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Brian: It's The Brian Lehrer Show on WNYC. Good morning again, everyone. We're delighted to welcome back now oncologist and author, Siddhartha Mukherjee. You know him as the Pulitzer Prize-winning author of The Emperor of All Maladies, A Biography of Cancer, and his other highly acclaimed book, The Gene, both of which were also made into Multipart Ken Burns Documentaries on PBS. Now, Dr. Mukherjee has a new book called The Song of the Cell: An Exploration of Medicine and the New Human. That's the full title, as he continues to explore the mysteries of human existence from the smallest level to the most cosmic you might say. Dr. Mukherjee, thanks for coming on for this. Welcome back to WNYC.

Dr. Mukherjee: Thank you very much.

Brian: For people who know your previous masterworks, where does this new book fit in according to you? Does it continue a story you started to tell in The Gene or The Emperor of All Maladies, or are you taking yourself and taking us on a brand new journey?

Dr. Mukherjee: In some ways this is a continuous journey. When I finished The Gene I realized that of course, the gene is the essential unit of information for life, but interestingly, the gene, which is encoded in DNA typically and sometimes in RNA is lifeless by itself. It's a molecule without life, and the cell enlivens it. Without the cell, there is no life. The cell is the smallest autonomous unit of life. In a strange way, these three books obviously form a trilogy, but the gene is actually the first of the trilogy. The cell is the second, and when cells go wrong, which is cancer, would be the third of the trilogy so they're part of the same. There are many themes that come back and forth between the books and that's important.

Brian: The song of the cell: An Exploration of Medicine and the New Human. Before we get to the idea of the new human, which some people might find a little chilling, a little scary, take us back to high school biology for a minute. Talk about how individual cells become our organs, like our heart and brain and everything else, and how they know what functions to begin to play.

Dr. Mukherjee: It's an extraordinary thing about human biology that we just take it for granted now, but each of us began as a single cell. Every single cell in your body can be traced back to that original cell. What happens is-- there was a huge debate about this in the 17th and 18th centuries going up to the 19th century. Some people thought that human beings were born pre-made and we were just blown up like balloons, like Thanksgiving parade balloons as we grew up but of course, that's not true.

What happens really is that these cells are informed by very specific signals to take on particular identities. These identities are reinforced. They are reinforced in terms of location, the timing that they appear. The first fetal heartbeat appears at a certain time. The nervous system is born at another time. These cells take on these functions and they become extraordinarily diverse in their functions. A heart cell very soon, even though it has the same genome, the same DNA for the most part does not look like a nerve cell or does not behave like a nerve cell.

This process in which you have a tumble of one thing leading to another was called epigenesis. It was contrasted with the other theory I told you that we were all born preformed that day was called preformation. There's an incredible diversity of cells and that's part of the reason that I wanted to write this book is to remind people that even though we have this iconic image of DNA and genetics and the gene, we almost have no iconic image of the cell because there is no such thing as a cell. They're thousands of different kinds of cells with thousands of different functions.

Brian: Looking even just at your chapter titles, you've got various bigger sections that are divided into shorter essays. Just, for example, part three of your book, Blood includes chapters called the restless cell, the healing cell, the guardian cell, the defending cell, the discerning cell, and the Tolerance Cell. These are all different kinds of cells that you're applying those adjectives to just within our bloodstreams.

Dr. Mukherjee: That's right. This is an unusually organized book because of the diversity of cells it would be impossible to write a book in which you said it was just chronological or just historical, although there's a historical part to this book, but it would be impossible to write just a simple history. Instead, what I did was I created a chapter-by-chapter description of a different kind of cell. Each chapter becomes a mini-history. A mini chronology and it talks about that cell and the functional properties of that cell and how that cell ultimately contributes to the function of life.

How for instance, the guardian cell becomes the guardian of immunity. How the restless cell, which is of course red blood cells carries oxygen and thereby enables metabolism and respiration. How the dividing cell, which is of course the first cell and also many cells that arise in our body contributes to the growth and reproduction in an organism. I would say in some ways a fun structure, in some ways a challenging structure, but it's the only way that I could think of writing this enormous history. Otherwise, because it's so diverse, you'd go into alleyways and byways of writing and that's one of the things in writing you have to figure out long before you know a book. You have to figure out the structure of the book and the mood of the book. It took the longest time to figure out how to structure this book.

Brian: Listeners, we welcome your calls for Dr. Siddhartha Mukherjee 212-433-WNYC. Did you read The Emperor of All Maladies? Did you read The Gene? Did you see the Ken Burns versions and what do you want to ask him relevant to any of those, either of those or the new book, The Song of the Cell: An Exploration of Medicine and the New Human. 212-433-WNYC, 212-433-9692 or tweet @Brian Lehrer. What do you mean by the new human?

Dr. Mukherjee: The new human is a very provocative idea in the cell or in this book, I should say. The idea is that as I wrote this book, I realized that the combination of gene therapy and cell therapy is leading us and possibly prosthetic devices that intervene on cells. Such as electrodes being put into our brains to heal Parkinson's disease or depression. I just began to realize that we're creating a new personhood. Personhood who is a chimera of their own cells. Other cells were rejuvenating cells, turning cells into things, giving them new properties.

Curing and healing sickle cell anemia and other diseases through bone marrow transplantation. I thought that we've thought about the new human in terms of some sci-fi version of someone who equipped with infrared devices and various abilities with what I call [unintelligible 00:08:30] in the matrix, but that's not the new human that we're actually seeing. The new human that we're actually meeting is a human that's genetically modified or could be genetically modified. Of course, if they're genetically modified, then they're cellularly modified.

We're standing at the precipice. We've already started making these personhoods. When Louise Brown, the first baby born with IVF, was born virtually every magazine or article called her a new human. No one had ever been born in a jar. When the first blood transfusions were done, people thought that you would emerge with a different psyche because blood was thought to be a carrier of the psyche. That's what I mean by the new human because this kind of assault, and I don't mean assault in a negative way, but this kind of changing of the body because we are understanding cells and the genes that cells carry are creating a new personhood, and that's the new human.

Brian: President, Biden, as I'm sure you know, announced a so-called Cancer Moonshot this year. How does cellular medicine apply to that, if it does? What might the people working on that Moonshot learn from your book?

Dr. Mukherjee: Well, it's a very important question. The Cancer Moonshot is of course a very brave and brazen attempt to change the trajectory of cancer. Now, that said, you cannot do that without learning about cells, and in particular about cancer cells. We've learned a lot about cancer genes, and that's extraordinarily important. There's a whole era of cancer genetics that were coming off, and that's, as I said, extraordinarily important, but we haven't fully understood the cancer cell.

The cancer cell has a unique metabolism. We haven't understood even simple questions like, why doesn't the spleen get metastases from cancer? While the bones and the liver, the liver's almost the same size of the spleen, it's just on the other side of the body easily gets metastases. What about cancer allows it to build its home?

What about some cancers allow them to resist immunotherapy while other cancers don't? These are cellular questions. You could read the genome back and forth, and you can't answer that question. You have to understand the cell biology of cancer to answer that question. I don't think the Cancer Moonshot project can only be a genetics project. It has to be a cancer cell biology project.

Brian: I think you've acknowledged being humbled, if I'm using the right word, by how little progress has been made toward eradicating cancer after the human genome was mapped. Some people thought genetic engineering to fight disease would produce more remarkable results more quickly or would you put it differently? How would you put that in your words for us?

Dr. Mukherjee: I think that there was a simplistic idea that when we mapped the cancer genome. First of all, the human genome, but then when we mapped the cancer genome, we would suddenly find almost magical ways to find cures for cancer. We'd sequence the genome, the genome would yield its secrets. We would find a lock to the right key. Cancer is a genetic disease. A disease that mutations. We'd find the genetic mutations and we'd find medicines for them.

We have tried for the last 10 years, and there have been some spectacular successes in that. There also have been very sobering moments, because it's not as if you can read the cancer genome and immediately from it deduce a medicine that will work for that cancer. It brings us back again to the point that you were just making, which is to say that we need to understand cell biology of cancer. The deeper cell biology of cancer, not just the genetics, to understand and hopefully prevent and treats and cure cancer.

Brian: My guess is Dr. Siddhartha Mukherjee, his new book, The Song of the Cell: An Exploration of Medicine and The New Human, and I think Ken in Manhattan has a basic science question for you. Hi, Ken. You're on WNYC.

Ken: Oh, hi. Dr. Mukherjee, you mentioned a while back that the gene is lifeless without the cell. I imagine that you would say the same about the cell. Now-

Brian: You mean lifeless without the gene, that it works both ways?

Ken: For that reason have pre-existed the other.

Brian: Go ahead.

Dr. Mukherjee: Go ahead.

Ken: No, that's it. [unintelligible 00:13:49]

Brian: Could either one have pre-existed the other, so is that a relevant question?

Dr. Mukherjee: Yes, it is. We now know a little bit about how cells came about. Obviously, you can't rewind history. There's a whole chapter in my book about the origin of the first cell or the proto-cell. You can't rewind history. You can't go back, 3 billion odd years ago when the first protocells came about. What we can say is that the first-- there had to be three components to this and I'll go through these three components. One is the information carrier. That almost certainly was not DNA, but RNA. DNA is that [unintelligible 00:14:32] come lately.

RNA is a molecule that's related to DNA, but it has other properties among which include the property to information, but also do things to itself. That's also an enzyme. It can have other functions. There had to be an information carrier. There had to be a duplicator, some way to make a second copy of that information carrier. Otherwise, you'd never get two cells out of one cell. The third, which is very important, is that there have to be some boundary, a membrane. We know that membrane is made out of fat molecules, particular kinds of fat molecules, lipid molecules.

We now know that membrane intrinsically, this is what's interesting about it. That membrane, if you keep adding more and more molecules of lipids to it, has the capacity to split. When these three things met each other and as I said, we can't reconstruct history, but when these three things met each other, I call this the most explosive love affair in the history of life. They began to carry out the functions of the first proto-cell. It's a fascinating idea that you can reproduce some of this in the laboratory today without rewinding history.

Brian: Thank you for your call Ken, interesting question. Jane, in Great Neck, you're on WNYC with Dr. Mukherjee. Hi, Jane.

Jane: Hi, How are you, Dr. Mukherjee? Thank you so much. My question has to do with your book on the Gene, and you're referring to the environment in which the gene finds itself. My question I'll use specifically is, there's a disease, it's cutaneous lymphoma, which is a Non-Hodgkin's Lymphoma.

Dr. Mukherjee: Yes, I know. I've [unintelligible 00:16:20].

Jane: Oh, okay. It's treated by narrowing UVB radiation. My question is, we generally read that there's a global Vitamin D deficiency. Is that related to a change in the atmosphere because of less UVB rays reaching us? In other words, how do you relate the outer environment in terms of climate change and so on to the inner environment of the body? Do you think about that? I'm sure you do, but how do you relate?

Dr. Mukherjee: Oh, absolutely. I'm very, very conscious of how climate change in general is affecting the way that our genes are expressed, not the genes themselves, of course, that too is important. I'm going to make two distinctions that are important here. One is a mutation, which is a change in the gene itself. The second is the way a gene is expressed, which ones are expressed when, and where. That's not a mutation, that's a pattern of expression.

Both are being affected by climate change. One, because obviously as time goes along, we begin to experience, just a simple idea, as time goes along changes in the deeper atmosphere expose us to UV radiation. UV radiation is a carcinogen. We almost certainly will have to figure out how to protect ourselves from that UV radiation, if it were to become more and more harmful. The other question you asked is how does climate change affect the expression of genes?

There're, again, hundreds of ways. We are used to living in particular climates. Those particular climates have existed for centuries. There's heating and cooling in parts of the planet and therefore our bodies will change based on that heat and cooling, our metabolism will change. Also, that leads to change in genes. The final question you were asking is about Vitamin D. Now, Vitamin D is a very funny story, because although we do recognize that there's a Vitamin D deficiency. Virtually, every study of replacing Vitamin D using standard methods has not shown a great effect.

We're missing something clearly that even though there's a deficiency, we're missing either the way to get the Vitamin D in, or we are missing some cofactor or something that will allow us to get more Vitamin D into the bodies. Whether it's relevant or not is always a question. We're still in the middle of exploring the importance of that vitamin in human biology.

Brian: Jane, thank you for that question. I see there's a short chapter at the end of the book on COVID-19 and The Song of the Cell. Where do you enter the pandemic?

Dr. Mukherjee: I wrote the book during the pandemic, so I obviously have a very deep relationship with the pandemic. Again, what I realized, Brian is that I couldn't write this book without writing about COVID-19, because so much of our understanding of why this virus, SARS-CoV-2, is so lethal to some people, has to do again with cell biology. Of course, it's a virus, and viruses much like the gene, the cells to some extent are inert without a cell. They're lifeless without a cell. They need cells to reproduce. One of the things that we've learned is that you cannot understand the dynamics of the COVID pandemic without understanding the cell. That's why the pandemic is so central. Our understanding of immune cells and our understanding of gastrointestinal cells. Obviously, there's a big mystery around long COVID. I am confident that we will not understand long COVID by just looking at genes or just looking at the virus. We'll have to look at the cells.

Brian: Chen in Brooklyn, as we have time for one more call for Dr. Siddhartha Mukherjee, you're on WNYC. Hello.

Chen: Hi, Brian and the good doctor. I haven't read any of your books, doctor, but I'm reading a book right now called The Theory of Stem Cell Renewal by Christian Drapeau. He covers the ability of adult stem cells primarily found in the bone marrow, I guess to become any other cell, I guess to replicate and become maybe a liver cell or a heart cell or pancreas, cell, et cetera. My question is, do you cover that area in any of your books or maybe your new book, and would it be maybe a good focus for the average guy to say, "Hey, whatever I can do to release more of those stem cells would be good for healing and rejuvenation." Can you comment on that?

Dr. Mukherjee: Yes, so first of all, it's just a factual correction. Cells that live in the bone marrow cannot form every cell, they cannot form liver cells, they cannot form neurons. They are dedicated to the stem cells in the bone marrow, are dedicated to forming blood cells and they can only form blood cells. Of course, they're bone cells also in the bone marrow, bone-forming cells. In fact, our lab discovered them, bone-forming skeletal stem cells. Those are two kinds of stem cells that live in the bone marrow and a couple of others, but they don't form everything.

There are ways that we've discovered that you can take a cell and make it an adult cell and make it form other cells through a process. A Japanese researcher, Shinya Yamanaka was awarded another Nobel Prize for this discovery. They're called induced pluripotent stem cells. Again, that's taking an adult stem cell and making it into a cell that becomes like an embryonic cell. Embryonic stem cells, excuse me, also, can form virtually every kind but virtually every kind of cell in the body. The question is how do we deal with this? The answer is, we don't know yet. We're trying to make, for instance, pancreatic cells so that they secrete insulin out of them. We're trying to make blood cells out of them, but this all remains early in the trial.

Brian: We've just got a minute left. I want to ask you a question. A science meets literature question, if you will to close, because your title, The Song of the Cell reminded me that one of the first books I ever read that got me into the connection between hard science and philosophy and human behavior and human existence was the book of essays called The Lives of a Cell by another physician, Dr. Lewis Thomas. Yes. You quote from the book. His big thought as I think of it was partly about how we can make connections between the tiniest parts of ourselves at the cellular level to the largest ecosystems of life like Planet Earth itself. A caller brought up climate change and everything on it, but also our consciousness. You read The Lives of a Cell. Were you influenced by it?

Dr. Mukherjee: Absolutely. It was on actually one of the first books that brought me into this field. I became a doctor, partly because I read that book way back when it was published. Science and literature had a very rich connection. Think of Charles Darwin, think of Schrödinger, What is Life? Think of many other books that have brought Carl Sagan, not books in his case [unintelligible 00:24:09] but have brought this into intimate connection. Absolutely Lewis Thomas has been a great influence on my life, and I come back to those essays many times.

Brian: One way to read your book, I think is as a series of essays. Of course, you can read it as a work of science from start to finish, but it reads to me like many wonderful essays about different kinds of cells.

Dr. Mukherjee: Well, that would be a wonderful thing to read it that way.

Brian: There we leave it with Dr. Siddhartha Mukherjee. His new book is The Song of the Cell: An Exploration of Medicine and the New Human. Thank you so much for joining us.

Dr. Mukherjee: Thank you.

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