The Secret History of Penicillin

Whether we know what he accomplished or not, we all know Alexander Fleming’s name. Like Isaac Newton or Jonas Salk, Fleming is one of those personalities behind a huge scientific breakthrough that propelled his name into posterity. He was the one who discovered penicillin in 1928. But before we talk about the mechanisms of its discovery and its consequences on the history of medicine and humanity, let us ask ourselves the following question: what is penicillin? Well, it’s a toxin that is found in… mold. This type of mold is part of the genus Penicillium. Within this genus, there are several types of penicillin, some of which are used in the production of many cheeses. The blue-green mold found on fruits, vegetables, cheeses or bread is penicillium. The one Fleming discovered is penicillin G, or penicillium notatum. It is harmless to humans and is a great remedy against bacterial infections. It was the first antibiotic to be discovered, and this discovery, you will see, was a turning point in the history of medicine and humanity. In particular, it provided a very rapid and effective treatment for diphtheria, syphilis, gonorrhea, and staphylococcus, all of which were devastating throughout history. In this episode, we will focus on the state of treatments before the discovery of penicillin, before mentioning Alexander Fleming and the large-scale development of this antibiotic during the Second World War. Finally, we will talk about the reception given to it by the public and the scientific world, as well as its misuse that will allow many bacteria to become more resistant.   

 

  1. Treatments before penicillin

Before Fleming’s discovery and the early use of penicillin on a large scale, it seems important to note that the treatments were very uncertain and extremely complicated. Without the modern medical machines we know today, doctors of the time often had no way of knowing what was causing the diseases. In his article entitled A History of Penicillin: The Miracle of Medicine, John Paul Rogers gives us an impressive number of treatments advocated in the United States, before the discovery of penicillin. I will give you a few examples, most of which date back to the second half of the 19th century:

Take, for example, a doctor from the city of Eugene, Oregon. This gentleman, in the last years of the 19th century, was taking blood from horses that had been exposed to diphtheria and had survived the infection. The blood of the animals was then injected into patients. Our doctor thought that the use of this blood would work in the same way as a vaccine. John Paul Rogers tells us that there is no record of the success rate of this treatment, but that a young girl was cured through the use of this method.

Another example is to be picked up in 1833, the date of the publication of the Manual of Treatments for Various Diseases, written by Daniel Whitney. In this book, Whitney advocated treatment for conditions such as gonorrhea. This treatment occurred in several stages. How surprising, if you follow our podcast channel from the very first days: the first step is the practice of bloodletting. Less than two hundred years ago, it was still thought that bloodletting allowed the disease to leave the body, thus restoring the perfect balance between Humours. The second step was to soak the affected area in a mixture of warm milk and water, followed by the injection into the urethra of a mixture of water, lead acetate and arabic gum, several times a day. The final step was to soak the patient’s genitals in lead water. If the disease was not defeated, Whitney recommended applying mercury ointment to the genitals. In fact, at the time, many of the doctors thought that these aggressive chemicals had the ability to eliminate the visible symptoms of the infection, which meant to them that the disease was defeated.

Our final example comes from 1894. That year, the Kansas State Health Department published Diphtheria: Prevention and Restrictions. As the name suggests, this document chose not to offer treatment, but to focus on preventing the spread of infection. This required isolating the patient in a sunny, ventilated room, and removing anything that may have been “contaminated” by the infection, such as sheets, curtains and pets. The idea was, without an official and effective treatment, it was better to focus on something else, such as avoiding a possible outbreak. The Kansas State Health Department had even provided a list of disinfectants to use in case the patient died.

 

            Looking back, most of the treatments used at the time seem far-fetched and dangerous. However, it seems important to point out that at the time, doctors could only focus on the symptoms themselves. They did not have a comprehensive understanding of diseases yet. For example, applying extremely aggressive chemicals sometimes helped to fight infections, but these successes were unknowing of the fact that the patient was receiving very high doses of poison. These treatments remained the norm for many decades to come, until a lucky, fortunate, unexpected discovery. It was that of a British scientist: Alexander Fleming.

 

  1. An unexpected discovery

September 3, 1928 was a homecoming day for Alexander Fleming. He had indeed gone on holiday during the summer and had left his laboratory located at Saint Mary’s Hospital in London, in disarray, as he used to do. Probably in a hurry to go on holiday, he had even forgotten to close the window when he left. Born in Scotland in 1881, Fleming was a bright young boy, which opened doors for him to go and study in London. He studied at the Royal Polytechnic Institution, as a teenager, then entered the medical school of Saint Mary’s on the advice of one of his brothers, in 1901. Seven years later, he won the gold medal from the University of London by finishing first in his class. In 1914, the First World War broke out, and Fleming joined the British Army. He was sensitive to the plight of wounded soldiers, who often succumbed to combat-related infections. There, he denounced the misuse of antiseptics by medical personnel on wounded soldiers, used systematically and in very large quantities. This misuse killed a large number of soldiers. During the war, he obtained the rank of Captain and was awarded the British military citation, a huge honor for a member of the military medical staff. Once back home, Fleming resumed his career, obsessed with what he saw during the war. His goal was to fight bacteria, and he was particularly interested in the immune system. In particular, he sought to understand why, in two people with the same type of infection, one would survive, and the other one would die. Understanding what caused this person’s survival might have helped him find an effective drug. In 1927 he was appointed to the Chair of Bacteriology at the Faculty of Medicine in London, and the following year, he was appointed Professor of Biology at Saint Mary’s Hospital.

A few months before that famous morning of September 3rd, 1928, Fleming had taken staph from a patient’s wound. These yellowish-colored bacteria had been carefully deposited in petri dishes, which Fleming forgot to close before he left. Upon his return, he noticed that the petri dishes were filled with green mold. He didn’t know it yet, but this mold would save millions of people. Alexander then began to tidy up the room and was about to throw away his mold-contaminated samples. But, as he was about to do so, he noticed something strange. Around the molds, the bacteria became translucent, a sign that they were killed. Fleming decided to take a closer look at the issue. He understood that, during his vacation, spores of the penicillium fungus probably infiltrated inside his laboratory, perhaps through the window left open, as the legend likes to suggest. They then came to settle on the petri dishes. He decided to try to understand what killed the staphylococci and realized that the toxin of the fungus was causing the deactivation of the wall of the bacterial cell. And it is precisely this wall that allows the bacterium to divide and multiply and then colonize the human body. Fleming also noted that the summer of 1928 was particularly cool. Temperatures ranged from 16 to 20 degrees Celsius in England, which allowed him to conclude that the environment had also been conducive to the development of the fungus. He isolated the mold and identified it as part of the penicillium genus. He called the synthesized toxin “Penicillin” and concluded that it had an antibacterial effect on staphylococci and other gram-positive bacteria, like many other cocci and bacillus.

He published his research in 1929, in an article entitled About the antibacterial action of penicillium cultures, with a special reference to their use in the isolation of the influenza B virus. That same year 1929, he presented his findings to his colleagues at the prestigious Medical Research Club. And it is an understatement to say that Fleming’s colleagues welcomed the results with great skepticism. Some criticized him for his method based on chance, others pointed to the many uncertainties related to his conclusions. Over the next few months, Fleming tried to purify the highly unstable compound, but this process proved to be above his skills. This failure caused Fleming’s work to be forgotten for a few years, until 1938.

 

  1. A trio who chose to believe in Fleming’s penicillin

In 1938, Ernst Boris Chain, a biochemist officiating at the University of Oxford, came across Fleming’s article, published almost ten years earlier. Ernst Boris Chain was born in Germany. A Jewish man, he was one of those who quickly felt the wind turn. He decided to leave his country in 1933, shortly after Adolf Hitler was appointed Chancellor. He then moved to England at the age of 27, and began working at the University of Cambridge, before accepting a position as a pathology research assistant at the University of Oxford in 1935. Four years later, his supervisor was Howard Florey. Florey, like Ernst Boris Chain, was not British either, but Australian. A very promising scientist during his early life in Australia, he quickly received a scholarship to study at Oxford University. After going to the United States and working for Cambridge University, he eventually returned to Oxford and became a team leader. It was Chain who invited him to read Fleming’s article. Both men were intrigued by the findings of the research paper. Florey’s predecessor, George Dreyer, had already applied for a sample from Fleming in the early 1930s. Fleming had sent it to him. But Dreyer had focused on a false lead. He wanted to know if bacteriophages were the cause of the antibacterial activity in Fleming’s penicillin. There was none. But the sample sent by Fleming was kept.

In 1939, Howard Florey formed a team with Ernst Boris Chain, of course, and Norman Heatley, a biochemist and fungal expert. The idea was to work on a filtrate from Fleming’s mold and why not, do clinical trials. The role of the newcomer to the team, Norman Heatley, was huge. It was his responsibility to produce penicillium in large quantities. Ernst Boris Chain’s role was to purify the penicillin extracted from the mold produced by Heatley. Finally, team leader Howard Florey was tasked with overseeing future animal trials. In May 1939, Heatley and Chain successfully completed their task. Trials then began on May 25. Our team then injected a virulent strain of streptococcus into eight mice, before injecting penicillin into 4 of these mice. The others were considered “controls.” This is how Norman Heatley told us what followed, in his diary:

“After having dinner with friends, I went back to the lab and met the Professor, to give one last dose of penicillin to four of the mice. The “control” mice looked very sick, but the treated mice appeared to be doing very well. I stayed in the lab until 3:45 a.m., when all the “control” mice were dead.”

The treated mice were doing perfectly well. Faced with the success of their trial, the three scientists couldn’t believe it. Ernst Boris Chain even called it a “miracle.”

 

On August 24, 1940, they published the results of their research in an article entitled Penicillin as a chemotherapy drug, in The Lancet. This publication aroused the interest of Alexander Fleming himself, who went to Oxford to meet the team. For them, the next step was to test on humans. In 1941, the first patient to receive treatment was a police officer from the city of Oxford. He was suffering from a nasty infection and had abscesses all over his body. 24 hours after the first injection of penicillin, the patient’s health improved significantly. Florey, Chain and Heatley then decided to treat other patients, and each time it was a success. In total, in 1941, 170 people were treated by the trio, and no toxic side effects were noted. They were now certain that the miracle had been confirmed. Unfortunately, the police officer’s infection, the first to be tested, was such that it began to take over. To hope to cure it, there was a need for a very large quantity of penicillin, which our three scientists did not have in stock. The patient eventually died of his infection a few weeks later, leaving the research team ill-at-ease, and with a major question to which they would have to work to find an answer: how to produce penicillin in very, very large quantities?

 

 

  1. Towards large-scale production: a gigantic task

When Florey and his team were seriously considering this issue, one would have almost forgotten that the world was, at the time, plunged in the Second World War. In Europe, the United Kingdom was the only one that had been able to withstand the Nazi juggernaut. But the British were suffering repeated and strategic bombings by the German military air force. It was the Blitz. Florey quickly realized that turning to the English authorities to start this large-scale production would be futile. The priority was indeed elsewhere, as the country’s chemical industry was fully focused on the war effort. In June 1941, Howard Florey and Norman Heatley flew to the United States, a country that had not yet entered the war, with real hopes. There, they met Charles Thom, chief mycologist of the U.S. Department of Agriculture, and Andrew Jackson Moyer, director of the Department’s affiliated Northern Research Laboratory. This was a crucial meeting for the future of penicillin. Both Americans were intrigued by the potential of this miracle drug. Very quickly, the partnership materialized, without being formalized, and Heatley decided to stay in the United States for six months, to accompany the research. During this time, progress was rapid. A new strain to produce six times as much penicillin as the one identified by Fleming was discovered. Andrew Jackson Moyer also had the idea of using corn steep liquor to facilitate the large-scale production of mold. Considered a waste in the manufacture of cornstarch, this liquor was available in large quantities in the Midwest. Within a few months, most of the questions were answered. Large-scale production was now possible, but the U.S. authorities needed to officially commit to launching it. This was the mission of Howard Florey, who travelled to the east of the country to try to convince the U.S. government and several pharmaceutical companies. He did not need to negotiate for long. On December 7, 1941, the U.S. naval base of Pearl Harbor was attacked by Japanese aero-naval forces, causing the United States to enter the war. The promise of being able to cure the civilian population, especially the soldiers, of potential infections, was too strong. From now on, the U.S. authorities would take over the production. By the end of the war, nearly 7 trillion units of penicillin would be produced in the United States and the United Kingdom.

 

  1. Towards Posterity: The Beginnings of the Fleming Myth

The expected results obtained, Florey and Heatley returned to England in January 1942. In August of that year, Fleming obtained doses of penicillin from the Oxford team, which he used to cure a patient who was dying of strep meningitis. Thanks to this unexpected healing, the scientific community and even the press began to take an interest in this new kind of drug. On August 27, 1942, the British newspaper The Times published an article entitled Penicillin. In this article, the journal evoked the patient’s healing and referred to this new substance, just discovered, which had miraculous healing properties. The article, on the other hand, remained very vague, and did not mention any name or location. This had the power to infuriate Fleming’s superior, Sir Almroth Wright, who decided to write a letter to the newspaper, which was published on 31 August:

” In the leading article on penicillin in your issue yesterday you refrained from putting the laurel wreath for this discovery round anybody’s brow. I would, with your permission, supplement your article by pointing out that, on the principle palmam qui meruit ferat, it should be decreed to Professor Alexander Fleming of this research laboratory. For he is the discoverer of penicillin and was the author also of the original suggestion that this substance might prove to have important applications in medicine.”

On September 1, many journalists went to Saint Mary’s Hospital to try to interview Fleming. The latter then showed up to be photographed but refused any interview. A few hours later, he finally accepted the proposal of Audrey Russel from the BBC. Overnight, Fleming went from anonymity to fame. The next day, another letter was published in The Times, but this time it came from Oxford. It was signed by Robert Robinson, Professor of Chemistry at the university:

“Now that Sir Almroth Wright has rightly drawn attention to the fact that penicillin was discovered by Professor Fleming and has crowned him with a laurel wreath, a bouquet at least and a handsome one, should be presented to Professor H. W. Florey, of the School of Pathology at this university. Toxic substances are produced by the mold alongside penicillin and Florey was the first to separate “therapeutic penicillin” and to demonstrate its value clinically. He and his team of collaborators, assisted by the Medical Research Council, have shown that penicillin is a practical proposition.”

As with Fleming, many journalists went to Florey’s lab the next day, but He did not give any interviews to the press, and even forbid members of his team to do so. Some might have thought that he was not looking for public recognition. Perhaps there was a different reason.

 

  1. A secret to be kept: The Second World War as a context

In September 1942, very few people in the world were aware of what was started by Fleming and Florey’s team. Sure, Fleming had tried to share his discovery with other scientists in the early 1930s. In particular, he had sent samples to several European scientists, without much more precision, such as the French André Lwoff of the Pasteur Institute, or the German doctor Hans Schmidt. But these two men were part of a very closed circle of about ten scientists. By 1942, the British and American authorities had already understood that the secret of penicillin production should remain well guarded. Even if Germany had a sample in its possession and the Anglo-Saxon media had already leaked its chemical formula, Florey was convinced that without more information, no one could initiate large-scale production of penicillin. This did not prevent requests from coming in. For example, the Swiss company CIBA applied to Florey for penicillium notatum. Aware of the stakes, Howard Florey decided to systematically inform the British authorities of this type of request. In a letter to the BBC, he criticized the enormous media attention given to penicillin, which, in his opinion, resulted in “a flood of pathetic letters from as far away as Western Australia and Saskatchewan…” What had to be avoided was that the secret would fall into the wrong hands and that Nazi Germany would catch up. For indeed, it was trying to catch up.

Also in 1942, but in occupied France, at the Institut Pasteur, the praise of the English press on penicillin prompted the Institute’s researchers to take out of the closet the stump Fleming had sent to André Lwoff ten years earlier. Soon, the work began. Frédéric Nitti quickly isolated a strain of penicillium notatum and managed to extract a very small amount of active penicillin. The German authorities get wind of the news and did not hesitate to demand a stump, in order to send it to Germany. The researcher first pretended to have lost his work, which left him with some time. A time that allowed him to plan for their next visit. He suspected that the Germans would not give up so easily. A few weeks later, as expected, they returned.  This time, Nitti pretended to protest, but eventually gave them a stump, which he had in fact prepared for this occasion. An amorphous penicillium strain, from which active penicillin extraction was impossible. It was an incredibly bold and courageous move on Nitti’s part, but it wasn’t his first. A little earlier in 1942, he had already entered the resistance, and was notably co-creator of a clandestine network supplying medicines, vaccines and medical equipment to the French Forces of the Interior (FFI). He was awarded the Resistance Medal in 1945.

In the Netherlands, which was also under German occupation, the situation was very different. In 1942, the Dutch were much further ahead than the Pasteur Institute. It must be said that at the time, the country had the largest collection of fungi and molds in the world. This collection belonged to the Central Bureau for the Culture of Molds. By 1937, the Bureau had published a list of the strains in its possession. The penicillium notatum was one of them. In February 1942, the Nazis asked the Central Office to send them their stump. The Bureau’s answer was clear: it did not have Fleming’s strain in its possession. It was a lie. Fleming, in the early 1930s, sent a sample to Johanna Westerdijk, Director of the Central Bureau for Mold Culture. The latter, like Nitti in France, understood that the Germans still had to be provided with something. She eventually gave them a strain of penicillium that did not produce active penicillin. The Dutch understood that if they wanted to produce penicillin, they would have to do it clandestinely. In 1943, F. G. Waller, Director of the Dutch Yeast and Spirits Factory, which was called UNLS, sent a secret letter to Johanna Westerdijk. In this letter, Waller asked her to provide him with all the strains to produce penicillin. Keeping these strains in the Bureau would have been too dangerous. Westerdijk agreed. The aim was to prevent the Nazi regime from becoming aware of the work in progress. At UNLS, a code name was given to penicillin. It would now be called “Bacinol.” Waller later wrote: “When we started looking in 1943, only one publication was available, Fleming’s in 1929. It was on this basis that we began our research.” In June 1944, an article was published in the Swiss Medical Journal. This article was entirely devoted to the production of penicillin, thus putting an end to many secrets: results obtained by allies, means of production, identification of antibiotic-sensitive bacteria and many others. UNLS teams got their hands on this article and started production. The only problem was that a German guard was on site to monitor the company’s activities. Fortunately, the guard knew nothing about microbiology, and very quickly, a way to occupy him was found: “We had a German guard whose job it was to keep us under surveillance, but he liked gin, so we made sure there he had plenty. He spent most of his afternoons napping.” By the end of the war, UNLS teams still did not know if their filtrate was really penicillin. They then compared their Bacinol to penicillin from England, and there, relief: it was the same compound. UNLS marketed its penicillin from January 1946 with great success.

As for the Germans, they finally managed to produce penicillin in October 1944. But it was too late. Allied air raids prevented large-scale production of the antibiotic, as German industry was systematically targeted by bombardments.

 

  1. A major asset in times of war

During 1942, Florey went to North Africa, where fighting was raging. He was accompanied by one of his colleagues, Hugh Cairns. Cairns was a small celebrity in the medical community. He was an internationally renowned neurosurgeon. It was he who had been called to Lawrence of Arabia’s bedside when he had his fatal motorcycle accident. For both men, the idea was to test the drug on wounded soldiers. Very quickly, the successes followed one another. This new type of patient, who did not suffer from the same conditions as patients treated in England, confirmed that penicillin was effective in combating infections related to gunshot wounds. This was a major advance for war medicine. From now on, one knew that many lives would be saved on the battlefield. With penicillin, soldiers knew that an infection related to a non-lethal gunshot wound would no longer be fatal to them. The objective of the British and American authorities was clear then: pharmaceutical companies, government bodies and scientists would have to work together to produce as much penicillin as possible. This collaboration was incredibly fruitful. By September 1943, stocks were already sufficient to support much of the war effort. In June 1944, there was enough penicillin to cover the largest military operation in history: Operation Overlord.

This is also why the British authorities did not prevent the press from talking about penicillin. What had to be avoided was that the means of production be revealed. To extol its merits and to speak of “miracle medicine”, on the other hand, had a real purpose. Let’s take the example of The Times. In 1943, 12 articles were devoted to penicillin. In 1944, more than 90 article referred to it in the newspaper. Penicillin was used to boost the morale of the troops, and of the civilian population, who had not yet been able to benefit from it. It became a real propaganda tool. In its August 14, 1944 edition, the famous American magazine Life left room for an advertisement for penicillin. It included two Americans, one was visibly a wounded soldier, the other was a military medic providing care. The title was: “Thanks to Penicillin… He will come home. This partly explained why the British authorities favored the establishment of Alexander Fleming’s legendary status. If we still know penicillin as well as Alexander Fleming’s name today, it is because at the time there was a real need to find heroes. For the rest of his life, he lived with a living legend status, and received countless invitations. He travelled the world, accepting awards and honors. In an article published in the journal Nature, published in 1984 and entitled Alexander Fleming: Man and Myth, Gwyn MacFarlane said:  He received praise from the crowd with modesty and certainly never succumbed to the folie des grandeurs.”

 

  1. After the war: available to the public and experiments

In 1945, Dorothy Hodgkin of the University of Oxford confirmed the chemical structure of penicillin, using X-rays. She was awarded the Nobel Prize in Chemistry in 1964 for having, according to the Nobel Prize website, “determined by X-ray techniques the structures of important biochemical substances.” The end of the war was approaching, and penicillin was already a drug produced on a very large scale. Very soon, the military world needed less and less penicillin, and it was time for the general public to benefit from it. The expectation of the public was strong. Imagine, however, that by the end of the war, most people had heard of the drug. But very few had benefited from this advertised “miracle of medicine”. On March 15, 1945, the U.S. authorities lifted all restrictions related to the sale of the drug. From now on, it was possible to buy penicillin at one’s local pharmacy. That’s it, penicillin was officially able to change the world.

At that time, however, it was known to be effective in treating conditions that had already occurred in the patient. At the sight of its incredible potential, some scientists began to explore other avenues. Could it, for example, be possible that penicillin could prevent disease, like vaccines? At the time, one condition was particularly targeted: syphilis. According to Prof. Susan Reverby:

“The U.S. Public Health Service was keen to know whether penicillin could be used to prevent, and not just cure, early infection of syphilis, whether better blood tests could be established for the disease, what penicillin dosages actually cured the infection, and to understand the process of reinfection after healing.”

A professor at the University of Wellesley in the United States, it was Prof. Reverby who discovered the syphilis experiment scandal in Guatemala. Between 1946 and 1948, 700 Guatemalans were unwittingly inoculated with venereal diseases by doctors from the United States Public Health Service. The aim was to test the effectiveness of penicillin in the face of these diseases, with a particular focus on syphilis. These 700 Guatemalans were prisoners, people suffering from mental illnesses and soldiers. The New York Times, in its October 1st, 2010 edition, even told us that:

“American tax dollars, through the National Institutes of Health, even paid for syphilis-infected prostitutes to sleep with prisoners, since Guatemalan prisons allowed such visits. When the prostitutes did not succeed in infecting the men, some prisoners had the bacteria poured onto scrapes made on their penises, faces or arms, and in some cases, it was injected by spinal puncture.”

To find this, Professor Reverby searched through the archives of several universities, and found documents at the University of Pittsburgh:

“I’m sifting through them, and I find ‘Guatemala … inoculation …’ and I think ‘What the heck is this?’ And then it was ‘Oh my god, oh my god, oh my god.’ My partner was with me, and I told him, ‘You aren’t going to believe this.’” The discovery led U.S. authorities to publicly apologize in 2010, 64 years after the events. Hillary Clinton, Secretary of State of the United States, and Kathleen Sebelius, Secretary of Health and Human Services of the United States, made the apology, stating that:

“Although these events occurred more than 64 years ago, we are outraged that such reprehensible research may have taken place under the guise of public health. […] We deeply regret that this has happened, and we apologize to all those who have been affected by such abhorrent research practices.”

The American physician in charge of these tests in Guatemala was John C. Cutler. He participated, a little later, in the study of Tuskegee on syphilis. It was in fact working on the Tuskegee study that Professor Reverby stumbled upon the literature related to the trials in Guatemala. This study lasted nearly 40 years, from 1932 to 1972, and aimed to better understand the evolution of the disease when it was not treated. It was launched, once again, by the US Public Health Service. In 1932, the program began in Tuskegee, Alabama, with 399 men with syphilis and 201 more. All of them were black. The study was conducted without the consent of the patients.  In fact, the doctors participating in the study assured patients that they were being treated for “bad blood”, a n unclear term used to describe several conditions, including syphilis, anemia and fatigue. In fact, they did not receive the appropriate treatment to cure their disease. In exchange for their participation in the study, they benefited from free medical examinations, free meals and funeral insurance. Although originally planned to last 6 months, the study actually lasted 40 years, until 1972. From 1947, penicillin was the preferred treatment to fight syphilis. It was also proven to be effective. However, the study, which could then be considered obsolete from that date on, continued for another 27 years. U.S. authorities decided to end it after the Associated Press published several articles highlighting it, sparking a national outcry.

According to Dr. Mark Siegler, Director of the Maclean Center for Clinical Medical Ethics at the University of Chicago’s School of Medicine: “It  is ironic – no, it’s worse than that, it’s appalling – that while the United States was prosecuting Nazi doctors for crimes against humanity, the U.S. government was supporting research that put human subjects at enormous risk.” In 1964, the Helsinki Declaration was adopted by the 18th General Assembly of the World Medical Association. It provided a framework and fundamental principles for medical personnel conducting human and animal research.  The focus was set on “respect for the individual, his/her right to self-determination and the right to make informed decisions about his or her participation in research,” whether before or during a clinical trial. The duty of medical and scientific personnel was also redefined. It was to be directed towards the patient. The well-being of the subject was to “always take precedence over scientific and societal interests, and ethical considerations were to always take precedence over laws and regulations.”

 

 

 

Conclusion

            The History of Penicillin is therefore an incredible story, rich in twists and turns. In 1945, Alexander Fleming, Howard Florey and Ernst Boris Chain were awarded the Nobel Prize in Physiology or Medicine “for the discovery of penicillin and its healing effects in several infectious diseases”, thus rewarding work that was a turning point in the history of medicine and humanity.  Before penicillin, the closest event in terms of impact on the world of health was undoubtedly the discovery of vaccination.  What the vaccines did for viruses, penicillin did for bacterial infections. What is all the more surprising, and what also makes all the charm of this story, is that this discovery was not caused by revolutionary or innovative research. As Howard Florey reminded us:

“The almost miraculous properties of penicillin should not blind us to the fact that the work carried out at Saint Mary’s Hospital in London and Oxford has not introduced any new chemical or biological principles. The results, however, were new and the effects on medicine widespread.”

Luck played a big part in this discovery. Louis Pasteur said, “ Chance favors only the prepared mind.” Alexander Fleming, in 1928, was unconsciously prepared to make this discovery. He could very well have thrown away his contaminated petri dishes, and the story would have ended there. But his genuine desire to fight infections, especially after being moved by the fate of soldiers wounded in the First World War, his curious nature and the skills acquired during his career, allowed him to take an interest in this mold, and to quickly understand that he had found something special, which could kill bacteria. Fleming also knew that misuse of penicillin could be detrimental to the drug’s proper functioning and could make bacteria more resistant. So he gave us a warning:

“Penicillin is for all intents and purposes non-toxic, so there is no need to worry about overdose and poisoning the patient. […] It is not difficult to make penicillin-resistant microbes in the laboratory by exposing them to insufficient concentrations to kill them, and the same thing has sometimes happened in the body… Then there is the danger that the ignorant man may easily under dose himself and by exposing his microbes to non-lethal amounts of the drug, make them more resistant. »

This discovery thus began the era of antibiotics, which is now reaching a turning point. Bacteria have become more and more resistant. The example of penicillin is therefore to be followed, now more than ever. The serendipity involved in its discovery is a great example that finding new effective antibiotics will be difficult but remains possible. Finally, I leave the final word to Alexander Fleming himself: “ One sometimes finds what one is not looking for.”

 

 

 

This episode, like all the other episodes in our channel, was written without bias or prejudice. We make every effort to provide you with clear, precise texts, and based on reliable sources.

 

 

Sources:

  1. Lucille Wright, Miracle Medicine Writing History at Army Hospital [La médecine miracle écrit l’histoire à l’hôpital de l’armée], The Ogden Standard-Examiner, July 5, 1943, Accessed November 10, 2020. https://www.newspapers.com/image/27174060.
  2. Antibiotiques : quand les bactéries font de la résistance. La lettre de l’Institut Pasteur, n°85, mai 2014.

https://www.pasteur.fr/sites/default/files/rubrique_nous_soutenir/lip/lip85-resistance_aux_antibiotiques-institut-pasteur.pdf

  1. Brian J. Werth, Pénicillines, Le Manuel MSD, Version pour professionnels de la santé, Maladies infectieuses, bactéries et médicaments antibactériens

https://www.msdmanuals.com/fr/professional/maladies-infectieuses/bact%C3%A9ries-et-m%C3%A9dicaments-antibact%C3%A9riens/p%C3%A9nicillines

  1. Gwyn Macfarlane, Alexander Fleming : the man and the myth [Alexander Fleming : l’homme et le mythe]. Cambridge (MA) : Harvard University Press; 1984.
  2. Howard Florey and others, Penicillin as a chemotherapeutic agent [la pénicilline comme agent chimiothérapeutique], The Lancet, p226-228, 24 aout 1940. https://www.ndorms.ox.ac.uk/files/news/19400824_florey_penicillinasachemotherapeuticagent_lancet.pdf
  3. B Lee Ligon. Penicillin: its discovery and early development [Pénicilline : sa découverte et son développement précoce]. Semin Pediatr Infect Dis. 2004 Jan ;15(1) :52-7. doi: 10.1053/j.spid.2004.02.001. PMID : 15175995.

https://pubmed.ncbi.nlm.nih.gov/15175995/

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http://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html

  1. Ronald Hare. The scientific activities of Alexander Fleming, other than the discovery of penicillin [Les activités scientifiques d’Alexander Fleming, autres que la découverte de la pénicilline]. Med Hist. 1983 Oct;27(4):347–372.

https://core.ac.uk/download/pdf/189449309.pdf

  1. Gladys L. Hobby, Meeting the Challenge [Relever le défi]. New Haven ; London: Yale University Press, 1985. Accessed November 12, 2020. http://www.jstor.org/stable/j.ctt1xp3smj.
  2. Jean-Charles Foucrier.L’épopée de la pénicilline, La guerre des scientifiques. 1939-1945, sous la direction de Foucrier Jean-Charles. Perrin, 2019, pp. 151-179.

https://www.cairn.info/la-guerre-des-scientifiques–9782262067939-page-151.htm

  1. Penicillin : opening of an era [Pénicilline, le début d’une nouvelle ère], US Department of Agriculture, Agriculture Research Service.

https://www.ars.usda.gov/midwest-area/peoria-il/national-center-for-agricultural-utilization-research/docs/penicillin-opening-the-era-of-antibiotics/

  1. Mariya Lobanovska, Giulia Pilla. Penicillin’s Discovery and Antibiotic Resistance: Lessons for the Future? [La découverte de la pénicilline et la résistance aux antibiotiques: Des leçons pour l’avenir ?] The Yale journal of biology and medicine 90,1 135-145. 29 Mar. 2017

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369031/

  1. Sir Ian Fraser. Penicillin: early trials in war casualties [Pénicilline : premiers essais sur les victimes de guerre]. Br Med J (Clin Res Ed). 1984 Dec 22-29 ;289(6460):1723-5. doi: 10.1136/bmj.289.6460.1723. PMID: 6440621; PMCID: PMC1444789.
  2. Gwyn Macfarlane, Alexander Fleming : the man and the myth [Alexander Fleming : l’homme et le mythe]. Nature, VOL 308, 26 APRIL 1984.

https://www.nature.com/articles/308804a0.pdf?proof=t

  1. Julian Davies, Dorothy Davies. Origins and evolution of antibiotic resistance [Origine et evolution de la résistance aux antibiotiques].  Microbiology and molecular biology reviews : MMBR 74,3 (2010): 417-33. doi:10.1128/MMBR.00016-10

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937522/

  1. Expérimentations : Washington s’excuse auprès du Guatemala, Par Constance Jamet

Publié le 2 octobre 2010 à 15 :27, mis à jour le 3 octobre 2010 à 15:28, lefigaro.fr

https://www.lefigaro.fr/international/2010/10/02/01003-20101002ARTFIG00344-experimentations-washington-s-excuse-aupres-du-guatemala.php

  1. S. Apologizes for Syphilis Tests in Guatemala [Les États-Unis présentent leurs excuses pour les tests sur la syphilis au Guatemala], par Donald G. McNeil Jr. Publié le 1er octobre 2010.

https://www.nytimes.com/2010/10/02/health/research/02infect.html

  1. Déclaration d’Helsinki de L’AMM – Principes éthiques applicables à la recherche médicale impliquant des êtres humains, Association Médicale Mondiale

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  1. Menachem Shoham, Michael Greenberg, Preventing the spread of infectious diseases: antivirulents versus antibiotics [Prévention de la propagation des maladies infectieuses : antiviraux contre antibiotiques], Future Microbiology, 2217/fmb-2017-0011, 12, 5, (365-368), (2017).

https://pubmed.ncbi.nlm.nih.gov/28339290/

  1. Alexander Fleming, Penicillin Nobel Lecture, Conférence du Prix Nobel, 11 décembre 1945. Nobelprize.org

https://www.nobelprize.org/uploads/2018/06/fleming-lecture.pdf

  1. Göran WennergrenHugo Lagercrantz, “One sometimes finds what one is not looking for” (Sir Alexander Fleming): the most important medical discovery of the 20th century [“On trouve parfois ce que l’on ne cherche pas” (Sir Alexander Fleming) : la plus importante découverte médicale du XXe siècle]. 20 décembre 2006, Acta Paedatrica, Volume96, Issue 1, January 2007, Pages 141-144 https://doi.org/10.1111/j.1651-2227.2007.00098.x
  2. Jonathan Wood, Penicillin: the Oxford Story [Pénicilline: l’Histoire d’Oxford], Oxford Science Blog, 16 juillet 2010.

https://www.ox.ac.uk/news/science-blog/penicillin-oxford-story

  1. Deborah Jowitt. (2005). The H-bug epidemic: the impact of antibiotic-resistant staphylococcal infection on New Zealand society and health 1955-1963 [L’épidémie de H-bug : l’impact de l’infection par le staphylocoque résistant aux antibiotiques sur la société et la santé en Nouvelle-Zélande 1955-1963.] Mai 2005, Thesis for: MHSc, Advisor: Associate Professor Lynne Giddings; Professor Linda Bryder

https://www.researchgate.net/publication/30040222_The_H-bug_epidemic_the_impact_of_antibiotic-resistant_staphylococcal_infection_on_New_Zealand_society_and_health_1955-1963

  1. Donald Gillies. (2006). Kuhn on Discovery and the Case of Penicillin [Kuhn sur la découverte et le cas de la pénicilline]. Contemporary Perspectives in Philosophy and Methodology of Science (pp.47-63)

https://www.researchgate.net/publication/332268883_Kuhn_on_Discovery_and_the_Case_of_Penicillin

  1. Eric Lax. The Mold in Dr. Florey’s coat: The Story of the Penicillin Miracle [La moisissure dans le manteaux du Dr. Florey: L’Histoire du Miracle de la Pénicilline]. Henry Holt and Company, 2 juin 2015 – 320 pages

https://books.google.fr/books?id=NFgXCAAAQBAJ&printsec=frontcover&hl=fr&source=gbs_atb#v=onepage&q&f=false

  1. Gilbert Shama. Zones of Inhibition? The Transfer of Information Relating to Penicillin in Europe during World War II [Zones d’inhibition ? Le transfert d’informations relatives à la pénicilline en Europe pendant la Seconde Guerre mondiale]. Department of Chemical Engineering, Loughborough University, Loughborough, Leics., LE11 3TU, UK

https://pubmed.ncbi.nlm.nih.gov/19729093/

  1. Jean-Paul Gaudillière, « 1. Entre biologistes, médecins et militaires : la production et l’évaluation des antibiotiques », dans : , Inventer la biomédecine. La France, l’Amérique et la production des savoirs du vivant (1945-1965), sous la direction de GaudillièreJean-Paul. Paris, La Découverte, « TAP/Histoire des sciences », 2002, p. 36-79. URL : https://www.cairn-int.info/inventer-la-biomedecine–9782707136077-page-36.htm
  2. John Paul Rogers. A History of Penicillin: The Miracle of Medicine [Une Histoire de la pénicilline: le miracle de la médecine]. Kansas State University. Dept. of History

https://krex.k-state.edu/dspace/handle/2097/38147

  1. La chance et la science de Sir Alexander Fleming, L’Histoire, Mensuel 92, septembre 1986.

https://www.lhistoire.fr/la-chance-et-la-science-de-sir-alexander-fleming

  1. Nitti, le chercheur resistant, fr

https://www.pasteur.fr/en/node/9050

  1. Marcella Alsan, Marianne Wanamaker. TUSKEGEE AND THE HEALTH OF BLACK MENThe quarterly journal of economics 133,1 (2018): 407-455. doi:10.1093/qje/qjx029

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258045/

  1. John Paul Rogers. A History of Penicillin: The Miracle of Medicine [Une Histoire de la pénicilline: le miracle de la médecine]. Kansas State University. Dept. of History

https://krex.k-state.edu/dspace/handle/2097/38147

  1. La chance et la science de Sir Alexander Fleming, L’Histoire, Mensuel 92, septembre 1986.

https://www.lhistoire.fr/la-chance-et-la-science-de-sir-alexander-fleming

  1. Nitti, le chercheur resistant, fr

https://www.pasteur.fr/en/node/9050