* While actinomycin’s cost-benefit relationship was unappealing for the treatment of tuberculosis and most other bacterial infections, it would be used effectively to treat a rare form of childhood kidney cancer known as Wilms’ tumor. In a 1983 reminiscence, Max Tishler of Merck recalled being awestruck by seeing half a dozen children at the Dana-Farber Cancer Institute who had been cured by the “commercially unimportant” drug.
* One observer would note that Waksman’s “real discovery was not streptomycin; it was the principle that a patient, systematic search for useful antibiotics will eventually pay off.”
* Mycobacteria, though they don’t stain, are actually Gram-positive. However, their membranes, constructed from another substance known as mycolic acid, are just as resistant to penicillin as Gram-negative bacteria like Y. pestis.
* Randolph Major put him to work with a Russian botanist named Boris Krukoff, who brought both the curare and a seven-foot-long blowgun from South America to Rahway.
* It is, nonetheless, worth noting that all the autopsied guinea pigs still showed evidence of the M. tuberculosis bacterium. Streptomycin had prevented disease, but hadn’t killed the pathogen causing it; that is, it was bacteriostatic, rather than bactericidal.
* In 1946, the War Department published George Merck’s report on Japanese biological warfare research, which concluded, “Intensive efforts were expanded [sic] by Japanese military men toward forging biological agents into practical weapons of offensive warfare [and] pursued with energy and ingenuity.”
* It would be awarded in 1948; significantly, the patent recognized that streptomycin was not a naturally occurring substance but a “new composition of matter.”
* Not clearly enough to convince the Royal Navy, though. It took another fifty years before the notoriously conservative Lords of the Admiralty issued an order that made drinking lemon, and later lime, juice—hence “limeys”—compulsory for sailors on long voyages.
* In the taxonomy of cognitive science, these are known, respectively, as anchoring, the availability heuristic, and confirmation bias.
* Not everyone was as punctilious about ethics as the Tuberculosis Trials Committee. At the moment in 1947 when the war crimes tribunal convicted seventeen of the twenty-three defendants in the so-called Doctors’ Trial and published the ten-point Nuremberg Code for human experimentation, the infamous Tuskegee syphilis experiments had already been under way for fifteen years, and would continue observing the course of untreated syphilis in African American men for another twenty-five years.
* Or so they thought. Later researchers have found a more plausible mechanism for the way PAS improved the effectiveness of streptomycin: The former drug slows down the bacterium’s ability to produce folate, while streptomycin inhibits RNA synthesis, thus exposing the bacterium to what is, effectively, a two-front war.
* The PAS-streptomycin cocktail was also the precursor of the so-called fixed-dose combination antibiotics that would be the target of the most far-reaching federal investigations of the drug industry since the Massengill debacle of 1938. See Chapter Nine.
* The land-grant colleges were, like the Agriculture Department itself, a creation of the 37th United States Congress, which passed the Morrill Act—named for its author, Vermont congressman Justin Smith Morrill—in July 1862 to “teach such branches of learning as are related to agriculture and the mechanic arts. . . .” In the same way as the Northern Lab and Selman Waksman’s lab at Rutgers, they are a reminder of the unpredictable but enormous returns earned by national investment in basic research.
* For more on Max Finland, see Chapter Nine.
* Rimosus translates roughly from the Latin as “leaking” or “full of holes,” which is vivid, though less metaphorically resonant than “gold maker.”
* Though not, perhaps at first. Max Tishler, Woodward’s colleague at Harvard before departing for Merck, later recalled, “None of us thought he was really that great when he came over from MIT. He had such a great press. Of course, we changed our minds pretty quickly.”
* For readers who want more detail only: Prokaryotes like bacteria produce the proteins needed for life using a different kind of ribosome than their eukaryotic descendants: everything from fungi to plants to readers of popular history books. The bacterial ribosome, with a different assortment of nucleotides, is broken into subunits, one smaller than the other. Streptomycin binds to the small bacterial subunit, and when it does so, the ribosome misreads the recipe for synthesizing proteins. This makes streptomycin deadly to them, and at least tolerated by humans. The tetracyclines, on the other hand, are far less toxic, because the patient’s eukaryotic cells don’t absorb them in anything like the same concentrations. This doesn’t mean they are completely free of side effects, as detailed below.
* It’s less clear that they were clinically superior. Though broad-spectrum antibiotics are effective against a wider range of pathogens, for most infections, penicillin and its synthetic analogues remain the treatment of choice to this day.
* To the Federal Trade Commission, this looked an awful lot like a conspiracy in restraint of trade, and therefore a violation of the Sherman Antitrust Act. In 1958, the three corporations and their chief executives—American Cyanamid’s Wilbur G. Malcolm, Pfizer’s John McKeen, and Bristol-Myers’s Frederic Schwartz—were sued for conspiring to limit competition and fix prices. The litigation would drag on for twenty-four years before the FTC lost its final appeal.
* Dr. Sackler is even better remembered as one of the great art collectors of the twentieth century, whose bequests appear in galleries at Princeton University, Harvard, the Brooklyn Museum, the Smithsonian, and, most prominently, the Sackler Wing at the Metropolitan Museum of Art.
* By convention, thirteen compounds are recognized as essential vitamins in humans. Diseases like scurvy, caused by a deficiency in vitamin C, were recognized for centuries before 1913, when the first vitamin—retinol, a component of vitamin A—was identified (the last, vitamin B9, was discovered in 1941).
* The mechanism for this is still not very well understood. The initial hypothesis—that the antibiotics reduced the amount of pathogenic bacteria in the gastrointestinal tracts of newborn chickens—hasn’t been borne out by subsequent research. A currently popular theory is that GPAs, or growth-promoting antibiotics, work by inhibiting the normal intestinal flora that inhabit the GI tracts of domestic animals, and by doing so reduce the “costs” to the animals of digestion. The less energy the chicks used for digesting food, the more they have available for growth. Another currently popular theory is that GPAs (sometimes STAT, for subtherapeutic antibiotic treatment) alter the animal’s microbiome: the complex ecosystem of bacteria that live within animals, frequently in numbers that dwarf the number of animal cells with which they coexist, generally not just peaceably, but productively. By killing some percentage of the bacteria in the digestive system, antibiotics, according to this theory, increase the amount of digestible food, and so promote weight gain.
* Such neutral changes are a little like acquiring books for a library that have no immediate impact on the reader’s life, but which nonetheless represent a potential future asset.
* From the 1950s, synthesizing new compounds that were penicillinase resistant led to the discoveries of oxacillin, methicillin, and other drugs with a narrower spectrum of activity than the penicillin G that was first produced in 1945. One of the most important beta-lactam antibiotics, cephalosporin C, was isolated by Abraham himself in 1955, and its structure published in 1961 (and decisively demonstrated by Dorothy Crowfoot Hodgkin’s X-ray crystallography). Cephalosporin was not merely effective against bacteria that had mastered the trick of producing beta-lactamase, but was also patentable. Unlike his Dunn School colleagues of a previous generation, Abraham was able to patent his discovery and earned enough from it to endow the Cephalosporin Trust at Oxford’s Lincol
n College with an initial bequest of £30 million.
* It’s not even a clear advantage in purely economic terms. A 2007 study of chickens raised on subtherapeutic doses of antibiotics showed that the higher cost of the feed outweighed—sorry—any increase in the value of the (somewhat) larger chickens.
* The most prominent were the émigré Russian sociologist Pitirim Sorokin and the evangelical psychologist Ernest Ligon. Though largely forgotten today, during the 1930s Ligon briefly became world famous for his “Character Research Project,” a Christian-themed combination of values education and personality measurement.
* Langham is a double footnote to biological history. Theodosius Dobzhansky also used him to find the fruit flies for his groundbreaking genetic research.
* Such was the impact of Waksman’s discovery of streptomycin that this became a common tactic for pharmaceutical researchers, occasionally reaching head-scratching levels. In 1951, Bristol-Myers’s annual report had a prepaid business reply envelope sewn in, with instructions to shareholders on how to obtain “a teaspoon of soil, slightly moist but not wet” and send it in for testing.
* Typhus is unrelated to typhoid fever, which is caused by a Salmonella bacterium.
* The many informal names for epidemic typhus include “ship fever,” “jail fever,” and “camp fever.”
* In the 1940s, the most reliable lab test for typhus, adding a colony of Proteus bacteria to the blood of an infected person and examining it microscopically to see if it clumped, found fewer than 40 percent of infections.
* To this day, the controversy over the authority of medical professionals to make clinical decisions has yet to be resolved. The terms that the debate adopts in popular accounts—should decisions about testing or surgery or drugs be made by “caring physicians” or “faceless bureaucrats” (whether representing insurance companies or governmental agencies like the FDA or the Centers for Disease Control and Prevention)—suggest why the controversy seems unlikely to be resolved soon.
* Though the phenomenon wasn’t well understood until the 1960s, the tetracyclines—because they bind with calcium—can also permanently discolor teeth when given to children.
* The risk of contracting aplastic anemia from chloramphenicol exposure is a constantly moving target. The reason is that it’s calculated by dividing the number of cases by the number of people who’ve been exposed, which is harder to measure than it sounds. Because no one collected data on the number of prescriptions written or filled, the at-risk population can only be inferred by dividing the total amount of chloramphenicol sold in a given year by the average dose, itself an estimate of between 3 and 8 grams for each patient. Thus, the risk was estimated to be 1 in 156,000 in 1958, and 1 in 227,000 in 1959. By 1964, though, a different study calculated the risk at 1 in 60,000. This doesn’t show the differential risk of dying from the drug, though. The best guess today is that the risk of dying from aplastic anemia in the absence of chloramphenicol exposure was about 1 in 500,000. For those exposed, the odds dropped to a still rare 1 in 40,000.
* Most of Flexner’s recommendations are jaw-droppingly obvious in retrospect. One required physicians to have completed at least two years of college (only sixteen schools required this at the time of the study). Another proposed that they receive clinical training in addition to lectures. A third recommended that medical schools, following the European model, should affiliate with universities, rather than operate as stand-alone, for-profit vocational schools. The result, once the AMA’s Council on Medical Education persuaded each of the state licensing boards of the merit of the report, was to cut the number of accredited medical schools in the United States by half.
* The level of what an objective observer might call unethical gift giving would, with the number of branded drugs, increase to stratospheric levels soon enough. See Chapter Nine.
* One reason that infants were at particular risk for adverse reactions to a medicine like chloramphenicol is that clinical trials hardly ever include children. Except for cancer research (and rarely even then), parents tend to be unwilling to enroll their children in double-blind randomized studies in which they might be part of a control group. Even today, pediatricians regularly prescribe medications for off-label use, precisely because so few drugs for children can qualify for clinical trials. See Chapter Nine for more on phased clinical trials.
* Chloramphenicol remains one of the drugs deemed essential by the World Health Organization and is still widely used in many parts of the world for everything from scrub typhus to eye infections. While the drug is still effective, it was supplanted by new and improved antibiotics in industrialized countries—though it did hang on for a fairly long time, and for a perverse reason: Because all the adverse publicity made it less frequently prescribed, it was far slower to develop antibiotic resistance than the beta-lactam or tetracycline antibiotics.
* Finland had actually opposed what he viewed as overreliance on RCTs the decade before, arguing that for many diseases in which the etiology was unknown, clinical trials would not necessarily reveal the truth. If physicians don’t know whether they’re treating bacterial or viral pneumonia, the information from even well-designed clinical trials can be not only useless but harmful, since it fails to control for the messiness of patients with similar symptoms but different diseases.
* Dirksen described Kefauver as combining the charm of a Victorian lady with the single-mindedness of an Apache.
* Worth noting: Austin Smith, the former editor of JAMA, had become president of the Pharmaceutical Manufacturers Association . . . and would succeed Harry Loynd as president of Parke-Davis.
* The mechanism by which thalidomide causes birth defects is still not very well understood. A currently popular theory is that one of the simpler compounds into which the liver breaks down the drug inhibits the formation of blood vessels at the end of embryonic development, and so damages the growth of structures that appear late in gestation, such as arms and legs. The drug remains in use today, for treatment of—among other things—leprosy and multiple myeloma; a reminder that drug “safety” is very much a relative thing.
* A large number of over-the-counter drugs were designated by the acronym GRASE (for Generally Recognized as Safe and Effective). Others that had appeared before 1938 were grandfathered . . . though hardly any qualify any longer, since one provision of the Kefauver-Harris Amendments required that it be identical to the version on sale in 1962.
* The first use of the term seems to be no older than 1957, when it formed part of the argument in a medical malpractice case.
* Her instinct to lecture drug companies on moral as well as scientific grounds soon made her as notorious among pharmaceutical companies as she was lionized by the general public.
* Not without controversy. When Burroughs announced the initial price for a year’s treatment with AZT—a then-unthinkable $10,000—they were vilified in the press as profiteering monsters.
* Coming full circle: Winthrop Chemical Company, in partnership with Bayer and I. G. Farben, was the first company to sell sulfanilamide in the United States.
* Just to remind pharmacologists that bacteria are always ahead of the game: In 1972, dried soil was extracted from an exhibit that had lain untouched in the British Museum since 1689. Bacterial spores in the soil, which predated Alexander Fleming by some 250 years, nonetheless contained penicillinase, the enzyme responsible for penicillin resistance.
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