Happy Accidents: Serendipity in Major Medical Breakthroughs in the Twentieth Century (12 page)

Even further success was then ensured by another stroke of good luck. America's entry into the war in December 1941 guaranteed a total dedication to a project that would ultimately benefit battlefield casualties. Military personnel were ordered to gather handfuls of soil from around the world in the hope of tracking down a fungus that produced high quantities of penicillin. Mold from soil samples flown in by the Army Transport Command from Cape Town, Bombay, and Chungking were the front-runners. In the end, the army was beaten by Mary Hunt, a laboratory aide who one day brought in a yellow mold she had discovered growing on a rotten cantaloupe at a fruit market right in Peoria. This proved to be
Penicillium chrysogenum,
a strain that produced 3,000 times more penicillin than Fleming's original mold!
²⁹
This made commercial production of penicillin feasible. The laboratory assistant was called Moldy Mary for the rest of her life.

In its first trial in the United States, penicillin proved miraculous. In early 1942 Mrs. Ogden Miller, the thirty-three-year-old wife of Yale's athletic director, hospitalized for a month at the university's medical center, was near death from hemolytic streptococcal septicemia (blood poisoning) after a miscarriage. She was often delirious, with her temperature spiking to nearly 107 degrees. Her doctors tried everything available, including sulfa drugs, blood transfusions, and surgery. All failed. In desperation, she was given a precious small supply
of penicillin made available by Merck in Rahway, New Jersey. The clinical response was dramatic, and she rapidly recovered. The record of this singular event, her hospital chart, is preserved at the Smithsonian Institution. (Mrs. Miller went on to live to the age of ninety.)

By the spring of 1943 some two hundred cases had been treated with the drug. The results were so impressive that the surgeon general of the U.S. Army authorized trial of the antibiotic in a military hospital. Soon thereafter, penicillin was adopted throughout the medical services of the U.S. Armed Forces and became a decisive factor in World War II. By the time of the D-Day invasion of Normandy in June 1944, the American drug companies Merck, Squibb, and particularly Pfizer were producing 130 billion units of penicillin per month, enough to treat all 40,000 wounded soldiers.

British pharmaceutical companies were able to produce only tens of millions of units of penicillin per month. This paled almost into insignificance in contrast to the large-scale American effort. Considerable friction between the two countries arose over legal protection of manufacturing methods. Chain, trained in the German tradition of collaboration between academic research and industry, vigorously advocated patenting penicillin for “protecting the people in this country against exploitation” (that is, he did not want to see penicillin used for personal gain). British law did not cover patenting a natural product, but the production process used various innovations that could be protected by patents. Chain was opposed by the head of the Medical Research Council and the president of the Royal Society on the grounds that patenting lifesaving drugs was unethical. In Britain there was a prevailing attitude that universities should keep a gentlemanly distance from collaboration with industry. This stemmed from the social distance the landed gentry had been anxious to maintain from the entrepreneurs during the Industrial Revolution. Florey acquiesced. Chain was furious.

The Americans had no such ethical qualms regarding patents and worked out a vast commercial enterprise. The money generated by U.S. pharmaceutical companies from penicillin production has underpinned the industry ever since. By 1979 sales topped $1 billion. Britain would be required to pay many millions of dollars to the United States
to use, under license, the culture methods developed in the United States in 1941.
³⁰

The Cocoanut Grove Miracle

The American public was largely unaware of the momentous cooperative effort among academia, government, and industry regarding penicillin. Little news had leaked out about it. In a disastrous fire on the night of November 28, 1942, at the Cocoanut Grove nightclub in Boston, 492 people perished. Penicillin was successfully used to treat 220 badly burned casualties. But the public remained ignorant of this “miracle,” as penicillin was then classified as a military secret.

With the end of the war, the necessity for secrecy came to an end, and in March 1945 commercial sales began. Pneumonia, syphilis, gonorrhea, diphtheria, scarlet fever, and many wounds and childbirth infections that had once been typically fatal suddenly became treatable. Deaths caused by bacterial infections plummeted.

And so began the modern era of antibiotics. The term chemo-therapy, referring to drugs manufactured by laboratories, would in time be replaced by the term antibiotics for substances produced by microbes that can be used to treat infections. Antibiotics are chemical substances produced by various species of microorganisms (bacteria, fungi, actinomycetes) that suppress the growth of other microorganisms and may eventually destroy them. Unlike the therapeutic agents pioneered by Ehrlich and Domagk from synthetic chemicals, antibiotics have always existed in the biological world as natural defenders. They are chemicals produced by one microorganism in order to prevent another organism from competing against it.
³¹

Out with Gout

Unexpectedly, attempts to counteract the flushing of penicillin into the urine led to development of a major drug for gout. Merck spent years searching for a compound that would conserve penicillin blood levels by inhibiting its excretion by the kidneys. By the time it came upon one, probenecid, in 1950, it was no longer needed, since penicillin was being produced in large quantities at low cost. But the drug was found to increase the excretion of uric acid and became an effective treatment for the crystallized uric acid that causes the crippling destruction of joints in gouty arthritis. Probenecid was developed for a specific purpose, but was found to be more useful than originally intended. The muse of serendipity had smiled again.

T
HE
F
LEMING
M
YTH
B
ECOMES
E
NSHRINED

Another fascinating element of the penicillin story involved a “return engagment” in the midst of the drama by its original discoverer, Alexander Fleming. In August 1942 a friend of Fleming's was dying of streptococcal meningitis at St. Mary's Hospital. Fleming telephoned Florey to ask if there was any chance of using some of his penicillin. Florey traveled down to London and handed over all the available stock. Fleming injected the drug into his friend intravenously, but then, when he discovered that the penicillin was not gaining entry into the fluid around the brain to kill the germs there, he courageously injected it through a spinal tap. This route of administration had never been used on humans before. The man's life was saved.

The story of this success was reported in the
Times,
without naming the researchers but referring to work in Oxford. In response, Sir Almroth Wright, Fleming's old mentor, wrote an effusive letter to the
Times
in which he credited the discovery to Fleming (and the Inoculation Department of St. Mary's). When interviews with Fleming appeared in the press, an Oxford professor informed the
Times
that
Florey's group deserved much of the credit. But Florey shunned the press, believing that publicity debased scientists and their work. In addition, he felt it would be a public disservice to raise hopes before he knew how to mass-produce the drug.

Thus Fleming alone was seen in the papers, and so was born the Fleming Myth, as the press and public, longing for good news during the grim war years, seized happily on the humble story of the moldy culture plate. Perhaps even more important was the fact that it was easier for the admiring public to comprehend the deductive insight of a single individual than the technical feats of a team of scientists. At first startled by and rather shy in response to the adulation, Fleming soon began to revel in it, as he went on to be lionized by the world. Nobody raised the question of what Fleming had done with his discovery between 1928 and the time it was evaluated by the Oxford group in 1940.

At war's end, the contributions of the Oxford group were finally recognized, and Fleming, Florey, and Chain shared the 1945 Nobel Prize for Physiology or Medicine. As for Norman Heatley, his official recognition was delayed until 1990 when Oxford University gave him an honorary M.D. degree.

In accepting the Nobel award in 1945, Fleming said: “In my first publication I might have claimed that I had come to the conclusion as a result of serious study of the literature and deep thought, that valuable antibacterial substances were made by moulds and that I set out to investigate the problem. That would have been untrue and I preferred to tell the truth that penicillin started as a chance observation.”
³²
In an informal setting, he reminisced: “Penicillin happened…. It came out of the blue.”
³³

In September 1945 Fleming was honored by the Académie de Médecine. In his speech, he asked his Paris audience, “Have you ever given it a thought how decisively hazard—chance, fate, destiny, call it what you please—governs our lives?” And he went on to hail the freedom of a scientist to pursue a serendipitous observation: “Had I been a member of a research team, engaged in solving a definite problem at the moment of this happy accident that led me to penicillin, what should I have done? I would have had to continue with the work
of the team and ignore this side entrance. The result would have been either that someone else would have discovered penicillin or that it would still remain to be discovered.”
³⁴

Fleming reportedly confessed to a scientific contemporary in 1945 that he didn't deserve the Nobel Prize but added disarmingly that he nevertheless couldn't help enjoying his fame. Perhaps this explains why to the end of his life he felt that his greatest achievement was the discovery of lysozyme. He spent his last ten years collecting twenty-five honorary degrees, twenty-six medals, eighteen prizes, thirteen decorations, and honorary membership in eighty-nine scientific academies and societies. There is even a crater on the moon named after Fleming. When he died of a heart attack in 1955, he was mourned by the world and buried as a national hero in the crypt of St. Paul's Cathedral in London, beside Nelson, Wellington, and Wren.

Fleming's discovery was a stroke of brilliant observation, but he simply lacked the ability to convince. It was not in his nature to develop his discoveries, as Florey and the Oxford group did, with perseverance, ingenuity, and organization. Florey's biographer (and later also Fleming's) writes: “Fleming was like a man who stumbles on a nugget of gold, shows it to a few friends, and then goes off to look for something else. Florey was like a man who goes back to the same spot and creates a gold mine.”
³⁵

Ernst Chain was generous in his appraisal of Fleming: “We ourselves at Oxford… had plenty of luck. Therefore it is petty and irrelevant to try to detract from the importance of Fleming's discovery by ascribing it entirely to good luck, and there is no doubt that his discovery, which has changed the history of medicine, has justly earned him a position of immortality.”
³⁶

Florey, known for his scientific integrity, also acknowledged the indirect, often stumbling nature of the Oxford accomplishment. But, as is typical of many researchers, this did not happen until long after the work was published and high awards bestowed. In his Dunham Lectures at the Harvard Medical School in 1965, Florey said: “We all know that when we compose a paper setting out… discoveries we write it in such a way that the planning and unfolding of the experiments appear to be a beautiful and logical sequence, but we all know
that the facts are that we usually blunder from one lot of dubious observations to another and only at the end do we see how we should have set about our problems.”
³⁷

Chain had observed with a keen eye how well government, industry, and academic research collaborated in a unique combination of resources to bring this wonder drug to the world. Yet he understood the futility of any “mass attack” on diseases where knowledge of fundamental biologic facts is lacking. In 1967 he shared this wisdom with the world:

But do not let us fall victims of the naive illusion that problems like cancer, mental illness, degeneration or old age… can be solved by bulldozer organizational methods, such as were used in the Manhattan Project. In the latter, we had the geniuses whose basic discoveries made its development possible, the Curies, the Rutherfords, the Einsteins, the Niels Bohrs and many others; in the biologic field… these geniuses have not yet appeared…. No mass attack will replace them…. When they do appear, it is our job to recognize them and give them the opportunities to develop their talents, which is not an easy task, for they are bound to be lone wolves, awkward individualists, nonconformists, and they will not very well fit into any established organization.
³⁸

6

Pay Dirt

One day in 1943 a New Jersey poultry farmer noticed that one of his chickens seemed to be wheezing. None of his other birds exhibited this symptom, but he was fearful that it might be the harbinger of an infectious disease that could afflict his entire flock. He rushed the chicken to a state laboratory for testing, which found that a clod of dirt with a bit of mold on its surface was stuck in the bird's throat. The lab's pathologist, knowing of the interests of Selman Waksman, the distinguished soil microbiologist at the New Jersey Agricultural Experiment Station of Rutgers University in the city of New Brunswick, took a throat swab and sent it to him.