Alexander Fleming

Alex Rover | July 8, 2023

Summary

Sir Alexander Fleming (born August 6, 1881, Darwell, Ayrshire, UK – March 11, 1955, London, UK) was a British microbiologist. He discovered lysozyme and first isolated penicillin from the mold Penicillium notatum, historically the first antibiotic.

Both discoveries occurred in the 1920s and were largely accidental. Fleming sowed mucus from his own nose onto a Petri dish that contained bacteria, and after a few days he found that the bacteria had been destroyed in the areas where the mucus had been applied. The first paper on lysozyme was published in 1922.

The mess in Fleming’s laboratory served him well once again. In 1929, he discovered that a colony of mold fungi had grown on agar in one of the petri dishes containing Staphylococcus aureus bacteria. The bacterial colonies around the mold fungi became transparent due to cell destruction. Fleming succeeded in isolating the active substance that destroyed the bacterial cells, penicillin, and his work was published. His work was continued by Howard Flory and Ernst Boris Cheyne, who developed methods of purifying penicillin. Mass production of penicillin was established during World War II.

In 1945, Fleming, Flory and Chane were awarded the Nobel Prize in Physiology or Medicine. In September 1945, on the eve of Alexander Fleming’s arrival in the French capital, the Paris newspapers wrote:

“For the defeat of fascism and the liberation of France, he did more than whole divisions.”

In 1999, Time magazine named Fleming one of the hundred most important people of the 20th century for his discovery of penicillin and reported:

This discovery would change the course of history. The substance that Fleming called penicillin is a very active anti-infective agent.

Once the compound’s capabilities were appreciated, penicillin became an integral part of any treatment for bacterial infections. By the middle of the century, Fleming’s discovery of the substance had become widely accepted in the production of pharmaceuticals, and its artificial synthesis was being carried out, which helped to cope with most of the oldest diseases, such as syphilis, gangrene and tuberculosis.

Fleming was born on August 6, 1881, at Lochfield Farm, near Darwell, located in the Ayrshire region of Scotland. He was the third of four children by the second wife (to the four children of his first marriage) of farmer Hug Fleming (1816-1888), Grace Stirling Morton (1848-1928), daughter of a neighboring farmer. His father married a second time at age 59 and died when Alexander (known as Alec) was only 7 years old.

Fleming attended rural school in Darvell until he was twelve, and then two more years at Kilmarnock Academy. At fourteen he moved with his brothers to London, where he began working as a clerk in a delivery office and also attended classes at the Royal Polytechnic Institute in Regent Street.

His older brother Thomas was already working as an ophthalmologist and, following his example, Alexander also decided to study medicine. His choice of medical school was greatly influenced by his participation in a water polo match with students from St. Mary’s Hospital. At medical school Fleming won a scholarship in 1901. Also MB and BS scholarships from the University of London in 1906 went to him.

At the time, he did not have a strong predilection for any particular area of medical practice. His work in surgery showed that he could have been an outstanding surgeon. But life took him down a different path, that of “laboratory medicine. As a student, he came under the influence of Professor of Pathology Almroth Wright, who arrived at St. Mary’s Hospital in 1902. Wright, while still in the military medical service, had developed a vaccination against typhoid. But Wright also had other ideas for treating patients already suffering from bacterial infections by stimulating their bodies to respond immediately to infections by producing “antibodies.” He tried to measure the amount of these antibodies in the patient’s blood. This required new methods and considerable labor. The group of young men who joined Wright, including John Freeman, Bernard Spilsbury, and John Wells, were no longer up to the job. So Fleming, too, was invited to join the team as soon as he received his degree in 1906.

Having thus entered the research laboratory attached to the hospital, Fleming worked there until his death fifty years later.

During World War I Fleming served as a captain in the Royal Medical Army. He and many of his colleagues worked in battlefield hospitals on the western front in France. In 1918 Fleming returned to St. Mary’s Hospital, where he was elected professor of bacteriology in 1928.

During his period of research, Fleming made a significant contribution to the development of medicine because, like his superior Wright, he was constantly trying to learn new things. Wright proposed many unusual ways to micro-measure using capillary tubes, glass, rubber nipples, and mercury calibration. Fleming was quick to point out that these could help in the syphilis detection diagnostics developed by Wasserman and some other scientists in Germany. His techniques made it possible to test with 0.5 ml of a patient’s blood drawn from a finger instead of the 5 ml that previously had to be drawn from a vein.

Very soon Wright was interested in Ehrlich’s discovery of the healing properties of dioxydiaminoarsenobenzene dihydrochloride, better known as “Salvarsan” or “drug number 606. The drug had to be injected into a vein, and at the time there were some difficulties associated with this. Fleming was able to overcome this problem, and in one of the first reports published in English, he described the technique and the results obtained with 46 patients.

During World War I, it became apparent that bacterial infection in deep wounds from explosives would kill a great many lives and rob a great number of people of their limbs. Wright was asked to set up a laboratory to study these infections in France, and he took Captain Fleming with him. This laboratory turned out to be the first wartime medical research laboratory and was set up in a casino building in Boulogne.

In early 1915, Fleming reported the discovery of a large number of microbial species in wounds, some of which were still completely unknown to most bacteriologists at the time; he also indicated that streptococci predominated in wounds. It turned out that many of the wound infections were caused by microbes present on clothing fragments and in the dirt that had entered deep into the body when wounds were inflicted.

Wound observation led to another important conclusion that the use of antiseptics for several hours after wounding did not completely eliminate bacterial infections, although many surgeons believed this was the case. Wright was not at all surprised, but he and Fleming had to spend many months working hard to convince surgeons that they were right.

Wright and Fleming were able to show that, first, antiseptics did not reach all microbes, because very often the latter penetrated deep into the tissues of bone, cartilage, muscle, etc., and, second, the antibacterial activity of the solution used decreased very quickly when interacting with the protein and cellular elements of lymph, pus, blood and surrounding tissue; the solution thus destroyed the leukocytes of patients, which in natural conditions effectively protect their bodies.

The work on which these two crucial conclusions are based was almost entirely Wright’s, but Fleming, who assisted in the work, made a valuable contribution to solving the technical problems. It was he who conducted experiments with the “artificial wound,” from which it became apparent that antiseptics were unable to reach deep areas of wounds and cause the death of microbes there.

Another simple device that Fleming was able to use (with due acknowledgement to its author, Dr. Beatty) in antiseptic research was to coat liquid cultures of organisms with liquefied petroleum jelly. Growth of the cultures led to the formation of gases and rise of the Vaseline in the column; the change in volume gave an approximate idea of the growth of the cultures. Using this method, it was easy to demonstrate that the activity of many antiseptics was greatly reduced in protein liquids such as blood serum. Also surprising was that at certain concentrations of antiseptics (including carbolic acid, iodine, hypochlorous acid, sodium hypochlorite and chloramine-T), bacterial growth even increased. Using the same device, Fleming was also able to demonstrate that the clostridium that causes gangrene disease yielded a much more abundant culture when grown in conjunction with aerobic organisms from wounds, such as staphylococci and streptococci.

Another aspect of the “antiseptic problem” was revealed when Wright and Fleming shifted their attention to the antibacterial effect of leukocytes in an infected wound. They found that, under favorable conditions, pus and blood leukocytes could destroy a very large number of staphylococci and streptococci, but under the influence of antiseptics this effect was often diminished. In this situation, Fleming proposed a simple experiment: first, he applied a glass plate to the wound and then immediately applied a nutrient agar-agar medium to it. He conducted several such experiments on the wound with different degrees of antiseptic washing and noticed that bacterial growth was more abundant in later cultures. Apparently, antiseptics ruined a lot of white blood cells, which are so necessary to prevent reproduction of microbes.

Convincing experimental confirmation of Fleming’s conclusions was carried out by him after the war using the “slide cell” technique. The technique made it easy to show that when microbes enter the blood, white blood cells have a very strong bactericidal effect, and when antiseptics are added, the effect is greatly reduced, or completely eliminated.

Fleming’s research on wound infections was described in his Hunterian Lecture at the Royal College of Surgeons in 1919, and in his same talk “A Comparison of the Activity of Antiseptics on Bacteria and Leukocytes” at the Royal Society in 1924.

Fleming and Wright’s long reflection on the physiological mechanisms of wound defense against infection led them in 1922 to the discovery of a micro-diluting enzyme contained in nasal secretions, which he called “lysozyme. In a sense, this discovery was twofold: the substance was a lytic agent and, as it turned out, many microbes were sensitive to its action.

At the Royal Society, Fleming described how he isolated cultures daily from a patient’s nasal secretion (actually his own) during a “cold.” For the first four days almost nothing appeared, but on the last day a “large number of small colonies arose, which proved to be gram-positive cocci, distributed irregularly but with a tendency to diplococcus and tetrad formation.” With Wright’s help, he subsequently succeeded in discovering a microbe that was not previously known and named it Micrococcus Lysodeicticus (i.e., soluble).

It is still not entirely clear what caused Fleming to examine nasal mucus and discover a substance that has a powerful lytic effect on microbes. Probably some areas of the plate where mucus particles were present suppressed or prevented micrococcus growth. In any case, he apparently suspected this, and his suspicion was confirmed when he prepared a suspension of microbes from the fresh culture and added to it a drop of diluted nasal mucus. To his surprise, the suspension became perfectly clear in a minute or two.

Subsequent experiments have shown that a similar effect of dissolving microbes can be demonstrated with human tears, sputum, saliva, with extracts of many human body tissues, as well as with egg protein and other animal and plant tissues.

Oddly enough, no other microbe dissolved as well as Micrococcus Lysodeicticus, although many other human pathogenic microbes were also exposed, but only to a lesser degree. A very important finding was that the enzyme lysozyme could be derived from human leukocytes. The bactericidal effect of leukocytes derived from human blood, which Wright and Fleming demonstrated during the war, may have been related to the action of this enzyme.

Overall, the discovery of lysozyme may not have been a huge intellectual feat, but we should remember that hundreds of bacteriologists around the world had been studying nasal secretions for years in the hope of finding the organisms responsible for the “common cold,” but none of them succeeded in discovering this enzyme. Fleming also failed to find the cause of the common cold, but the discovery of lysozyme was undoubtedly an important step in the development of immunology.

“When I woke up at dawn on September 28, 1928, I certainly did not plan to revolutionize medicine with my discovery of the world’s first antibiotic or killer bacteria,” Fleming then said: “But I suppose that’s exactly what I did.”

In 1928, Fleming was researching the properties of staphylococci. He was already known for his early work and had gained a reputation as a brilliant researcher, but his laboratory was often unkempt. On September 3, 1928, Fleming returned to his laboratory, spending August with his family. Before he left, he collected all of his staphylococcus cultures on a table in a corner of his laboratory. When he returned, Fleming noticed that mold fungi had appeared on one culture plate and that the staph colonies present there had been destroyed, while the other colonies were normal. Fleming showed the fungus-contaminated cultures to his former assistant Merlin Price, who said: “That’s how you discovered lysozyme.” Fleming assigned the fungi that grew on the plate with his cultures to the genus Penicillium and, a few months later, on March 7, 1929, called the isolated substance penicillin.

Fleming investigated the positive antibacterial effects of penicillin on many organisms, and noticed that it acts on bacteria such as staphylococci and many other Gram-positive pathogens that cause scarlet fever, pneumonia, meningitis, and diphtheria, but does not help against such diseases as typhoid or paratyphoid, whose causative agents are Gram-negative bacteria, which Fleming also tried to treat at the time. It also works on Neisseria gonorrhoeae, which causes gonorrhea, although these bacteria are gram-negative.

Fleming was not a chemist, so he was not in a position to extract and purify the active ingredient in order to use penicillin as a therapeutic agent, but thoughts of doing so never left his mind. He wrote:

“Penicillin has some advantages over known chemical antiseptics when interacting with sensitive microbes. A good sample will completely destroy staphylococci, Streptococcus pyogenes and pneumococci even at a dilution of 1 to 800. It is a more potent inhibiting agent than carbolic acid, and can be applied to contaminated surfaces and in undiluted form without causing irritation or intoxication. Even at a dilution of 800 times, it is more potent than other antiseptics. Experiments related to the treatment of purulent infections have confirmed that this discovery has indeed led to advances in medicine.”

The last of the above-mentioned experiments is not described. It should be noted that at this time Fleming had in mind only the local application of penicillin, he could not imagine that (Fleury quote) “It could circulate in the blood and body fluids in sufficient quantity to kill bacteria sensitive to it, combined with the natural protection of the body without harming other tissues.

Before exploring other issues, Fleming showed how even an untreated filtrate containing penicillin could be used in bacteriology as a means of suppressing the growth of undesirable microbes in certain cultures, for example, to isolate from B. pertussis in pertussis.

Fleming published his discovery in 1929 in the British Journal of Experimental Pathology, but his article received little attention. Fleming continued his research, but found that working with penicillin was very difficult, and that once the mold grew, it became even more difficult to isolate the antibiotic from the agent. Fleming’s production of penicillin proved rather slow, and he feared that for this reason penicillin would not be important in treating the infection. Fleming also became convinced that penicillin could not exist in the human body (in vivo) long enough to be able to effectively kill bacteria. Many clinical trials were inconclusive, probably because penicillin was used as a surface antiseptic. Fleming continued his experiments through the 1940s, trying to develop a technique for rapid isolation of penicillin that could be used later for more extensive use of penicillin.

Soon after Fleming stopped working with penicillin, Flory and Cheyne continued research and mass production at the expense of the U.S. and English governments. After a while they still managed to produce enough penicillin to treat all the wounded.

An attempt to purify and isolate penicillin was made by Cheyne and Flory at Oxford in 1940. By extraction with ether they managed to isolate sufficiently pure material for preliminary tests of its antibacterial effectiveness on laboratory animals infected with virulent staphylococci, streptococci, and chlostridiumsepticum, respectively. (Later it turned out that the compound used in these studies contained only about 1% penicillin.) The experiments were remarkably successful, and the scientists encouraged Flory and his team to participate in developing extraction methods. The ether solution was replaced with amyl acetate, followed by acidification. In this way, more stable samples of penicillin were obtained and excess impurities were removed.

Fleming’s conclusions about penicillin’s nontoxicity to laboratory animals and human leukocytes were confirmed and extended, and as early as 1941 positive results were obtained on the treatment of several severe human infections. Other satisfactory results immediately followed in the treatment of this antibiotic, so that penicillin was destined to occupy a unique place among the effective remedies against human diseases. Osteomyelitis and staphylococcal septicemia, maternal fever and other invasive streptococcal infections, pneumonia, wound and burn infections, gas gangrene, syphilis and gonorrhea were all treated very successfully. By 1944, thanks to the tremendous efforts of American manufacturers and research groups, it was possible to treat every wounded man on the front with penicillin. When the war was over, supplies were sufficient to treat the population of this country and North America. In the postwar years it was discovered that even bacterial endocarditis, previously thought to be a fatal disease in nearly 100% of patients, could often be cured by large doses.

Fleming was modest in his participation in the development of penicillin, describing his fame as “The Fleming Myth. He was the first to discover the active properties of the substance, which gave him the privilege of naming it: penicillin. He also stored, grew and distributed the original mold for twelve years, and continued to do so until 1940, trying to get help from any chemist who might have enough skill to isolate penicillin from it. Sir Henry Harris said in 1998, “Without Fleming there would be no Chane; without Chane there would be no Flory; without Flory there would be no Heathley; without Heathley there would be no penicillin.

All of these discoveries were made through the efforts of Fleming on the one hand in 1928-1929, Cheyne and Flory and their colleagues on the other in 1940-1943. It has been noted that Fleming’s work with penicillium stood on a par with other earlier work on the continent. In one, Vaudremer of the Pasteur Institute in Paris reported that prolonged contact with the mold Aspergillus fumigatus resulted in the death of the tubercle bacillus infection and, based on this observation, he tried to treat over 200 patients suffering from tuberculosis. But the experience was completely inconclusive. Similar experiments were carried out with other forms of mold and bacteria. Clearly, antagonism between the various microbial genera and species had been “up in the air” for several years, and Fleming himself acknowledged this in his Nobel Lecture in 1945.

It is also clear that Fleming’s work brought to light a new substance that proved to be non-toxic to animal tissue and to human leukocytes. Everything would have remained at the same stage for decades if Fleury had not taken up his research, and if it had not been for Chane’s chemical know-how and their combined patience and enthusiasm for overcoming many difficulties, and perhaps penicillin could not yet have been used as a practical therapeutic agent.

Fleming’s accidental discovery and isolation of penicillin in September 1928 marked the beginning of modern antibiotics. Fleming also discovered that bacteria were resistant to antibiotics if they acted on small amounts of penicillin or if the antibiotic was used for too short a time. Almroth Wright predicted antibiotic resistance even before it was discovered experimentally. Fleming talked about the use of penicillin in his many speeches around the world. He warned against using penicillin until the disease is diagnosed, and if an antibiotic is still needed, penicillin should not be used for a short time and in very small amounts because the bacteria develop antibiotic resistance under these conditions.

The popular story that Winston Churchill’s father paid for Alexander Fleming’s education after the future microbiologist’s father saved the young Winston from death is no more than a legend, and it had a sequel, according to which Winston Churchill, already in his late teens, suffering from a severe form of pneumonia, was saved allegedly by the penicillin discovered by Alexander Fleming. Alexander Fleming, in a letter to his friend and colleague André Grazia, described the story as “marvelous fairy tales. “I did not save Winston Churchill’s life during World War II,” he stated. – “When Churchill fell ill in Carthage, Tunisia, in 1943, he was saved by Lord Moran, who used sulfonamides with no experience with penicillin. Although the Daily Telegraph reported on December 21, 1943, that Churchill had been cured with penicillin, he was in fact helped by a new drug of the sulfonamide group, sulfapyridine, known at the time under the code name M & B 693, discovered and obtained by May & Baker Ltd (Dagenham, Essex), a subsidiary of the French Ron-Poulenc Group. In a subsequent radio broadcast Churchill mentioned the new medicine, “Wonderful M & B.” It is likely that reliable information about sulfonamides did not reach the newspapers for political reasons. After all, the first drug of this group and in general the world’s first synthetic antibacterial drug, Prontosyl, was discovered by the German laboratory Bayer, and since Great Britain was then in a state of

Fleming’s first wife, Sarah, died in 1949. Their only child, Robert Fleming, later became a doctor. Four years after Sarah’s death, Alexander Fleming married Amalia Koutsouri-Vourekas, a Greek woman, a colleague at St. Mary’s Hospital, on April 9, 1953; she died in 1986.

Fleming was a very active and active Mason. His Masonic biography describes his positions and ranks as follows: a member of a number of English Masonic lodges, in 1925 Fleming became the Honorable Master of St. Mary’s Lodge No. 2682, then its secretary, in 1935 – the Honorable Master of Mercy Lodge No. 3286, then its treasurer. In 1942, Fleming was elected the first Grand Deacon of the United Grand Lodge of England. He was also initiated into the 30° Ancient and Accepted Scottish Statutes.

In 1955 Fleming died at his home in London of a heart attack. He was cremated, and a week later his ashes were buried in St. Paul’s Cathedral.

Fleming’s discovery of penicillin changed the world of modern medicine by creating a number of life-saving antibiotics. Penicillin saved and still saves millions of people worldwide.

The laboratory at St. Mary’s Hospital in London, where Fleming discovered penicillin, is now the Fleming Museum. Also in Lomita, Los Angeles, California, a school named after Alexander Fleming has been established. The University of Westminster named one of its student buildings near Old Street after Fleming, and Imperial College buildings are also named after him. They are located on the South Kensington campus and house a large number of students in a variety of medical specialties.

Sources

1. Флеминг, Александр
2. Alexander Fleming
3. ПЕНИЦИЛЛИ́НЫ : [арх. 20 июня 2022] // П — Пертурбационная функция. — М. : Большая российская энциклопедия, 2014. — С. 570. — (Большая российская энциклопедия : [в 35 т.] / гл. ред. Ю. С. Осипов ; 2004—2017, т. 25). — ISBN 978-5-85270-362-0.
4. ФЛЕ́МИНГ : [арх. 15 июня 2022] // Уланд — Хватцев. — М. : Большая российская энциклопедия, 2017. — С. 427. — (Большая российская энциклопедия : [в 35 т.] / гл. ред. Ю. С. Осипов ; 2004—2017, т. 33). — ISBN 978-5-85270-370-5.
5. Karl Grandin, ed. (1945). «Alexander Fleming Biography». Les Prix Nobel. The Nobel Foundation. Retrieved 2008-07-24.
6. «Alexander Fleming Biography». Retrieved 2010-04-11.
7. Il bénéficia en outre d’une bourse.
8. Doué pour les études, il avait du temps pour s’adonner au sport ; alors qu’il avait la possibilité de devenir chirurgien, le capitaine du Rifle Club auquel il appartenait voulant retenir Fleming dans l’équipe, lui suggéra d’entrer au département de recherche de l’hôpital Sainte-Marie : il devint assistant-bactériologiste de Sir Almroth Wright, un pionnier de la thérapie vaccinale et de l’immunologie.
9. « Without Fleming, no Chain; without Chain, no Florey; without Florey, no Heatley; without Heatley, no penicillin »,[11].
10. ^ Ralph Landau et al., Pharmaceutical Innovation: Revolutionizing Human Health, Phildelphia, Chemical Heritage Press, 1999, p. 162, ISBN 0-941901-21-1.
11. ^ V. Tiberio, Sugli estratti di alcune muffe, in Annali di Igiene sperimentale, vol V, 1895.
12. ^ Walter Sneader, Drug discovery: a History, John Wiley & Sons ldt, 2005, p. 314, ISBN 0-471-89980-1.
13. ^ (EN) From the archive, 12 March 1955: Alexander Fleming, who discovered penicillin, has died, su theguardian.com, 12 marzo 2013.
14. 2,0 2,1 (Αγγλικά) SNAC. w6cz3kdf. Ανακτήθηκε στις 9  Οκτωβρίου 2017.
15. J. M. Berg· J. L. Tymoczko· G. J. Gatto· L. Stryer (2015). Βιοχημεία. Πανεπιστημιακές Εκδόσεις Κρήτης. σελ. 1081. [νεκρός σύνδεσμος]