Alexander Fleming

• 1. Introduction

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  Alexander Fleming, a Scottish physician and microbiologist, walked back into his London laboratory on the 3rd of September 1928 after a family holiday in Suffolk. Before leaving, he had spread staphylococci across culture plates and left them on a bench in a corner of the room. One plate now carried a fungus. The bacterial colonies crowding closest to it had been destroyed, while those farther away looked normal. Fleming studied it and remarked, "That's funny."

  That small remark opened the age of antibiotics, and later writers would call the result the "single greatest victory ever achieved over disease." Yet when Fleming told the scientific world what he had seen, it barely noticed. Why did a find of that size sit ignored for years? Who finally turned a curious mould into a medicine that could be injected into a dying patient? And what did Fleming himself fear would happen once the drug became cheap enough to buy over a shop counter?

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• 2. Making of a Bacteriologist

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  Lochfield farm, near Darvel in Ayrshire, is where Alexander Fleming was born on the 6th of August 1881. He was the third of four children of the farmer Hugh Fleming and Grace Stirling Morton, the daughter of a neighbouring farmer. Hugh already had four surviving children from his first marriage. He was 59 when he married Grace, and he died when Alexander was seven.

  Loudoun Moor School and Darvel School gave the boy his first lessons. A two-year scholarship then took him to Kilmarnock Academy. After that he moved to London and attended the Royal Polytechnic Institution. Medicine was not yet his plan, and he spent four years working in a shipping office.

  An inheritance from his uncle John Fleming arrived when Alexander was twenty. His elder brother Tom, already a physician, suggested he follow the same career. In 1903 Alexander enrolled at St Mary's Hospital Medical School in Paddington. In 1906 he qualified with an MBBS degree, with distinction.

  A rifle club steered him toward research. From 1900 to 1914 Fleming served as a private in the London Scottish Regiment of the Volunteer Force, and he shot for the medical school's club. Its captain wanted to keep him on the team and suggested he join the research department at St Mary's. There Fleming became assistant bacteriologist to Sir Almroth Wright, a pioneer in vaccine therapy and immunology. In 1908 he earned a BSc with gold medal in bacteriology and became a lecturer at St Mary's.

  In 1914 Fleming was commissioned a lieutenant, and he was promoted captain in 1917. He served throughout World War I in the Royal Army Medical Corps and was Mentioned in Dispatches. Many of his colleagues worked beside him in battlefield hospitals on the Western Front in France.

  At the British military hospital in Boulogne-sur-Mer, Fleming, Leonard Colebrook and Wright practically moved the whole Inoculation Department of St Mary's. Fleming watched many soldiers die of sepsis from infected wounds. The antiseptics then used to treat those wounds, he noticed, often made the injuries worse.

  A 1917 article in the medical journal The Lancet set out his explanation. He backed it with an experiment that his own glassblowing skills had made possible. Antiseptics worked well on the surface of a wound. Deep wounds, however, sheltered anaerobic bacteria from the chemical. The antiseptics also seemed to strip away protective agents the body had produced, at least as effectively as they removed germs, and they left the unreachable bacteria alone.

  Wright strongly supported these findings. Even so, most army physicians kept using antiseptics through the war, including in cases where patients got worse. Fleming returned to St Mary's in 1918, and in 1928 the University of London elected him Professor of Bacteriology.

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• 3. Lysozyme and Tears

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  V. D. Allison, a research scholar who worked under Fleming, remembered his chief as anything but tidy. Fleming expected odd growths to appear on his culture plates, and he teased Allison about his "excessive tidiness in the laboratory." Allison drew a lesson from this. He said, "If he had been as tidy as he thought I was, he would not have made his two great discoveries."

  In late 1921, Fleming was maintaining agar plates when he found one contaminated with bacteria from the air. He added nasal mucus to it and saw the mucus hold back bacterial growth. A clear, transparent circle surrounded the mucus, about 1 cm wide, marking a killing zone. Beyond it lay a glassy, translucent ring, and then an opaque area of normal growth.

  His next test used bacteria kept in saline, which formed a yellow suspension. Within two minutes of fresh mucus being added, the yellow liquid turned completely clear.

  Tears came next, supplied by his co-workers. Allison recalled that for five or six weeks their tears fed the experiments. "Many were the lemons we used (after the failure of onions) to produce a flow of tears," he wrote. Demand grew so great that laboratory attendants were pressed into service, and each was paid threepence per contribution.

  Sputum, cartilage, blood, semen, ovarian cyst fluid, pus and egg white all showed the same bacteria-killing agent. Fleming reported the finding to the Medical Research Club in December and to the Royal Society the next year. Allison, who sat in the room at the club, recalled that the paper drew no questions and no discussion. He took that silence as a sign the work was judged unimportant.

  On the 1st of May 1922, the Proceedings of the Royal Society B printed Fleming's paper "On a remarkable bacteriolytic element found in tissues and secretions." Because the substance behaved like a ferment, he named it a "Lysozyme." He wrote that it was first noticed during work on a patient suffering from acute coryza.

  That patient was Fleming himself. His research notebook entry of the 21st of November 1921 shows a sketch of the culture plate, with the note "Staphyloid coccus from A.F.'s nose." He named the bacterium Micrococcus lysodeikticus, a species name meaning "lysis indicator." It was reassigned as Micrococcus luteus in 1972, and the "Fleming strain," NCTC2665, has since become a model in many biological studies.

  Egg whites gave him larger amounts of lysozyme. Even so, the enzyme only worked against small counts of harmless bacteria, so it offered little as a treatment.

  Fleming knew its importance was overlooked. On the 18th of October 1932, in his presidential address to the Royal Society of Medicine, he said he had a "fatherly interest in the name." In his Nobel lecture on the 11th of December 1945, he said briefly, "Penicillin was not the first antibiotic I happened to discover." Only toward the end of the 20th century did lysozyme's place become clear, as the first antimicrobial protein found to be part of our innate immunity.

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• 4. The Mould

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  Merlin Pryce, Fleming's former assistant, was the first person he showed the spoiled plate to. Pryce reminded him, "That's how you discovered lysozyme." Fleming had been studying staphylococci since 1927. In 1928 he was tracing how Staphylococcus aureus varied when grown under natural conditions, following work by Joseph Warwick Bigger, who had found that the bacterium grows into a variety of strains.

  Fleming identified the mould as belonging to the genus Penicillium. He suspected it was P. chrysogenum, but his colleague Charles J. La Touche identified it as P. rubrum. It was later corrected to P. notatum and then officially accepted as P. chrysogenum. In 2011 it was finally resolved as P. rubens.

  A mystery lingered over where the spore came from. In 1966, the source of the contaminant was traced to La Touche's room, which sat directly below Fleming's. The laboratory where Fleming found and tested penicillin survives today as the Alexander Fleming Laboratory Museum at St Mary's Hospital in Paddington.

  Fleming grew the mould in pure culture and found that the broth held an antibacterial substance. He tested it against many organisms. It attacked staphylococci and many other Gram-positive pathogens, including those behind scarlet fever, pneumonia, meningitis and diphtheria. It did not touch typhoid fever or paratyphoid fever, which are caused by Gram-negative bacteria. Those were the very diseases he was hoping to cure at the time. It did affect Neisseria gonorrhoeae, the cause of gonorrhoea, even though that bacterium is Gram-negative.

  For some months he called the liquid "mould juice" or "the inhibitor." On the 7th of March 1929, he gave the antibacterial substance its lasting name, penicillin.

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• 5. Years of Neglect

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  On the 13th of February 1929, Fleming stood before the Medical Research Club with a talk titled "A medium for the isolation of Pfeiffer's bacillus." It drew no particular attention or comment. Henry Dale, then Director of the National Institute for Medical Research, chaired the meeting. He later said he had not sensed any striking point of importance in what Fleming said.

  Fleming published the discovery in 1929 in the British Journal of Experimental Pathology, and again few people noticed. His real obstacle was making penicillin in large amounts and isolating its main compound. Harold Raistrick and his team of biochemists at the London School of Hygiene & Tropical Medicine tried to help. Chemical purification still failed. In Milton Wainwright's words, "As a result, penicillin languished largely forgotten in the 1930s."

  The Second International Congress of Microbiology, held in London in 1936, brought another rebuff. When Fleming spoke about penicillin's medical importance, no one believed him. Allison, who sat with him at both this meeting and the Medical Research Club, said there was minimal discussion and no support for Fleming's view that penicillin might one day prevent or treat human infection. Fleming was keenly disappointed, but he bore it stoically and kept investigating. As late as 1941, the British Medical Journal noted that penicillin "does not appear to have been considered as possibly useful from any other point of view."

  In Oxford, Ernst Chain and Edward Abraham were studying the molecular structure of the antibiotic, and Abraham was first to propose the correct structure. Shortly after the team published its first results in 1940, Fleming telephoned Howard Florey, Chain's head of department, to say he would visit within a few days. Chain heard the news and exclaimed, "Good God! I thought he was dead."

  Norman Heatley supplied a key trick. He suggested moving the active ingredient back into water by changing its acidity, which yielded enough of the drug to start animal tests. Many more people joined the Oxford effort, and at one point the entire Sir William Dunn School of Pathology was involved in production. The team reached an effective first stable form in 1940. Clinical trials followed, and their striking success pushed the team to develop mass production and distribution in 1945.

  Fleming was modest about his own part. He praised Florey and Chain for turning a laboratory curiosity into a practical drug. Still, he had been the first to learn the properties of the active substance, which earned him the privilege of naming it. He had also kept, grown and distributed the original mould for twelve years, and until 1940 he kept trying to recruit any chemist skilled enough to make penicillin. In 1998 Sir Henry Harris summed up the chain of dependence: "Without Fleming, no Chain; without Chain, no Florey; without Florey, no Heatley; without Heatley, no penicillin."

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• 6. Patients and Armies

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  The 9th of January 1929 marks Fleming's first clinical trial. His patient was his research scholar Stuart Craddock, who had developed a severe infection of the nasal antrum. The treatment did nothing. The infection was probably caused by Haemophilus influenzae, a bacterium Fleming had already found to be unaffected by penicillin.

  A colleague and surgeon, Arthur Dickson Wright, received some of the original penicillin samples from Fleming in 1928. Wright reportedly said it "seemed to work satisfactorily," but no records show how it was used. The first successful medical use came from Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield and a former student of Fleming. On the 25th of November 1930, Paine cured the eye infections of one adult and three infants, a condition known as neonatal conjunctivitis in the babies.

  In 1932, Fleming himself cured a severe case of conjunctivitis. The patient was Keith Bernard Rogers, who had joined St Mary's as a medical student in 1929 and captained the London University rifle team. Rogers was about to enter an inter-hospital shooting competition when his eyes became infected. Fleming applied penicillin and cured him before the match. As the story goes, the "penicillin worked and the match was won." The claim that Rogers was the first patient treated with penicillin ointment no longer holds, because Paine's medical records came to light.

  A popular claim holds that Fleming largely abandoned penicillin in the early 1930s. One reviewer of a biography went as far as saying Fleming had abandoned it in 1932. That is false. Fleming's notebook shows attempts as late as 1939 to improve penicillin production using different media. In 1941 he published a method for assessing penicillin's effectiveness.

  Purification fell to others. Howard Florey and Ernst Chain, at the Radcliffe Infirmary in Oxford, took up the work of mass production with support from World War II military projects run by the British and US governments. By mid-1942 the Oxford team had produced the pure compound as a yellow powder.

  In August 1942, Harry Lambert, an associate of Fleming's brother Robert, was admitted to St Mary's Hospital with a life-threatening infection of the nervous system, streptococcal meningitis. Fleming treated him with sulphonamides, but Lambert's condition got worse. Fleming then tested which antibiotics the bacteria were susceptible to and found that his penicillin could kill them. At his request, Florey sent an incompletely purified sample. Fleming immediately injected it into Lambert's spinal canal. Lambert showed improvement the next day and recovered completely within a week. Fleming published the case in The Lancet in 1943.

  Allison used this breakthrough to tell the British Ministry of Health why penicillin mattered and why it had to be mass produced. The War Cabinet was convinced. Sir Cecil Weir, Director General of Equipment, called a meeting on the drug's mode of action on the 28th of September 1942. The Penicillin Committee was created on the 5th of April 1943, with Weir as chairman. Its members included Fleming, Florey, Sir Percival Hartley and Allison, along with representatives from pharmaceutical companies.

  The committee aimed to produce penicillin rapidly and in large quantities, working with American companies. The supply would go exclusively to the Allied armed forces. By D-Day in 1944, enough penicillin had been made to treat all the wounded of the Allied troops.

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• 7. Warnings About Resistance

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  Sir Almroth Wright had predicted antibiotic resistance before anyone saw it in experiments. Fleming discovered very early that bacteria became resistant whenever too little penicillin was used, or when it was used for too short a period. He cautioned about this in many speeches around the world.

  On the 26th of June 1945, he made his warning blunt. He said "the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out." He then addressed the careless user, saying that the "thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism." He ended with a hope: "I hope this evil can be averted."

  His practical advice was plain. Penicillin should not be used without a properly diagnosed reason. If it was used, it should never be given in too small a dose or for too short a time, since those are the conditions under which resistance develops.

  The laboratory had already confirmed his fear. An experiment in 1942 showed that S. aureus could develop penicillin resistance under prolonged exposure. In his Nobel Lecture, Fleming spelled out how it could happen in ordinary life. He said, "The time may come when penicillin can be bought by anyone in the shops." Then, he warned, "the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant." Around that time the first clinical case of penicillin resistance was reported.

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• 8. Fables and Honours

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  The Times turned Harry Lambert's recovery into major news in 1942. Almroth Wright was surprised to find that neither Fleming nor the Oxford team was named in the story, although Oxford was credited as the source of the drug. Wright wrote to the editor, and The Times eagerly interviewed Fleming. Florey, however, forbade the Oxford team from seeking media coverage. Only Fleming was widely publicised, and the public came to believe he alone was responsible for the discovery and development of penicillin. Fleming called this episode "the Fleming myth."

  Another fable involves Winston Churchill. The popular story says Churchill's father paid for Fleming's education after Fleming's father saved young Winston from death. According to Kevin Brown's biography Penicillin Man: Alexander Fleming and the Antibiotic Revolution, Fleming called it "A wondrous fable" in a letter to his friend and colleague André Gratia.

  Fleming did not save Churchill during the war either. When Churchill fell ill in Carthage, Tunisia, in 1943, Lord Moran treated him with sulphonamides, having no experience with penicillin. Even so, The Daily Telegraph and The Morning Post wrote on the 21st of December 1943 that penicillin had saved him. In truth it was a new sulphonamide drug, sulphapyridine, known by the research code M&B 693. May & Baker Ltd of Dagenham, Essex, made it, as a subsidiary of the French group Rhône-Poulenc. In a later radio broadcast Churchill called it "This admirable M&B."

  In 1944 Fleming learned that Robert D. Coghill and Andrew J. Moyer had patented a penicillin production method in the United States. He was furious. He said, "I found penicillin and have given it free for the benefit of humanity. Why should it become a profit-making monopoly of manufacturers in another country?"

  On the 24th of December 1915, Fleming married a trained nurse, Sarah Marion McElroy of Killala, County Mayo, Ireland. Their only child, Robert Fleming (1924-2015), became a general medical practitioner. After Sarah died in 1949, Fleming married Amalia Koutsouri-Vourekas, a Greek colleague at St Mary's, on the 9th of April 1953. She died in 1986. Fleming came from a Presbyterian background, while Sarah was a lapsed Roman Catholic, and he is said to have been not particularly religious.

  From 1921 until his death, Fleming owned a country home named "The Dhoon" in Barton Mills, Suffolk. On the 11th of March 1955, he died of a heart attack at his home in London. His ashes are buried in St Paul's Cathedral.

  Honours had arrived in his lifetime. He was knighted in 1944 for his scientific achievements. In 1945 he shared the Nobel Prize in Physiology or Medicine with Howard Florey and Ernst Chain "for the discovery of penicillin and its curative effect in various infectious diseases." Later polls and lists kept his name alive. Time magazine named him among the 100 Most Important People of the 20th century in 1999. The BBC's 2002 television poll included him among the 100 Greatest Britons. In 2009 an STV poll voted him third "greatest Scot," behind only Robert Burns and William Wallace.

  Penicillin has saved, and is still saving, millions of people around the world. His alma mater, St Mary's Hospital Medical School, merged with Imperial College London in 1988. The Sir Alexander Fleming Building opened on the South Kensington campus in 1998, and his son Robert and great-granddaughter Claire were presented to the Queen there. It is now one of the main preclinical teaching sites of the Imperial College School of Medicine. His other alma mater, the Royal Polytechnic Institution, now the University of Westminster, named a student hall of residence Alexander Fleming House, near Old Street.

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