Book Extract | The Emperor of All Maladies: A Biography of Cancer

Excerpted with permission from the publisher The Emperor of All Maladies: A Biography of Cancer (Revised Edition, 2026), Siddhartha Mukherjee, published by‎ Fourth Estate, HarperCollins India.

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The View from Ninth Avenue 

The greatest battles are not fought with swords or armies, but within ourselves. 

—Confucious, attributed

Moments of the past do not remain still. 

—Marcel Proust, The Fugitive 

About a decade and a half ago, I took a trip to visit a practitioner of traditional medicine in Old Delhi. The driver parked the car on the outskirts of the neighborhood, near Urdu Bazaar, named after the colloquial language spoken there, for this is where a large fraction of Delhi’s Muslim community lives. From there, the lanes narrow and divide, and divide again, like the body’s arteries becoming arterioles and arterioles becoming capillaries.

Cars cannot enter, and, save a few scooters and motorcycles, the only traffic is human, either on foot or pulled in rickshaws by other humans. I walked by Nayi Sarak, or New Road (“new” only in the sense that it was built by the British after the war in 1857), with stores piled high with used college textbooks. There were a million fluttering pages, making the market sound as if this was a conference of birds. Then up through a series of narrow and narrower roads, wide enough for just two humans to pass, towards Khari Baoli, or Salty Well, for a brackish well that once stood there, into the redolent thickets of a market that may well be Asia’s largest spice bazar. Past a shop with human-sized sacks of dried chilis and vats of demonic-appearing pickles. Up a steep flight of stairs, into the pharmacy—a single dark, humid room that was lined on the side by a wall of books. In front was a hakeemkhana, a dispensary, with dozens of glass vials in a cabinet.

The pharmacist was an elderly hakim, a practitioner of Yunani medicine—a form of medical learning that traces its roots to the Arabic world. Let me clarify at the onset that I have nothing less than the deepest respect for so-called traditional medicine. As a drug developer, I possess enough humility and knowledge of history to realize that many of our modern drugs come from the plant and animal worlds, and that even our best synthetic chemistry is yet to build molecules of anywhere near the complexity that come from these domains. 

Organic chemistry is called “organic” for a reason.

I asked the hakim if he had any medicines for cancer.

He looked at me quizzically, studied my clothing and manner, and concluded that was a Western doctor. I told him I specialized in the treatment of cancer.

“Kemo?” he said, barely concealing his disdain. Had I been out of hearing distance, he may have spit the word out.

I noted the resemblance of the word to the Hindi word keema (mincemeat).

Yes, I said, shrugging apologetically.

“I have some medicine here.” He pointed to a vial of turquoise material.

“For the prevention or the cure of cancer?”

“Both,” he said. It was clear that he thought the distinction absurd. He sold me a vial, folded his hands, and wished me good luck. I did not bother to ask him the formula for the liquid in the bottle, for I knew it would be a secret. I made my way out. The dispensary was busy. A long line of customers, with various ailments, was waiting behind me. Let me assure you that they weren’t waiting for my kind of kemo.

Alas: if we, too, had both. Despite decades of research on cancer prevention and cancer treatment, we are yet struggling to unify both worlds. The irony is that—far from unified—they seem to lie in opposition. Cancer prevention—for example, the cessation of cigarette smoking, the elimination of cancer-causing agents—saves the largest numbers of lives, is the most impactful, and yet garners the lowest profits for companies and receives the least attention in the media. Cancer prevention is the base of the pyramid of any strategy against cancer. Cancer treatment, in contrast, lies at the tip of the pyramid. Compared to prevention, treatment saves far fewer lives in absolute numbers, yet receives the most attention. As one physician reminded me: saving a million lives that might get cancer does not stir the imagination anywhere as deeply as saving a single life that does have cancer.

It is with an acknowledgment of this ironic inversion that I now turn my attention from cancer prevention to cancer treatment: What has happened in cancer therapy since I published Emperor in 2011?

Three significant advances come to mind. Of these, the single most important is the birth, growth, and ascendancy of the discipline of cancer immunology and its translation into novel therapeutics. The second is the appearance of new biological compounds to treat cancer—antibodies conjugated to toxins, for instance. And third, the successes and disappointments of targeted, personalized therapies that depend in large part on cancer genomics.

Let’s begin with cancer immunology—a discipline that I trained in and that has been a large focus of my own research since the 1990s. Many readers of Emperor were surprised that I had not addressed immunology. The reason for that omission was simple: in 2009, when the book was finished, the first studies on immunotherapeutic drugs were still incomplete. Early data had been mixed. In August 2010—just as early copies of Emperor were mailed to reviewers—a landmark positive study of immunological therapy against melanoma was published. And in March 2013, another study showed that a patient with lymphoma had responded to a “living drug”—i.e., their own immune cells that had been genetically modified to attack their cancer. In both cases, although I was aware of the long preclinical history that had preceded these advances, I was waiting to assess their human impact.

Fifteen years since the publication of Emperor, immunotherapy has ascended to occupy a central theme in the treatment of some cancers—and so it is with the birth of cancer immunology and immunotherapy that we will begin.

In October 1890, William B. Coley, a Harvard-trained bone surgeon and cancer researcher at New York Hospital (now part of Weill Cornell Medical Center), encountered Elizabeth Dashiell, a seventeen-year-old woman with a sarcoma. Despite aggressive attempts to treat her, including amputation of her arm (from which the tumor arose), Dashiell died of widespread metastatic disease within ten weeks. Dejected by the failure of his treatment on one of his very first patients, Coley began to look for alternative methods to treat cancer. He scoured hospital records and found cases of patients whose tumors had seemingly disappeared when they had suffered from concurrent, unrelated infections. An inoperable neck tumor had vanished when the patient had developed a soft tissue infection of the neck. Intrigued, Coley himself went looking for this man—doctor seeking patient. He ultimately found the patient in the tenements of the Lower East Side, likely in one of the dingy, half-lit two-room apartments that clung above the garment and tailoring shops below. The man was still alive. His tumor never returned.

Obsessed by the connection between the infection and tumor regression, Coley pored through the literature and found dozens of case reports documenting the beneficial effect of bacterial infections—typically soft tissue and skin infections, termed “erysipelas”—on tumors. In a few cases, doctors had deliberately injected the tumor with bacteria and reported a regression of the cancer.

Between 1890 and 1891, Coley cut his own course through the treatment of tumors with induced erysipelas. In 1893, he published reports of a series of cases (some of the patients treated by his colleagues) of people with various tumors who had either developed infections on their own or had been purposely injected with infectious material. Some of these findings stunned him. A middle-aged sailor with a neck sarcoma had developed an infection and his malignant mass had “entirely disappeared” (Coley’s italics).

Others were not as successful. Perhaps the most prescient and important sentence in Coley’s paper was written with a mix of frustration and humility: “a larger theory [. . .] is necessary to explain the curative action of erysipelas.”

Coley spent much of the rest of his scientific career investigating this “curative action.” Suspecting that some material from the bacteria was responsible for the antitumor effect (and noting the danger of using live bacteria, which could spread indiscriminately and cause septic reactions), Coley created a concoction, which he called Coley’s toxins, using a mixture filtered from killed bacteria of Streptococcus pyogenes and Serratia marcescens.

Over the next two decades, Coley treated multiple patients with Coley’s toxins. As before, he noted anecdotal cases of responses, but a systematic, or randomized, study with a standardized preparation was never published (the mixture was usually compounded; by one account there were at least thirteen variations). The medical community was critical. As one observer put it: “During the last six months the alleged remedy has been faithfully tried by many surgeons, but so far not a single well authenticated case of recovery has been reported.”

Part of the problem was that Coley was caught in the changing tides of medicine. And his increasingly antagonistic relationship with James Ewing, the leading expert on sarcomas, did not help his case. In the late 1890s and early 1900s, medicine itself was trying to emerge from the

chrysalis of its past; its goals were to transcend anecdotes and ad hoc reports towards standardization, objectivity, reproducibility, and scientific method. The 1910 Flexner Report, by the scientist and educator Abraham Flexner, laid out a highly influential mandate for the future education of doctors and sought a new direction for medical education based on scientific rigor. The nearly surgical severance of the “old” medicine and “new” medicine would soon begin. Coley’s treatment seemed to belong to the wrong side of this chasm.

At the turn of the century, the pharmaceutical company Parke-Davis began to produce and sell Coley’s toxins. But the hit-and-miss responses, the absence of a standardized preparation, the toxicity of the mixture, and absence of an appropriately conducted study caused a steady decline in their use. Variations of the toxin can still be found in certain clinics outside the United States, but the FDA has never approved the drug or its variations. Like Coley, his invention has been relegated to medicine’s quixotic past. 

But memories of the past, as Proust reminds us, are never still—particularly in medicine. Coley had expressed his desire for a “larger theory” to explain the response to the toxin. Injection of the toxin caused a fever, swelling, pain, and an infiltration of immune cells—all characteristics of inflammation. Could the immune response, and the accompanying inflammation, be responsible for the responses?

The human immune response broadly contains two wings—the so-called innate wing and the adaptive wing (the word “adaptive” conveys the idea that this wing of the immune system “adapts” to the particular characteristics of a pathogen and is able to carry a memory of a prior infection).

In both, the fundamental actors are cells. In the innate response, cells—called macrophages, neutrophils, and monocytes, among others—dash towards a site of infection. These cells recognize the presence of bacteria and viruses based on patterns of common molecules present in these agents. They seal off the infected area. Some bombard the bacteria with toxic substances. Others physically engulf the pathogens and chew up its parts. Yet others secrete chemicals, called cytokines and chemokines, to summon and coordinate the immune response. Notably, this innate response does not record or learn any feature of a particular pathogen: it is “innate” in the sense that it is already preprogramed to detect these pathogens. It has no memory. Rather it uses pattern recognition—i.e., it detects common chemical components of bacteria and viruses as activation signals. Some species of bacteria have a particular sugar-coated chemical on their cell surfaces, and cells of the innate system are triggered by that chemical. Some viruses insert their genetic material into cells; and this free-floating DNA in the cell (wrong chemical in the wrong place at the wrong time; in normal, nondividing cells, DNA should be in the nucleus) triggers an innate immune response.

The “adaptive” immune response consists of two fundamental cell types: B cells and T cells. B cells “learn” to make antibodies—Y-shaped, harpoon-like molecules—that bind to proteins on a pathogen’s surface. Once the B cells have evolved to make these antibodies, the memory of that response stays for a prolonged time, possibly for life (for a deeper, mechanistic description of how B cells create antibodies, turn to The Song the Cell, pages 186–201). When the organism is invaded by the same pathogen, the same response is briskly activated. It has “learned” the prior infection, and now retains the memory of it.

If the B cell is the harpoon-slinging action figure of the immune system, the T cell is the dogged gumshoe. The T cell has evolved to detect pathogens that live inside cells. Normal cells have an elaborate system to send up a sampling of proteins (or rather, peptides—the smaller, chewed up bits of proteins) from their interior. It is as if they are capable of turning their insides out—exposing peptides synthesized inside the cell. One type of T cell, called the CD8 cell, surveys this interior sampling with the help of a receptor on its surface. You can conceptualize this receptor as the antennae of a detector carried by a custom’s official at the border. It touches and feels its partner receptor on a cell, and asks: Are you carrying something foreign? Anything contraband in your luggage?

This T cell isn’t looking for an intact virus floating in blood or a whole bacterium swarming through tissues. Imagine the virus inside the cell hidden from the outside. The virus hijacks the cell to start making proteins so that it can reproduce (this is the mechanism by which viruses replicate). As the virus makes its “contraband” new proteins, the cell breaks some of these down into peptides. These peptides are loaded, like cargo, onto a protein called Major Histocompatibility Complex that brings them to the surface of the cell (the Nobel Prize–winning scientist Ralph M. Steinman discovered specialized cells, called dendritic cells, that are particularly adept at activating T cells). Imagine the MHC as a hand that keeps dipping into the cell, searching the cells’ innards, finding peptides and “presenting” them for surveillance to T cells.

CD8 T cells use their receptors (the foreign-sensing “antennae”) to detect the peptide-loaded MHC. Once a T cell detects the contraband peptide, it kills the virus-infected cell. This type of T cell also “learns” a prior infection: if the pathogen returns, the T cell stands ready to eliminate it.

The other type of T cell, called the CD4 cell, or “helper” cell, also detects fragments of foreign proteins from pathogens. And once activated, it enables the CD8 T cells and innate cells to do their work. It transforms into one of the central commanders of the coordination between the innate and learned immunity. Its job sounds mundane—administrative, even—but calling it a “helper” is like calling Thomas Cromwell a bureaucrat. It is, rather, a master machinator, a regulator beyond regulators. The importance of this cell type is evidenced by its absence: The human immunodeficiency virus infects and weakens or destroys CD4 cells, leading to a total collapse in immunity—the syndrome we know as AIDS.

Shuttling between T cells, B cells, macrophages, and other immune cells is a system of chemical messages that coordinate the immune response. Like messages in bottles, these are afloat in blood, and they move through the entire body. When an infection occurs, these messages shuttle between cells, carrying information to mount and then dampen an immune response—activating the cells during an infection, and then deactivating them once the infection has been quelled.

A cancer cell and a virally infected cell are very different entities, but the immune system can recognize abnormalities in both. Malignant cells occasionally make proteins that a normal cell does not make, thereby making these cell potentially immunogenic. A cancer cell may be infected by a virus—human papilloma virus, say, or Epstein-Barr virus—and it may produce viral proteins (“foreign” to normal cells) that a T cell may detect. Or the physiology of a cancer cell, as it is progressively corrupted by malignant, dysregulated growth, may tip towards such abnormalcy that the cell might start making “cryptic” proteins (indeed, a recent paper proved that a pancreatic cancer cell makes thousands of such peptides— called “cryptic” because they are come from enigmatic sources, including parts of the genome that are usually never translated into proteins in normal cells).

A cancer cell might start producing fetal proteins, for instance, in a cellular form of regression. Or it might produce a protein with a mutation, or one that is misfolded—crumpled—and thus deliberately targeted to the waste disposal mechanism present in each cell. In every such case, the spectrum of proteins made by a malignant cell can be sufficiently different from the norm that it can be potentially detected by the system. When a tumor breaks normal anatomical barriers and invades tissues, it sets off the trip wires of inflammation in the same manner that an invasive pathogen sets off inflammation. In some cases, macrophages flood to the site of the invasion. They engulf the cancer cells, digest their contents, and then present a sampling of their innards—including the “foreign” peptides—to T cells.

 This, then, was the “larger theory” that Coley had sought: cancer can also activate an immunological response. Even though the malignant cell arises from the “self,” it is nonetheless a pathological version of the self. And at times, that alteration, even though it resembles the self, can be discerned as pathological.

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Siddhartha Mukherjee, Writing The Emperor of All Maladies: A Biography of Cancer (Revised edition, 2026),‎ Fourth Estate, HarperCollins India, 2026. Pb. Pp. 720

The story of cancer is a human one-a tale of chance discoveries, seized opportunities and human endurance. From innovative early surgeries to the Curies' ultimately tragic work with radiation, from Sidney Farber's hugely risky discovery of chemotherapy to the author's treatment of his own patients, The Emperor of All Maladies is a profound and revelatory portrait of an enigmatic disease humans have lived with, and perished from, for more than five thousand years.

In this updated edition of Siddhartha Mukherjee's instant classic, four new chapters reveal what has changed in the universe of cancer in the years since the book was first published. With moving eloquence, he offers an insight into our evolving understanding of cancer's causes and the emerging, revolutionary new treatments that might shape its future, including those that Mukherjee himself has helped devise.

The excerpt from the book that has been published here is from the updated section of The Emperor of All Maladies. 

Siddhartha Mukherjee M.D., Ph.D., is a cancer physician and researcher. He is an assistant professor of medicine at Columbia University and a cancer physician at the CU/NYU Presbyterian Hospital. He has published articles in Nature, New England Journal of Medicine, Neuron, the Journal of Clinical Investigation, The New York Times, and The New Republic. He lives in New York with his wife and daughter.