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

Hey everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode, I'll explain what those benefits are. Or if you want to learn more now, head over to peterattiamd.com subscribe now. Without further delay, here's today's episode. My guest this week is Siddhartha Mukherjee. Sid was a previous guest on episode number 32, way back boy December 2018 I believe believe Sid is a cancer researcher and a cancer physician. A practicing oncologist, he's an assistant professor of medicine at Columbia University and a staff cancer physician at the Columbia University NYU Presbyterian Hospital. He also happens to be a luminary author. He's written four books, the Emperor of All Maladies, the Laws of Medicine, the Gene, and his most recent book, the Song of the Cell, an exploration of medicine and the New Human. In my first podcast with Sid, we mostly discussed the Emperor of All Maladies, the biography of cancer, a book that won him the Pulitzer Prize. In this podcast, we primarily discuss his most recent book, the Song of the Cell. This is a book that I just devoured and I wouldn't have thought I could find a book about the history of the cell so interesting. But as you can tell by the fact that we're doing this podcast, I clearly did talk about so many things that I think to sort of try to do it in the intro would do it no justice. But we go everything really, from the evolutionary drive to go from single cell to multicell organisms, all the way up to cell therapy, gene therapy, crispr, of course, all these things. So we talk a lot about Sid's writing process as well, given that he's such a prolific writer and frankly, some very personal things, including his decision to open up about his own depression in his writing. So it's always a pleasure for me to sit down and talk with Sid, especially when we can do it like this and record it. So without further delay, please enjoy my con conversation with Sid Mukherjee. Hey Sid. So great 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 in a different time zone. Congratulations on the success of your most recent book. For folks listening or viewing, give us a sense of where this book fits into the prior work. We talked at great length about one of your books, the Emperor of All Maladies, but there was a book that followed that. And then, of course, there's this. So maybe put this in the context of those books.

This is part of a trilogy and possibly a quartet that I'm working on, 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, living things, obviously, particularly humans. In an odd way. 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, would be to probably start with the gene. Now, the gene being the least unit or the smallest unit of information, and then realize as you end the gene, that genes, which are encoded in DNA, the molecule DNA, are lifeless. They don't have any autonomous life. A gene is just a molecule. It's a chemical, and 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 the human genome or any genome to a score of music, but a score is lifeless. There's no music in a score. It's just a code. You need a musician to bring it to life. And the cell is that musician, Hence the title of the book, A Song of the Cell. The Cell brings it to life. So the second book, to some extent, is the Cell. And then the third book, bizarrely enough, is the first book. It's sort of like Star wars, the prequel to the sequel to the prequel, where you learn about what happens when cells become aberrants. So that would be one way to read the series of books. Start with the gene, move on to the second unit, which is the cell, and finally end up with the dysfunctional aberrant cell and what happens to it when its genes go haywire. A completely different way would be to read them as they appeared. And the reason behind that is that they progressively 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, obviously, genes and genetics? What did we not understand about cancer in terms of its cell biology, when the Cancer Genome Atlas was, for instance, completed. And what do we understand now? So they can also be read chronologically from the first to the third. You would get a different kind of story. And that's what's interesting about it. You can read it either way.

It's possible that my question statement here is tainted by a bit of recency bias, because I read them in order. And of course, I've just finished reading the Cell because we decided on a very last minute basis we were going to try to do this podcast last minute for the way my podcast works, which is months of preparation. So I was reading the book in the period of the last 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, 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. Does that statement surprise you or how does that resonate with you?

It's not surprising. It's because the characters in this book are enunciating things that are, I think, very fundamental. If you take, for instance, a comparison, if you were to do a historical comparison with the history of genetics in the scientific world, you would start with Mendel, Gregor Mendel, of course, being the pioneer here. And then there's an enormous period of silence that follows Mendel almost 40 years in which basically nothing happens. And then, you know, his work is picked up by other people, ultimately picked up by folks like Thomas Morgan and others. But for a long period of time, nothing happens and nothing's relevant. What you see in this book is very different because you see a sort of continuation of development. So once the microscope is invented in the 17th century, you see from the 17th century a kind of gradual blossoming of the science, ultimately ending up with someone like Rudolf Virchow, who can make really audacious stuff, statements that are missing in the history of genetics until much later. The audacious statement that Virchow makes is every function that we carry out, 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. This conversation is a consequence of something happening in some cells. 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 illness is the consequence of some cell behaving incorrectly. And these statements are made in the mid to late 19th century. They're in fact, almost contemporaneous with Mendel. So you have enormous sets of leaps in cell biology, which is why this book might feel that these characters are doing things while genetics is still plotting its way, trying to understand Mendel's first very important paper. And there's a remarkable 40 years of silence, whereas in cell biology, there isn't that 40 years of silence.

And I think also 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 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 piece of physiology.

It's an incredible. I tried to make one myself. I tried to make one of Leeuwenhoek's microscopes. And I can tell you, Peter, it was not an easy task. It was a disaster. And he made 500 of them. These are single lens microscopes, and they're about this big. It's about the size of half a sheet of paper. And the lens is smaller than the size of your eyeball. So you have this sense in which you have 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, in a droplet of water, you can actually see these microscopic forms. So there's an enormous sense of wonder about how people even began to see these and how they found them and what the consequences of that finding were and are.

People who listen to my podcast are probably used to an idea that I talk about. And you have come across this nasid because you were kind enough to be one of the people who read my book. But I talk about this transition from medicine 1.0 to 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 they weren't momentary events, they were transitions of process. One was, of course, the way we changed the way we thought. Right. So it was the scientific revolution. So once we introduced the scientific method, late 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 obvious when I say it that way. But in effect, this book describes how medicine went from, effectively, witchcraft into where we are today. We're going to talk about this in more detail, by the way, but does that make sense to you?

Oh, absolutely. It makes sense to me in the sense that it makes sense, because the introduction of being able to ultimately see germs and connect germ theory with human disease, as you say, took medicine from witchcraft to the modern era. Think of any procedure, childbirth, 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 these antibiotics are now available and the life saved. I mean, just childbirth alone. The capacity of saving lives through antibiotics has been enormous and transformative in terms of, as you say, moving medicine from witchcraft. What's astonishing in the piece that I write about microbial biology and the discovery of microbes, Peter, is that microbes were imagined in the abstract long before they were seen. So what's interesting is people like Lister, the great surgeon who began to sterilize his instruments, folks like Semmelweis. And I have a small biography of him in the book. Almost ignored by medical history now, but Semmelweis discovered that doctors were transmitting microbes.

Tell the story. I have it in my book. You have it in your book? 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 is the example of that. And it's a heartbreaking story, but it's a remarkable example of this transition.

So Semmelweis was a junior obstetrician in Vienna. It's important that he was so junior. And he made a very important and incredibly important discovery. So Semmelweis was delivering children, and there were two maternity wards, Ward 1 and Ward 2. And this is why it's important in medicine, I think, to listen to your patients. You know, the famous adage in medicine is the most important question that you ever ask in medicine when you're trying to diagnose a patient is to ask the patient, what do you think the problem is? And it's the one we forget the most. Right. Doctors never ask that question, but usually the patient will tell you. They'll say, you know, I think I have an infection in my lungs, or, I think I'm depressed because of X or Y reason because I lost my father. So Semmelweis learned to ask people of a bizarre aberration that was going on, which is that in World one, the maternal mortality rates from childbirth were astronomically high, whereas in Ward 2, same people, same women coming in, were much lower. And he knew this because, you know, at least the story goes, whether it is apocryphal or not, that in Ward 1, mothers would beg to be admitted into the safer ward, while they would beg not to be admitted, where they would have a 30% mortality rate or a 20% mortality rate, one out of five women, this is an incredible number if you think about it. So Semmelweis began to ask the question why? And he looked at all sorts of variables. He was sort of a classical epidemiologist, so he looked at all sorts of variables. And the variable that he found was that in the first ward, where there was a high mortality rate, it was run by doctors. And these doctors, he figured out, were running between autopsy rooms doing autopsies on probably the very patients that they had killed, and then running and then, without cleaning their hands, delivering babies, essentially examining patients, delivering babies, etc. Word 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, that what doctors were doing is they were transferring, and these are his words, some material substance from the decaying, 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 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 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. This is all in the abstract. But he made this argument that this material substance was responsible for what was then called childbed fever or maternal infections, and the transfer of the material substance could be removed by hand washing. So in the abstract sense, he had basically founded germ theory.

Completely prescient.

Yeah. And the idea of a material substance, that's what's important about it, right.

It wasn't just bad air in a vague sense.

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

And the sad thing, the epilogue to the story is the guy dies in an insane asylum, basically having been ridiculed.

That's right. So he's ridiculed. The last thing that the doctors want to do is to admit that they've been infecting other women. So Semmelweis is ridiculed and he's sent off to an insane asylum. And ultimately he dies impoverished and never vindicated.

Medicine is full of these stories. But this is what it was about the book that really captivated me. This thing that I've taken for granted so much of my existence in medicine is what really allowed this leapfrog. 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? In some ways, yes. In some ways, no. We thought, 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 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? 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. You go through this very elegantly.

Let's pause for a second to contemplate single cell organisms. So they are bacteria, 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? The bizarre question that you should Ask is why we exist at all? What is the reason that we have trillions of cells? Why do we exist? Why aren't we all bacteria? And people have been trying to answer the question. And the initial idea in the 80s was that there was 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. It used to be called a major transition. It actually turns out to be a minor transition. In other words, there was a great evolutionary drive towards becoming multicellular. And you can ask the question then, well, if single cell 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 several possibilities. The leading possibility is predation. It's much harder for 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 is that it can move away from predators through specialized apparati. So that's one idea. The other idea is food and resources. Multicellular organisms can access food and resources. And there are other ideas about how multicellular organisms 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 in the world. If you took by weight all the single celled organisms in the world and their diversity, you would be shocked at how successful they still are.

Remind us what Ratcliffe's experiments with yeast demonstrated. I had never heard of that experiment before. So I'm reading this like I'm reading a thriller novel.

William Ratcliffe is a professor who studies this evolutionary transition from single cell to multicellular organisms. And he did this, actually an extraordinary simple experiment. And he just thought about it over Christmas with Travis Zano, his advisor. He said, well, why don't we just take some yeast and culture them and we basically allow them to grow. And so remember, yeast are single celled organisms and we just collect the sediment. So anything that's multi celled is obviously going to 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. So we allow that to evolve another cycle, collect the sediment, allow that to evolve another cycle. And by about 30 or 40 cycles, he found that the yeast had evolved. And this is astonishing, I have pictures of this in the book, into these sort of snowflake, like multi fingered, multicellular forms, 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 continue to propagate as multicellular yeast. So in other words, he had basically created a new life form 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 yeasts could reproduce is that one cell could butt off and create a new multi fingered, multicellular yeast. That would be one way that these organisms 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 commit a purposeful cellular death. I repeat the word, they commit a purposeful cellular suicide, such that this snowflake can break into two parts, two snowflakes, and grow out new fingers. So this organism has now, evolutionarily speaking, learned. The word learned implies that it has some consciousness, but that's not true. This is just an evolutionary 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 Ratzer has done many versions of this experiment. He's done it with algae, he's done with various other organisms. And what he finds is that there's even more specialization. So these new creatures, that's the only thing I can call them, form little channels to deliver nutrients, they form pores, they form secondary structures. 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, which may be 60, 80, 90 days. So you can imagine over the course of 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.

Because my kids who are 5 and 8 at this point, they're as you can probably imagine, obsessed with dinosaurs. So we're non stop watching every imaginable thing. 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 in existence so many millions of years ago? And are we basically seeing a correction now? In other words, was that just the pendulum swinging too far towards multicellular, where 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 volcanic eruptions and things like that, maybe we just wouldn't be here today and dinosaurs would be the sentient, higher order creature.

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

I just wonder if there's something about their size that became their downfall beyond the obvious external factors. And it just made me think of that when I was reading that segment about the fitness of the single cell.

There's a beautiful essay, if I remember correctly, by Stephen Gould, where he talks about a natural biophysical limitation on size. And that's because the volume to surface area of any creature reaches a place where the volume to surface area becomes no longer sustainable, because the surface area of a creature is no longer able to deliver the oxygen and the nutrients required for aerobic living. I'd encourage people to read it. I don't remember the name of the essay, but we'll find it. It has to do with the rhinoceros and what the size limits of creatures can and cannot be.

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

I tried to create a typology of the four types of ways in which we could use cells as medicines. 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 a microbial cell while you're sparing normal human cells. That's one. The second one is the transfer of cells from one body to another body without any modification. The simplest example of that would be blood transfusion. 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 I remember I said 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 those proteins could be very useful. So insulin, for instance, you can only make insulin in cells, or you can. That's how insulin is generally made. Antibodies are made by cells. The antibody herceptin that you use in breast cancer is made by cells. So that's a third use. And the fourth and the final is the one that is coming up and now becoming more and more prominent 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 use it for a therapeutic reason. So, for instance, car T cells, which I'm sure we'll talk about, are examples of genetically modifying T cells and putting them into a human body. I've been doing, as you very well know, series of experiments on bone marrow transplants in which we genetically modify the bone marrow using CRISPR and other techniques and then transferring them into human bodies and essentially creating genetically engineered cells. People often talk about gene therapy, and I always remind them that gene therapy is really cell therapy. If you put the gene in the wrong cell in the wrong place at the wrong time, you get nothing. You get the disaster. So gene therapy is really a mechanism to put a gene inside a cell. And that would be the fourth typology, as it were. And then the book goes through elements of these four typologies, Examples and elements of these four typologies as medicines.

Well, let's touch on a few of them, because you and I don't have the ability to sit here for the next three days, which is what it would take to do each of these their appropriate service. There are a handful that I really want to talk about. So let's Talk about the story of Jesse Gelsinger, because that is one of the earliest examples of gene therapy in a human. We could talk about what went wrong. But 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 let's just start with kind of, what disease did Jesse have? Why was gene therapy viewed as the solution as opposed to whatever the other three methods would have offered Jesse?

So Jesse had a genetic disease. He was a young kid, I think 14, 15 years old, 16 maybe. And I've had a very, very moving interview with his father. He had a defect in an enzyme which is related to the processing of ammonia and ammonia related substances in the body. The idea back then, and we're now.

Talking it was about 22 years ago. Yeah, it was about 2000.

Yeah. Early 2000s at the University of Pennsylvania. The idea was that if they could create a virus which would then go to Jesse's liver and start making the correct version of the gene, then Jesse's disease would be ameliorated. So they created a virus that they thought was going to be harmless. 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. 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 and thereby correct Jesse's disease. So that was the idea behind that therapy.

Let's explain two things before we go on with the story. 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? Do we consider them living things? Are they not living things on their own? I mean, they basically just contain DNA and rna, but they're sort of parasites in it. They need us to replicate. So.

That's right. So viruses are not. They don't meet the criteria of living things. They are essentially a strand of RNA or multiple strands of RNA or DNA that have been packaged, usually with an envelope and decorated with some proteins on top. But they, 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 go and attach themselves to cells, let's say to human cells or any other cells, 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 and then they go and infect more cells and make more copies of themselves and so forth. That's what a virus is. And in Jesse Gelsinger's case, the idea was that this virus would essentially infect his cells. And because the virus was genetically modified, it would insert its genetic payload, which consisted of the normal gene, into Jesse's liver cells. The liver cells would now start making the protein that was defective in Jesse's case. This is gene therapy. And then in doing so, it would reverse his relatively mild disease.

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

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

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

Well, there are many things that have happened. It's not just safe places. I'll Give you some examples. Again, I'll try to create a typology for you. So one thing you can do is there are safe harbors in the body. By safe harbors, I mean places that the immune system doesn't usually reach easily. The retina turns out to be one of them. There's not a lot of immune cell infiltration into the retina. So you have a chance to use gene therapy. And in fact, there are now several gene therapies that have been approved that allow you to insert or inject viruses so that you can correct a gene that's missing or abnormal in the retina. So that's one place. There are some other places in the body. Turns out the testes is another place, although we've not used that for gene therapy. That's one thing you can do. The other thing you can do is 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. What you can do is you can dial the immune response down so that the immune response doesn't respond so briskly to the gene therapy. You can hide the virus so you can make a virus such that your body has not seen such a virus before. So you can actually use a novel kind of virus that won't raise a brisk immune response. The fourth thing you can do is you can actually give the gene therapy in small doses. It's called hyperfractionation fractionation, small fractions so that the immune system doesn't again go berserk 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 the number of deaths from this hyperactive immune response still remain, but they're much, much, much more controlled than in Jesse Gelsinger's times.

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

Well, so CAR T cells are a very special example of gene therapy. So in a CAR T cell, what happens is that you extract T cells from a human being who has cancer, 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 a T cell. A T cell is part of the immune system. Its job is to hunt out and kill 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 foreign cell detector built into your body. So now you take that T cell and weaponize it to recognize the cancer cells as foreign, and then you re inject them. You grow them in a petri dish in the laboratory, and you re inject them into the body. And you know, our laboratory has done a lot of this work. We are now doing this in India. The costs of doing this are astronomical. In the United States, almost $500,000 to a million dollars per person. We're trying to reduce that cost dramatically 20 fold, perhaps even 50 fold in India, using new technologies, et cetera. We've treated about 11, 12 patients already, and we've just released a data. It looks very good. 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 cancer cells in your body.

What is the difference? 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 beacons of success. But cancer is full of marginal treatments, you know, extend median survival by two months at a cost of $100,000. How much of that is just a structural American problem versus people that are able to go outside of the existing channels of ip?

Some of it is a structural American problem and some of it is not. So obviously, the structural American problem is that for reasons that we're trying to still investigate, 90% of drugs, including drugs in the cancer space, fail. And pharmaceutical companies make the argument that they're trying to recoup the R and D costs of those failed drugs with the ones that are successful. Now, that's a complicated and I would say somewhat specious argument because 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 therefore took this drug all the way to spend millions, perhaps even billions of dollars on the drug? So that's one reason. So that would be the standard argument. The second reason Is that car keys are intrinsically expensive to make. Their success rates are incredible. So these are not just one month, two month survival. My book begins with the story of Emily whitehead. She was 7 when she was treated with car T therapy. She's now 17 or 16, applying to college, completely cured. So you have a situation in which these are miraculous drugs. We've seen people who've had terrible leukemia, Essentially eradicated leukemia forever 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 any other tablet. And then, of course, growing the T cells, you have to grow them in an incredibly sterile environment where you have to basically put on a hazmat suit to go in. It's called a GMP facility, but it's a highly, highly sterile environment. It has to be monitored, it has to be checked. A single bacteria or a fungal infection in that flask of a T cell Will now basically take that entire batch away. You can't give those back. So there are some intrinsic expenses. Now you ask the question, how can you reduce the cost? Well, we reduce the cost by several ways. One is that we've learned to make the virus in a much cheaper way. We've reduced the cost of the patent burden by essentially really making successful products and not spending millions of dollars on unsuccessful products. So we don't have to recoup all that R and D cost. We've changed the machinery, 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. Adding them all together comes to, you know, almost a tenfold to 20 fold reduction in cost.

Let's now use another example of gene therapy, which is maybe the harder of the problems. You have a person more like Jesse, where they have a germline mutation that results in a pathology. And the goal is as an adult. Let's pick sickle cell anemia as an example. 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. We know exactly what genes drive that. How does one go about doing that? And where are we in the realm of approaching success there?

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

So this dovetails nicely into, I think, a term that most people have heard of. But the details of this are pretty important. And this is the idea 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 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 how they interact with viruses, a way to protect themselves. But I now want to use the story of CRISPR to talk about another tool by which one can impart this type of cell therapy.

So the world of genetics was turned upside down in a very important way by the discoveries of Jennifer Doudna, Emmanuel Charpentier and several others. I should mention Peng Zhang and George Church. And there's a history of this which is in the book. For a long time. There was the question. So the human genome is a library. Imagine the human genome as a massive library. If it was printed in normal text, it would contain 80,000 books, a massive encyclopedia stretching across a massive library. 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 in that library. This was a dream of scientists for a long time and no one could could do it. And then Jennifer Doudna Choppointier, assisted by Peng 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. Either deleting that word, in other words, erasing it, simplest change, or potentially changing the word to another new word. 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 a processed manner. So just take 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 a mutant or abnormal cystic fibrosis gene to a normal gene, the normal version or the wild type version using this technology. So it's obviously extraordinarily important and there are many, many applications of this technology. 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 variants or their more common variants and so forth. So we now 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, T cells, car T cells. It's a revolution. And all I can emphasize is the depth and breadth of this revolution because it's enormous.

Two follow up questions. The first is explain, using the library analogy, how this system differs from the approach that was used 20 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 80,000 books, you can go to one page, one word, and make the change versus that other approach.

So again, imagine the human genome as a massive library, 80,000 books printed on a page. So the old technology, the technology that was used with Jesse Gelsinger is the technology in which we. I'm using metaphors and analogies here. We would insert a new page into that 80,000 page library. So you would go into the library, 80,000 books around you, and you would take a page and insert a new page, a foreign page, into that 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 a page that belongs. And that's what happened with Jesse Delsinger and other people. Librarian being a human body, would come and say, wait a second, you're inserting new pages into a library that's no good and would prevent that.

And it seems to me that 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 87 and 88. You might accidentally insert it somewhere, somewhere else.

Right, exactly. And the librarian would say, well, why are you putting it into Jennifer Egan's book on the Goon Squad? It doesn't belong there. You've just inserted that new page, the new gene, into a place where it doesn't belong. And he or she would say, I don't buy this. I'm not going to let you do that. That's absurd. You're reading along with Chekhov or Egan or 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, and you say, well, wait a second, that doesn't belong there. And that was where the technology sat for years and years and years. Then 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 words that they could change was just deleting a word. 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 by changing a single letter and for the most part, leave the library intact. And if you were a very vigilant librarian, you would say, that's okay. You haven't put in an extra page in 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, which would not be possible otherwise.

So you alluded to this at the outset of your description, which was you could make changes to an embryo, 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 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. Maybe briefly tell the story of JK and the CCR5 gene. More importantly, what are the implications of that pretty unethical episode?

Again, I would encourage people to read the book the Song of the Cell to get all the details about it. But a Chinese scientist, J.K. hui, made a somewhat bizarre decision. I'll talk about why that decision was bizarre. There is a gene in the human genome that makes cells resistant to HIV infection. There are many genes, but this is one of them. The Chinese scientist in this case, he, Joong Ken, decided that he was going to 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 in which the man was HIV positive, the woman was HIV negative, and 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. So sounds great on paper. The problem is that their risk, the risk of these children to acquire hiv, because they were produced by ivf, is basically zero. It cannot get hiv. The sperm doesn't carry hiv. So if you produce a child by this method, you basically have a zero risk of HIV infection.

It wasn't medically necessary. Right?

It wasn't medically necessary. Let me take a step back. I make a very big distinction between disease and desire. Disease is fundamentally linked to suffering. When we talk about disease, we talk about human suffering. When we talk about desire, we talk about the idea or 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 altered cells. So he went ahead with this project and he created two girls. We don't know their real names. They've been called Lulu and Nana. 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 a much cruder version of that. And scientists across the world were concerned about did he, absent informed consent, 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 is no disease. And so the scientific world became extraordinarily incensed about the idea that this scientists had 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 twins that were born, had a zero risk, zero risk of acquiring HIV from their fathers because the sperm had been watched. Sperm don't get infected with hiv. They had no risk of the disease. So what was left was desire, the desire to be first the desire to create new human embryos. That's what incensed the scientists and the community of scientists.

You know, there's probably no greater example of the relationship between science and philosophy. People might want a little bit of a reminder about what a doctorate degree is formally called.

Right.

A Doctor of philosophy. When you think about this question, it becomes kind of difficult. And I think in Walter Isaacson's biography of Jennifer Doudna, in your book, this topic is explored. Where does one draw the line? So Huntington's disease is a great example in the sense that 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.

Right. So APOE4 is a risk factor for early Alzheimer's disease. Just to give you an example of how devastating it can be for particular people who have combinations of AP4 and other genetic mutations that increase their risk for early Alzheimer's disease. 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. You might inherit BRCA1 gene, but you may escape having breast cancer in your lifetime. Huntington's disease has a very high penetration. 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, whatever that intervention might be. But the biomedical community would say that for, in this case, in hiv, it's not warranted.

Yeah, this is obvious.

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

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, which is we understand, for example, autism and schizophrenia have an enormous genetic component. 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 upon which we have no idea what we could lose as a society if we were to sort of see, sterilize, quote, unquote, some of these conditions. You've obviously touched on this. And I want to come back to mental health because in some ways where we're going to go next in this discussion, I think, is to the last cellular territory, right? The cells of the brain. To me, that's 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. Part of it has to do with the complexity of these genes. 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 brain?

Well, the brain is the most complex of all organs and it's important to understand that complexity. What we know about diseases like autism and schizophrenia is that there are, broadly speaking, two kinds of genes in the entire spectrum of genetics 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. Height 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. 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 told for sure. There's a story that Abraham Lincoln may have inherited the Marfangi. So that's a shove gene. Those are relatively rare in the human population of very tall people. The more common variant is what I call nudge genes. Nudge versus shove nudge. Genes move you little by little, by Little by little by little towards increasing height. And they 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 5ft, 10 inches, 5ft, 11 inches, 6ft, et cetera, et cetera. It's not one gene, but hundreds, if not tens of hundreds. Now transfer that same idea to mental health. There are certainly genes in the human genome that change your neuron physiology, the physiology of your nerves, that are shoved genes. In other words, if you inherit them, just like Marfan syndrome, you are likely, much more likely to have mental illness in whatever form it is. They're relatively rare and they are inherited in families. There's a great book on this written recently about a family that has multiple kids with schizophrenia, etc. I think it's called Fallen River Road, if I remember correctly. But most mental illness, just by analogy with height, is not the consequence of this shove 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 capacity to change those genes is very limited because 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 shove genes, because it just won't happen.

So let's now dig into this complexity issue around the brain. 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, and you came up with a way to describe it that I thought was fantastic, which was. And I want to 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 movement of electricity, these action potentials, they were figuring this out, but they had a little piece of sand in their eye. What was that piece of sand? And again, feel free to expand on this if I haven't provided an eloquent enough setup, but it was a beautiful.

Description, it's a fanciful description, and it's an important distinction, and it's a philosophical distinction. The eye in the sandstorm problem is a problem in which you encounter something in medical sciences where the information just doesn't fit. It's being in a sandstorm. And I give the example when we made the transition in physics between Newtonian physics and quantum mechanics and Einsteinian understanding. So in other words, you reached a place and all of a sudden everything didn't fit. The bending of light, the presence of relativity, etc, nothing fit. So you needed a completely new theory, a new paradigm, a total shift in paradigmatic thinking. That's the eye in the sandstone problem. So in other words, there's sandstorms everywhere and you can't make sense of the real world. That's one kind of problem, and I'm interested in those problems. The sand in the eye problem, as I call it, is a different kind of problem, is when everything fits except one fact. And it's very important to understand that both of those are 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. And the particular example I use is neuronal transmission. So when people discovered neurons in the brain, they figured out basically by looking at an anatomy, that neurons in the brain, there was a space between them, that nerves weren't just wires. If you were an electrician fitting out an electrical situation in an apartment, what you wouldn't do is put spaces between the wires so that all of a sudden that space would become a communication between wires. You just hook the whole apartment up. But when people like Ramoni, Cajal and other scientists figured out how to solve this problem, they understood all of a sudden that nerves have spaces in between them. In fact, they had a name for these spaces. It's called a synapse. 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 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 and electrical conduction. So you're going chemical, electrical, chemical, electrical, chemical, electrical. And you could say, what mad person or what evolutionary process would ever devise a system like this? And the answer is, the reason is very important. Because what your nervous system is doing is in that transmission between electrical, chemical, electrical, chemical. What your nervous system is doing is it's putting weights so that in the chemical transmission, an electrical 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, etc, etc 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 neural networks work. There are weights put on how one layer of communication communicates with the 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 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. We don't know this for sure because this is an 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 a neutral signal? The answer is because if it was just an electrical signal, 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 cannot understand how to construct a learning network between 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 simulation, such that we can really actually learn a process.

Another way that I like to explain it is using music, which is the electrical signals that travel down the axon are digital. And maybe because I'm an engineer, I do tend to think in terms of digital versus analog processes. But if you explain that 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 have the analog adjustment of music. That's how we make songs. That's probably a cruder analogy, but I think it also gets at this point, which is, how did evolution figure this out? How much trial and error went into producing something so remarkable, so brilliant? Again, you wouldn't think to engineer this system necessarily.

Well, I mean, I think the reason evolution figured it out is, again, learning a purely electrical system, which is sort of like saying you're playing some music, but you don't have any modulation. You're listening to a score, and the score has no modulation, so you play everything at the same volume, at the same tempo at the same time. That's not music. That's not the song of the cell. What evolution figured out, and by figured out, I don't want to put an anthropomorphic idea on it, but what evolution converged on is the idea that music has tempo, it has space. 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 output of the score. And your musical analysis 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 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.

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, 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 want to 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 bestowed on you from an education perspective, from a learning perspective, as a doctoral student that we don't really get in medical school. You would go on to Harvard Medical School. You'd get a great medical education. But I think anybody who spent time in a lab will understand that there are just certain things that can't be taught in a classroom. You have to learn things by being in a lab, if that's the language you want to be able to speak. What are your recollections of 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.

It's a very different kind of thinking process. I like to make medicines, and when I make medicines, I like to make medicines that are important for human life, hopefully for saving lives. I've talked about some of them. We've spoken in prior podcasts about some of the new medicines that I've been involved in inventing. Textbook knowledge in medicine is important, and biology is important because it lays the groundwork and the foundations 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 eye in the sandstorm and sand in the eye problems, which are very important, you learn to recognize failure. You learn to recognize how to troubleshoot your way out of failure. 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 the most standard way to. 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 1, phase 1, 2B clinical trial. 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 complications from a clinical trial. There is no information anywhere in that textbook about running that trial. Similarly, run an Experiment which will set you up for a clinical trial. There is no information in that textbook about how to troubleshoot where and how to do that science that allows you to make it into human medicine. What if, for instance, you suddenly find that the medicine that you're working with, that you're trying to create is impure, that there's a contamination? How do you remove that contamination? There is no method. 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. 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 cannot be found in any book or textbook in the medical sciences. And there's no way around it.

There are a couple of really personal things I want to ask you about. Some of them for selfish reasons. I want to start with writing 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 when I call it a gift, I don't want to undermine it, Sid, because I don't want to suggest it doesn't require an obsession 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? 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 outstanding, Sid.

Well, thank you for the compliments. You know, writing is not an easy process for me, but it's also a somewhat weird process for me. And by weird, I mean I throw in everything 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. I have this policy in which there's nothing that's outside my box. It's all part of the box, all part of the whole story. I find that writing is a way for me to think, a way for me to work through my thoughts. And the analogies and the metaphors and 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 another phenomenon. I draw from history. I draw from mythology, from philosophy, from our conversations, from interviews, and everything goes into a book. And in some ways, I feel as if I had to invent that genre because it was so siloed. Medical writing was about medicine. It wasn't personal. There was sharp distinction between memoir and case histories. There were sharp distinctions between deep history and an interview or journalistic writing. And I said to myself, these distinctions are arbitrary. They only exist to serve a kind of secondary purpose. Why not erase all of them and make a new kind of writing in medicine or in life? Because the most important thing that I think people told me about medical writing 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. And so I said, okay, I'll show them. What is it like to be like me? Well, it's like to experience absolutely intense exhilaration when a clinical trial is successful. Absolute depths of depression and crisis when a clinical trial fails. Absolute anticipation, absolute apprehension, absolute admiration for people on whose shoulders I stand. That's what it's like to be like me. 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 a way that's like to be like me. What is it like to be like me? I. I am like you. I have terrible days. I have very good days. I have exhilarating days. I make inventions. I. Those inventions work, some of them don't work, and all of it is wonderful and 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, everything. I'll throw everything in there so that you understand what it's like to be like me.

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. 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. An older person, I don't mean a 10 year old. And these two things that you write about, and again, totally different parts of the book, you talk very openly about your own depression that really 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 was not aware of. How Virchow died. 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 know, Sid, from a person over the age of 65. If a person at that age or above falls and breaks their femur, depending on the study, it's anywhere from 10 to 30% mortality at 12 months. And you do a very good job of explaining the why, because 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 the swim coach of Stanford, while I was there. Of course I didn't swim at Stanford, but many of my friends did. And I knew him and I got to know him later after he had retired. 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's interesting to me. But what I couldn't believe was how you tied it back to this cell, 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. It starts with the osteoclast and the osteoblast and the matrix of the hip. And ultimately it leads to organ failure. That's not a leap that I think is easy to make. It's not obvious.

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

Yeah, well said.

And the citizenship falls when one part of the citizenship falls. Imagine a citizenship in any capacity. All of a sudden your Bureau of Transportation decides to take a leave for 20 days. The trains in New York City stop running. Therefore, people can't go to work. And the economy collapses. The economy collapses and all of a sudden people who are dependent on small changes in their lifetimes wage workers collapse. And then the entire system, the network of systems, collapses. All because the Department of Transportation closed down for two days. 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, your brain doesn't make insulin. You depend on your brain for sensuous and consciousness. You depend on your muscles for movement. Your brain can't produce movement without muscles. So there's a citizenship that bodies develop and have developed with each other so that we together perform as organisms. And if you take away one piece of that, a broken bone, it pings into a capacity not to move. The capacity not to move wastes your muscles. Your wasted muscles then communicate with the rest of your body. You and I have talked about hormonal systems before that conduct hormones between wasted muscles, etc. And then this pinged system then goes on and on and on until you end up with, as I said, say it again.

Another personal question. How much did you weigh the pros and cons of writing about such personal matters as your own depression? We do still live in a world where it's not entirely clear to me why we view depression different from hypertension. For example, if a person says, I have hyperlipidemia and I take 10 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. Again, I don't know why that is. I really don't. But in the presence of that knowledge, you still chose to talk about this. Why?

Well, period was a very conscious choice. It was not unconscious. I talked to my family about it, and I made the choice after that conversation. I agree with you. I think that depression can be 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. The reason it's different, I think, is that we associate a kind of victimhood to mental disorders. And that kind of victimhood is punitive. 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 have genetics or behaviors, etc. Etc. That are related to your hypertension. But depression and mental disorders, grief, depression and perhaps even more complex disorders, schizophrenia, have a sense of blaming the victim and the victim being the person who's experiencing the disorder. 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. 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 and talk about the brain as a cellular cluster, which is in some ways just a cellular cluster, like the pancreas or the heart or the liver is a cluster, and thereby remote remove this or defend or even challenge this idea of victimhood 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. But there are neuronal or nervous nerve cells and nerve cell circuits that push them in biochemical and chemical ways towards the state in which they cannot function. And I wanted to highlight that, that absence of function, if Virkha was alive today, Virka would say that absence of function or that dysfunction is not dissimilar to a person who has a failing heart 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 insulin regulating cells in the pancreas. And that idea, again, is, I think, very important and I think radical in this book and in all my books.

I agree with you completely. I think it is entirely radical and it's, I think, very difficult. I spoke about this with Carl Deseroth. If you haven't read his book, by the way, it's a fantastic book as well.

I have read his book. It's incredible.

And Carl was a classmate of mine in medical school and he was equally brilliant then as he is now. 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, 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 I find it very interesting. And I can't help but wonder where we will be in 20 years. Like, 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.

I think you've hit the nail on the head, which is to say that biomarkers will help and are always helpful, but ultimately it's a clinical decision. I always tell people who haven't been in clinical medicine, when you see depression, you know depression, you know that this person has a dysfunction of the neural circuits that regulate mood, just like a patient with type 1 diabetes has a dysfunction in the cells that secrete insulin. And even if there are no biomarkers, you know, it. This is what humans can see about other humans. There is a disproportionality or a disconnection between the level of grief that a person experiences and the level of grief that persists ennui, the level of psychomotor inability to move that a person experiences when they're clinically depressed. So I think that even in the absence of biomarkers, I think there is a new age that is coming and a respect, I think, for the autonomy of patients who experience neurological and psychiatric diseases. And I think, as you said before, Deserot writes about them very carefully and very thoughtfully. There are many people. Andrew Solomon has written about all of this, and I think it's very important because 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, alterations in human physiology that could reset brain circuits, electrical stimulation, as Helen Mayberg and others have been doing. And to treat the problem as if it was just a problem that is sort of an epiphenomenon is to minimize what the problem is.

Sid, there's so much more I wanted to talk with you about, but not surprisingly, 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 talk about some of these other factors. You have a wonderful way of explaining complicated ideas 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 propagating. 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 with your blessing like to postpone that as yet another topic we can Explore hopefully in 2023.

Would love to and good luck. I love your podcast and I love being on it so well.

Thank you Sid and congratulations again on another masterpiece and I'm looking forward to helping to spread the word so that many more people experience the joy of reading your work. Thank you Sid thank you for listening to this week's episode of the Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in depth, exclusive of content, without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription now. To that end, membership benefits include a bunch of things. One Totally kick ass comprehensive podcast show notes that detail every topic, paper, person, thing we discuss on each episode. The word on the street is nobody's show notes rival these monthly AMA episodes or Ask Me Anything episodes. Hearing these episodes come up completely access to our private podcast feed that allows you to hear everything without having to listen to spiels like this the Qualys, which are a super short podcast that we release every Tuesday through Friday, highlighting the best questions, topics and tactics discussed on previous episodes of the Drive. This is a great way to catch up on previous episodes without having to go back and necessarily listen to everyone. Steep discounts on products that I believe in but for which I'm not getting paid to endorse and a whole bunch of other benefits that we continue to trickle in as time goes on. If you want to learn more and access these member only benefits, you can head over to peterattiamd.com subscribe you can find me on Twitter, Instagram and Facebook, all with the ID Peteratti md. You can also leave us a review on Apple Podcasts or whatever podcast player you listen on. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or Advise, please visit PeterAttiamD.com about where I keep an up to date and active list of such companies.