One afternoon in 1942, Randolph Major called John Clark Sheehan into his office. Major, the balding, self-effacing director of research at Merck Pharmaceuticals, was offering Sheehan his choice of research projects. Merck was looking into two interesting compounds: the steroid cortisone and the antibiotic penicillin. Sheehan said he was comfortable with steroid research, but Major interrupted him to say that Lewis Sarrett, a recent hire, was also qualified in this area.

Sheehan had heard of penicillin. “I knew that it was supposed to be a remarkable drug but very difficult to work with chemically,” he later recalled. This did not deter him. “If it is all right with you, Dr. Major, I’ll take the penicillin,” he said. At twenty-seven years old, Sheehan was about to begin the scientific mission that defined his career.

At this time, penicillin research was just taking off. In 1928, Alexander Fleming had discovered the compound by accident. The British bacteriologist noticed a contaminant, which turned out to be Penicillium mold, inhibiting growth on his plate of staphylococci bacteria. The specific antibiotic within the mold was not isolated for another decade, but World War II brought increased demand for lifesaving drugs. By the end of the war, factories were pumping out penicillin for civilians and soldiers alike.

Because Penicillium mold was slow-growing and difficult to extract, scientists became determined to make the drug synthetically. Synthetic vitamins had already proven cheaper and more reliable than naturally isolated ones. And since penicillin is a fairly small molecule, many scientists believed it would be relatively easy to reproduce in the laboratory.

But chemists soon learned otherwise. Penicillin synthesis became known as “the impossible problem.” One researcher even suggested “the penicillin molecule was designed by nature to teach organic chemists a little humility.” Ultimately, only one man proved up to the task.

In 1946, John Sheehan left Merck to take a position at MIT, bringing the “impossible problem” with him. His friends pressured him to give up penicillin research in favor of more impressive academic projects, but the challenge haunted him. Sheehan had a personal interest in antibiotics: As a college student, he’d lost a year, and nearly his life, to pneumonia and mastoiditis. “If my doctors had had a course of treatment as effective as that made possible by penicillin, I would probably not have lost that year,” he said later. He also felt that someday, someone would solve the puzzle of penicillin. “I wanted to be that person,” he said. In 1948, he decided to work at the problem until he either synthesized the drug or “became Professor Emeritus at M.I.T.”

It was a monumental venture. The penicillin molecule was “fragile and reactive,” according to Sheehan, and attempting to synthesize it with the available methods was “like attempting to repair a fine Swiss watch with a blacksmith’s anvil, hammer and tongs.” Sheehan’s laboratory progressed slowly, developing several compounds he described as “foothills on the way to the peak.” The search was not only arduous, but unusually lonely. Nearly forty different laboratories researched penicillin at the height of the war effort, but all were repeatedly thwarted in their attempts to make it from scratch. “Chronic frustration does odd things to people,” Sheehan said. From 1948 onward, he was the only one striving to synthesize penicillin. Other chemists, he believed, “were simply tired.”

As the first snow blanketed MIT in October, 1952, Sheehan wrote a letter congratulating Lewis Sarrett at Merck. Sarrett had synthesized cortisone, completing the project that Sheehan had forgone a decade before. Today, the steroid is used to treat inflammation, arthritis, and more. “Thanks for your good wishes,” Sarrett replied. “We are banking on you to put the final nail in the coffin of the superbugs!”

Sheehan moved slowly toward that goal. “Accounts of scientific discoveries often oversimplify the bewildering complexities of research,” he said later, referencing the long periods of work required to reach an “Aha! experience.”

That all changed in 1955 when Sheehan’s group at last had a breakthrough, finding a new way to form a chemical bond necessary in the construction of penicillin. By the next year, Sheehan’s laboratory also successfully synthesized the chemical center of penicillin—two rings of sulfur, carbon, and other organic atoms known as 6-aminopenicillanic acid.

On March 22, 1957, Sheehan sent a chemical sample off for analysis at Bristol Laboratories in New York. The vial contained a chain of carbon, hydrogen, and oxygen atoms called an acyl group, fused to 6-aminopenicillanic acid. This matched the structure of penicillin V, a form of penicillin previously found only in nature. Sheehan heard back quickly: his sample showed antibiotic activity. After nine years of work at MIT and fifteen years since making his decision in Major’s office, Sheehan had synthesized penicillin from scratch.

Sheehan later thought of that day at Merck and of Lewis Sarrett, who took the path he left behind and later became President of Merck Sharp & Dohme Research Laboratories. “I have sometimes joked with [Sarrett] about what would have happened if we had reversed roles,” Sheehan said. “My own guess is that we both would have failed.”