This is especially true for the tetracyclines. Low doses of Aureomycin and Terramycin and all the other antibiotics related to them actually increase the virulence of large numbers of pathogens. Subtherapeutic doses of tetracycline help bacteria to form what is known as the type III secretion system, which is one of the key elements of any pathogen’s arsenal: a tiny hypodermic needle that Gram-negative bacteria—salmonella, chlamydia, even the organism responsible for bubonic plague—use to inject themselves into animals cells.
Which is one reason why feeding subtherapeutic doses of antibiotics to uncounted millions of pigs, cows, and chickens seems to have been a riskier than optimal strategy.* It might have been designed to select resistant organisms, killing only the “weakest” bacteria—that is, those with the least resistance to the various antibacterial actions—and allowing the stronger to survive. Because so many of the bacteria exposed to low doses of antibiotics had a hormetic reaction to them, the surviving bacteria frequently acquired an even wider arsenal of pathogenic weapons. At the dosages used to promote growth in domestic animals, tetracycline doesn’t even slow down an organism like Pseudomonas aeruginosa, the bacterium responsible for dozens of opportunistic infections, from pneumonia to septic shock. It strengthens it.
In the early 1950s, however, this was still a problem beyond the time horizon of the pharmaceutical companies, to say nothing of physicians, patients, and regulatory agencies that, if they cared about antibiotics in the food supply at all, were happy to see increased beef and pork production. Antibiotics, particularly broad-spectrum antibiotics, were regarded as an unmixed blessing, the final triumph of medicine over infectious disease: a miracle, one that Americans and Europeans were starting to take for granted.
A society that comes to expect miracles will, sooner or later, have their expectations disappointed.
EIGHT
“The Little Stranger”
After Selman Waksman and Albert Schatz’s discovery, every pharmaceutical company on the planet began obsessively collecting dirt from as many exotic locations as possible in order to improve the odds of finding the next wonder drug in situ. The method was replicated again and again, because it worked.
The organism that produced the crude exudate that would become the world’s next great antibiotic was discovered by Abelardo Aguilar, a Filipino physician employed by Eli Lilly, who found a promising soil sample in the country’s Iloilo province and, in 1949, sent it to James McGuire at Eli Lilly’s Indianapolis headquarters for testing. The sample contained yet another of the ridiculously fecund Streptomyces, this time S. erythreus: the source for erythromycin, the first of the macrolide antibiotics, compounds that were effective against the same Gram-positive pathogens as penicillin, though via a different mechanism: The macrolides act by inhibiting the way the pathogens make critical proteins, rather than by corroding their cell walls.
Lilly was, compared to upstarts like Pfizer and Merck, very much an old-line American drug company. The firm had been founded in 1876 by Colonel Eli Lilly as “the only House in the West devoted exclusively to the Manufacture and Sale of PHARMACEUTICAL GOODS,” which, at the time, largely consisted of botanicals and herbals containing components with memorable names like Bear’s Food, Scullcup, and Wormseed. His grandson, also named Eli Lilly, graduated from the Philadelphia College of Pharmacy in 1907 (the same year Paul Ehrlich first described a drug that would attack disease-causing microbes without killing their hosts as a “magic bullet”) and joined the company as the de facto director of production shortly thereafter. The younger Lilly was, in some ways, a midwestern version of George Merck: a disciplined and successful twentieth-century industrialist whose enthusiasm for his corporation’s larger mission seems to have been as uncomplicated, sincere, and sentimental as the poetry of his fellow Hoosier James Whitcomb Riley. During the Second World War, when the company was furiously producing plasma for American troops overseas, he famously observed that he “didn’t think it was the right thing for anybody to make any profit on blood which has been donated.”
It has been easy for Lilly’s biographers to emphasize his wide though wonky interests. An early enthusiast for the time-motion studies of Frederick Winslow Taylor, Lilly was also, in no particular order, an amateur archaeologist with a special interest in the Native American cultures of his much-loved home state of Indiana; a sophisticated art collector, largely of Chinese paintings and pottery; a compulsive writer of childish rhymes; a devotee of uplifting self-improvement manuals and the music of Stephen Foster; and, for decades, the patron of choice for leaders of now-forgotten academic fads.* He was also, during his lifetime, one of the half dozen most generous American philanthropists. If he did nothing else than initiate a meeting with Frederick Banting, J. J. R. Macleod, and Charles Best at the University of Toronto in 1922, his legacy would be secure. Lilly persuaded them to join in what was then a groundbreaking partnership in developing their discovery—insulin—into a commercial product, which the company launched as Illetin in 1923. For doing well by doing good, it’s hard to top; as late as 1975, Eli Lilly still supplied the lifesaving compound to three-quarters of the entire American market.
Insulin was scarcely Lilly’s only great innovation prior to the 1950s. Through the 1940s, the company’s labs produced the sedative Tuinal and Merthiolate, a widely used antiseptic. Sales rose from $13 million in 1932 to $115 million in 1948 (a year in which Eli Lilly thought the profits—21.7 percent—were “unreasonably high”). But while the company was part of the penicillin consortium, and was, for a time, the number one distributor selling Merck’s version of streptomycin, they were not one of the major players in the first wave of the antibiotic revolution—not until Abelardo Aguilar’s samples arrived in Indianapolis.
Three years later, McGuire applied for a patent on the new drug, which he named erythromycin, a “novel compound having antibiotic properties.” It would take decades before the compound could be successfully synthesized; Robert Burns Woodward (who would be credited, posthumously, with solving the problem) wrote in 1956, “Erythromycin, with all our advantages, looks at present quite hopelessly complex,” but that did nothing to dissuade Lilly from producing it using the tried-and-true fermentation method. In 1953, Lilly started selling the drug under the name Ilotycin.
Erythromycin was, and would remain, a powerful weapon in the battle against infectious disease. But narrow-spectrum antibiotics like Ilotycin were never going to attract the level of enthusiasm of the new broad-spectrum drugs like the tetracyclines. Broad-spectrum antibiotics accounted for large percentages—as much as half—of the profits of Pfizer, Abbott, Bristol Laboratories, Squibb, and Upjohn. Those five companies, all of whom were selling versions of tetracycline, were splitting about two-thirds of the total market for broad-spectrum drugs.
The other third? In early 1950, a few months before Pfizer’s John McKeen joined with Arthur Sackler to transform drug advertising forever, McKeen offered the marketing rights for the oxytetracycline compound to one of his competitors. Their president, however, turned him down, believing that Terramycin was a direct competitor to his own blockbuster broad-spectrum antibiotic. The drug was Chloromycetin, and the company Parke-Davis.
Parke-Davis was then one of America’s oldest and largest manufacturers of ethical drugs, compounds that were subject to patent—and, therefore, confusingly, the opposite of “patent medicines”—clearly labeled, and prescribed by physicians. The company’s origins date back to 1866, when Hervey Coke Parke, a onetime copper miner and hardware store owner, joined the Detroit drug business of Dr. Samuel Pearce Duffield. Duffield, like New York’s Edward R. Squibb, had started a business to serve the needs of the Grand Army of the Republic during the Civil War: distilling alcohol and selling “ether, sweet spirits of nitre [ethyl nitrate, in a highly alcoholic mixture; the spirits were used to treat colds and flu], liquid ammonium [sic], Hoffman’s [sic] anodyne [ether and alcohol, used as a painkiller], mercurial ointment, etc.”
In 1867, a twenty-two-year-old salesman named George Solomon Davis became the firm’s third partner; and, when Duffield retired in 1871, the company was incorporated as Parke-Davis and Company. Parke was its first president; Davis its general manager.
Almost immediately, Parke-Davis established a reputation for seeking out medicines in exotic corners of the globe. In 1871 alone, the company financed expeditions to Central and South America, Mexico, the Pacific Northwest, and the Fiji islands. In January 1885, George Davis read Sigmund Freud’s infamous article, “Über Coca,” in which the young Viennese neurologist (not yet the father of psychoanalysis) wrote:
The psychic effect of cocaïnum muriaticum in doses of 0.05–0.10g consists of exhilaration and lasting euphoria, which does not differ in any way from the normal euphoria of a healthy person. . . . One is simply normal, and soon finds it difficult to believe that one is under the influence of any drug at all.
Davis immediately dispatched Henry Rusby, a doctor and self-described “botanist and pharmacognosist,” to South America to make “a critical study of the different varieties of coca.”
Rusby’s expedition, “involving four thousand miles of travel by canoe and raft on the Madeira and Amazon rivers, and occupying eleven months of suffering and danger escaping narrowly from death,” became part of the company’s founding myth, and the beginning of its prosperity. Shortly after his return, the company was using cocaine in dozens of different Parke-Davis products, including coca-leaf cigarettes, wine of coca, and cocaine inhalants. (Davis even hired Freud himself to perform a comparison of Parke-Davis’s cocaine products against Merck’s.)
Cocaine made the company, but wasn’t its last success story. Within twenty years, it had introduced fifty new botanically based drugs to the (still very informal) United States Pharmacopeia. One of them, Damiana et Phosphorus cum Nux—damiana is a psychoactive shrub that grows wild in Texas and Mexico; nux is nux vomica, or strychnine—was guaranteed to “revive sexual existence.” Others, marketed as “Duffield’s Concentrated Medicinal Fluid Extracts,” included ingredients like aconite, belladonna, ergot (the cause of St. Anthony’s Fire), arsenic, and mercury. All were extremely pure—the firm’s motto was Medicamenta Vera: “True Medicines”—but are also reminders of the danger in believing “natural” equals “safe.” Virtually every page in the catalog of Parke-Davis medications included a compound as hazardous as dynamite, though far less useful.
By the early twentieth century, the company had expanded into areas slightly less dependent on Indiana Jones–like adventuring. In the late 1890s, they were selling their version of Emil Behring’s diphtheria antiserum; in 1900, a Parke-Davis chemist, the Japanese-born, Glasgow-educated Jokichi Takamine, isolated adrenaline (also known as epinephrine), which the company marketed as Adrenalin, a drug whose ability to constrict blood vessels made it invaluable to surgeons, especially eye surgeons. The company expanded nationally and internationally, opening offices in Canada, Britain, Australia, India, and, in 1902, opened the country’s first full-scale pharmaceutical research laboratory, blocks from their Detroit headquarters. In 1938, Parke-Davis introduced Dilantin, the first reliable treatment for epilepsy; in 1946, Benadryl, the first effective antihistamine, which had been developed by a onetime University of Cincinnati chemist named George Rieveschl, who left academia for a research position at Parke-Davis.
Davis and Parke’s successors never lost a taste for treasure hunting, which might explain why they were uninterested in Pfizer’s offer. They had a broad-spectrum antibiotic of their own.
The development of Parke-Davis’s signature antibiotic began at roughly the same moment in time that the Office of Scientific Research and Development was assembling the participants in the penicillin project. In July 1943, Oliver Kamm, Parke-Davis’s director of research, met Paul Burkholder, the Eaton professor of botany at Yale. Six months later, Parke-Davis agreed to fund his research.
It was only a little more than a year before the company’s investment in Burkholder—and its long-standing presence in South America—paid off. In April 1945, a month before the surrender of Germany, Derald George Langham,* a plant geneticist simultaneously teaching at the University of Caracas and working as a Parke-Davis consultant, sent Burkholder a crate full of bottles containing compost he had collected from the farm of an émigré Basque farmer named Don Juan Equiram. Hundreds of different soil-dwelling bacteria were isolated from the sample. Most of them were familiar, as was true, too, of the more than seven thousand samples Burkholder received in a single year. Culture A65, however, was different: an entirely new species, a cousin to Waksman’s actinomycetes. Burkholder named it Streptomyces venezuelae and proceeded to subject it to more or less the same tests that Waksman and Schatz had performed on their soil dwellers: samples of S. venezuelae were placed in vertical strips on an agar-containing Petri dish, while colonies of pathogenic bacteria were aligned horizontally. From the warp and weft, it was hoped, a new antibiotic-producing organism would be woven.
Burkholder sent a colony of S. venezuelae to John Ehrlich at Parke-Davis.
By the time Ehrlich joined the company in December 1944, he had already collected degrees in phytopathology, mycology, and forest pathology; had worked for the Bartlett Tree Expert Company as an arborist; and served as deputy director of the penicillin program at the University of Minnesota, where he had led the team irradiating variants of the Penicillium mold. At Parke-Davis, he had recruited the company’s entire sales force as field researchers, issuing them plastic bags in which they were told to collect soil samples.* Thousands came in, from golf courses, flower gardens, and riverbeds, but until Burkholder’s package arrived, none had yielded anything particularly interesting.
Culture A65 was far more than interesting. Quentin Bartz, one of the company’s research chemists, isolated the active ingredient using a proprietary technique developed at Parke-Davis that could rapidly reduce thousands of promising molecules to a few dozen. Bartz mixed cultures of A65 and water with fourteen different solvents, each at different levels of acidity. He then removed the water and solvent, filtered what was left (which told him the size of the molecule), and checked whether it adhered to a specific substance (which told him its likely structure). In March 1946, he had a crystalline substance that was effective against not just Gram-positive pathogens, but Gram-negative pathogens as well. It was well tolerated, highly potent against pathogens that were unaffected by either penicillin or streptomycin, and, as an unexpected bonus, could be taken orally, rather than by injection. The chemists at Parke-Davis gave it a nickname: “the Little Stranger.”
By February 1947, they had even better news. Chemist Mildred Rebstock had derived the structure of the A65 molecule, whose key component was a ring of the organic compound nitrobenzene. Nitrobenzene had been used for decades as a precursor to the aniline dyes that had been so important to the original sulfanilamides like Prontosil. And nitrobenzene wasn’t just familiar; it was simple. Parke-Davis had found a molecule that was far less structurally complex than penicillin, or streptomycin, or erythromycin. This suggested that, unlike its predecessors (or its immediate successor, chlortetracycline), it had the potential to be synthesized rather than grown in fermentation tanks. If so, it could be produced at considerably less expense and, more important, far greater consistency. By November, Rebstock delivered a completely synthetic and active version of the molecule, which was generically known as chloramphenicol. The company named it Chloromycetin.
Each of the golden age antibiotics, from their introduction to today, is most closely associated from its moment of discovery with a hitherto untreatable disease. As penicillin performed its first miracles on septicemia, and streptomycin was the long-awaited cure for tuberculosis, Chloromycetin (or chloramphenicol) was greeted enthusiastically mostly because of its activity against insect-borne bacterial diseases, particularly typhus.
Epidemic typhus is a most adept and subtle killer. Victims unlucky enough
to encounter a louse carrying a colony of the Gram-negative bacteria known as Rickettsia prowazekii* typically infect themselves: The lice carry bacteria in their digestive systems and excrete them when they defecate. Humans scratch the lice bites, thus sneaking the pathogen-carrying feces past their skin and into their bloodstreams. The result is the appearance of flu-like symptoms within days: fevers, chills, and aches. A few days later, a rash appears on the victim’s torso and rapidly spreads to arms and legs. Then, if the immune system fails to destroy it, the disease progresses to acute meningoencephalitis: an inflammation that simultaneously attacks both the membranes surrounding the brain and spinal cord, and the brain itself, causing delirium and light sensitivity, eventually leading to coma. If untreated, typhus kills between 10 and 60 percent of those infected.
Typhus has been a scourge of humanity since at least the fifteenth century, and very likely for many centuries before. Epidemics were common throughout early modern Europe, especially in conditions where large numbers of susceptible hosts were placed in the path of lice, such as prisons and among armies on campaign.* During the Thirty Years’ War, typhus killed as many as one German in ten. A little less than two centuries later, it killed more soldiers in Napoleon’s Grande Armée during the retreat from Moscow than the Russian army. A century after that, a typhus epidemic in the new Soviet Union produced more than twenty million cases, and at least two million fatalities.
The U.S. Army had a long history of concern about the impact of epidemic typhus. The Army Medical Corps dusted more than a million Neapolitan civilians with lice-killing powder enriched with DDT in 1943 out of fear of a typhus outbreak, and the fear didn’t vanish at the end of the war. So when the army learned that Parke-Davis had a promising rickettsial antibiotic under development, they were eager to put it through its paces. From late 1946 to early 1947, Dr. Joseph Smadel of the Department of Virus and Rickettsial Diseases at Walter Reed Army Hospital ran A65 through a series of animal experiments, followed by clinical trials. In December 1947, he and two other Walter Reed physicians dosed themselves over a ten-day period with pills of the newly named Chloromycetin in order to discover whether the drug was excreted safely and completely, and more to the point, whether a stable concentration could be maintained in the body. Fortunately for Parke-Davis (and even more so for the physicians themselves), the drug passed both tests with flying colors.
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