Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (11 page)

Fleming would have remained an obscure figure in medical history but for the accomplishments several years later of dedicated researchers a few miles away at Oxford University. They transformed penicillin from a laboratory curiosity to keep unwanted bacteria out of culture dishes into a miraculous medicine. When it was finally recognized for what it was—the most effective lifesaving drug in the world—penicillin would alter forever the treatment of bacterial infections.

A Profoundly Ignorant Occupation

Lewis Thomas, author of
The Youngest Science,
commented on his experience as a medical student in the early 1930s: “It gradually dawned on us that we didn't know much that was really useful, that we could do nothing to change the course of the great majority of the diseases we were so busy analyzing, that medicine, for all its façade as a learned profession, was in real life, a profoundly ignorant occupation.”
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All feared the scourge of infectious diseases. Before the discovery of penicillin, a doctor's black bag contained digitalis, insulin, and some powerful plant-based painkillers and sedatives, such as morphine and cocaine, but not much else of scientific value. Doctors could do little else than offer palliative treatment and reassurance. Such a scene is captured in Sir Luke Fildes's 1891 painting
The Doctor,
in which a physician keeps watch at the bedside of a seriously ill child as the anxious parents look on. Ironically, the painting was reproduced on a postage stamp in 1947 to commemorate the centennial of the American Medical Association.

A N
UGGET OF
G
OLD
T
RANSFORMED INTO A
G
OLD
M
INE

Howard Florey, a pathologist and physiologist, was appointed at the age of thirty-seven as director of Oxford's large new Sir William Dunn School of Pathology in 1935. With forceful vision and superb organizational skills, he set out to recruit to his department researchers with interdisciplinary skills. It was a radical concept at the time. He was joined by a talented and supremely self-confident biochemist, Ernst Chain, a twenty-nine-year-old Jewish refugee from Nazi Germany. The differences in personality and temperament between the two were sharp, but they had an amicable relationship with highly productive complementary talents for several years before conflicts arose.

Florey, handsome and square-jawed, had a laconic, undemonstrative, frequently prickly and dismissive manner. His driving enthusiasm for research was concealed by a tendency toward understatement: “We don't seem to be going backwards” meant real progress.
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Chain, short, dark-haired, with a large bushy moustache and an unfashionably long mane of hair, likened by many in appearance to Albert Einstein, was excitable and contentious but radiated infectious enthusiasm. In contrast to his starchy British colleagues, Chain half-mockingly described himself in a phrase Cole Porter would have admired as a “temperamental Continental”;
¹⁷
he was nicknamed Mickey Mouse for his bouncing, smiling energy.

Another biochemist, Norman Heatley, who was painfully shy but extremely ingenious and skillful, with a remarkable flair for designing and constructing laboratory equipment to overcome analytic and production problems, joined the team.

All these individuals were certainly astute, but their talents would likely have come to naught without a series of lucky circumstances. Florey and Chain's journey of discovery was directed by the muse of serendipity. Florey, long involved in a systematic investigation of the mucus of the digestive tract, was interested in its biochemistry and saw lysozyme as a possible lead. After discovering the presence of lysozyme in intestinal secretions, he wondered if he had found the cause of intestinal ulcers. Chain's primary interest was the chemistry of cell walls. Florey asked Chain to undertake a study to determine
how lysozyme broke down the cell walls of the intestinal lining. Chain based his experiments on Fleming's original observations on lysozyme's effect on bacteria. He found that it was a protein that destroyed the cell walls of bacteria, in effect killing them. This seminal work laid the foundation for understanding the chemical structure of the bacterial cell wall. It did not produce any direct advance in therapeutics, but was valuable for showing that powerful antibacterial agents were not incompatible with living human tissues, and that an understanding of chemistry was essential to an understanding of biology.

In 1938 Florey and Chain decided to extend their investigations to other natural antibacterial compounds. They happened across Fleming's original description of penicillin published nine years earlier and wondered if his mold extract might be a sort of mold lysozyme. Chain believed that a detailed study of how penicillin lysed the bacterial cell wall would afford much useful information on the structure of this wall, just as his studies on lysozyme had done.

Chain was surprised and delighted to find that he needed look no further for a source of
Penicillium notatum
than the hallways of his own laboratory. “I was astounded at my luck in finding the very mould about which I had been reading, here, in the same building, right under our very noses.”
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He encountered a lab assistant carrying germ culture flasks on the surface of which a mold had grown and asked her what the mold was. She told him it was the mold Fleming had described in 1929. The Oxford laboratory had been culturing
Penicillium notatum
for years simply to keep Petri dishes free of contamination! He requested a sample of the mold and started experiments with it right away.
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“We happened to go for penicillin,” he later said, “because we had a culture growing at the school.”

Chain accepted the challenge abandoned by Fleming. The idea was to crystallize penicillin by cooling it in order to obtain it in stable form. Neither he nor Florey contemplated possible medical uses. “So,” in 1938, “we started our work on the isolation and purification, not in the hope of finding some new antibacterial chemotherapeutic drug, but to isolate an enzyme which we hoped would [inactivate a chemical] common on the surface of many pathogenic bacteria.”
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Years later, Chain reaffirmed the serendipity of the devious, unintended paths
leading to this: “That penicillin could have a practical use in medicine did not enter our minds when we started work on it.”
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For his part, Florey admitted, “I don't think it ever crossed our minds about suffering humanity; this was an interesting scientific exercise.”
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Meanwhile, Chain and Heatley's task of extracting enough material of sufficient purity from the penicillium cultures was enormous. And with the start of World War II in 1939, resources for research became extremely limited. The mold grows only in the presence of oxygen. Large surface areas seemed essential so that every bit of mold would come into contact with air. Heatley borrowed sixteen sterilized bedpans from the Radcliffe Infirmary and filled them with nutrient meat broth so the mold could grow on the surface. By early 1940 a small sample of brown powder, no more than 0.02 percent pure, was obtained. Its injection into two mice produced no ill effect.

What happened next involved luck on three different counts. First, they chose mice rather than guinea pigs, the other common lab animal in use at the time. Penicillin is nontoxic to mice but quite toxic to guinea pigs. Second, there was an extremely high content of impurities in the powder they injected into the mice; had the impurities been toxic to the mice, the scientists would not have realized how safe penicillin actually is and might have terminated the study. Third, Chain and Florey noted that the urine of the injected mice had a deep brown color, signaling to them that penicillin is mostly excreted unchanged in the urine. This meant not only that it is not destroyed in the body but also that penicillin could seep through any fluids to fight infections wherever they existed in any tissues.

The team now fully appreciated the extraordinary antibacterial activity of penicillin for the first time. Furthermore, they found that penicillin would stop bacteria from growing even at a dilution of one part in a million. They began to grasp the therapeutic potential of the substance and pressed Florey to begin full-scale animal experiments. With refinements in technique, Heatley was able to increase the purity to 3 percent.

On May 25, 1940, Florey, Chain, and Heatley carried out a groundbreaking experiment to demonstrate penicillin's effects on eight white mice infected with lethal doses of streptococci. Four were injected
with penicillin, while the other four, the controls, were not. Heatley, excited, stayed in the laboratory all night. By morning, all the controls were dead. Three of the four mice who had received penicillin survived. While Chain broke into an exuberant dance, Florey cautiously allowed that “it looks like a miracle.”

These crucial experiments were taking place as Britain was plunged into war and the British Expeditionary Force was being evacuated from Dunkirk. Florey and Chain's first paper, “Penicillin as a chemotherapeutic agent,” appeared in August 1940 in the
Lancet,
the most widely read British medical journal.
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The journal's editors, recognizing the landmark results, had rushed it into print, two weeks before the Battle of Britain began. It was a brief account of only two pages, but it said everything that could be said. For the next two years, Florey applied his time and energy to persuading people to take notice of what he was convinced was the medical discovery of the century.
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Sulfa drugs had proved their usefulness, but they had drawbacks. In time of war, more powerful antibacterial drugs would be immensely valuable. The experiments on mice had used up the team's entire stock of penicillin, and a mouse is 3,000 times smaller than a human being. It was clear they were going to have to expand the operation on a massive scale. Needing more containers, Florey decided to turn his department into a penicillin factory to produce enough for a clinical trial on human patients and commissioned a pottery to produce six hundred ceramic vessels modeled after bedpans. Between February and June 1941, these tests spectacularly confirmed the results of the animal experiments: penicillin was far more effective and nontoxic than any known antibiotic.

The first patient was a forty-three-year-old Oxford policeman, Albert Alexander, who was near death from a mixed staphylococcalstreptococcal septicemia that developed at the site of a scratch at the corner of his mouth that he had sustained while pruning his roses. He had not responded to sulfapyridine, had undergone removal of his infected left eye, and had numerous abscesses on his face, scalp, and one arm. Only about a teaspoon of the unrefined penicillin extract was available. After being treated with it, he improved dramatically, only to suffer a fatal relapse when the minute supply ran out. The last three
days of his treatment were maintained by collecting all his urine and extracting and recycling as much of the drug as possible. Florey likened the situation to “trying to fill the bath with the plug out.”
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While shaken by the tragedy, Florey nevertheless knew that only logistical problems remained to be solved before penicillin could begin to save lives.

During the summer of 1941 four children seriously ill with streptococcal or staphylococcal infections were treated with penicillin at Oxford. Children were chosen in the hope that they would need less of the substance than an adult. All were cured. Penicillin not only was active against a range of bacteria but it also had no harsh side effects, such as the kidney toxicity that had been reported with sulfanilamides, or their tendency to destroy the ability of the bone marrow to produce white blood cells. The results were promptly published in the
Lancet.
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Modestly titled “Further observations on penicillin,” the article served to announce the dawn of the antibiotic era.

Events now took on the character of an Eric Ambler thriller. Florey was determined to keep penicillin from the Germans. When a German invasion of the British Isles under Hitler's Operation Sea Lion seemed likely, the Oxford team smeared the lining of their clothes with the penicillin mold in the hope that spores of the precious discovery could be smuggled to safety.

As the war dragged on, the need for penicillin to treat Allied soldiers became more crucial. Realizing that an adequate supply could not be produced in wartime England, Florey and Heatley left for the United States at the end of June 1941. They flew via neutral Lisbon in a blacked-out Pan Am Clipper to New York City, storing their precious freeze-dried penicillin mold in the plane's refrigerator. Arriving several days later, in 90-degree heat, they rushed across Manhattan with their precious sample by taxi to a midtown hotel where it could be refrigerated. The American government was easily persuaded to undertake large-scale production of the drug, and events progressed from there at lightning speed.

The two men were referred to the regional research center of the Department of Agriculture in Peoria, Illinois, located in the heart of the Midwest.
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This facility had a large fermentation research laboratory for the production of useful chemicals from agricultural by-products.
Heatley set to work with Robert Coghill, head of the fermentation division, and Andrew J. Moyer for the large-scale cultivation of the mold.

As luck would have it, Coghill's and Moyer's experiences had been with corn steep liquor, a cheap syrupy by-product of the manufacture of cornstarch. They found that the mold thrived in this valuable nutrient, and with the deep fermentation technique in 15,000-gallon tanks, the yield of penicillin was greatly increased. They had yields of 900 units per milliliter of brew, whereas Florey had gotten only 2 at Oxford. The serendipitous nature of this turn of events, which resulted in the large-scale production of penicillin, was emphasized by Coghill: “One of the least understood miracles connected with it [penicillin] is that Florey and Heatley were directed to our laboratory at Peoria—the
only
laboratory where the corn steep liquor magic would have been discovered.”
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