The Laws of Medicine: Field Notes From an Uncertain Science

by Siddhartha Mukherjee

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  To Thomas Bayes (1702–1761), who saw uncertainty with such certainty

  “Are you planning to follow a career in Magical Laws, Miss Granger?” asked Scrimgeour.

  “No, I’m not,” retorted Hermione. “I’m hoping to do some good in the world!”

  J. K. Rowling

  The learned men of former ages employed a great part of their time and thoughts searching out the hidden causes of distemper, were curious in imagining the secret workmanship of nature and . . . putting all these fancies together, fashioned to themselves systems and hypotheses [that] diverted their enquiries from the true and advantageous knowledge of things.

  John Locke

  AUTHOR’S NOTE

  Years ago, as a medical student in Boston, I watched a senior surgeon operate on a woman. The surgeon, call him Dr. Castle, was a legend among the surgical residents. About six feet tall, with an imposing, formal manner that made the trainees quake in their clogs, he spoke in a slow, nasal tone that carried the distinct drawl of the South. There was something tensile in his build—more steel wire than iron girder—as if his physique had been built to illustrate the difference between stamina and strength. He began rounds at five every morning, then moved down to the operating theaters in the basement by six fifteen, and worked through the day into the early evening. He spent the weekends sailing near Scituate in a one-mast sloop that he had nicknamed The Knife.

  The residents worshipped Castle not only for the precision of his technique, but also because of the quality of his teaching. Other surgeons may have been kinder, gentler instructors, but the key to Castle’s teaching method was supreme self-confidence. He was so technically adept at surgery—so masterful at his craft—that he allowed the students to do most of the operating, knowing that he could anticipate their mistakes or correct them swiftly after. If a resident nicked an artery during an operation, a lesser surgeon might step in nervously to seal the bleeding vessel. Castle would step back and fold his arms, look quizzically at the resident, and wait for him or her to react. If the stitch came too late, Castle’s hand would reach out, with the speed and precision of a falcon’s talon, to pinch off the bleeding vessel, and he would stitch it himself, shaking his head, as if mumbling to himself, “Too little, too late.” I have never seen senior residents in surgery, grown men and women with six or eight years of operating experience, so deflated by the swaying of a human head.

  The case that morning was a woman in her fifties with a modest-size tumor in her lower intestine. We were scheduled to begin at six fifteen, as usual, but the resident assigned to the case had called in sick. A new resident was paged urgently from the wards, and he came quickly into the operating room, tugging his gloves on. Castle walked up to the CAT scans hung on the fluorescent lightbox, studied them silently for a while, then moved his head ever so slightly, signaling the first incision. There was a reverential moment as he stretched out his right hand and the nurse handed him the scalpel. The surgery began without incident.

  About half an hour later, the operation was still under perfect control. Some surgeons liked to blast music in the operating room—rock and roll and Brahms were common choices—but Castle preferred silence. The resident was working fast and doing well. The only advice that Castle had offered was to increase the size of the incision to fully expose the inner abdomen. “If you can’t name it, you can’t cut it,” he said.

  But then the case took a quick turn. As the resident reached down to cut the tumor out of the body, the blood vessels surrounding it began to leak. At first, there was only a trickle, and then a few more spurts. In a few minutes about a teaspoon of blood had run into in the surgical field, obscuring the view. The carefully exposed tissues were submerged in a crimson flood. Castle stood by the side, his hands folded, watching.

  The resident was clearly flustered. I watched a pool of sweat forming over his brow, mirroring the pool of blood in front of him. “Does this patient have a known bleeding disorder?” he asked, his desperation mounting. “Was she on a blood thinner?” Usually he would have studied the chart the night before and known all the answers—but he had hurriedly been assigned to the case.

  “What if you didn’t know?” said Castle. “What if I told you that I didn’t know?” His hands had already reached into the woman’s abdomen and closed the vessels shut. The patient was safe, but the resident looked devastated.

  But then, it was as if a tiny bolt of knowledge had moved, like an electric arc, between Castle and his resident. The resident modified his approach. He walked over, past the surgical drapes above the woman’s head, to confer with the anesthesiologist. He confirmed that the anesthesia was adequate and the patient was safely sedated. Then he returned to the surgical field and blotted out the remnant blood with some gauze. Now, he began cutting around the blood vessels when he could, charting their course with the tip of his Babcock forceps, or separating them with his fingers with exquisite delicacy, as if polishing the strings of a Stradivarius. Each time he neared a blood vessel, he turned the blade of the scalpel to its flat side and dissected with his hands, or moved farther out, leaving the vessel untouched. It took significantly longer, but there was no further bleeding. An hour later, with Castle nodding approvingly, the resident closed the incision. The tumor was out.

  We walked out of the operating room in silence. “You might want to go and check her chart now,” Castle said. There was a note of tenderness in his characteristic nasal twang. “It’s easy to make perfect decisions with perfect information. Medicine asks you to make perfect decisions with imperfect information.”

  ....

  This book is about information, imperfection, uncertainty, and the future of medicine. When I began medical school in the fall of 1995, the curriculum seemed perfectly congruent to the requirements of the discipline: I studied cell biology, anatomy, physiology, pathology, and pharmacology. By the end of the four years, I could list the five branches of the facial nerve, the chemical reactions that metabolize proteins in cells, and parts of the human body that I did not even know I possessed. I felt poised to begin practicing real medicine.

  But as I advanced through my training—becoming an intern, then a resident, a fellow in oncology, and then an attending doctor treating patients with cancer—I found that a crucial piece of my education was missing. Yes, I needed the principles of cell biology to understand why, say, a platelet transfusion lasts only two weeks in most patients (platelets live in the body for only about two weeks). Anatomy helped me recall why a man had woken up from a surgical procedure with his entire lower body paralyzed (an unusual artery that supplies the lower spinal cord had become blocked by a clot, resulting in a “stroke” of the spinal cord, not the brain). An equation from pharmacology reminded me why one antibiotic was dosed four times a day while its close molecular cousin was given only once a day (the two chemicals decay at different rates in the body).

  But all this information could, I soon realized, be looked up in a book or found by a single click on the Web. The information that was missing was what to do with information—especially when the data was imperfect, incomplete, or uncertain. Was it appropriate to treat a forty-year-old woman with acute leukemia with an aggressive bone-marrow transplant if her health was declining rapidly? A
t first glance, textbooks and published clinical trials gave you an answer. In this instance standard wisdom held that patients with declining health and performance should not be given a transplant. But what if that answer did not apply to this woman, with this history, in this particular crisis? What if the leukemia itself was causing the rapid decline? If she asked about her prognosis, I could certainly quote a survival rate pulled from a trial—but what if she was an outlier?

  My medical education had taught me plenty of facts, but little about the spaces that live between facts. I could write a thesis on the physiology of vision. But I had no way to look through the fabric of confabulation spun by a man with severe lung disease who was prescribed “home oxygen,” but gave a false address out of embarrassment because he had no “home.” (The next morning, I got an irate phone call from the company that had attempted delivery of three canisters—to a Boston storefront that sold auto parts.)

  I had never expected medicine to be such a lawless, uncertain world. I wondered if the compulsive naming of parts, diseases, and chemical reactions—frenulum, otitis, glycolysis—was a mechanism invented by doctors to defend themselves against a largely unknowable sphere of knowledge. The profusion of facts obscured a deeper and more significant problem: the reconciliation between knowledge (certain, fixed, perfect, concrete) and clinical wisdom (uncertain, fluid, imperfect, abstract).

  This book began as a means for me to discover tools that might guide me through a reconciliation between these two spheres of knowledge. The “laws of medicine,” as I describe them in this book, are really laws of uncertainty, imprecision, and incompleteness. They apply equally to all disciplines of knowledge where these forces come into play. They are laws of imperfection.

  The stories in this book are of real people and cases, but I have changed names and identities and altered some contexts and diagnoses. The conversations were not recorded verbatim, but have been paraphrased from my memory. Some situations, tests, and trials have also been changed to maintain the anonymity of patients and doctors.

  In Harry Potter, that philosophical treatise disguised as a children’s book, a teacher of wizardry asks Hermione Granger, the young witch-in-training, whether she wishes to learn the Magical Laws to pursue a career in magic. “No,” says Granger. She wishes to learn the laws so that she can do some good in the world. For Granger, magical laws do not exist to perpetuate magic. They exist as tools to interpret the world.

  ....

  In the winter of 2000, during the first year of my medical residency, I lived in a one-room apartment facing a park, a few steps from the train station at Harvard Square.

  Lived is a euphemism. I was on call every third night at the hospital—awake the whole night, admitting patients to the medical wards, writing notes, performing procedures, or caring for the acutely ill in intensive care units. The next day—postcall—was usually spent in a dull haze on my futon, catching up on lost sleep. The third day we named flex, for “flexible.” Rounds were usually done by six in the evening—and the four or five hours of heady wakefulness that remained were among the most precious and private of all my possessions. I ran a three-mile circuit around the frozen Charles River as if my life depended on it, made coffee on a sputtering Keurig, and stared vacantly at the snowdrifts through my window, ruminating on the cases that I had seen that week. By the end of the first six months, I had witnessed more than a dozen deaths, including that of a young man, no older than I, who died of organ failure while awaiting a heart transplant.

  ....

  I spoke to no one, or, at least, I have no memory of speaking to anyone (I ran through a park by night, and through friends by day). “Illness reminds you that spontaneity, too, is a human right,” a patient once told me. Part of the horror of hospitals is that everything happens on time: medicines arrive on schedule; the sheets are changed on schedule; the doctors round at set times; even urine is collected in a graduated pouch on a timer. Those who tend the ill also experience some of this erasure of spontaneity. Looking back, I realize that I lived for a year, perhaps two, like a clockwork human, moving from one subroutine to the next. Days folded into identical days, all set to the same rhythm. By the end of my first month, even “flex” had turned into reflex.

  The only way to break the deadly monotony was to read. In the medieval story, a prisoner is sent to jail with just one book, but discovers a cosmos of a thousand books in that single volume. In my recollection, I also read only one book that year—a slim paperback collection of essays titled The Youngest Science—but I read it as if it were a thousand books. It became one of the most profound influences on my life in medicine.

  ....

  The Youngest Science was subtitled Notes of a Medicine-Watcher and was about a medical residency in another age. Written by the physician, scientist, author, and occasional poet Lewis Thomas, it describes his tenure as a medical resident and intern in the 1930s. In 1937, having graduated from Harvard Medical School, Thomas began his internship at Boston City Hospital. It was a grueling initiation. “Rewarding might be the wrong word for it, for the salary was no money at all,” Thomas wrote. “A bedroom, board, and the laundering of one’s white uniform were provided by the hospital; the hours of work were all day, every day. . . . There was little need for pocket money because there was no time to spend pocket money. In any case, the interns had one sure source of spare cash: they were the principal donors of blood transfusions, at $25 a pint; two or three donations a month kept us in affluence.”

  Lewis Thomas entered medicine at one of the most pivotal transitional moments in its history. We tend to forget that much of “modern medicine” is, in fact, surprisingly modern: before the 1930s, you would be hard-pressed to identify a single medical intervention that had any more than a negligible impact on the course of any illness (surgery, in contrast, could have a transformative effect; think of an appendectomy for appendicitis, or an amputation for gangrene). Nearly every medical intervention could be categorized as one of three P’s—placebo, palliation, and plumbing. Placebos were, of course, the most common of drugs—“medicines” that caused their effects by virtue of psychological or psychosomatic reactions in patients (elixirs for weakness and aging, or tonics for depression). Palliative drugs, in contrast, were often genuinely effective; they included morphine, opium, alcohol, and various tinctures, poultices, and balms used to ameliorate symptoms such as itching and pain. The final category—I’ve loosely labeled it “plumbing”—included laxatives, purgatives, emetics, and enemas used to purge the stomach and intestines of their contents to relieve constipation and, occasionally, to disgorge poisons. These worked, although they were of limited use in most medical cases. (In an epic perversion, the tool and the therapy were often inverted. Purging was a common medical intervention in the nineteenth century not because it was particularly effective, but because it was one of the few things that doctors could actually achieve through medicines; if you had a hammer, as the saying goes, then everything looks like a nail.)

  The paucity and ineffectiveness of therapeutic interventions had created what Thomas recognized as the reigning philosophy of medicine: “therapeutic nihilism.” Despite the negative connotations in its name, therapeutic nihilism was arguably one of the most positive developments of early twentieth-century medicine. Recognizing the absolute uselessness—and the frank perniciousness—of most nineteenth-century medical interventions, a new generation of doctors had decided to refrain from doing much at all. Instead, luminaries such as William Osler, at Johns Hopkins, had chosen to concentrate on defining, observing, categorizing, and naming diseases, hoping that this would allow future generations to identify bona fide therapeutic interventions. Osler, for instance, hospitalized patients in medical wards in Baltimore with no other purpose, it seemed, than to watch the “natural history” of an illness unfold in real time. The all-too-human temptation to do something was purposefully stifled. (A doctor’s job, Thomas once told an interviewer, “was to make a diagnosis, make a prognosis
, give support and care—and not to meddle.”) Osler’s students didn’t meddle with useless medicines; instead, they measured volumes, breaths, weights, and heights; they listened to hearts and lungs, looked at pupils dilating and contracting, abdomens growing and shrinking, neural reflexes appearing and disappearing. It seemed as if the Hippocratic oath—First, do no harm—had been transmuted to First, do nothing.

  And yet, doing nothing would have a deeply cleansing effect. By the 1930s, the careful bloodletting of the past had radically altered the discipline; by observing the evolution of diseases, and by constructing models of how diseases occurred and progressed, doctors had begun to lay the foundations of a new kind of medicine.

  They had recognized the cardinal features of heart failure—the gradual overloading of the body with fluid and its extrusion into the lungs, the altered sounds of the stretched, overworked heart, or the lethal disruptions of rhythm that followed. Diabetes, they had learned, was a dysfunction of the metabolism of sugar—the body’s inability to move sugar from blood into tissues; that in patients with diabetic acidosis, blood became gradually saturated with glucose, yet the tissues were starved of nutrition, like the Mariner who finds water everywhere, but cannot get a drop to drink. Or that streptococcal pneumonias often followed influenza infection; that patients recovering from the flu might suddenly develop relapsing fevers and a hacking, blood-tinged cough; that through the earpiece of a stethoscope, a single lobe of the lung might be found to exhibit the characteristic dull rustling of consolidation—“like a man walking on autumn leaves,” as one professor of mine described it. Or that a patient with such a pneumonia might experience two very different trajectories: either the microbe would overwhelm his physiological defenses, resulting in sepsis, organ failure, and a swift death; or, about ten days into the infection, the body would mount an exquisite immunological defense against the organism, resulting in the sudden abatement of fever and the elimination of the bacterium from the blood. Pathophysiology—the physiology of pathology—was thus constructed, observation upon observation, and it would be the platform on which modern medicine could be built.