Miracle Cure

by William Rosen

  Pure penicillin, they quickly learned, was benign. The same separation process that Chain and Abraham were using to decipher its structure could also purify it sufficiently, using a more stringent method of chromatography to eliminate the poisons hitchhiking alongside. Mrs. Akers reacted to a second round of injections with neither fever nor trembling.

  Safety, though, wasn’t the same thing as therapeutic value. For the next test, the Dunn team needed someone suffering not from cancer, but infection.

  They didn’t need to look far. The previous September, an Oxford policeman named Albert Alexander had been working in his rose garden when he scratched his face on a thorn. The scratch became infected, first just at the site of the injury, but soon the bacteria that had been so abundant in the soil around the Alexander garden—streptococci and staphylococci, at a bare minimum—began to multiply and deposit their own toxins in the victim’s body. By October, his scalp had become obviously infected, and Mr. Alexander was admitted to the Radcliffe Infirmary, where, despite the use of sulfanilamides, the infection spread to his lungs. By February, he had abscesses growing in his torso, on his arms, and in his left eye, which he would soon thereafter lose. When Norman Heatley saw him in early February, he noted in his diary that the constable “was oozing pus everywhere.”

  On February 12, 1941, Mr. Alexander was given an intravenous injection of 200 milligrams of penicillin—still, though his physicians wouldn’t know this until much later, less than 5 percent pure—and a follow-up intravenous drip of 100 milligrams every three hours. After a single day, the eight injections had caused a miraculous improvement. Alexander’s fever had vanished, he was no longer discharging pus, his face was no longer swollen, and he was able to eat.

  The problem was keeping the penicillin flowing at a rate sufficient to maintain the therapeutic effect; it took Heatley’s machines days to produce the amount of penicillin Alexander needed every hour. The Dunn team had learned during the mice experiments that penicillin was quickly excreted by the kidneys, while still retaining its antibacterial properties, so the doctors set up a procedure for collecting Alexander’s urine after each dose, then carrying it via bicycle from the Radcliffe Infirmary to the Dunn laboratory (a mile and a half each way) in order to extract more of the precious stuff.

  Alexander wasn’t the only one who needed it. Another patient, a fifteen-year-old boy named Arthur Jones who had contracted a life-threatening infection after a hip operation, was getting a similar course of treatment. The Dunn physicians hadn’t known how effective penicillin would be, nor did they have a clue how much was required for a therapeutic dose. By the end of February, the supply of penicillin, even the recycled variety, was exhausted. Arthur Jones survived. Albert Alexander, however, died on March 15, 1941.

  The stuff worked—when, that is, there was enough of it. However, no British university lab was equipped to produce the kilogram of pure penicillin Florey estimated would be needed for the next round of clinical trials. Neither was any chemical firm in the Commonwealth. France was occupied, Germany, Japan, and Italy enemies. Only one place was left.

  After the fall of the Soviet Union, it became something of a cliché to describe the United States as the “world’s lone superpower.” In economic terms, it had already earned the title by 1912. The year that Paul Ehrlich discovered Salvarsan, Germany’s gross domestic product was a bit more than $227 billion, just ahead of the United Kingdom’s $216 billion. That year, the United States economy was larger than both of them combined: $498 billion. By 1940, the GDP of the just-out-of-the-Great-Depression United States was closing in on a trillion dollars a year.

  To be sure, American economic dominance wasn’t uniform. Though U.S. steelmakers rolled out 43 million metric tons in 1940, nearly a third of the world’s total (Germany’s 22 million metric tons earned it only a distant second place), American chemical and pharmaceutical firms were minnows next to I. G. Farben’s whale. And while researchers in U.S. universities and industries were well on the way to the dominant position they would assume after the Second World War, Germany’s scientific reputation, particularly in physics and chemistry, was still dramatically higher. Though the Nobel Prize is a notoriously imperfect yardstick of scientific achievement, it isn’t a coincidence that by 1940 Germany had won thirty-three of the science Nobels. Americans had won twelve . . . three of them, in 1934, for the same discovery: pernicious anemia.

  In one area, however, the United States was unmatched: Both the sophistication and productivity of America’s agricultural sector was like nothing else in the world. Farms, forests, and ranches still made up nearly 20 percent of the largest national economy in the world.

  Which is why, when Warren Weaver of the Rockefeller Foundation visited Oxford on April 14, Florey proposed a visit to the United States, explicitly to find “some American mold or yeast raiser who would undertake a large-scale production of this material for a test, say, 10,000 gallons. . . .” Weaver was convinced almost immediately, and authorized $6,000 in expenses for the trip. Florey needed only one authorization: to leave England. In late April, he wrote to Edward Mellanby asking for help in getting the required wartime exit permits for himself and Norman Heatley, Florey’s choice for an expedition devoted to cultivating penicillin in large quantities. A few days later he received this reply: “I have come to the conclusion that the only way that this most important matter can be pursued is for you and Heatley to go to the United States of America for three months.”

  On June 27, 1941, Florey and Heatley left Oxford by car for a trip to a top-secret airfield, where they boarded a Dutch passenger plane and flew to Lisbon, landing seven hours later. There they met representatives of the Rockefeller Foundation, and three days later continued their journey aboard the Pan American Airways’s Dixie Clipper. The flying boat discharged its passengers at the Marine Air Terminal of La Guardia Field on the afternoon of July 2. Within hours, Florey was sitting at the head of a conference table in the Rockefeller Foundation offices in Manhattan, explaining the significance of the penicillin experiments to Alan Gregg, the head of the foundation’s Medical Science Division. To be fair, American awareness of penicillin had preceded Florey and Heatley. The Lancet article had prompted a team at Columbia University College of Physicians and Surgeons to request samples of the compound from Chain and to set up a production line in Manhattan similar to Heatley’s in Oxford. By October 1940, in fact, the Columbia team had produced enough penicillin—still the crude and impure filtrate—to inject two humans with it, even before the Dunn team had done the same with Mrs. Akers. A soil scientist at Rutgers College in New Jersey, Selman Abraham Waksman, started some investigations into P. notatum,* as did researchers at the Mayo Clinic in Rochester, Minnesota.

  Nor were America’s small but energetic pharmaceutical firms slow to show interest. Decades before, Parke-Davis had agreed to a cooperative relationship with St. Mary’s Inoculation Department; after reading the Lancet article, Parke-Davis executives asked Almroth Wright whether he or Fleming could help to secure a sample of penicillin from Oxford. (This may explain Fleming’s surprise visit to the Dunn School the preceding September.) Pfizer, a chemical company headquartered in the Williamsburg section of Brooklyn, that made most of its income from producing the preservative and flavoring compound citric acid, also had a small interest in medicines. So did E. R. Squibb, another Brooklyn-based company and a major producer of surgical drugs like ether. Even more interested was the American branch of the German drug company Merck, which had begun cultivation of P. notatum as early as January 1940, and whose president, George Merck, was so well known to Alan Gregg that the Rockefeller Foundation executive proposed a meeting with Howard Florey.

  Florey was interested, but he had more immediate business. In July of the preceding year, with the Battle of Britain raging, the Floreys had sent their two children, Paquita and Charles, to New Haven, Connecticut; Howard’s onetime Rhodes Scholar companion John Fulton, now the Sterling
Professor of Physiology at Yale, had agreed to take them in for the duration. On July 3, Florey headed to Connecticut, intending to surprise his children* and to meet with some like-minded scientists. Fulton was able to perform a dozen different introductions, but none were more significant than those he brokered between Florey and Ross Harrison, chair of the Executive Committee of the National Research Council, which had been responsible for applying “scientific methods in strengthening the national defense” since 1916. Harrison, in turn, arranged an introduction to Charles Thom, a mycologist in the Department of Agriculture’s Bureau of Plant Industry in Beltsville, Maryland, and the following week, Florey and Heatley headed for Washington to meet him.

  Thom already had a long-standing connection to the world of penicillin research. He was the scientist who had originally corrected Fleming’s misidentification of his penicillin-producing fungus—not P. rubrum, as Fleming originally had it, but P. notatum, using a sample sent to him by his old friend Harold Raistrick.* More important, though, than Thom’s previous achievements were his current interests and capabilities. Only a few months earlier, a number of his protégés had been relocated from their own labs in Arlington, Virginia—the War Department had taken the land for building what would become the Pentagon—to the Agriculture Department’s largest midwestern lab. As a direct result of their discussions with Thom, on July 12, Howard Florey and Norman Heatley boarded a train leaving Washington, DC’s Union Station bound for Chicago, where they would make a connection to the Peoria Rocket. Their final destination was the Department of Agriculture’s Northern Regional Research Laboratory, in Peoria, Illinois.

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  In July 1862, Abraham Lincoln signed the Morrill Act, establishing “at the Seat of Government of the United States, a Department of Agriculture.”* In late 1864, during his last address to Congress Lincoln said, “The Agricultural Department . . . is rapidly commending itself to the great and vital interest it was created to advance. It is precisely the people’s Department, in which they feel more directly concerned than in any other.”

  Eight decades later, the United States was a considerably less agrarian society, but the USDA was, if anything, even more important to its prosperity. In addition to its programs promoting American food production and providing credit to American farmers, it funded more than forty experimental stations, research centers where farmers, ranchers, and agronomists worked to improve existing agricultural products and practices and develop new ones; provided ongoing education in agronomy and animal husbandry through its cooperative extension programs; and was the primary enforcer of the provisions of the 1906 Pure Food and Drugs Act, including the penalties for misbranding medicine. Of more immediate relevance to Florey and Heatley, though, were the USDA’s four regional labs, the very top of the pyramid in agricultural research.

  The four labs—in addition to the Northern Regional Research Lab in Peoria, the USDA operated an eastern lab in Wyndmoor, Pennsylvania; a southern lab in New Orleans; and a western lab in Albany, California—were responsible over the years for literally thousands of innovations, patented and otherwise, from instant mashed potatoes to wrinkle-free cotton. It seems safe to say, though, that the regional labs’ finest hour can be dated from the arrival of Howard Florey and Norman Heatley on the Peoria Rocket on July 14, 1941.

  The Northern Lab looms deservedly large in any history of penicillin—in any history of medicine, really. It was where three of the most urgent objectives in transforming the Dunn discoveries from a laboratory process to an industrial one were achieved: first, the discovery and identification of the most productive strains of Penicillium mold; second, a protocol for accelerating the growth of penicillin-producing mold; and third, improvement of the fermentation technique by which the exudate appeared. In traditional agricultural terminology, they were looking for better seeds, better soil, and better cultivation and harvesting.

  Better seeds first. Even before Florey and Heatley arrived in July, the Northern Lab’s chief mycologist, Kenneth Raper, had sent messages to researchers all over the globe (even to the point of enlisting crews in the U.S. Army’s Air Transport Command) requesting that they collect samples of Penicillium mold and send them to Peoria. By early 1941, he had started testing dozens of different strains. The most significant, by far, was found by one of Raper’s lab technicians, a bacteriologist named Mary Hunt, who had been charged with the task of visiting Peoria’s markets in search of moldy fruit and vegetables. In 1943, she hit the jackpot: a cantaloupe infested with a mold so powerful that it would, by the end of the 1940s, be the ancestral source for virtually all of the world’s penicillin.

  At roughly the same time he sent Mary Hunt on her tour of Peoria’s fruit stands, Raper had charged another of his subordinates, a microbiologist and mycologist named Andrew Moyer, with finding a better soil: a superior growth medium for the fungus, one that improved the best speed that Heatley’s bedpans had been able to achieve using Czapek-Dox and brewer’s yeast. Serendipitously, he had access to an extremely promising replacement. The Northern Lab had been established explicitly to investigate “industrial uses for the surplus agricultural commodities.” In practice, this meant searching for some commercially valuable way of exploiting the waste products left after the American corn harvest—in 1940, more than 56 million metric tons, much of which was turned into corn flakes, animal feed, sweeteners, and a dozen other commodities. The most significant of these, corn steep liquor, was what was left behind after extracting cornstarch. In weeks, Moyer and Heatley, working together, discovered that corn steep liquor plus sugar increased penicillin production significantly. Actually, more than significantly—a thousandfold. This is not a misprint. Earlier that year, the Dunn team had defined what became known as the “Oxford unit,” the quantity of penicillin that, when dissolved in 1 cc of water, inhibited a standard measure of bacterial growth.* The new growth medium was able to improve production from 2 Oxford units per cc of broth to 2,000.

  Credit: Peoria Historical Society

  The Northern Lab team, including Andrew Moyer (left side, fifth from left) and Robert Coghill (back table, fourth from left)

  This left the harvesting problem: fermentation itself, which was a challenge not just of biology, but geometry. The metabolic process by which sugars are converted to acids, gases, and alcohol had many forms, as had been known even before Pasteur, but the Penicillium mold had, thus far, fermented only on the surface of a growth medium, usually agar (this is why flat Petri dishes were and remain so common in biology experiments). Since surface fermentation meant only two dimensions were available for the growth of the compound, expanding the harvestable quantities of the mold seemed to require very large surfaces—Heatley’s bedpans blown up to the size of basketball courts.

  It was Robert Coghill, the chief of the Fermentation Division at the Northern Lab, who first proposed using the same sort of deep fermentation used in brewing beer for growing penicillin.

  Deep fermentation wasn’t a completely novel idea. A German-speaking Czech chemist named Konrad Bernhauer had published dozens of papers on the subject from 1920 onward.* Even earlier, as far back as the First World War, Pfizer had been investigating deep (or, as it was then known, “submerged”) fermentation in order to improve yields of what would become their core product: citric acid, the age-old flavoring agent and preservative.

  The only way to produce citric acid had been extracting it from fruit, particularly lemons, until the German chemist Carl Wehmer had shown that it was produced by molds as well, specifically Penicillium. However, making citric acid by extracting it from a mold was just as likely to produce oxalic acid, which was both unwanted and dangerous. In 1917, Pfizer’s brilliant research chemist James Currie* discovered that Aspergillus niger was a factory for citric acid—feed it sugar, harvest the acid—and started the program the company christened SUCIAC, Sugar Under Conversion to Citric Acid. Enough citric acid, in fact, that, by 1929, Pfizer was selli
ng more than $4.5 million of it.

  Such fermentation was aerobic, with A. niger exposed to air using Heatley-like shallow trays. By 1931, though, Pfizer’s chemists had graduated, if that’s the right word, to production of citric acid in relatively small flasks, about 1 liter in volume, in which a powerful stirrer kept the fluid aerated, a process for which they applied for a patent.

  At the time Moyer and Coghill started their researches, the technique had been used only for citric acid. Why not penicillin? As Pasteur had been the first to notice, all forms of fermentation are largely similar. In theory, therefore, the same industrial processes used to manufacture citric acid—or, for that matter, beer—could be enlisted for the new miracle drug. The differences weren’t trivial: Beer and citric acid could be fermented in relatively unclean environments, but the air used by fungal cells to produce penicillin needed to be sterile in order to avoid introducing dangerous impurities; the temperature within the hypothetical vat needed to be kept constant; and the process required some way of keeping the whole mess mixed so that each liter had the same amount of growth medium and mold as every other. But they weren’t insuperable. As early as 1937, the USDA’s By-Products Lab at Ames, Iowa (a predecessor of the Northern Lab), had designed an aluminum rotary fermenter. By the fall of 1941, the Peoria team had a demonstration vat—a drum with a washing machine–like agitator, and an injector through which sterile air could be constantly introduced to the soupy contents. Rotary drums like it would be manufacturing penicillin in industrial quantities for the next five years.

  At the same time that the Peoria scientists and engineers were cultivating ever more powerful and pure strains of penicillin, the new drug’s potential was exceeding even the hopes of its most passionate advocates, particularly in Britain. Henry Dawson, at Columbia University College of Physicians and Surgeons, injected two patients with a crude filtrate of penicillin broth, though at such a low concentration that it was both safe and ineffective. Between June and August 1941, five more staph-infected patients in Britain—more volunteers from Oxford’s Radcliffe Infirmary—were treated with it; three of them were children, precisely because the quantity of the drug was so limited, and a child could be expected to respond to a lower dose. On August 16, the Lancet featured another article from the Dunn team that reported “that in all these cases a favourable therapeutic response was obtained . . . ,” though in one—the tragic case of four-and-a-half-year-old John Cox—the penicillin cured the staph infection that had caused septicemia in his sinus orbits, lungs, and liver, but could do nothing about the ruptured spinal aneurysm that killed him two weeks after he started antibiotic treatment.