The federal government did put an end to patent medicines. It was not, however, the result of new laws or enforcement directed at nostrums. Instead the patent industry was decimated as the indirect result of historic legislation that outlawed its core ingredients, narcotics and alcohol. The first blow was the 1914 Harrison Narcotics Tax Act. The second was the Eighteenth Amendment to the U.S. Constitution five years later that kicked off thirteen years of alcohol prohibition.1
The Harrison Act was Congress’s response to worldwide fears about skyrocketing demand for opiate-based painkillers. World War I had caused a seismic shift inside the pharmaceutical industry. The outbreak of hostilities in Europe in July 1914 led to the suspension of the International Opium Convention treaty, a sweeping anti-narcotics agreement signed a couple of years earlier by a dozen countries at The Hague.2 Knowing that war was good for business and free of government regulation, drug firms ratcheted morphine production to record levels. Some, like Britain’s Whiffen & Sons, doubled their annual output to twenty tons, much of it leaking to the black market. Overproduction in Swiss, Dutch, and German pharmaceutical companies also fed illegal syndicates.
Congress passed the Harrison Act only six months after the war started. It prohibited most distribution and use of cocaine as well as much of the importation of opiates. Bayer’s lobbying, however, earned Heroin an exemption. The law created a national registry to track every person and company that dealt in opiate- or cocaine-based drugs. The AMA and other medical groups successfully petitioned to exclude physicians and hospitals that dispensed narcotic painkillers, so long as the drugs were not given to addicts (before the Supreme Court struck down that provision a decade later, 25,000 doctors were charged with violating the narcotics ban and 3,000 went to jail).3
The law sanctioned one class of opiate manufacturer and distributor: pharmaceutical companies. The only authorized purveyors were the manufacturers of drugs listed on the USP/NF. It was criminal for anyone else to import, make, or sell the same drugs.4 The drafters of the Harrison Act mistakenly thought that making narcotics legal under the exclusive control of the medical/pharma industries would reduce the country’s huge hunger for narcotics.
The underlying problem was the appetite pharmaceutical firms had developed for the staggering profits from their highly addictive products. It was an international malaise. When opiate production declined after World War I, drug companies turned to cocaine. French pharma firms conspired to divert their cocaine overproduction to drug traffickers for enormous profits. In Switzerland, one of the few countries to have opposed all drug treaties, a postwar report concluded the country’s pharmaceutical industry had produced “100 times more [cocaine] than was required for [domestic] medical and scientific purposes.” Anyone who simply attested to being a physician could buy ten kilos of cocaine from Swiss drug firms. Compounding the problem was that Switzerland was the only nation without any drug export controls. In Germany, Bayer, Merck, and competitors such as Hoechst AG had trouble keeping up with demand for cheap kilos of 99 percent pure cocaine.5
The situation was little different in the United States where narcotics provided upward of half all pharmaceutical profits. Barred by the Harrison Act from competing with the sanctioned pharma companies, and forbidden by Prohibition to use alcohol, most nostrum makers had finally given up. Philadelphia-based Smith, Kline and French, one of the most successful mail order companies, abandoned 5,800 of its 6,000 medications. It had enough left in its Eskay line of baby nutrition and food products to survive.6 Meanwhile, for traditional drug companies, sales had increased since the demise of the patent remedy industry.
Press reports of addiction and overdoses with Heroin had spurred some companies to search for a less addictive substitute. In 1916, two German chemists had discovered Oxycodone, a synthetic opioid that was chemically similar to Heroin. They thought it was a “gentler codeine.”7 Four years later, two different German researchers developed hydrocodone, a semisynthetic opiate derived from codeine. The scientists believed both drugs matched Heroin’s therapeutic benefits without the downside of addiction.
It was difficult, though, to wean the industry off its narcotics reliance since there were few other types of drugs to drive the market. “You could count the basic medications on the fingers of your two hands,” noted a later president of Merck.8 Most pharma companies were simply manufacturers who depended on research and discoveries in academic labs to find and license products.9
The pharma companies knew the drugs they sold cured virtually no disease. Although the public bought them for everything from smallpox to typhoid to diphtheria, the medications at best reduced symptoms and eased pain. Sales mattered more than cures to most pharma companies.10 The most promising new drug category measured by revenues was barbiturates. Discovered in 1903 by Bayer, it had nothing to do with treating an illness but was marketed as “a new class of hypnotics” to provide relief for insomnia, anxiety, nerves, and depression. Overnight barbiturates replaced bromides, a cruder and more primitive class of patent drug sedatives.11 Bayer released its most powerful version, phenobarbital, in 1912 (the press nicknamed it a “downer” because it made people drowsy).12 Millions of patients flocked to barbiturates, all sold without prescription.
American companies that did not have their own branded barbiturate concentrated on getting their other medications listed on the USP/NF. Consumers believed the USP/NF drugs had the best quality control.13 That allowed Merck, Lilly, Squibb, Pfizer, and others to charge several times more than the identical formula from small, family-run compounding pharmacies. When Bayer’s copyright on Aspirin expired, the company’s legal effort failed to stop others from manufacturing and selling it. So, Bayer’s slogan became “Genuine Bayer Aspirin,” and it sold for double the price of generic aspirin.14 The same was true with Parke-Davis’s Adrenalin, a compound of pure adrenaline it had patented. The company won a lawsuit in which a federal appeals court ruled that because of the similarity between the name of Parke-Davis’s drug and the body’s natural hormone, all other U.S. drug companies could only market their adrenaline medications as epinephrine. That ruling allowed Parke-Davis to charge triple the price of its competitors.15
A grim example of the downside of pharma’s overall lack of innovation came during the deadly influenza epidemic of 1918. Called the Spanish Flu since Spanish newspapers were the only ones in Europe that ran stories about it, it infected half a billion people, about a third of the world’s population. By some estimates it killed 100 million over a brutal sixteen weeks. In comparison, the fourteenth-century bubonic plague had wiped out a quarter of the planet over ten years.16 Pharma companies had nothing to slow or treat the pandemic. It stopped only after the lethal microbe had run its course.
The Spanish Flu spurred academic and private researchers to redouble their efforts to find treatments for contagious infections and illnesses. By this time, bacteriologists realized that the trillions of self-sufficient, single cell microbes, including those that make up about 70 percent of every human, are friendly. Or at the very least they had evolved to coexist with people.
What researchers did not yet know was that microbes, especially the predatory ones that cause disease, are the ultimate examples of Charles Darwin’s survival of the fittest theory. Bacteria metamorphose incredibly fast to better replicate, sometimes in ways that rival science fiction. The germ responsible for tuberculosis, for instance, dies in about twenty-one days unless it can infect a new host. In many early cases, the TB germ attacked a patient’s kidneys, lymph nodes, and sometimes even the skin. Over time that pathogen mutated so as to target the lungs. That resulted in a persistent cough and converted TB into an airborne pathogen that was easily spread in crowded cities. The same is true of other deadly bacteria. Rabies germs evolved to attack the part of the brain that controlled aggressive biting, making it more likely than an infected animal would try to pass it to other animals or humans by biting them. The microbes behind the Black Plague, Yersinia pestis, originally infected only rats but transformed over time so that fleas on those rats became the carriers to humans. It later morphed again so that humans who developed plague pneumonia spread the infection. When Lyme disease passed slowly from rats and deer, the infectious microbe evolved to infect ticks that fed on those animals. The ticks passed it much faster to people.17
Some pathogens lay dormant after an infection and then much later reappear as a different illness. Children infected by the chicken pox germ recover usually in a couple of weeks. The virus, however, hides in nerve cells along the spine and brain and often remerges decades later as shingles.18
The researchers made little headway on fighting infectious diseases. The hit drugs that came from the labs had nothing to do with eliminating pathogenic bacteria. A Los Angeles pharmacologist and chemist, Gordon Alles, was searching for an improved decongestant when he isolated the stimulant amphetamine sulfate.19 He teamed with Smith Kline, who already marketed a cotton strip soaked in a slightly unstable liquid and sold it as a decongestant inhaler.20 Smith Kline bought Alles’s patent rights in exchange for a 5 percent royalty. The company’s inhaler was wildly popular; 10 million sold in the first five years. And it was the first to market pure amphetamine pills, branded as Benzedrine Sulfate (bennies in street slang).
The most significant medical breakthrough was a treatment for diabetes, a deadly physiological condition. A team of University of Toronto researchers announced their discovery of insulin in 1922. The Indianapolis-based family who owned Eli Lilly won the exclusive right to develop and market insulin to diabetics in North and South America. The following year Lilly got a patent on its process to collect and extract large quantities pure enough for clinical distribution. The insulin market grew exponentially over a couple of decades.21
It was a second revolutionary drug discovery, however, that upended the pharmaceutical business. Penicillin might have remained undiscovered had it not been for some good luck in a science lab in 1928. A Scottish microbiologist, Alexander Fleming, returned from his summer vacation and noticed something unusual. His research involved growing bacteria and observing its behavior under different conditions. Along the edges of a stack of petri dishes he had left to be washed were colonies of staph bacteria. During his absence, a blue-green mold had grown on the plates. What caught his attention, though, was that staph bacteria near the mold on the plates had disappeared.22 As a doctor at a British Army Hospital in northern France during World War I, Fleming had learned firsthand that bacteria were often as deadly as enemy shelling. He wondered whether some of the discharge from the mold had stopped the bacteria from growing.
Tests on his “mold juice” isolated it to a rare strain of the penicillium family.23 Further tests were promising, demonstrating the mold killed a wide range of common microorganisms.24 Fleming and his assistants could not, however, isolate a pure alkaloid from the chemically unstable mold juice. When Fleming wrote about his discovery in a 1929 scientific paper, he anglicized the Latin penicillium to penicillin, and he downplayed hope for possible therapeutic benefits. Penicillin went mostly unnoticed.25
A few other researchers also tried and failed to extract a pure alkaloid.26 It took seven years before a team from Oxford’s School of Pathology in 1936 chanced on Fleming’s paper and restarted experiments. The previous year a German chemist had discovered Prontosil, a brick-red dye whose active ingredient was sulfonamide. That sulfa drug, and others that followed, were the first capable of combating streptococcal infections.I27 Sulfa medications piqued the interest of the Oxford team to investigate the mold that Fleming had described as being lethal to dangerous microorganisms.28
Howard Florey, a Rhodes Scholar and Australian pathology professor, ran the Oxford lab. He assigned to the penicillin project a brilliant twenty-nine-year-old chemist, Ernst Chain, who had emigrated from Berlin in 1933. Chain’s family were devout Jews and he had left Germany “because I felt disgusted with the Nazi gang.… I did not believe that the system would last more than six months at the most.”29 Initially, Chain, a self-described “temperamental Continental,” seemed an odd fit with the small lab’s more reserved Oxford- and Cambridge-trained researchers.30 With his bushy black hair, thick mustache, and rumpled clothes, he seemed at times to relish his outsider status. Although his colleagues thought he was argumentative and brusque, they came to respect his considerable biomedical skills. In less than a year, Chain singlehandedly developed a process for extracting and purifying tiny amounts of penicillin.31 It was twenty times more powerful in destroying colonies of bacteria than anything they had previously tested.
It took another four years, until 1940, before trials demonstrated penicillin shielded mice from deadly streptococci bacteria.32 Still, the Oxford researchers worried that anything capable of so thoroughly obliterating bacteria might harm humans though it had not proven toxic to mice. The following January, Florey invited Charles Fletcher, a young doctor from Oxford’s Radcliffe Infirmary, to meet his team. Florey asked Fletcher to “find a patient with some inevitably fatal disorder who might be willing to help.”33
Fletcher recalled there “were no ethical committees in those days that had to be consulted, so I looked around the wards and found a pleasant 50-year-old woman with disseminated breast cancer who had not long to live.”34 She agreed to the experiment after Fletcher told her it was for a “new medication that could be of value to many people.” That unnamed woman was the first of several terminally ill patients who volunteered over several weeks. Oral and rectal administration proved useless since tests revealed those procedures did not get enough penicillin into the blood. A stomach tube tried on another patient showed some promise. But doctors found the greatest concentration of the drug after an intravenous injection.
Fletcher hoped to next test penicillin’s curative powers on a person seriously ill, but not at death’s door as were the first group of patients. Fletcher found a forty-three-year-old British policeman in the hospital’s septic ward. He had scratched his face while pruning roses and the scratches had become infected. His face and arms were covered with abscesses. He had excruciating infections in his bones and was coughing up pus from lung cavities. Doctors had already removed his infected left eye. “There was all to gain for him in a trial of penicillin,” recalled Fletcher, “and nothing to lose.”35
On February 12, 1941, Fletcher started the treatment, 300 mg every three hours through an IV drip. In just a day the policeman felt better. By the fourth day “there was a striking improvement,” and by the fifth he had made a miraculous recovery. His temperature was normal, he was eating regular meals, and the abscesses on his face, scalp, and arms were almost gone.36 The problem was that the lab—still struggling with developing an efficient means of extracting purified penicillin—ran out of the drug. Florey watched in frustration as the bacteria roared back. The policeman died a few weeks later.
“We then decided to avoid using large amounts of the precious penicillin by concentrating on children and localized infections,” recalled Fletcher. Five more patients, four of them children, were treated over the next few months. The serious bacterial infections cleared from each. There were few side effects and it did not have the toxicity associated with sulfa drugs.37 Florey and his team realized by then that the drug might be one of the most important medical discoveries ever.38
By the time the Oxford team realized that penicillin was a momentous breakthrough, England had been at war with Nazi Germany for nearly two years. The constraints of a wartime budget left little money for an ambitious rollout of what many politicians considered an experimental drug. Even if Florey roused political support, war had consumed Britain’s chemical industry. It had no spare capacity to produce the new drug. Florey’s Oxford team continued its research on a tiny budget and with improvised equipment. Against the backdrop of what many expected to be an imminent Nazi land invasion of Britain, they prepared to destroy their lab and research files if the Germans arrived. Each of them rubbed some of the brown penicillin spores into their clothing; if one managed to evade capture by the Nazis, those spores would remain untraceable yet could be recovered years later.39
Chain tried to convince Florey to patent penicillin; at least it might bring in royalties to pay for more research. Florey asked the advice of two of Britain’s leading authorities, Sir Edward Mellanby, director of the Medical Research Council, and Sir Henry Dale, a Nobel Laureate. Both were aghast at the idea of a patent, although their German, French, Swiss, and American counterparts did so regularly. Chain knew there had been little advancement on Prontosil, the sulfa drug discovered by Bayer. A German patent court had ruled its active ingredient—sulfanilamide—was in the public domain since it had been discovered and used in the dye industry in 1908. Some firms had figured out molecular modification to produce sulfanilamide derivatives, so-called me-too drugs.40 Those chemical cousins qualified for patent protection.41
When Sirs Mellanby and Dale met with Chain, they were not moved by his impassioned argument. It was unseemly commercialization, they told him. If he persisted, they warned, it might not only scuttle his career but reflect badly on his fellow Jewish refugees.42
Forced to look for money abroad, Florey successfully lobbied for funding from the American-based Rockefeller Foundation, where he had had a fellowship a decade earlier.43 Florey and one of his key researchers, Norman Heatley, planned a trip to the U.S. hoping the government and American pharmaceutical firms might help figure how to increase the yields of pure penicillin.
The day before departing for the States, Florey told Chain he was not included. Chain, shocked, thought it was an “underhand trick and act of bad faith.”44 He argued that the penicillin project had always been a “joint venture” only between him and Florey, and he cited reasons why he believed that Heatley had played a “very minor part.” Florey refused to change his mind.
In the summer of 1941, Florey and Heatley were in Peoria, Illinois, where the Department of Agriculture had its Northern Regional Lab specializing in fermentation.45 Heatley opted to stay there and work on increasing the yields while Florey lobbied U.S. pharma companies to commit resources to the project.
Over several weeks, the Peoria lab made progress. Substituting lactose for the sucrose used by the Oxford team produced significantly better yields. The Peoria lab next found that adding corn steep liquor during fermentation increased the results tenfold. Enhancements made to penicillin precursors again upped the yield. Still, it was a fraction of what was needed for the war. In late summer the Peoria researchers tried growing penicillin submerged in huge tanks. The Oxford strain still produced only small traces of the drug. So the Peoria lab launched an international search for a penicillium strain that might produce better yields. Soon, soil samples and produce with mold from around the world arrived at the small government lab. To the surprise of the researchers, the most productive strain came from the mold of an overripe cantaloupe a local housewife found at a Peoria fruit stand less than a mile from the lab. The Carnegie Institution used X-rays to create a modified and more powerful version of the cantaloupe strain. A team at the University of Wisconsin used ultraviolet radiation to boost its productivity even further.46
While Heatley and the American researchers in Peoria worked to mass-produce the drug, Florey was making little headway in his efforts to interest American pharmaceutical companies in the penicillin project. He knew that independent of the Oxford experiments, Merck, Eli Lilly, and Squibb had shown sporadic interest in the drug.47 Florey’s expectations were particularly high since he had enlisted the help of an old acquaintance, Alfred Newton Richards, a respected University of Pennsylvania pharmacology professor. Richards was chairman of the Committee on Medical Research, an influential branch of the Office of Scientific Research and Development (OSRD). Franklin Roosevelt had created the OSRD only a couple of months earlier (June 1941), and tasked it with prioritizing scientific and medical efforts needed to bolster national defense. If the OSRD deemed a project critical to the war effort—as it did with the atomic bomb—it could provide massive research and development funding. Civilian scientists served as key OSRD directors and Roosevelt cited national security to empower it to bypass most of the bureaucratic obstacles and contract directly with both universities and private industry.48 Once Florey had persuaded Richards that penicillin was a breakthrough, Richards personally lobbied the drug firms.
Getting involved in penicillin would serve the national interest, Richards told senior management at each company. They were hesitant though to make any commitment. They had heard widespread tales of the difficulty in achieving significant yields with the existing fermentation methods. And they were concerned about whether the penicillin project would be subject to the regulations of the federal Food, Drug, and Cosmetic Act that had passed three years earlier, the first significant legislation about the drug industry since Harvey Wiley’s 1906 Pure Food and Drug Act.49 II 50 In fact, variations of the final law had been stuck in Congress for five years before a lethal drug disaster shamed Congress into acting (just as it had taken Upton Sinclair’s stomach-wrenching The Jungle to get the 1906 law passed).51 One hundred and seven people, mostly children, had died from Elixir Sulfanilamide, a sulfa-based cough syrup mixed with a chemical used in antifreeze and brake fluids to give it a sweetish flavor.52 There was fury when the Tennessee-based patent drug maker maintained “we violated no law” since there was no legal requirement to test drugs for safety before selling them. The company was found guilty only on a minor violation: it marketed its lethal syrup as an elixir and by law elixirs had to contain alcohol; its did not.53
The new law was Congress’s reactive effort to put a premium on safety regulations in medicine (medical devices and cosmetics joined drugs now under FDA oversight). New drugs had to be submitted to the FDA and demonstrated as safe before they could be sold to the public. Another key provision was that the burden of proof to demonstrate safety shifted from the government to the drug company. It established the first ever rudimentary animal and human clinical testing for toxicity. Package inserts with dosing information and warnings about possible dangers had to be sent to pharmacists. The new law required all drug manufacturers to register with the FDA, which was now empowered to inspect factories and to recall medicines judged dangerous at the pharma company’s expense.54 That same year Congress also passed the Wheeler-Lea Act. It gave limited power to curb deceptive and false drug advertisements to the Federal Trade Commission (FTC), the government’s agency created in 1914 for consumer protection and civil antitrust enforcement.55
American pharma companies detested any regulation. They had always operated in an industry built on the inviolable right of consumers to self-medicate.56 What had them in a fury, though, was when the FDA issued operating regulations that proposed that some drugs deemed too dangerous should be prescription only since no warning label would be adequate.57 It was the FDA’s feeble attempt to rein in the explosive growth of barbiturates and amphetamines. There was ample evidence by the time of the 1938 law that both drugs were addictive and deadly in large doses. The law did not cover them since they were on sale before it was enacted. The FDA’s effort failed. It managed to only mandate prescriptions for narcotic-based medication and powerful sulfa drugs.58
What about penicillin? The American pharma firms asked to help develop the drug worried what might happen if they were successful. Would penicillin be subject to a warning label by the FDA? Would it demonstrate some toxicity if developed and distributed widely, thereby becoming prescription only? The companies were particularly concerned because the FDA had managed to require prescriptions for sulfa meds. Those were antibacterials and marketed for some of the same infections that penicillin might target.59 No drug company wanted to commit major resources to an experimental medication when the FDA might later try limiting its commercial use. Alfred Newton Richards tried inducing pharma to join the project by agreeing to put penicillin and all the related research for it outside the reach of the 1938 law.60
At an October 1941 meeting in Washington organized by Richards, although the drug chiefs were no longer worried about obstacles from the FDA, they were still ambivalent about making any commitment. Most looked to George Wilhelm Merck to take the lead.61 Merck wielded great influence, even with his bitterest competitors. He had a widespread reputation as a pioneer who put research and drug innovation ahead of short-term profits.62 When he opened the Merck Institute for Therapeutic Research in 1933, in the middle of the Great Depression, it was the industry’s first research lab. It attracted some of the country’s top academic chemists and pharmacologists.63 They produced breakthroughs in antibiotics, hormones, sulfas, and vitamins (the discovery of B12 as an effective therapy for pernicious anemia accounted for 10 percent of Merck’s sales in the mid-1930s).64 Other companies followed; Lilly opened a research lab in 1934 and Abbott and Squibb christened theirs in 1938.
Given Merck’s emphasis on drug innovation, Florey and his Oxford colleagues expected him to be their ally when it came to penicillin. They made the case that penicillin held the promise of fighting often lethal bacterial infections, including chicken pox, mumps, meningitis, rheumatic fever, pneumonia, and syphilis. The greatest cause of death for mothers was from infections following childbirth. Complications from simple contagions like tonsillitis were particularly deadly for children younger than ten. Fatalities from blood poisoning and gangrene, resulting often from a minor wound, accounted for about half of the 10 million soldiers who died in World War I.
Richards had warned Florey that Merck was “pessimistic” about penicillin.65 He thought that was because Merck had little financial incentive to chase an experimental antibacterial. It was one of the first U.S. firms to obtain a license from Bayer to sell Prontosil, a sulfa drug targeted to fight pneumonia. Sales were strong.66 What Florey and his team did not know was that Merck’s company had little proficiency in fermentation, the part of the penicillin process that had stymied researchers. No one outside the company knew Merck’s efforts to synthesize penicillin had gone poorly.67
At the October 1941 meeting, Merck surprised Florey. “We won’t do it,” he insisted.68
Everything changed two months later on December 7, when the Japanese launched a surprise attack on the American naval fleet at Pearl Harbor. Richards organized another meeting between Florey and a cross section of U.S. government scientists and pharma chiefs. They met in Manhattan ten days after Pearl Harbor. America had by then declared war on Japan and Germany. How many lives on the battlefield might be saved by penicillin was no longer a matter of idle speculation for the American drug executives. George Merck had overcome his reluctance. He surprised those at the meeting by announcing that if the yields reported by the Peoria lab could be replicated consistently, the American pharmaceutical industry would commit to a crash program.69 One government official there thought that Merck’s reversal marked the moment “a new pharmaceutical industry was born.”70
To encourage their collaboration the government announced that the penicillin project was exempt from antitrust laws.71 Merck and Squibb agreed to share all their research and to own equal shares in any patents and inventions from the work. Pfizer joined the following year after it resolved concerns that penicillin spores might contaminate the citric acid that was the backbone of its business.72 Lilly, Abbott, Upjohn, and Parke-Davis soon entered their own information-sharing agreements.73 The War Production Board enlisted the help of the U.S. Department of Agriculture and a broad cross section of government scientists.74 The Office of Scientific Research and Development used public funds to sign fifty-six contracts with universities and research hospitals for penicillin-related studies.75 Florey returned to Oxford while Heatley joined the team at Merck and worked with a noted chemist, Max Tishler (Tishler was also directing research on a synthetic hormone derived from the adrenal gland, cortisone).76 The American drug firms discovered that the low yields that had frustrated the British researchers was a problem not easily solved.
It took until March 1942 to manufacture enough penicillin to treat the first American patient. Anne Miller, the thirty-three-year-old wife of Yale’s athletic director, was in a New Haven hospital in critical condition from blood poisoning after a miscarriage. Such bacterial infections were especially lethal for young mothers. Every treatment her doctors tried—powerful sulfa drugs, blood transfusions, rattlesnake venom, even surgery—had failed.77 A hospital physician was friends with Howard Florey, who had told him about the secret experimental antibiotic. Florey put him in touch with Max Tishler. Merck’s team crashed around the clock for three days to purify 5.5 grams—a teaspoonful—of pure penicillin powder. It was half the entire stock in the U.S.78 They rushed it by plane to Miller.79 By the time the drug arrived, Miller was slipping in and out of consciousness. Her fever had spiked to 107. No one had any idea of what the correct dosage might be, so the physicians diluted a gram into her intravenous solution. Her astounding turnaround is recorded in her hospital chart (now a permanent part of the Smithsonian Museum). Miller’s temperature was normal the following morning for the first time in a month, she was no longer delirious, and in less than a day she ate her first meal in a month. Her blood tested negative for bacteria only twenty-four hours after the first injection.80 Miller’s miraculous recovery was not only big news inside Merck, but it encouraged other U.S. pharmaceutical firms to redouble their efforts to find the best industrial process for mass-producing penicillin.81
Because of its potential military value, the penicillin work under way at the pharma companies was a national secret. That changed inadvertently that November following the deadliest nightclub fire in American history. Nearly five hundred died at Boston’s Cocoanut Grove and hundreds were terribly burned. The federal government covertly asked for Merck’s help. Tishler’s lab worked around the clock. The best they could produce on such short notice was a diluted liquid containing some concentrated penicillin. What Merck sent to Massachusetts General was not of the clinical purity used to treat Anne Miller. Still its anti-infective qualities helped dozens of victims successfully fight the infections from their burns.82
By the time of the Cocoanut Grove fire, both the American and British governments had declared penicillin production a national security priority. In 1943, the War Production Board had two all-consuming priorities, developing an atomic bomb and mass producing penicillin.83 The government knew that making it on an industrial scale required enormous federal resources and a collaboration of pharma firms with agricultural and chemical companies that specialized in fermentation. One hundred and seventy-five companies were evaluated. Seventeen made the final cut, including Merck, Squibb, Pfizer, Abbott, Eli Lilly, Lederle, Parke-Davis, and Upjohn. Once on board they learned that while making penicillin was their top mission, the government wanted them also to focus on developing antimalarials to slash the death rate for American troops fighting the Japanese in the Far East.84 III 85 There was also ongoing research for a new group of corticosteroids, originally fueled by false reports that the Nazis were using them to enable “super pilots” to fly at altitudes over forty thousand feet. When that research did not pan out, the Air Force bought millions of Smith Kline’s Benzedrine pills and distributed them to bomber and fighter pilots. The Army stocked up on barbiturates, which were widely dispensed to sedate wounded soldiers, alleviate pain, and offset shock and anxiety in the battlefield.86 (All the frenetic projects on corticosteroids and developing antimalarials led to unintended advances in immune globulins to fight infections and blood substitutes.)87
The government recruited researchers from thirty-six universities and hospitals.88 It also approved and paid for six huge new penicillin manufacturing plants. The pharma firms, meanwhile, got tax incentives on all investments to retrofit their factories to maximize penicillin production. Lilly, for instance, reconfigured a plant used to produce two-quart milk bottles into penicillin manufacturing, complete with a three-thousand-gallon fermentation tank. Pfizer turned a former ice factory into a fermentation plant. Sensing the potential in penicillin, the previous year Pfizer had reincorporated in Delaware and went public with 240,000 shares of common stock.89
The results were dramatic. In the first five months of 1943, the government project produced 400 million units of penicillin, only enough to treat 180 severely sick soldiers. In the last seven months of the year, as the pharma firms got far more proficient, production increased 500 percent to more than 20 billion units. By D-Day, June 6, 1944, the joint effort churned out 100 billion units monthly, enough to treat 40,000 troops. By the end of the war in Europe, May 1945, American companies were producing a stunning 650 billion units monthly.90
I. Sulfa drugs stop bacterial infections by interfering with their metabolism. Antibiotics such as penicillin are more effective as they destroy the bacteria. The chemist who isolated the first sulfa drug, Gerhard Domagk, worked for the Bayer pharmaceutical subdivision of Germany’s I. G. Farben conglomerate. When Domagk was awarded in 1939 the Nobel Prize in Medicine, Hitler—angry that a previous Nobel Peace Prize had gone to a German pacifist—barred Domagk from accepting the award. The Gestapo arrested Domagk and briefly jailed him because he had been “too polite” in the letter he had sent refusing the award.
II. The 1938 statute also created limited powers for the FDA to certify food colorings as “harmless.” Foods would be considered adulterated if they contained a coloring agent not approved by the government. While the 1938 law was the most sweeping legislation about drugs since the turn of the century, there had been a series of limited-scope laws during the 1930s that did reduce some of the remaining patent medicine abuse of opiates, cocaine, and marijuana. In 1937, marijuana was put under federal control with the Marihuana Tax Act.
III. As part of the frenzied research effort to perfect a drug to combat malaria, the Army-controlled Malaria Research Project conducted human experiments at four prisons, with the largest at Stateville Penitentiary outside Chicago. Prisoners were offered reduced sentences, cash stipends, and extra amenities for agreeing to be infected with malaria and then treated with experimental drugs. The prisoners were encouraged to keep meticulous notes. University of Chicago researchers selected 200 men, from 487 volunteers, for two years of testing at the prison hospital. The trial drugs had toxic side effects that sickened many and resulted in one death. In 1947, defense attorneys for Nazi doctors charged with war crimes for human experimentation at concentration camps cited the malaria experiments in a failed effort for an acquittal.