My mother-in-law passed away this year after a long and courageous battle with uterine cancer. I picked up this Pultizer-prize winner in an attempt to educate myself as she went through a battery of surgeries, radiation and chemotherapy. “The Emperor of All Maladies” is a truly remarkable book, charting the course of humanity’s battle with a terrible disease from the Egyptian physician Imhotep in 2500BC to the cutting edge research on oncogenes today. Gripping and beautifully written, it’s amazing that the author, Siddhartha Mukherjee, is an oncologist.
Nearly 500 pages long, Mukherjee breaks the book into six parts, atomizing the history of the fight against cancer into sweeping epochs.
Part One, “Of blacke cholor, without boyling”, begins with the Egyptian physician Imhotep in 2500BC and ends with the launch of the “Jimmy Fund” by Sidney Farber in Boston in 1948. Mukherjee brilliantly synthesizes and explains five millennia worth of cancer understanding and treatment, from Herodotus’ history of a breast cancer of Darius’ wife in 400BC to the influential “four humors, black bile” assessment by Hippocrates and further promoted by the second century Roman physician Claudius Galens. Cancer is an ancient and feared disease, but one that for most recorded history existed on the fringes of medical science and social consciousness. In the pre-modern world there were many, many more things to worry about than cancer, Mukherjee writes. Cancer is mainly a disease of age and, until recently, many other ailments would have likely killed you before cancer got the chance. Also, medical science has gotten much better at detecting cancer in its many forms. For centuries, if not millennia, deaths by cancer have been attributed to other, often mysterious causes. For thousands of years cancer surgery stagnated with the black bile theory. Then, in the mid-nineteenth century, a pair of discoveries in close order (anesthesia in Boston in 1846, anti-septics in Scotland in 1865) led to an explosion in invasive tumor surgeries for nearly a century, driven by the “radical mastectomy” performed by the brilliant (and cocaine and morphine addicted) Johns Hopkins surgeon William Halsted. Finally, there was the discovery of cellular mechanics, which opened the possibility of targeting cancer cells directly.
Part Two, “An Impatient War,” introduces philanthropist Mary Lasker and early oncologist Sidney Farber as they take over the American Cancer Society, injecting a new sense of urgency and hope in an organization that had become staid and moribund. They would champion a massive concerted government campaign against cancer, often employing the analogies of the Manhattan and Apollo projects. For all of his passion, Mukherjee essentially confirms that such lofty ambitions were misguided; it was like undertaking the moon landing without a basic understanding of Newton’s law of gravity. The early findings with chemotherapy were similar to the line of reasoning followed by Halsted with surgery – only correct (i.e. the more the better). For most of cancer’s history the disease has been treated as monolithic – the rapid division of cells – and thus the efforts to cure it have also been monolithic, from Halsted’s surgery to early chemotherapy. By the late 1960s all seemed to be coming together for winning the war against cancer. There was widespread (but ultimately premature) conviction that the scientific community had found both the cause of cancer (because of the chicken experiment of eventual Nobel laureate Peyton Rous) and a cure (in the form of a combination of chemo drugs) – and that this explanation for cause and cure essentially applies to all cancers. It led to the National Cancer Act of 1971, which poured billions into cancer research and would, in the end, be a dud.
Part Three, “Will you turn me out if I can’t get better?”, begins with the clinical trial wars. The author stresses how the surgeons and chemotherapists were split into opposing, often hostile camps, which for a long time limited experiments involving both surgery and chemotherapy. The tradition of the radical mastectomy of William Halsted was only buried in 1981 when it was shown conclusively that the survival rates were no better than more limited procedures. If radical surgery was dead, radical chemotherapy was arrogantly reaching its apex in the 1970s, with doctors utterly convinced that a universal cure was just around the corner, if only the right combination of chemicals could be found. The consequences of these treatments on patients, who were literally pushed to the verge of death, were not considered, but merely treated as the ugly side effects of an all-out war. Palliative care for terminal cancer patients would only emerge in the 1970s, and when it did, it came from Europe, not the technology obsessed United States. Perhaps the most important insight to emerge from this period was that cancer is incredibly heterogeneous (i.e. there is no “one disease, one cure”) and that it is thus critical to know the type of cancer you’re battling before you try to treat it, as the type will dictate the treatment strategy.
Part Four, “Prevention if the Cure,” is a section largely devoted to the effort discovering the link between smoking and cancer and the multi-decade campaign of cancer advocates against the tobacco industry. The central theme here is the importance of large and statistically significant trials to pinpoint causality. The case central method worked well early on in tying together rare professions with rare cancers (e.g. asbestos insulation installers and lung cancer), but what was the intrinsic characteristic of a carcinogen? Through serendipity (another theme of this book) it was discovered that certain chemicals increased mutation rates in bacteria and that these mutagens were also often carcinogens. Knowing what they were looking for, researchers could start looking for carcinogens prospectively, rather than merely retrospectively. Yet, progress still came frustratingly slowly, compounded by some major setbacks, perhaps none worse than the discovery of massive research fraud on the part of South African oncologist Werner Bezoda, something of the “Bernie Maddoff of cancer research,” who argued for a combination high dose chemotherapy and bone marrow transplant. Mukherjee highlights the moral challenge of conducting solid, rigorous (but also slow and diverting half of the participants to near certain death) clinical trials in an age that demands results now. By the end of the 20th century, the War on Cancer, some many times trumpeted as being on the verge of victory, was at best a stalemate. Some cancers had seen real improvement in treatment; others had gotten worse. Clearly, there was no “magic bullet” in the war; it would have to be “back to basics.”
Part Five, “A Distorted Version of Our Normal Sevles,” focuses on the discovery of retroviruses (i.e. viruses that “go the wrong way down a one-way street” allowing the virus to change the composition or structure of a cell it attacks) and feels a bit like a primer on molecular biology, which may make this the hardest section for the layman to follow and absorb. Intensive research on a wide range of cancer types found that the cells tended to “slouch toward malignancy” (i.e. cancer was a very slow developing disease), requiring a combination of rare and gradual events: 1) proto-oncogenes need to be mutated, which is a rare event; 2) tumor suppressor genes need to be inactivated and this mutation had to happen twice, an even more rare event; and finally 3) these mutations had to happen to many genes over time. Thus, by the year 2000, the history and understanding of cancer had seemed to come full circle: from a view of cancer as a single, unitary disease, to one that was very heterogeneous with all types of potential causes (e.g. virus, external, genetic), to a return to some common principles, a few (six, actually) hallmarks of cancer that applied to all types.
Part Six, “The Fruits of Long Endeavors,” reviews the present cutting edge of cancer research and the most promising paths to future success, from the new cancer drugs like Herceptin and Gleevac to the possibilities unlocked by the Human Genome Project. Yet, it ends on a sobering note, even more sobering because it feels true. Mukherjee writes that cancer may very well be a “natural process,” a normal part of life and aging, something inevitable, unstoppable and therefore incurable. Given enough time, cells and genes will mutate and cancer will arrive.
Thank you, Dr. Mukherjee, for writing this important book and making it so accessible to so many.
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