244 ‒ The history of the cell, cell therapy, gene therapy, and more | Siddhartha Mukherjee

1. 0:00 – 0:08

   Intro

   1. PAPeter Attia0:00

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

2. 0:08 – 9:13

   How the cell brings the genome to life, and how Sid’s recent book fits into his prior work to tell a story

   1. PAPeter Attia0:09

      Hey, Sid. So great to, to see you again. It's been a long time since we've seen each other in person. The last time we sat down for one of these, of course, it was in person and we didn't have video. Now we've got video, but we're, you know, uh, in a different time zone. Um, congratulations on the, uh, success of your most recent book. Um, for folks listening or, or viewing, give us a sense of kind of where this book fits into the prior work. Uh, we, we talked at great length about one of your books, "The Emperor of All Maladies," uh, but there was a book that followed that, and then of course, there's this. So m- maybe put this in the context of, of those books.

   2. SMSiddhartha Mukherjee0:43

      Well, so, um, it's an interesting-- So, you know, this is part of a trilogy and possibly a quartet that I'm, I'm working on, um, broadly called the Life series. And the attempts of these books is to try to explain and understand how we understand life and how we're manipulating life, um, living things, obviously, particularly humans. Um, and so i- in an odd way, um, the, the, the place to begin, to some extent, the trilogy right now, so the first book, "The Emperor of All Maladies", the second, "The Gene", and now "The Song of the Cell", um, would be to probably start with "The Gene". Now, the gene being the, the, the least unit or the smallest unit of information. Um, uh, and then realize as you end "The Gene" that, that genes which are encoded in, in, in DNA, the molecule DNA, uh, are lifeless. They don't have any autonomous life. A gene is just a, um, a molecule. It's a chemical. And it's the, it's the cell that brings it to life. And without the cell, there would be nothing. All of that code would be useless. I liken this to the g- the, the human genome, um, or any genome, to a score of music. Um, but a score is lifeless. Uh, there's no music in a score. It's just a, it's the code. You need a musician to bring it to life, and the cell is that musician, and hence the word, hence the title of the book, "The Song of the Cell". Um, the cell brings it to life. Um, so the second book, to some extent, is "The Cell". Um, and then the third book, bizarrely enough, is the first book. Uh, it's sort of like Star Wars, the prequel to the sequel to the prequel, um, where you learn about what happens when cells become average. So that would be one way to read the book, uh, read the series of books. Start with "The Gene", um, move on to the second unit, which is "The Cell", and finally end up with the sort of dysfunctional aberrant cell and what happens to it when its genes, uh, genes go haywire. A completely different way would be to read them as they appeared. Um, and the reason behind that is that they, uh, progressively, um, go downwards. I mean, the first book was, of course, a history of cancer and cancer therapy. They progressively go downwards and delve deeper and deeper into mysteries of that history. You know, missing pieces. What did we not understand about cancer? Um, obviously genes and genetics. Um, what we, did we not understand about, um, cancer in terms of its cell biology, um, when The Cancer Genome Atlas was, for instance, completed? Um, and what, what do we understand now? Um, so, uh, so there's-- it, it can also be read chronologically from the first to the third, but you, you would get a different kind of story, and that's what's interesting about it. You can read it either way.

   3. PAPeter Attia3:43

      It's possible that my question/statement here is, um, a bit of a, uh, tainted by a bit of recency bias because I read them in order. And of course, I've just finished reading "The Cell" because, you know, we decided on a very last-minute basis we were gonna try to do this podcast. Last, last minute for the way my podcast works, which is months of preparation. So, you know, I was sort of, you know, reading the book in the period of, of the last, uh, week and a half, which I enjoyed immensely. But here's the thing: I felt more surprised and in awe of the characters in this book than the previous books. And that might sound crazy because you'd think, God, the, you know, decoding the human genome, what a Herculean feat. But in many ways, the characters of this story blew my mind even more because of the time and the era in which they had to do their science. There were fewer tools at their disposal. Is that-- Does that statement surprise you, or h-how does that resonate with you?

   4. SMSiddhartha Mukherjee4:45

      Well, so it, it, it's not surprising. Um, it's because, um, the characters in this book, um, are enunciating things that are, I think, very fundamental. Now, with-- If you, if you take, for instance, a comparison, if you were to do a historical comparison with the history of genetics, so, you know, you would start potentially in the, in the scientific world, you would start with Mendel. Um, and, you know, Gregor Mendel, of course, being the, the, the, the pioneer here. And then there's an enormous period of silence, um, that follows Mendel, almost forty years, in which basically nothing happens. Um, and then, you know, his work is picked up by other people, um, ultimately picked up by folks like Thomas Morgan and others. Um, but for a long period of time, nothing happens and nothing's relevant. Um, here, what you see in this book is very different because you see a, a sort of continuation, um, of development. So once the microscope is invented in the seventeenth century, um, you see from the seventeenth century a k- a kind of gradual blossoming, um, of, of the science, um, ultimately ending up with, you know, someone like Rudolf Virchow Um, who, who can make really, really audacious statements that, you know, are missing in the history of genetics until much later. Um, the audacious statement that Virchow makes is every, um, e- every function that we carry out, uh, regardless of its origin or regardless of what that function is, is a consequence of cellular physiology. We ourselves and everything that we do is cellular, is a consequence of something happening in some cell.

   5. PAPeter Attia6:34

      Mm-hmm.

   6. SMSiddhartha Mukherjee6:34

      This conversation is a consequence of something happening in some cell. So that's one piece, that's statement one, and then you get the other converse statement, which is equally audacious, in which he says that every, um, every illness is, um, the consequence of some cell behaving incorrectly. Um, and these statements are made in the late 19th century, or sort of mid to late 19th century. They're, in fact, almost contemporaneous with, uh, with Mendel. So you have, uh, enormous sets of leaps in cell biology, um, which is why this, this book might feel sort of, you know, that these characters are, are, are doing things while sort of, you know, genetics is still plodding its way, trying to understand sort of Mendel's first very important paper and this, uh, a remarkable 40 years of silence, whereas in cell biology there isn't that 40 years of silence.

   7. PAPeter Attia7:32

      And, and I think also just m- maybe we take it for granted sometimes today, but the ingenuity that was necessary to even build the tool to permit the visualization. I mean, we just glossed over the fact that in the 17th century we're putting together microscopes, but you, you actually describe in some detail what the process is like to grind the glass, to create the lens, to even have the window into this otherwise microscopic and invisible to our eye, uh, piece of physiology.

   8. SMSiddhartha Mukherjee8:02

      Well, it's an, it's, it's an incredible... I tried to make one, uh, myself. Uh, I tried to make, uh, one of Leeuwenhoek's, uh, microscopes. Um, and I can tell you, Peter, it was not, um, an easy task. It was a, it was a disaster.

   9. PAPeter Attia8:16

      [laughs]

   10. SMSiddhartha Mukherjee8:16

       Um, and he made 500 of them. Um, these are single lens microscopes, and they're about, uh, you know, this big. It's about the size of, I would say, half a, a sheet of paper. Um, and the lens is literally the s- smaller than the size of your eyeball. Um, and so you have this, a sense in which you have a, an enormous amount of labor of love put into making this thing that's mounted with tiny screws and tiny little apertures so that when you look through your eye, through the lens, through in a droplet of water, um, you can actually see these, you know, microscopic forms. So, so there's a, there's an enormous sense of wonder about how people even began to, um, to see these and how, um, how they found them and, and what, what the consequences of that, of that finding were and are.

3. 9:13 – 18:46

   How the germ theory of disease and an understanding of the cell fueled a big leap in medicine

   1. PAPeter Attia9:14

      People who listen to my podcast are probably used to an idea that I talk about, um, and, and you have come across this now, Sid, because you were kind enough to be one of the people who, who read my book. But I talk about this transition from Medicine 1.0 to Medicine 2.0, and then of course, where I hope we're going is the transition from 2.0 to 3.0. And I typically talk about Medicine 1.0 to 2.0 as two big events happened, and, um, they, they weren't, you know, momentary events, they were transitions or process. One was, of course, the way we changed about... the, the way we changed the way we thought, right? So it was the scientific revolution. So once we introduced the scientific method, late f- 15th century, we had a new way of thinking about observation and hypothesis, and all of a sudden the idea of bad humors and all that stuff sort of went away. But really the big moment became germ theory. Once we understood microbial agents and that we had a way to treat them, we really leapfrogged into the era of modern medicine. And if you look at the mortality rates as a result of that, it's outstanding. I mean, there has been no bigger reduction in human mortality than the reduction of death that comes from infectious diseases. What I had never really thought of until I read your book was that couldn't have happened without this deep understanding of the cell. I mean, it's, it's obvious when I say it that way, but in effect, this book describes how medicine went from effectively witchcraft into where we are today. And, and of course-

   2. SMSiddhartha Mukherjee10:45

      Yeah

   3. PAPeter Attia10:45

      ... you're gonna, we're gonna talk about this in more detail, by the way, but, but I mean, does that make sense to you?

   4. SMSiddhartha Mukherjee10:50

      Oh, absolutely it makes sense to me in the sense that it makes sense because the, um, uh, the, you know, the introduction of, of, of, of being able to ultimately see germs, um, and connect germ theory with, um, with human disease, um, as you say, took medicine from witchcraft to the modern era. Um, you know, think of any procedure, childbirth, um, uh, any surgical procedure, anything that we do, and think of the effect of antibiotics on that procedure, and think of how important it is that, that these antibiotics are now available and, and the lives saved. I mean, just childbirth alone, um, uh, the, the capacity of saving lives through antibiotics has been enormous and has just really been transformative in, in terms of, you know, again, as you say, moving medicine from, from witchcraft. And, and, and, and that's because what's astonishing in, in, in this, in the piece that I write about microbial, uh, biology and the discovery of microbes, Peter, is that microbes was, were imagined in the abstract, uh, long before they were seen. So, um, what's interesting is, you know, people like L- Lister, the great surgeon who began to sterilize his instruments, um, folks like, um, you know, uh, and I have a, a small biography of him in the book, uh, folks like Semmelweis, um, almost ignored by medical history now. But, uh, Semmelweis discovered that, that, you know, that people, that, that doctors were transmitting microbes-

   5. PAPeter Attia12:34

      Tell, tell the story. Uh, y- you know, I have it in my book, you have it in your book. I, I am really glad that more and more people are writing about him, because it always breaks my heart when someone dies without their due. And Semmelweis-

   6. SMSiddhartha Mukherjee12:46

      Right

   7. PAPeter Attia12:46

      ... is the example of that. And, and it's, it's, it's a heartbreaking story, but it's a remarkable example of this transition.

   8. SMSiddhartha Mukherjee12:54

      So Semmelweis was a junior obstetrician in Vienna. Um, it's important that he was so junior, and he, uh, made a very, um, important, uh, and incredibly important discovery. Um, so Semmelweis was delivering children, um, and there were two maternity wards, Ward One and Ward Two. Um, and this is why it's important in medicine, I think, to listen to your patients. You know, the, the famous adage in medicine is the f- the most important question that you ever ask in medicine when you're trying to diagnose a, a patient is to ask the patient, "What do you think the problem is?" Um, and it's the one we forget the most, right? Doctors never ask that question. But usually the patient will tell you what the problem is.

   9. PAPeter Attia13:41

      Right.

   10. SMSiddhartha Mukherjee13:41

       They'll say, you know, "I think I have an infection in my lungs," or, you know, "I think I'm, you know, uh, depressed because of X or Y reason. Um, because I lost my father." So, so Semmelweis, uh, learned to ask people, uh, of a s- of a bizarre aberration that was going on, which is that in Ward One the m- the infant, uh, the maternal mortality rates from childbirth were, uh, astronomically high, whereas in Ward Two, same, sim- similarly, same people, same women coming in, were much, much lower. And he asked a very simple... And he knew this because he, the, you know, at least the story goes, whether it's apocryphal or not, the story goes that, um, that in Ward One, um, the, you know, mothers would beg to, to be admitted into, into the, the safer ward, while they would beg not to be admitted to the ward, you know, they would have a 30% mortality rate or a 20% mortality rate, one out of five women.

   11. PAPeter Attia14:49

       Hmm.

   12. SMSiddhartha Mukherjee14:49

       This is an incredible number if you think about it. So Semmelweis began to ask, ask the question why, and he looked at all sorts of variables. Um, he was sort of a classical epidemiologist, so he looked at all sorts of variables, and the variable that he found was that in, in the first ward where there was a high mortality rate in, in childbirth, the, um, it was run by doctors, and these doctors, he figured out, were running between autopsy rooms, so doing autopsies on probably the very patients that they had killed, um, and then running, and then without cleaning their hands, um, delivering babies, essentially examining patients, delivering babies, et cetera. Ward Two, on the other hand, was run by nurses. Nurses were not doing autopsies, not touching any decaying or dead material, and there was no mortality. So Semmelweis made the hypothesis, again, remember, this is a junior obstetrician in Vienna, made this hypothesis that what doctors were doing is they were transferring some, and this is, these are his words, some material substance from the decaying, de- decomposing dead bodies that they had autopsied into the bodies of the women that they were examining internally, and thereby transmitting that material substance, and that material substance was re- was the source of the putrefaction or the infection that these women were getting. And he insisted that the doctors wash their hands with a diluted, sort of a, a, a diluted version of bleach, and he saw that suddenly now the mortality rate plummeted. And so he made this argument. Now remember, he didn't have a microscope.

   13. PAPeter Attia16:37

       Mm-hmm.

   14. SMSiddhartha Mukherjee16:38

       He didn't have... This is all in the abstract, but he made this argument that s- this material substance was responsible for this, what we, what was then called childbed fever or maternal, uh, infections, and the transfer of the material substance could be removed by washing hands, by handwashing. And so he, in the abstract sense, he had basically founded germ theory.

   15. PAPeter Attia17:04

       Yeah, I mean, uh, completely prescient.

   16. SMSiddhartha Mukherjee17:07

       Yeah. And incredibly prescient. And the idea of a material substance, that's what's important about it. Um, and, and-

   17. PAPeter Attia17:13

       Right. Right, it wasn't just bad air in a vague sense.

   18. SMSiddhartha Mukherjee17:16

       It was not bad air. It was not, you know, uh, bad humors. It was not... It was a material substance. And of course, if you had, if he had the capacity to look down the microscope, he would have found out that that material substance was in fact, uh, nothing else but, uh, but, um, but germs.

   19. PAPeter Attia17:35

       And the sad thing w- you know, the, the, the, the, the sort of the, the epilogue to the story is the guy dies in an insane asylum, basically having been ridiculed.

   20. SMSiddhartha Mukherjee17:44

       He's ridiculed. His, the doctors don't want to... The last thing that the doctors want to do is to admit that they've been, you know, um, uh, infecting other women. So he's, Semmelweis is ridiculed, and he's sent off to an insane asylum, and ultimately he dies, um, in, in, impoverished and, and never vindicated.

   21. PAPeter Attia18:07

       Yeah. It's, um, it, again, m- medicine is full of these stories. But But, but yes, this is th- this is what it was about the book that really captivated me, was th- this thing that I've taken for granted so, so much, you know, of my existence in, in medicine is what really allowed this, this leapfrog, and, and frankly, far more so than the genetic revolution. I mean, we could sit and talk about has the genetic revolution delivered on its promise? I mean, in some ways, yes, in some ways, no. We thought, of course, in whatever it was, 22 years ago when the human genome was coded, that was basically going to be an equal leapfrog forward. It turned out not to be. We'll,

4. 18:46 – 29:21

   What is the evolutionary drive for multicellular life?

   1. PAPeter Attia18:46

      we'll come back to talk about some genetic stuff. But I want to go back to a question that you pose in the book that I had never contemplated and I have not been able to stop thinking about it and I love it, which is, what's the evolutionary drive for multicellular life? So like, like let's talk through-

   2. SMSiddhartha Mukherjee19:08

      Yeah, it's a, it's a-

   3. PAPeter Attia19:08

      ... you know, kind of, yeah, we go from these single-cell organisms that have all of their own evolution built into them, and then look at the complexity that we are today. I'd lo- uh, you go through this very elegantly.

   4. SMSiddhartha Mukherjee19:21

      Well, I mean, it's, the, the, let's pause for a second to contemplate single-celled organisms. So they are bacteria, you know, uh, protozoa, yeast, et cetera. They're extraordinarily successful. You can't imagine how successful they are. They live in virtually every environment that you can think of. You know, they live in boiling water. They live in thermal vents. They live in inside volcanoes. They live, I mean, how successful is a single-celled organism? So you could, the, the, the bizarre question that you should ask is not why, uh, you should ask why we exist at all. Why is-

   5. PAPeter Attia19:58

      Yes

   6. SMSiddhartha Mukherjee19:59

      ... why, w- w- why, w- what is the reason that, you know, we, we have about, you know, several trillion cells or trillions of cells? How did we, why do we exist? Why not, why aren't we all bacteria? Um, and people have been trying to answer the question, and the initial idea in the '80s was that there was an, a massive leap, evolutionary leap from single-celled organisms to multicellular organisms. But what's surprising is that if you look at evolutionary history and if you look at all the evidence from evolutionary history, it turns out that multicellularity evolved from single-celled organisms not once, but independently multiple times. And it's, it's, you know, it used to be called a major transition. It's actually turns out to be a minor transition.

   7. PAPeter Attia20:47

      Mm.

   8. SMSiddhartha Mukherjee20:47

      In other words, there was a great evolutionary drive towards becoming multicellular. And you can ask the question then, well, if single-celled organisms are so damn successful, why ever be a multicellular organism? The quick answer is we don't know, but all the evidence suggests that it has to do with, um, several possibilities. The leading possibility is predation. So it's much more hard, it's much harder for, um, a predator to eat a multicellular organism for several reasons. One of them is that it's bigger. Number two is that it has defense systems. Number three it, is that it can move away from predators, uh, through specialized apparatus, apparati. Um, uh, so that's one idea. The other idea is, is food and resources. Multicellular organisms can have, uh, you know, can access food and resources. Um, and there are other ideas about how multicellular organisms, um, uh, came to exist and essentially conquered the world, as we know. But that said, single-celled organisms are still the champions. We are just a minor fixture, uh, in the world. If you took by weight all the single-celled organisms in the world and their diversity, uh, you would be shocked at how successful they still are.

   9. PAPeter Attia22:09

      R- remind us what Ratcliffe's experiments with yeast demonstrated. I, I, that was, I, I mean, I, [laughs] I had never heard of that experiment before, so it was, uh, you know, I'm, I'm reading this like I'm reading a thriller novel.

   10. SMSiddhartha Mukherjee22:22

       Well, William Ratcliffe is a professor, um, uh, who studies this transition, this evolutionary transition from single cell to multicellular organism. And he did this, actually an extraordinary simple experiment, and he sort of just thought about, thought about it, uh, over Christmas, um, with Travisano, his, uh, his advisor. He said, "Well, why don't we just take some yeast, um, and culture them? And we, um, l- we basically, uh, allow them to grow." And, and so just remember, yeast are single-celled organisms, and we just collect the sediment. So anything that's multi-celled is obviously gonna sink to the bottom of a flask. We collect the sediment, and then we allow that sediment to grow again in another cycle of evolution. So this is sort of Darwin in a bottle. Um, so we allow that to evolve another cycle, collect the sediment, allow that to evolve another cycle. And by about 30 or 40 such cycles, he found that the yeast had, had evolved, and this is astonishing, I have pictures of this in the book, into these sort of snowflake-like multi-fingered, multicellular, uh, forms, a really a new organism, a multicellular yeast. And what's interesting about them is that when he let them be by themselves, so no more recollection, no more sedimentation, they continued to propagate as multicellular, uh, yeast. So in other words, a, he had basically created a new life form, um, which is multicellular. And what is even more interesting is that when he looked at these multicellular yeast, they started to acquire specialized functions. So you would imagine that one way that these multicellular yeast could reproduce is that one cell could bud off and create a new multi-fingered multicellular yeast. That would be one way-

   11. PAPeter Attia24:10

       Mm-hmm

   12. SMSiddhartha Mukherjee24:10

       ... that these, um, organism could reproduce. But that's not how they reproduce. The way they reproduce is that a specialized series of cells that sit in the middle ... of this snowflake, uh, commit a purposeful cellular death. And I, I repeat the word, they commit a purposeful cellular suicide such that this, this snowflake can break into two parts, two snowflakes, and grow out new fingers.

   13. PAPeter Attia24:38

       [laughs]

   14. SMSiddhartha Mukherjee24:39

       Um, so this organism has now, evolutionarily speaking, learned, uh, the word learned im- implies that it has some consciousness, but that's not true- true. This is just an evolutionary, uh, uh, process. It has created a specialized furrow in its middle where these cells basically can divide into two forms. And what's more is that he's now, Ratcliff has done many versions of this experiment. He's done it with different organisms. He's done it with algae. He's done it with various other organisms. And what he finds is that there's even more specialization. So these, um, these new creatures, I- that's the only thing I can call them, form little channels to deliver nutrients. They form pores. They form secondary structures. So he c- he's really sort of created a new kind of life, and just by doing nothing. I mean, just by allowing it to evolve naturally. And remember, this is 30, 40 cycles, uh, which may be, you know, 60, 80, 90 days. So you can imagine over the course of, you know, several billion years of history, the extraordinary amount of diversity and specialization that could happen in evolution that leads to people like you and me having trillions of cells very committed to doing one thing or another thing or many other things.

   15. PAPeter Attia26:03

       You know, because my kids, who are, my, my boys are five and eight at this point, they're, as you can probably imagine, obsessed with dinosaurs. So we're nonstop watching every imaginable thing. I, you know, I, I... Paleontologists are the most important people in the world at this point. I can't help but wonder when I watch these recreations of what we assume dinosaurs to have looked like, I mean, at least we know about their size, how did evolution allow something so large to be, you know, in existence so many millions of years ago? And are we basically seeing a correction now? In other words, was, was that just the pendulum swinging too far towards multicellular where, you know, boy, here you have things that can really defend themselves, that can really get away, that can really go after prey, but of course, they're too sensitive to a reduction in food or something like that? Or is that just totally unrelated, and had it not been for, you know, volcanic eruptions and things like that, maybe we just wouldn't be here today and dinosaurs would be the sentient, uh, higher, you know, um, higher order s- s- creature?

   16. SMSiddhartha Mukherjee27:09

       A little bit outside my, uh, my pay, my pay grade in some ways.

   17. PAPeter Attia27:13

       [laughs]

   18. SMSiddhartha Mukherjee27:13

       But, um, but you know, there's lots of theories. Uh, uh, I'm certainly not a pa- paleontologist, so there are lots of theories about the, the extinction of dinosaurs. Um, what we do know is that, that, that, you know, that these life forms were also very successful in their environments. The problem was, as many people have hypothesized, um, that, um, that they, they sort of reached a, a maximal capacity of size. Um, and, um, smaller mammals, um, m- or mammal-like creatures, um, were much, became much more adapted or adaptable to the environment. But there are a thousand theories about dinosaur extinction, um, including, uh, changes in the atmosphere, changes, y- you know, meteors and various other volcanoes and, and events which, uh, you know, you can read in, in, in most paleontology textbooks.

   19. PAPeter Attia28:12

       Yeah, I just, I just wonder if there's something about their size that became their downfall beyond, you know, the obvious external factors. And, and it just made me think of that when I was reading that segment about-

   20. SMSiddhartha Mukherjee28:24

       Yeah. I mean, there's a beautiful-

   21. PAPeter Attia28:25

       ... the fitness of the single cell. Yeah

   22. SMSiddhartha Mukherjee28:27

       There's a beautiful essay, if I remember correctly, by Stephen Gould, um, where he talks about a natural biophysical limitation on size, and that's because the volume to surface area of a- any creature, um, reaches a place in, uh, where the volume to surface area becomes no longer sustainable because the, the, the, the surface area of a creature, um, does, i- is no longer able to deliver the oxygen and the nutrients required for aerobic living.

   23. PAPeter Attia29:06

       Yeah.

   24. SMSiddhartha Mukherjee29:06

       Um, I'd encourage people to read it. Um, I don't remember the name of the essay, but-

   25. PAPeter Attia29:10

       We'll find it

   26. SMSiddhartha Mukherjee29:11

       ... um, it, it, we'll find it. It has to do with the, a rhinoceros and, and, and what the size limits o- o- of creatures, uh, can and cannot be.

   27. PAPeter Attia29:20

       Interesting.

5. 29:21 – 42:09

   Four types of cell therapies and the challenges of gene therapy

   1. PAPeter Attia29:21

      So let's go back to something in, in the book where you talk about the four types of cell therapy. Um, w- when you spell it out, it, it sort of makes sense, but I'd never considered this before. Um, I think it's, I think it's, I think it's an illustrative framework for people to think about the era of medicine that we live in. What, so what are these four areas of cellular therapy?

   2. SMSiddhartha Mukherjee29:42

      You know, I, I tried to create a typology of, uh, the four types of, of, uh, ways in which we could use cells as medicines. Um, the first is the simplest one of all, which is to use a drug or a substance to change the behavior of a cell. So the simplest example would be an antibiotic. You're using a drug to kill, uh, a microbial cell while you're sparing normal human cells. So th- that's one. The, the second one is, um, the use of, um, the transfer of cells from one body to another body without any modification. The simplest example of that would be blood transfusion. Um, so you're transferring red blood cells, platelets, and other cells from one body to another body for therapeutic effect, but you're not essentially changing the cell itself. The third is the use of a cell either transferred or by itself in a dish, in a bioreactor, in a chamber to synthesize something. So remember I said that, that DNA is inert. It's a lifeless molecule. If you put it inside a cell in the right context, the right cell in the right context, the cell will start making proteins out of DNA, and, um, those proteins could be very useful. So insulin, for instance, you can only make insulin in cells, um, or you can-- That's how insulin is generally made. Um, so antibodies are made by cells. The, you know, the antibody Herceptin, uh, that you use in breast cancer is made by cells, so that's a third use. And the fourth and the final is, is the one that, you know, is, is coming up and, and now becoming more and more prominent as we, as we move into this new era, and that is the use of a cell where you make a genetic modification in a cell and then either transplant it or, or use it for a therapeutic, uh, uh, reason. Um, so for instance, uh, CAR T-cells, which I'm sure we'll talk about, are examples of, uh, genetically modifying T-cells and putting them into a human body. Um, I've been doing, as you very well know, um, series of experiments on, on bone marrow transplants in which we genetically modify the bone marrow, uh, using CRISPR and other techniques and then transferring them into human bodies, um, um, and, and essentially creating a, a gen- a, a genetically engineered cells. Now, people, uh, just to finish up a little bit on that last point, people often talk about gene therapy, and I always remind them that gene therapy is really cell therapy. Uh, if you put the gene in the wrong cell in the wrong place at the wrong time, you get nothing. You get the, you get the disaster. Um, so, um, gene therapy is really a, a, a mechanism to put a gene inside a cell, and that would be the fourth, uh, the fourth, uh, typology, as it were. And then the book goes through elements of these four typologies, uh, examples and elements of these four typologies as medicines.

   3. PAPeter Attia32:49

      Well, let's touch on a few of them. I, you know, because you and I don't have the ability to sit here for the next three days, uh, which is what it would take to do each of these their, their appropriate service, there are a handful that I really want to, to talk about. So let's talk about the story of, of Jesse Gelsinger, because that is one of the earliest examples of, you know, gene therapy in a human. Um, we could talk about what went wrong, but let's, let's use it-- Let's use Jesse's story just as much to explain the state of the technology at the time, the vectors, the vehicles, the methods by which genes were transferred. So, um, you know, let's just start with kind of what disease did Jesse have? Why was gene therapy viewed as the, the, um, the solution as opposed to whatever the other three methods would have offered Jesse?

   4. SMSiddhartha Mukherjee33:38

      So Jesse had a genetic disease. Uh, he was a young kid, I think fourteen, fifteen years old, sixteen maybe. Um, he was a young kid. Um, and, uh, you know, I've interviewed his father. I've interviewed-

   5. PAPeter Attia33:50

      Mm-hmm.

   6. SMSiddhartha Mukherjee33:51

      Um, I've had a very, very moving interview with his, with his father. Um, but nonetheless, Jesse was a young kid. He, um, had a, a, a defect in an enzyme, uh, which, uh, is related to the processing of ammonia, um, and, uh, uh, ammonia-related substances in, in the body. Um, and so, um, uh, the idea back then, um, and we're now talking, uh, um, I think in the two thou-

   7. PAPeter Attia34:20

      About twenty-two years ago. Yeah, it was about two thousand.

   8. SMSiddhartha Mukherjee34:22

      Yeah.

   9. PAPeter Attia34:23

      Yeah.

   10. SMSiddhartha Mukherjee34:23

       Yeah, early two thousands. Um, at, at, at the University of Pennsylvania, the idea was that if they could create a virus, uh, which would then go to Jesse's liver, um, and start making this, the correct version of the gene, um, then the, uh, then Jesse's disease would be ameliorated. So they created a virus, um, that they thought was going to be harmless. Um, it was a variant of an adenovirus, and then they genetically modified that adenovirus to now include the corrected version of the gene that Jesse had a problem with. Um, and then they infused that virus into Jesse's body, hoping that the virus would go and infect, because viruses infect cells, and deliver its cargo, the cargo would be the corrected gene, um, and thereby correct Jesse's disease. Um, so that was the, that was the idea behind, behind, uh, that therapy.

   11. PAPeter Attia35:24

       Let's explain two things before we go on with the story. Um, we, we didn't say this earlier, so I think it's worth clarifying. We don't really consider viruses in the same category as bacteria, yeast, fungi. Why is that? What is it about viruses that... Do we consider them living things? Are they not living things on their own? I mean, they basically just contrain- contain DNA and RNA, but they're sort of parasites in that they need us to replicate, so.

   12. SMSiddhartha Mukherjee35:52

       That's right. So viruses are not-- They don't meet the criteria of, of living things. Um, they are, uh, essentially, uh, uh, a, a strand of RNA or two strands of RNA or multiple strands of RNA or DNA, uh, that have been packaged usually with an envelope and with some, uh, decorated with some proteins on top. But they themselves, by themselves, they can't reproduce. They can't make copies of themselves, which is one of the reasons that they're not considered living. The only way they can reproduce is they went-- they go and, they go and attach themselves To cells, to, let's say, to human cells or, um, any other cells. Um, and then they use the reproduction apparatus, the duplication apparatus, and the reproduction apparatus, and the synthetic apparatus that's present in the cell to make copies of themselves. And once they've made copies of themselves, they bud out of the cell, um, and then they go and infect more cells and make more copies of themselves, and so forth. So that's, that's what a virus is. And in Jesse Gelsinger's case, the idea was that this virus would essentially infect his cells and create now b- it, it would insert, because the virus was genetically modified, it would insert the, its genetic payload, uh, which consisted of the normal gene, into J- uh, into Jesse's liver cells. The liver cells would now start making the protein that was defective in, in Jesse's case. It was gene, this is gene therapy. Um, and then by the, uh, by, in doing so, it would reverse his, his, um, relatively mild, but his, his disease.

   13. PAPeter Attia37:36

       So what, what happened then? They used this adenovirus, they injected him, and it went pretty bad pretty quick.

   14. SMSiddhartha Mukherjee37:44

       Yeah, so, um, a, a rather terrible thing happened. And again, I have a very, very moving testimony from his father, um, which is in The Gene, not, a little bit in this book, but, but really in The Gene. Um, a, a terrible thing happened. So, um, in retrospect, we think what happened is that, um, Jesse mounted a, a very, very vigorous immune response. A virus is a foreign, uh, object, a foreign body, um, and you mount an immune response to it, especially if you, for, for whatever reason, have been exposed to that virus before. And people now suspect, we don't know for sure, that first, you know, adenoviruses cause common colds, they cause, they, they, you know, in circulation. Um, there's a suspicion that Jesse had been exposed to that virus, uh, the, the, the wild form of that virus, uh, before, um, perhaps through a common cold or something like that, and his immune system went berserk. Um, because it was now recognizing not one virus particle, but millions of particles suddenly, uh, into his body. His immune system went berserk, and when the immune system goes berserk like that, you basically have terrible consequences because your body is recognizing your cells as foreign, the virus as foreign, the, you know, it goes on what I call a, a kind of immune rampage. Um, and that immune rampage can kill you. Um, and unfortunately, Je- Jesse, um, died from the consequences of this, uh, very hyperactive, brisk immune response raised against that virus and, and died. And, and in fact, the whole field of gene therapy was frozen for almost a decade, uh, as we learned n- to slowly understand the cause of that death and how we could prevent it in other people.

   15. PAPeter Attia39:39

       And so I think in response, the field said, "Look, we need to look at slightly more immune protected or privileged sites to, to dip our toes back in the water." And, and, and so, so tell folks a little bit about w- what's a safer place to maybe consider gene therapy as, as, as the field moves closer to that?

   16. SMSiddhartha Mukherjee40:00

       Well, there, there are many things that have happened. It's not just safe places. So I'll give you some examples. Again, I'll try to create a typology for you. Um, so one thing you can do is you can, uh, there are safe harbors in the body. Um, by safe harbors, I mean places that the immune system doesn't usually reach easily. Um, so it just by chance, the retina turns out to be one of them. Uh, there's not a lot of immune cell infiltration into the retina, so you have a chance to, to use gene therapy, and in fact, there are now several gene therapies that have been approved, um, it's, that, uh, allow you to insert, um, or inject viruses, um, so that you can get, um, some, uh, correct a gene that's missing or abnormal in, in the retina. So that's one place. There are some other places in the body. It turns out by coincidence, the testes is another place, although we've not used that for gene therapy. Um, so that's one thing you can do. Um, the other thing you can do is you can actually, there are new drugs that can dampen down or tack down the immune response. So you can think of the immune response as a dial. Um, what you can do is you can dial the immune response down so that the immune response doesn't respond so briskly, uh, to, uh, the gene therapy. Um, you can hide the virus, so you can make a virus such that your body has not seen such a virus before. Um, so you can actually use a novel kind of virus that has not, not been, that won't raise a brisk immune response. Um, the fourth thing you can do is you can actually give the gene therapy in small doses, it's called hyperfractionation, um, so that, uh, fractionation being small fractions, um, so that the immune system doesn't, again, go berserk, um, seeing this massive bolus of a dose of a virus. So those are some of the strategies, and they've been very successful. So that now, um, you know, the, the, the number of deaths from this hyperactive immune response still remain, um, but they are much, much, much more controlled than in, than in Jesse Gels- Gelsinger's times.

6. 42:09 – 48:25

   CAR T-cell therapy: promising gene therapy for cancer

   1. PAPeter Attia42:10

      So you alluded to an example earlier of, of CAR T-cells, um, that I, I think it's, you know, one of the great successes of cancer when it comes to treating, uh, CD19 or, or B-cell cancers. Um, let's, let's use that as an example to explain, um, how, how gene therapy can, can work in that regard.

   2. SMSiddhartha Mukherjee42:29

      Well, so CAR T-cells are a very special example of gene therapy. So In a CAR T-cell, uh, uh, what happens is that you extract T-cells from a human being who has cancer. Um, you extract their normal T-cells, and you use gene therapy to weaponize them so that they can attack cells, including cancer cells. So you're essentially turning the, a T-cell... A T-cell is part of the immune system. Its job is to hunt out and kill, uh, foreign cells, including cells that have been infected by viruses or foreign cells that have somehow entered the body. That's their job. That's the job of a T-cell. It's a, it's a, it's a cell, it's a foreign cell detector built into your body. So now you take that T-cell and s- and weaponize it to recognize the cancer cells as foreign. Um, and then you re-inject them. You grow them in a Petri dish in the laboratory, and you re-inject them into the body. Um, and, you know, our laboratory has done a lot of this work. We are now, um, uh, doing this in, in India. Um, the, the, the costs of, of, of doing this are astronomical in the United States, um, almost $500,000 to a million dollars, uh, per person. We're trying to reduce that cost dramatically, 20-fold, perhaps even 50-fold, um, in India using new technologies, et cetera. We've treated about 11, 12 patients already, um, and we've just released the data. It looks very, very, very good. Um, and so they're usually used in blood cancers like lymphoma, leukemia, and myeloma. They've not been so successful in solid tumors for reasons that we don't fully understand, that we're still trying to understand, but that's what a CAR T-cell is. It's a weaponized T-cell that goes and kills, uh, cells in your, uh, cancer cells in your body.

   3. PAPeter Attia44:23

      Sid, what, what is the difference? Why, why is there a 20 to 50-fold reduction in cost doing this in India as opposed to the United States? Because this is, of course, one of the jugular issues with oncology, is marginal treatments. Not that I'm saying CAR T-cell is marginal. It's actually one of the few s- beacons of success, but cancer is full of marginal treatments, you know, extend median survival by two months at a cost of $100,000. Um-

   4. SMSiddhartha Mukherjee44:52

      Yeah

   5. PAPeter Attia44:52

      ... how much of that is just a structural American problem versus, um, sort of, uh, you know, people that are able to go outside of the existing channels of IP?

   6. SMSiddhartha Mukherjee45:03

      Uh, some of it is a structural American problem, and some of it is not. So, um, obviously the structural American problem is that, um, for reasons that we're, we are trying to still investigate, uh, 90% of drugs, including drugs in the cancer space, fail. And, uh, pharmaceutical companies make the argument that they're trying to recoup the R&D costs, the r- the research and development costs of those failed drugs with the ones that are successful. Now, that's a complicated and, and I would say somewhat specious argument because you could ask, you could say to them, "Well, why did these drugs fail in the first place? Is it because drugs always fail? Is it because you didn't understand something about the human body that you, um, therefore took this drug all the way to spend millions, perhaps even billions of dollars on the drug?" Um, so that's one reason. Um, the second reason is... So, so that would be the standard argument. The second reason is that CAR Ts are intrinsically expensive to make. Um, their success rates are incredible, so these are not just one-month, two-month survival. Uh, my, my book begins with the story of Emily Whitehead. She was seven when she was treated with CAR T therapy. She's now 17 or 16, uh, applying to college, completely cured. So you have a situation in which these are, these are miraculous drugs. Um, you, you, you know, we've seen people who've been, had terrible leukemia essentially eradicated leukemia forever, um, and become cured. The problem is that they're intrinsically hard to make. To weaponize the T-cells, you need to make a virus. That virus is expensive to make. It's labor-intensive. The quality control that's required is much, much greater than, you know, making aspirin or making, um, any other tablet. So, um, and then of course growing the T-cells, you have to grow them in an incredibly sterile environment, um, you know, where you have to basically put on a hazmat suit to go in. Um, it's called a GMP facility, but it's a highly, highly sterile envir- environment. It has to be monitored. It has to be checked for, you know, a bac- a single bacteria or a fungal infection in that flask of a T-cell will now basically take that entire batch away. You, you, you can't give back, give those back. So, um, there are some intrinsic expenses. Um, now you asked the question, why, uh, how, how can you reduce the cost? Well, we reduce the cost by several ways. One is that we, um, basically we've learned to make the virus much, uh, in a much cheaper way. Um, we've, uh, reduced the cost of, uh, you know, the, the, the patent burden, um, by essentially, I, I, I think by really making successful products and not spending billions of dollars on unsuccessful products, so we don't have to recoup all that R&D cost. Um, we've changed the machinery. Um, we've changed the way the cells are harvested. And finally, of course, hospital treatment and therapy in India is much cheaper to start off with. So that, uh, you know, adding them all together, um, comes to, you know, almost a 10-fold to 20-fold reduction in cost.

7. 48:25 – 52:54

   The possibility of using gene therapy to treat germline mutations like sickle cell disease

   1. PAPeter Attia48:25

      So let's now use another example of gene therapy, which is [clears throat] maybe the harder of the problems, which is you have a person more like Jesse, where they have a germline mutation that results in a pathology

   2. SMSiddhartha Mukherjee48:42

      Yep

   3. PAPeter Attia48:42

      And the goal is, as an adult, you know, let's pick sickle cell anemia as an example. Um-

   4. SMSiddhartha Mukherjee48:49

      Mm-hmm

   5. PAPeter Attia48:49

      ... in some ways, sickle cell is so amazing that one single amino acid difference can have such catastrophic consequences on the life of a person. But you want to now just change that. I mean, it's a single amino acid. It's very, you know, we know exactly what genes drive that. Um, how does one go about doing that, and where are we in the, um, in the realm of approaching success there?

   6. SMSiddhartha Mukherjee49:15

      Um, so, um, fantastic new results in sickle cell anemia, um, published in very major journals, um, and will continue to get published. So, um, a- ancient disease, as you know, single amino acid mutation. If you inherit two copies, then you get sickle cell anemia, terrible disease. Um, uh, uh, your blood cells, um, in, in low-oxygen environments form sickles. You get, you know, they basically clog up. It's like plumbing clogging up. Um, and, uh, you get essentially what you might consider sort of micro strokes all over your small, uh, the small blood vessels in your body. Terrible pain, um, associated with this. Um, so the answer would be in gene therapy, you know, what if we could change the, uh, the, the, the mutated gene? So there are two or three approaches that have been so far tried. One is, um, using new technologies, uh, gene editing technologies, to basically change both copies of the gene to now make them into normal. So, so take out your bone marrow, which is where blood is made, um, change the gene from the abnormal gene to the normal sickle, uh, normal hemoglobin gene, um, and then reinfuse that back into the, into the patient. So that's a gene correction strategy. There's another strategy which is very attractive and, and fascinating, um, and I'll just briefly mention it. So it turns out that the fetus, the human fetus, um, has a special kind of hemoglobin, which is different from adult hemoglobin. And the reason it's different is that the fetus has to extract oxygen from mom's blood, and mom's blood, um, it, when it, by the time it reaches the fetus, has already been depleted of oxygen because it's gone through her body. So this is called fetal hemoglobin. Um, and so, um, basically, the fetus has a special form of hemoglobin, the oxygen carrier in blood, that can even extract oxygen out of mom's blood. Um, and so another approach to sickle cell anemia is to forget about the sickle gene problem and basically, in an adult, somehow reactivate, um, or express or make, uh, uh, fetal hemoglobin. Um, in that case, you don't need to correct the gene. The gene, you leave the gene as it is. You just make fetal hemoglobin, which is very, very avid as an oxygen, um, oxygen delivery machine, and the cells don't sickle anymore because they don't have this, this oxygen problem. And that too has been successful. There have been several trials now showing that if you activate fetal hemoglobin, uh, you can do that. So just to summarize then, you can either do gene therapy to, um, express the corrected version of the sickling gene, that would be, the gene is called beta globin. Um, that has been performed. The second approach is to use, uh, gene editing technology to change the, the, the gene back to its normal form. And the third approach is to reactivate fetal hemoglobin, um, in, in adults, uh, to essentially correct the, the, the hemoglobin defect. And all three are being c- uh, all three of them are in trials, and all three have shown various measures of, of success. My, my impression is that during our lifetime we'll see a cure, um, a permanent cure for sickle cell anemia.

8. 52:54 – 1:02:13

   The incredible revolution of gene editing with CRISPR

   1. PAPeter Attia52:54

      So, so this kind of dovetails nicely into, I think, a term that most people have heard of, but I think the, the details of this are pretty important, and this is the idea of, of, of CRISPR. Now, I haven't had Jennifer Doudna on the podcast yet. I would love to at some point. So we don't need to necessarily go into the great depths of, of CRISPR, but I think some history is probably relevant, especially as it pertains to the topic of our discussion, which is cells, bacteria and viruses, or bacteria as the cells and, and how they interact with viruses as a way to protect themselves. But I now want to kind of use the story of CRISPR to talk about another tool by which one can, can, you know, im- impart this type of cell therapy. So-

   2. SMSiddhartha Mukherjee53:33

      You know, the world of genetics was turned upside down in a very important way, um, by the discoveries of Jennifer Doudna, Emmanuelle Charpentier, um, and several others. I should mention Feng Zhang and George Church, among others, and there's a history of this which is in the book. Um, for a long time, there was the question of whether... So the human genome is a library. Imagine the human genome as a massive library. Um, if it was printed in normal text, it would contain 80,000 books, a massive encyclopedia stretching across a massive library. Um, and imagine that you wanted to make a change in one word in that library. You want to take book 61 on shelf 47 and make a change from verbal to herbal, um, in that library Um, this was a dream of scientists for a long time, and no one could do it. And then Jennifer Doudna, Charpentier, and then assisted by Feng Zhang and other people, figured out that there was a bacterial system evolved millions of years ago that could make that precise change in one word in that entire library, um, either deleting that word, in other word, erasing it, simplest change, or potentially changing the word to another new word. Um, that's -- it's an incredible genetic revolution. So as we move forward into this new universe, we have the capacity to change the human genome in a deliberative and, um, I would say a, uh, a processed manner. Um, so just take the, the example of sickle cell anemia that we gave before. We can change that sickle cell anemia gene to a normal gene by using this technology. We can change, uh, the, a mutant or abnormal cystic fibrosis gene to a normal gene, the normal version, um, or the wild-type version using this technology. So, um, it's obviously extraordinarily important, um, and there are many, many applications of this technology. Um, and it's exciting because we can do things that we couldn't do before involving changing genes to new genes, changing genes to their wild-type, uh, variants or their more common variants, and so forth. So, um, we h- now have ca- have the capacity to do this. We can do this with embryonic cells, we can do this with embryonic stem cells, we can do this with bone marrow cells, we can do this with T cells, CAR T-cells. The, the, it, it's a revolution, and all I can emphasize is the depth and breadth of this revolution because it's enormous.

   3. PAPeter Attia57:26

      So, uh, uh, two, two follow-up questions. The first is explain using the library analogy how this system differs from the approach that was used twenty years ago in the case of Jesse Gelsinger that we described, where an adenovirus was used. I mean, what's the difference in scale and elegance between what you just described, which is in the eighty thousand books, you can go to one page, one word, and make the change, versus that other approach?

   4. SMSiddhartha Mukherjee57:57

      Yes. So, um, so again, imagine the human genome as a massive library, eighty thousand books, um, printed on a page, um. And so the old technology, Jesse Gels-- the technology that was used with Ges- Jesse Gelsinger, is the technology in which we, uh, by analogy, I'm using metaphors and ana- and, and analogies here, we would insert a new page into that eighty thousand-page library. Um, so you would go into the library, eighty thousand books around you, and you would take a page and insert a new page into that library, a foreign page. The library, the librarian could come, in this case, the immune response, the T cell or the B cell immune response, and come and say, "Wait a second. That's not-- It doesn't belong. That's not a page that belongs." And that's what happened with Jesse Gelsinger and other people. The librarian would come and say, librarian being the human body, would come and say, "Wait a second. You're inserting new pages into a library. That's no good," um, and would prevent that.

   5. PAPeter Attia59:27

      And it seems to me that you didn't even-- it was much harder to know where to put that page. I mean, if you knew a priori, I really want that P to be between page eighty-seven and eighty-eight, you might accidentally insert it somewhere else, right?

   6. SMSiddhartha Mukherjee59:42

      Exactly. And the librarian would say, "Well, why are you putting it into, you know, Jennifer Egan's book on the Goon Squad?"

   7. PAPeter Attia59:50

      [laughs]

   8. SMSiddhartha Mukherjee59:51

      Um, because it doesn't belong there. You, you, you've just inserted that page, new page, the new gene, into a place where it doesn't belong. And he or she would say, "I, I don't, I don't buy this. I, I'm not, I, I, I'm not gonna let you do that. That, that, that's, that's absurd." You're reading along with, you know, Chekhov or Egan or where- whoever, and all of a sudden you find a new page that's been taped in, the virus that's carried in the new gene, the new virus, um, and you say, "Well, wait, wait a second. That, that doesn't belong there." And that was where the technology sat for years and years and years. Then, um, Jennifer Doudna, Charpentier, and others discovered a method in which you would do just quite the opposite. You would go into a page and say, "Listen, I have the right page in the right- ... volume of the right book, and I'm going to change one word. The first kind of word that they, that they could change was just deleting a word. Um, and this was using a viral system called CRISPR, and you could just erase a word. And then more and more research showed that you could change the word. And as I said, you could change the word verbal to herbal, uh, by changing a single letter, and for the most part, leave the library intact. And if you were a, a very vigilant librarian, you would say, "That's okay. You, you haven't put in an extra page in, you know, uh, Charles Dickens' book. You've actually gone to the right book and changed the right word in the right space in the right time from one to another." And that's the subtlety of what CRISPR allows us to do. It allows us to make extraordinarily precise changes in extraordinarily precise ways in a massive library, uh, which would not be possible otherwise.

9. 1:02:13 – 1:14:24

   Ethical questions around human gene editing

   1. PAPeter Attia1:02:13

      So you alluded to this at the outset of your description, which was, um, you could make changes to an embryo, right? You could take an embryo and you could make a genetic change, which now has pretty significant consequences because it is now a germline change. This is different than, you know, if you made a change in a non-germline cell way down the line. And I guess as things would have it, the first documented example of this created quite a controversy. Um, so maybe briefly tell the story of JK and the, the, the CCR5 gene and, um, and why that... A- a- and I guess more importantly is what are the implications of that, um, pretty unethical, uh, uh, episode?

   2. SMSiddhartha Mukherjee1:03:08

      So, um, again, I would encourage people to read the book, The Song of the Cell, um, to get all the details about it. But, um, a Chinese scientist, uh, J- He Jiankui, um, made a somewhat bizarre decision. Um, and I'll ta- I'll talk about why the decision is it or was bizarre. Um, there is a gene in the human genome that, um, makes cells resistant to HIV infection. Um, there are many genes, but that's-- this is one of them. The, the Chinese scientist in this case, uh, decided, uh, He Jiankui decided that he was gonna make a change in human embryos with gene editing technology, the technology that I just described, which would make the child of a parent couple, um, in which the man was HIV positive, the woman was HIV negative, and impl- make that change in the embryo and implant those altered embryos into the mom so that they would be HIV resistant because of this change. Um, the problem... So sounds great on paper. The problem is that their risk, the, the risk of these children to acquire HIV bec- uh, because they were produced by IVF is basically zero. They don't-- They-- It cannot get HIV. The sperm doesn't carry HIV. Um, so if you produce a child by, by this method, you, you basically have a zero risk of HIV infection. And so despite that-

   3. PAPeter Attia1:05:21

      Which is-- It wa- it wasn't medically necessary, right? That's, that's-

   4. SMSiddhartha Mukherjee1:05:25

      It wasn't medically necessary. Um, let me take a step back, um, Peter. The book makes a-- I make a very big distinction between disease and desire.

   5. PAPeter Attia1:05:39

      Mm-hmm.

   6. SMSiddhartha Mukherjee1:05:41

      Um, disease is fundamentally linked to suffering. Um, when we talk about disease, we talk about human suffering. When we talk about desire, we talk about the capa- the idea or the aspiration to ameliorate suffering even where there's no suffering involved as far as we can tell. Now, in this case, there was no disease. The children had no risk of disease. They couldn't have any risk of disease. The desire was an entirely scientific desire to create a genetically modified embryo. So in this case, in particular, the desire was that they would create a modified embryo and that He Jiankui would be the first in human history to create a human embryo with genetically al- altered stem cell, uh, um, cells. So, uh, he went ahead with this project and he created two, uh, girls. We don't know their real names. They're Their names have been called, they've been called Lulu and Nana. Um, and what he obtained was not exactly what he hoped to obtain, which is not that precise erasure of verbal to herbal in a single book in the entire library of 80,000 books. What he obtained was, um, a much cruder version of that. Um, and scientists across the world were concerned about, you know, did he obtain informed consent? Was there appropriate, uh, use of, you know, did the parents even understand the language that we're using? Now remember, because of this was an IVF procedure, the risk of these children getting HIV was zero. So again, we come to the question of disease versus desire. They had no disease. The only desire was to create someone who was potentially resistant to HIV infection. So we have this situation, which is very unusual, where desire, the desire to change human embryos, the desire to push the frontiers of science overwhelms the disease where there's no disease. And so the scientific world became extraordinarily incensed, uh, about the idea that, you know, this scientist had, had really crossed the boundary between disease and desire. Now, if this had been some disease that the children had inherited, cystic fibrosis, sickle cell disease, Huntington's disease, some terrible thing that they would encounter in their lifetime, the scientific community would have been much more sanguine about it. But these children, these two twins that were born, had a zero risk, zero risk of acquiring HIV from their fathers because the sperm had been washed. Sperm don't get infected with HIV. So they're, they, they were basically, um, they had, they had no risk of the disease. So what was left was desire, the desire to be first, the desire to be, create new human, human embryos. And that's what was very incent, you know, that's what incensed the scientists and the community of scientists.

   7. PAPeter Attia1:09:48

      You know, there's probably no greater example of the relationship between science and philosophy. You know, people might want a little bit of a reminder about what a doctorate degree is formally called, right? A doctor of philosophy. And so when you think about this question, it becomes kind of difficult, right? And I think in Walter Isaacson's biography of Jennifer Doudna, you know, I think this topic is explored. In your book, this topic is explored. Where does one draw the line, right? So, you know, Huntington's disease is a great example in the sense that you have a genetic, you have an acquired genetic mutation that is 100% penetrable in a devastating disease that shortens life and leads to immense suffering. Would we find many philosophers of science who would say that it is wrong to alter the embryos of adults who have Huntington's disease or carry that trait, that gene, to prevent it from going to their offspring? Which, by the way, if you play the thought experiment out, would eliminate Huntington's disease altogether because these are germline mutations. Like, how does the scientific and philosophical community merge over questions of that nature? And then, of course, just to tell you, eventually do we move that further to APOE4, LPA, other genes that are not as penetrant?

   8. SMSiddhartha Mukherjee1:11:24

      Right. So APOE4 is a risk factor for Alzheimer's disease or early Alzheimer's disease, just to give you an example of how devastating it can be for particular people who have combinations of APOE4 and other genetic mutations that increase their risk for early Alzheimer's disease. But I think the scientific community would say for Huntington's disease, the scientific community would say, listen, this is a devastating disease with a huge penetrance. By penetrance, we mean if you inherit the gene, the chances that you'll have the disease is very high. Sometimes that's not the case, right? So you might inherit a mutation in some gene, whatever it might be, but you might not get the disease. BRCA1 is a good example, right? You might inherit BRCA1 gene, but you never may have, you may escape having breast cancer in your lifetime. Huntington's disease has a very high penetrance. So in other words, if you inherit the mutation, the likelihood that you'll have the disease is very high. I think the biomedical community would say that for diseases like Huntington's disease, it's probably worthwhile doing an intervention of whatever that intervention might be. But the biomedical community would say that for, in this case, in HIV-

   9. PAPeter Attia1:13:06

      Yeah, this is obvious

   10. SMSiddhartha Mukherjee1:13:07

       ... it's not warranted.

   11. PAPeter Attia1:13:12

       The place-- Oh, sorry, go ahead

   12. SMSiddhartha Mukherjee1:13:15

       And, and I think that, that the biomedical community would say it's not necessary. It, it's not part of the-- it's, it's not part of the continuum of disease versus desire. It's-- it, it, it'll, it, it moves towards desire without moving towards disease.

   13. PAPeter Attia1:13:34

       I think the other examples of things on the clearly desire spectrum are pretty obvious, right? Like enhancing intelligence or physical traits like strength, size, et cetera. Of all of these areas, the one I find most interesting is around mental health, right? Which is we understand, for example, autism and schizophrenia have an enormous genetic component. Um, on the surface, it might seem like, hey, wouldn't it be great if fewer people were born with autism and/or schizophrenia? But it's really nowhere near that simple, is it? And there's a Pandora's box, uh, uh, upon which we have no idea what we could lose as a society if we were to sort of sterilize, quote-unquote, some of these conditions. Um,

10. 1:14:24 – 1:20:33

    The complex role of genetics in mental illness

    1. PAPeter Attia1:14:25

       y-you've obviously touched on this, and I want to come back to sort of mental health, because in some ways, where we're going to go next in this discussion, I think, is to the last cellular, uh, territory, right? The, the, the, the cells of the brain. To me, that's kind of like the most complicated cells of the body in a sense. And of course, this is one area where it's very difficult to appreciate a phenotype under a microscope or in a scanner. Um, and, and so I think part of it has to do with the complexity of these genes. But, but how do you think about what might be inevitably questions that society faces around the use of this type of precision gene editing when it comes to genetic conditions of the, of the brain?

    2. SMSiddhartha Mukherjee1:15:16

       Well, the brain is the most complex of all organs, and, um, it's important to understand that complexity. Um, what we know about, uh, diseases like autism and schizophrenia is that there are, broadly speaking, um, two kinds of genes in the entire spectrum of genetics, uh, that have to do with mental diseases. One kind of gene is what I call a shove gene. Shove meaning it pushes you really hard. So think about height. Forget about autism for a second. Think about height. Height is a genetic comp-- has a strong genetic component. Tall parents tend to produce tall children. Short parents tend to produce shorter children. So we know there's a genetic component to it. Now, there are genes in the spectrum of controlling height that are very powerful shove genes. They shove you in one direction or the other. So one example is Marfan syndrome. Marfan syndrome is a genetic disorder, a single gene. One gene, if you inherit copies of that gene, you will likely be extremely tall, and you might have other medical and other complications, but you will be tall for sure. Um, there's a story that Abraham Lincoln may have inherited Marfan's, uh, the Marfan gene, okay? So that's a shove gene. Um, those are relatively rare in the human population of very tall people. The more common, uh, variant is what I call, uh, nudge genes. Nudge versus shove. Nudge genes move you little by little by little by little by little towards increasing height. And there may be hundreds, there may be tens of hundreds of genes that may increase your height little by little by little by little by little until you get five feet ten inches, five feet nine inches, five feet eleven inches, six feet, et cetera, et cetera. It's not one gene, but hundreds, if not tens of hundreds. Now, transfer that same idea to mental health, okay? There are certainly genes in the human genome that change your n-neuron physiology, the physiology of your nerves, that are shove genes. In other words, if you inherit them, just like Marfan syndrome, you are likely to get-- much more likely to have mental illness in whatever form it is. Uh, they're relatively rare, and they are inherited in families. There's a great book, um, on this, um, written recently about a family that has multiple kids with schizophrenia, et cetera. Um, I think it's called Fallen River Road, if I remember correctly. Okay. But most mental illness, just by analogy with height Is not the consequence of this SHUG phenomenon, but are consequences of what I would call death by a thousand cuts. Small nudges that would push you towards depression, schizophrenia, autism, et cetera. And in fact, we haven't even found those genes yet, even though we know they exist. In some cases, we haven't even found those genes yet. So the, the capacity to change those genes is very limited because, you know, the examples that I gave you of gene editing, gene alteration technology are limited to one gene, two genes, three genes. But it's very, very hard to find a way to change those genes, hundreds, potentially tens of hundreds of genes in the mental health spectrum. So it's not as if we can all of a sudden wake up one morning and say, "I'm going to change your mental health or change the mental health of your embryo based on the understanding of our SHUG genes," because it just won't happen.

11. 1:20:33 – 1:23:38

    Two types of problems in science: the “eye in the sandstorm” problem and the “sand in the eye” problem

    1. PAPeter Attia1:20:34

       So let's now dig into this complexity issue around the brain. Um, you know, it's, uh, I, I've tried to explain this to people, and I've never been able to do a great job of it. You do a great job of it in the book describing the mystery, right? And, and you came up with a way to describe it that I thought was fantastic, which was... And I, I wanna make sure I'm getting this right, so correct me if I'm wrong. You said there were two types of problems in science. There are the eye in the sandstorm problems versus the sand in the eye problems. And as the cellular biologists and neurobiologists were getting deeper and deeper into the brain, and it really seemed like they had figured out this thing, these axons, the, the movement of electricity, these action potentials, they were figuring this out, but they had a little piece of sand in their eye. Uh, what was that piece of sand? And, and, uh, a-again, feel free to expand on, on this if I haven't, if I haven't provided an eloquent enough setup, but it was, it was a beautiful description.

    2. SMSiddhartha Mukherjee1:21:43

       Um, it's, um, um, it's, it's a fanciful description, and it's, um, it's an important distinction. Um, and it's a philosophical distinction. Um, the eye in the sandstorm problem is a problem in which you encounter something in medical sciences where the information just doesn't fit. Um, it's, it's being in a sandstorm. And I give the example of when we made the transition in physics between Newtonian physics and quantum mechanics and, um, Einsteinian understanding. So in other words, you reach a place, and all of a sudden, everything didn't fit. The, the, the bending of light, the presence of, uh, relativity, et cetera, nothing fit. So you needed a completely new theory, a, a, a new paradigm, a total shift in paradigm, paradigmatic thinking. That's the eye in the sandstorm problem. So in other words, there's sandstorms everywhere, and you can't make sense of the real world. Um, that's one kind of problem, and I'm interested in those problems. The s- the, the sand in the eye problem, as I call it, is, is a different kind of problem. The sandstorm in the eye problem is when everything fits except one fact. And it's very important to understand that both of those are really, really interesting because the sand in the eye problem says that our theory is almost right, but it's not right because there's something, a fact, that won't fit.

12. 1:23:38 – 1:33:16

    Understanding neural networks: an example of the “sand in the eye” problem being solved

    1. SMSiddhartha Mukherjee1:23:38

       And the particular example I use is, is neuronal transmission. So, so when people discovered neurons in the brain, they figured out basically by looks, looking at an anatomy, that neurons in the brain weren't-- that there was a space between them, that nerves weren't just wires. If you were an ele- electrician putting out an electrical, uh, situation in a, in an apartment, right? You, what you wouldn't do is put spaces between the wires so that all of a sudden, the s- that space would become a communication between wires. You just hook the whole apartment up. But when people like, uh, Ramón y Cajal and other scientists figured out how to solve this problem, they understood that all of a sudden, that, that, that nerves have spaces in between them. In fact, they had a name for these spaces. It's called a synap- a synapse. And that is an eye in the sand problem because you say to yourself, "Wait a second. If the nervous system is just electrical wires strung together, why would you place a space between two electrical wires?" And the solution to that problem turns out to be extraordinarily important for neuroscience because What happens between nerves is that an electrical conduction moves between, from one end of a nerve to the other. And then, and here's the kicker, it changes from an electrical conduction to a chemical signal between one nerve to another. And that chemical signal re-sparks or sparks an e- an electrical conduction. So you're go- going chemical, electrical, chemical, electrical, chemical, electrical. And you could say, what mad person would ever devise, um, or what evolutionary process would ever devise a system like this? And the answer is, the reason is very important, because what your, what your nervous system is doing is in that transmission between electrical, chemical, electrical, chemical, electrical, chemical, what your nervous system is doing is it's putting weights so that in the chemical transmission, and the, in an electrical sy- impulse could come down a nerve. But let's say there are 10 nerves or 10 neurons, nerve cells, that are impinging on one nerve cell. You could assign a weight as to how much this one was transmitting versus another one. And by assigning those weights, by assigning those calibrations, you could say one is louder than the other, one is softer than the other, one inhibits the other. And it's those combinations of inhibition, loudness, et cetera, et cetera, that allow profound things like sentience and conversation and consciousness and so forth. The analogy that's very important is this is exactly or similarly to how, and I say it's an analogy, this is exactly or similarly to how neural networks work. There are, there are weights put on how one layer of communication communicates with a second layer of communication. In other words, some are louder than others, some are softer than others. Imagine discriminating a dog from a cat. You could say that a very loud signal in that discrimination if the animal happens to bark. You know that for sure that's not a cat. That's a very loud signal. A very soft signal could be the weight of the animal. Some dogs are lighter than cats. A very loud signal could be the way that, you know, the snout of an animal is fixed with the head of the animal. Dogs have a particular snout-head combination. Cats have a particular snout-head combination. So by adjusting the weights of these combinations, we think by analogy that this is how the brain can discriminate between dogs and cats. Um, we don't know this for sure because this is an ar- area of science that's still in process. But this is a classic example in the 1950s of the idea that why on earth would you take an electrical signal, convert it to a chemical signal, and then convert it back to an electrical signal? The answer is because if it was just an electrical signal, you know, we'd be a box of wires. And a box of wires without the weight between individual signals between the wires is a useless box because we don't understand or we cannot understand how to construct a learning network between these, a box of wires. Whereas we can understand how we can construct a learning network between electrical and chemical stimulation because we can modulate the strength of that chemical stimulation such that we can really actually learn a process. Does that make sense?

    2. PAPeter Attia1:30:02

       It, it, it really does. I mean, another way that I, I like to explain it is using music, right? Which is the electrical signals that travel down the axon are digital, and m- maybe because I'm an engineer, I do tend to think in terms of digital versus analog processes. But if you explain that, look, digital means it's either completely on or completely off. There is no modulation. And imagine an orchestra that every instrument could only play at one maximum decibel level or not at all. You couldn't have any modulation of sound. It would be a very awful sounding music. But if now each of those instruments can go up and down and crescendo and decrescendo and modulate, you now basically ha- have kind of the analog adjustment of music. That's, that's how we make songs. And I think-

    3. SMSiddhartha Mukherjee1:30:56

       Right

    4. PAPeter Attia1:30:56

       ... that's probably a cruder analogy, but I, I think it kind of also gets at this point, which is, I mean, again, it, it comes back to how did evolution figure this out? How much trial and error went into producing something so remarkable, so brilliant, right? I mean, the, like you, again, you wouldn't think to engineer this system necessarily.

    5. SMSiddhartha Mukherjee1:31:20

       Well, I mean, I think the, the, the, the reason evolution figured it out is, is again learning. Um, uh, a purely electrical system, uh, which is sort of like saying you're playing some music, but you don't have any modulation.

    6. PAPeter Attia1:31:38

       Yeah.

    7. SMSiddhartha Mukherjee1:31:39

       Um, you know, you're, you're, you're listening to a score, and the score has no modulation, right? So you play everything at the same volume, at the same tempo, at the same time.

    8. PAPeter Attia1:31:50

       [chuckles]

    9. SMSiddhartha Mukherjee1:31:51

       That's not music.

    10. PAPeter Attia1:31:52

        Yeah.

    11. SMSiddhartha Mukherjee1:31:53

        That's not the song of the cell. What evolution, uh, figured out, and by figured out, I don't want to put a, a anthropomorphic idea on it, but what our evolution converged on is the idea that music has tempo, it has pace. Some pieces are softer, some pieces are louder. And by altering this loudness, softness as we move along in our neurons, that we can produce not just a mechanical, um, output of the score, but a re- but real music. And, and, a- and your musical analogy is very interesting because that's what we're producing. We're producing not a mechanical output of the score. We're producing a learned output, a mature output of the score, and that mature output has to do very much with, y- you know, modulation. Some parts are louder, some parts are softer, some parts speed up in rhythm, some parts slow down in rhythm, and that is ultimately the music of the cell, but also the music of the brain.

13. 1:33:16 – 1:38:45

    Importance of learning by doing: comparing the learning styles of a doctoral student to a medical student

    1. PAPeter Attia1:33:17

       So there's many systems we haven't spoken about, but there's one we would be remiss not to speak about because it's near and dear to both of our hearts. So you, um, when you went to Oxford to do your PhD as a Rhodes Scholar, you ended up in a lab where you learned immunology, which of course would come to serve you very well as an oncologist and a hematologist today. I wanna talk about a couple of things there. First is you spoke, of course, of your mentor, Enzo, in the lab. Help us understand what it is that was sort of bestowed on you from an education perspective, from a learning perspective as a doctoral student that we don't really get in medical school. I mean, you, you know, you would go on to Harvard Medical School, you'd get a great medical education, but I think anybody who's spent time in a lab will understand that there are just certain things that can't be taught in a classroom. You, you have to learn things by being in a lab if that's the language you wanna be able to speak. What are your, what are your recollections of that, that, that period of time, especially in the beginning when presumably the learning curve was very steep and you're drinking from a fire hose and you don't know much of what's going on, but you've committed to this path of becoming a scientist first, a physician second?

    2. SMSiddhartha Mukherjee1:34:39

       It's a very different kind of thinking process. Um, uh, Peter, I like to make medicines, and when I make medicines, I like to make medicines that are important for, for human life, hopefully for saving lives. I've talked about some of them, um, and we, we've spoken in prior podcasts about some of the new medicines that I've been involved in inventing. Um, textbook knowledge in medicine is important, and biology is important because it lays the groundwork and the foundations of, of what we know and what we understand. But textbook knowledge only gets you so far because when you come into the actual laboratory, you understand that there are things that are predictable, there are things that are not predictable, and then you get into these eyes-- eye in the sandstorm and sa- sand in the eye problems, um, which are very important. Um, you, you learn to recognize failure. You learn to recognize how to troubleshoot your way out of failure. Um, none of this is in a textbook. Open a textbook of biology, any textbook of biochemistry, biology, and try to find me a section on troubleshooting. You won't find one. Troubleshooting your way out of failure is a, the most standard way that we think about medicine and biology. Run a clinical trial. How do we select a patient? So let's say you're running a phase I, phase I/IIb clinical trial. I'm r- I, I run-- I have six open trials right now. How do you run a clinical trial? Read a textbook. Nothing will tell you about how you select a patient for a clinical trial, how you manage a patient with, uh, complications from a clinical trial. There, there is no information anywhere in that textbook about running that trial. So similarly, run, run an experiment which will set you up for a clinical trial. There is no information in that textbook about how to troubleshoot how and where and how to do that science that allows you to make it into human medicine. Um, what if, for instance, you suddenly find that, um, the medicine that you're, that you're working with or you're trying to create, um, isn't pure, that there's a contamination? Um, how do you, how do you re-remove that contamination? There is no method that y- y- you can't find a textbook. And so what you do is you ask your peers who've done this before you, and you say, "What did you do?" And that's not in a textbook. That's not in any book. That's not in a book that's ever been written. And so I wanted to write about that. I wanted to write about that process of learning by doing, learning by being, learning by experiencing, and that's why that whole chapter exists in the book. There is a kind of learning that we do by doing, that we be by being, that we acquire by acquiring, that is not-- it cannot be found in any book or textbook in the medical sciences, and there's no way around it.

14. 1:38:45 – 1:44:34

    Sid’s unique and brilliant style of writing

    1. PAPeter Attia1:38:46

       You know, there are a couple of really personal things I wanna, I wanna ask you about, some of them for selfish reasons. Um, I wanna start with writing. Um, for all the times we've had meals together, I don't know how this hasn't occurred to me to ask you, but how and when did this... And I, I, and I-- when I call it a gift, I don't want to undermine it, Sid, because I don't wanna suggest it doesn't require an obscene amount of hard work. But the reality of it is if I spent the rest of my life writing, I would still write like a child compared to an adult in the way that you write. So at what point in your high school, undergraduate, et cetera, did you realize that you had a brilliant way to write? Uh, and I, and I will say this, I think you are hands down the best medical writer. I mean, best writer who happens to write about anything that has to do with science and medicine. I mean, it's really, it's outstanding, Sid.

    2. SMSiddhartha Mukherjee1:39:42

       Well, man, thank you for the compliments. Uh, you know, writing is not an easy process for me, um, but it's also a, a, a somewhat weird process for me. And by weird, I mean I, I throw in everything. Um, in the next book that I write, maybe this conversation that we're having or some aspect of this conversation, some question that you ask in this conversation will find its way into the book. So, um, I, I, I, I have this policy in which I don't make any, uh-- th-there's nothing that's outside my box. It's all part of the box, all part of the whole story. So, um, again, I, I, I find that, that, that writing is a way for me to think, a way for me to, to work through my thoughts. Um, and the analogies and the metaphors and the, the metaphorical parts of my writing are really not in service of writing. They're in service of making me think. They're in service of making me understand why a certain phenomenon is related to s- another phenomenon. I draw from history, I draw from mythology, from philosophy, from our conversations, from interviews, a-and everything goes into, in-into a book. Um, and in, in some ways, I feel as if I had to invent the genre because, you know, it was so siloed. Medical writing was about medicine. It wasn't personal. It wasn't me- There was sharp distinction between memoir and case histories. Uh, there were sharp distinctions between, you know, uh, deep history and an interview or journalistic writing. And I said to myself, "You know, these distinctions are arbitrary. They are-- They only exist to serve a, a kind of secondary purpose. Why not erase all of them and make a new kind of writing in medicine or in, in, in life?" Because the, the most important thing that I think people told me about medical writing was like-- was that when people read writing about medicine, they want to enter your cosmos. They want to enter your world. They want to know what it's like to be like you. Um, and so I said, "Okay, I'll, I'll show them." What is it like to be like me? Well, it's like to be-- to experience intense, um, a-absolutely intense exhilaration when a clinical trial is successful. Absolute depths of depression and crisis when a clinical trial fails. Um, absolute anticipation, absolute apprehension, absolute admiration for people who-- on whose shoulders I stand. That's what it's like to be like me. And And when people said to me, "Show me your world," I said, "Okay, I'll show you my world, but I'll show you my world in, in, in a way that, that's like to be like me." What is it like to be like me? I, I, I am like you. I have terrible days. I have very good days. I have exhilarating days. Um, I make inventions. I-- Those inventions work, some of them don't work. Um, and all of it is wonderful and terrible at the same-- terrifying at the same time. I want to bring you into that, and that means I will combine memoir, journalistic writing, travel writing, philosophy, mythology, and everything. I'll throw everything in there so that you understand what it's like to be like me.

15. 1:44:34 – 1:49:05

    Falling as the leading cause of accidental death: a liability of multicellular existence

    1. PAPeter Attia1:44:34

       There were two things you talked about in the book, Sid, that were completely unconnected, but immediately in my mind were connected, and it probably has to do with my own world. Um, as, as you know, Sid, I think a lot about the end of life. I think a lot about how we can delay and push off the end of life. And one of the things that I think a lot about is how quickly life can vanish in a person when they fall. In an older person, I don't mean a 10-year-old. And these two things that, uh, you write about, and, and again, totally different parts of the book. One, you, you, you talk very openly about your own depression that really kind of kicked in a year after your father's death, which resulted from a fall. And near the very end of the book, you talk about the end of Virchow's life, which I didn't-- I was not aware of how Virchow died. I, I was completely unaware of that, that he ultimately died as a result of a fall and a broken femur, and within less than six months he was dead, which is unfortunately far more common than people realize. I mean, it is the leading cause of accidental death, and the mortality, as you, you know, Sid, from a person over the age of sixty-five, if a person at that age or above falls and breaks their femur, depending on the study, it's anywhere from ten to thirty percent mortality at twelve months. Um, and you do a very good job of explaining the why. 'Cause a lot of people, when confronted with that fact, simply can't understand it. And I was again confronted by it just two days ago when, um, the, the swim coach of Stanford while I was there, and I-- of course, I didn't swim at Stanford, but, but many of my friends did, and I sort of knew him, and I got to know him later after he had retired. Um, and he fell two weeks ago, broke his hip, and two weeks later he's dead. Never really recovered from the surgery. That's a very extreme example. It, it's, it's, it's interesting to me, but, you know, um, what I, what I couldn't believe was how you tied it back to the cell, right? Which was here we have one of these giants of cellular biology who falls and dies, but it's actually the result of a cellular process. One cell, you know, it starts with the, the osteoclast and the osteoblast and the matrix of the hip, and ultimately it leads to organ failure. Um, that's not a, that's not a leap that I think is easy to make. It's not, it's not obvious.

    2. SMSiddhartha Mukherjee1:47:13

       Well, it's, it's, it's obvious when you think about Virchow's own idea that the body is a citizenship.

    3. PAPeter Attia1:47:20

       Yeah. [laughs] Well said.

    4. SMSiddhartha Mukherjee1:47:23

       Um, and the citizenship falls when one part of the citizenship falls. Imagine a citizenship in any, in, in, in any capacity, right? All of a sudden, your Bureau of Transportation decides to take a leave for twenty days. The, the trains in New York City stop running. The trains stop running, and therefore people can't go to work. Uh, people can't go to work, and the economy collapses. The economy collapses, and all of a sudden, people who ha-- are dependent on small changes in their lifetimes, wage workers collapse. Um, and then the, the entire system, the net- the network of, of systems collapses, all because, you know, the Department of Transportation closed down for two days. Um, that's what happens in the human body. That's the liability in some ways of multicellular existence. There are many advantages. We talked about multicellular existence as advantages, but there are also liabilities because you depend on your pancreas for insulin. You don't depend on your brain. Your brain doesn't make insulin. You depend on your brain for senses and consciousness. You depend on your muscles for movement. Your brain can't produce movement without muscles. And so there's a citizenship that, that bodies develop and have developed with each other so that we together perform as organisms.

16. 1:49:05 – 2:00:13

    Sid’s struggle with depression and his desire to change the stigma around mental illness

    1. PAPeter Attia1:49:05

       Sid, again, another personal question. How much did you weigh the pros and cons of writing about such personal matters as y- your own depression? I mean, we, we do still live in a world where it's not entirely clear to me why we view depression different from hypertension. Um, y- you know, for example, if a person says, "I have hyperlipidemia, and I, I, I take ten milligrams of Lipitor a day," I don't think anybody bats an eye. But if somebody says, "I'm really struggling with depression, and I take an antidepressant It just has a different valence to it for some reason. I don't-- Again, I don't know why that is. I really don't. Um, but in the, in the, in the presence of that knowledge, you still chose to talk about this. Um, why?

    2. SMSiddhartha Mukherjee1:50:02

       Well, Peter, it was a very conscious choice. It was not unconscious. I talked to my family about it, um, and I made the choice after that conversation. Um, I agree with you. I think that depression is, it can be, um, what's called an organic disorder, a disorder in mood-regulating neurons in your brain, just like type 1 diabetes is an organic disorder, a disorder in the inability of pancreatic beta cells to secrete insulin. Um, the reason it's different, I think, is that we associate a kind of victimhood to mental disorders. Um, and that kind of victimhood is punitive. It is, it, it blames victims for being victims in a way that, you know, you don't say that, "Oh, you know, you're hypertensive because you, uh, have genetics or have behaviors," et cetera, et cetera, that are related to your hypertension. But depression and mental disorders, uh, grief, depression, and perhaps even more complex disorders, schizophrenia, have a sense of blaming the victim, and the victim being the person who's, um, the, the, the experiencing the disorder. Um, that victimhood, I think, has to do with the idea that the brain is separate from the rest of the body. It's a special organ.

    3. PAPeter Attia1:51:46

       Mm-hmm.

    4. SMSiddhartha Mukherjee1:51:47

       And yes, of course, it's a special organ. There's no doubt about that. But on the other hand, it's also an organ that has physiology, just like your pancreas has physiology, just like your heart has physiology. And so what I wanted to get away from is this idea of special victimhood, um, and talk about the brain as a cellular cluster, which is just a cellular-- in some ways, just a cellular cluster like the pancreas or the heart or the liver is a cellular cluster, and thereby remove this or defend or even challenge this idea of victimhood and, and responsibility. Because most people who experience severe clinical depression experience it as a consequence of, of course, of environmental and emotional stimulation, the grief of dying, the grief of their situation, et cetera. But they, but, but there are neuronal or nervous ce- uh, nerve cells and nerve cell circuits that push them in biochemical and chemical ways towards a state in which they cannot function. Um, and I want to highlight that that absence of function, if Werther was alive today, Werther would say that absence of function or that dysfunction is not dissimilar to a person who has a failing heart, um, or a failing liver, because that function is a dysfunction of mood-regulating circuits and neurons in the brain, just as type 1 diabetes is a dysfunction of, of insulin-regulating cells in the pancreas. And that idea, again, is I think very important and I think radical, um, in, in, in this book and in all my books.

    5. PAPeter Attia1:54:12

       I, I agree with you completely. I think it is entirely radical, and it's, I think, very difficult. You know, I ha- I, I, I spoke about this with Carl Desiroth. Um, if you haven't read his book, by the way, it's a fantastic book as well.

    6. SMSiddhartha Mukherjee1:54:25

       I have read, I've, I have read his book.

    7. PAPeter Attia1:54:27

       Yeah.

    8. SMSiddhartha Mukherjee1:54:28

       It's, it's incredible.

    9. PAPeter Attia1:54:29

       And, and Carl was a classmate of mine in medical school, and he was equally brilliant, um, then as, as he is now. But, but he talks about this idea, right, which is it's this entire field of medicine, I'm referring to psychiatry, for which we have not one biomarker, for which we have not one radiographic finding that lends itself to a diagnosis. And so in the example of that failing heart and that failing liver, I mean, we have a menu of things to aid in the diagnosis. In fact, it's much easier to make that diagnosis today than when William Osler had to make the diagnosis 125 years ago. I mean, today, a medical student can diagnose a failing heart and a failing liver given enough data, and yet there's still this black box inside of our brains in some ways. And, um, I, I, I think, uh, um, I just, you know, I find it very interesting, and I, I can't help but wonder where we will be in 20 years. Like, when I, when I think about oncology today and I think about what the wish for oncology is in 20 years and I think about psychiatry today and psychiatry in 20 years, I feel like there's even more potential in psychiatry. And of course, I think the potential in oncology is enormous.

    10. SMSiddhartha Mukherjee1:55:54

        Well, um, uh, I, I think, I think you, you hit the nail on the head, which is to say that, you know, biomarkers will help and are, are always helpful, but ultimately it's a clinical decision. Um, when you see-- Uh, I always tell people, you know, um, who haven't been in clinical medicine, when you see depression, you know depression. You know that the, that, that this person has a dysfunction of the neural circuits that regulate mood, just like a patient with type one diabetes has a dysfunction in the neu- in the, um, cells that secrete insulin. Um, and even if there are no biomarkers, you know it, and this is what humans can see about hum- other humans. Um, there's a, there's a disproportionality or a, uh, dis- um, a, a, a, a disconnection between the level of grief that a person experiences and the level of grief that persists, uh, the level of ennui, the level of, um, psychomotor inability to move, um, that a person experiences when they're, when they're clinically depressed. So, so I think that, that there are, even in the absence of biomarkers, I think there, there is a new age that is coming, um, and, and a respect, I think, for the autonomy of patients who experience neurological and psychiatric diseases. And I think as you've said before, Desrosiers writes about them, um, very carefully and very thoughtfully. There are many people, Andrew Solomon-

    11. PAPeter Attia1:57:50

        Mm.

    12. SMSiddhartha Mukherjee1:57:50

        ... has written about, um, uh, about all of this. And I think it's very important because, you know, we could find therapies for these. Some of them may be related to things that you and I are very interested in, like alterations in diets, alterations in diets plus medicines, uh, alterations in, in human physiology that could reset brain circuits, um, electrical stimulation as Helen Mayberg and others have been doing. And to treat the problem as if it was, you know, just a problem that is sort of an epi phenomenon is to minimize what the problem is.

    13. PAPeter Attia1:58:35

        Sid, there's so much more I, um, wanted to talk with you about, but as, uh, not surprisingly, we, we, we've, we've gone pretty deep in a few things, and there are topics like the entire immune system, the epigenetic phenomenon and how we get into cellular reprogramming and Yamanaka factors. I mean, there's-- We got through about half of what I wanted to talk about. So I think the only reasonable thing to do here is to say, once the book tour is behind you, once we've both got a little bit more breathing room, we should sit down again and do part three where we, where we talk about some of these other factors. You, you have a wonderful way of explaining complicated ideas. Um, and, and frankly, I think perhaps the single most important thing I wanted to talk about today, which was to bring all of this around the future of science and the culture of anti-science that is, that is propagating. I, I, I, I, I hesitate to not touch on that now, but I don't think we could do it justice with a glib and short discussion, and I'd, I'd, I'd, I'd, with your blessing, like to postpone that as, as yet another topic we can explore, uh, hopefully in twenty twenty-three.

    14. SMSiddhartha Mukherjee1:59:41

        Would love to. Would love to. Um, and, and good luck. I love your podcast, and I have loved being on it, so.

    15. PAPeter Attia1:59:49

        Well, thank you, Sid, and, uh, congratulations again on another masterpiece and, um, I'm looking forward to, uh, to, to helping to spread the word so that many more people, uh, enjoy the, uh, or experience the joy of, of reading your work. Thank you, Sid.

    16. SMSiddhartha Mukherjee2:00:02

        Well, thanks. [outro jingle]

Episode duration: 2:00:13