that you won't go through five pages

without understanding what the payoff of these pages that you've really worked your way through often as a reader, what the payoff is. So if you look carefully through that book, every five to seven pages, the story comes alive in a human story, in a scientific story, and in a scientist's story. They all intersect. They, and sometimes through my stories, there are times that are tough, and I'm writing what the description of the first cancer causing genes, oncogenes and their mutations. It's tough to say, well, what's the human being?

This is a laboratory experiment in which you sprinkle tens of thousands of bits of genetic material onto cells and ask the question, which cells become turned from normal to cancerous? And that's the way you trap one of these cancer-causing oncogenes. What's the human story behind it? Well, there are two stories. One story is quite lovely. It's a story of Bob Weinberg, the scientist who you know, walking through Boston in a snowstorm, and suddenly realizing not in a one-to-one manner, but this idea of sprinkling tens of thousands of genes onto pieces of genetic material onto cells, like a snowstorm of genes. There's a kind of congruence to that story. It's not like Bob Weinberg woke up one morning and saw a snowstorm and said that the experiment I should do, but there's a kind of emotional congruence to the back story of a scientist.

But then, the second story that illustrates this point is to walk through a patient telescoping down or rather microscopic downwards from their outer cancer, a tumor, a lump, a mass that is about to kill them, a real patient of mine, a man with lung cancer. And slowly in that same story of this man's illness, begin to microscope down to the fact that he actually has in his cells this mutant gene that Bob Weinberg

once caught in this no storm of sprinkling genes on cells. And all of a sudden this man's cancer is sitting in a Roman Boston surrounded by by his family, dying of metastatic lung cancer. But at the heart, at the root of that lung cancer, is that very same gene, that very same oncogene, that was discovered, described 10, 20 years before in a paper, in a kind of dry, abstract scientific paper. And all of a sudden, that gene, the genetic material that can drive the growth of a normal cell and make it malignant, make it metastatic, so metastatic, so malignant, that our best medicine, our best minds can't stop the growth of this aberrant cell, all being driven in part

by that very same gene that was trapped 20 years ago in a laboratory experiment on rat cells. So all of a sudden, this thing comes alive to you in a way that becomes consequentially. If you didn't know the identity of the gene, you would not understand why on Earth this 70-year-old man in perfectly good health is all of a sudden decimated by one or two or four mutant genes in his cells that suddenly take over and drive the growth of these cells. Anyway, that's one example and comes up over and over again. That was the first tenet.

That was the first tenet. So it was the second one. There are many, so I'm not going to go through all the tenets. But the second one was that this book, all these books should be fundamentally readable by everyone. You talked about this already. It should be like a kaleidoscope. That if you turn the book left words in you you see it as an oncologist, it's still interesting. The pattern changes if you turn the book right words and say you're an anthropologist.

It still is interesting. If you turn the kaleidoscope upside down and shake it and there's a new pattern that's formed, it's because you're reading the book now as a clinical scientist. Or you're reading the book because your daughter has leukemia and you're the father of a patient with leukemia. Or you're reading it because you yourself have been diagnosed with breast cancer. Or your mother has. And all of a sudden the kaleidoscope changes, but the point is that the object remains the same. It's the same book, but you can read the book in various different ways. You can come into it different ways. Often when I'm in this sounds like a strange statement, often when I come back from the words, I reread my own writing to figure out sort of what

was I thinking then in 2008 when I wrote those sentences and how does that change now? It's really been 10 years. It's been 10 years. So I should tell you that there will be a 10-year update to the emperor. There will be three other three additional chapters. I assume one of them will be immunotherapy as an update. That's right. So they're very broadly three sections that are updated and I've thought about it for a long time. So there'll be an updated section on prevention. There'll be an updated section, an early detection, and an updated

section on treatment. So that's the very broad three big broad chapters. But in every chapter, there will be deeper dives into what's happened now since the last 10 years and within the treatment section. And potentially within the prevention section there'll be a huge role of the immune system, which was not fully appreciated in 2010. I thought that was the biggest distinction between the book when I read it, and then the PBS Special, a Ken Burns Special, which of course again will link to all of these things

in the show notes here, but one, you gotta read the book, but two, I can't recommend enough, the Ken Burns Special, they did an unbelievable job, I think, sharing your voice. And that was the biggest, I can't recommend enough that Ken Burns special. They did an unbelievable job, I think, sharing your voice. And that was the biggest, I remember watching it thinking, oh wow, there's a big difference here because there's three installments or five I can't remember. Yeah, the third installment felt like it was half immunotherapy.

It was half immunotherapy. Well, because part of the reason was that, again, this brings me to the next tenet in the book, or writing the book. The next tenet was that there's so much cancer research in laboratories going on everywhere. And the tenet or the principle was that unless that research has manifest itself in a human drug, in a human medicine, in a reconception of how we think about preventing treating or detecting cancer, in a fundamental reconception of those ideas, it won't get into the book. So tumor immunology, of course, had been around for a very long time,

colleagues, toxins famously and other such efforts very, very early on. But in 2010, we were at the edge of that moment in which we began to use tumor immunology in human beings as powerful medicines to change the course of the disease. It was just the first trials that come out. In fact, the book was complete in 2009, and the first trials had not even come out then. This is a little funny trivia story that I'd almost forgotten about this until somebody mentioned it to me a year ago. I think the first real paper that I wrote as a fellow was on CTLA4. It was looking back at the series at NCI of patients

who had been given CTLA4 and responded in this paper basically identified the strong association between auto-immunity and their response to it. Of course, this will be interesting later in our discussion because we want to, of course, talk about James Allison. So we'll come back to that, but you're right. That was sort of when it went from, you had interleuking too, that worked in maybe 10%, 15% of patients, but you couldn't predict why.

That was the bigger question. You didn't know why we're some responding, and why were they only responding with certain cancers to where we are today, where it's really been a transformation in the last 15 years? Absolutely. And so, when we started the film version of Emperor with Ken Burns, which I obviously was very close, I worked very closely with Ken. I should say that the gene is also being made into a film by Ken Burns. Oh my God, it's like Christmas all over again.

It's almost completely short. We're sort of moving towards editing phases and so forth. When can people expect that? It's already been scheduled. I think it's winter or fall 2019. So it's on the scale. It's about a year from now. Yeah, about a year from now. Yeah. We're working through footage and historical footage

and archival footage and so forth. But to wind backwards, the crucial piece that had been added since the book was, of course, immunological therapy. So much of what the last episode was around this new burgeoning field. I mean, in the first meeting that we had around the transformation of the book

into the documentary film, the first thing that was raised is what's changed. And the answer was very obvious. What's changed is immunological therapy. It might have been emphasized as much in the book, and I may have just missed it, or it's possible you also observed this as a change, but I believe it will factor into the 10th edition,

which I can't wait to get my hands on, is the role of obesity in cancer. As if I recall in the documentary, you said, look, this is now becoming basically the second leading preventable cause of cancer after smoking, which was, again, I was aware of that at that point in time because of the work that I'd been doing and sort of my little echo chamber. But I thought, this is a PBS, this is not something that I think most people would appreciate. This is becoming a first for many people to hear. That's right. And the one thing that we should make clear is that every word in that PBS document was vetted by some of the most important and thoughtful scientists and cancer biologists and physicians and physician scientists and cancer advocates across the world.

There's a backstory, in other words, the script was vetted over and over again so that we wouldn't say things that were misinforming the public or because this is a documentary for all time, Ken Burns' work is evergreen. Hopefully my work is evergreen. So it was very, very carefully vetted. And it was quite clear by the time the documentary came out that the signals that we were picking up around obesity and cancer were becoming extraordinarily clear for some cancers, obviously not for other cancers. And the provocative statement that sits behind all of this is that really since the last 20

odd years, I mean even 30 odd years, we have been struggling, struggling to find preventable human chemical carcinogens of substantial impact. Every word in that sentence is important. We have certainly found chemical new chemical carcinogens in humans, but often that affects small pockets of people who are exposed to those carcinogens. We have found lots and lots of chemical carcinogens, which have moderate to very small impact if you look at populations overall. The bar might be smoking. So smoking is a good bar. This is a smoking or tobacco smoke is a chemical carcinogen, which is removable or preventable and it has substantial human impact across populations. Changing smoking behavior can change fundamentally the epidemiology

of cancers across nations. If that bar is smoking, we have struggled for the last 20 odd years to find things of that magnitude and effect. The direct impact of that is when people come to me and they say, well, what do you do to prevent cancer in yourself and your family? I have to sort of casually, or not so casually admit that, not very much. I obviously don't smoke, but I'm not like I'm eating goji berries or avoiding some fundamental thing that everyone else is not in the know about, because there aren't any. I mean, you know, I'm obviously not exposing myself to these rare, unusual occupational cancer carcinogenic agents, but I'm not doing something fundamentally changed that's different from

you or anyone else to prevent cancer. The exception to this rule of the 20-odd years of the hunt for chemical carcinogens is obesity. Now, you and I can have a debate, is obesity a chemical carcinogens is obesity. Now, you and I can have a debate. Is obesity a chemical carcinogen? No, not in the traditional sense. Is it even preventable? Maybe, but we have to think twice or three times about it. There's a role of genetics and environment in all of this.

And even do we think it's obesity per se or hyperinslenemia or any other endocrine? For instance, exactly. First of all, is it an endocrine problem? Is it an inflammatory problem? Or is it a metabolic problem? At least three more. Yeah, or there's a metabolic problem. There are at least three more obesity as such a crude phenotype.

That's right. At least the year point has at least three, if not six underlying phenotypes, that each of which mechanistically would make a lot of sense for accelerating cancer. There's an immunological phenomenon that is the cytokines, the inflammatory, all these things.

Going back to your general point, that obesity was becoming identified more and more clearly as one of the potential causes of cancer, or I should say strongly correlated with the development of cancer so strongly, that we think that there's a cause and link based on all everything that we know about epidemiology, some cancers, that we began to take this serious, and we're still taking it seriously, but as you're pointing out, there are several horns underneath that blanket of obesity that we understand very crudely. And we have to figure out which of these is driving the cancer risk.

I would like to spend the next six hours discussing with you the tenets of writing for selfish reasons, but instead I'll punt that to a, we'll do, we'll have dinner in a couple weeks and we'll finish that discussion. I want to talk about another book you wrote that doesn't get as much attention, which is the laws of medicine. You wrote that after Emperor before the gene, correct? That's right. So laws of medicine is very different mandate as it were. And that's because the book came out in association with Ted. They had commissioned 10 books by 10 thinkers around the world.

And they asked me to write a book on that. And it's necessarily necessarily a small book. It's really a you know the mandate was to write basically a 75 page book expanding on a single very very incisive idea. So that's the laws of medicine. Yes. If I if I got them correctly the three laws are a strong intuition is much more powerful than a weak test. Uh-huh. How did you think of that and what is the most important application of that law to the way you think about medicine or specifically oncology today? This to me is one of the great neglected ideas in medicine. Perhaps one of the great neglected ideas in the world. This idea initially comes from Thomas Bayes. This is a Bayesian idea.

Thomas Bayes was a cleric, but by evening he was a mathematician and an economist and he let his work leads to one of the most seminal and funny thought experiments that I've ever encountered, which is the following. And I sometimes quiz my daughters with it, which is the following. This is not Thomas Bays' own example, but it arises out of Thomas Bays' work. And he one might imagine going to a street fair and encountering a man whose tossing coins. And he tosses coins and your job is to predict whether the next flip coin flip is going to be heads or tails. And so he tosses the coin 20 times and all 20 times its tails. So then he turns to the crowd and he says, what's the next coin flip

going to be heads or tails? Now, the mathematician in the crowd who's the professor of mathematics says 50 percent. Says 50 percent. And, you know, everyone says absolutely right. But the child in the crowd says, no, no, you don't understand. This is a stupid problem. It's the coins rigged. The coin has only, it has two heads or two tails, as case may be. And the child's right. And what's important about that insight is that the mathematician imagines the world, this in this case, this is not a stab at mathematicians in general, but the professive mathematics, thinks of the world as having no history, as

having no a priori. It's a world that's created in over every time. The coin is flipped and it's heads and tails equal every time. But the child knows, and humans know, that in fact the world doesn't behave like that. Everything has priors, and you need to understand those priors before you can understand the posterias as wisdom in that idea. And it took someone like Thomas Bayes to figure that out that most of our lives, we aren't living our lives like the crazy mathematician, professor. We are living our lives like the child we're thinking to ourselves, what was the prior antecedent?

Imagine this is true for any corner of your life. The first question you ask yourself when you're trying to solve a problem, trying to understand the cosmos, trying to understand something, you ask yourself, what was the prior life? Did the Sun set in the West last night? And how about the night before? And maybe I don't need to create a formula to figure out whether the sun is going to set on the West or the East tomorrow.

It's because it's set on the West every time. There are obviously loopholes and gaps to this kind of thinking. There are surprises that you can miss. So Bayes' fundamental idea was that you can only interpret a test in the light of what that test is predicted in the past. It's an extraordinarily important idea in the way we think about the universe, that the

past performance of a test tells you something, not everything, but tells you something about the future performance of a test. And you can apply it to many, many things in the world. You can apply it to any kind of thinking, economic thinking, climate change oriented thinking, that the past is a guide to the future, not only in a kind of loose way, but you're really using a real stat weighted strongly by the past. And this, of course, applies to medicine. And it's a forgotten rule in medicine. Although it does seem like one of the things that I've always felt physicians innately

do well without realizing it, which is the opposite of where I want to be not to take the pot shots, but I think where we do very poorly isn't understanding asymmetric risk. So Nassim Taleb has written a lot about asymmetric risk. And I think he's absolutely right to be critical of not just physicians, but basically most people.

So my argument is we are innately wired to be critical of not just physicians, but basically most people. So my argument is, we are innately wired to be Bayesian. We are absolutely not innately wired to appreciate risk. And both of these are important. That's right. And so one of them we have to hone so much more, because I think it just doesn't come naturally. I played a funny experiment, which you'll appreciate. I'll send you the list and you'll have a field day with it.

It's 20 questions, and each one is a quantitative question with an answer, but they're not obvious. You would never, it's not like how many, you know, presidents were there or something where you might know the answer. You ask the group, we're going to give you these 20 questions. I want you to answer each question, not with a number, but with a 95% confidence in a row. You know the game? No, I don't know the game.

So it's a game, yeah. Okay, so it's a game. So at the end of 20 questions, if you've done it correctly, you should have 19 out of 20 of those ranges correct. I've never met a person who can come close. You almost without exception get like seven of the 20 right. You can't even contemplate what that variability is. So the second law was that normal teach us teachers rules outliers teach us laws. So this of course, these were very carefully, I mean, I thought I spent a lot of time thinking about them.

Of course, this is the anti-Basian law. This is the exactly what you're talking about. This is the idea that simultaneously in the medical brain has to live the idea that the Bayesian idea that when you hear who's think horses not zebras, famous medical tenet, hooves beats outside your window are likely to be horses. They're very unlikely to be zebras. The second law is once in a while they are zebras and you need tools, you need special ideas, special tools to figure out what these outliers look like, who they are, how to find them, and how to quickly find them so that you can identify them and triage them differently. So in some ways these two laws are yin yang, they polarize against each other. And what's interesting about them is that they both

in medicine can both can be simultaneously true in the same way as our assumption of a symmetric risk is simultaneously true with the idea that our understanding of the base of a world in the Bayesian way is helpful and important. So the second law is about how do you identify outliers? How outliers tell us about the nature of normalcy? How they tell us about how complex interactions can produce occasional far outsiders and how those outsiders really challenge us to define what these interactions look like in real life. I mean, the simple example is it's very, very hard to figure out the genetics of any disease without finding the rare people who have the disease as a consequence of a mutation.

The classic example, of course, is that we would not have an idea how to regulate our body or to prevent heart attacks. If we hadn't paid extraordinarily close attention to a small family, small groups of families, that had a mutation in the gene that controls cholesterol metabolism. Most people don't have this mutation because those families are quickly extinguished, we think, because they die of heart attacks. They have all sorts of problems, they die of heart attacks. But by paying extreme attention to this one family that has a mutation, they're rare.

Scientists all of a sudden uncovered a whole cosmos in which we understand now cholesterol metabolism. And because of that cholesterol metabolism, other scientists eventually develop the first statins. So all of this, you know, the fact that hundreds of thousands And because of that cholesterol metabolism, other scientists eventually developed the first statins. So all of this, you know, the fact that hundreds of thousands of people in the world are taking this medicine to prevent artifacts, tracks back to a rare family, because of a genetic mutation they had, and very, very high risk of cardiac disease.

And of course, now we know there's a whole family of those people. There's at least 2,000 of those mutations that produce that phenotype. And these natural experiments are actually a remarkable thing. And of course, to bring it back to the gene, to now have a tool, a probe, to be able to explore that is amazing. The third law, for every perfect or exceptional medical experiment,

there is a human bias that goes along with it. Again, these are unique to medicine. And what's interesting about them is that they are unique, not to me, at least those interesting, is that they're unique to the day-to-day practice of medicine, but they apply for every, I think, they apply to every corner of life. You don't have to be a doctor to realize that for every time

we think of something, if you're really skeptical thinkers, we have to think about the bias that comes in trinsically with that thought. In other words, every single declarative claim about the universe that we're making must have necessarily a declarative bias that comes with it. They're matched. If you want to be a scientist, we want to be a skeptic. Your real job, aside from being creative and designing experiments, is to find for every single declarative claim that you're making, the bias that's driving sitting like a little devil buried inside that declarative claim, because I promise you everyone has one. Each one of these claims has one. And Richard Feynman, who listeners of this podcast know is one of my heroes, one of my kids is named after him.

Is he named Feynman or Richard? His middle name is Feynman. Yeah. And my wife at first was like, why would we do that? But then once she had read, surely you're joking, Mr. Feynman a couple of times, because she'd read it once before she realized why. But Feynman said eloquently, right? The job in science is not to fool yourself, and you're the easiest person to fool. That's right.

So to your point, the only thing I would disagree with what you've said is, I don't think these are unique to medicine. I think these are laws of science. And maybe laws of life on some of the mentioned. Yeah, so the mandate here really was to use this book as a kind of springboard to challenge the way we think about virtually all aspects of how we live. You're going to read an article in the New York Times tomorrow that will make some claims about some politicians somewhere in Oklahoma, or you're going to read about an economic paper that is now being presented to the feds.

And your job is to be adequately skeptical about it and understand what are the priors? How do we explain this particular fact based on the priors? Are the priors the priors matter to use a very topical example? Does someone's past behavior in college or in school, high school tell us about how he or she's going to be a judicial candidate? Or does their behavior under scrutiny in any way predict their behavior when no one's looking? That's right. That's another question. The second question that you might ask here is,

again, it's an outlier question, right? Screwed-in-eversus, not screwed-in-e. Do they become outliers to themselves if they're scrutinized, if they're versus when they're not scrutinized? And the third question is, when I read this story, what are my biases? Am I reading it because I'm a man?

Am I reading it because I have a particular experience of my, in my own lifetime, myself, my sister, my daughter, my friend, my colleague. Is that coloring the way that I read this particular story? So absolutely. And you know, this thinking goes on over and over again. These are circular processes. Do those biases of priors. Do the priors have biases and so forth.

So you can use these, I mean, I certainly use these tools in clinical practice. Yeah, it's a beautiful, as you said, it's a very short book, but again, well, we'll certainly make sure people have those links to it because I think it's a great way of teaching people how to think. And that's, again, I just don't think we're innately wired for every facet of thinking. Now, going back to your background in immunology, very, we had a very exciting for those of us in this space, very exciting Nobel Prize awarded. And it was, as we were discussing before, we started recording.

It wasn't so much around immunotherapy, but a very specific element of it, which are the development of checkpoint inhibitors. Two of them, in particular, were basically acknowledged here, CTLE-4, which I mentioned earlier, and PD-1. Tell me why these are so exciting. They're exciting for many reasons. They are exciting for, again, some history and some background.

The story, as it were, is exciting because if you ask the question in the 1990s, what's the relationship between cancer and the immune system? You get a kind of diffuse answer. You get an answer which could be very unclear because there were all sorts of complicated lines of evidence. One line of evidence was that in patients

with a complete collapse of the immune system, such as patients with HIV, or complete collapse of at least one wing of the immune system. They would get these cancers you nobody else could get. But what's interesting about them, and this is where the thought experiment with this with the brain cells start sort of ticking and wondering, they would typically get viral cancers. Viruses that would now get unleashed, we now know many of them, viruses like human papilloma

virus, they would get cervical cancers, they would get anal cancers. So a lot of viral cancers, but patients with HIV did not generally get lung cancer. I never even thought of that said. So we have enough data to know that they either at no greater prevalence or even at a lower prevalence when you start to talk about, you know, for example, lung cancer or GBM or pancreatic cancer, I never thought of that. Yeah, it's a very important. So the data are mixed because, of course, in the 1980s, they weren't living long enough. So all that we know is that the first groups of cancers that cropped up in these men and women were not lung cancers, they were not pancreatic cancer. So at the first pass with that cut short data set, you might begin

to imagine then if that's the case, the immune system completely collapses, you only get a certain kind of cancer. Then what is the possible role of the immune system in cancer control? And if you were a nailist, you might have given up in the 1990s and said, well, you know, take the whole immune system away, and nothing really happens even with this cut short data set. So maybe there isn't such a complex interaction. Well, it turns out that people like Jim Allison and his Japanese colleague did not put the immune system away. They put that data aside, said, this goes back to the laws of medicine. They said, you're

sure. It tells you a little bit, but it doesn't tell you the full story. The full story turns out, there's one layer deeper. And the full story turns out that in people who don't have a collapse with the immune system, whose immune system is otherwise intact, cancer cells, not all cancers, but some cancers, make specific factors. In fact, they evolve. The word make is the wrong word here. They evolve so that they put up specific factors,

put up specific signals that inactivate the immune system or that make the immune system no longer able to kill or recognize the cancer cell. And the identification of the specific pathways, the specific factors was what led to the Nobel Prize because in further work, Jim Allison and again his colleagues, this is a big wide field, showed that if you inactivate these specific factors, if you drive nails through them using a variety of methods, then all of a sudden the cancers become revisable to the immune system and the immune system can attack and kill the cancer cells.

Now, why is it exciting? It's exciting for many reasons. First of all, it's important to realize that not all cancers respond. We don't know why some do it, some don't. Melanoma is highly responsive. It's immunologically engaged too much. Is it because the melanoma has so many antigens that it will suddenly be more recognizable? Is it because the skin is such a lymphoid organ?

Is it the right environment? We don't know all of these questions. The other thing to realize is that people have responses and some people continue to respond. Some other people sadly will relapse and the cancers will start growing back in the context of their reeducated immune system. And that leads to the second question, which is, what happens then? Is there a second pathway? And this is an important idea, I think, that goes back to your first question, which

is about whether this is depressing or not. The important thing is once you drive a single stake through cancer's heart, it's like placing the first cramp on a climb. You see, if you have no cramp on that's placed on the climb, you can't climb a mountain. It seems like a wall. It's a blank wall, and you don't know where to go left or whether to go right or what to do Once you plant that first cramp on and it sticks and it sticks You all of a sudden the whole face of the mountain becomes to different mountain It's a different mountain now because now you can ask the question because the first cramp on was planted in that particular place And it's stuck and it stuck I have a new vantage point exactly That's right And so this is the important piece to realize about cancer research.

And perhaps about all research is that the first cramp on or the first stake through cancer's heart is an incredibly important stake. Because then you can ask what I call linear questions. Before that first one is placed, the questions are non-linear. You don't know where to place it. The whole map is open. Once you drive a stake through the first question, the world becomes more linear. You can now ask the question, what's the mechanism of resistance to that? And when you find that,

what's the mechanism of resistance to that? And so all of a sudden, the perspective is different because we've climbed through that first. And that's usually where the Nobel prizes are given. The Nobel prizes are given often for planting the first steak through the heart of a disease, through the heart of a problem.

And that's why this Nobel Prizes is important. It's not, of course, as you're saying, this does not encapsulate the field of tumor immunology in general. It's a wide field. Our own lab does a whole bunch of work in tumor immunology, but we're on the shoulders of those prior giants, as it were. And so that's the recognition that's been given here.

You said something that I think is so important and worth reiterating. There's also something about immunology and immunotherapy that's quite interesting as far as planting that stake, which is the durability of response. It is often the case that when you have an immunologic remission, it is a durable remission. It is not always the case, but it is much more likely the case

than when you say, for example, see a chemotherapy to remission or even a surgical remission. On a personal level, I have a very close friend who was diagnosed with colon cancer 10 years ago at a very young age, you know, he might have been 40. And that was unusual in and of itself. I remember talking, I went to the hospital when he had his collectum, he spoke with the surgeon after, it sounded like a horrible case. Huge tumor.

The mezzanteri was full of nodes, which I assumed would be positive. Every 26 nodes sampled all came back negative. My friend was adopted. We later realized he had Lynch syndrome. Eight years later, he goes on to develop pancreatic adenocarcinoma, unresectable. So it's encased the mezzanteric vessels. He cannot have a whipple procedure. And as you know, and unfortunately many people listening to this will know, that is a death sentence.

It's a non-negotiable. You will not be alive in nine months. And he was put on an anti-PD1 therapy because he happened to have, as you would know, these patients with linch are going to be much more likely to be susceptible to checkpoint inhibitors. Two years later, he's disease-free. Just unbelievable stories. And I think your point is an elegant one that I'd never really thought of before, which is focus less on the fact that we haven't solved the problem and more on the fact that we have made a finite and real step towards establishing a new place, a new location for which to view

this disease. So I describe this as taking a nonlinear problem into a linear problem. Now, of course the answers are often not linear per se, but it gives you a route. I mean, we'll come back to the metabolism study that we did with Lucanthly. That is a great example of taking a nonlinear problem and converting into a linear problem now.

I'll tell you about that in a second. But any time, this was the case with Levek too. Let's tell people what Levek is. Yeah, it's a good story. Levek is a good example of a drug where we learned to target a mutant cancer gene and it's actually the gene product. So in that case, the cancer, it's a blood cancer called chronic myologinous leukemia was also a death sentence.

And also GI stromal tumors. And GI stromal tumors? Yes, stromal tumors. Yeah. Chronic myologias leukemia was a death sentence. People had to go through transplants. I watched probably a dozen in the pre-gleevech era. A dozen patients die of chronic myologias leukemia or the complications of transplant.

I trained briefly as a transplanter. And then all of a sudden, through the work of many people, including Brian Drucker, a drug was discovered. So before that, scientists figured out, based on very careful genetic analysis, that the tumor was being driven by really the work of one gene. And the gene was called BCR Able. It's an oncogene. It's a not found in normal cells, but found in these cancer cells.

And the product of that gene became like an engine, like a manic engine that was driving these blood cells to go crazy and make more blood cells and proliferate and proliferate. And it was this engine gone wired inside a cell. And every time the cell asked the question, should I divide, rather than looking at its normal state or nutrients, metabolic state, et cetera, the only we would ever get was from this engine saying, yes, go ahead and make another cell, divide, etc., etc.

So this was identified, the gene product was identified, the protein product of the gene was identified. And then through an elaborate series of experiments and circumstances, chemists found a way to actually jam the engine. One molecule, human beings may, we stitch this molecule together, it's a remarkable achievement. And once the engine is jammed, it suddenly turns out that the disease goes into a remission.

This was one of the first examples of so-called targeted therapy, where you synthesize a chemical to jam cancer's engines in a cancer-specific way, it doesn't affect normal cells. But what's interesting about that is that some people develop resistance because the engine, cancer cells evolve and they find a way of resisting. But that resistance, it becomes a linear problem. You figure out what the mechanism the resistance is and you drive a second stake through cancer is hard and when it becomes resistant to that, you drive a third stake and so forth. So all of a sudden, the problem

would seem like a big blank rock became a linear problem. So that goes back to another example of how that first stake or the first cramp on really helps with the problem. And now for immunotherapy, immunological therapy, the road map is much clearer. Why do some tumors respond and why some don't respond? Is it a question of the environment that the

tumor is sitting in? Is it blood vessels? Is it tumor cells? Is it immune cells? These are answerable questions. These are so-called linear questions. But the first big step here was to define the problem. This is really a nice step off to exactly where I know we want to go, which is we've got surgical oncologists, medical oncologists, radiation oncologists, in many ways a subset now of medical oncology is immunobased oncology. The work that you, Lou, and many others are now doing is potentially a another branch of oncology called metabolic oncology. So you're beyond gracious in your suggesting I have even something to do with helping that evening turn into what sounds like a very productive collaboration between you and Lou.

And I'll be talking with Lou as well when the next month I'm sure. But let's talk a little bit about what came out of that collaboration and certainly bring it back to Ben Hopkins paper that was in nature, I believe. Was in nature, yeah, two, three weeks ago, yeah. So let's talk a little bit about the question. What were you trying to understand? So the question is there's a very wide question and then there's a very narrow question. The wide question is how does the body's metabolic state affect cancer? It's a very big question because

cancers like all cells are eating nutrients as well in order to grow. And the question, therefore, is the cancer eating a different set of nutrients than normal cells? This work goes back to famous work by Otto Warberg, done in the early 1920s. Where Otto Warberg was one of the first people to make the hypothesis that there's something fundamentally different about, I mean, we won't go into great details, but it's fundamentally different in which the cancer cells metabolize compared to normal cells. They use fundamentally different pathways to metabolize. And if you could find a way to target these metabolic alterations in cancer cells, you would

find an anti-cancer drug. So that question has been hanging around our field for a long time. And as our understanding of normal metabolism has changed, we've begun to identify not just one, but dozens of nutrient pathways that cancers use that may or may not be different from normal cells, maybe slightly different from normal cells, maybe a lot different from normal cells. So that's one big question. The second question, which is a slightly narrower question, is that when you give a drug,

whatever drug it might be, your favorite chemotherapy, give a drug, whatever drug it might be, your favorite chemotherapy, your favorite drug, any drug, does it change the metabolism of the cancer cell and does it change the metabolism of the body, and could this be a mechanism by which cancer cells become sensitive or resistance to chemotherapy. So these are two related questions. Again, to reiterate one question is, how is the cancer cells metabolism different from the normal cell in normal circumstances? And the second question is, how is the cancer cells metabolism differ from a normal cell in the context

of giving a drug? Yeah, in other words, can a nutritional state be exploited and or a drug sensitivity be exploited through nutrition? Exactly, those are the two questions. So we focused in this particular cell, we actually were interested in both. I'm interested in questions. So we focused in this particular study, we actually are interested in both. I'm interested in both. But we focused on the second question, and the second question in this particular case was that there was a very promising group of medicines that was being used in clinic.

In fact, I had used them as a trialist. They had come really out of Luke Handley's path defining work. He had defined the pathway or the signals that these medicines attack. And there was an enormous amount of optimism because this was considered a fundamental pathway. This is the beauty, by the way, of being in a place like New York or Boston. You can talk about someone doing this, or even Lou is in Boston when much of this work is done. He's now here in New York and you don't have to collaborate with a guy across the world. You can collaborate with the guys on the Upper East Side instead of Chelsea. That's right.

So lose work over the last decades had been to define this pathway and ultimately led to the formation of the creation of these new medicines. They're called PI3 kinase inhibitors and they go by fancy names like duvelosib and things like that. But anyway, when they came to clinic, surprisingly, there were some responses, but there was a lot of resistance in patients that tumors were resistant to the drugs and didn't respond. And that was a puzzle that Lou had come up with in his own work. And then separately, seven miles uptown, I was scratching my head about the same

puzzle because I'd been using these same drugs in cancer patients and finding that patients became resistant. Or were resistant to start. And so what was shocked out that on an app in that evening was we had thought of lots of ways that these patients could become resistant. We had thought, oh, maybe the tumor had a mutation. Well, and there's one other point, I guess, to add, just that we remember, but maybe it's worth reiterating is a lot of the patients that were on these began to develop phenotype, like they looked like they were diabetic. Yeah, so that's the point that I was coming to in a second. We didn't know if that meant that that was the source of the resistance, but it was

a true, true, and unrelated. Yeah, the question was, was it true, true, and unrelated? I mean, you can think of many other mechanisms of resistance. You can say the tumors became a mutation. You can say the host had some problem. You could write down on the piece of paper, 1,000 ways. Those were the traditional ways that one would explain resistance.

The traditional ways of thinking what tumor resistance is, mutation, the host eats up the drug. The non-traditional way, and this is what the innovation in the study was, that what if there's diabetes that we were observing the high levels of sugar and the high levels of insulin, insulin being the most important piece of this, what if the drug was causing diabetes separately from the tumor, given to normal people

that the drug would cause diabetes, in some people worse than others, and that diabetic phenotype, that diabetic state, the hyper-insulinemic state, was being used or exploited by the tumor to essentially become resistant to the drug. It's a little bit like, and the analogy that I drew, I remember, on the napkin. It's funny, I still remember the table we saw.

I remember the table. Yeah, exactly right. The drawing, so Lu and I were batting this idea back and forth while you were eating nothing. And the idea was that to me it reminded me of the famous story of the woodcutter who's sitting on a tree limb and chops off his own limb and falls down. And I drew this picture. I remember of the woodcutter on a tree limb because what happens is that the body

mounts an insoleneic response to the drug. That insoleneic response goes to the cancer and starts feeding the cancer, and then the cancer becomes resistant. So you essentially undo all the good that you've done with the drug by cutting off your own limb because of this intrinsic circuit. And the long and short of it is that that's basically an animal model, that happens to be true. So we showed it using formal systems and formal methods that this insolidemia is a consequence of the drug, has nothing

to do with the tumor, has nothing to do with anything else. If you give the drug, the drug goes into the liver and the pancreas and causes sort of a prediabetic state that's often worsen that if you're already in a prediabetic state, this hyperinsulinemia is used then by the tumor to become resistant even while the drug is present. It becomes a pathway by which the tumor becomes resistant. And most interestingly, that you can paralyze this resistance by putting animals on a ketogenic diet. So basically, there's never any sugar source to drive the insulin. You blunt the insulin response so acutely that you can no longer get the insulin high. And this is not to be confused with the idea that this is a sugar-feeding

tumor idea. This is not a sugar-feeding tumor paradigm. Because to be clear, on a ketogenic diet, your glucose levels might go down from normal, but it's not an enormous reduction. Even in a complete fast, you'll still maintain at least three millimolar of glucose. It's the insulin that becomes virtually unmeasurable. That's right. So it's an insulin feeding the tumor question.

And so I think the three points that need to be made about the study to be very clear. First of all, it's an animal study. We're now launching a human study that will launch in November with patients with lymphomas, endometrial cancer and breast cancer, particularly triple negative breast cancer. I'm very keen on studying. Because this is a cancer that has so few options. That's right. There are very, very few options. So that's the human study.

The second point that it's worthwhile making is that it's sort of like folks don't try this at home. This is a very particular study with a very particular drug on cancers, combined with a diet. The study only worked when the drug and the diet were combined. It does not mean that the ketogenic diet is gonna prevent cancer.

We don't know this, it's an open question. We're actually studying that separately. Yeah, and I wanna talk just a little bit about that paper because that's, boy, I sure want everyone to make sure they hear that loud and clear because a few things upset me more than when I spend a little too much time on Twitter and I come across people who seem to wanna claim

that if you're on a ketogenic diet, you can't get cancer or if you have cancer, just go on a ketogenic diet. That's not, in fact, do we very clear? Well, Or if you have cancer, just go on a ketogenic diet. You're going to be fine. That's not to, in fact, to be very clear. Well, the study, in fact, demonstrated that that was not the case. Not only that, the study also demonstrates that some cancer models, including leukemia,

is accelerated on the keto diet. In fact, we have a big follow-up study to try to figure out why some cancers are accelerated by keto alone, but when you combine it with the drug, they actually go back down into a deep remission. The third point to make is that it seems to be mutation agnostic and that by that I mean, this is a very important idea, which is that 12 tumor models responded. 12. I was not aware that it was that high.

Yeah, 12 and actually all 12 that we tested responded. Every one of them responded. And it didn't matter what oncogenes you had or what tumor suppressor genes were mutated. They all responded to different levels. leukemia is respond, then they relapse, at least in the models. Endometrial cancers, we can't get them to grow. Pancreatic cancers respond extremely strongly.

So it's another example where you're not targeting, it seems, a mutation. This is not like Gleevec, in which you're driving a stake into the engine of the cancer, or that engine. This is a much more global assault. Yeah, it seems. It's a much more global assault. In fact, in some ways, it's parallel akin to this immunotherapy in the sense that the

immune system doesn't care if you have a race or doesn't seem to care at the first approximation, whether you have a mutation in one gene or another gene, a race or not, a race. It will kill the tumor cells based on its characteristics of what it sees in the tumor. Similarly here, the metabolism seems to be tumor-wide, but not single kinds of cancer specific. We don't know this to be the case. The 13th model that we try will maybe this was the one that won't work. But this is generated a lot of excitement for this reason.

You know, I have a friend who has definitely heard two new positive, maybe ER positive, here negative, but has stage four breast cancer is an APA 3K inhibitor trial out of Dana Farber, has been on the trial for probably five years. She's the only survivor. Here's the interesting thing. She's been on a ketogenic low carbohydrate diet the entire time. While she was taking inhibitor. Yes. She's still on the ketogenic low carbohydrate diet the entire time. While she was taking inhibitor. Yes. She's still on the inhibitor.

And so what's interesting is I've told Lou about her case because she's festidious in this. And she's able to get her hemoglobin A1C now under six, which for many of those patients is very difficult. Very talked to you. When you and me had lunch once, about two years ago. This is the very first time you ever showed me the data. Yeah, that's right. We were at that Indian place or the Chinese place on Second Avenue. That's right. Yeah. And when you showed me those data, I just immediately thought of her.

So it's actually been on my list to introduce Luke because she doesn't live in New York. No, I would love to meet him. I want to bring her out and I want you guys to meet her because the combination of this PI3K inhibitor and this dietary choice she's made, going back to your second rule, right? She's the outlier that is giving you something to probe. We hopefully will have many such patients. I don't know, you know, this is why we're running this study.

As you can probably imagine, I could spend another 12 hours speaking with you, but I want to be respectful of your time. I know we're a little late in the day, we got a later start then we wanted, and you've got a long trip home, and I want you to get to see your family. The last question I want to ask you really is one that I need you to be a little bit imodest with,

which is how do you do what you do? I don't meet a lot of people that I look at and realize that on every level of their life, they are better than me. You know, you see I meet people, and it's like, yeah, they're better at me at those three things, but I can do this one thing better. And I'm sure I could think of something I do better than you, but it's... That's a lot of things.

Many things, do you know my sense of balance? I can probably shoot a bow and arrow better than you. But when I think about how you balance the devotion you have to your patients, to your family, to your research, to your writing, to your research, to your writing. It humbles me. I don't know, have you put any thought into that? The fact that you created these tenets around writing is very interesting to me.

It says that you weren't just a natural gifted guy that fell out of the sky who figured out how to write. You had to work at your craft. So how do you work at this craft of just excellence in general? The simple rules that I have is I'm a very question and project driven person. If I set projects, I'll usually fulfill them. Again, it's the same sort of cramp on in the mountain rule, which is that in order to write a book, you have to write the first line of the book.

And inevitably, that's not going to be the first line that survives. In order to do research, you have to do one experiment. And inevitably, that experiment is going to not work out. You're going to do 10, 15 iterations of it, etc. To me, the fundamental rule that works for me is just to throw something at the world, the first line, the first experiment, the first idea. And then keep at it. I keep at it over and over again.

I come back to it. I come back to it over and over again. And I keep asking questions. And then at some point of time, and that's another moment of sensitivity, is to figure out when the work speaks back to you. The experiment starts talking back to you. You have to be really open. Your ears have to be really open.

And that's really the skill of a scientist, I think. A scientist, I think, is even a writer. They have really two skills that they mix together. The first one is the creative step. Putting out the first line, thinking of the idea, I'm going to write a biography of cancer. I'm going to write the history of genetics, et cetera. But the second one is to be open enough to realize

when the work starts speaking back to you and let that happen, let the experiment start talking back to you. Be skeptical, but have a conversation with it. Those I think are the two skills that I bring to my puzzle. The rest of it is just like everyone else trying to balance, eating a meal versus riding in two more lines, stopping, starting, sleeping, the usual. Well said, I don't expect this will be the last time

we sit down and do this. I hope so. I'm gonna be a lot more stuff to talk about. I can't thank you should. Well, sit, I don't expect this will be the last time we sit down and do a lot more stuff to talk about. I can't thank you enough. I consider you, Lou, some of the other folks you talk about, I mean, real mentors of mine and it's a privilege. It's a real privilege to call you a friend and to be able to sit down with you and just get even the tiniest insight into how you work.

Thank you. You can find all of this information and more at pterotiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the Nerd Safari at pterotiamd.com. What's a Nerd Safari you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email, where I'll update you on what I've been up to,

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