ALEXANDER FLEMING (1881-1955) AND THE DISCOVERY OF PENICILLIN
King-Thom Chung
Department of Microbiology and Molecular Cell Sciences, The University of Memphis, Memphis, TN 38152
Molds have been used for therapeutic purposes for centuries. Ancient Chinese used molds to treat boils and infected wounds, while Indian physicians used them to treat dysentery. Ancient Mayan tribes used a cuxum fungus as a therapeutic agent. American Indians dressed war wounds"`ó?h molds. Hippocrates (460-377 B.C.), the father of medicine, described the use of mold to treat infected female reproductive organs. Molds were widely used for virtually every disease in the Medieval era. They worked! Who cared why they worked ?
Antibiotics are secondary metabolites of microorganisms (including molds). Gosio in 1896 first discovered an antibiotic that was named mycophenolic acid by Carl Lucas Asberg alsº. F. Black in 1913. But this antibiotic was not widely used medically. An important medically widely used antibiotic is penicillin. The discovery of penicillin marks the beginning of an important era of microbiology and modern medicine, and has a great impact on our civilization. It is therefore of great interest to know the key person involved in this discovery—Alexander Fleming.
Have you ever wondered what ymbº ay have been growing in your refrigerator when you pull out a piece of cheese and find that it has turned into a hairy green piece of fuzz! You might also experience surprise to find that a loaf of bread has dramatically formed itself into another ugly black or green form of life! How in the world could anyone become curious about something so ugly? When you find moldy, transformed pieces of food in your refrigerator, think of what Alexander Fleming was looking at when he walked kyî! his laboratory only to find that he had a couple of culture plates with green fuzzy mold, instead of neat bacterial cultures.
Alexander Fleming was born on August 6, 1881, in Lochfield, Ayrshire, Scotland. His father was Hugh Fleming, a Lowland farmer. Hugh Fleming married his first wife Mary Craig and had four children: Mary Craig died during childbirth with her fifth child who also died. At the age of sixty Hugh Fleo~ô( remarried Alexander‘s mother Grace Morton. In addition to Alexander, Grace Morton gave birth to Grace, John and Robert. Therefore, he was one of eight children in this family, and there was no telling then what this young boy who grew up on a farm would become?
We can imagine that Alexander (Alex) and his brothers and sisters explored the valleys and moors there in Scotland during their childhood. He got the chanarº$o observe nature intimately. Since he was poor, he enjoyed simple pleasures. At a very young age, he participated in the annual sheep-shearing by helping to round up the animals. His father passed away when he was seven. Between the ages of 5 and 10, he attended a tiny moorland school. Then he attended a school of Dorval, a small town, four miles from his home, and he had to walk to school every day. He went to school in all kinds of weather. When it was cold, he carried hot potavxÿ" to keep his hands warm, and later he would eat them for lunch. When it rained, he took a change of boots and stockings slung around his neck. When the weather was good, he went to school barefooted. Later, he attended Kilmarnock Academy, which was 12 miles from home. At the academy, he took courses covering inorganic chemistry, geography, physics, and physiology. He had a very sincere respect for learning, and he always received top grades. Fleming had a solid basic education, a"gè=digious memory, and a tempered disposition. He was very quiet and kept his personal life to himself.
When just past thirteen, he and his older brother John went to London to follow his stepbrother Thomas who practiced medicine there. His younger brother Robert, also joined them a little later. His only sister was to keep house at home.
In London, Alexalsÿ! attended classes at the Regent Street Polytechnic for 2 years, and then became a clerk in a shipping company, the American Line. He did not like the job, but he performed well his assignments. In 1900, he enlisted in the London Scottish Regiment but he did not go overseas as the Boer War (1880-1902) ended. He was good at rifle shooting, enjoyed the military and stayed attached to this regiment until 1914.
In 1901.7û the age of twenty, his uncle died, left him a small legacy, and his brother Thomas encouraged him to study medicine. He passed the competitive examination and enrolled at St. Mary’s Hospital School from which he received a scholarship. Alexander was a bright student and rewarded for his academic achievements with scholarships and prizes.
While at St. Mary’s, he took biology from Dr. W. G. Ridewood, a diqcó;guished zoologist and Director of the Natural History Department of the British Museum. He took chemistry from Sir William Willcox, a well-known toxicologist. Fleming also enjoyed anatomy and became a student demonstrator in 1903, received the senior anatomy prize in 1904. As he became a very keen observer, Alexander had become a naturalist with the habit of noticing everything that went on around him.
During his yearq7ó8 school, Fleming was slow in making friends because of his shyness and reserve. Nevertheless, he belonged to the St. Mary’s Hospital School Amateur Dramatic Society. On one occasion, he played the part of a woman, a sprightly French "widow". He did a very good job on the play and was highly praised. Also, he was a member of the Medical and Debating Societies. Not forgetting sports, he joined the rifle team and water polo team.
Despite his impenetrable silence and shyness, he enjoyed companionship and liked competition. Fleming would always win in every competitive test that they would enter. He won the competition in chemistry and biology as well as anatomy.
A significant event while a student at St. Mary’s was that he met Sir Almroth E. Wrigh, a pioneer of the vaccine treatment of disease in 1906. The same year.7ò= obtained the Conjoint Board Diploma. He began to work in the "Inoculation Department" which was under the directorship of Sir Wright. He was paid one hundred pounds a year. The Department was in a small room and the laboratory equipment was rudimentary. It had an incubator, a sterilizer, some Petri dishes, a few test tubes, and a microscope. The department had 8 to 9 graduates and many visiting doctors.
Fbè0ng this period of time, he spent a lot of time studying phagocytosis. He put a drop of blood containing phagocytes onto a test microbe on a slide with a test microbe and covered it to prevent it from drying. The blood was spread into a thin film, dried, and then stained. In this way, the phagocytes were easily seen, counted and compared. Another attraction of interest to Fleming was therapeutic vaccination, the treatment of acne. He examined the specific organisms acne bacillus (>~¤ ropionbacterium acnes) and made a vaccine from a culture of this organism. He studied the therapeutic effect of this vaccine and published a paper in the Lancet in 1909. In 1908, he graduated M. B., B.S. with honors and a gold medal from the University of London. In 1909, he published another paper on "The diagnosis of acute bacterial infection" in St. Mary’s Gazette, which won him the Cheadle Medal for Clinical Medicine awarded by St. Mary’s"_õ(pital. Starting in 1908, Fleming was also the Causalty House Surgeon while still working in the laboratory of Wright. He gained experience by performing minor surgery and assisted in major surgery. Fleming never truly practiced surgery but in 1909, he completed the fellowship examinations of the Royal College of Surgeons of England.
From his thesis on bacterial infections, we can picture the line of research that jrº:ollowed during his life. Fleming sought to find a way to fight the infections that were considered the most dangerous to the human race. He was well equipped for this line of research and was fully conscious of his abilities.
Wright proposed specific immunization against bacterial infections and demonstrated the presence of opsonins and antibodies in the blood. Although Fleming upheld and practiced the principles od7Í/ight, he later questioned "What was the point in adding dead microbes (as vaccine) to a body which was already carrying on battle against living ones?" He suggested that intravenous administration was not suited to the injection of a vaccine. He once injected himself intravenously with millions of dead staphylococci, and experienced nausea, fever and headache. He concluded that inoculation of dead bacteria into the blood stream, produced the maximum toxic effect with mil~÷+m immunization benefits. Fleming also was among the first doctors to treat syphilis with salvarsan (compound 606) discovered by Paul Ehrlich. He invented a very simple apparatus, two glass jars, a syringe, two rubber tubes, and two taps with double nozzles. This apparatus made it possible to treat four patients at the same time. He became known as "Private 606" and had an enormous number of patients.
While Fnr÷6ng was busy as a bacteriologist at St. Mary’s, he still made time for some social activities. He joined the Chelsea Arts Club. He went to the club whenever he had time, and he attended the Chelsea Ball on several occasions.
When World War I (1914-1918) broke out, Fleming joined the Royal Army Medical Corps as lieutenant. He served under colonel Wright in a wound-research laboratory in Boulogne, France. During "cò s period, he made a careful study of new wounds of soldiers. He took swabs from all wounds, examined and identified the bullets, shell fragments, shreds of clothing, dead tissue and bits of bone removed by the surgeons. He cultured and identified the most common infecting organisms. He found that men’s clothing was a major source of infection. These findings resulted in two papers published in the Lancet in 1915.
In 1919, he was demobilized from the Army with the rank of captain, and immediately returned to St. Mary’s to continue working on antibacterial mechanisms. Through sharp observations, pertinacious curiosity, and prepared mind, he observed two important antibacterial effects. In 1921, he noted that nasal mucus dissolved a yellowish colony. This was recorded in his notebook labelled XVIII, March 16, 1921. Fleming took three cultures of cocci isolated from his own nose and qcèaked across a blood agar plate. He then took some of his nasal mucus, diluted with saline and centrifuged it, and placed a drop of the clear fluid (supernatant) on one of the three cultures. After 18 hours of incubation, he noticed that there was no growth in the vicinity of the mucus while other plates without mucus had heavy growth. He recorded that "obviously something had diffused from the nasal mucus preventing the germs from growing near the mucus, and beyond this zone"|óling and dissolving bacteria already grown." He continued to study the effect of mucus on bacteria, and found some bacteria were sensitive to it, but some were not. On December 21, 1921, he presented his findings to the Medical Research Club in the hospital. However, because of his poor presentation, the audiences were not impressed and left with the feeling of "so what"?
He named the bacteriolytic aerô lysozyme and the susceptible organism (his nose cocci) Micrococcus lysodeikticus. In collaboration with Dr. V. D. Allison, Fleming detected lysozymes in human blood serum, tears, saliva, milk, leucocytes, egg white, and turnip juice. He also engaged many studies involved with lysozymes. He showed that lysozymes were very useful for bacterial cytology and other studies. Although it is a very significant finding, the finding did not attract much attention from the sckrôific community, but in 1922, Wright nominated Fleming
for fellowship in the Royal Society.
He continued to work on antibacterial mechanisms. In 1923, he tested the antibacterial activity of more than 20 different antiseptics used by surgeons. He noticed that antiseptics seemed to promote infection instead of fighting infection. He condemned the intravenmbéFadministration of chemical antiseptics, and asserting that ideal therapeutical antibacterial agents should arrest the growth of bacterial invaders without affecting the host tissues. Now more than ever, Dr. Fleming was determined to find a bacterial inhibitor not harmful to animal or human tissues.
One morning in the fall of 1928, Fleming noticed a culture plate displaying a colorful green mold. The culture plate was cmaÿed with staphylococci except in the vicinity of the mold, which was near the edge of the plate where there was a transparent zone of inhibition. The bacteria that were close to the mold had not grown. Fleming photographed the plate and made it permanent by exposing it to formalin vapor that killed and fixed both the bacteria and the mold. (The original plate is now in the British Museum.) Being a person that thrived on curiosity, he found the culture filtrate of the mold would kin{º he bacteria. Fleming investigated a list of microorganisms that were inhibited by the mold, among them were streptococci, staphylococci, pneumococci and meningococci. Fleming identified the mold as a Penicillium that Charles Thom placed in the species notatum that is similar some molds grown on bread. Fleming called the active filtrate penicillin. He also discovered that the penicillin was not a protein. He proved that the penicillin was harmless to the leucocyte and would"ÿp leucocytes fight against infections. In 1929, he reported that the penicillin was nontoxic to laboratory animals, and might be an efficient antiseptic for application to, or injection into, areas infected with susceptible microbes. He did many experiments with this mold, but he found it hard to isolate the active antibacterial substance even with the help of a biochemist H. Raistrick. At that time, no one seemed ready to seek more information on penicillin.
It was around 1939 that Dr. Howard Walter Florey from Oxford University became interested in investigating the Penicillum mold Dr. Fleming had given him. Along with Ernst Boris Chain who came from Germany cyþLother assistants, Dr. Florey worked diligently on Penicillium notatum.
Florey and his co-coworkers had little knowledge of how Penicillium notatum worked, but he mixed it with a sugar solution. The mold flourished, forming a mat, and soon golden droplets developed on its surface. The droplets were then dried to a yellowish-brown powder, which was usable form of penicillin. They injected mice wivº strain of deadly streptococci. Half of the mice were left untreated and half the mice were injected with penicillin at different intervals. All the untreated mice died overnight and all the treated mice survived.
Penicillin was first used on February 12, 1941 on a man that was dying of a blood infection. The drug was used for five days and the young man appeared to be feeling much better, but the limited amount of pel~ùllin available did not cure the infection and the man died.
With an increase in supply, Florey’s cases then began to improve. A young girl who was dying of gangrene was cured and so was a man dying from a bone infection.
In the United States, Dr. Wallace E. Herrell and other doctors were interested in penicillin at the Mayo Clinic in Rochester, Minlré ta. Florey visited them and brought 50 milligrams of penicillin as a gift. Their clinical trials were successful.
The biggest problem was how to produce large quantities of penicillin. American microbiologist Dr. Andrew J. Moyer devised methods for producing penicillin in large scale. The mounting war casualties entailed securing the highest priority for its large-scale manufacture, and steps were taken to achieve thiq7ó the United States, Britain, and Canada. In the United States, the mass production of penicillin led by Dr. Chester S. Keefer (1897-), chairman of the National Research Council’s Committee on Therapeutic Agents and director of the Evans Memorial Hospital in Boston. Having the reassurance of the clinical success made by Keefer, the War Production Board took penicillin under its wing in May 1943, and hired Fred Stock to take charge of the mass production of it. In less than a {rû, more than 300 billion units of penicillin were available.
As supplies of penicillin increased and its efficacy became widely known, Alexander Fleming became more recognized. In 1943, Fleming was elected fellow of the Royal Society. In 1944, he was knighted and awarded the Moxon Medal by the Royal College of Physicians. Both Florey and Fleming received the Award of Distinction from the American Pharmaceutical Manudvùurers Association the same year. In 1945, Alexander Fleming, Ernst Chain and Howard Florey received the Nobel Prize in Medicine and Physiology. Fleming also was awarded numerous foreign decorations and medals, honorary memberships in medical and scientific societies, and was decorated by several famous universities. He was elected president of the newly founded Society of General Microbiology in 1945.
It was in August,"xüS1945, that Fleming came to the United States. His purpose was to see the advancements that Americans had made with penicillin. He visited many hospitals and several laboratories. Many people followed this quiet, laconic and mysterious man but they were unable to uncover any interesting facts about his past life.
Dr. Fleming was married on December 23, 1915 to Sarah Marion McElroy, an Irish
farmer’s daughter, who operated a private nursing home. They had a happy marriage despite dissimilar characters. Sarah was more outgoing while Alexander was quiet. She often spoke for both of them. Sarah’s twin sister Elizabeth was married to Alexander’s brother John. So there were two bonds between the Flemings and the McElroys. Alexander and Sarah bought a house called Dhoon. It was a Georgian house with a red-tiled roof, built od7öth and plaster on a timber frame. It had six bedrooms and three living rooms and a three acre garden, overlooking the river Lark. The river was big enough for boating and fishing which Alexander enjoyed and they both enjoyed gardening. The Dhoon was Sarah’s main interest and Alexander’s main relaxation. In a few years, they added a croquet lawn and a tennis court. Fleming enjoyed croquet, tennis, fishing, boating, swimming, and playing billiards and snooker. They had ong7én, Robert, born on March 17, 1924 who became a physician. The family spent a lot of time at the Dhoon during the summer along with nephews and nieces. They were often surrounded by children. At Christmas they had huge family get together. The family remained close. Unfortunately, Alexander’s mother passed away in 1928, and Alexander’s brother John died unexpectedly in 1929. The worst was the death of Sarah in 1949, which was a big blow to Fleming. He became very withdrauy´WHe devoted himself even more to his laboratory.
While Fleming traveled throughout the United States, he received many awards from several institutions and universities. President Franklin Delano Roosevelt (1882-1945) paid a tribute to this perspicacious scientist.
Even though penicillin was well accepted and used overseas, the United States was the mass prodwtÿ of the drug itself. The manufacturers of penicillin in the United States formed the Alexander Fleming Fund. The money went to St. Mary’s Hospital in London for Dr. Fleming to continue his research.
As the years passed, he recovered from the loss of his wife. He was elected rector of Edinburgh University in 1951. He also began to work closely with a female doctor by the name of Amalia Coutsouris-Voureka from Gprÿe. She spent long hours in his laboratory, mastering the science of bacteriology. She decided to continue her studies in Athens, and Dr. Fleming followed her. They were married in 1953. Friends of Fleming remarked that he was a new man after his marriage. Back in London, Fleming developed a cold, a few days later he died of a heart attack on March 11, 1955. He was buried in St. Paul’s Cathedral.
Fleming had a lone7û sociation with the St. Mary’s Hospital. Fleming was assistant director of the Inoculation Department in 1921. The Department merged with the Institute of Pathology and Research in 1933, and it was renamed the Wright-Fleming Institute in 1948. In that year, Fleming retired as professor of bacteriology from the University of London, where, he held the chair since 1928. He became director of the Institute in 1946 when Sir Wright retired, and remained there until January of 1955.7î o months before his death.
Fleming was a very modest man. He accepted the honors and acclaim diffidently. He once said: "Professional jealousy can be a most brutal and terrifying phenomenon." Although he became known world wide, he remained a man of humility who was very quiet and kept his personal life to himself. He enjoyed an evening game of snooker at the Chelsea Arts Club, where he held a long-treasuprþ\honorary membership. He was the sole or senior author of about 100 scientific papers. Among Fleming’s best papers were those prepared as addresses for endowed lectureships. He also published novel techniques or wrote brief biographic memoirs. He was not interested in philosophy or rhetoric. His dedication to science and human health is fully reflected in his writings. A collection of Fleming’s published work and unpublished manuscripts including letters, diaries, laboravxè notebooks along with other documents are available from the Wright-Fleming Institute.
Penicillin was merely the first of a long list of antibiotics that were proven to have antibacterial qualities. There are problems with penicillin. It is only effective in fighting infections caused by streptococci, staphylococci, gonococci, pneumococci, bacterial endocarditis, and gas gangrene bacilli. It is powerless against malarkv¶^tuberculosis, typhoid fever, and viral diseases such as influenza and yellow fever. It caused allergic reactions in certain patients. But it was the first drug in demand that revolutionized the pharmaceutical industry and laid the groundwork for the antibiotic descendents to continue to fight against microbial infections. Fleming’s work inspired many pharmaceutical companies and research institutions to investigate the production of antibiotics from different microorganisms."Zûy new antibiotics were later found to be very useful in combating diseases. Antibiotic production today is estimated at a value of more than $16 billion per year. To call Fleming a pioneer for the antibiotics era is very appropriate.
As Maurois put it, Fleming was gifted with steadfastness and loyalty that created respect and affection. He also possessed the quality of hard and sustained work, a true humility and c7ùïmbative spirit that refused to admit defeat. Fleming also had a keen curiosity and perceptiveness, an excellent memory, the technical inventiveness and skill of a highly artistic order and the mental and physical toughness that is characteristic of a great man in many walks of life. Fleming was attentive to things that many other scientists would probably have merely overlooked. Therefore, above all the characteristics mentioned, Fleming kept his eyes and mind open, and he was aluvãò prepared for something significant. Success always is given to those who are prepared. Who would care about anything as ugly as a green mold on an apple or a piece of bread? Yet it proved to be the source of life saving antibiotics. The lesson of Fleming is a worthy learning for all microbiologists.