A Commotion in the Blood: Life, Death and the Immune System

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A New York Times Notable Book, 1997 Library Journal, Best Book of 1997

Beginning with the "occasional miracles" of a mysterious turn-of-the-century cancer vaccine called Coley's toxins, Stephen S. Hall traces the story of how doctors have learned to harness the immune system and its "commotions" to develop a wide array of cutting-edge therapies. Moving deftly between laboratory and bedside, Hall's absorbing narrative navigates the politics of ...
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Overview

A New York Times Notable Book, 1997 Library Journal, Best Book of 1997

Beginning with the "occasional miracles" of a mysterious turn-of-the-century cancer vaccine called Coley's toxins, Stephen S. Hall traces the story of how doctors have learned to harness the immune system and its "commotions" to develop a wide array of cutting-edge therapies. Moving deftly between laboratory and bedside, Hall's absorbing narrative navigates the politics of discovery and elucidates the dazzling complexities of the microscope slide, tracking the curiously potent cells and molecules at the heart of the immune response. From the author of "the best book written about the new age of biology" (Nobel laureate Philip Sharp), who "succeeds marvelously in making science accessible to the general reader," (New York Times), this fast-paced account of medicine in the making is part of the Sloan Foundation Technology Book series.

Stephen S. Hall traces the story of how doctors have learned to use the immune system and its "commotions, " as one physician put it, to develop a wide array of cutting-edge therapies. "(Hall) succeeds marvelously in making science accessible to the general reader."--The New York Times Book Review.

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Editorial Reviews

Publishers Weekly - Publisher's Weekly
While guiding readers through a century of immunological breakthroughs related to the treatment of cancer, Hall (Mapping the Next Millennium) focuses on the high stakes, big money and oversized egos of the last 30 years. He details the pressures these scientist-doctors are under from constantly treating terminally ill patients, competing to be the one to make the next major research breakthrough or attempting to convince a governmental panel to permit the next experiment to be performed. The descriptions of their actual work, while comprehensive and clear, are not for the casual reader; technical details abound, making it easy to confuse interferon with interleukin or a "monoclonal anti-idiotype antibody" with an antigen. More effective is Hall's characterization of the role the media and the drug companies play in manipulating the research agenda. Too much attention focused too early on a potentially productive treatment, he says, has repeatedly created false expectations and influenced the flow of research money. Drug companies have, he claims, ignored certain successful forms of therapy because the profit margins have not been large enough. This is an impressive, if not entirely successful, look at scientists' understanding of the immune system, and at the marketing culture that now surrounds it.
Library Journal
In his latest book, science journalist Hall (Mapping the Next Millennium, LJ 12/91) chronicles the history of immunotherapy as a treatment for cancer. He begins with a discussion of William Coley's early attempts to treat cancer by deliberately injecting patients with a bacterial culture. He then examines numerous critical advances in the science of immunotherapy such as the discovery of cytokines and the impact of molecular genetics. Hall concludes with a lengthy review of some of the latest attempts at immunotherapy, including monoclonal antibodies, adoptive immunotherapy, and interleukin-12. The author does an admirable job of explaining the extremely complicated subject of immunology in understandable terminology. While much is still to be learned in this area, this book gives the reader a true appreciation of the complexity of human immunity, the "commotion in the blood" is not chaotic but rather a beautifully orchestrated intricate system. Highly recommended for all libraries. Tina Neville, Univ. of South Florida at St. Petersburg Lib.
Kirkus Reviews
Immunotherapy seeks to get the immune system to stir up a molecular "commotion in the blood" to battle disease. This sweeping yet remarkably detailed report focuses on the efforts to use immunotherapy in the fight against cancer.

Science journalist Hall (Mapping the Next Millennium, 1991, etc.) opens with an account of William Coley, a 19th-century American physician whose pioneering use of a crude cancer vaccine can now be seen as the beginning of cancer immunotherapy in this country. As Hall points out, neither Coley nor his critics had "the foggiest notion of the cells, the molecules, and the order of interaction involved in the immune response," an ignorance that today is finally lifting. The scene next shifts to 1950s London and the discovery of the much-ballyhooed interferon, which in turn led to the discovery of a host of other factors involved in immunological responses. Among these are interleukin-2, discovered in 1976 in one of Robert Gallo's laboratories and made famous by Steven Rosenberg in his work at the National Cancer Institute, and interleukin-12, the current favorite. Along the way, Hall details the development of T-cell-specific antibodies, the tumor necrotizing factor, and monoclonal antibodies. He seems to have interviewed just about every major immunology researcher, and he makes vivid their political maneuverings in the race for scientific primacy. The journey of a new therapeutic tool from laboratory to clinic is a hazardous one, and Hall makes it both understandable and exciting. He also shows us the hype that surrrounds each new "magic bullet" and the inevitable letdown when each one fails to live up to its hype. In the end, Hall leaves the reader optimistic that the "commotion in the blood" is not random noise but a "beautifully scored piece of music" that future researchers will be able to read. As gripping as a spy thriller.

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Product Details

  • ISBN-13: 9780805037968
  • Publisher: Holt, Henry & Company, Inc.
  • Publication date: 6/1/1997
  • Series: The Sloan Technology Ser.
  • Edition number: 1
  • Pages: 520
  • Product dimensions: 6.48 (w) x 9.56 (h) x 1.74 (d)

Meet the Author

Stephen S. Hall is the author of the critically acclaimed Invisible Frontiers and Mapping the Next Millenium and has written for Science and Health. He lives in Brooklyn, New York, with his wife and daughter.
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Read an Excerpt

Chapter One


1

"LAUDABLE PUS"

"The first hope of therapeutic success comes with the observation of the efficiency of unaided nature to accomplish cure.... These cases, rare though they be, are the sum of our hope." —Pearce A. Gould, "The Bradshaw Lecture on Cancer," 1910

There survives from the beginning of this century an intriguing bit of paper ephemera, notable less for the celebrated names marked down upon it than for a medical future it unknowingly foretells. As the year 1903 drew to a close, a rather well known New York businessman went to a Manhattan doctor of his acquaintance for a routine blood test, which was sent for analysis to an increasingly prominent pathologist at the Cornell University Medical College. The results of these tests, typed out on a half-sheet of paper and dated December 7, 1903, are quaintly minimalist and read as follows:

Hb 95% Red cells 4496000 Leucocytes 5000 Mononuclear 44% Polynuclear 55% Eosinophile 1%

"In the stained specimens," the pathologist noted, "I find nothing abnormal."

There is nothing abnormal about the blood chemistry, either. In quick translation, the results indicate a healthy number of red blood cells, the cells that carry oxygen to the tissues; a low but acceptable number of white blood cells (or leukocytes), which are now known to comprise the main cellular components of immuneactivity; and a reasonable proportion of the various cells that make up the "white blood." What at first seems so remarkable about this lab report is the confluence of names, interests, and destinies attached to it. The pathological analysis came from James Ewing, who would go on to head Memorial Hospital in New York and become one of the most influential cancer authorities of the twentieth century. The doctor ordering the tests was William B. Coley, who in the early days of the century claimed to have cured a number of inoperable cancer patients with a crude antitumor vaccine. And the blood itself belonged to John D. Rockefeller, even then in the process of establishing the great medical institute that would bear his name and whose philanthropic largesse advanced the interests and causes, to greater or lesser extent, of the other two men whose names appear on this otherwise forgettable bit of biochemical trivia.

All three men were dedicated, in their own way, to a cure for cancer, little realizing that certain clues lay in the very cells whose mundane numbers were dutifully recorded in the blood report. And it bespeaks the twists and turns of nearly a hundred years of research into cancer and immunology that the most important word on that fragile piece of paper is not the celebrated names that have come to symbolize wealth or medical authority but rather the word blood. All of Mr. Rockefeller's millions, all of Dr. Ewing's encyclopedic knowledge, and all of Dr. Coley's clinical intuition could not together purchase the knowledge we have painstakingly acquired in a century of research into the remarkable qualities of blood—its leukocytes and other cells, its proteins, its molecules and factors then unimaginable—all of which are now understood to function, like sections of an orchestra, in the daily biological symphony that is the immune system. In telling the story of how much of that knowledge has come to be won in the treatment of patients, it is most appropriate to begin with that crucial intersection of Coley and the Rockefellers and a disease whose diagnosis, then even more than now, was tantamount to a death sentence: cancer.

The destinies of the Rockefellers and Dr. Coley first crossed more than a decade earlier in a tragedy that, as the tabloids might put it, left one young woman dead and the lives of two men changed forever. It began in the fall of 1890, shortly after twenty-eight-year-old William Coley had finished his residency as a surgeon at New York Hospital and entered private practice. He was still a green and impressionable physician, still learning his trade, when a young woman named Elizabeth Dashiell came to see him, complaining about a nagging pain in her hand.

She was seventeen at the time, thoughtful and self-possessed, with a face so firmly etched with determination and good humor that she appears in surviving photographs almost preternaturally poised and mature. Born in Minneapolis, Dashiell had moved with her family to Lakewood, New Jersey, when she was two years old; her father, a minister named Mason Dashiell, had died when she was very young. She might have been one more young woman from small-town New Jersey save for the fact that she claimed as a close friend and confidant one of the most famous, and upon his majority one of the wealthiest, Americans ever produced by this nation: John D. Rockefeller Jr. Painfully shy and awkward as a youth, the customary solitudes and discomforts of adolescence no doubt heightened by the attention drawn by his family's notoriety, the only son of the founder of Standard Oil befriended Bessie Dashiell through her older brother Lefferts, who attended the same private school in New York as Rockefeller; one of Rockefeller's three sisters was also named Bessie, and he came to think of Bessie Dashiell as his "adopted sister." They took carriage rides together, rode horses along the Hudson Palisades, and exchanged long, thoughtful letters. There survives a formal portrait of the two of them: "Johnny Rock," as he would later be known to classmates at Brown University, looking less granitic than Fauntleresque, a soft-featured, frail-looking tulip of a youth, all four buttons of his pinstriped suit firmly fixed, a derby in his gloved right hand, and Bessie Dashiell, seeming to tower over him though she sits to his left, clear of eye and with a slight, knowing smile, gussied up in an overcoat with a fur collar, firm of jaw and beguiling in her self-aware sense of humor. That the stars brought this young woman and her notable friend into the orbit of Dr. William Coley ultimately had a profound effect on American philanthropy and cancer research, to say nothing of Coley's career.

Dashiell had a taste for daring. In the summer of 1890, she had undertaken what in retrospect qualifies as Victorian America's equivalent of adventure travel—a railroad trip across the continent, followed by a jaunt up to Alaska. During the trip, as she later wrote young Rockefeller, she had hurt her hand and thought it had become infected. By the time she had returned to New Jersey in August, the hand was still swollen and painful. As it turns out, the injury stemmed from the most trivial of accidents. Dashiell's hand had at some point become caught and pinched between two seats of the Pullman car in which she was riding. That "slight blow," as her doctor would later describe it, left an ordinary bruise upon the back of her right hand.

After some initial swelling and pain, the injury appeared to improve, but after a week, both pain and swelling grew more severe. To all appearances, it was a typical bruise, and a local physician recommended nothing more than "the usual local applications," probably ice. Nothing about so minor a bump seemed ominous, and hardly anything about this young woman suggested frailty—she had been in excellent health her entire life. Little more than a month later, back in New Jersey, Bessie Dashiell went to her own doctor complaining of continued pain; it seemed more pronounced with motion, she reported. In an attempt to alleviate the mysterious and persistent pain, the hand and wrist were placed in a splint, but that brought only temporary relief. During September, the pain grew so persistent, with occasional sharp and shooting flashes of discomfort, that Dashiell had trouble sleeping. Finally, her family decided to seek medical help in New York City. The man to whom they were referred was William Coley.

Coley, barely a year out of medical school, was already a rising star in New York surgical circles, at a time when surgery itself was the ascendant medical art. He examined her for the first time on October 1, and in the manner of the day, characterized the swollen area according to the scientifically imprecise but useful idiom of the farmer's market; he noted a small, spindly swelling "about the size of half an olive" on the back of her right hand, just above the large joint leading to her small finger. When he pressed down hard to determine if the swelling was mobile, his young patient complained of the pain. He checked for inflammation of the lymph glands under the armpit, which might indicate an infection, and found none.

Several days after this initial consultation, Coley made a more detailed examination. He suspected the problem was caused by a low-grade inflammation of the membrane, or periosteum, covering the bone, a condition known then as subacute periostitis. To make sure, he ventured a closer look; for a shy country boy who'd dithered over the choice of a profession scarcely five years earlier, Coley had quickly learned to wield the knife without conspicuous indecision. Applying cocaine as a local anesthetic, as was common at the time, he made a small incision through the center of the swollen area down to the bone. He noted a few drops of thin pus, but nothing in an amount suggestive of infection. Puzzled, he probed the tender area and observed that the tissue through which he'd cut "seemed abnormally hard and more of a grayish color than normal." He closed the wound with antiseptic dressings and placed the hand once again in a splint.

Coley probably expected to find telltale traces of a discharging infection when he later changed the dressing, but he did not, and when Dashiell reported that the pain and swelling had increased yet again, he must have felt uncertain about what to do next, because the following week he sought the advice of his mentor at New York Hospital, the celebrated surgeon William Bull. Bull, too, thought it was periostitis. He advised "waiting for further developments." Up to this point, Bessie Dashiell may well have viewed the problem as a nuisance, exceedingly painful but hardly more than a lingering, inconvenient bruise. Indeed, her friend John D. Rockefeller may have been more concerned than she; unaware at first that she had been hospitalized, he wrote her a nine-page letter on October 19 detailing his worry ("I cannot tell you how I shall miss my adopted sister on such occasions") and concluding, "I shall hope to receive just a word from you telling where you are and how your hand is doing before many days."

Her hand was not doing well, and sometime toward the end of October Dashiell must have read considerably greater concern in the face of the young surgeon. As her symptoms slowly but steadily worsened, Coley decided on yet a more detailed look. This time he administered ether and expanded his previous incision to expose a three-quarters-inch length of bone. The membrane covering the bone was thick, but the bone itself appeared clean and free of pus, thus seemingly free of infection. The young surgeon scraped away what he referred to as "grayish granulations" and closed the wound once again. Temporary relief ensued for a day or two, but the pain returned "as severe as before" with redness and swelling, and then Dashiell's condition became ever more frightening: she reported losing sensation in several fingers of her right hand. "The pain soon became so severe," Coley remarked, "that I was obliged to give morphine to secure relief."

Clearly, some process other than routine inflammation seemed to be causing the excruciating pain. Coley wracked his neophyte's brain for an answer. There was one other remote possibility to explain what was going on, and Coley reluctantly began to entertain it. The gradual increase in pain, swelling, loss of sensation, and impaired motion, absent an obvious infection or other inflammation, suggested something much more serious: cancer. Specifically, it suggested sarcoma, a malignant disease of the body's connective tissue, such as muscle, bone, and the miscellaneous gristle in between that holds us together (carcinoma, the other main form of cancer, arises in the epithelial, or surface, layer of tissues, and typically affects major organs like the lung, breast, liver, ovaries, and colon). After securing the consent of Bull and Robert F. Weir, chief surgeon at the hospital, Coley obtained a biopsy sample in early November by cutting away a small, wedge-shaped bit of tissue, which was given to a pathologist at the New York Hospital for microscopic examination. On November 6, the worst-case diagnosis came back: the cells on the slide bore the typical signature of cancer, and the pathologist's report read "Round cell sarcoma."

It is not hard to imagine the consternation with which this news might have been received by Bessie Dashiell, if she was told; doctors who practiced nineteenth-century medicine (by which is implied its concealing discretions as well as its often fruitless interventions) were famously circumspect about delivering bad news to patients, to say nothing of delivering it bluntly. In circumstances as dire as these, etiquette hardly mattered. In early July Dashiell had caught her hand between two train seats; now, barely five months later, three of the finest doctors in New York were telling her that, as Coley would later record, "amputation at the middle of the forearm offered the best chance of saving the patient's life." What Coley probably didn't tell her was that even that "best chance" made her odds of surviving at best only about one in ten; and what Coley himself almost certainly did not realize is that his initial exploratory incisions to diagnose the problem may have not only promoted the spread of cancer but accelerated what would become a harrowingly rapid decline, one that would haunt him for many years to come as "one of the most malignant tumors I had ever seen."

Many patients refused such radical treatment, but in this case the family had no choice. On November 8, 1890, little more than a month after he first examined Bessie Dashiell and shortly before her eighteenth birthday, Will Coley amputated her right arm below the elbow.

There is no record of Coley's personal reflections on the operation, whether he considered it a reasonable intervention or thought it a last-ditch, well-intentioned act of barbarism by professionals who had nothing better to offer. His not-quite-matter-of-fact recitation of Dashiell's ensuing decline suggests he expected a better outcome. "The appetite remained very poor and she did not regain strength as rapidly as I had hoped," he admitted to colleagues later.

Three weeks after the operation, Dashiell experienced extreme abdominal pain lasting several days before it went away. There was "no indiscretion in diet," as Coley put it, to account for the sudden pain. A more seasoned physician might have recognized it as a sign that seeds of malignancy, hatched in one part of Dashiell's body, had spread and nestled in other hospitable niches of the body, there to expand and proliferate as satellite malignancies known as metastases. Indeed, like some cruel, time-lapse movie of malignancy, tumors began to sprout up on Bessie Dashiell's body with alarming speed. On December 11, her doctors discovered a small lump, about the size of "a small almond," in her right breast; the following day, two smaller nodules appeared on her left breast where none had been the day before. A week later, the lymph glands under one armpit became swollen and painful. More lumps appeared in the breasts. Severe aches developed in the left thigh, and she experienced "almost complete anorexia," too weak to go out walking by Christmas. "The pain was so severe," Coley noted, "that the patient had to be kept under the influence of opiates."

The course of Dashiell's illness became a grim seminar for Coley on the speed with which an aggressive cancer can sweep through and conquer the human territory. She began to lose sensation in her lower lip and chin, then in some lower teeth. Dull pain returned to her abdomen. By the first of the year came jaundice; now the liver was failing. More small nodules cropped up on her chest and trunk; more lymph nodes hardened. "From this time," Coley noted, "the loss of strength and flesh was very rapid. She could take almost no nourishment, even liquid causing severe pain in the abdomen." Two weeks after Christmas, Coley located by touch a well-defined and enormous tumor occupying the whole of the abdomen above the stomach; he estimated it to be the size of "a child's head." The liver was enlarged, the heart began to fail. Like street sweepers tidying up after a nuclear holocaust, doctors plied her with large amounts of digitalis and as much brandy as she could stomach. By January 20, the end was in sight.

The endgame in cancer is never pretty, less so in an era where doctors chased rather than managed the last ghastly symptoms. The breast tumors had become the size of goose eggs, the abdominal tumor even larger; the length of her body from head to toe was stippled by small tumors that Coley likened to buckshot or split peas. Last came the vomiting, several times a day, though she had had no solid food; soon, she was regurgitating copious amounts of blood. "The attacks occurred almost hourly," Coley noted, "and were very exhausting to the patient in her extremely weak condition." Elizabeth Dashiell remained conscious of this horrific piracy of her eighteen-year-old body until very nearly the end, when finally, mercifully, she died at home in New Jersey at 7 A.M. on January 23, 1891. Coley was at her bedside and signed the death certificate.

How much meaning can such a short and tragic life embrace? John D. Rockefeller Jr., no doubt frantic when he finally learned of the gravity of Dashiell's illness, visited her at home not long before her death and attended the January 25 funeral. Mary Dashiell later sent him a keepsake, a celluloid court-plaster case that her daughter had cherished. "I cannot tell you how deeply I appreciate your kindness in sending me something which belonged to Bessie and which she enjoyed," he wrote in reply. "This token will be a continual reminder of her beautiful life and death, and I shall never look at it without being thrilled with the thought of her patient endurance of such continued suffering, and tender regard for those about her, lest they should be made unhappy or sad by her pain."

His grief had two consequences, one short-term and one of truly visionary sprawl. The shock of Dashiell's death left Rockefeller in no shape to attend college; slated to begin his first term at Yale University during the period following Dashiell's death, he spent the time instead tending to the grounds of Forest Hill, the Rockefeller estate in Cleveland. The raw adolescent wound of losing a beloved soul mate, especially for a boy who probably didn't have many, could only leave a deep and lasting scar, and although many a mourner vows to channel her or his grief into practical good, few in history were as well placed as John D. Rockefeller Jr. to translate such resolve into something of enduring impact, and few were as good to their word. As a young adult, he dedicated much of his philanthropic effort to the conquest of cancer; those efforts began five years after Dashiell's death, in 1896, with dabbling support for William Coley's research (the two men remained friends throughout life), grew prodigiously with his family's creation of the Rockefeller Institute for Medical Research (now Rockefeller University), and led ultimately to a multimillion-dollar gift that allowed creation of Memorial Hospital (now Memorial Sloan-Kettering Cancer Center) at its present site in New York City. Asked many years later how he became interested in cancer research, Rockefeller replied, "I think it goes back to Bessie Dashiell ... Her death came to me as a great shock."

Dashiell's swift death left her physician no less shaken. Only ten years older than Bessie, William Coley was too young, too professionally unseasoned, to shrug off the case. In his very last scientific paper, written nearly half a century later, he reiterated that Dashiell's case made a "deep impression." He felt helpless in the face of Dashiell's illness, and was naive enough to think he could do something about it. The case sobered Coley not only because of the speed with which the cancer killed, but because of the crude, puny, and utterly ineffectual obstacles hurled by her doctors to impede its fatal course. Medicine, as it was practiced then at New York's finest hospitals, had nothing better to offer than morphine, brandy, and the bone saw, and nothing to show for the effort. William Coley appears to have been one of those stoic personalities who betray no emotion, not because he didn't feel any but probably because he felt too much; when he related Dashiell's case history to surgical colleagues several months later at the New York Academy of Medicine, cataloging each decrement of her mortal illness with the detached precision of the keen clinical observer he had already become, he hinted at his own frustration only in his concluding remarks. "A disease that, starting from an insignificant injury, can attack a person in perfect health, in the full vigor of early maturity, and in some insidious, mysterious way, within a few months, destroy life, is surely a subject important enough to demand our best thought and continued study."

Coley's "continued study" began almost immediately. Curious about such a starkly malignant disease, he decided to search the hospital records for past cases of sarcoma to learn more about this generally rare disease. In the course of this research, he stumbled upon an unusual case—an aberration, really—that stopped him in his tracks. And that is how, several months after the death of Elizabeth Dashiell, in the spring of 1891, Coley found himself in the midst of a most unusual epidemiological manhunt on Manhattan's teeming Lower East Side. For several weeks, during the hours after work, he searched the tenement neighborhoods, climbing interminable flights of stairs, inflicting his pidgin German on startled tenement dwellers who opened their doors to an earnest young doctor, certainly not the kind of man regularly seen paying house calls in those precincts. At each door he inquired after a German immigrant, a house painter, last seen at New York Hospital in February 1885. The man's name was Stein, and he probably bore a large, telltale scar behind his left ear.

"Nature often gives us hints to her profoundest secrets," Coley said on another occasion, "and it is possible that she has given us a hint which, if we will but follow, may lead us on to the solution of this difficult problem." Nature had given Coley a hint; now he determined to follow it down whatever avenue, up whatever steps, through whatever door, to find this man Stein; and through Stein to explore the biology of an apparent medical miracle.

Banging on tenement doors may seem like a profligate waste of a surgeon's valuable time, to say nothing of a professional hazard to his valuable hands, but medicine was different at the turn of the century in many respects, and in Coley's case his willingness to augment knife and gown with medical gumshoeing speaks well of his ability to practice a new kind of medicine. If there has been a reluctance to accord him recognition as the father of immunotherapy, it may in part relate to a tendency to hold this thoroughly nineteenth-century physician to twentieth-century scientific standards, and perhaps also to overly extravagant claims made on his behalf by champions of alternative approaches to cancer treatment. In order to appreciate what William Coley accomplished, it is essential to appreciate who he was—and just as important, who he was not. He was a wonderful clinician, a superb surgeon, an esteemed colleague of the major medical workers of his generation, including William Welch of Johns Hopkins, Harvey Cushing of Harvard, and the Mayo brothers. One thing he was not, however, was a scientist; he never trained in any form of laboratory work, and never truly understood the rules by which the increasingly scientific approach to medicine was being played. Yet in straddling two distinct medical eras, he managed to be a modernist and old-fashioned all at once; and in order to understand why Coley's anticancer vaccine received the largely indifferent reaction it did, it is essential to understand Coley as a man ahead of the times and yet behind them, too.

His roots were strictly rural. William Bradley Coley was born on January 12, 1862, in the small Connecticut community of Saugatuck, just north of Westport, in a district that formed part of a heavily wooded, gently rolling sixty-five-acre parcel of land granted to the Coley family by King George III in 1763 and informally known as "Coleytown." His father, Horace Bradley Coley, taught in a one-room schoolhouse and farmed corn, onions, and potatoes to make ends meet while his mother, Clarina Wakeman Coley, tended the house. The family traced its American roots back to Samuel Coole, who arrived in the Massachusetts Bay Colony in 1631. Theirs was a clan of solid (and stolid) citizens: militiamen, selectmen, church deputies, known for their farming, teaching, and upright lifestyles.

An empathetic physician throughout his career, Coley may have acquired the skill involuntarily, beginning at an early age. His immediate family suffered devastating losses to the kinds of common mortal illnesses that would, by the end of Coley's career in medicine, be regarded as novelties. Horace Coley's first wife, Polly Sophia Wakeman, died in 1854, probably of puerperal (childbirth) fever; his second wife, Clarina, mother of William Coley (and sister of the recently deceased Polly), succumbed to typhoid fever when her son was only nine months old. Of Coley's first two stepsisters, one later died of peritonitis, the other of an unknown fever; Coley's sister Carrie, probably the most beloved of all in his immediate family, died in 1892 after a life-threatening pregnancy and an emergency abortion late in the first trimester (which Coley reluctantly performed himself), and Coley also lost his second-born son Malcolm, who died in 1901 at age five of an acute gastrointestinal infection, after less than a week of illness. Following the death of William's Coley's natural mother, Horace Coley remarried a woman named Abbie Augusta Gray; a much-beloved stepmother to William Coley during the crucial years of his upbringing, she too died, in November 1879. By the time Coley turned eighteen, in other words, he had lost two mothers.

By that age, however hardened by the deaths around him, Will Coley had developed into a slender, handsome young man of five feet eight, brown-haired and brown-eyed, of notoriously shy demeanor. Intelligent and deeply religious, he attended a private academy in Westport, where his first exposure to the classics would initiate a lifelong love affair with great literature and account for two of his greatest extracurricular passions: reading and the collection of rare books.

Nothing about the upbringing or education of William Coley advertised the imagination with which he perceived the importance of his toxin therapy or the genial tenacity with which he defended it against many detractors over many decades. When he set off by train to New Haven for his first year at Yale College, having been accepted into the class of 1884, it was like crossing some intellectual Bosphorus and setting foot upon a newly discovered and exotic continent of books, ideas, society, culture—all the more so for someone who, if truth be told, probably reminded no one of a worldly, urbane dandy. As the journal he began to keep suggests, life before Yale was virginal in every respect ("Played cards! I never knew the name or value of a card before but learned so quick," he wrote, in a brief verbal frisson, familiar to all undergraduate initiates to the pleasures of sin, in February 1882; the wonder is that it took until his sophomore year to make the discovery). The language quoted in his diary is of someone just learning that he has a voice, much less testing its limits: painfully earnest and literal, rarely witty, uncomfortable with strong opinions, Coley's journal rarely dares to scratch beneath superficial observation. "Completely carried away with it," he wrote glowingly of Longfellow's poem The Courtship of Miles Standish.

Coley had never played cards before going to college, had never gone to the theater, had never smoked. He found time each week to teach Sunday school, read his Homer and Aeschylus for classes and his Paradise Lost and Samson Agonistes with greedy pleasure during breaks, and supplement his always threadbare finances by ghostwriting compositions for less gifted students while tutoring others in math and physics. He must have been an excellent tutor: he once commanded $32 for several sessions, which sum covered roughly 20 percent of the annual tuition at Yale. He was not "tapped" for membership in a secret society, did not compete in sports, did not join clubs [except the freshman debating society), and decided against attending the Junior Promenade one year because he could not afford the $4 ticket. As for recreation, he tended toward the more economical diversions: ice-skating, boating, most of all walking. As his classmates later recalled, Coley was "very quiet and reserved at Yale—no extracurricular activities and never athletic." Of his personality, all we are told is that he possessed a "merry laugh."

To anyone who has made the acquaintance of that humble and self-effacing creature, the surgeon, Coley's ultimate migration to that branch of medicine seems almost temperamentally precluded by his earnest indecisiveness. His initial exposure to the medical profession came by way of his extended family; when he was home on break from college, he would sometimes accompany his uncle, Dr. Joseph Henry Wakeman, on house calls in the Redding, Connecticut, area in the doctor's horse-drawn buggy. But he was far from decided upon a career in medicine. In January 1884, just a few months short of graduation, he described a fitful night in bed trying to solve the problem: "I lay awake a good part of the night listening to the fierce blast of the wind and rain upon the roof and meditated whether to study the Chemistry Optional next term and take Medicine as a profession or to take Law. I could not come to a satisfactory decision, although I did not give up until nearly morning."

After much fretting and procrastination, he punted—he decided to accept a post as "assistant principal" (a glorified term for an overworked instructor) at the Bishop Scott Grammar School in Portland, Oregon, where he could set aside some money and ponder the decision anew. The school was run by a Yale graduate named Joseph Wood Hill, who happened to be the husband of a distant cousin, Jessie, which fact undoubtedly complicated negotiations when Coley insisted on timely installments of his $600 a year salary, always seemingly in arrears. After taking the Northern Pacific railroad across the continent, he remained two years in Portland, teaching everything from Greek and Latin to mathematics, gazing out the window of his room at Mount Hood, saving close to $750 with which to further his education, and still pondering in which profession to invest it. Here his reading brought him into contact with two influential figures, one medical and the other spiritual.

The latter, interestingly enough, was Giordano Bruno, the radical sixteenth-century Italian humanist. This Renaissance scholar championed the Copernican, sun-centered view of the solar system; believed the universe was infinite and composed of many systems like our solar system; posited an atomic-based concept of matter; spoke of the Bible as a book of moral but not scientific authority; lectured on a peaceable utopia where all religions coexisted in an atmosphere of harmony and dialogue; dabbled, fatefully, in mysticism; and aroused the fury of ecclesiastical authorities by steadfastly sticking to these radical, unorthodox, and clearly erroneous beliefs. Bruno did not, like Galileo, mumble his defiance under his breath to save his skin, for which insolence Bruno was ultimately burned at the stake in Rome's Campo de' Fiori in 1600. Coley filled several pages of his notebook with admiring observations about Giordano Bruno. "Drank deeply of the spirit of the Renaissance," he wrote. "Accepted the discoveries of Copernicus, and used them as a lever to push aside antiquated systems of Philosophy." Coley never thought of himself as a martyr, but the lifelong vicissitudes of winning acceptance for his work might easily have reminded him of Bruno's travails.

Another book exerted a more immediate impact. Coley happened to read the autobiography of J. Marion Sims, the celebrated surgeon who had helped found the New York Cancer Hospital in 1884. "I have been asked many times why I studied medicine," Sims wrote in a passage Coley dutifully copied into his notebook. "There was no premonition of the traits of a doctor in my career as a youngster; but it was simply in this way: At that day and time, the only avenues open to a young man of university education were those of the learned professions.... A graduate of college had either to become a lawyer, go into the church, or to be a doctor.... I would not be a lawyer; I could not be a minister; and there was nothing left for me to do but to be a doctor." Not only did Coley reach the same conclusion, but twenty years later, this Oregon schoolteacher would play a major role in shaping the hospital founded by Sims into the city's—and ultimately the nation's—preeminent cancer research institution, Memorial Hospital.

In September 1886 Coley began his medical education at Harvard; it says something about the somewhat less rigorous standards of medical training in the days prior to Abraham Flexner's historic 1910 report, which urged massive reform in medical training and modernized American medicine, that Coley was allowed to enter the three-year program at Harvard Medical School as a second-year student largely on the strength of spending several months during the summer of 1886 accompanying his uncle on rounds in a horse and buggy. At that time many medical schools were not affiliated with a university, most required only two years of study, and hardly any used a standardized examination to test the competence of would-be practitioners before unleashing them on an increasingly wary public. Harvard was certainly among the best of the lot, but it too was struggling to absorb and incorporate the profound changes in medical science, of which there were many in the latter half of the nineteenth century: Joseph Lister had introduced the concept of treating surgical wounds with antibacterial substances (antisepsis) in 1866, followed soon after by the technique of using sterile conditions (asepsis) in the operating theater, and these concepts remained so new during the period of Coley's education that their merits were still heatedly debated in some American hospitals; Louis Pasteur had proposed the germ theory, thereby implicating infectious microorganisms as the cause of infectious disease; and Robert Koch had, just four years before Coley's matriculation, identified the mycobacterium that caused tuberculosis, a disease then claiming roughly 5 million lives worldwide each year. Medicine was in the throes of the most profound changes since the Renaissance, although not all the changes had sifted down to the schools.

Nonetheless, Coley managed to engineer for himself—and it was quite as much his doing as Harvard's—a remarkably liberal, unusually modern medical education. Whereas the conventional curriculum involved little more than an endless series of lectures on anatomy and physiology, chemistry and pathology, Coley had extraordinary good luck in obtaining on-the-job training. During the summer following his first year of medical school, in 1887, he happened to be visiting two friends from Yale who served on the staff of New York Hospital, and they invited him on the spot to fill in for a doctor who had taken sick leave, which is how—at age twenty-five, still without a medical degree, and at a moment's notice—Coley found himself patrolling the corridors of a major metropolitan hospital as "Acting Junior Surgeon" for six weeks. The title almost certainly exaggerated largely factotum responsibilities, but in an era that had barely begun to embrace the educational wisdom of exposing students to actual clinical situations in the wards of hospitals, Coley found himself not merely exposed but plunged into real doctoring: dressing wounds, handling the "etherizing" at operations (that is, serving as anesthesiologist), observing the modern technique of surgical asepsis, acquiring hands-on experience during a hands-off era of medical education. His very first medical paper discussed heat-related illnesses, based on the many sunstroke victims he treated during the summer of 1887. To his sweetheart he wrote with an apprentice's pride, "I sewed on a finger the other day and expect to amputate one today."

Even Coley could not have realized at first how fortuitous that summer's employment would turn out to be. He not only landed in one of the premier private hospitals in New York, but in fateful proximity to two of the best surgeons in the country. Robert Fulton Weir, described in Walter Graeme Eliot's Portraits of Noted Physicians of New York, 1750-1900 as "one of the three greatest surgeons of the day in N. Y. City," was a wiry, gray-bearded fellow with a hooked nose and sharp, hooded, deep-set, and lively eyes, who in formal portraits appears like someone too restless to dress well, pose well, or let go of a raptorlike intensity that stiffened his face with impatience. In addition to a teaching appointment at the College of Physicians and Surgeons, Weir later served as president of the New York Academy of Medicine. The other was a disciple of Weir's named William Tillinghast Bull. The name conjures up an image of Taftlike bulk and Ashmolean sideburns: Bull was indeed a heavyset young man thirteen years older than Coley, his mustache slicked to pinpoints, hair parted smartly down the middle as befits the ladies' man and befriender of nurses he was said to be, a sharper dresser than Weir, with less delicate hands and chilling, distant eyes. He achieved early celebrity in 1884 when, pioneering a form of emergency surgery at the Chambers Street Hospital that has lamentably become ever more essential to twentieth-century medicine, he is said to have performed the first exploratory operation to treat an abdominal gunshot wound; Bull enjoyed such local celebrity that when he became ill with cancer in 1908, the diagnosis and his subsequent months-long struggle against the disease was front-page news in the New York Times and other papers. His influence on Coley is obvious: the young surgeon's second paper, "Treatment of Penetrating Shot-Wounds of the Abdomen," appeared the following year in the Boston Medical and Surgical Journal, forerunner of the New England Journal of Medicine.

The historian Paul Starr has written of the transformation of American hospitals "from places of dreaded impurity and exiled human wreckage into awesome citadels of science and bureaucratic order," and Coley had the good fortune to enter the field just as the foundation stones of that massive new edifice were set into place; indeed, he later claimed to have entered medicine "at the most opportune time in a thousand years." Weir and Bull, for example, aggressively championed the use of aseptic conditions in the operating theater, and Coley learned the technique at their elbows. With each passing year, medicine became more of a science-driven enterprise. Bacteriology's assault on infectious disease represented the leading salient, and collateral fields like microbiology and immunology moved swiftly through the breaches that breakthroughs against infectious diseases created; aseptic techniques allowed surgeons to treat otherwise minor but problematic conditions like hernias and fractures without fear of mortal infection. And significantly, Coley's career would enact in miniature one of the emerging and most enduring conflicts of twentieth-century medicine, when for the first time the duties of the conscientious physician sometimes worked at cross purposes to the needs of the rigorous researcher. With the rise of "scientific medicine" came a newly hyphenated medical creature, the physician-researcher, who straddled with great difficulty the chasm between bedside and laboratory bench.

With the summer experience under his belt and, a year later, his Harvard education behind him, Coley accepted an invitation to be a surgical "Interne" at New York Hospital, beginning in January 1889 (as a last grand adventure before New York, he signed on in August 1888 as ship's surgeon to the Kennard, a barkentine that plied the human trade bringing cheap immigrant labor from the Azores to the textile mills surrounding Boston). Coley's first year in New York was exhilarating, depressing, determining. He arrived in November 1888 and found an apartment at 18 West Sixteenth Street, just next door to New York Hospital, then located on Sixteenth Street between Fifth and Sixth Avenues.

This venerable institution, founded five years before the Declaration of Independence was signed, had relocated to Sixteenth Street in 1875 and received a handsome face-lift, with a redbrick facade and mansard roof. There were nine house physicians at the hospital, who hustled to attend some 375 patients daily; Coley served until July 1889 as a "junior walker," or intern, graduated to senior walker that summer, and was promoted to house surgeon early in the spring of 1890. His skill in surgery must have been considerable, for in addition to his internship at New York Hospital, William Bull secured appointments for Coley at the Post Graduate Medical School, where he had an instructorship in surgery, and at the Hospital for the Ruptured and Crippled, where he would serve for some forty years, ultimately as chief surgeon (this latter is now the Hospital for Special Surgery, where New York Mets and Jets and other professional athletes take their well-heeled joints and bones for repair). There he championed the use of the "Bassini procedure" to treat hernias, a technique he performed thousands of times during his career. At one point in the midst of this intense apprenticeship, Coley's beloved Alice Lancaster broke off their relationship, though they would ultimately reconcile and marry on June 4, 1891, after several intense months of activity that would forever shape the trajectory of Coley's future years.

With early success came lifelong paradox. The boy who milked cows and plowed the fields of his father's Connecticut farm later ministered as personal physician to a rich dowager on one of her European vacations; the boy who walked six miles to Sunday school at the Methodist church in Easton became the man about town who insisted on a chauffeur, in part because he never learned to drive a car. The teenager who shunned college social events for want of money (and, probably, want of social confidence) would later join fifteen medical societies and ten social clubs, reorganize the Sharon, Connecticut, golf club, and exchange chummy letters with robber barons and their kin. The boy raised in a culture of thrift and deprivation became the successful surgeon who perpetually lived beyond his means, who dabbled in real estate speculation, and whose financial adventurism was so ill-advised that near the end of his life he could barely pay for medical treatment for his dying wife.

Yet here is the most fascinating paradox of all. The man who made quite a good living by use of medicine's crudest utensil, the knife, stumbled upon its subtlest of healing tools: the blood, with its cells and its wondrously potent ensemble of molecules. Because he was never trained as a scientist (and never really became a great one during his lifetime), Coley failed to cast his work into a rigorous, molecular idiom; nor could he have, given the technical limitations of the day. Whatever credit he deserves—and he deserves a great deal—derives from the fact that he was an exceptionally conscientious physician who made careful observations, believed what he had seen, and clung to those beliefs with a tenacity that emulated what he regarded as Charles Darwin's greatest virtue as a scientist: doggedness.

Of all his many qualities, that was perhaps the one that served him best. And he would have a lifetime of controversy to put his doggedness to good use.

James Thurber
His Life and Times


By Harrison Kinney

Henry Holt and Company

Copyright © 1995 Harrison Kinney. All rights reserved.
TAILER

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Table of Contents

"Shooting Rubber Bands at the Stars" 3
I * THE OCCASIONAL MIRACLE
1 * "Laudable Pus" 21
2 * "The Man Who Does the Most Work Does the Best Work" 51
3 * Bleak House 76
4 * The Method of Choice 96
5 * The Coley Phenomenon 115
II * THE PATRON SAINT OF CYTOKINES
6 * In Search of an Interferon 131
7 * Lymphodrek 159
8 * "The Cloning of Interferon and Other Mistakes" 178
9 * "One of My Best Known Accidents" 209
III * THE RISE OF THE T CELL CHAUVINISTS
10 * The Silk Purse Years 231
11 * The Rise of the T Cell Chauvinists 242
12 * To Be in Motion 257
13 * The End of the Beginning? 285
14 * "There's Just So Much You Can Learn from a Mouse" 314
IV * IN VIVO VERITAS
15 * "One Plus One Equals Ten ..." 349
16 * "Beautiful Living Things ..." 375
17 * "Dr. Levy's Favorite Guinea Pig" 391
18 * A Piece of Misleading News 409
19 * The Next Great MagicBullet 423
Epilogue:
Metaphors, Manic Depression, and the "C" Word 449
Notes 459
Acknowledgments 516
Index 521
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