Siddharta Mukherjee

Medicine begins with storytelling. Patients tell stories to describe illness; doctors tell stories to understand it. Science tells its own story to explain diseases.

Siddhartha Mukherjee,
The Emperor of All Maladies: A Biography of Cancer[1]

Siddhartha Mukherjee is a physician, researcher, and scholar who has become one of the most acclaimed science writers of our time. He takes on deeply complex challenges in science today and communicates them in a way that is intensely personal; relating stories from his own family, the patients he has treated, and the lives of the scientists and physicians who came before him. There is a tenderness and humility in his writing that draws out meaning and relevance from grave stories of where we have been and where we are headed. At times painful, frightening, dangerous, and foreboding, his work deserves our attention in this moment of rapid change in medicine and technology.

Mukherjee is frequently asked how he manages to be so prolific a writer while continuing to see patients and pursue research as a staff cancer physician at Columbia University Medical Center and assistant professor of medicine in the Department of Medicine at Columbia. His interest in cancer may have begun when he was an undergraduate biology major at Stanford, where he worked in Nobel Laureate Paul Berg's laboratory defining cellular genes that change the behaviors of cancer cells. He later won a Rhodes Scholarship to Oxford University, where he earned a doctorate (DPhil) in immunology from Magdalen College, then a doctorate of medicine (MD) at Harvard Medical School.

Mukherjee describes himself as having a physician’s brain. He has a poet’s brain as well. His writing — for example his description of wiping spittle from his unconscious father’s mouth after a fall, and handing 20 rupees to an off-duty nurse to help him lift his father’s body into a makeshift ambulance — is not clinical, it’s personal. And his stories are told in a way that reaches beyond the specific to the universal. He points again and again to the uncertainties and the generosities that are fundamental to our human condition, and how the mundane often leads us to the ineffable. The Emperor of All Maladies: A Biography of Cancer, Mukherjee’s first book, won both the Pulitzer Prize and the PEN/E. O. Wilson Literary Science Writing Award in 2011 and was a finalist for the National Book Critics Circle Award and the Wellcome Trust Book Prize. His most recent book, The Gene: An Intimate History (2016) was shortlisted for the Royal Society Insight Investment Science Book Prize 2016 and the Wellcome Trust Book Prize. His writings do not romanticize illness, nor do they romanticize science. Rather, he uncovers the beauty and wonder within the pain and complexity of human existence.

In an address to the 2016 graduating class of Johns Hopkins University School of Medicine, he revealed his drive to open up science to scrutiny, but also (and mostly) to public engagement. Mukherjee praised the university for its willingness to throw open the curtains that shroud clinics and waiting rooms, as it did when it became the site for the filming of the documentary film version of The Emperor of All Maladies, produced by PBS and directed by Ken Burns. And he regularly praises the patients who share their stories so that we might all better understand the confounding and insidious disease that is cancer. He writes eloquently about the power and simultaneous frailty of the human body and mind with respect, tenderness, and an inquisitiveness that sustain the lay reader through long, in-depth, and rather technical histories. Exposing the science of medicine and making it understandable to all of us is clearly what he has endeavored to do, not only in his books, but in his many magazine articles and public appearances.

‘Why are we doing this and where are we going?’

In conversation with biochemist Jennifer Doudna at the University of California at Berkeley in February of this year, Mukherjee’s telling of how he came to write The Emperor of All Maladies is more personal than his account in the book itself. To Doudna he explained that he wrote the book in response to a particular patient’s question:

She was in the middle of chemotherapy for sarcoma, and she said, ‘Why are we doing this and where are we going?” It seemed to me just astonishing that, here was this disease that has occupied our culture—cancer has become more than a disease, it is a metaphor, it is an allegory. People use it to describe states of mind. Very few illnesses in human history have ascended to this kind of space in human culture. And, yet we had no real history, we had no book about it.

He acknowledges that his 600-page response to that patient’s question is a daunting text that he did not imagine anyone other than his editor and his mother would read. But the work is not only readable, it is nurturing.

Cancer has touched so many of our lives, and The Emperor of All Maladies has become a guide for many of us through the pain and fear of the unknown. Matt Marostica, one of Stanford’s Associate University Librarians, was browsing a bookstore for Christmas gifts with his daughter a few years ago, when she became captivated by Emperor, poring over it while they were still in the store. She eagerly dove back into the book on Christmas day. Shortly after the holidays, her mother was diagnosed with a devastatingly fatal brain cancer. Not only was his daughter better prepared than anyone to face the challenges their family was soon to experience; her seemingly random selection of the book seemed to the family like a message from the divine, becoming a small miracle that anchored them during indescribably excruciating times. However readers come to find the book, Mukherjee’s weaving together of science and humanity, turns knowledge of ourselves, with all of the uncertainty, into comfort. He shows that knowing can bring us to understanding and compassion in the face of the most painful truth of being human: our fragility and vulnerability.

Mukherjee writes about the hope that gives us courage in the face of uncertainty, but also the false hope that can convince us — in spite of the data — to hold fast to incorrect theories about illness and its treatment. A prime example is a surgeon whose story Mukherjee tells in Emperor and returns to in Laws of Medicine: William Stuart Halsted, the champion of the “radical” mastectomy. The underlying assumption of the radical mastectomy was that cancer spread outward into the body from a single, central location. In Mukherjee’s telling, the accepted logic was the more you cut, the more likely you are to cut out all of the cancer. If the cancer appeared again, the surgery had not been radical enough. Halsted was seduced by the apparent logic of his method. And despite the fact that the cancer was not being cured, while patients were suffering extreme disfigurement and complications, few were willing to challenge him.

But Cancer’s biography, as Mukherjee tells it, is not the story of overly ambitious doctors subjecting vulnerable patients to unproven therapies. He artfully weaves together the many factors at play in persisting inappropriate treatments: the political motivations for a cure, the fear of challenging the dominant theory, and the individual’s desire to survive—to try anything in order to survive. In Mukherjee’s telling, the impatience of physicians who want desperately to find a cure is detailed alongside the impatience of those carrying the disease who know that waiting for the approval of some therapy may mean waiting too long. He reveals the complicated and often frustrating path to progress in research and therapy, propelled by fallible humans, striving for answers and solutions.

“The medical revolution will not be algorithmized.”

In 2015, Mukherjee wrote a short, incisive volume titled The Laws of Medicine: Field Notes from an Uncertain Science, to accompany his 18-minute TED Talk, “Soon We’ll Cure Diseases with a Cell, Not a Pill.” The laws that he lays out in this brief book (of less than 100 pages) are laws of imperfection: uncertainty, imprecision, and incompleteness. He presents medicine as a very young science, which seemed at one stage to have found it stride by keeping at its core a catalogue of human ‘normalcy.’ But then Mukherjee goes on to illustrate, with reference to Thomas Bayes’ statistical theories, that we learn more about phenomena by starting with the outliers than we do by focusing on the norm.

If you have ever visited your doctor with some unfamiliar malady and were told, “we cannot determine what the problem is until we know what we’re looking for,” medical science can seem useless and seeking a cure, futile. Mukherjee explains,

…a test can only be interpreted sanely in the context of prior probabilities. It seems like a rule taken from a Groucho Marx handbook; you need to have a glimpse of an answer before you can have a glimpse of an answer…The prior knowledge that I am describing is the kind of thing that old-school doctors do very well, and that new technologies in medicine often neglect.

Part of the unique challenge for medical science, according to Mukherjee, is that patients are active participants in what is an ongoing experiment. He references Heisenberg’s uncertainty principle: the device used to measure the subject transforms the nature of the subject. This paradox of attempting to define laws in a context that is perpetually in flux is part of what makes Mukherjee’s writing about medicine so accessible to those of us outside of the field. He makes us feel a part of the research process by acknoweldging that, as patients, we are central to the research process.

Stories weave through Mukherjee’s books, each one highlighting a different facet of complex phenomena. The story of William Stuart Halsted’s radical mastectomy procedure in Emperor is about hubris — a heroic attempt to cure cancer that failed with horrible effects. In Laws, he tells Halsted’s story in the context of human bias. He writes, “…untested and uncontested, a theory became a law: …cutting more had to translate into curing more.” And he shifts our assumptions about the practice of medicine in reference to the real, complex questions that doctors face regularly, but that do not have clear answers. He tells us that doctors do not hunt diseases, they hunt bias. Priors, outliers, and biases all involve limits and constraints on our human knowledge, and yet they define the science and art of medicine.

It is for this reason that Mukherjee argues that algorithms will not replace doctors. “Big data is not the solution to this bias problem; it is merely a source of more subtle (or even bigger) biases.”

“How long until the first transgenic human?”

Mukherjee begins his most recent book, The Gene, An Intimate History, with the ominous warning that our newfound ability to tamper with evolution is one of the most powerful and dangerous ideas in the history of science. If Emperor is about a war within, a struggle against ourselves, The Gene is about deciphering the code of life, and, along with that, the possibility of re-writing our own lives. In conversation with Bill Gates, he puts the question that The Gene asks this way:

When a machine starts to understand its own code of instructions, what happens to that machine? Does it change its code of instructions? Does it learn to limit those changes? Is that limiting of the instructions part of the instructions themselves?

In this case, the machine is us, but the reference to artificial intelligence and our fictional fantasies about living with intelligent machines and even being taken over by them, is intentional. The first half of the book tells the stories that led us to today’s genetic science from Aristotle to Mendel’s pea plants to Morgan’s fruit flies to Paul Berg’s gene-splicing work. He steps us through a history of biology from observation and classification to experimentation and, most recently, engineering. Berg’s discovery of Recombinant DNA serves as a turning point in the book from recounting the past anticipating the fast-approaching future where technology seems to be taking the lead. He writes, “It is the impulse of science to try to understand nature, and the impulse of technology to try to manipulate it. Recombinant DNA had pushed genetics from the realm of science into the realm of technology.”

Mukherjee presents this move of genetics into the realm of technology in terms of fast-forwarding evolution. Already, we can identify and select out defects in embryos through preimplantation genetic diagnosis (PGD). But CRISPR/Cas9-based genomic engineering now makes it possible to add information to the genome; to change genes intentionally. When we cross that boundary, Mukherjee tells us, we are writing a new genetic code into the human genome:

The crux, then, is not genetic emancipation (freedom from the bounds of hereditary illnesses), but genetic enhancement (freedom from the current boundaries of form and fate encoded by the human genome). The distinction between the two is the fragile pivot on which the future of genome editing whirls. If one man’s illness is another man’s normalcy, as this history teaches us, then one person’s understanding of enhancement may be another’s conception of emancipation.

This is the slippery slope that Mukherjee reminds us of throughout The Gene, and he grounds those stories in individual experience. He shares with us the specific details of moments of inspiration in the lab and chance conversations at academic conferences which lead to new research developments. He also delves into the ugly history of eugenics practiced in the United States through sterilization long before the imposition of laws of genetic cleansing in Europe. And he is careful to remind us that this impulse to employ ‘unnatural selection’ continues in India and China today where female children are intentionally eliminated through abortion, infanticide, and neglect. It is within that context that he asks, “Can we make our genomes a ‘little better’ without risking the possibility of making ourselves substantially worse?"

In the early decades of the twenty-first century, we are learning to speak yet another language of cause and effect, and constructing a new epidemiology of self: we are beginning to describe illness, identity, affinity, temperament, preferences—and, ultimately, fate and choice—in terms of genes and genomes. This is not to make the absurd claim that genes are the only lenses through which fundamental aspects of our nature and destiny can be viewed. But it is to propose and to give serious consideration to one of the most provocative ideas about our history and future: that the influence of genes on our lives and beings is richer, deeper, and more unnerving than we had imagined.

“The boundaries of what is natural are being redrawn.”

The Gene is a call to action and call to engagement. In the final chapter of The Gene, Mukherjee does not simply leave us with a predicament, he leaves us with a manifesto: suggested guidelines for how to move forward into this period of radical change we are all rushing headlong into, whether we realize it or not. Having distilled the profound nature of the changes happening in this era to three irreducible units: The atom (matter), the byte (digitized information) and the gene (hereditary and biological information); he focuses our attention on the effects of manipulating those elements, thereby redefining what is natural.

Whereas some accounts present new developments in gene editing in terms of controlling evolution, Mukherjee provides a more nuanced challenge, asking us to consider the implications of tampering with evolution. Leaning on historical precedent and human nature he makes it clear that our hubris gets us into trouble. Thinking that we can ‘control’ evolution throws us into that very blunt, binary, mindset that either we shut down the science or we plunge ahead and dominate nature. Mukherjee never draws us into that either/or battle. He reminds us that it’s complicated and encourages balance in our approach to change.

“Technology, I said before, is most powerful when it enables transitions—between linear and circular motion (the wheel), or between real and virtual space (the Internet). Science, in contrast, is most powerful when it elucidates rules of organization—laws—that act as lenses through which to view and organize the world. Technologists seek to liberate us from the constraints of our current realities through those transitions. Science defines those constraints, drawing the outer limits of the boundaries of possibility. Our greatest technological innovations thus carry names that claim our prowess over the world: the engine (from ingenium, or ‘ingenuity’) or the computer (from computare, or “reckoning together”). Our deepest scientific laws, in contrast, are often named after the limits of human knowledge: uncertainty, relativity, incompleteness, impossibility.

Throughout his books he reminds the reader of ways that advances in medicine, science, and technology transform culture, society, politics, language. Though he writes about the challenges we are facing in terms of the tension between science and technology, he also points, indirectly, to the influences of the arts on the imagination that drives science and technology, at the same time guiding us along the edge between laws and freedom from constraints. In the epilogue to The Gene, Mukherjee shares a verse inspired by a classical Sanskrit poem suggesting that, while science and technology are forcing us to tackle challenging questions about our future, these questions are, at the same time, enduring and fundamental to our humanity.

Show me that you can divide the note of a song;
But first, show me that you can discern
Between what can be divided
And what cannot.

1. Mukherjee makes this statement in The Emperor of All Maladies: A Biography of Cancer (p.390) after telling the story of the first patient who died in his care while he was a fellow at Massachusetts General Hospital. He follows the story of his patient with another story of how a conversation between two biologists, Douglas Hanahan and Robert Weinberg, outside a conference in Hawaii, led to a seminal article, "The Hallmarks of Cancer" arguing that the complexity of cancer can be reduced to a small number of underlying principles. This approach of placing patient stories alongside those of scientific discovery help to make the process of scientific research and discovery more accessible to those of us who do not participate in it, but often benefit from the work.

Text by Nicole Coleman, Digital Research Architect.
Stanford Libraries, 2018.