Within days, the results were tallied. The control group of untreated mice had all died, as had six of the seven groups treated with the newly synthesized compounds. The four mice injected with Prontosil/Rubiazol were alive. So were the four given pure sulfanilamide. “From that moment on,” wrote Bovet, “the German chemists’ patents had no more value.”
And they knew it. At virtually the same moment that Bovet was testing his mice in Paris, in Elberfeld, Klarer and Mietzsch tested a compound—KL-821—that was nothing but sulfanilamide alone: no azo dye. It not only worked just as well as Prontosil, it was even more useful, treating staph infections as well as strep. The reason that Prontosil worked only in vivo and not in vitro—in a living animal and not a test tube—was finally clear: Living animals produced enzymes that separated the dye from sulfanilamide.
It was disappointing enough that all those experiments with different azo combinations had turned out poorly. The really bad news was this: Since a Viennese chemist named Paul Gelmo had identified sulfanilamide as part of his 1908 doctoral thesis and patented it in 1909, the substance was now in the public domain.
At Bayer, the news was devastating. No one yet knows how so many skilled researchers could fail so totally—the original documents remain sealed away—but a good guess is that Prontosil was a particularly acute example of the cognitive bias that psychologists call “functional fixedness” and civilians know as “if the only tool you have is a hammer, everything looks like a nail.” The large chemical industries had been built on dyes and wore blinders that shielded them from just about anything else. Which also explains why, even after Bayer knew that adding azo dyes to sulfanilamide did literally nothing to improve the drug’s antibacterial effectiveness, and that the active ingredient in the drug was freely available to anyone with the 1935 equivalent of a home chemistry set, they still persisted with the launch of Prontosil.
They tried to brand their product, so far as they could, selling something they called Prontosil Album (white Prontosil, also known as pure sulfa) alongside Prontosil classic for a year. It helped, a bit. Sales were strong and getting stronger when, in November 1936, the son of the president of the United States, Franklin Delano Roosevelt, Jr., contracted a vicious strep infection and, after weeks at death’s door, was miraculously cured by the still-experimental drug. The front-page headline for the December 17, 1936, edition of the New York Times read:
YOUNG ROOSEVELT SAVED BY NEW DRUG
DOCTOR USED PRONTYLIN ON STREPTOCOCCUS INFECTION OF THE THROAT CONDITION ONCE SERIOUS
But Youth, in Boston Hospital, Gains Steadily; Fiancée, Reassured, Leaves Bedside
This wasn’t all bad for Bayer. “Prontylin” was the trade name under which sulfanilamide was sold in the United States by the Winthrop Chemical Company, which was half owned by Bayer’s parent, I. G. Farben. It was even manufactured at the old Bayer factory in Rennselaer, New York, which had been seized during the First World War. But the combination of unprecedented American demand and a complete lack of patent protection had the predictable result. By the end of 1937, a hundred different companies were selling sulfanilamide under a hundred different names. And not just in the United States; a Japanese version was named Pratanol; a Dutch one, Streptopan. In Brazil it was being sold as Stopton, in Czechoslovakia as Supron. The French had five different versions; the British, more than thirty. Forty-six years later, the physician Lewis Thomas wrote, “I remember the astonishment when the first cases of pneumococcal and streptococcal septicemia were treated in Boston in 1937. . . . Here were moribund patients, who would surely have died without treatment, improving in their appearance within a matter of hours of being given the medicine and feeling entirely well within the next day or so. . . . Medicine was off and running.”
Off and running, though not always in a helpful direction. For the first time, though far from the last, a truly effective medicine was wildly overprescribed. Physicians used it for head colds. Expectant mothers were regularly given sulfa prophylactically, before they showed any signs of puerperal fever.
The immediate consequences of the sulfa craze were significant enough. The side effects of the drug, including nausea and painful crystals in the urinary tract, affected hundreds of thousands of patients who got no benefit in return. The first high-profile sulfa treatments are just as historically consequential, though, marking the moment in time when large numbers of patients first demanded a specific therapy from their physicians by name. It would be some time before it was accurate to refer to the sick as “consumers” of health care, but that’s how they—and what were not yet known as the “worried well,” patients with no need for doctoring, but a lot of demand for it—started to behave. Physicians, finally armed with a treatment that actually cured infectious disease, were only too happy to oblige.
Sequelae is the word physicians use to describe the chronic and persistent consequences that follow an acute episode: back pain after an automobile accident, for example. The long-term sequelae of the public embrace of sulfa include the belief that doctors ought to be able to cure just about anything. One result was that everything else they provided—typically comforting their patients with knowledge of the likely course of a disease or condition—started to be devalued by both doctors and patients. Antibiotics, and the transformation they ignited, professionalized health care in a way like nothing before or since. That professionalism was a huge benefit, but it wasn’t cost free.
Nor was sulfa itself. Among other things, the drug remained difficult to administer, since it wasn’t easily soluble in water, or really much of anything else. This limited its appeal to patients, particularly in the United States, who preferred to take their medicine orally. This problem, all by itself, led to the single largest scandal in the history of antibacterial drugs, as well as the birth of drug regulation in America.
When the sulfa craze began in 1937, laws protecting patients from the dangers of the new drugs weren’t unknown, but they might as well have been. Though the first code of ethics of the American Medical Association barred direct-to-consumer advertising of drugs from “ethical medical practice,” the first federal law to address the administration of powerful and dangerous compounds in service of medicine was the Biologics Control Act of 1902. It was followed by the Pure Food and Drugs Act of 1906, which set out penalties for adulterating or misbranding medicines. Those penalties were determined by the United States Department of Agriculture’s Bureau of Chemistry, headed from 1906 to 1913 by Harvey Washington Wiley, whose feelings about pharmaceutical regulation can be summed up by the title of a book he wrote in 1929: The History of a Crime Against the Food Law: The Amazing Story of the National Food and Drugs Law, Intended to Protect the Health of the People, Perverted to Protect Adulteration of Food and Drugs.
Even when Wiley wrote his “amazing story,” most of the drug business remained in patent medicines, a predictable consequence of a widespread American belief in self-medication (or “autotherapy”). The number of advertised compounds grew from about a thousand in 1858, generating about $3.5 million in annual sales, to twenty-eight thousand by 1905, with revenues of nearly $75 million. By 1912, that number had increased to more than $110 million. To call them fraudulent is to compliment them. Some of the most popular were targeted at the same market that would eventually turn Viagra into a multibillion-dollar business: “Persenico” promised to combat “low vitality . . . of sexual origin” while “Revivio” simply told men they could “improve your vigor.” Those that weren’t ineffective were frequently poisonous; “Gouraud’s Oriental Face Cream” contained possibly toxic levels of mercury. The most famous of all patent medicines wasn’t quite that dangerous. The recipe that Confederate army veteran John Pemberton concocted to wean himself from an addiction to the morphine he had been given after the Battle of Columbus, a mixture of alcohol, coca leaves, and kola nuts that was first sold as Pemberton’s French Wine Coca, and later, sans alcohol, as Coca-Cola, took the nation b
y storm beginning in 1886.
The standardization of “real medicines dates back as far as 1820, when one of Benjamin Rush’s former students, Jacob Bigelow, published the first edition of a catalog of more than two hundred drugs he entitled the United States Pharmacopeia.” Nonetheless, it took nearly a century before the 1906 Pure Food and Drugs Act established the USP as a national formulary standard and used it to require that drugs not be adulterated. It also set out punishments for misbranding, such as selling under a false name, or not identifying the presence of narcotics, like morphine, opium, cocaine, and heroin. The word “penalties” should be used advisedly, however, since they only called for confiscation of adulterated or misbranded drugs, not prosecution of dealers.* Moreover, because the original law focused exclusively on labeling, rather than safety, it was virtually useless. Robert N. Harper’s “Cuforhedake Brane-Fude” was marketed as an entirely safe “brain tonic” containing alcohol, caffeine . . . and acetanilide, a highly toxic analgesic that causes cyanosis. When the government, under Harvey Wiley, won the maximum penalty of $700, it represented a tiny fraction of the thousands the compound had earned.
And so it went. In 1911, the 1906 act was amended to allow a misbranding prosecution if the package included statements that were “false and fraudulent,” which created a loophole big enough to drive an entire industry through. Remedies that promised to cure everything from pneumonia to tuberculosis to cancer were protected so long as the manufacturer could claim that it believed the claims, and thus had no fraudulent intent.
Which was the state of play when Franklin Delano Roosevelt, Jr., became the poster boy for the new wonder drug, sulfa. Though his father’s New Dealers (primarily Walter G. Campbell, one of Wiley’s protégés, and the agricultural economist Rexford Tugwell) had been trying to expand the reach of the Pure Food and Drugs Act ever since they took office in 1933, they failed each and every time.
They probably would have gone on failing, if sulfa had been an easily soluble powder.
The S. E. Massengill Company of Bristol, Tennessee, was one of the dozens of American patent drug manufacturers eager to get on board the sulfanilamide gravy train. The sales staff at Massengill, and Samuel Evans Massengill himself, believed that the most successful version of the new drug would resemble cough syrup: a sweetened liquid. Harold Watkins, the company’s chief chemist, tried a number of solvents before he happened on a solution of 58 pounds of sulfa, along with raspberry flavoring and saccharine, dissolved in 60 gallons of diethylene glycol, a component of resins, brake fluid, and coolants whose properties in living animals—dizziness, intoxication, and nausea an hour after ingestion; within days, an elevated heart rate, muscle spasms, and acute kidney failure—were evidently unknown to him. In October 1937, Massengill’s Elixir Sulfanilamide went on sale.
On October 11, 1937, the president of the Tulsa County Medical Society sent a telegram to the American Medical Association’s chemical lab, alerting them to six deaths that occurred shortly after administration of the elixir. Eight days later, the Washington Post’s headline read “VENEREAL DISEASE ‘CURE’ KILLS 8 OUT OF 10 PATIENTS IN OKLAHOMA.” On October 25, the New York Times ran a story about the “nationwide race with death.”
The response from Washington was uncharacteristically decisive. The Food and Drug Administration put its entire field force—239 inspectors—to work tracking down every drop of Massengill’s initial shipment: 240 gallons of the diethylene glycol–laced sulfa syrup. They secured 234 gallons and 1 pint. It is presumed that most of the remaining 57⁄8 gallons never made it down the throats of anyone, since fewer than a hundred people were killed.*
Massengill, despite protesting its innocence (and blaming sulfa, rather than diethylene glycol, for the deaths), was brought to trial, though not, as one might expect, for poisoning its customers. In doing so, it hadn’t actually broken any law. Instead, it was prosecuted under the only permissible statute: for mislabeling, since they had marketed the deadly syrup as an “elixir” and elixirs were required to contain alcohol. In fact, the existing law only allowed FDA agents to seize bottles that had been shipped across state lines, and whose seals had not been broken. Massengill eventually pleaded guilty to 174 counts of mislabeling, fined $150 each plus costs, for a total of $26,100.
Nonetheless, the scandal had at least one salutary effect: The 1938 Federal Food, Drug, and Cosmetic Act was signed into law by President Roosevelt on June 25, 1938. It was, in many ways, a dramatic improvement over existing law. Section 502, for example, extended the “misbranding” violation to include “adequate warnings for use in those pathological conditions or by children where its use may be dangerous to health, or against unsafe dosage or methods or duration of administration . . .” and required listing of all ingredients, not simply the “active” ones (diethylene glycol, after all, hadn’t been the active ingredient in the Massengill syrup). Secret remedies were now prohibited. Interstate shipment was forbidden without approval from the secretary of agriculture. The act’s final clause created new regulations for a new category: “New Drugs.” Henceforth, manufacturers needed governmental permission to market any drug not already available.
It’s hard to know whether in 1938 anyone knew just how many “new drugs” would appear over the next ten, twenty, and fifty years. For the immediate future, however, sulfa remained king. In 1939, a variant known as sulfapyridine, developed in Great Britain by the firm May & Baker, a subsidiary of Rhône-Poulenc, was used to quell a meningitis outbreak in Sudan—significantly, one caused by meningococcus, not streptococci. Sulfapyridine was also far more effective against pneumococcal pneumonia than its predecessors like Prontosil, reducing mortality in one test from 27 percent to 8 percent. Popularly known as M&B 693, it was approved for sale by prescription in the United States in March 1939 (and would famously cure Winston Churchill from a strep infection in December 1943).
Also in 1939, Gerhard Domagk was awarded the Nobel Prize in Physiology or Medicine. He was forbidden to appear in Stockholm to accept the award by his government, then only months from plunging Europe into a war more impactful than the First World War of 1914–1918, but offended at the Peace Prize given to the German pacifist Carl von Ossietzky in 1936 for exposing German rearmament. Domagk was even briefly jailed for being “too polite to the Swedes” in his response to the prize.*
By then, the British chemists Donald Woods and Paul Fildes had discovered the mechanism by which sulfa drugs do their magic. Sulfa inhibits an enzyme essential for the production of the B vitamin required for folate production in bacteria. Sulfanilamide essentially tricks bacterial enzymes into latching onto it, rather than the correct compound, para-aminobenzoic acid, or PABA (which is why sulfa remained limited in its effectiveness; not all bacteria use PABA).
Despite those limits, sulfa was used throughout the Second World War to treat everything from wound sepsis to gonorrhea. The first wonder drug, however, was no more immune to the resourcefulness of bacteria than any of its successors.
The phenomenon known as acquired antibiotic resistance is no simple thing, and is imperfectly understood even today.* Bacteria are exquisitely sensitive to environmental change; the single-celled organisms are quick studies of evolutionary innovation, able to acquire new genetic blueprints for just about every imaginable function from other bacteria, and even from free-floating viruses. Moreover, they reproduce so quickly—some bacteria have generations only twenty minutes long—that a useful bit of DNA spreads extremely rapidly. Under strong selection pressure, such as the presence of a powerful bactericide like the sulfanilamides, a new gene that codes for a folate-producing enzyme unaffected by sulfa appears seemingly overnight. Which is why, given its widespread use in wartime, the phenomenon of sulfa resistance appeared quickly. The first soldiers treated for gonorrhea with sulfa experienced a 90 percent cure rate in the late 1930s. By 1942, the rate was 75 percent and falling fast.
By then, however, Domagk’s miracle was abo
ut to be preempted by a new weapon against bacterial disease; not just a single magic bullet, but an entire arsenal.
THREE
“Play with Microbes”
The consulting room of Dr. Colenso Ridgeon, KBE, was, in the spring of 1903, located on the second floor of an unremarkable building in London’s Marylebone neighborhood, indistinguishable from a hundred other Victorian apartments. In addition to an overstuffed couch and chairs, the green-wallpapered room featured a marble-topped console table with gilt legs ending in the claws of a sphinx; a mirror so covered with paintings of palms, lilies, and other plants that it was no longer useful as a reflecting surface; and a writing table, on which a microscope, test tubes, and a small alcohol stove fought for space with piles of papers and journals. Like the doctor himself, the room made some concession to modernity—it had replaced gas lighting with electricity—but otherwise looked, in the first years of the twentieth century, almost exactly as it had in the middle of the nineteenth: a very model of bourgeois solidity.
If Dr. Ridgeon’s place of work was conservative, the work he did there was positively revolutionary. So revolutionary, in fact, that in June 1903 he received a knighthood for it. After thirty years as a practicing physician, Dr. Ridgeon had discovered a cure for tuberculosis, an historic achievement if anything was.
You will, however, search in vain through any history of medicine looking for him, or his discovery. Colenso Ridgeon was and remains a creature of the imagination whose genius (and taste in furniture) was described, and his knighthood awarded, in the first act of a 1906 play entitled The Doctor’s Dilemma, written by the Irish iconoclast George Bernard Shaw.
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