Siddhartha Mukherjee Brings History and Humanity to Medicine

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Katie O'Connor: Hi, listeners. I'm Audible Editor Katie O'Connor, and today I'm honored to be speaking with Dr. Siddhartha Mukherjee, oncologist, researcher, associate professor at Columbia University, and Pulitzer Prize–winning author of The Emperor of All Maladies, The Gene, and his latest, The Song of the Cell. Welcome, Dr. Mukherjee.

Siddhartha Mukherjee: Thank you for having me.

KO: The Song of the Cell is broken up into six organized sections, and you've said in a recent interview that when you sit down to write, it's like a compulsion. It just pours out of you. And I'm curious which section was the first spring of that well. Or perhaps was there a particular case or patient that anchored the book for you?

SM: Interesting question. In my clinical life, I'm a cancer doctor, but in my research life, I'm a cell biologist. And I was trained as an immunologist. So, the idea of our immune systems and our T cells being used to fight cancer was obviously very exciting to me. And then the field really took off. There was this whole phenomenon, which I discuss in the book, of CAR T cells. These are T cells that have been extracted from human bodies and weaponized, using gene therapy, to fight cancer. Emily Whitehead's case was particularly interesting to me. She was one of the first survivors of this incredible therapy.

There were new angles in cellular therapy that were coming from all directions. People were trying to make new pancreas cells so that they could treat type 1 diabetics. Bone marrow transplantation had been around for a while, but now there was modified bone marrow transplantation with gene therapy to cure diseases such as sickle cell anemia and beta-thalassemia. And I began to really think that this is a kind of change that we haven't seen in medicine before, where the cell becomes the unit of pathology, and also the unit of therapy. And the power of that approach, where you suddenly begin to think about the human body as an accumulation or agglomeration of cells, and the cell becomes the center of pathology, as [Rudolf] Virchow and others had imagined nearly a century before. That was when the book started coming out, in some ways, from me.

I wrote the book through the middle of the COVID pandemic, and it was very important, because while I was writing this book, I also began to realize that to understand COVID, you had to understand human immunology and human cell biology. And so these forces accumulated together to make this book happen. This book begins with the story of the cell, when humans first found cells, but it really becomes very quickly a contemporary story about how we understand the human body and how we deal with that understanding in the context of a massive global pandemic.

"To understand COVID, you had to understand human immunology and human cell biology."

KO: Yeah, I think that arc makes sense, and also translates so well to the book itself. You mentioned Virchow, and throughout the book, you walk us through so much rich history, and Rudolf Virchow is one of the figures that you introduce us to, the German physician who is known as the father of modern pathology. Now, he lived in the 19th century, and there you were in Boston in 2002 working on a perplexing case. And you turned to one of his lectures and had this light-bulb moment in your own work. How often does that happen to you, where you turn to history or to these pillars in your field, and find the solution even centuries later?

SM: I think it happens surprisingly often. You would think that the progress of science is so rapid that history would be relegated to the past. But often, you have to go back to what I think are first principles. I mean, I teach medical students and I teach my residents and I teach on the faculty, and one of the things I always ask them to remember is that medicine and science are continuous conversations. They're unbroken conversations. And it's important to realize that they have not been broken for hundreds of years, potentially thousands of years. We've been exploring the human body, and we've been exploring how to heal the human body. And so when you're stuck, you can go back to history and ask the question, “What did they do when they were stuck? What principles?" And I don't mean facts. I mean principles. What principles did Virchow and others turn to in trying to solve very complex medical cases? And how can those principles be enlivened today? What relevance do they have today? How can they become the principles that guide our way of thinking today?

It's surprising how much of that is so relevant. I was just taking care of a patient that we had treated with T-cell therapy and went into a very well-known but desperate syndrome, which happens once in a while, three to five percent of the cases, where T cells go on a rampage. And they start going so crazy that the body can't deal with their hyperactivity. It's called cytokine release syndrome in treating cancer patients, and what was interesting about that case was that, as I was treating the case, I was trying to manage all the complications. And I had to remind myself of the very basics of human physiology. A patient has to have a pulse. She must be able to breathe. Just the basics, the so-called ABCs of human physiology, and it's amazing that you can do all of this very complex therapy, but ultimately, you're drawn back to the fundamental principles that guide all therapies, which is how to take care of very sick patients, what are the basic principles, and how to apply them.

KO: Yeah, I appreciate that there's always that relevancy, and I like how you describe it to your students as a conversation that hasn't stopped. The Song of the Cell is history, it's biology, but it's also part memoir, and you share pieces of yourself along the way, cases that you've worked on. And I particularly enjoyed the anecdote of you MacGyvering a microscope during the pandemic so that you could look at raindrops. I was wondering, as you're writing, how do you decide which sections could benefit from or be enhanced by a personal story?

SM: You know, the funny thing is, I don't make a distinction, and I don't make a conscious effort either. When I write a book, like this book, which spans the enormous arc of history, from Aristotle to the most contemporary T-cell therapies and cancer therapies and diabetes therapies of our time, bone marrow transplants, I've tried not to be bound by the conventions of “what should one write.” I try to be free about it, and that freedom allows me to enter pieces of memoir, spaces of personal history, a patient's history, an anecdote, sometimes a poem. I just let it rip, as they say, so that I don't feel as if I'm trying to write a textbook or trying to write a book that has a particular form. I let the form be secondary to where I'm trying to take the reader.

"I've tried not to be bound by the conventions of 'what should one write.' I try to be free about it, and that freedom allows me to enter pieces of memoir, spaces of personal history, a patient's history, an anecdote, sometimes a poem."

So, in that section that I'm MacGyvering a microscope myself, when I was writing it, I thought to myself, “You know what? Here's Antonie Leeuwenhoek and [Robert] Hooke sitting in the late 1600s making microscopes. And I'm trapped in my house during COVID, and I'm trying to MacGyver a microscope along their lines. And I'm trying to convey the excitement of that moment. I'm trying to bring you to Leeuwenhoek's or Hooke's moment in history. And I'm trying to show you what it must feel like, because that's the most important thing. I'm trying to show you the excitement, but I can't show you the excitement without showing you what it must feel like. So, that's how I write. I'm always trying to bring you there as a reader, because if you're there with me, watching my patients, watching the first patient, watching the discovery of some aspect of the immune system—being there is really important to me. And if I'm there, I want my readers to be there with me, and that's why these sections sort of free-float between one and the other. Does that make sense?

KO: It does, and I think it's something that all writers can find inspiration from. You want your listener to be taken along for the ride, but also you don't want to have to obey whatever form or whatever genre that you're picking, right? It's all about how you can best communicate your story, your point.

SM: Yeah, and as I said, how do you take them there? How do you take yourself there? If I hadn't built that primitive, not-so-great microscope, I wouldn't have known the excitement that someone like Leeuwenhoek or Hooke would've felt in looking down their microscope. That excitement is real. It's part of science. It's when you look down the microscope and you find something that's new or interesting or different. There's a second part of the book where I look down a microscope and begin to think about how bone is made and cartilage is made. It's very hard to describe that without personally looking down a microscope and figuring out how did they do it, and what kind of special thrill or chill of excitement would've gone through their brains at that time. And then moving two centuries forward, and saying, "Wow, look at how that changed the world today."

KO: Speaking of bones and cartilage, which is not a transition that I ever thought I would employ, I have always been fascinated by this idea of simultaneous discovery. It happens across fields. You mentioned some historic examples in the beginning of your book, but it also happened to you and your colleagues, Dan Worthley and Tim Wang, as you published a paper at the same time as Chuck Chan and Irv Weissman about what you dubbed OCHRE cells, cells that contribute to the growth of bone and cartilage. And I was curious about this event, this simultaneous discovery. Why do you think that happens?

SM: I think that it has to do with enabling technology. And people in the field have questions—often big, unanswered questions. So, the question in the field of bone and cartilage was “How do we grow bone and cartilage?” And I was not the only person who was thinking about this. Lots of other biologists were thinking about this, and then, all of a sudden, I found a tool through Dan's work and through Tim Wang's work. I found a tool that would allow me to answer that question, but it was totally serendipitous that I found the tool.

Irv Weissman, Michael Longacre, and Chuck Chan found a different tool, but they were asking the same question, because the question was sort of sitting on the field. How does bone grow? How does cartilage grow? Are there cartilage stem cells? Are there bone stem cells? Can the skeleton regenerate itself? What are the constraints on the regeneration, et cetera? These questions sit in the field because as you explore the biology of a certain organ, like bones or cartilage, you ultimately bang up against a kind of wall of these questions.

And then you look for techniques or technologies that will solve those questions, and those techniques and technologies often come from outside the particular field. In my case, it came from a particular form of genetic engineering of mice. In Irv Weissman and Chuck Chan's case, it came from being able to find markers for these cells and identifying them in crushed-up and ground-up bone. They were completely different, but they converge on the same idea, that the skeleton, rather than being a kind of static organ, is actually extraordinarily dynamic, and the dynamism has to do with the fact that it can regenerate cartilage and regenerate bone. And that's one of the reasons that we don't fall apart and decay, because, of course, the skeleton holds us together as organisms.

Now, what I can tell you, in part, is that we have one of the most intriguing papers that we've ever written in our lives. There's a little reveal in the book, which I won't go into, that really goes beyond just that. We have early evidence to show that maybe diseases of the skeleton, such as osteoarthritis, very common disease, are in fact linked to this regenerative potential of the skeleton. We always think about the skeleton as if it's like a hanger for the rest of the body. But what our work and Irv's work and Chuck Chan's work, and others, have shown is that it's not just a wooden hanger for the rest of the body. It's actually a very active participant in regeneration and repair. And if it doesn't do the regeneration and repair that's necessary, you get terrible diseases, crippling diseases, like osteoarthritis, which is actually one of the most common diseases in the world.

So, all of this goes back to the idea that you have to really think of organs and cells as dynamic systems. They're not just sort of sitting there, doing nothing. They're functionaries, and that function, and the dysfunction, links to very common diseases, with massive effects on the human population.

KO: Something else that has happened for centuries are scientific threads that drop off. Cellular pathology was one such thread. You talk about how stem cells had largely vanished from the biological literature by the 1950s. In your mind, are there threads that we are ignoring now that we should be turning our attention to?

SM: Yes, a couple. The whole idea of metabolism—how do cells obtain energy, how do they use energy, how do they dispense energy—was a field, particularly in cancer, that was relegated to sort of a sidenote, but all of a sudden has been rejuvenated as an idea, and a potential target for therapy. So, that's one arena.

The second arena—we are in the middle of doing clinical trials through a company that I've founded called Vor—is the idea that cells don't sit in isolation. They sit surrounded by other cells. They sit in an environment, and a lot of the toxicities that we see in cancer, when we use a drug in cancer, are not the result of toxicities against the cancer cell, but are the result of toxicities against normal cells that sit around the home of the cancer. And when you destroy that home, you also destroy the tissue that forms normal biology, that forms normal systems. That home is called the microenvironment of cancer. So, I think these ideas have been around for a long time. The English Surgeon talked about the micro-environment, called it seed and soil. The seed was cancer; the soil was the environment in which cancers could grow. The physiologist Otto Warburg talked about the so-called Warburg effect, in which he said cancer cells use different metabolic pathways than normal cells. They use energy differently.

But all of this work was relegated to the background, because we began to have a kind of monomaniacal focus on how to kill the cancer cell, and the cancer cell became the antagonist in all of this. But now we've started realizing that, in fact, one of the ways to prevent or treat or cure cancer, is to concentrate on, for instance, metabolism, and the differences between the metabolism of a normal cell and a cancer cell. Or also focus equally on the microenvironment. How does breast cancer go and start living inside your bone? It must be doing something, must be making itself a home in the bone, such that the bone cells and the immune cells brush by your breast cancer cells that are growing in the bone, and say, "Looks fine to me. It's just part of normal physiology.” Of course, it's not.

I’m giving you two ideas, and there are many more. But I'm giving you two ideas from the world of cancer where things were ignored for a while, and they've now come back and shown us that they actually are very relevant to the treatment of cancer today.

KO: That's fascinating. Thank you for your insight there. So, in The Song of the Cell, you say that you couldn't write this book without writing about COVID, and you discuss the humbling impact it had regarding our knowledge of cell biology. Do you find this gap of knowledge it uncovered overwhelming at all, or is the potential of it invigorating in some way?

SM: Well, I think it's invigorated an incredible amount of science and scientists. I think it's good for scientists to be humbled once in a while, and perhaps more than once in a while, because it shows you gaps in knowledge, gaps in technology, and it reveals what needs to be revealed.

"It's good for scientists to be humbled once in a while, and perhaps more than once in a while, because it shows you gaps in knowledge, gaps in technology, and it reveals what needs to be revealed."

Yesterday, I was reading this totally surprising paper in Nature, in which it turns out that one of the ways that the COVID virus, SARS-CoV-2, succeeds in parasitizing our cells and making many copies of itself and becoming such a nasty virus, is by altering or mimicking a protein that regulates genes. It's a protein that has to do with epigenetics and gene regulation at a very broad level. Totally surprising finding, which we had no idea about. And so we are slowly finding out about aspects of this virus that, in turn, illuminate aspects of our own cell biology and physiology. It's been incredibly invigorating. I mean, who would've known that a particular form of immunological dysfunction, which I describe in the book as immunological misfiring, would cause this kind of pathology? No one knew this, because we hadn't experienced this kind of virus before.

That particular dysregulation of immune biology would've been hidden to us had it not been for the COVID pandemic. So, I think it's really invigorated the field. It's made us ask questions like, “Is it true for other viruses too?” Maybe we've been looking away. I mean, think about chronic viral infections like Epstein-Barr virus, or acute viral infections like influenza. There's so much discussion about long COVID syndrome, right? Maybe there's a long influenza syndrome that we haven't explored because we sort of relegated that to an acute infection. Maybe there's a long Epstein-Barr virus syndrome that we need to know about, and in fact, in the wake of COVID, we've actually found that Epstein-Barr virus, which most of us are infected with it chronically, there are syndromes associated with EBV. A great, interesting paper suggests that it's one of the major risk factors for multiple sclerosis.

KO: Wow.

SM: Who would've thought? You know, this autoimmune disease that we always thought was related to neurological destruction, all of a sudden is strongly linked to infection and activation of Epstein-Barr virus. There's a whole universe of these, what I would call long viral syndromes, that has been uncovered because we've experienced and begun to understand long COVID syndrome. What's funny about it is that I can sense my voice has permanently changed. And my voice has permanently changed after I had COVID.

KO: Wow.

SM: I had a very mild case of COVID months ago, but my voice has now permanently changed. And I can feel that tingle. It's one of the many long COVID syndrome aspects. It's a very minor piece of it. But my voice has changed, and I can sense it. And maybe every acute viral infection and some chronic viral infections that are part of our body cause long-tail syndromes, and we've been ignoring them until we've had a global pandemic. And we've now finally turned our attention to them so we don't ignore them and we try to understand them.

KO: Speaking of voice, I would be remiss not to mention your narrator, Dennis Boutsikaris, who also performed The Gene. He returns to perform The Song of the Cell, and one of the many reasons that people gravitate towards you, I would say, is your ability to translate complex scientific matters in a way that the average person can understand and relate to. And I think Dennis is such a complement to that work. He really brings a conversational tone to your writing. I was curious if you have listened to his recordings of your work, or if not, what's that collaboration like?

SM: Absolutely. I chose Dennis to do The Gene, and this new book, and I've stuck with him because I find his tone very conversational, very approachable. I don't interfere or do anything. I was given a set of maybe 20 people to listen to, and I found Dennis's voice and his tone the most commensurate with my writing. I don't actively collaborate, in the sense I don't go and say, “This is how this should be narrated," but I find him a great narrator and have great respect for him. And I find the Audible version of The Gene and The Song of the Cell very approachable because of his ability to do it like that.

KO: You wouldn't guess it, given the subject matter, given the length, but it was easy listening. I think you guys work very well together. So, you've mentioned that The Emperor of All Maladies, The Gene, and now The Song of the Cell are part of what you're calling the life quartet, an exploration really of what it means to be human. I was curious at what point in your writing and exploration did you decide that this was a four-part series, and also, what can you tell us about the fourth and final piece of the life quartet?

SM: It came about a little bit naturally. There was a joke, a dig in my ribs when The Emperor of All Maladies won the Guardian First Book prize. There was a journalist who said, "It should've won the Only Book prize, because this writer, they're done." I've recounted my story, and I'm done, you know? I'm an oncologist. I study cancer cells. I wrote a book about the history of cancer. It won the Guardian First Book prize, the Pulitzer Prize, and many other prizes, and they were like, “You're done.”

And I thought to myself, actually, I'm not done, because The Emperor was about a particular angle of cellular pathology and genetic pathology. So that led me to the gene, which then led me to the cell and the life quartet, if that's where it ends up. It’s going to end up with things that are not in these other three books. I talked about some of them. Looking at pathology in a very, very narrow way, through cancer, looking at genetics, genes being the cause of cancer, among other diseases, the cell being the unit of life. And then the largest piece of this is the organism. How do we make ourselves? The human organism, our behavior, our ecology, why it's been so hard to change any of these. Why is it so hard to change behavior ecologies?

And then finally, death. How do we mature? How do we age? What are the limits of aging? How do we regenerate? And then finally, how do we die? And maybe it'll be a quartet. Maybe it'll be a quintet. I just don't know. I just don't know how much I can capture in one book about the next rung in the ladder, which is the organism, and our history. There's so much more to be told in this story.

KO: Yeah, and we look forward to listening to it when the time comes.

SM: Oh, and I'm sure you will.

KO: And listeners, you can get The Song of the Cell right now on Audible.