SEVEN
The perennial known as timothy grass, which grows from two to five feet tall, covers thousands of acres of the American Midwest. It is famously hardy, resistant to both cold and drought, and prospers in almost any kind of soil, from the heaviest bottomland to the poorest sands. Like many New World plants, it is a relatively recent invader, introduced to colonial America by European settlers—one popular theory suggests that the name comes from an eighteenth-century New England farmer named Timothy Hanson—and it is widely grown as animal feed for everything from domestic rabbits to cattle and horses.
Timothy grass was and is important enough as a commercial commodity that agronomists at the University of Missouri started planting it in Sanborn Field, the university’s agricultural test station, as soon as it opened in 1888. They were still experimenting with it—testing varieties for improved yields, or more weather hardiness—in 1945 when William Albrecht, a soil microbiologist, received a letter from a former colleague, now working in New York. The letter included a request that Albrecht obtain soil samples from a dozen different Missouri locations, including Sanborn Field’s Plot 23. Its author was a botanist and mycologist named Benjamin Minge Duggar.
Duggar was then seventy-three years old and an accomplished and respected plant pathologist. Ever since receiving his PhD in 1898, he had studied fungi and disease, more or less nonstop, at the Department of Agriculture and at a number of prominent land-grant universities including Cornell, the University of Wisconsin, Washington University in St. Louis, and, of course, Missouri.* In 1944, he departed his last academic post and joined Lederle Laboratories to work under its remarkable head of research, Dr. Yellapragada Subbarao.
Lederle Antitoxin Laboratories, as it was originally known, had been founded in 1904 by Dr. Ernst Lederle, a former New York City health commissioner, to produce an American version of the diphtheria vaccine developed by Emil Behring, Paul Ehrlich, and Robert Koch at the end of the nineteenth century, one they could sell to American physicians and hospitals royalty free. Vaccines and antitoxins, for tetanus, typhoid, anthrax, and smallpox, remained the company’s primary business for the next forty years, through the death of its founder in 1921, its subsequent acquisition by the agricultural chemicals manufacturer American Cyanamid in 1930, and the hiring of Subbarao in 1940.
Subbarao, an Indian-born physician and physiologist, arrived in the United States as a penniless immigrant in 1923, but with an admissions letter to Harvard University’s School of Tropical Medicine, a division of the university’s medical school. His tuition expenses were paid by his father-in-law, but in order to pay for his room and board he was given a job at Harvard Medical School, where he spent the next seventeen years. His achievements were nothing short of stellar; among other endeavors, he isolated the components of adenosine triphosphate, or ATP, the fuel for all cellular respiration. In fact, a complete account of Yellapragada Subbarao’s accomplishments is almost literally too long to list—not only fundamental discoveries about ATP, creatine, and of B12, but half a dozen chemical breakthroughs still in use today, including discovering how a mimic of folic acid known as antifolate could be used to combat leukemia. Despite that, U.S. immigration law’s baroqueries (among other things, immigrants from British India were allowed to stay only if they fell into professional categories that the State Department deemed valuable . . . a list that changed regularly) required him to register as an alien for his entire professional career.
The most consequential result of Subbarao’s problematic immigration status is that one of the university’s most brilliant investigators was denied tenure. Academia’s loss was industry’s gain; in 1940, he left to join Lederle as its director of research. A year after that, he represented Lederle at the first meetings of the Committee on Medical Research called by A. N. Richards to discuss what would become the penicillin project. Three years after that, he hired Benjamin Duggar.
By this time, Selman Waksman’s researches at Rutgers were making him the most famous soil scientist in the world; more, they were inspiring everyone in the entire discipline to emulate his approach: testing literally thousands of actinomycetes for antibacterial properties. It certainly inspired Subbarao and Duggar, who initiated a global program of soil collection. Remarkably enough, in the middle of the world’s largest war, they successfully recruited dozens of soldiers and sailors to seek out soil samples everywhere from the Caucasus to North Africa to South America.
In 1945, they hit pay dirt—literally—closer to home, with the sample from Plot 23 at Sanborn Field. Living in Plot 23 was a yellow actinomycete, a relative of Selman Waksman’s Streptomyces griseus that they designated A-377. It took nearly three years of testing and experiment before Duggar announced his discovery to the world in an article in which he named his newly discovered organism Streptomyces aureofaciens: the “gold maker.”
The name was almost certainly an attempt to describe the appearance of the bacterium, but Duggar’s employers at Lederle may have had a different meaning in mind. S. aureofaciens produced a chemical of unknown identity and structure, but one that checked the activity of an enormously wider variety of bacteria than either penicillin or streptomycin. The substance, which Duggar christened Aureomycin (aurum is Latin for gold), was effective against Gram-positive and Gram-negative bacteria, including the pathogens responsible for common ailments like urinary tract infections, and rare ones like bubonic plague. It even seemed to have a powerful effect against a number of viruses. The first broad-spectrum antibiotic had been discovered.
In 1948, after a series of highly successful animal experiments, Aureomycin was ready for clinical investigation in humans. The facility chosen was Harlem Hospital, where Louis Tompkins Wright had spent years studying the treatment of diseases, such as the sexually transmitted lymphatic infection caused by the bacterium known as Chlamydia trachomitis. Wright—the most famous African American physician in the United States, the first admitted to the American College of Surgeons—succeeded brilliantly, not just against chlamydia, but also on the variety of pneumonia caused by a virus, rather than the pneumococci bacteria.
Aureomycin looked like a true magic bullet: the hoped-for drug that would cure nearly everything. The Harlem Hospital results didn’t convince everyone; Maxwell Finland of Harvard Medical School, perhaps the country’s most respected expert on infectious disease, found that Wright’s reports were “tinged with enthusiasm,” and he didn’t mean it as a compliment. In 1948, this made him a voice in the wilderness.* Lederle promoted it as “the most versatile antibiotic yet discovered, with a wider range of activity than any other known remedy.” It wasn’t just that it was superior to existing antibacterial treatments in treating disease (though it was). Unlike Prontosil, or penicillin, or—thanks to George Merck—even streptomycin, Aureomycin was patentable, and, on September 13, 1949, it was granted U.S. patent number 2,482,055. Even before the patent had been approved, in 1948 the company spent a then-unheard-of $2 million shipping samples of their gold maker to 142,000 doctors. Lederle had the first blockbuster drug in history, but it wouldn’t have the stage to itself for long.
In 1945, Brooklyn-based Pfizer had initiated its own global soil collection program with the same goal as Lederle: to find a patentable antibiotic. They went about it the same way that Waksman and Schatz had discovered streptomycin, by testing large numbers of soil samples—very large numbers. Within a few years, Pfizer had collected more than 135,000 of them. One of Pfizer’s chemists, Ben Sobin, later recalled, “We got soil samples from cemeteries; we had balloons up in the air [that] collected soil samples that were windborne; we got soil from the bottoms of mine shafts . . . from the bottom of the ocean.” By the beginning of 1949, its investigators had conducted more than twenty million tests on them at the company’s Terre Haute, Indiana, facility, a state-of-the-art microbiology laboratory.
In a replay of Lederle’s experience, the payoff came not from an exotic location but from the land around one of Pfizer’s own Midwest plants. They had found a yellowish actinomycete that Alexander Finlay, Pfizer’s team leader, named Streptomyces rimosus.* The canary yellow crystals it produced were given a code name: PA-76, for the seventy-sixth culture of a Pfizer antibiotic.
At first, PA-76 seemed to be virtually identical to Lederle’s Aureomycin, which made it interesting but commercially problematic. Pfizer nonetheless proceeded to invest, since PA-76 had enormous potential to become Pfizer’s own blockbuster. It killed or at least slowed down Gram-positive and Gram-negative bacteria as well as dozens of fungi and, seemingly, even viruses. The honor of naming it was given not to its discoverer, but Pfizer’s new president, John McKeen. McKeen had designed and converted Pfizer’s Brooklyn fermentation plant, a former ice factory, for the wartime penicillin project. He had risen through the ranks to succeed John L. Smith as Pfizer’s president, and named it Terramycin, because, as he later wrote, “I wanted a name connected with the earth, and one that could easily be recalled by doctors and scientists and people in general, because it came from the earth.”
In 1949, McKeen assigned Gladys Hobby, the microbiologist who had been part of the Columbia University team that led the way in American experimentation on penicillin, now a Pfizer team member, to take charge of testing the new drug. She wasted little time. On December 31, 1950, Hobby conducted Terramycin’s first human trial at Harlem Hospital, which had demonstrated in the Aureomycin experiments that it had the personnel and structure in place (including carefully identified pathogens) to perform a high-quality clinical trial.
Her employers couldn’t have been more enthusiastic about her results. Though Pfizer had produced huge quantities of penicillin and streptomycin—far more than any other pharmaceutical company in the world—they weren’t making much money selling it. In March 1950, McKeen famously gave a speech to the New York Society of Security Analysts, in which he told them, “If you want to lose your shirt in a hurry, start making penicillin and streptomycin.” The surest way out of the trap that had swallowed up the first antibiotics was finding a new drug that was superior to its competition, so the company that found it could profit from a de facto monopoly.
Now Pfizer had their drug: Terramycin was just as good as hoped. However, no one at Pfizer or elsewhere thought it was demonstrably superior to Aureomycin, and the Lederle drug already had a head start in winning the hearts and minds of America’s physicians and pharmacists. By the beginning of 1950, Aureomycin accounted for 26 percent of the entire antibiotic market in the United States.
Moreover, Pfizer wasn’t even really in the business of selling drugs. All of the penicillin and streptomycin they had produced to date had been sold under the label of other companies, ones that had consumer sales and marketing capabilities that Pfizer—which had, after all, been largely a manufacturer of citric acid before joining the penicillin project—lacked. McKeen was undaunted. Terramycin would be a company changer: Pfizer’s first branded drug.
But first, the company needed to know more about both Terramycin’s mechanism and its structure, a task requiring the most sophisticated understanding of organic chemistry. Pfizer needed the best organic chemist in the world. They needed Robert Burns Woodward.
Woodward was a rare bird: a prodigy—he entered the Massachusetts Institute of Technology in 1933 at age sixteen, and left four years later as a twenty-year-old PhD in chemistry—whose adult achievements were even more prodigious. During his forty-one years at Harvard’s Department of Chemistry, he authored or coauthored nearly two hundred peer-reviewed papers, received twenty-four honorary degrees and twenty-six medals and awards, including the National Medal of Science, the Royal Society’s Copley and Davy Medals, and the 1965 Nobel Prize in Chemistry for his “outstanding achievements in the art of organic synthesis.”
Woodward was the first to synthesize cortisone, cholesterol, strychnine, and chlorophyll. In 1944, as an advisor to the War Production Board, he discovered how to synthesize the antimalarial compound quinine, which was utterly essential for the war effort in both southern Europe and throughout the campaign in the Pacific . . . especially so since, from 1941 forward, the world’s entire supply of the only natural source for quinine, cinchona tree bark, was under the control of the Imperial Japanese Army. And, seven years after winning the Nobel, Woodward succeeded in one of the most impressive tasks in the then-brief history of chemical synthesis, leading the international team that spent twelve years decoding and producing the notoriously complicated molecule known as vitamin B12.
But calling Woodward a master of chemical synthesis, though true, understates his gifts. To his contemporaries, he was even more brilliant at describing complex organic chemicals—deciphering the incredibly complicated three-dimensional shapes adopted by the stuff of life—than in making them.* In January 1945, it was Woodward who demonstrated that the beta-lactam structure of penicillin, the one proposed by Ernst Chain and E. P. Abraham, had to be correct, thus anticipating Dorothy Crowfoot Hodgkin’s X-ray crystallography by five months. In the words of one of his biographers, he could integrate facts “both clear and misleading into a coherent whole better than any chemist who ever lived.”
Credit: Getty Images/Keystone
Robert Burns Woodward, 1917–1979
Readers living in a time when technologies like nuclear magnetic resonance imaging are routinely able to determine molecular structure at a relatively low cost in a single afternoon may find it difficult to understand the value placed on Woodward’s talent during the 1940s and 1950s. Instead of simply examining a three-dimensional picture of a complicated organic molecule on a screen, chemists of his era could only derive structure by working as enormously sophisticated puzzle solvers: taking all the known facts about a molecule, such as whether, and how quickly, it reacted to heat or cold, to acids or bases, or to other molecules; and from that information, and a detailed knowledge of the laws of chemistry, figuring out which atoms connected to one another, through what sort of bonds, and in what configuration. This is a little like drawing the blueprint of an office building knowing only its floor-by-floor heating bills and the number of people who used its elevators daily.
At this, at the manipulation of what chemistry students know as stereoisomers—alternative spatial configurations of three-dimensional molecules—Woodward was unmatched, not merely because of what might be called his architectural eye, but his profound understanding of the underlying physics of the molecules in question. So, when John McKeen went looking for the chemist best equipped to aid Pfizer in understanding Terramycin, he didn’t have to look far.
Nor did he have to do much persuading. Any qualms about working for a commercial employer, which had earlier stymied A. N. Richards during his imbroglio with the American Society of Pharmacology, had disappeared, seemingly overnight. Woodward wasn’t ever going to be an industrial chemist per se, but he was more than happy to consult with industry. (One of his best friends was Edwin Land, the founder of Polaroid, who started paying Woodward as a consultant as early as 1942, and eventually made him the only nonemployee to be given options on Polaroid stock, and thereby made him a very wealthy man.) Pfizer had a puzzle that needed solving, and Woodward, who famously completed the New York Times crossword daily, needed puzzles to solve.
After dozens of other chemists had tried and failed to figure out the compound’s molecular blueprint, Woodward, in legend anyway, took a large piece of cardboard, wrote on it every fact known about the compound, and “by thought alone, deduced the correct structure for Terramycin.”
What he reported might have seemed, at first, problematic. Pfizer’s new drug was, indeed, not just functionally similar to Aureomycin. It was structurally similar as well. Both compounds were built around a four-ring structure, which gave them the generic name “tetracyclines.” But Aureomycin had a single chlorine atom—generically chlortetracycline—that Terramycin lacked. Meanwhile, Terramycin (or oxytetracycline) had an oxygen atom that was missing from Aureomycin. From a medical standpoint, the differences were negligible. But as intellectual property, the discovery was huge. Terramycin was novel enough to be patented. Pfizer filed a patent for Terramycin in November 1949; the FDA approved it five months later. Pfizer was ready to start its production line.
And this time, they wouldn’t just be producing a drug for other companies. They decided to sell it themselves.
This was, to put the nicest possible construction on it, ambitious. In 1950, Pfizer’s sales force, including the sales manager, numbered only eight people. Undaunted, McKeen sent telegrams to eight hundred drug wholesalers—essentially, every wholesaler in the United States—announcing Terramycin’s availability as soon as it was cleared for sale by the FDA. And, on March 23, 1950, within an hour of receiving the formal approval, each of Pfizer’s eight sales representatives was manning a switchboard, telephoning a hundred wholesalers each, offering a very steep introductory discount.
Within a year, Pfizer was employing a hundred salesmen. In 1951, the company supplemented them with seventy third-year medical students, hired to work for the summer, and sent them to forty cities to sing the praises of Terramycin. By 1952, three hundred Pfizer reps were selling Terramycin as fast as the company could manufacture it.
Pfizer’s efforts—and success—were matched by the tactics Lederle was simultaneously employing with Aureomycin. In the battle for America’s antibiotic dollar, featuring ever more elaborate sampling campaigns, twenty-four-hour telephone blitzes (and competition to see which sales reps could drain their respective employer’s travel and entertainment budget faster, by entertaining more lavishly), Pfizer and Lederle both emerged victorious, equipped with an arsenal of anti-infective drugs that exhibited a new, and far wider, range of effectiveness.
The biggest reason was that the broad-spectrum antibiotics really were new and improved. Penicillin works by weakening the molecules that form the bacterial walls of Gram-positive pathogens; streptomycin disrupts the way that bacteria make protein, though with some nasty side effects, including kidney damage and deafness. Tetracyclines also fight pathogens by inhibiting protein synthesis, but far more effectively: Both Aureomycin and Terramycin hijack the system that bacteria use to accumulate needed molecules from their environment, and so concentrate the bactericidal molecules precisely where they can do the most good, and fast; tetracyclines can accumulate in concentrations more than fifty times greater inside a bacterium than outside.* This made the new drugs effective against virtually every sort of pathogenic bacterium, from the spirochetes that cause syphilis to the bacilli responsible for anthrax and bubonic plague. Moreover, because protein synthesis is such a universal requirement of life, the tetracyclines were also useful against the pathogens that cause malaria—not bacteria, but protozoans, single-celled organisms with nuclei, which evolved billions of years after the first bacteria appeared.
Largely because they generated greater revenues, which supported ever more aggressive marketing, broad-spectrum antibiotics completely overtook penicillin and streptomycin in sales.* By 1952, Americans were spending more than $100 million annually for broad-spectrum antibiotics, more than three times as much as they were spending on penicillin. The profit margins for the former ranged from 35 to 50 percent, while the profit on penicillin and streptomycin barely topped 5 percent. Pfizer accounted for 26 percent of all antibiotic sales; Lederle a bit more than 23 percent. And the pie was growing larger every year. By the early 1950s, more money was being spent on antibiotics than on all the new and improved patent medicines, toothpastes, mouthwashes, vitamins, hormones, botanicals, and even sulfanilamides, combined.
It took some time before the complicated effects of broad-spectrum antibiotics like the tetracyclines were understood; in some respects, they’re not fully grasped even today. At their introduction, the results seemed simple enough: They were true wonder drugs. Unfortunately, though Aureomycin and Terramycin were distinctive enough to have “exclusive” patents, they weren’t truly different in any other important way. By late 1952, in fact, Woodward had demonstrated that the molecule that was doing all the heavy lifting for Terramycin wasn’t oxytetracycline, but simple tetracycline; inferentially, this meant that Aureomycin, or chlortetracycline, didn’t need its chlorine atom, either. It could have been Prontosil all over again: a discovery that the active ingredient in a branded medication was far simpler than the one described in the patent that protected it from competition.
The difference was that sulfanilamide had been discovered so long before it revealed its antibacterial properties that Bayer couldn’t protect it as a piece of intellectual property. Simple tetracycline, on the other hand, was new. In October 1952, the Pfizer team filed a patent application for the four-ring molecule at the heart of Terramycin: tetracycline itself. A few months later, in March 1953, Lederle’s parent, American Cyanamid, filed its own application. And, just to keep things interesting, in September both Bristol Laboratories and Heyden Chemical—members of the penicillin consortium that had independently discovered how to make tetracycline without starting from either chlortetracycline or oxytetracycline—filed patent applications both for the tetracycline molecule and for their own distinctive methods of producing it.
This complicated aspect of the patent system—two molecules that differed from one another by the placement of a single atom could be separately patented, even if the atom was unnecessary to the therapeutic activity of the molecule; two different processes by which identical molecules were produced could, likewise, receive separate patent protections—made for a monumental mess. Though Pfizer was attempting to secure patent protection for simple tetracycline, they had no method for making it that didn’t require starting with the chlortetracycline produced by S. aureofaciens. This meant that producing a Pfizer-branded tetracycline—they named it Tetracyn—could only be done by licensing (or buying) Aureomycin from Lederle. Lederle, on the other hand, could produce tetracycline only by getting a process license from Bristol or Heyden before they could sell their version of plain vanilla tetracycline, which they called Achromycin. Since Lederle planned to launch Achromycin with a $2.5 million campaign—$1 million for samples alone—that included promoting it at two hundred separate professional meetings and sending more than a hundred mailings to every physician (and seven more to every dentist) in the country, some resolution of the license impasse was urgently needed.
Meanwhile, Bristol Laboratories, which was awaiting patent approval for its own method of making tetracycline, would still need a license for the product patent. When they couldn’t get one, Bristol initiated a lawsuit against Pfizer, whose own patent application was looking cloudier by the day, as they had apparently withheld information about the original discovery that would have damaged their claim.
The only solution that worked for everyone was a complicated roundelay of cross-licenses. American Cyanamid acquired Heyden’s pending patent application for a method of producing tetracycline, then withdrew its own application for a patent on the tetracycline molecule itself. In return, Pfizer granted American Cyanamid/Lederle a license to manufacture the drug. Finally, on the theory that a competitor makes less trouble when its attorneys are inside the boardroom sending cease-and-desist letters out than outside the boardroom sending cease-and-desist letters in, Pfizer and American Cyanamid agreed to grant cross-licenses to Bristol Laboratories as well: They would be allowed to continue making tetracycline, but to supply only Squibb and Upjohn.
The peace treaty worked brilliantly at achieving its intended objective: propping up the price of the various tetracycline antibiotics, which had fallen by two-thirds between 1948 and 1952, but stabilized thereafter for another decade, mostly for sales of the simplest, most generic form. In 1951, Lederle’s Aureomycin was 41.5 percent of the broad-spectrum market; five years later, it was barely 12 percent; but Achromycin, its version of tetracycline, represented 66 percent of sales, and virtually all of the company’s $43 million in profit. And they weren’t the only ones making money. Squibb sold the antibiotic as Steclin; Upjohn had Panmycin. Even Bristol Laboratories, once they eased out of the restrictions of the original cross-license, sold tetracycline under the name Polycycline.*
Though selling what were, chemically, identical drugs, the companies didn’t stop competing. But since they were no longer competing to supply a superior product, and had agreed not to compete on price, victory would go to the best drug marketer. And it is in no way a criticism of Pfizer’s research and production brilliance to say that, when it came to marketing, they were truly in a class by themselves.
Their teacher was the legendary advertising executive Dr. Arthur M. Sackler.
For a man whose critics recall him as one of the twentieth century’s great hucksters,* Sackler’s academic credentials are certainly impressive enough. He graduated from New York University’s School of Medicine in 1937 and founded the Laboratories for Therapeutic Research in 1938, while simultaneously completing his residency in psychiatry at Creedmoor State Hospital in Queens. Over the years, he would publish more than 150 research papers, largely in the most rarefied realms of neuroendocrinology and the metabolic basis of schizophrenia. His outsized place in the history of medicine, however, is a result of his mastery of a different aspect of human behavior. In 1942, he joined the William Douglas McAdams advertising agency, which he would, shortly thereafter, acquire.
The timely encounter between a brilliant and ambitious physician, a newly sophisticated advertising business, and a seemingly inexhaustible supply of miracle drugs changed medicine forever. Because Pfizer lacked the long-standing relationships with doctors and hospitals of its competitors, Sackler proposed the company persuade physicians to try Terramycin and Tetracyn not simply at one-on-one sales calls, but through their trade journal: the Journal of the American Medical Association. His strategy was clear enough, at least in retrospect. Before 1952, advertising in JAMA was almost entirely free of branded drugs. Readers of America’s premier physician’s journal were far more likely to be introduced to ads for generic medical supplies (“Doctors Get a Heap of Comfort from Grinnell Gloves”) and, of course, ubiquitous ads for cigarettes: “More Doctors Smoke Camels Than Any Other Cigarette.” Even with that level of support, advertising in JAMA was still, by the standards of midcentury magazine publishing, sparse. Drug companies—“ethical” drug companies, as they were still known—hadn’t quite erased the line separating medicine from marketing.
By 1955, though, the journal was carrying more advertising pages annually than Life magazine, and the number of pages with branded ads increased by a whopping 500 percent, almost all of it from Sackler’s number one client. From 1952 on, Pfizer purchased more than two-thirds of all the antibiotic advertising in JAMA. And, if that weren’t enough, between 1952 and 1956 virtually every issue of JAMA arrived in the offices of hundreds of thousands of physicians with Pfizer’s house newsletter, Spectrum, bound in. The ads were ubiquitous, and striking. One resembled an eye chart:
O
CU
LAR
INFEC
TIONS
RESPOND
TO BROAD
SPECTRUM
TERRAMYCIN
Eye infections, respiratory ailments, skin lesions: Terramycin treated them all. As part of the strategy of positioning the drug as the antibiotic of choice for the maximum number of potential users, the company even produced a cherry-flavored suspension for children, Pfizer promising to “Turn Satans into Seraphs.”
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As the various tetracycline producers battled over market share, the impulse to exploit every possible application for their wonder molecules found an unexpected niche.
Almost all of the pharmaceutical firms that were jump-started by the antibiotic revolution had been in the business of manufacturing vitamins since at least the 1930s. Millions of dollars had flowed to the Wisconsin Alumni Research Foundation to license the technology for supplementing milk with vitamin D by irradiating it with ultraviolet light; the New Zealand company Glaxo had grown to be the preeminent supplier of vitamins in the United Kingdom. Ten percent of Merck’s sales in 1940 was from vitamins, and they were a significant source of revenue for both I. G. Farben in Germany and Hoffmann-La Roche in France. The discovery that vitamin deficiencies were at the root of dozens of human diseases, from scurvy to rickets, created an enthusiasm for a vitamin-fortified diet that continues to this day.*
One of the most dangerous such diseases had been discovered and named even before vitamins themselves. For nearly a century, medicine had recognized the condition known as pernicious anemia, which is caused by a lack of what had been called, since the middle of the nineteenth century, the “intrinsic factor” needed for production of red blood cells. The disease, sometimes known as Addison’s or Biermer’s anemia (for the English and German doctors who first identified it), was treatable by eating large amounts of calves’ liver, then later liver juice, and even later, liver extract. The lifesaving ingredient in the liver that corrected the deficiency, however, wasn’t identified until 1938 by a team led by Merck’s Karl Folkers: vitamin B12.
A dozen different ailments, all of them serious, can be helped by adding B12 to the diet, from inflammation of the gastrointestinal tract, to immune system disorders like lupus, to celiac disease. As the medical community learned of the lifesaving properties of more and more vitamins, however, they made a monumental though understandable error. Although a deficiency of a particular vitamin was frequently the cause of serious disease—scurvy, from a lack of vitamin C, for example—the reverse isn’t true. Taking fewer vitamins than the body needs causes illness; taking more than it needs doesn’t promote health. This proved a difficult concept for people, including most doctors, and explains to this day why some of us take five times the recommended daily allowance of vitamin C in the mistaken belief that it will ward off colds. We want to believe that whenever some is good, more must be better. This is also why dozens of biochemists in the 1940s and 1950s dosed domestic animals with massive quantities of vitamins, particularly the “animal protein factor” known as B12.
The search for an inexpensive compound that would make for healthier cows, sheep, pigs, and chickens was well under way by the end of the Second World War, and the researchers working for the newly ambitious pharmaceutical companies were as eager to discover it as they were new weapons in the battle against disease. One such biochemist at Lederle, Thomas H. Jukes, had learned from a review of published research that Merck had discovered that Waksman’s world-changing actinomycete, S. griseus, produced not just streptomycin, but also B12. He hoped his own search for soil-dwelling bacteria would hit a similar double jackpot, and in December 1948 Jukes received a sample of Aureomycin to test on chickens as a possible cheaper source for the animal protein factor than liver extract, one that was cheap enough for animal feed. The sample was extremely small: enough for Jukes, and his colleague Robert Stokstad, to give supplements to a few laying hens that had been starved to the point that their eggs would normally die within two weeks. The hope was that Aureomycin-produced B12, the protein factor, would allow the chicks to survive.
The results surprised everyone. A dozen young birds had been given Aureomycin, others liver extract, and a control group nothing at all. The chicks given the Aureomycin grew at a rate far faster than those whose hens had been fed a normal diet, which was expected. But they also grew faster than the chicks dosed with liver extract. The reason couldn’t be B12. Something in the antibiotic itself was accelerating their growth.* Streptomyces aureofaciens had proved to be a gold maker in an entirely different realm.
The demand for Aureomycin as a human antibiotic was so great that Lederle could provide no more of the product to Jukes and his team. In a burst of resourcefulness fully worthy of Norman Heatley at the Dunn School’s penurious best, Jukes “dug residues out of the Lederle dump” in order to extract tiny quantities of Aureomycin from the waste products of the fermentation process by which the company manufactured it. He sent the resulting samples to agronomists all over the country to verify its effect, and when a researcher at the University of Florida reported that he had tripled the growth rate of young pigs, even Lederle was convinced. They started marketing Aureomycin to farmers, not as an antibiotic per se, but as a source of B12 in order to avoid the annoying regulatory hand of the Food and Drug Administration.
Stokstad and Jukes presented their findings at the annual meeting of the American Chemical Society on April 9, 1950. The following day, the front page of the New York Times announced that the new “Wonder Drug . . . had been found to be one of the greatest growth-promoting substances so far to be discovered.” They further reported that the use of Aureomycin as a supplement represented “enormous long-range significance for the survival of the human race in a world of dwindling resources and expanding populations.” The Times even speculated that the drug’s “hitherto unsuspected nutritional powers” might aid the growth of malnourished and underweight children.
They wrote truer than they knew. That same year, in one of the more disturbing sidebars to the antibiotic revolution, a Florida physician named Charles Carter started a three-year-long study during which he gave a daily dose of 75 milligrams of Aureomycin to mentally disabled children. As a moment in history when even a wealthy country like the United States worried more about food scarcity than obesity (and hardly at all about the ethics of experimentation on thementally disabled), Jukes could proudly announce, “The average weight for the supplemented group was 6.5 pounds, while the control group averaged 1.9 pounds in yearly weight gain.”
The use of Aureomycin as a method for increasing the growth rate of children did not, luckily, catch on. Not so with domestic animals. Because of the peace treaty that settled the tetracycline patent competition, Lederle wouldn’t be alone in pursuing the agricultural market with tetracycline-derived nutritional supplements. In 1950, Pfizer had already put its corporate toe in the water with a compound they named Bi-Con, which combined streptomycin with vitamin B12 as a growth additive. If Aureomycin was being profitably sold to farmers, why not Terramycin? In 1952, Herb Luther, an animal nutritionist at Pfizer, started what he called “Project Piglet” in an attempt to find a feed that could be given directly to young pigs, accelerating their growth in order to limit the risk of sows rolling over and crushing their too-small offspring. (Morbid fact: In 1950, more than a third of newborn piglets died each year in this way.) Luther’s experimental animals, who were awakened to the stirring sounds of the “William Tell Overture,” and put to sleep to “Brahms’ Lullaby,” were fed on the nursing formula that Pfizer branded as Terralac. Jukes had opened another front in the antibiotic revolution, and here the battlefields wouldn’t be pharmacies and hospitals, but feed stores.
It would be more than a little disrespectful to discuss Thomas Jukes without mentioning that he was also a groundbreaking evolutionary biologist, one of the pioneers of what has become a mainstream element of current thinking about molecular evolution—the powerful idea that much evolutionary change is not adaptive, but neutral. This theory, which Jukes first called non-Darwinian evolution, was independently proposed by the Japanese biologist Motoo Kimura in 1968, holds that most evolutionary variability isn’t due to natural selection, in which adaptations spread because they improve survival or reproductive productivity, but the random drift of mutations that aren’t particularly “superior.” In other words, most of the changes that are observed in a species over time are inconsquential; they do nothing to improve survival or reproduction.*
Though Jukes’s reputation in the world of biology rests mostly on his work on evolution, he was best known during his lifetime as a journalist who, for more than four decades, fought against pseudoscience and creationism from the bully pulpit of a regular column in Nature magazine. In addition, he was a polemicist and public intellectual well remembered today for battling against proposed bans on the insecticide DDT, arguing that the number of lives it saved (by killing malarial mosquitoes) was dramatically greater than any possible ecological risk.
But it was his discovery that antibiotics accelerated the growth of meat-producing animals that has had, by far, the longest tail of consequence. It’s not simply, or even mostly, that it led to the increased consumption of animal protein around the world at a dizzying rate. Far more important, it exposed untold quintillions of bacterial pathogens to antibiotics in doses too small to kill them. The result was the cultivation of some of the most robust bacteria the planet has encountered in the last billion years.
The causes of antibiotic resistance are, of course, much greater and more varied than the promiscuous use of drugs like Aureomycin in animal feed. Even before penicillin had been completely isolated or tested on humans, Ernst Chain and E. P. Abraham had identified an enzyme produced by Staphylococcus aureus—penicillinase—that cleaves the chemical bonds holding the beta-lactam ring together, and so degrades the antibiotic action of nearly an entire family of antibiotics.* It wasn’t until 1945, though, that the phenomenon was documented: An Australian study tested 159 different strains of S. aureus, 128 collected before the advent of penicillin, the other 31 from hospital wards where penicillin was used therapeutically. Only the 31 showed resistance.
But this was just one study, and the first flush of the enthusiasm for the miracle drugs ignored problems of resistance. Articles published during the first years of widespread antibiotic use, roughly 1944 to 1948, seemed to assume that the practice of medicine had largely become a matter of sorting through an array of wonder drugs, and, when in doubt, prescribing them all. Given the uncritical acceptance of the first antibiotics by clinicians—an understandable bit of blinkered thinking, since even when antibiotics were ineffective, they were generally very safe—and the widespread appetite for them by patients, antibiotic resistance was certain to appear, and to appear quickly.
Nonetheless, it was dramatically accelerated by Jukes’s discovery. Since their introduction, up to a quarter of all the antibiotics manufactured have been administered to animals. Sometimes those drugs were restricted to animal use; in May 1940, milk cows on display at the “Foodzone” exhibit of the 1939 World’s Fair—including the first of Borden’s “Elsies”—came down with the mammary gland infection known as mastitis, which was cured by the too-toxic-for-human-use gramicidin. Much more frequently, however, the antibiotics prescribed were identical to those used by humans. By the 1950s, as much as 10 percent of the milk consumed in the United Kingdom and the United States was contaminated with penicillin, which had been used to treat mastitis in cows who were then milked before the penicillin cleared their systems.
And that was just when antibiotics were used more or less as intended. Because Aureomycin and Terralac were given not only to cure (or even prevent) infection, but to promote growth, the dosages were very small: generally around 200 grams per ton of feed for a two-week period—enough to grow animals to their slaughterhouse weight as quickly as possible, but far below the level needed to stop a bacterial infection. In fact, these exposures more closely replicate the concentrations of antibiotic molecules in nature, such as Alexander Fleming’s mold juice or Selman Waksman’s soils.
There, they behave very differently. The standard explanation for the phenomenon of bacterial effectiveness—the fact that some microbes produce substances that are highly toxic to other microbes—was historically couched in distinctly martial, not to say anthropomorphic, terms: Bacteria (and fungi like the penicilliums) produce the molecules we call antibiotics to defend themselves in an eternal Hobbesian war of all against all.
Plausible, but for the uncomfortable fact that the molecules that microbes produce aren’t usually toxic in the concentrations that occur in nature.
The natural history of antibiotics is not, it turns out, the obvious one, in which unicellular life evolved defense mechanisms during billions of years of natural selection. Antibiotic molecules in nature aren’t always, or even usually, weapons. Bacterial populations react to the presence of low concentrations of antibiotic molecules in a variety of ways, and many of them are actually positive. Many antibiotics are what biologists call “hormetic”: beneficial in low doses, even promoting the creation of what are known as biofilms, matrices that hold bacterial cells together with a polymer “glue” and make them far more durable in the presence of both the animal immune system, and antibiotics themselves.
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.