Shaw was a Fabian Socialist, a sometime atheist, an antivivisectionist, and an Irish patriot, but his real passion was satire, and he had written the play to skewer the medical establishment of his day. Debating the “dilemma”—whether Ridgeon should use his tuberculosis cure to treat an honorable but inconsequential friend, or a deeply immoral but brilliant artist, a choice complicated by the doctor’s lust for the painter’s wife—are a group of physicians with what might charitably be called blinkered approaches to the healing profession. A onetime schoolmate of Dr. Ridgeon, Dr. Leo Schutzmacher, offers the two-word secret to his successful practice—“Cure Guaranteed”—while confiding, “You see, most people get well all right if they are careful and you give them a little sensible advice.” Cutler Walpole is a frighteningly eager surgeon who believes all disease is a version of blood poisoning, which is invariably cured by the removal of an entirely invented organ he calls the “nuciform sac.” Sir Ralph Bloomfield Bonington, having read a page or two from Koch and Pasteur, treats each of his patients with the most dangerous microbes he can find, expecting thereby to promote a natural cure. “Drugs are a delusion. Find the germ of the disease; prepare from it a suitable anti-toxin; inject it three times a day quarter of an hour before meals; and what is the result? The phagocytes* are stimulated; they devour the disease; and the patient recovers.” Of them all, only the now-retired Sir Patrick Cullen escapes Shaw’s barbs, pointing out to Ridgeon that, despite his newfound cure, “I’ve known over thirty men that found out how to cure consumption. Why do people go on dying of it?”
For a satire to work at all, its targets must be familiar to its audience, and so it was with The Doctor’s Dilemma. Every one of the London playgoers who attended its premiere would have known physicians who reflexively removed each of their patient’s tonsils or appendix irrespective of their presenting symptoms; or those who monomaniacally prescribed antitoxins or antiserums for everything from skin lesions to cancer. And they would have recognized the model that Shaw used for Colenso Ridgeon: the nation’s most famous physician, Dr. Almroth Edward Wright.
In 1906, Wright, a friend and occasional debating opponent of Shaw, was forty-five years old, and already frequently referred to in the press as “Britain’s Pasteur.” He had come to medicine by a somewhat circuitous route; before graduating as a physician from Trinity College, Dublin, in 1883—Wright was partly Irish by descent—he had already taken First-Class Honours in modern literature, and would later read “Jurisprudence and International Law with a View to the Bar.” From 1895 on, though, he was completely devoted to medicine, and his particular area of interest was the discovery of an immunization against typhoid fever, one of the deadliest diseases in history.
Variously blamed for the fifth century B.C.E. Plague of Athens, the destruction of the English colony of Jamestown in the seventeenth century, and the deaths of tens of thousands of American Civil War soldiers, typhoid fever is one of a dozen different diseases caused by a strain of bacteria from the genus Salmonella, specifically S. typhi.* Typhoid fever is a killer, but not a sudden one; a typical infection lasts up to a month, beginning with a characteristic low-grade fever and slowed heartbeat. As the fever rises, the heart continues to slow, frequently accompanied by delirium. The bacteria reproduce rapidly, causing the host’s abdomen to distend and severe diarrhea to follow. Internal organs like the spleen and liver enlarge. Intestines hemorrhage, and sometimes perforate, spreading infection to the internal membrane: the peritoneum. Unless the victim’s immune system is successful in fighting off these sequential attacks, death results; mortality can run as high as 25 percent in untreated typhoid fever.
The destructiveness of any infectious disease is a function of both virulence and mobility: how much damage the pathogen causes, and how easily it travels. Because S. typhi spreads by consumption of drinking water contaminated with human feces and urine, it was particularly deadly wherever large numbers of people with poor access to sanitation lived in close contact: the poorer quarters of rapidly growing nineteenth-century cities, for example. Or—even more lethally—armies in the field. During the Spanish-American War, typhoid fever killed more American soldiers than either battle wounds or even the feared viral disease known as yellow fever.
For obvious reasons, then, military doctors were particularly concerned about the disease, none more so than Wright, whose first job after becoming a physician was at the Army Medical School at Netley, near Southampton. There, in 1895, he developed the first effective vaccine against typhoid, inoculating subjects not with a weakened version of the S. typhi bacterium (this was the method tested by Robert Koch), but, far more safely and effectively, a dead one. He tested it first on himself, then on fifteen volunteers, and finally on a regiment’s worth of British soldiers headed to India. It was Wright’s first, and greatest, triumph: Of nearly three thousand subjects, only ten contracted the disease.
Despite this success, he was unable to persuade the conservative policymakers in Britain’s War Department to inoculate troops being sent to South Africa in 1899 to fight in the Second Boer War. As a result of their reactionary hostility to even modern medicine, even in the face of what seems its inarguable success in India, over the next three years typhoid proved more deadly to the British army than the combined efforts of the Afrikaner Transvaal Republic and the Orange Free State. At least twenty thousand British soldiers contracted the disease, and more than nine thousand of them died. Disgusted, Wright left the War Department in 1902, and moved to St. Mary’s Hospital. On Praed Street in London’s Paddington neighborhood, St. Mary’s was one of the last of London’s so-called “voluntary” hospitals, set up for the care of the working poor, and one of the first conceived of as a teaching hospital with an attached medical school. There, following the model of Pasteur and Koch, he opened a laboratory—the “Inoculation Department”—that he would direct for the next forty-five years.
In retrospect, Wright’s accomplishments at St. Mary’s never soared as high as his reputation, and his place in history has suffered in consequence. During his lifetime he was hugely famous and influential, eccentric and intimidating. In legend, at least, his memory was so remarkable that he had committed a quarter of a million lines of poetry to it. Wright was tall and striking, careless of his dress but wickedly entertaining in his speech, a brilliant raconteur and lecturer, and a public figure whose opinion was sought on issues scientific, social, and political until his death in 1947. He was also a fine and innovative experimentalist, and a master of laboratory technique. With little more than a microscope, a Bunsen burner, and a supply of rubber nipples and glass tubing, he was able to perform extraordinarily sophisticated research* in ways that remind historians of science just how much the lab once depended on the steady hand of a craftsman. The vials that Wright used to collect blood, his so-called blood capsules, were custom-made bits of glass pipette that he melted and drew in the flame of a Bunsen burner into narrow tubes that he then bent at an angle. Snipping the glass at one end provided a needle, and the curve allowed the glass straw to draw the blood by capillary action.
Credit: Wellcome Library, London
Almroth Wright, 1861–1947
Wright’s lab skills were, however, something of a two-edged sword, since they made him prone to accept his acute clinical observations as irrefutable proof. Yet he was hopeless with numbers; the original dead-cell typhoid inoculation he performed on 2,835 India-bound soldiers was almost certainly successful, but you couldn’t prove it by Wright’s statistics. According to Britain’s leading mathematical biologist, Karl Pearson, the data Wright collected were useless for concluding anything: no control groups, no attempts to show what statisticians call the “null hypothesis”—the assumption that there is no relationship between two phenomena, such as “being inoculated” and “getting typhoid.” Wright’s statistical illiteracy was likely a consequence less of his temperament than of his eccentric education, which was almost willfully deficient in pr
actical mathematics, even by the standards of nineteenth-century Great Britain. Wright had been home tutored, and spent far more time on Latin declensions and the history of the common law than on regression analysis.* It is almost certainly that blind spot that explains his devotion to one of the great dead ends in medical history: vaccine therapy, the use of substances that activate the adaptive immune system to fight a specific disease as a therapy, rather than a preventative.
Wright was a vaccine absolutist, famously observing, “The physician of the future will be an immunizator.” The key, to Wright, was the particular character of an individual patient’s immune system, not an attack on pathogens using chemicals such as Ehrlich’s Salvarsan or, later, Domagk’s sulfanilamide. This debate—whether disease was best understood as what occurs when a healthy host encounters a pathogen, or as the consequence of what happens when an unhealthy host does so, with the latter providing evidence of a deficiency in the host’s internal environment—dates back to Pasteur, and, in some senses, remains alive today.* Convinced by the promising results of serum therapy to treat illnesses such as rabies, Wright predicted that similar techniques could be used “to exploit the uninfected tissues in favor of the infected.” Wright named this phenomenon the “opsonic mechanism.”
In explaining the wholly fictional tuberculosis cure at the heart of The Doctor’s Dilemma, Colenso Ridgeon says to Sir Patrick Cullen that “opsonin is what you butter the disease germs with to make your white blood corpuscles eat them.” Shaw was prescient. A story in the New York Times from March 31, 1907—a year after the premiere of the play—is headlined: “THE NEW HOPE FOR TUBERCULOSIS: DISCOVERY OF ‘OPSONINS’ PROMISES TO REVOLUTIONIZE MEDICINE.” The newspaper goes on to quote Wright on his discovery that opsonins do their work “by uniting with the micro-organisms, the invading germs, and rendering them more palatable, so to speak, to the white corpuscles.”*
Opsonins are real. Any molecule that enhances the way white blood cells ingest and kill invading pathogens is, technically, an opsonin, as are those that activate the complement that is part of the innate immune system. Opsonic therapy, however, never lived up to its initial promise; nor did Almroth Wright. “Britain’s Pasteur” almost certainly saved hundreds of thousands of lives during the First World War; the British army that fought on the western front was given Wright’s typhoid inoculation, and only twelve hundred soldiers died of it, out of more than two million. He performed heroically during the war itself, demonstrating the limits of antiseptic pastes and liquids like Lister’s carbolic acid to treat battlefield wounds—carbolic acid didn’t just attack pathogens, but the immune system’s leukocytes as well—and the dangers of airtight bandages, which encouraged the growth of nasty, gangrene-causing bacteria like Clostridium perfringens that thrive in anaerobic environments. Nonetheless, he is now mostly remembered as Britain’s leading opponent of women’s suffrage. And, of course, as the inspiration for Colenso Ridgeon, Shaw’s dilemma-facing doctor.
This scants Wright’s real legacy: the Inoculation Department he founded and ran for decades at St. Mary’s, and that he made into an incubator for the next generation of antibacterial researchers. One of his subordinates there, who followed him to France, was Leonard Colebrook.
Another was a Scottish physician named Alexander Fleming.
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When Fleming joined Almroth Wright at the Inoculation Department in 1906, the then twenty-five-year-old physician was a promising if not yet accomplished researcher. He was also a sort of anti-Wright—where Wright was tall and physically imposing, Fleming was short and slender; Wright had a mustache that made walruses envious, Fleming was clean-shaven; and while Wright was never happier than when speaking publicly, Fleming was so self-effacing that students had to strain to hear his lectures. He had graduated with distinction both from the Royal Polytechnic Institution (now the University of Westminster) and from St. Mary’s Hospital Medical School, where he had trained as a surgeon before discovering a talent for experimental research. In 1909, Fleming designed a new test for syphilis that required less blood, and was more effective, than the eponymous diagnostic invented three years before by the German bacteriologist August Paul von Wassermann. The following year, Fleming began working with Leonard Colebrook to investigate the properties of Ehrlich’s magic bullets: Salvarsan and Neosalvarsan.
When the First World War broke out, Fleming and Colebrook accompanied Wright to France, where the core of St. Mary’s Inoculation Department joined the British military hospital at Boulogne-sur-Mer. That hospital, one of several built to accommodate the huge number of casualties from the first Battle of Ypres—the same battle in which Gerhard Domagk received his wound—would prove a remarkably productive research facility, even without considering the circumstances under which it had been established. While working at the hospital, the St. Mary’s team discovered that the standard of care for wounds—antiseptic ointments and airtight bandages—actually promoted infections rather than preventing them. As Fleming recognized, the cause was the variety of bacteria that grow even in the absence of oxygen,* particularly under the skin’s surface. And those bacteria were, literally, everywhere, even after exposure to powerful antiseptics. It took some experimental skill to demonstrate why.
As he described in a now-classic paper written for the Lancet, Fleming exposed two sets of glass tubes to a highly concentrated bacterial soup. One set was left whole, while the other was broken to create a ragged edge that would simulate a battlefield wound. After both were washed with antiseptics, the unbroken test tubes were completely disinfected, but the bacteria in the broken tube’s hidden recesses stubbornly reappeared, even after washing in carbolic acid. Fleming had demonstrated experimentally why even unbloodied uniforms from soldiers with supposedly disinfected wounds remained rife with pathogens. Dangerous ones. Fifteen percent of battlefield wounds contained staph, 30 percent tetanus, 40 percent strep . . . and 90 percent were infected with the gangrene-causing C. perfringens.
In November 1918, the First World War ended. For Fleming, now returned to St. Mary’s, the war against pathogenic bacteria was just getting started. He had acquired a more sophisticated understanding of the resourcefulness of his opponents, but was no closer to victory over them until, in 1922, he made his first improbably accidental discovery. As his laboratory assistant, V. D. Allison, later recalled, Fleming:
. . . was busy one evening cleaning up several Petri dishes which had been lying on the bench for perhaps ten days or a fortnight. As he took up one of the dishes in his hand, he looked at it for a long time, showed it to me, and said: “This is interesting.” . . . It was covered with large yellow colonies which appeared to me to be obvious contaminants. But the remarkable fact was that there was a wide area in which there were no organisms. . . . Fleming explained that this particular dish was one to which he had added a little of his own nasal mucus, when he had happened to have a cold. The mucus was in the middle of the zone containing no colony. The idea at once occurred to him that there must be something in the mucus that dissolved or killed the microbes. . . .
Fleming named the substance found in his mucus lysozyme: the first purely organic substance shown to have antibacterial properties. However, the unlikelihood of the discovery as reported seems almost too much to credit. First, Fleming later revealed that the mucus had accidentally dripped from his nose onto one of the Petri dishes. Not just dripped, but dripped onto the one Petri dish that had, somehow, picked up a bacterial contaminant from a fortuitously open window . . . and, even less probably, since most bacteria (and all important pathogens) are unaffected by lysozyme, the contaminant on the twice-lucky dish would have had to be one of the few bacteria with lysozyme sensitivity. This is the laboratory equivalent of buying winning lottery tickets twice on the same day.
However improbable its discovery, lysozyme was an interesting, but relatively inconsequential compound, one that Fleming accurately recognized as an enzyme: a large molecule tha
t increases the speed of organic chemical reactions. Some years later, it was identified as one of the components of the body’s innate immune system, whose activity works to damage bacterial cell walls. This is a nontrivial ability that offers some protection against infection, particularly in newborn children, but isn’t much use against most pathogens. The same can’t be said of Fleming’s next encounter with good fortune, which occurred some five years later.
Credit: Wellcome Library, London
Alexander Fleming, 1881–1955
The canonical story of the discovery of penicillin is eerily similar to the one describing the chance discovery of lysozyme. As Fleming later recalled, he had sloppily left Petri dishes containing staph cultures unattended on a bench in his St. Mary’s lab when he departed for vacation in August 1928. When he returned, on September 3, he found that one of the Petri dishes had been contaminated, again via a conveniently open window, this time by a fungus. The evidence was even more startling than five years earlier: Around the fungal contamination was a ring in which all the staphylococci had disappeared. Something had killed them.
For weeks, Fleming worked to cultivate the fungus, Penicillium notatum, technically a mold (molds—in Britain, “moulds”—are fungi that take the form of tiny multicellular filaments, which gives them their characteristically fuzzy appearance; unicellular fungi are yeasts). The mold was producing some substance that was deadly to the staph bacteria, a substance that Fleming first named “penicillin” in March 1929 in an article entitled “On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to Their Use in the Isolation of B. Influenzae.”
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