Alexander Fleming
1881 - 1955

A spore that drifted into his lab and took root on a culture dish started a chain of events that altered forever the treatment of bacterial infections
By DR. DAVID HO for Time Magazine
 

The improbable chain of events that led Alexander Fleming to discover penicillin in 1928 is the stuff of which scientific myths are made. Fleming, a young Scottish research scientist with a profitable side practice treating the syphilis infections of prominent London artists, was pursuing his pet theory — that his own nasal mucus had antibacterial effects — when he left a culture plate smeared with Staphylococcus bacteria on his lab bench while he went on a two-week holiday.

When he returned, he noticed a clear halo surrounding the yellow-green growth of a mold that had accidentally contaminated the plate. Unknown to him, a spore of a rare variant called Penicillium notatum had drifted in from a mycology lab one floor below. Luck would have it that Fleming had decided not to store his culture in a warm incubator, and that London was then hit by a cold spell, giving the mold a chance to grow. Later, as the temperature rose, the Staphylococcus bacteria grew like a lawn, covering the entire plate — except for the area surrounding the moldy contaminant. Seeing that halo was Fleming's "Eureka" moment, an instant of great personal insight and deductive reasoning. He correctly deduced that the mold must have released a substance that inhibited the growth of the bacteria.

It was a discovery that would change the course of history. The active ingredient in that mold, which Fleming named penicillin, turned out to be an infection-fighting agent of enormous potency. When it was finally recognized for what it was — the most efficacious life-saving drug in the world — penicillin would alter forever the treatment of bacterial infections. By the middle of the century, Fleming's discovery had spawned a huge pharmaceutical industry, churning out synthetic penicillins that would conquer some of mankind's most ancient scourges, including syphilis, gangrene and tuberculosis.

Fleming was born to a Scottish sheep-farming family in 1881. He excelled in school and entered St. Mary's Hospital in London to study medicine. He was a short man, usually clad in a bow tie, who even in his celebrity never mastered the conventions of polite society. Fleming probably would have remained a quiet bacteriologist had serendipity not come calling that fateful September in 1928.

In fact, Fleming was not even the first to describe the antibacterial properties of Penicillium. John Tyndall had done so in 1875 and, likewise, D.A. Gratia in 1925. However, unlike his predecessors, Fleming recognized the importance of his findings. He would later say, "My only merit is that I did not neglect the observation and that I pursued the subject as a bacteriologist." Although he went on to perform additional experiments, he never conducted the one that would have been key: injecting penicillin into infected mice. Fleming's initial work was reported in 1929 in the British Journal of Experimental Pathology, but it would remain in relative obscurity for a decade.

By 1932, Fleming had abandoned his work on penicillin. He would have no further role in the subsequent development of this or any other antibiotic, aside from happily providing other researchers with samples of his mold. It is said that he lacked both the chemical expertise to purify penicillin and the conviction that drugs could cure serious infections. However, he did safeguard his unusual strain of Penicillium notatum for posterity. The baton of antibiotic development was passed to others.

In 1939 a specimen of Fleming's mold made its way into the hands of a team of scientists at Oxford University led by Howard Florey, an Australian-born physiologist. This team had technical talent, especially in a chemist named Ernst Boris Chain, who had fled Nazi Germany. Armed with funding from the Rockefeller Foundation, these scientists made it their objective to identify and isolate substances from molds that could kill bacteria. The mission was inspired by the earlier work of Gerhard Domagk, who in 1935 showed that the injection of a simple compound, Prontosil, cured systemic streptococcal infections. This breakthrough demonstrated that invading bacteria could be killed with a drug and led to a fevered search in the late 1930s for similar compounds. Fleming's Penicillium notatum became the convenient starting point for Florey's team at Oxford.

In a scientific tour de force, Florey, Chain and their colleagues rapidly purified penicillin in sufficient quantity to perform the experiment that Fleming could not: successfully treating mice that had been given lethal doses of bacteria. Within a year, their results were published in a seminal paper in the Lancet. As the world took notice, they swiftly demonstrated that injections of penicillin caused miraculous recoveries in patients with a variety of infections.

The Oxford team did not stop there. Rushing to meet the needs of World War II, they helped the government set up a network of "minifactories" for penicillin production. Florey also played a crucial role in galvanizing the large-scale production of penicillin by U.S. pharmaceutical companies in the early 1940s. By D-day there was enough penicillin on hand to treat every soldier who needed it. By the end of World War II, it had saved millions of lives.

Pneumonia, syphilis, gonorrhea, diphtheria, scarlet fever and many wound and childbirth infections that once killed indiscriminately suddenly became treatable. As deaths caused by bacterial infections plummeted, a grateful world needed a hero. Fleming alone became such an object of public adulation, probably for two reasons. First, Florey shunned the press, while Fleming seemed to revel in the publicity. Second, and perhaps more important, 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.

Awards and accolades came to Fleming in rapid succession, including a knighthood (with Florey) in 1944 and the Nobel Prize for Medicine (with Florey and Chain) in 1945. By this time, even Fleming was aware that penicillin had an Achilles' heel. He wrote in 1946 that "the administration of too small doses ... leads to the production of resistant strains of bacteria." It's a problem that plagues us to this day.

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. Although Fleming's scientific work in and of itself may not have reached greatness, his singular contribution changed the practice of medicine. He deserves our utmost recognition. At the same time, we must bear in mind that the "Fleming Myth," as he called it, embodies the accomplishments of many giants of antibiotic development. Fleming is but a chosen representative for the likes of Florey, Chain, Domagk, Selman Waksman and Rene Dubos, many of whom remain, sadly, virtual unknowns. Their achievements have made the world a better, healthier place. In commemorating Fleming, we commemorate them all.
 

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The Scottish bacteriologist Sir Alexander Fleming (1881-1955) is best known for his discovery of penicillin, which has been hailed as "the greatest contribution medical science ever made to humanity."

Alexander Fleming was born on Aug. 6, 1881, at Lochfield, Ayrshire, one of the eight children of Hugh Fleming, a farmer. Nature, which he considered his first and best teacher, developed his power of observation and taught him to apply his powers of reasoning to what he observed and to act in accordance with his observations. Like many Scots who were forced to leave their native land for better career opportunities, Fleming, at the age of 13, left for London, where he lived with his brothers. He attended lectures at the Polytechnic School and worked for 4 years in a shipping office. In 1901 an uncle left Fleming a legacy that enabled him to study medicine, and he entered St. Mary's Hospital Medical School in Paddington, later a part of the University of London.

In 1906 Fleming received his licentiate from the Royal College of Physicians. He chose a career in bacteriology and immediately joined the Inoculation Department, now the Wright-Fleming Institute, where he spent his entire career. He assisted Sir Almroth Wright, the originator of vaccinotherapy (therapeutic inoculation for bacterial infection) and the first doctor to use antityphoid vaccines on human beings. Fleming's research at this time primarily involved the use of Paul Ehrlich's Salvarsan in the treatment of syphilis. In 1908 Fleming passed his final medical examinations, winning the Gold Medal of the University of London. He was awarded the Cheadle Medal for his thesis "Acute Bacterial Infections," which foreshadowed the line of work he followed throughout his life.

During World War I Fleming served in the Royal Army Medical Corps, specializing in the treatment of wounds by antiseptics. He noticed that phagocytosis (the ingestion and destruction of infectious microbes by the cells) was more active in war wound infections than in ordinary wound infections, and he advised surgeons to remove all necrotic tissue as soon as possible. He observed that antiseptics not only did nothing to prevent gangrene but actually promoted its development by destroying leukocytes. Although Fleming's later discoveries have overshadowed this work, some authorities believe that he never conceived anything more perfect or ingenious than these brilliant experiments by which he demonstrated the danger to human tissues of incorrectly administered antiseptics.

In 1915, while on leave, Fleming married Sarah Marion McElroy, an Irish nurse who operated a private nursing home in London. The couple had one son, Robert.


Lysozyme Research

In 1921, the year he became assistant director of the Inoculation Department at St. Mary's, Fleming discovered that nasal mucus, human tears, and, especially, egg whites contain a chemical substance with marked bactericidal properties. Inasmuch as it lysed (dissolved) microbes and had the properties of an enzyme, Fleming called it lysozyme. Élie Metchnikoff believed that bodily secretions removed microbes by mechanical rather than chemical means, an opinion held in 1921 by most bacteriologists. Fleming now challenged this view, but his work met a cold reception. Between 1922 and 1927 he published five more articles on lysozyme: he proved that antiseptics then in use, even in much weaker solutions than necessary to fight septicemia, would destroy leukocytes, and that "whereas egg white … has no destructive effects on the leukocytes, it has considerable inhibitory or lethal effect on some of the bacteria."


Discovery of Penicillin

The leitmotiv of Fleming's career was his search for a chemical substance which would destroy infectious bacteria without destroying tissues or weakening the body's defenses. In 1928 an accidental observation, which was a direct result of his apparently disorderly habit of not discarding culture plates promptly, led to the fulfillment of his goal. Fleming noted that on a culture plate of staphylococci a mold (Penicillium notatum) which had been introduced by accidental contamination had dissolved the colonies of staphylococci - an example of antibiosis. He found that the broth containing the bactericidal substance (penicillin) produced by the mold was unstable and rapidly lost its activity. Furthermore, it could not be used for injections until freed from foreign protein. Clearly, a method of extraction and concentration of the crude substance was required. Fleming had no chemist or biochemist on his staff, and he encouraged others to attempt the task.

In 1935 Howard W. Florey, an Australian experimental pathologist, and Ernst B. Chain, a Jewish chemist who had fled from Nazi Germany, came to Oxford University, where in 1939 they took up Fleming's work on penicillin. By employing the relatively new technique of lyophilization, Florey and Chain isolated the drug in completely purified form, which was a million times more active than Fleming's crude substance of 1928, and in 1940 they published the results of their successful treatment of infected white mice. A completely successful test involving a human being was not accomplished until 1942 because of the limited supply of the drug. By 1943 factories in England and the United States were producing penicillin on a large scale, and it became available for military use. By 1944 the miracle drug became available for civilian use.

Fleming never collected royalties on penicillin. In 1945 he received the Nobel Prize in physiology or medicine and toured the United States, where he was hailed as a hero. American chemical firms collected $100,000 and presented it to him in gratitude for his contribution to medical science. He refused to accept the money personally but used it for research at St. Mary's.

In 1946 Fleming became director of the Institute, a position he held until 1955. In 1951 he was elected rector of Edinburgh University. His wife had died in 1949, and in 1953 he married Amalia Coutsouris-Voureka, a Greek medical worker who had come to London in 1946 to work with him. Fleming died on March 11, 1955, and was buried in the crypt of St. Paul's Cathedral in London. According to André Maurois, "No man, except Einstein in another field, and before him Pasteur, has had a more profound influence on the contemporary history of the human race."

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