Miracle Cure

by William Rosen

  * In 1928, Poulenc would merge with Société Chimique des Usines du Rhône—roughly, Rhône Chemical Factory Inc.—to form Rhône-Poulenc.

  * In fact, in 1911 the U.S. Supreme Court decided in United States v. Johnson (221 US 488) that a concoction sold as a cancer remedy wasn’t, by the terms of the act, misleading, since it didn’t misrepresent the “strength, quality, or purity” of the compound. Misleading therapeutic claims weren’t the government’s business, since any claim of therapeutic efficacy, in those days, was protected opinion.

  * The actual provable count was seventy-three, but no one seriously believes that all were accounted for. One additional victim was Harold Watkins, who committed suicide while awaiting trial.

  * In 1947, he finally collected his medal, though not, by Nobel rules, his cash award. In his Nobel Lecture, on “Further Progress in Chemotherapy of Bacterial Infections,” he observed: “The problem . . . could be solved neither by the experimental medical research worker nor by the chemist alone, but only by the two together working in very close cooperation over many years.”

  * Antibiotic resistance refers specifically to pathogenic bacteria. However, the same phenomenon can, and does, occur in fungi, viruses, and multicellular parasites.

  * Phagocyte was a then-current term for the white blood cells known today as macrophages, discovered in 1884 by the Russian biologist Ilya Mechnikov.

  * In a moderately perverse bit of medical history, the family of bacteria that causes typhoid fever—a disease that affects only humans—is named for Daniel Elmer Salmon, a doctor of veterinary medicine, whose assistant first isolated the bacterium in 1885, and named it for his boss.

  * In 1912, he wrote a classic book on laboratory methods entitled Technique of the Teat and Capillary Glass Tube, a title that is responsible for a large but unknown number of cases of uncontrollable giggles among generations of medical students.

  * It wasn’t that the required mathematical tools hadn’t yet been invented. The German mathematician Carl Friedrich Gauss had taught the world how to minimize measurement errors in the first decade of the nineteenth century.

  * The original conflict about the nature of disease, between Pasteur and his friend and fellow physiologist Claude Bernard, has been co-opted by twenty-first-century advocates of alternative medicine; some use it to attack the germ theory itself.

  * The Times continued: “The opsonic theory explains for the first time the undoubted value of blisters and poultices and the old-time counter-irritants. Take the case of an open wound. If the blood is poor in opsonins, the wound will refuse to heal, bacteria will attack its lacerated surfaces, and suppuration will set in. . . . The poultice encouraged the flow of blood and lymph to the infected area.”

  * A huge number of dangerous infections are caused by such anaerobic bacteria, not just gangrene, but tetanus and peritonitis. Anaerobes come in two basic flavors: obligate anaerobes like clostridia, for which oxygen is a poison; and facultative anaerobes, including staphylococci and streptococci, which are able to grow without oxygen, but can often use it if it is present.

  * More about this below.

  * The Gram-positive/Gram-negative distinction isn’t as clean as introductory biology textbooks suggest. Some taxonomists recognize as many as twelve different bacterial phyla, only two of which are “totally” Gram-positive.

  * Even experienced chemists found penicillin a puzzle. Harold Raistrick, a biochemist at the University of London, was equally unable to purify the mercurial—in this case, only metaphorically—compound.

  * Technically, Southern Rhodesia. The northern half of the colony became the country of Zambia in 1964.

  * Florey would later recall that his inability to master higher mathematics was the reason he turned to medicine rather than physics; unlike Almroth Wright, however, he was mathematically competent enough to know what he didn’t know . . . and to seek out help when it was needed.

  * One of them, John Fulton from Missouri, will reappear in our story.

  * Sherrington, a brilliant and innovative scientist himself, would share the 1932 Nobel Prize in Physiology or Medicine with Cambridge’s Edgar Adrian for “their discoveries regarding the function of neurons.”

  * Between 1923, when it was founded, and 1938, when it was folded back into the Rockefeller Foundation, the IEB made grants to fifty-seven institutions and 603 Fellows, including Niels Bohr and Enrico Fermi.

  * For those who care: The number, ever since the 2008 merger of Green and Templeton Colleges, is now thirty-eight.

  * Like the Rhodes Scholarship, and Dunn itself, the Dyson Perrins Laboratory was a twentieth-century monument to the philanthropic vanity of Britain’s seemingly inexhaustible supply of nineteenth-century tycoons. In this case, the money for the lab was a bequest from the grandson of William Perrins, the originator of the secret recipe in Lea & Perrins Worcestershire Sauce.

  * Since 1885, presidents of the Royal Society have served for five-year terms. In between Florey’s mentor, Charles Sherrington (1920–1925), and Hopkins (1930–1935), the president was another Nobel laureate: the physicist Ernest Rutherford. In fact, from 1915 to 1990, fifteen consecutive presidents of the Royal Society were Nobel Prize winners . . . and the streak was broken only with the election of Sir Michael Atiyah, a mathematician whose discipline is unrecognized by Alfred Nobel’s trust.

  * Of Chain’s downside—his Jewishness—Hopkins continued: “I feel that if his race and foreign origin will not be unwelcome in your department, you will import an acceptable and very able colleague in taking him. Incidentally I have found that his remarkable genius as a musician has made him acceptable in certain social circles. . . .”

  * Perhaps to cover all bets—researchers, then and now, live from grant to grant, and are obsessively careful to include any information that might interest a patron—the application also promised to expand on an exciting new discovery from the French-born American microbiologist René Dubos, then working at the Rockefeller Institute for Medical Research: tyrothricin, an antibacterial compound produced by a member of the class of soil-dwelling bacteria then known as the actinomycetes. For more about Dubos and the actinomycetes, see Chapter Six.

  * This was a very small proportion; though neither Raistrick nor Fleming could know this, the concentration of penicillin in the original mold juice was less than one part per million.

  * Vitamin D occurs naturally in oily fish and some animal organ meats, such as liver. Trace amounts are sometimes found in full-fat milk, but not enough for dietary sufficiency. Since milk was so widely consumed by the children at greatest risk for rickets, the deficiency disease associated with a lack of vitamin D, fortifying milk by a number of different processes had become a common practice since the early 1930s.

  * The early company had prospered by adapting machinery initially invented for the manufacture of ground and compressed graphite for pencils for use in producing consistently pure pills, typically alkaloids like morphine and codeine. This is why it was a Burroughs Wellcome marketing genius who first coined (and trademarked) the word “tabloid” as a combination of tablet and alkaloid. In the fullness of time, the term was transmuted into the common name for a newspaper with a policy of compressing lengthy news stories into something briefer, but to this day the company’s Web site boasts of Burroughs Wellcome’s ownership of the term.

  * Margaret Jennings, who would become the second Mrs. Florey after Ethel’s death, was, in many respects, the polar opposite of her predecessor, and many of Howard Florey’s biographers have made much of it. Margaret was robust where Ethel was both deaf and sickly. She was English gentility (the daughter of a baronet), physically affectionate, and compliant; Ethel was none of the above. But it’s also worth remembering that both of Howard Florey’s wives were highly skilled scientists, each of whom played a significant role in the most important medical dis
covery of the twentieth century, which cannot be a coincidence.

  * More about Waksman—much more—in Chapter Six.

  * In this, he would be only half successful; the ten-year-old Paquita was already off to summer camp, and only her five-year-old brother was there to meet his father.

  * Thom’s position as a government scientist required him to balance the needs and demands of commerce—his work on two industrially important members of the Penicillium family, P. roqueforti and P. camemberti, made him a hero to American cheese producers—and society: His primary job, almost from the moment he joined the Department of Agriculture in 1904, was enforcement of the provisions of the Pure Food and Drugs Act of 1906.

  * Lincoln also signed, on March 3, 1863, the charter authorizing the predecessor of the National Research Council.

  * By 1944, this would be adopted as a “unit” of penicillin, the amount of the drug that, dissolved in 50 milliliters of broth, inhibited growth in a colony of staphylococcus, which was effectively the specific activity contained in .6 micrograms of the International Penicillin Standard, essentially the original Oxford unit.

  * Because Bernhauer was an early and fanatic member of the Nazi Party, much of his pioneering work doesn’t appear in the standard histories of fermentation.

  * Currie, like Charles Thom, the mycologist who directed Florey and Heatley to Peoria, was a graduate of the Department of Agriculture’s Research Division. In fact, the two had been collaborators on the department’s attempt to produce an American version of Roquefort cheese, which required both extensive knowledge of fermentation, and, coincidentally enough, the variant of the penicillin mold known, for obvious reasons, as Penicillium roqueforti.

  * Bernal, another of the key figures in the development of X-ray crystallography, was not only Hodgkin’s mentor, but her lover. Both were devoted Socialists as well, and lifelong supporters of the Soviet Union; Bernal so much so as to become Britain’s most passionate advocate for the bogus genetic theories of Trofim Lysenko.

  * The first recipe for penicillin was in the form of a sodium salt. As a barium salt, the chemical formula was (C14 H19 04 N2 S)2 Ba, and was named penicillin F. A slightly different version was known as penicillin G.

  * Palma qui meruit ferat translates as “Whoever earned the palm should wear (or bear) it,” and was the motto of Lord Horatio Nelson. Also, and completely coincidentally, it is the motto of the University of Southern California.

  * Years later, in 1957, Bush was named chair of Merck’s Board of Directors. It was a largely ceremonial job, but not to Bush. A year after his arrival, he was writing to George Merck scolding him that his corporate organization was “atrocious” and Merck himself far too easygoing.

  * In 1921, three-quarters of the children in New York City showed signs of rickets: bow legs, joint pain in the extremities, and deterioration of teeth and bones.

  * Not coincidentally, the patent was also used to prevent manufacturers of margarine from enriching their product by irradiation, which was a matter of some significance to the most important agricultural industry in Wisconsin.

  * Merck wasn’t singled out: Bayer’s American subsidiary was the largest German company sold, for more than $5.1 million. Cassella Manufacturing and Farbwerke Hoechst were held in trust until the war’s end.

  * When Merck approached Richards in 1930, the American Society of Pharmacology and Experimental Therapeutics banned anyone associated with a commercial firm from membership. Richards, who “saw in them no signs of the horns or tail,” accepted Merck’s offer, and submitted his resignation to the society. Faced with a choice of losing its most respected member, the pharmacological society swallowed its pride, changed its bylaws, and opened its rolls to industrial members . . . possibly one of the most far-reaching achievements of Richards’s highly accomplished life.

  * Weicker was a gifted chemist, but an even better marketer. In 1921, aware of the potential of advertising but wary of the risk of offending physicians, he enlisted Raymond Rubicam, then a copywriter at the Philadelphia agency N. W. Ayer & Son, to square the circle: promote Squibb to the public without insulting the professionals. Rubicam—or possibly Weicker, different accounts give credit to each—came up with a parable, told by “Hakeem the Wise Man,” that ended with the moral: “The ‘Priceless Ingredient’ of every product is the honor and integrity of its maker.” Hakeem was discarded soon enough, but the slogan appeared on practically everything that bore the Squibb name for more than twenty-five years.

  * This was an actual ad in Time magazine from the York Refrigeration and Air Conditioning Company touting the importance of refrigeration in preserving the drug for use.

  * Under the heading, “strange connections”: Commercial Solvents’s business was the manufacture of acetone using a process developed by, and licensed from, Chaim Weizmann, the first president of Israel. Notable by their absence were a number of companies approached by Florey during his U.S. tour, such as Smith-Kline, Connaught Laboratories, Lambert Pharmacal, and Mulford.

  * After the war, the newly enriched pharmaceutical companies, having gotten a taste for public-private partnership, spent an additional $11.6 million buying or leasing war surplus plants in order to convert them to antibiotics manufacture. Eli Lilly bought an airplane propeller plant. Pfizer a submarine repair base in Groton, Connecticut, and an ammunition loading plant in Terre Haute—648 buildings on more than 6,000 acres—and converted it to the manufacture and packaging of antibiotics. Merck bought the Cherokee Ordnance Works at Danville, Pennsylvania.

  * At around the same time, another member of the penicillin consortium, Eli Lilly, converted its own penicillin production “line” from 175,000 two-quart milk bottles to a 3,000-gallon fermentation tank. The first tankful of penicillin was achieved on January 1, 1944.

  * As early as 1930, Fleming had given a sample of his broth to C. E. Coulthard, Boots head of bacteriology, though they, like everyone else, had failed to produce anything useful from it.

  * By July 1943, back in the United States, Squibb had managed to crystallize penicillin itself, as a sodium salt, rather than one of its degradation products, as had E. P. Abraham at the Dunn School. Abraham’s sodium penicillin was the more complex of the two, but had been isolated first, and so was named penicillin F. The Squibb salt, penicillin G, was grown from the mold found on Peoria’s cantaloupe, and was already becoming the dominant variant of penicillin.

  * In the great though occasionally embarrassing tradition of English scientists with leftist politics, she was also a recipient of the Lenin Peace Prize and the Lomonosov Gold Medal, awarded by what was then the Soviet Academy of Sciences. One consequence is that she was frequently barred from traveling to the United States. Just to keep everyone on their toes, however, her most famous student, Margaret Thatcher, née Roberts, was a lifelong friend who kept Hodgkin’s portrait in her Downing Street office.

  * Florey’s innovation, “instillation therapy,” called for closing infected soft tissue wounds as fast as possible, leaving rubber tubes for irrigating the site with penicillin. Not until the end of 1944 was enough penicillin available to replace instillation with intramuscular injection.

  * The proper name for scrofula, a disease that manifests with swollen and eventually ulcerous growths on the lymph nodes of the neck, is tuberculous cervical lymphadenitis, a form of tuberculosis that presents outside the lungs.

  * Streptococcal toxins are a terrifying bunch. One of them, known as pyrogenic exotoxin C, causes the distinctive rash of scarlet fever; another, streptolysin, does to cell membranes what boiling water does to a sugar cube.

  * One of them was Robert Louis Stevenson, who spent the winter of 1887–88 at Saranac Lake. His timing was not the best; in March 1888, the Great Blizzard dumped more than four feet of snow on the sanatorium.

  * Despite its reputation, leprosy, or Hansen’s disease
, is several orders of magnitude less infectious than tuberculosis.

  * Though the BCG vaccine—for Bacilli-Calmette-Guérin—is today the most widely prescribed vaccine in the world, it has shown only a 20 percent level of effectiveness against pulmonary tuberculosis; its greatest value seems to be in forestalling tubercular meningitis. This is one reason that, in the twenty-first century, M. tuberculosis is still resident in more than two billion people, a hundred million of whom will develop the disease.