Siddhartha Mukherjee’s oncology fellowship more than a decade ago left him with more questions than answers, so he researched, reported, and wrote the book Emperor of All Maladies: A Biography of Cancer, which went on to win the 2011 Pulitzer Prize for General Nonfiction. In it, Mukherjee detailed the history of the fight against cancer with a sensitivity that is rare in science writing and an authority that could only come from years of studying and fighting the disease.
And so when his work on Emperor of All Maladies raised even more questions, Mukherjee realized he had another book to write. “If cancer is a distortion of genetic normalcy, then what does genetic normalcy mean?” he recalls wondering. Six years after his non-fiction debut, Mukherjee is back with what he’s calling a prequel, rather than a sequel to his first book, The Gene: An Intimate History. Like Emperor, it’s a genre-defying tour de force. “It is memoir, it is family history, it is science, it is medicine,” said Mukherjee to Smithsonian.com.
While his first book dealt with a disease that has, in some way or another, touched all of our lives, Mukherjee might argue that The Gene hits even closer to home. “I did feel that although I was writing about my family, it could really be about anyone's family,” he says. And this book isn’t purely about history and ancestry. It sets the stage for the breakthroughs in the genetics that will enable us to read and write the human genome. “This is actually required information. We need to know,” says Mukherjee.
In a conversation with Smithsonian.com, Mukherjee described the process behind his second book, the hallmarks of his writing style, and how our present moment fits into – and will shape – the course of human history.
Let’s start at end of the book. In the acknowledgements you write that The Gene is a prequel to Emperor of All Maladies. It seems that as you wrote Emperor, you must have circled back to the field of genetics over and over again. At what point did you realize you were going to write this second book?
While I was writing Emperor, the centrality of genetics became clearer to me. How do our cells and our bodies keep making versions of our cells that are not distorted? How does a code become a code? That's what motivated much of the book. It's interesting because in Emperor, we visit [Gregor] Mendel, we visit [Thomas Hunt] Morgan, we visit all of the main characters in this book, sort of in the background I realized that in writing about cancer, you cannot not write about genetics.
Interestingly, you chose to frame Emperor with the story of one of your patients, Carla, but you chose to frame The Gene with the story of your father's family and the mental illnesses that have plagued his brothers and some of your cousins. Was your family history a major motivation to researching and writing about genetics?
This book was in conception, right from the start, as a book about family. You cannot write about heredity without writing about family. Whether it’s resemblance, whether it’s illness, whether it’s whatever happens across generations, it's the questions, "What aspects of me resemble them? Which aspects of me are not the same?" The topics demand that kind of intimacy, that's why [the book] is called an intimate history. It's very distinct, I think, from what I’ve read other people writing about genetics. It’s not an abstraction, it's very real. And it's [all] becoming even more real today as we begin to change the genome, or read and write the genome as I call it. The idea that this would be told through my family’s history came in very early. It was in the very conception of the book.
Your books begin each chapter with powerful quotes from history, literature, art and poetry. How do you find these quotes and how do you work them into the text?
Sometimes they come in flashes from other reading I've done. They could be borrowed from a poem that I've read. Sometimes they're from the actual text that is in that chapter. To give you a couple of examples: In the chapter “A Village of Dancers, an Atlas of Moles,” there are two quotes there. One of them was from George Huntington, from his original paper describing Huntington's disease. He says, "We suddenly came upon two women, mother and daughter, both tall, thin, almost cadaverous, bowing, twisting, grimacing.”
It's there reminding us exactly what it looked like to witness the first patient suffer and decline from Huntington's disease, the bizarre image of it. There’s this idea of suddenly coming across, on a darkening road, these two people that are dancing together, but the word dances probably isn't the right word, it’s such a macabre feeling.
The quote that precedes it says, "Glory be to God for dappled things." So you say to yourself, "Why are these two quotes here together?" But then you realize, you begin to understand, it's the freckles in the genome, it's the small little pieces that are different between you and me, which allow us to have different traits. But also to have Huntington’s disease.
There’s also a chapter that begins with my father's illness and there is a quote from King Lear, "How have you known the miseries of your father?" "By nursing them, my boy." Lear and Shakespeare were also obsessed with heredity and inheritance. The idea of the miseries of your father: How do you know the miseries of your father? Is it because you inherit them by fate? Is it because you inherit them because of genes? Do you have to nurse them to inherit them? All of these ideas are central to the book. This book is about a very universal theme, a very universal search.
Those quotations also humanize the topics, which in The Gene, often have names that might intimidate a casual reader: transgenic, mitochondrial lineages. Family history and historical narratives bring the abstract science of genetics to life, as well. How do you balance the science with the narrative?
Readers are never casual. They come into books extremely informed. Just like you and I can sit in a musical performance, and while we may not be musicians ourselves, we can detect a false note immediately. I think readers detect false notes very quickly. I believe that we are hungry for this information. We need to be able to have a language that is not simplistic but is clear enough, simple enough.
I like this quote form one of my mentors: "If you can't describe what you're doing in science to a fifth grader using language that is easily understandable, it's probably not worth the effort of what you're doing.” Even if you're working in string theory, you can basically describe why you're doing what you're doing, what the basic method is, and why it's important. You may not be able to get to all the details, but I think striking the right balance is important.
Were there twists and turns in the narrative of genetics that surprised you?
Two moments come to mind. Obviously Mendel's story is one that needs to be told. He was a monk sitting in Moravia, he had never published any scientific paper. By himself, he creates the founding discovery of modern biology. Nothing will be the same again after Mendel is done, after that paper is published. Mendel is totally forgotten. People could not believe in the 1890s, in the early 1900s, that all this epic variance we have in human beings, you know, different temperaments, different bodies, different forms, are all being transmitted in these unitary, atom-like bits of information. Of all people, it wasn’t the great biologists working with massive experimental equipment or teams of people, it was an outsider looking in. The tenderness of that labor was incredibly surprising.
But also moving forward, the other story that surprises me is the story of the first gene therapy trial, Jesse Gelsinger's story. On the eve of the great revolution in genetics, a child's death reminds us that we can be moving forward, but there might be things that will surprise us. We may not have predicted everything. Just like in Emperor, we need to be reminded of what happens when the enthusiasm for a particular kind of radical therapy became too much.
The history of eugenics has, in cases like how the Nazis used it, given genetics a bad rap. Can you talk about the evolution of the way we’re embraced and also been repulsed by genetic research?
We need to revisit the history of eugenics several times in order to be careful with what we're doing now, now that we can do astonishingly dexterous things with the human genome. In the book, I try to provide a framework for how we might think about it.
We're all struggling right now to think about it. What should be allowed? What should not be allowed? Should we allow parents to screen for mutations that might cause devastating diseases? What if it's a devastating disease where there isn't one gene that is predictive, but many genes, and the prediction might not be accurate, but on the other hand, the suffering is devastating? Should we intervene? In what way should we intervene? These are questions that are not going to be abstract. These are going to be very personal questions very soon. You can't answer those questions in an ahistorical context. You have to answer them with a full knowledge of human history, understanding what happened, what went wrong and what went right in the past, and what the really terrifying history of eugenics teaches us about the past.
At the end of the book, you describe three breakthroughs in genetics that we seem to be on the brink of. Could you discuss those, and also update these predictions if they’ve changed since you finished writing the book?
We have to know what exactly the genome encodes. We've been talking about genes a lot, but one future area is what does a [single] gene mean? We now know that beyond genes there are things in the genome, for instance, RNAs that will not be made into proteins. There are parts of the genome that allow it to exist three dimensionally in space and change the function of a gene. The way the gene is packaged using histones can change if genes are active or inactive. One project is to figure out what is the nature of the information in the human genome? How complex is it?
The second is to figure out, with the information [we have], how do we use it in a predictive manner? Can we predict, based on your genome, what diseases you're going to get? What your personality is going to be like? What your temper might be like? To what extent is the human genome predictive of the future, and how much of it is random, how much of it is chance, fate? Those are big words, but we're talking about a template in which those big words come into play. So that's what I call reading the genome.
The third one is writing the genome. If we really understand it, we now have the technologies to begin to change the genome. We are now beginning to possess technologies that have the capacity to change the human genome in a deliberate manner. Those technologies are coming. They’re being invented, they're becoming more and more sophisticated, they're having greater and greater fidelity and efficiency. In fact, while I was finishing the book, every week there was a new finding that has made it more and more possible to manipulate the human genome in a directional manner. Which means you can go into a human genome, potentially in the future, and you can change the qualities of the human genome, change one gene to another kind of gene, etc. These technologies demand that we take a step back and ask the question: What do we know about the past, to understand the future.
Your book explores the achievements of many of the rock stars in the history of genetics: Gregor Mendel, Thomas Hunt Morgan, Frederick Griffith. Is there anyone working today who is on that rock star level?
It's nice to think of a Moravian monk as a rock star. I think the work of Jennifer Doudna on CRISPR stands out as being a new direction in the manipulation of genes. There are incredible new gene therapy trials that we will witness in our lifetimes. The great gene decoders will come up. The one person whose name comes to mind is Fred Sanger who really showed us how to read genetic information. CCGGTCCC, how do you know that's the sequence? Fred Sanger figured out how to understand the sequence of genes. This story is littered with rock stars.