The Drug That Changed the World

BY ERIC OATMAN

WE ALL LEARNED THE STORY OF PENICILLIN IN SCHOOL: HOW Alexander Fleming, in 1928, seeded an agar plate with staphylococci, took a two-week holiday, and returned in late August or early September to find a ring of death around a penicillium mold that had taken root in his absence. It's a wonderful story, not least because it shows the role serendipity can play in a scientist's success. You leave a Petri dish uncapped, leave a window open, leave town, and leave the hard stuff to God.
The trouble with the story, which Fleming recounted in 1944, is that it can't be true. As Eric Lax explains in his entertaining "The Mold in Dr. Florey's Coat," Fleming appears to have been away from his lab not for two weeks but for five. By then Fleming should have found his penicillium claiming the agar's entire surface. Fleming's account suggests that he misunderstood the order of events (to lyse or dissolve a colony of bacteria in a Petri dish, the penicillium must be planted first) and failed to realize how a summer cold snap might have produced a unique phenomenon (mold grows best at 20C, staphylococci at 35C). These are two of several possibilities suggested by those who tried and failed to replicate Fleming's discovery.
Sixteen years after the 1928 experiment, it's likely that Fleming's memory was frayed and that without clear records (there's no reference to penicillin in his notebooks until late October), he was unable to refresh it. "What mattered most to Fleming was not the recording of his experiments but their performance," recalled the bacteriologist Ronald Hare, who was his research assistant in the Inoculation Division of St. Mary's Hospital in London.
Penicillin wasn't Fleming's only major discovery. In 1922 he identified the enzyme lysozyme, a component of tears and mucus that guards the body's entrances against mild-mannered airborne bacteria. If he hadn't worked six years with lysozyme (or, for that matter, in a cluttered lab), it's probable that he would have dipped the Petri dish in disinfectant before pausing to ponder the halo of transparent cells around the mold. "A good scientist," said the Nobel Laureate Peter Medawar, "is discovery-prone."
Fleming abandoned penicillin after four years of study. Like all scientists, he was a prisoner of history. He was unable to isolate or stabilize the active substance, and he couldn't imagine its being used systemically. In 1928 much of the medical community was suspicious of the idea of using drugs to destroy pathogens throughout the body. The effectiveness of the sulfonamides, the synthetic antibacterial drugs developed in Germany, wouldn't be established until 1935.

Chapter Two
Karl Meyer, 1952
Karl Meyer, 1952
The researchers who began their study of penicillin at Oxford University in 1939 had the advantage of hindsight. Starting out with a sample of Fleming's penicillium, they nurtured it on the surface of a crude broth, extracted the drug from the broth, purified it, freeze-dried it to preserve its potency, tested it on lab animals and human subjects, and lobbied to get it mass-produced in England and the United States.
The work at Oxford began in earnest in September 1939. By August 1941, U.S. Department of Agriculture scientists in Peoria, Ill., were producing a high-yielding mold, and a few pharmaceutical companies were showing interest in the drug. In 22 months, with World War II raging around them, about a dozen determined scientists, clinicians, and lab assistants had changed the world.
The central figure in the Oxford chapter was Howard Florey, the direct, even blunt Australian physiologist who headed the Sir William Dunn School of Pathology. He designed the study with the biochemist Ernst Boris Chain, a proud and testy German émigré. The plan was for Florey to grapple with the biological problems, Chain to tackle the chemical ones. Norman Heatley, another biochemist, produced the needed penicillin. He coaxed the mold to yield yellowish-gold droplets rich with penicillin, had them drawn off with pipettes, and processed them.

A Miracle
Also of Note
Drug store in New York City, 1945 Anne Sheafe Miller met Sir Alexander Fleming in 1945, as Dr. Francis Blake, Yale Medical School dean, looks on.

> The first person thought to have been not simply cured but snatched from death by penicillin was Anne Sheafe Miller, a 1931 graduate of Presbyterian Hospitalís nursing school. In March 1942, fighting a streptococcal infection that transfusions, sulfonamide, and surgery had failed to conquer, Miller lay days from death at New Haven Hospital. Norman Heatley, then on loan to Merck in New Jersey, obtained the penicillin that restored her to health. Miller died in 1999 at age 90.
> The first recorded use of a sulfa drug in the United States took place at Babies Hospital in July 1935. The patient was Katherine Woglon, the 10-year-old daughter of a Brooklyn physician; the target was the bacterium that caused her meningitis. After an apparent cure, Katherine suffered a relapse a few months later and died.
While performing a toxicity test on a mouse early in 1940, Florey and Chain made a pivotal discovery. The mouse's urine contained a high concentration of penicillin. "From this we concluded," Chain wrote, "that . . . it was therefore probable that [penicillin] would display its antibacterial activity in the body fluids."
Two classic experiments proved them right. In late May 1940 they injected eight white mice with potentially lethal doses of streptococci. They injected four of the mice with penicillin. Two mice received a single injection; one lived for two days, the other for six days. Two mice were given five injections over a period of 11 hours. One lived for 13 days, the other indefinitely. All four of the untreated mice died within a matter of hours. "It looks like a miracle," Florey said.
Two months later, they ran a more elaborate experiment on nearly 300 mice. Some were injected with streptococci, some with staphylococci, and some with Clostridium septique (the cause of braxy, a deadly sheep disease). The results were as spectacular as the earlier ones. The team reported them in the Aug. 24, 1940, issue of The Lancet.
To Florey's disappointment, the paper didn't create much of a stir in England. But it had an immediate impact on Dr. Martin Henry Dawson, a clinician and associate professor of medicine at P&S. Dawson, 44 years old, had a keen interest in microbiology and infectious diseases. At the time, he was working with Dr. Karl Meyer, a biochemist, and Dr. Gladys Hobby, a microbiologist, to identify diseases produced by hemolytic streptococci. Meyer, 41, headed the biochemistry department at the Eye Institute. Hobby, 30, was just beginning what would become a high-profile career as a researcher and administrator. After Dawson acquired a sample of the mold, the three scientists were off and running.

Making It, Testing It
"We naively undertook 'to make some penicillin,'" Hobby recalled in her book "Penicillin: Meeting the Challenge." Doing that, she quickly learned, meant becoming a kind of brewmaster, an expert in the fermentation processes required to produce the drug. "Soon hundreds of two-liter flasks . . . lined every classroom laboratory bench at the Columbia University Medical School," she wrote. "We had no adequately large incubators and no space in our own small laboratory for such large numbers of flasks, but moved in and out of classrooms as the students moved out and in."
Eventually they discovered that the school's twostory amphitheater was an excellent incubator, and they stored their flasks under the seats. "At last the penicillium cultures could be grown under stationary conditions ó at least during the eight to nine months of the year when room temperatures were within the range suitable for growth of the mold."
To vent the fumes produced when the solvents used to extract the drug were evaporated, Meyer and an assistant set up a still on a fire escape overlooking Fort Washington Avenue. "Later," Hobby wrote, "the techniques we used seemed very primitive, but they provided enough concentrated and partially purified penicillin to convince us of the efficacy of the drug and enough even to help save a few patients' lives."
Dawson's interest in penicillin stemmed from his concern for patients with subacute bacterial endocarditis, an infection of the heart lining or valves that in 1940 was invariably fatal. On Oct. 16 and 17, 1940, less than a month after research began and three months before the first human tests in Oxford, he tested what little penicillin Meyer had been able to produce on two men who were suffering from this disease. The doses, administered at Presbyterian Hospital, were too small to produce a therapeutic response. (Almost two years would go by before they had enough penicillin to treat a patient adequately.) But the test confirmed the Oxford group's observation that penicillin wasn't toxic.

Getting the Word Out
Dawson's team tested the drug on 10 other patients, two of them with bacterial endocarditis and eight with chronic staphylococcal blepharitis (inflammation of the edges of the eyelids). They presented their findings in Atlantic City at a meeting of the American Society for Clinical Investigation on May 5, 1941. "Penicillin," the paper concluded, "probably represents a new class of chemotherapeutic agents which may prove as useful or even more useful than the sulfonamides." At the time, the only medicines active against bacteria were sulfa drugs, often too toxic to use at therapeutic levels.
Several newspapers carried news of the team's findings on its front page. "'GIANT' GERMICIDE YIELDED BY MOLD," the New York Times announced over its lead story on May 7. "New Non-Toxic Drug Said to Be the Most Powerful Germ Killer Ever Discovered. TRIED ON HUMAN BEINGS."
The press coverage got researchers in academia and in pharmaceutical companies to take note. Merck & Co. and E.R. Squibb & Sons began studying the drug. Chas. Pfizer & Co. (now Pfizer Inc.), a small producer of chemicals in Brooklyn, began studies of its own and soon struck up an informal partnership with Dawson's group. By fall, Pfizer was sending big glass jugs of its fermentation liquor to the medical center every morning for Dawson's team to test and use.
No one seemed more amazed at the turn of events than Gladys Hobby. "All we had going for us in this endeavor," she said, "was an enthusiastic team consisting of an extremely able chemist, a microbiologist, and a clinician with drive, purpose, dedication, and vision." She might have added the word "courage" to Dawson's description, for in 1941 he was diagnosed with myasthenia gravis, a progressive nerve disorder. After overseeing the treatment of more than 100 patients, he died in 1945.
By June 1941, the Oxford group had concluded its first round of human testing. In July, Florey and Heatley flew to the United States to persuade government and drug company officials to manufacture enough penicillin to permit large-scale trials. U.S. drug companies produced 21 billion units of penicillin in 1943. They produced 1.6 trillion units in 1944 and 6.8 trillion units in 1945, the year seven British companies rushed out 30 billion units a month.

The 2nd General Hospital
All through the war, Presbyterian Hospital staffed a completely equipped and mobile Army hospital. From July 1942 to July 1944, this 2nd General Hospital was situated on the outskirts of Oxford. It was a fortuitous posting. When Major Rudolph Schullinger'23, an associate professor of surgery at the medical school, embarked on a study of the proper use of penicillin in military medicine, he had Howard Florey's wife, Dr. Mildred Florey, to guide him. Despite the scarcity of the drug, Schullinger's team was able to test it on a variety of infections. (Patients' urine was collected daily and taken to the Dunn School, where any unused penicillin was harvested for future use.) Medical officers from U.S. hospitals throughout the European theater came to the 2nd General Hospital for training in penicillin therapy. The project ended in March 1944, three months before the invasion of Normandy.
In July 1944, after the 2nd General Hospital had been relocated to Normandy, Lt. Albert Richard Lamb Jr.'40, who wrote the history of the 2nd General Hospital, needed to create a blood bank from scratch. As the Army had failed to supply materials for banking, he made the rounds of evacuation hospitals to scavenge used saline bottles and tubing. "During that treasure hunt," he said, "a boxcar filled with penicillin was pointed out to me by a supply colonel at a rail siding near Cherbourg." All the hard work had paid off. Penicillin would save thousands of soldiers before the war was over.
Of all the weapons developed during World War II, penicillin was probably the most important. Along with the microbial drugs that came afterwards, it lowered the incidence and severity of infectious diseases and made medical advances such as burn management, open-heart surgery, and organ transplantation possible. That's not too shabby a result for a substance discovered among a stack of neglected plates by a rested, discovery-prone scientist, incubated in bedpans in Oxford and under auditorium seats at P&S in New York, and extracted from a soupy culture medium on a fire escape.

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