Miracle Cure

by William Rosen

  In 1925, Howard Florey received his first Rockefeller Foundation fellowship, spending nine months, from September 1925 to May 1926, at various Rockefeller-funded labs in New York, Chicago, and Philadelphia, where he would establish a relationship with Alfred Newton Richards, the future president of the National Academy of Sciences.

  Florey’s transatlantic connections would prove enormously important, as, too, would his links to continental Europe—he had spent part of 1922 and 1923 at labs in Copenhagen and Vienna—though forging them proved a challenge. By the 1920s, scientific research had become so much more international than it had been when Koch and Pasteur were dueling over the relative importance of vaccination and sanitation as to be unrecognizable. German, French, British, Swedish, and American scientists collaborated regularly, published together, and—this isn’t a contradiction—still fought fiercely over discoveries and priority. National affiliation wasn’t completely forgotten, but the real competition was between laboratories, not nations.

  All that collaboration and competition, however, wasn’t free. Over the course of the next two decades, two different schemes for the funding and direction of scientific research were on offer. The industrial model, which had produced Paul Ehrlich’s Salvarsan, and would, soon enough, be responsible for Gerhard Domagk’s sulfa drugs, had the advantage of tremendous focus and discipline, but it was also highly dependent on confidentiality. The philanthropic model, on the other hand, benefited from collaboration and the ability to follow multiple lines of investigation, but even with the world’s wealthiest families supporting it, it was still underfinanced. Worse, unlike corporations like I. G. Farben, philanthropists, whether individuals like Sir William Dunn or trusts like the Carnegie and Rockefeller foundations, lacked ruthlessness. They were temperamentally ill-suited to disinvest from programs rapidly, and, as a corollary, foundation-led research had difficulty reinforcing success. Even with Lord Beaverbrook’s money, Alexander Fleming’s department at St. Mary’s couldn’t afford to hire the chemical talent needed to exploit the original penicillin discovery. The same story—brilliant and promising research in a constant scuffle for money—was about to play out at Oxford, with a somewhat different conclusion.

  In 1926, Florey married Ethel, his former medical school classmate, now a doctor herself. Even by the standards Florey had established for bluntness and interpersonal tone deafness in his professional life, his courtship, conducted via slow-motion correspondence between England and Australia, had been stormy. It was calmness itself compared to the marriage that followed, though, which featured score settling of a particularly vitriolic (and difficult to read) nature. By the time the Floreys’ marriage was five years old, Ethel was complaining that her husband had sabotaged her career, while he, in turn, accused her of desertion, lack of affection, a disappointing frequency and variety in their sex lives, lousy cooking, and poor personal hygiene, even reminding his—deaf—wife that she was “not a physically normal woman.”

  As miserable as Florey was in his marriage—or, to be accurate, as miserable as both Floreys were—it did little to divert his career. In 1927, he received his PhD from Gonville and Caius College at Cambridge, where he was appointed a lecturer in special pathology—a discipline about which he had known nothing before Sherrington took an interest in him, but which would be the subject to which he would devote the rest of his life.

  Establishing himself in the field of pathology meant studying pathogens. For two years, Florey produced a huge volume of work, on subjects as varied as cerebral circulation, capillary action, and mucous secretions: an “experiment a day, including Sundays,” in the words of a colleague. He spent the summer of 1929 on another grant-paid trip to Madrid, mastering the art of cell staining with Professor Santiago Ramón y Cajal, the pioneering histologist and neurologist who had won his own Nobel Prize in 1906 for describing the cellular nature of the nervous system. And he began thinking about the gut. In 1931, Florey took his investigations to the University of Sheffield, which had offered him the Joseph Hunter Chair of Pathology. Four years later, he returned to Oxford.

  By then, the Dunn School had been open for eight years, led by George Dreyer, a brilliant pathologist who had made his name analyzing diphtheria toxin. Specifically, and following in the steps of Paul Ehrlich, who had established the standard for measuring the toxin, Dreyer standardized the agglutinating power of blood serum into a single numerical value.

  Standard setting is the sort of unexciting but vital scientific research that tends to be scanted in most histories. It was, however, hugely important, and about to become more so, as pathology and pharmacology became a matter of testing large numbers of different compounds: the more, the better. Consider the hundreds of azo-plus-sulfa side chains that were, at virtually the same time, being produced by Klarer and Mietzsch at Bayer’s tropical medical group. The ability to compare samples using a single number was critical, and Dreyer understood this better than anyone in Britain. Among his notable achievements while at the Dunn School was building Britain’s first Standards Laboratory, a repository for pure samples of many pathogens.

  Dreyer died in 1934, which opened up what, in the ornate language of Oxford, was known as a “Statutory Professorship”—a position within the university that was, by tradition, administered by one of Oxford’s thirty-nine residential colleges.* For the Dunn School, that was Lincoln College, whose rector was importuned by a number of dignitaries supporting Florey’s candidacy. They included an old mentor—Charles Sherrington—and a new one: Edward Mellanby, the pharmacologist who had discovered vitamin D and demonstrated its relationship to the deficiency disease known as rickets. Mellanby had been one of Florey’s supporters on the Sheffield nominating committee, and had since become even more prominent as secretary of Britain’s Medical Research Council, which had been founded in 1913 as a publicly funded agency charged with financing medical research, initially on tuberculosis, but from 1920 on, on all diseases. In 1934, those funds were still extremely hard to come by, particularly as compared to the investments being made by the German chemical conglomerates, but the MRC did have one advantage that they lacked: a Royal Charter that authorized collaboration between researchers in academic settings like the Dunn and those in the chemical and pharmaceutical companies.

  It was clearly the right moment for such collaboration, and the Dunn was the right place. It remained to be seen whether its new leader—Florey was named director in December 1935—had the right research agenda. It’s unclear when, or why, Florey started a series of investigations into the well-known but poorly understood phenomenon that the wall of the gastrointestinal tract was impermeable to bacteria—why potential pathogens didn’t infect the wall itself. A number of theories were currently popular, and one of them was the presence of the antibacterial compound lysozyme, discovered by Fleming eight years before.

  Florey had been interested in lysozyme ever since, and had even gotten a grant to extract it in a pure form from egg whites. The need for purifying lysozyme led directly to one of the most important decisions in the history of medical research, a decision not about technique or theory, but personnel. Florey, like Domagk, needed chemists to give him the raw material (or, more precisely, the refined material) for his experiments. Even while at Sheffield, he had been begging the Medical Research Council for just such a collaborator, to purify Fleming’s lysozyme and identify its substrate: the molecular component on which the compound did its work. At Oxford, though, he had considerably more to offer, and, in 1936, he finally got his chemist: E. A. H. Richards, from one of the world’s most innovative organic chemistry departments, Oxford’s Dyson Perrins Laboratory.* By 1937, Richards had succeeded where Fleming had failed, producing lysozyme in pure form. Even more consequentially, in the same year Florey charged another staff chemist with the job of identifying lysozyme’s substrate. The staffer was a Jewish émigré from Germany named Ernst Chain.

  Certainly, Chain’s background seems, on fi
rst glance, to have been wildly different from Florey’s. Born in Berlin in 1906, the son of a German mother and a father who had emigrated from Russia’s “Pale of Settlement”—the region in eastern Russia that, from 1791 to 1917, had permitted permanent Jewish residency—to Germany, where he studied chemistry, changed his name, and opened the Chemische Fabrik Johannisthal Adershof, a factory that produced pure elements like copper and nickel for industrial use.

  This hides more than a few similarities. Florey’s father, too, was an immigrant, though from England to Australia. Both fathers took the entrepreneurial path followed by immigrants everywhere, in John Florey’s case starting a business manufacturing boots. Both fathers died while their sons were still at school, Florey’s in 1918, Chain’s a year later, a financial hardship for both families. The death of Chain’s father left his family—including Ernst’s mother and sister, Hedwig—somewhat strapped, though not so distressed that Ernst could not take advantage of Germany’s extraordinary educational system; and in 1927, he graduated from Friedrich-Wilhelm University (now Humboldt University). In 1930, he added a D.Phil. from the Institute of Pathology at Berlin’s Charité Hospital, the alma mater of more than half of Germany’s Nobel Prize winners, including Emil von Behring, Robert Koch, and Paul Ehrlich. In April, with his new degree and, as he later recalled, £10 in his pocket, he left for England, leaving his mother and sister behind.

  Within two years, Chain was publishing papers in scholarly journals and, despite a passport endorsement that should have forbidden him from accepting “paid or unpaid employment,” had joined the chemical pathology lab at University College Hospital. In May 1933, despite that pesky business about employment—he was then living on a stipend of £250 annually from the London Jewish Refugees Committee and Liberal Jewish Synagogue—he got a job in the Department of Biochemistry at Cambridge, working for his own mentor: Frederick Gowland Hopkins, who had been awarded half of the 1929 Nobel Prize in Physiology or Medicine (for the discovery of vitamins) and had been, since 1930, president of the Royal Society.*

  And, like Florey, Chain was ambitious, confident, and resourceful. In the words of one biographer, he provided an “inexhaustible flow of ideas and suggestions for overcoming difficulties,” which would have made him a desirable colleague but for an unhealthy dose of arrogance and a habit of condescending to others, aspects of his personality he was either unable or unwilling to hide. Unsurprisingly, this was, again as with Florey, the cause of frequent irritation among his coworkers. They put up with him, and even sought him out, for his excellent experimental technique, and for a truly remarkable, near-photographic memory. Chain’s ability to summon every pertinent reference in the scholarly literature of biology and chemistry without recourse to a library made him the 1930s equivalent of a laboratory connection to the Internet. A dozen different colleagues would later recall his ability not merely to quote page and volume from relevant journal articles, but to quote text verbatim, even citing where on the page the important passage would be found.

  Chain had another advantage in the lab. Long before he had become a scientist, he was a piano prodigy, good enough to give concerts in Berlin in his teens, and one who maintained his technique with constant practice. He was gifted enough that at least one account has him visiting Buenos Aires on a concert tour in 1930; certainly, as late as 1933 he was so torn between biochemistry and music that he interviewed for a job in the BBC’s orchestra.

  Chain’s musicianship gets mentioned frequently in biographies, often as evidence of the “artistic temperament” that made him a creative experimentalist. Far more valuable, though, for the laboratories of the day, was Chain’s combination of a pianist’s muscle control and hand-eye coordination. Steady hands are as valuable to a chemist as they are to a stage magician; the simple experimental technique of titration depends on adding one liquid to another, a droplet at a time, in order to observe the beginning and end of a chemical reaction in a precisely calibrated vessel. Growing crystals by diffusing one solvent into another has to be done slowly and steadily enough to keep the boundaries between them distinct. Small wonder that Chain’s colleagues were as likely to recall his deftness with beaker and pipette as they were his memory.

  Credit: Wellcome Library, London

  The Dunn School team: Howard Florey (back row, second from left) and Ernst Chain (back row, second from right)

  Florey didn’t have Chain in mind when he made recruiting biochemists a priority for the Dunn after he took over in 1935. His first choice for the job was another of Frederick Gowland Hopkins’s Cambridge protégés, Norman Pirie, a Scottish biochemist and virologist. Pirie was either uninterested or unavailable, and it was Hopkins who suggested Chain. “I find his biochemical knowledge is more than merely adequate . . . he has really become a well-qualified biochemist. . . .”* Chain was interested in the job. As he would later write, his “principal motivating principle . . . was always to look for an interesting biological phenomenon which could be explained on a chemical or biochemical basis, and attempting to isolate the active substances responsible for the phenomenon and/or studying their mode of action.”

  Of course, he wrote that long after he had departed Oxford as one of the most famous scientists in the world. When he arrived there, his priority was less on the disinterested search for scientific explanation and more on, well, the toys. After training in the state-of-the-art facilities at Berlin’s Charité Hospital, he had been regularly, and loudly, disappointed at the quality of the equipment available at Hopkins’s lab in Cambridge. So, when he arrived at the Dunn, and Florey’s chief technician, Jim Kent, escorted him to his lab and Chain saw—through the window of the neighboring Dyson Perrins lab—a Soxhlet extractor (a fairly rare piece of lab apparatus designed to extract lipids from solids, and used for all sorts of purifying exercises), his eyes grew as large as a child’s visiting a chocolate factory. Asked by Chain if the Dunn School used them, Kent said he believed they had one, to which Chain said, “One! I shall want ten!”

  If only. The Dunn was well equipped only by the standards of other British laboratories, and Florey’s group still depended on the unpredictable largesse of individuals and foundations, and modest subsidies from the Medical Research Council. In the middle of a worldwide depression, none of them was what one might call generous. When Chain arranged for enlarging and modernizing the lab’s refrigerator—it had been manually operated by a steward, who turned on the compressor when he thought it was getting too warm—and exceeded the budget by £15, it “caused a terrific upheaval, and Florey never forgot this incident and reminded me of it until I left the Institute.”

  Over the course of the next year, Chain worked diligently (and parsimoniously) on everything from snake antivenin to protein proteolysis, despite some disabling but undiagnosed diseases that caused him bouts of such severe depression and anxiety that he began keeping a health diary, where, in August 1935, he carefully noted his “periodic fear attacks.” Part of his anxiety was, no doubt, financial; with the title of departmental demonstrator, he was paid only £200 annually, and frequently enough needed to get advances on even this modest sum, which he supplemented with the occasional grant.

  By the beginning of 1936, Chain had started another research program, this time on skin cancer, and needed an apparatus for measuring the very small amounts of oxygen uptake during the metabolism of cancerous tissues. While devices, known as respirators, existed for less granular investigations, Chain needed something on an order of magnitude more sensitive. To design his “microrespirometer,” he suggested one of his former Cambridge colleagues to Florey. Florey agreed, but—surprise of surprises—while he could afford the man, he had no money for the needed equipment.

  Once again, the Rockefeller Foundation was tapped. Florey wrote to Daniel P. O’Brien, a former circuit rider, now associate director of the foundation’s Division of Medical Sciences, begging for money to expand “the chemical aspect of Pathology.” Soon after,
O’Brien’s boss, Wilber Tisdale, visited Oxford, agreed with the request, and approved a grant that allowed Florey to buy “balances, micro balances, vacuum distillation apparatus, etc. to a value of £250.” Far more important than the equipment, though, Florey also agreed to hire Chain’s onetime colleague, a mechanical genius named Norman Heatley.

  Heatley was then barely twenty-five years old, a newly minted PhD from Cambridge, and, luckily for his colleagues, possessed of a very different temperament than both Florey and Chain. Heatley even looked different. Chain was mustached, short, and intense, his head always set slightly forward, as if ready to attack; Florey was square jawed and robust, laconic and brusque. Heatley was tall, elegant, and slender. Where Florey and Chain were confident, verging on—generally passing over into—arrogant, Heatley was diffident, perhaps to a fault: He was known to have said, “I was a third-rate scientist whose only merit was to be in the right place at the right time.” He was also unfailingly courteous, so much so that he was regularly shocked by the egotism and ambition regularly on display at the Dunn. Certainly he got on better with Florey than with his putative supervisor, Chain, especially after the latter insisted on a credit in the journal article that described the microrespirometer, despite the fact that, as Heatley recalled four decades later, the device “was wholly my conception and design” and that Chain had demanded credit out of ambitious careerism.