Like any good student’s, Boger’s reformation encapsulated sweeping changes in a struggle that was mainly personal. He was less intent on perfecting than replacing the old order.

His ambitions, as always, befit his precocity. Medically, the twentieth century may be remembered as a time of two great pandemics separated by more than six decades and bracketing the most productive period in scientific history. The first contagion, influenza, obscured by the horrors of World War I, swept westward with calamitous speed in the fall of 1918: Covering the globe in just two months, it killed 22 million people, almost twice as many as the war itself. Though the general nature of infectious disease had been understood for more than forty years, science was scarcely more able to identify the infectious agent or stop it with drugs than in the 1340s, when the Black Death claimed one third of Europe and even the most learned thinkers ascribed the affliction to a bizarre conjunction of planets and treated it with powdered stag’s horn and potable gold. The century’s second great contagion appeared slumberingly in 1980 and, by contrast, has spread much slower since, granting a vastly more knowledgeable and priority-driven research establishment a rare chance to catch up. Within four years, when nationally still fewer than 3300 were dead and less than 4500 new cases were reported, the cause of the contagion was known. By 1988, an array of promising molecular targets had been identified. The second contagion—AIDS—epitomized the challenges to the new religion of molecular pharmacology that Boger, by the mid-1980s, had embraced as one of its leading apostles. But it was the 1918 flu epidemic, one of the three deadliest contagions in history, from which the old religion—the strikingly successful combination of soil screening and medicinal chemistry—first arose.

The pandemic reached America last, coming ashore in Boston in the first days of September, three months before the end of the war. Four days later the first cases were reported at an overcrowded 45,000-man military cantonment at nearby Fort Devens, where within three weeks the slate-colored bodies of up to ninety men a day were being “stacked like cordwood” for burial. The flu itself was not the killer. With no antibiotics or other treatments available, the victims’ lungs became saturated with pneumonia-causing bacteria. Many died, drowning in their own fluids, less than forty-eight hours after their first cough. In an age when American prosperity and technology had seemed capable of conquering any problem, the fact that organized medicine offered only palliatives against the plague struck many as its most apalling aspect. “Science,” the New York Times editorialized, “has failed to guard us.”

In Boston, eleven-year-old Max Tishler raced among disease-infested brick tenements, delivering aspirin to the families of the dead and dying. The fifth and next-to-last child of poor Jewish immigrants, Tishler had gotten a job washing bottles and filling them with powders for a druggist. Despite tentative advances in other areas, the pharmacopeia for acute infectious disease still consisted mostly of metals and extracts; aspirin, with its wondrous painkilling and fever-reducing properties, was one of only a few drugs owing their discovery to science. It was derived chemically from coal tar, a noxious sludge that one hundred years earlier became the first major toxic by-product of the industrial age. Aspirin didn’t cure people, but it comforted them, and only in hindsight does young Tishler’s diligence seem futile.

Ministering to the sick gave Tishler “a feeling that I might want to do something in the line of disease,” but his circumstances were bleak, prohibitive. His Romanian-born father left when he was four years old and would stay away more than thirty years. His mother and siblings all worked, and within the family only he and a younger sister would finish high school. Tishler was undaunted. Lean and small boned, with a helmet of wiry rust-colored hair, sprightly ears, and a piercing grin, he had a bristling intelligence and fiery resolve. He worked constantly—hawking newspapers at trolley stops before school, baby-sitting, answering phones—all in addition to holding down jobs at various drugstores. After graduating from Boston English High School, he won a scholarship to Tufts, where he majored in chemistry and graduated magna cum laude. He obtained his pharmacist’s license the same year.

Eschewing medical school, Tishler opted for a career in chemistry. A professor told him that “Jews have a hard time getting placed and you won’t get anywhere,” but Tishler, irascible and determined, disregarded the advice. He enrolled at Harvard in the fall of 1929, the near aftermath of the most blatantly antisemitic period in its history.

As a graduate student, Tishler was drawn to organic synthesis; he wanted to make biologically active molecules, although what use such molecules might have as drugs remained much in doubt. Like many aspiring synthetic chemists, Tishler had been seduced exultantly by Paul Ehrlich’s prophecy of a “magic bullet,” a molecule that attacked the cause of disease but not its host. To his professors, however, what a molecule did was not as important as how it was made, its architecture. Tirelessly, Tishler immersed himself in the developing new reactions by which compounds could be broken down and put back together. He was an intrepid bench chemist. Working once in a tiny lab with wet hands, he dropped a bottle of highly flammable benzene, which burst into flames: With the billowing smoke blocking his exit, he climbed out onto a third-story ledge and stayed there until several students rescued him. “What I think bothered me about the whole thing was the fact that I caused a fire,” he would recall, “and we used up all the carbon dioxide extinguishers.”

Tishler excelled at Harvard and was hired as an instructor, then as now a slap on the back as Harvard gave tenure only to those who had proven themselves elsewhere. By 1936, married now and with his wife, Betty, expecting at the height of the Depression, Tishler began looking for a more permanent job. Hoping for an academic post, he applied widely but received no offers. Meanwhile, one of his sisters had recently died of tuberculosis, and Tishler, who had continued to work as a druggist through graduate school, grew even more deterimined to work in medicine. Slowly, he began considering what until just a few years earlier would have been unthinkable for a promising chemist, much less a young Harvard professor. He began applying to drug companies.

Ehrlich aside, the U.S. drug industry in the mid-1930s was still a tainted business, more likely to produce such parodies as William Radam’s Microbe Killer or Wendell’s Ambition Pills than a genuine therapeutic. Science’s failure eighteen years earlier during the flu epidemic had not been erased by its few successes since nor by the attempts of several companies to establish their own research labs. Companies were small, good at selling old products but with little idea of how to find new ones. As in Arrowsmith, Sinclair Lewis’s 1925 novel in which a scientist who goes to work for a drug company is given up as “gone wrong” and “dead,” an academic scientist who went into industry risked losing not only his credibility but his friends.

Tishler was not averse to working in business, but he also had no choice. Barred from a significant future at Harvard, unable to find another academic post, he plunged into applying to the major drug houses. After months of trying and apparently being rejected by at least one company—DuPont—because he was Jewish, he finally received an offer. It was from a small company in New Jersey that had a reputation for doing high-quality, interesting science but had yet to develop its first drug.

The company was Merck.

•  •  •

Since he’d taken over his family’s fine chemical company in 1925 at age thirty-two, George Wilhelm Merck had devoted himself equally to three goals: expanding the business, becoming a scientific patron in the noble style of his forebears, and assimilating himself and his company at ever higher levels of American life. His firm, Merck and Company, ensconced on 150 acres adjacent to the Pennsylvania Railroad’s main line in semirural Rahway, New Jersey, was not yet a drug company, but then hardly any American pharmaceutical manufacturer was. There were drugs and companies that made them, but the idea of discovering new medicines through research—the sine qua non of the modern drug house—was still new. It was also notoriously unsuccessful and, in the baldness of its profit motive, aggressively opposed by both doctors and patients. Merck, six foot five inches and 250 pounds and brimming with postwar optimism, was undaunted. The key to finding powerful new drugs, he knew, was having the most advanced labs, which, with the extraordinary promise of allowing its scientists to publish their work, Merck and Company began developing in the early 1930s.

Tishler, happy to be employed, subsumed himself in his first project: vitamin B₂. Without its own drug leads, Merck had decided to manufacture vitamins, an uncommercialized field where the limitations were the very opposite of those during the flu pandemic. Here the cures were well known; the failure was that no one had found incentive to make them. Scientists had known for nearly twenty years that those deprived of even one- to two-thousandths of a gram daily of B₂suffered an array of ailments: Their mouths cracked at the corners, their tongues swelled, their eyes hurt, their skin grew inflamed. Among starch-eating sharecroppers in the South, who didn’t get enough B₂or a related vitamin, niacin, the suffering was extreme: skin lesions, wrenched bowels, depression, apathy, and the so-called three D’s (dermatitis, diarrhea, and dementia) of pellagra. Two years earlier, German and Swiss chemists had patented a method for making B₂, but, seeing no market, had refused to license them in the United States.

Tishler was a dynamo. He quickly developed a novel synthesis free of all European patents, then, as the company began building a $5 million manufacturing plant, commandeered its scaleup. Chain-smoking, avoiding sleep, he arrived at his lab before dawn, left at night after everyone else, then returned after hours to prod and cajole the plant’s engineers into reproducing his fine-tuned organic reactions on an industrial scale. A molecule, he knew, was worthless, a laboratory curiosity, if it couldn’t be made cheaply enough to sell at a profit. On the job less than a year, thirty-one years old, he now showed that Merck could produce a complex organic molecule to compete with the lordly Germans.

In 1935, while Tishler was still at Harvard, a German dye chemist named Gerhard Domagk stunned the world by announcing that he had fed a white powder synthesized from coal tar to infected mice and had cured their infections in every case. The drug, called sulfanilamide, was the first “magic bullet” to be synthesized since Ehrlich’s discovery, thirty years earlier, of a cure for syphilis and the first specifically to target bacteria. Like most coal tar derivatives, it was originally made as a dye: Binding tightly to the protein cells in wool, it had been expected to stand up well to washing.

To a world whose notions of bacterial infection were forged in 1918, the sulfa drugs were nothing short of miraculous. People were now suddenly being cured of agonizing, often fatal diseases like spinal meningitis and childbirth fever that previously had defied treatment. Gonorrhea, more prevalent than syphilis, could be reversed in a matter of days with a shot or two. Twenty years after the most devastating outbreak of pneumonia in history, doctors began speculating on a day in the near future when “people just won’t die of pneumonia anymore.”

Nowhere was the effect more electric than in the drug industry. There, Domagk’s discovery seemed divine confirmation of Ehrlich’s prophecy. A land rush ensued, with legions of chemists suddenly synthesizing and filing patents on thousands of new sulfa derivatives, then, as Fortune observed, “sending new substances every day to other investigators who force them down the throats of infected mice and rabbits and monkeys—and watch.” Occasionally, in the race to exploit the public’s hunger for miracles, the animal tests were simply overlooked, as when the S. E. Massingill Company of Bristol, Tennessee, began selling Elixir Sulfanilamide, a poison concoction that killed 108 people in the South—107 patients and the chemist, who killed himself. Recognizing the need for regulation in the new speculative climate and spurred by the Massingill case, the federal government responded by expediting passage of the Food and Drug Act, which strictly controlled the testing, development, and sale of new drugs.

Merck, still chiefly a chemical supplier, quickly began making large amounts of sulfanilamide under other companies’ patents. It also tried to develop its own novel sulfas, placing Tishler in charge. The effort, half-successful, was bitterly disappointing. Tishler’s group made a molecule he hoped would combat malaria but that turned out to be too toxic for humans. However, it prevented coccidiosis, a poultry disease, and Merck helped revolutionize the broiler industry by introducing the antibiotics that would soon pave the way for factory farms.

But by then, the synthetics war between the U.S. and German chemical industries had become subsumed in the larger competition of World War II, a war in which emergent goal-oriented research was to be not just a bystander, but the decisive feature of the conflict.

•  •  •

The Carnegie Institution, ten blocks north of the White House, was founded in 1902 by steel magnate Andrew Carnegie “to secure for the United States leadership in the domain of discovery” and was governed in its early years by a genteel agenda ranging from stargazing to corn hybridization. A colonnaded mass of Federalist office and conference space girdling an imperial rotunda, it had become by the tropical summer of 1941 a citadel, the central marshaling point for science as the nation vacillated toward war. It was a novel idea—channeling research to achieve prescribed goals—and the Carnegie’s normally clubby air was squelched in wartime officiousness and secrecy. Iron grilles covered the first-floor windows and armed secret service agents guarded the building around the clock.

The Carnegie was the impromptu headquarters of the Office of Scientific Research and Development (OSRD), the federal government’s ad hoc commissariat for applied science and the brainchild of Carnegie’s president, Vannevar Bush. As chief science advisor to President Franklin D. Roosevelt, Bush had pressed for and won extraordinary control over the nation’s war-related research, most famously the Manhattan Project, which produced the first atomic bomb. Sharp-eyed and tireless, he also persuaded Roosevelt to allow the agency to direct the nation’s wartime medical efforts and in May had engineered the choice of Alfred Newton Richards, a sixty-six-year-old pharmacologist from the University of Pennsylvania, as chairman of the federal government’s nascent Committee for Medical Research (CMR). Richards, a staunch Republican and, like Bush, a minister’s son, was best known as a kidney researcher and Solomonic man of science, eminent and wise. Bush trusted him to corral the merciless egos of the country’s medical people just as he himself was having to restrain the physicists and engineers on the atomic bomb project.

Richards had another connection. When George Merck began steering his company into drug research in 1930, he had turned to Richards, who became the company’s chief consultant and scientific architect. At a time when the drug industry was still suspect, Richards had given Merck and Company uncommon credibility, sacrificing his formal membership in the pharmacologists’ fraternity to do so. He helped establish its labs, recruited its leaders, and allowed it to support some of his own work, explaining to contemptuous colleagues, “I saw in them no signs of the horns or tail.” Now, assigned to the national interest, Richards pulled George Merck with him. Volunteering his company’s services, Merck would soon be appointed head of the country’s biological warfare program.

On August 7, 1941, the CMR held only its second meeting in the Carnegie’s richly paneled library. Four months before Pearl Harbor, its goal was to assess the research already under way in the nation’s labs and determine how best to apply it if and when the United States entered the war. Several vital areas came up—tropical and infectious diseases, nutrition, the blood supply—though the committee soon focused on one: aviation medicine. World War II was quickly becoming the first conflict in which air power was decisive. Between July 1940 and May 1941, Germany had dropped 54,420 tons of bombs on London during the Blitz. As bloody as the fighting on land had become, Germany’s dominance of the skies over Europe was the most chilling augury of its claims of a thousand-year reich.

Germany, anticipating the primacy of air power, had begun exploring ways to sustain its pilots through the rigors of combat as early as 1934; Great Britain, Canada, and the United States had lagged, in that order. Now, the committee heard rumors that the Germans had isolated the active substance from the cortex of the adrenal gland—cortisone—and were giving it to their pilots, enabling them to fly at up to 40,000 feet. According to the reports, they were said to have cornered the Argentinian supply of calf adrenals and were importing it by U-boat.

Richards had little trouble believing the rumors. The development of performance-enhancing drugs—pharmacological warfare—had been a concern of his since World War I. And yet he also knew that efforts to isolate adrenal hormones had proven uniformly bewildering in the United States. Philip Hench, a biochemist at the Mayo Clinic, had isolated six such compounds but was unable to purify enough of them to identify their chemical structures, much less test them as drugs. He had turned in desperation to Merck, which for eight years had piled up its own failures in the area. If the Germans truly had identified the active molecule and devised a way of extracting it, the war could be over before Allied pilots would recover against drug-emboldened German fliers.

As Richards began formulating his own view of the nation’s research goals, the necessity of a crash program in cortisone assumed instant priority. But Richards’s day was far from over. Later, returning to Philadelphia by train, he was met by a British scientist, Howard Florey, who had once worked briefly in his lab. Florey and a colleague, Ernst Chain, were traveling the country to gather support for a promising new antibacterial agent that they believed might be better than the sulfas.

Now familiar, Florey’s story was extraordinary. In 1928, a Scottish researcher named Alexander Fleming had been trying to identify the microbe that caused the 1918 flu epidemic when a green mold wafted through the open window of his lab in a London hospital and, landing in an open petri dish while he was on vacation, began to destroy one of his cultures. Growing more of the mold, Fleming noted that it was deadly to a variety of harmful microbes. Like Hench, Fleming couldn’t find a chemist to produce enough of the pure substance, which he called penicillin, to test it in animals. But Florey and Chain, tantalized by penicillin’s qualities, had painstakingly purified enough of the material to feed it to infected mice. By February they had obtained enough of it to give to a deathly ill London policeman. Within twenty-four hours after receiving his first dose, the man improved dramatically, but doctors soon exhausted their supply of the drug. Desperate, they began harvesting miniscule amounts of it from his urine and futilely reinjecting it. Still, by then penicillin’s wondrous germ-fighting abilities were clear. With Britain’s research infrastructure in ruins, Florey and Chain had come to the United States—and, ultimately, to Richards—to try to enlist American labs to develop the drug.

Richards was enthusiastic, though here, too, there were obstacles. U.S. laboratories had little experience with growing microbes and extracting their active ingredients, and penicillin was notorious. “The mold is as temperamental as an opera singer,” a frustrated drugmaker would later declare. “The yields are low, the isolation is difficult, the extraction is murder, the purification invites disaster, and the assay is unsatisfactory.” Too, there was a thicket of organizational issues. The birth of drug research in the 1930s had introduced a bristling new competitiveness as companies sought to protect their investments. Where patents were once reviled, they were now pursued ruthlessly. Squibb, which had one patent in 1920, had more than 200 by 1940. In 1937 alone, Merck had filed forty-six domestic and foreign patent applications. Any drug company willing to take on penicillin was unlikely to want to forfeit the exclusive right to manufacture and sell it, and even if it was, antitrust laws would bar it from collaborating with its competititors.

On August 11, 1941, four days after the CMR meeting and his discussion with Florey, Richards wrote urgently to Hans Molitor, whom he’d been instrumental in recruiting to head Merck’s fledgling Institute of Therapeutic Research: “I want very much to discuss with you . . . the whole question of how such a laboratory as yours can contribute to medical research contributing to national defense.” He wrote a similar letter to George Merck. Responded Merck on September 10, “We are anxious to help you in any way we can.”

•  •  •

Elevated swiftly to head Merck’s penicillin project, Tishler drove his scientists blisteringly, himself even harder. He seemed fated to do so. Determined since he was a boy to fight ravenous infection, intent on vanquishing German chemical superiority and Hitler, spurred to prove Merck’s primacy over academic and industrial labs alike, driven to make his mark in developmental research and overcome the failure with sulfas, he resolved to stop at nothing in developing the new drug. “The plant health department came out with a rule that you had to take a vacation,” recalls Robert Denklewalter, who went to work for Tishler in 1943. “They decided we were risking our health by working all the time. Max’s position was that he’d go along with it as long as it didn’t interfere with getting things done.”

Four companies in all—Merck, Pfizer, E. R. Squibb and Sons, and Lederle Labs—attended a secret meeting in Bush’s Carnegie office in early October to discuss with government fermentation experts the prospects for growing the mold and isolating its active ingredient. From the beginning, none moved as determinedly or was as openly favored by Richards as Merck. The company vowed to make penicillin a priority and volunteered to share its methods and findings to the extent allowed by antitrust laws. The others, Richards observed, were “noncommital” and “less positive,” a position he deplored and that, at least in one case, elicited his considerable wrath. “The imperfection in the Squibb material has given me much concern, not to say annoyance,” he wrote scathingly in the spring of 1942 after a batch of the company’s drug caused phlebitis in 100 percent of test patients with battle wounds at a Utah military hospital. “It is damn near criminal of them to have shortcut a process without finding out what the shortcut would do.” Exacting, Tishler took no shortcuts. He was deadly serious, even reverential, about drugmaking, telling his chemists, “When you are working with those fifty to one hundred milligrams of penicillin”—about one-tenth the weight of a good breath of air—“you are working with a human life.”

On March 14, 1942, barely five months after the October meeting, the CMR concluded that Merck had produced enough pure penicillin to begin testing it in humans. For four weeks, Anne Miller, the wife of Yale’s athletic director, had been dying of an acute streptococcal infection, commonly called childbirth fever, in a New Haven hospital. Despite maximum doses of sulfa drugs, she was delirious with a temperature that had peaked at 106.5 degrees. At 3:30 Saturday afternoon, when she received her first shot of Merck’s penicillin, her fever was 105 and she had “well over” fifty bacteria per cubic centimeter of blood. By 4 the following morning, her temperature was normal. By Monday, her blood was sterile. She was still alive in 1990 and living in Connecticut.

The world knew nothing of Mrs. Miller’s wondrous salvation: It was a state secret. But as the companies and the government’s laboratory in Peoria, Illinois, began producing enough penicillin to conduct widespread clinical trials, stories began to circulate about a new, unnamed miracle substance—superior to the sulfas and made, incredibly, from a mold. The CMR, tightly controlling its supply, released it sparingly to just a handful of leading infectious disease specialists, who gave it to their patients often without telling them what it was.

On November 28, 1942, as celebrants from the Boston College-Holy Cross football game poured through downtown Boston, a sixteen-year-old busboy lighting a match near an artificial palm tree in the city’s oldest nightclub—the Coconut Grove—ignited a fire that killed 487 people. Suddenly, a major American city was plunged into a medical crisis that simulated the ravages of battletorn Europe. In a grisly reprise of the flu epidemic that brought home World War I, Boston once again became a laboratory for the nation.

Moving swiftly to release all available penicillin to Boston, the CMR ordered Merck to step up production. For three days, several groups, including Tishler’s, concentrated and purified all the crude penicillin broth in the company’s fermenters. Fending off sleep, Tishler pushed his people around the clock in relays until they had enough of the drug. Finally, a thirty-two-liter steel container filled with injectable penicillin was packed into a car on the night of December 1. Picking up police escorts from four states as it moved slowly up the coast through steady rain, the “mercy vehicle” arrived at Mass General the next morning.

Far from providing aspirin to the dying, Tishler now delivered a drug that attacked not the symptoms of disease but the cause—a drug that worked. Eight months earlier, there had been enough penicillin in the United States for one patient; within fifteen months, by April 1944, all American military requirements would be met, and it would be the drug of choice for an array of infectious diseases. The federal government and the adolescent American drug industry, working cooperatively, had achieved a stunning success and a scientific landmark. And yet for Tishler, their triumph was just the beginning. For if science could identify and make this molecule, what else could it make? “The logic of survival in modern warfare,” he would later write, “had dragged science from the periphery of our society right into the maelstrom of its center.” It was there, after decades of boring inward, that Tishler and American biomedicine now prepared to punch through, to explode.

•  •  •

More than its own rewards, which were inestimable, penicillin proved that it was possible to find drug molecules of extraordinary power and precision in the world’s simplest living things. Ever since Pasteur, biologists had known that every pinch of soil was a miniature Brooklyn, teeming with micromolecular competition. They knew that when an infected body dies and molders in the ground, the germs that killed it don’t survive and assumed that other microbes destroyed them in self-defense. But they hadn’t yet found any that could be ingested safely while having the same effect inside the body—until now. Penicillin bespoke a microbial Promised Land, and it did for microbiology what the sulfas had done for chemical synthesis. It exalted it.

In fact, the idea of harvesting “good bugs” to kill “bad bugs” had been developed around the same time that Fleming inadvertently discovered penicillin—and not by accident. René Dubos, an audacious twenty-six-year-old French microbiologist in his first job, at Rockefeller University in New York, started screening soil samples for disease-fighting agents as early as 1927. Like Fleming, he was looking for a substance that would destroy the deadly pneumococcus bacteria that had turned the 1918 flu outbreak into a cataclysm. By 1930, Dubos, who would later become better known as an environmentalist and Pulitzer Prize-winning author than as a researcher, found such an organism in a dirt sample from a New Jersey cranberry bog, not a drug but potent enough to cure mice infected with pneumonia. He quickly began expanding his experiments, exiling at least one early associate to a hospital roof to scour an “unpleasant brownish material . . . congealing into a sticky substance resembling uncouth ear wax.”

Spurred by Dubos’s success, other microbiologists were drawn to the search. Selman Waksman, a modest, bookish Ukrainian Jew barred from studying medicine in Russia, had come to the United States and through a series of detours had taken up identifying and classifying new strains of bacteria in soil at Rutgers University in New Jersey. Dubos had gotten his Ph.D. in Waksman’s lab. In 1939, when Dubos announced he had finally isolated a bacteria-destroying molecule that was not the product of synthetic chemistry but of another microorganism, Waksman decided to launch the first large-scale screening effort for discovering other such compounds.

The idea of prospecting for what Waksman would soon come to call “antibiotics” failed to impress the university, which later tried to fire him, and the CMR, which turned down his proposal for funds. But it did interest another party—Merck. Desperate for money and a guarantee that if he found something, it would be developed for testing, Waksman agreed to grant the company exclusive rights to his discoveries.

From the beginning, Waksman was plagued by a nightmarish array of contingencies. Not only were there an infinite variety of organisms with numerous variations in each type, but the slightest change in diet, temperature, even the shapes of the flasks in which they grew, could alter them chemically. In its first year, Waksman’s group found a promising germ killer, actinomycin, but it was so toxic that a single milligram could kill a five-pound chicken. Next, they discovered streptothricin, another potent antibacterial that first appeared safe enough for human trials. Feeding the drug to animals, Merck quickly discovered that it was fatal to kidney cells and canceled its development. By early 1943, Waksman decided to concentrate on finding an antibiotic to treat tuberculosis (TB), so-called captain of the men of death, which killed millions annually. Surely there were tubercle-killing substances in Waksman’s petri dishes, but whether they would ever be safe enough to take and whether he could even find them remained increasingly in doubt.

Waksman persisted. Finally, in September, having cultured and tested thousands of strains of bacteria, he found what he’d been seeking. The organism—streptomycin—had come from the infected gizzard of a chicken that had died of TB and was apparently harmless to kidneys. Tishler and his chemists seized on the molecule. In the extraordinary time of four months—penicillin, by comparison, had taken more than a dozen years from discovery to clinic—enough of the substance was produced to begin animal tests. By October 1944, the first human trials were begun at the Mayo Clinic with a young woman hospitalized a year earlier with TB. Within six months, the lesions on her lungs disappeared. Eighteen months later, her sputum was free of bacilli. Released from the hospital in 1947, after four years, she later got married and had three children.

The implications of streptomycin were striking: It was the first drug deliberately discovered by screening natural products, found because it had been pursued; it had been developed in the United States by means of a technological paradigm that surpassed anything developed by the German chemical trust, which had spent the war producing not drugs but compounds to use in the Reich’s gas chambers; Merck, by dint of its contract with Waksman, owned exclusive rights to a drug that might save the lives of millions of people.

Of all, only the last was troubling, as it raised the specter of one company profiting from a monopoly in an area where suffering was profound and there were no other treatments. Penicillin, with its joint development and diversified patents, ensured that the first of the “wonder drugs” would be distributed, at least initially, as a kind of public trust. But Waksman worried especially about the appropriateness of having turned over streptomycin to one company, however well intentioned, for “exploitation.” Appealing to George Merck personally, he asked to be released from his contract. Merck willingly agreed. Tishler, who had watched his sister die of TB, was struck by Merck’s magnanimity: “He used to say that if we discovered a cure for cancer, he’d not patent it,” Tishler would say. “How can you keep it away from people? How can you charge a lot of money? What’s the excuse? You can’t do that.”

Two years after World War II, the combined sales of penicillin and streptomycin equaled half that of all synthetic drugs, yet Merck, which had pioneered them both, was not the country’s dominant maker of antibiotics (Pfizer was). But Merck had enthroned a new way of finding drugs: microbial screening. “Out of the earth shall come thy salvation,” said Waksman, a self-taught talmudic scholar, paraphrasing Ecclesiastes in accepting the Nobel Prize in 1952. Asked later by reporters for the exact reference, he found a more precise translation with the aid of several rabbis: “The Lord created medicines out of the earth, and he that is wise shall not abhor them.”

•  •  •

Hardly could Merck and the American drug industry abhor the lineaments of such a prosperous upheaval. Drugs from underfoot suddenly were making them richer and more respected than they’d ever dreamed, and they raced to discover the next great antibiotic like wildcatters in the neighborhood of an oil strike. Virtually every company began screening dirt samples, reaching literally to the ends of the earth to find new patentable molecules that their competitors might have missed. Squibb distributed vials to its employees and paid half their airfare if they returned from vacation with dirt samples. An Italian bacteriologist discovered cephalosporin, a broad-spectrum antibiotic, in the sewage outfall of the Sardinian city of Cagliari. Compost, humus, sewage, sludge (bogs, construction sites, cellars, sewage lagoons), wherever microbes swarmed, science now followed. Drug profits skyrocketed.

At Merck, Tishler was placed in charge of all drug development. Unmatched at synthesizing complex molecules, at knowing every detail of a problem, at pushing drugs through to market, he had become a dominant figure and one of just two rivals for managing Merck’s rapidly expanding labs. His rise was a rebuke to the norms of science, which placed far more value on discovering new molecules than making them into drugs, but Tishler was overwhelming. “He knew everything,” recalls Denklewalter. “If Max said something, it was almost as if it had come from God.”

Idolized as omniscient, he also was ubiquitous, working on every project and at every level. No one knew what time he arrived in the morning or left at night because his car was always in the parking lot before and after everyone else’s. He took his family to the Catskills every August, renting a cottage without a phone, but otherwise he never ceased driving himself.

In 1949, despite its success with antibiotics, Merck faced near certain failure with a far more complex and beguiling molecule. Virtually alone, the company had continued to pursue cortisone long after the initial intelligence reports of “hopped up” German superpilots proved false and national security was no longer an impetus. Merck’s persistence paid off in 1944 when a twenty-seven-year-old chemist, Lew Sarrett, synthesized minute quantities of cortisone from ox bile. But Sarrett’s synthesis—forty-two steps, with a final yield of one-hundredth of 1 percent—only reinforced the hopelessness of Merck’s situation. Using his method, it was estimated, would take the slaughter of 14,600 cows to produce enough cortisone to treat one patient for a year. The cost per ounce was $4800, more than one hundred times the price of gold. With Merck sinking more and more money into the project, the company had produced by 1948 barely a total of ten grams of the substance.

No one knew what cortisone would do, but it was a spectacular trigger of a molecule, one of the body’s master compounds for infiltrating and hot-wiring immune cells. It was of special interest to rheumatologists, who had no drugs at their disposal for fighting inflammation and were reduced to experimenting, without any particular rationale, with every new medicine that came along. In September 1948, Merck shipped six of its ten grams of cortisone to the Mayo Clinic for treatment of a twenty-nine-year-old woman so crippled with rheumatoid arthritis that she couldn’t roll over in bed. The woman had already received massive doses of penicillin, streptomycin, gold salts, and sera with no improvement. Three days after her first injection, she was able to raise her hands above her head. Four days later she went shopping, declaring, “I have never felt better in my life.”

If penicillin and streptomycin were miracle drugs, cortisone was Oz. Never before had a compound promised so much for such a panoply of chronic, incurable, and untreatable diseases. More, its wonders were preserved on film. Prefiguring Awakenings, the Oliver Sacks phenomenon, Mayo’s doctors made a movie of the first fourteen cases in part to quiet disbelieving critics. It included footage of a woman who had been barely able to walk friskily running up and down steps and a man who had been in such pain he could not stand to be touched dancing a jig. In April 1949, Mayo’s doctors would unveil the film triumphantly to the world, but they first brought it to Merck, where, trying to preserve their thunder, they insisted on a private showing with only the heads of research. Tishler exploded. He refused to let the film be shown unless those who had labored at the bench to make the molecule—some thirty-five to forty people—be allowed in. Reluctantly, the Mayo group agreed. “It was,” one of Tishler’s researchers would remember more than forty years later, “the most dramatic thing I’d ever seen.”

Tishler now hurled himself into making Sarrett’s synthesis viable. “I used to tell my teams, ‘You worry about the first five steps,’ ‘You worry about the next five steps,’ all the way through.” Chainsmoking, gulping coffee by the thermosful, he seemed to be everywhere—in the labs, in the pilot plants. He was aflame, a pillar of fire. Once, a chemist dropped a highly valuable scarlet-colored intermediate compound on the floor. “That better be your blood!” Tishler thundered before ordering the precious liquid sopped up and its contents reisolated. He ultimately drove the synthesis down to a manageable—and potentially profitable—twenty-six steps, still the most complicated commercial process ever but adequate to begin large-scale production.

Scientists talk stoically about the rate-limiting step in their experiments, the one that ultimately determines its final yield. With cortisone, Tishler, in one fell swoop, had fractured the major rate-limiting step of all drug research—the inability to make complex organic molecules into synthetic drugs. “It is probably not too much to say,” wrote Robert Burns Woodward of Harvard, arguably the century’s greatest chemist, nominating Tishler to the National Academy of Science, “that Tishler’s work in this field represents the most striking achievement in practical organic synthesis in the history of that art.” Suddenly, chemists could conceive of making entire new classes of molecules—ones that were far more varied and sophisticated as drugs than anything they’d dared imagine. “If you took the kinds of molecules we’re sythesizing today back to the 1930s, it would have the same effect as if you showed them your pocket TV,” Boger would say forty years later. “That was Max.”

Cortisone elevated Tishler and glorified Merck. Newspapers quickly filled with miraculous stories—cripples walking; a “statistically dead” eight-year-old girl still alive after being burned over two-thirds of her body; small children with severe eczema healed after nearly scratching themselves to death; a formerly gray seventy-four-year-old man made “bald as a billiard ball” by illness growing a complete head of dark new hair. “The number of diseases upon which it is reported to have at least some analgesic impact now approaches the galaxial,” The New Yorker soon reported, naming some twenty-eight illnesses, ranging from asthma to ulcerative colitis, poison ivy to gout, as well as “shock, burns and fractures.” By 1951 interest in the drug was so great that Merck, with Tishler now in charge of all research and development and again driving his production crews around the clock, was forced to take out full-page newspaper ads blaming shortages on the huge surge in demand. Even as cortisone’s extraordinarily violent and far-reaching side effects—deterioration of joints, gross obesity, moonface, hypertension, diabetes, softening of the bones, nausea, headaches, skin eruptions, and, occasionally, madness—also began to surface, the company was exalted for its scientific leadership and progressivism. In August 1952, George Merck was pictured on the cover of Time, above the caption “Medicine is for people, not for profits.”

Yet even as he was being lionized publicly for his altruism, Merck was being forced to move quietly to pay for it. Despite leading the world in the production of cortisone, Merck and Company’s sales dropped from 1951 to 1952, leading it to merge the following year with Sharp and Dohme, a Philadelphia drug firm best know for its aggressive sales force and over-the-counter throat lozenges, Sucrets. Tishler resented the merger and feared its consequences. Recalls Denklewalter, “Max had an almost militaristic respect for authority, but we had this new CEO [Henry Gadsden] who’d come up through marketing at Sharp and Dohme. We had a meeting in research where he said to us, ‘There are more well people than sick people. We should make products for people who are well.’ He gave us three examples. Man-Tan was big at the time and he wanted us to develop a quick-tanning formula. He also thought we should have a morning-after pill and that we could do well with something for straightening kinky hair that would sell to blacks. I remember wanting to vomit when he was talking, but Max was silent. He would never say a word. On the other hand, we never heard of any of those projects again.”

Now firmly in control at Rahway, Tishler continued as he always had, pushing to find important new drugs. With the apparent rout of infectious disease, the company—and its competitors—began focusing on the next major matrix of killers: cancer, heart disease, and stroke. Meanwhile, Merck began screening 50,000 new microbes a year at a plant it had built in Spain. Tishler had become convinced that the near infinite variety of active organic molecules in soil might produce drugs other than antibiotics. The key was in being able to test them against the right targets. With chemistry fulfilled, biology now became the rate-limiting step in devising new drugs, and Tishler turned Merck’s science against it forcefully.

Merck continued to grow, but haltingly. In mid-1957, Tishler was named president of Merck, Sharp and Dohirie Labs and placed in charge of 1600 reseachers at Rahway and at Sharp and Dohme’s former campus in West Point, Pennsylvania. In November, George Merck died at home of a cerebral hemorrhage. Vannevar Bush, recruited by Alfred Newton Richards, became the company’s new chairman. Though Bush worried about Tishler’s insistence on doing everything himself—“He keeps all the threads in his own hands,” Bush complained to Richards—the two worked closely. Bush also distrusted the “opportunism of the sales organization” and saw Tishler’s vaunted labs as his chief bulwark against it.

Facing mandatory retirement, Tishler left Merck in 1970. His name was on 109 patents, including ten of the top-selling drugs of all time. He had set in place a scientific legacy that would soon pay off mightily with a succession of billion-dollar drugs and that would make George Merck’s company, ironically, not only Wall Street’s favorite drug stock but its favorite stock, period—a company with the fourth highest market capitalization in the country. He was not sorry to go. Tishler was not retiring. He was merely redirecting his energies, resuming the career he had left off in 1937 as an undergraduate chemistry professor.

•  •  •

Arriving at Wesleyan University within the same year—a year when the seismic outfall of Cambodia and Kent State suffused all cross-generational contact with a near-toxic edginess and distrust—Tishler and Boger found each other with surpassing speed.

Boger was nineteen when they met, obviously brilliant, superior, and more in need of a mentor than he would like to admit. His parents had begun to fight bitterly throughout his high school years, drawing sides and forcing him and his younger brother to choose between them (both boys favored their mother), and the young freshman chemistry teacher whom he admired, Peter Leermakers, had died that summer after flipping a Jeep onto himself at his California ranch. Though he’d gotten the highest grade in his freshman physics class, Boger had quarreled adolescently with his professor. “I found out he was a devout Roman Catholic, so for my extra independent project I wrote a computer program to launch a missile from Middletown and bomb the Vatican,” he recalls. “Josh didn’t suffer fools,” says a friend from his CRAW days. “And he didn’t suffer stupid science.”

Tishler, sixty-four and released at last from the pressures of industry, had always been keenly interested in young scientists but had been too consumed by his work not to feel often violently impatient with them. Now teaching Boger as a sophomore, he saw at once the inquisitiveness, intellectual rigor, capacity for hard work, and raw insistence on knowing everything and being right that he believed all great scientists shared. For his part, Boger saw in the stooped, white-haired Tishler an archetype, someone for whom science was not a dry exercise, but a powerful tool for changing the world.

Tishler taught Boger to be a chemist. “I have a distinct visual snapshot of me holding a burette and having Max’s hand over the top of my hand to show me how to grab it one-handed and open and close down the stopcock,” Boger says. Nurturing Boger’s pedigree, Tishler sent him to interview Selman Waksman in a New Haven nursing home just weeks before Waksman died. Moreover, he instilled in Boger the ethos he had cultivated at Merck. For an extra-credit question on a final in medicinal chemistry, Tishler offered $50,000 to any student who could develop a synthetic step that was cheaper than using microbes for making vitamin C. Like everyone else, Boger couldn’t find one—the drug industry had been toying with the question unsuccessfully for almost forty years—but the problem itself qualified all Boger’s assumptions about what science ought to be and what he wanted to do with it.

At Harvard, Boger continued to go his own way. He completed a postdoctorate with future Nobel Prize-winner Jean Marie Lehn, visiting from Strasbourg, while finishing all his course requirements in one semester and doing exceptional work on enzymes under Jeremy Knowles. His hair, grown long at Wesleyan, grew longer. He had a ninety-pound black Labrador retriever named Isaac that accompanied him everywhere on campus. Knowles, fresh from Oxford, told Boger he didn’t allow pets in his laboratory, to which Boger asked if Knowles had ever had a dog in his lab before. When Knowles was forced to concede that he hadn’t, Boger responded, “Well, Jeremy, don’t you think you ought to do the experiment?” Knowles did, and the dog stayed. On the few weekends Boger managed to get away from Cambridge, he drove to North Carolina—stopping off in Middletown to visit Tishler—with Isaac sitting upright in the passenger seat of his VW.

By now Tishler saw in Boger the makings of a great drug maker and promising scientific leader, and he helped him along. Merck had a hiring freeze the year Boger finished at Harvard, but Tishler called Ralph Hirshmann and told him to find him a job. Boger was an instant anomaly at Merck. Most of its chemists had been trained like Tishler, if not by Tishler and his minions, in synthetic organic chemistry: They were expert at making molecules. But Boger was interested in how proteins, and particularly enzymes, worked as drug targets. His thinking was inverted from theirs. He was more interested in what drugs needed to do—what spaces they had to fill, what contacts to make—than in their actual configurations. Of locks and keys, he saw locks as primary.

Boger’s insurgent attitude—“angular,” Knowles described it—won him few friends. He was not above gloating. Dismissing the first project proposed to him as “snooze time,” Boger began designing molecules he believed would reduce hypertension. His target, a molecule in the bloodstream called renin, was obscure, one of those proteins that, like HIV protease, snips apart other proteins with atomic scissors. Within eighteen months, working with one assistant and using the X-ray structure of a related enzyme to produce crude models, he made a molecule 1000 times more potent than the company’s previous best inhibitor. Quickly, Boger’s star began to rise. His results were published in Nature, attracting international attention and, of equal importance, the attention of Merck’s publication-sensitive management. Merck had another hypertension drug, Vasotec, which would eventually make more than $1 billion a year, causing Boger’s accomplishment eventually to fade. But by that time he was being quickly pulled up through the ranks. By 1987 he was not only in charge of Merck’s rational drug design but head of a task force of another hundred researchers on a project in immunology. Two years earlier, he had had two assistants.

Tishler witnessed Boger’s ascent proudly but with diminishing influence. In 1984 at age seventy-eight, he got pneumonia. The disease, though curable now, immobilized him, and he was forced to slow down. It had remained his habit at Wesleyan to arrive at work before 7 A.M., but now he could barely shuffle a dozen steps without sitting down on one of the small wooden chairs he had placed about the halls and in the labs. A lifelong smoker, he also had emphysema and had to retreat to his office twice a day to breathe through an oxygen machine. Merck helicopters still arrived on campus when his successors needed to consult with him, and he never missed a faculty meeting, but Tishler was increasingly ravaged by his condition. Retirement seemed not to cross his mind.

Boger stayed in close touch, writing warmly on Tishler’s eightieth birthday that Tishler had taught him the value of becoming “engulfed in all facets of a problem” and that “only important problems are interesting.” Yet as he mastered the system of science that Tishler had bequeathed, he also found it increasingly inadequate for his ambitions. “What you need in this business,” he would say, “is more information than the other guy. Not more smarts. Not more intuition. Just more information. I began to realize that Merck wasn’t set up to generate and use the kind of information I was going to need.”

In mid-1988 Boger received a phone call at home from Kevin Kinsella, a San Diego venture capitalist. Once before Boger had been approached to start his own company and had gone so far as to write a business plan before opting to stay at Merck. However, Kinsella is a force of nature. The son of a Broadway actor and a fashion model, his résumé reveals a breakneck ambition and fathomless drive: Eagle Scout; B.A. in electrical engineering from MIT; M.A. in economics from Johns Hopkins; founder, at age forty-four, of seventeen companies, including his San Diego venture firm, Avalon, a name that he picked because A names sit atop alphabetical lists. Six feet three inches and built like a ski racer, Kinsella stands over most people in conversation the way Lyndon Johnson did, enveloping them, blocking their sky, as irresistible, consummate, and overachieving an entrepreneur as Johnson was a politician. Unambiguously motivated by wealth and power, he once posed for a business magazine cover with his hands steepling a stack of $100 bills; if he couldn’t be a venture capitalist, he has said, he’d like to be president.

“Kevin can leave a trail of people wondering what’s hit them,” says the president of one of his companies. “It’s like being exposed to a vacuum cleaner; he Hoovers out every piece of information.” Now, Kinsella wanted to launch a structure-based drug company and had decided, of one hundred names he’d collected, that he had to have Boger to lead it. Boger was intrigued enough to listen. During the next few months, the two met several times in person and Kinsella began calling nightly, turning up the heat. But Boger wanted more control than Kinsella was offering and dismissed Kinsella’s West Coast SAB as “suboptimal . . . not enough horsepower.” Simultaneously, Kinsella’s financing began to unravel. “I’m on the phone in the Reno airport,” recalls Kinsella, who’d gone skiing one weekend at Lake Tahoe believing everything was sewn up, “and this fucking deal has turned to ashes.”

Kinsella immediately flew to Boston, arriving at Harvard unannounced and not leaving until he had recruited the entire SAB that Boger had insisted upon. Six weeks later he flew to New Jersey with a new proposal, taking Boger and his wife, Amy, to dinner and unloading full force. Kinsella had once recruited an entire section of the National Cancer Institute—fourteen scientists—moving them from Bethesda, Maryland, to Seattle to launch another company. He was not about to be refused now.

“I want to ask you a question,” Kinsella said, after laying out terms that effectively gave Boger complete control over the new company. “Do you remember who the person at Apple was who developed the personal computer?”

“Steve Jobs,” Boger replied.

“Now who’s the largest PC maker in the world?” he asked rhetorically.

Again Boger answered effortlessly, “IBM.”

“OK. Do you want to be the guy at IBM or the guy at Apple? Do you want to end up with a good watch? What kind of credit do you want for your work?”

Boger’s departure from Merck was swift, determined; ten days after submitting his resignation—ten days, fittingly, in which Navia’s paper on the structure of HIV protease, announcing the first concrete inroad of the new religion of structure-based drug design in AIDS, was being vouchsafed by Nature—he was gone. It was the final week of 1988, and Tishler was ailing gravely. “Why didn’t Merck manage to keep Josh?” he asked Knowles feebly. “What’s wrong?” Merck sent Ralph Hirshmann, now retired from the company and a professor at the University of Pennsylvania, by helicopter to visit Tishler in the hospital, and Scolnick wrote him a letter detailing the company’s efforts to keep Boger. Neither assurance was satisfactory. Tishler died in mid-March, just as Boger was flying around the country scrounging start-up capital with Kinsella, who carried a camera so that he could have his picture taken in each moneyed suite they visited. At Tishler’s funeral, Betty Tishler, his widow, refused even to acknowledge Boger.

“Joshua,” she says icily, “is a great disappointment to us.”