Penicillin: More than a Moldy Petri Dish

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Speaker 1: Welcome to Stuff you Missed in History Class, a production of I Heart Radio. Hello, and welcome to the podcast. I'm Tracy V. Wilson and I'm Holly Fry. Holly, when you were a kid that you learned the story of penicillin, I feel like I didn't get it until later. Okay, do you remember what you learned? Um? You know, accidental grew on mold because there was a rumor at our school that you could make your own antibiotics in your bedroom. Well, we'll talk about something similar to that, and you better believe my crafty little brain was like, could I could I start a little apothec area out of my classes? Uh? Maybe? Um so, I, like a lot of people learned this very basic story about Alexander Fleming leaving a Petri dish out and a getting taminated with mold, and then it's just sort of presented as voila penicillin. He did it all by himself. That is not remotely accurate. Like the Petri dish and mold part, that part kind of accurate, at least we'll talk more about it. But like it was not suddenly he had invented penicillin by himself at all. Uh, so that's one of the things we're going to talk about in today's episode. Also, though, this was just inspired by an email from listener Abbey, which we actually read on the show recently, and Abby mentioned that after World War Two there was a penicillin recycling project and I was like, I need to know more about this, uh, And I didn't talk about it a lot in that listener mail segment because it is gross. So just as a heads up, there is a lot of mold in this episode and if a Phray is like mold Broth bothers you, maybe this is not the episode for you. That's your punk band, mold Broth were also just there's a lot of bodily fluids. There's also some animal testing, just you know, I know people can be squeamish about particular things. Just a heads up on all of that. So, like we just said, the development of penicillin started but definitely did not end, with the chance discovery of some mold in a petri dish. We're going to get back to that. But the discovery of a seemingly miraculous treatment made from mold piqued the interest of medical historians who started looking for earlier uses of mold as a treatment for wounds or diseases, and it turned out there were actually a lot of them. Yeah, the people who had been using these obviously already knew about them, but there had not really been a systemic historical look at it. Uh. The vast majority of the treatments involved using mold to make a topical preparation for wounds. So this included using moldy soybeans and China, and moldy bread in Egypt, and cheese mold in Greece, with all of those dating back roughly three thousand years or more. Aboriginal and indigenous peoples all around the world have used molds medicinally as well. There's also some evidence that more than two thousand years ago, people in northern Africa consumed something that contained enough tetracycline to leave evidence of that on their bones. Tetracycline actually comes from bacteria, not from mold, but the bacteria and question form these branching filaments that look enough like a fungus that it was classified as a fungus for a really long time. In more recent times, herbalists and apothecaries in Europe described medicinal mold preparations all through the seventeen and eighteen centuries, and researchers looking into the historical use of mold in the twentieth century found that a lot of full remedies using mold were still around. One biochemist described traveling through Europe and finding that each home had a moldy loaf of bread stored in the kitchen rafters, which would be used to prepare dressings for cuts or other wounds. Other oral accounts described people intentionally growing mold on oranges or other fruit or substances, or collecting it from meat as it was being cured. We don't really have a lot of detail about how effective these treatments actually were. There weren't clinical studies or things like that to reference. But there are so many different medicinal uses for molds to treat infections in so many different parts of the world that some medical historians have concluded that at least some of them probably did have some real antimicrobial efficacy. Some of the folks that were interviewed about their folk remedies after penicillin was developed and they learned that penicillin was made out of mold, they were kind of like Oh yeah, we've been doing that forever, and by the time Fleming spotted that contaminated culture plate, it was already established that various bacteria, molds, and other organisms could inhibit one another's growth. The term antibiosis was coined by the end of the nineteenth century to describe this antagonistic effect that micro organisms could have on one another, and there may have even been some work with penicillium mold specifically before Fleming made his discovery. Joseph Lister may have successfully treated a patient with a filtrait made from Penicillium glaucum as early as eighteen seventy seven. Around the same time, there were other doctors and scientists experimenting with whether penicillium mold killed other micro organisms in a lab. None of this is totally certain, though, the taxonomy for molds and other fungi was not very robust yet, and the people who were doing this work were not experts in mycology. It's possible that they were working with totally different molds that they were just calling penicillium, and then aside from that, none of them published a thorough description of their work, So a lot of this conclusion is based on notes which we're not necessarily complete. You cannot replicate an experiment to test it if you don't really know what went down right. The early twentieth century saw the development of the first drugs that killed specific bacteria. In the eighteen seventies, German physician Paul Erlick had noticed that chemical dies changed the color of some bacteria and not others. This was a precursor to the Graham staining method that is still used today to broadly classify bacteria as gram positive and gram negative based on how they respond to the stain. Erlick started to wonder if it was also possible well to discover a substance that killed some bacteria but not others. In nine researchers in Erlick's lab discovered that the arsenic compound arsphenamine killed the bacteria that caused syphilis. This drug was marketed as salver sand, and it was also known as six oh six because it was the six hundred and sixth preparation that had been tested in Erle's lab. As part of this project. Salver sand was found to be effective against other infectious diseases as well. This was really the first effective treatment for syphilis and the first modern antimicrobial compound. Erlick described this use of a chemical to kill cells in the body using the word chemotherapy, and he coined the term magic bullet to describe the drug's ability to target pathogens. Erly's lab had been systematically testing one arsenic compound after another when it developed salversen. On the other hand, Alexander Fleming's discovery of pennas sill in a little less than twenty years later, was an accident. He was interested in the anti microbial properties of the body's own fluids and secretions. He coined the term licensign to describe a substance in things like mucus, tears, and saliva that seemed to inhibit bacterial growth. He reportedly made this discovery when he had a cold. He cultured his own mucus in a petri dish and then later discovered that the area around the mucus wasn't growing bacteria. In some versions of this story, his office was perpetually untidy, and this petrie dish had sat there forgotten in some clutter for a couple of weeks before he made the discovery. His discovery of penicillin had some similarities. This time, he was studying staff bacteria, and all of his petri dishes were supposed to be in an incubator when he left for a two week vacation in nineteen eight. One of them, though, was apparently left on a lab bench by accident. When he got back to the office on September three, he noticed the misplaced Petrie dish that had been contaminated with mold, and the area around the mold, he saw colonies of staff bacteria that we're dying. We don't know exactly where the mold contamination came from. One possibility is an open window, and another is a mycology lab that was in the same building. And this discovery was only possible because the petrie dish was left out on a bench. If it had gone into the incubator like it was supposed to, the staff bacteria would have flourished, but the temperature would have been wrong for the mold to grow. Beyond this, other details are really hazy. Fleming did not take careful notes about exactly what he was looking at when either he or one of his assistants spotted this petrie dish. His later descriptions about exactly how the mold and the bacteria were interacting with one another could be contradictory. When he published his discovery and the British Journal of Experimental Pathology in June of nine, he made it sound as though he routinely left his staff culture on plates on the bench for extended periods, rather than that often repeated story that this was one that was forgotten while he was on vacation. He also described the mold as most resembling Penicillium rubrum, and other researchers later corrected that identification to penicillium notatam. That June paper describes various experiments Fleming and his colleagues did with a filtrate made from the broth the mold was growing in. He coined the term penicillin to describe this fil trait because writing quote mold broth filtrate over and over was apparently cumbersome. He did some basic toxicity tests and small mammals by injecting them with this fil trait, and it did not seem to be toxic. But he doesn't seem to have tried injecting animals with one of the bacteria that he knew penicillin killed in a petri dish to see if that worked in a living body as well. He did test penicillin's activity against various microbes in a petri dish, including Staphylococcus, streptococcus, and new Macoccus, as well as what was described at the time as Basillus influenza and Basillus diph theory a penicillin was particularly effective against all the pyogenic cocai, so the ones that ended with caucus in that list, but it wasn't as effective against the bassilla. So if he had a petri dish that was growing both staff bacteria and Bacillus influenza, he could use penicillin to kill only the staff, leaving that Basillus culture in place. Side note. Today Basillus influenza is known as Hemophilis influenze. It got the influenze moniker when people thought that it caused influenza, which it does not. Influenza is caused by a riss. Just to keep things a little confusing for everybody. That was one of the things about reading this paper was then needing to go and look like, what did they call that? Now? I don't think that's what they call that now. Fleming didn't really have the skills or expertise to try to extract this fil trait into a usable medicine. His research students Stuart Craddock and Frederick Ridley both worked on this, and both of them were credited at the end of the published paper. Fleming also sent samples of the mold to anyone who asked for it, but he didn't really make any headway into turning penicillin into a medicine, and he stopped working with it in ninety one. We'll talk about how it did become a medicine after a sponsor break. When Alexander Fleming was working with penicillin at the end of the nineteen twenties, he was mostly approaching it as something would have uses in a laboratory, such as using it to isolate different cultures from one another depending on whether they were sensitive to penicillin. One of his students, Cecil George Payne, does seem to have successfully used penicillin to cure eye infections in newborns in nineteen thirty, as well as to treat a minor who had an infected scratch on his cornea, but Pain did not publish anything about this success, and he also does not seem to have realized until much later that he had been looking at something that could have revolutionized medicine. Meanwhile, in nineteen thirty two, German bacteriologist Gerhard Domac was studying a red dye that hadn't been in effective antibacterial in a petri dish, but turned out to treat strip infections in mice and staff infections in rabbits. This die was developed into the drug Protonsal, the first sulfa drug and the first drug used to treat and prevent a ray inache of bacterial infections in humans. Unlike Salversen, which was primarily used to treat civilist Protonsal could treat a variety of grand positive bacteria. Do Mac was awarded the Nobel Prize and Physiology or Medicine for this work in nineteen thirty nine, but the Nazi Party had forbidden Germans to accept the Nobel Prize. This was because the Nobel Peace Prize had previously been awarded to German pacifist Carl von Ostiski in nineteen thirty five. Do Mac accepted the prize anyway. Afterward, he was arrested by the Gestapo and forced to write to the Nobel Committee rejecting the prize. He wasn't able to get his medal for having won the Nobel Prize until after the end of World War Two, and he never actually got the monetary award. As a side note, we mentioned Paul Erlick earlier in the episode. The street in Frankfurt where his institute was located was named after him, but it was renamed to the Nazis came to power because he was Jewish. Erlake was no longer living at this point. He had died after a stroke in nineteen fifteen. So the same year that Domac was awarded the Nobel Prize for developing the first sulfa drug, researchers at the Sir William Dunn School of Pathology at Oxford University started studying penicillin. There had been a Department of Pathology at Oxford for decades, but this school was almost brand new. It had opened in nineteen thirty five after the university received funds from the estate of the late Sir William Dunn, which is what funded the new school. Australian pathologist Howard Walter Florey had been appointed Professor of Pathology and the research team he recruited included Ernst Chaine, who was a Jewish biochemist who had fled to the UK from Germany after the Nazi Party came to power. Floory, Chain and others at Oxford had been inspired by Domac's success with sulfa drugs, and in eight they started studying the enzyme lyssyme, which Alexander Fleming had discovered. Chain also found Fleming's earlier paper on the anti microbial effects of penicillium mold, and Oxford already had a sample of Fleming's mold on hand. The team started working with it in nine. Fleming and his team at St Mary's had been mostly working with small amounts of mold and a petri dish. Florian Chain, on the other hand, we're trying to extract enough of the active substance to test whether it could be used as a medicine. Even though they were going to start with mice, which are very small, this required a lot of mold, so much more mold than Fleming had been working with. Hospital bed pants turned out to be just about the right size and shape to grow this mold in, but most of the ones on hand were needed by hospital patients, so the team at Oxford started repurposing what her vessels they could scrounge up, jars and food tens, milk churns, fuel cans, all kinds of things. I love that it's a little hodgepodgy. It's very hodgepodgy. It was also really a team effort. Over the course of the project, six women were paid two pounds a week to tend to the fermenting mold. They were Ruth Callo, Claire Eniot, Betty Cook, Peggy Gardner, Megan Lancaster and Patricia mckegney, and they were nicknamed the Penicillin Girls. Norman Heatley developed a method to extract penicillin from the mold broth into amyl acetate and then back into water. Edward Abraham developed techniques to purify it, and on May nine, almost exactly ten years after the British Journal of Experimental Pathology received Fleming's paper on penicillin, they conducted an experiment involving eight mice. All eight of the mice were injected with Streptococcus bacteria. Then four of the mice were injected with penicillin and the other four were left untreated. The four untreated mice died but the other four who got penicillin all survived. Other tests on animals followed, including studies on rats and cats. They tested penicillin's efficacy against multiple bacteria. In addition to strep and staff, there was Claustridium septicum, which can cause gas gang green, and penicillin was dramatically effective against all of them with little to no toxicity to their test subjects. In August of nineteen forty, Chain, Floury, Heatley, and others published Penicillin as a Chemotherapeutic Agent in the journal The Lancet, detailing the basic findings of their research. It was clear from this work that penicillin could potentially be a life saving drug for human beings, and at this point, aside from the medicines we have talked about in this episode, there just weren't many effective options to treat bacterial infections. That meant that minor illnesses like strep throat could lead to much more serious problems like rheumatic fever. Life threatening infections could develop an injuries that had seemed really superficial. People like Ignace cell Vice and Joseph Lister had advocated for things like hand washing and sterile surgical techniques to cut down on the likelihood that a person would contract an infection during childbirth or surgery, but infections could still happen, and often there just was not much that could be done about it SELFA drugs had been a huge step forward in providing broadly effective treatments for bacterial infections, but a lot of people were allergic to them, and most of them could also cause a range of unpleasant side effects. So figuring out whether penicillin could be a usable drug in people and not just small mammals was a huge priority. And since people are significantly bigger than mice, that meant that the team needed to grow a lot more mold. But at this point the UK was a war Germany had invaded Poland on September one, nine and both the UK and France had declared war on Germany two days later. That meant that a lot of equipment and materials were now dedicated to the war effort. For the sake of time and expense, Norman Heatley designed a flat, rectangular pottery vessel with a spout that was stackable and glazed on the inside to make it watertight. The team eventually used seven hundred of these vessels to produce about five hundred liters of mold broth every week, but this was a slow and cumbersome, kind of fiddly process. Even with all seven hundred vessels in use, it took about four weeks to make enough penicillin to treat one human patient, and it took once for all seven hundred of those vessels to be ready. At the end of nineteen forty, only about ninety of them were all set and had been seated with mold spores. The first attempt to treat a person with penicillin made from all of this mold started on February twelve, ninety one. That patient was Albert Alexander, and there are multiple conflicting descriptions of how he became injured. In some accounts, he cut himself shaving, In others, he scratched himself while pruning roses, and still others he was injured in a bombing during the Blitz. But regardless of the cause, it is documented that he had a very serious infection that was certain to be fatal if left untreated. Alexander showed promising signs of recovery within twenty four hours of being treated with penicillin, but because so little penicillin had been made at this point, they had to collect his urine and extract the pen sillin out of it and then reuse it. So the body excretes penicillin really rapidly, and roughly seventy percent of it comes out in the urine unchanged, it could be more or less than that. I saw numbers that were literally from one percent to It's possible to recover half or more of that excreted penicillin using the same basic method that was used to extract it from the mold broth in the first place. Even with the penicillin that had been reclaimed from his urine, there wasn't enough to totally cure Alexander's infection. Eventually, the team had given him all of the penicillin they had, and after they ran out, his infection returned and he died on March fift So it's clear that making enough penicillin to do a clinical trial it was going to be a huge challenge. With all this effort, they had not made enough to successfully treat even one patient, Although folk sing on treating children would have allowed the team to use smaller doses. At this point, the priority was really confirming the penicillin worked in adults, and then if it did, supplying Allied troops with it. Infections were a major major cause of death for wounded soldiers, and effective treatments for bacterial illnesses could also allow six soldiers to return to duty faster, but the prospects for doing that in the UK were grim. Although there were British companies that were interested in working with penicillin, most were dedicated to critical wartime work involving drugs and other chemicals that were already known to have a use. Plus British factories were at risk of being bombed or otherwise attacked. Floor and his team also understood that if Britain were invaded, they might need to destroy their research work to prevent it from being captured by the Germans. But they were also really unwilling to risk loseing their penicillium mold entirely. Norman Heatley suggested that several of them intentionally rub mold into their coats so that if they had to flee, they could just wear their samples with them undetected. Why does everybody a miss on this transport? Smell weird? Smells well, Musty in one, Floor and Heatley went to the United States to try to find pharmaceutical companies that could help. Work in the UK didn't stop at this point or in other countries that had started experimenting with penicillium, but the focus on mass producing penicillin shifted to the US, and we'll talk more about that. After a sponsor break in June of one, Howard Florey and Norman Heatley took a series of flights to get from the UK to US. These flights were paid for by the Rockefeller Foundation, which had also done some of the funding for their research. When they left, they had treated a total of six patients with penicillin. In addition to Albert Alexander. One other patient had died, but that patient died of a ruptured aneurysm, not of the infection that the penicillin was treating. There was just not enough penicillin to treat more people than that. As Floor and Heatley were preparing to go, the Oxford team was preparing and freeze drying as much penicillin as possible for them to take with them. Floor was also finishing a second paper titled Further Observations on Penicillin, which went on to be published that August. There had been a lot of debate about whether to publish this paper. On the one hand, it contained a lot of information that could save people's lives, but on the other hand, there were scerns about Germany or its allies producing penicillin, which could provide them with an advantage in the war, and that paper would give them a lot more information to do it. There were similar debates among the Oxford team about whether to patent penicillin. A lot of them found the idea of patenting any medicine to be just appalling, while Ernst Shane argued that penicillin was their work and it deserves to be protected. Chane also thought that their ongoing struggles to get enough funding for their work would be totally resolved if it could just be paid for through licensing fees from a patent. Chane was also deeply disappointed by not being part of this trip to the United States, and this is something that seems to have caused a huge rift between him and Floor since the whole purpose of this trip was to try to get manufacturing started, and Heatley was the person who had been focused on manufacturing like it makes sense that Heatley would be the person ago. They also wanted to minimize the number of people going for the sake of secrecy. This decision made sense, but Chain seems to have been incredibly upset by it. The US had passed the Lend Lease Act in March of ninety one, which established a framework for the United States to provide the allies with things like weapons, vehicles, materials, machinery, and facilities that would promote the defense of the United States. The manufacturer of penicillin seemed to fall under that definition, but Floury and Heatley still had to find a pharmaceutical company that had the interest and the ability to try to produce penicillin on a commercial scale. They had a series of meetings and disappointments and kind of stops and starts, and then Floury and Heatley wound up at the Department of Agriculture's Northern Regional Research Laboratory or n r r L and Peoria, Illinois, which already had a fermentation division, which was very handy since they grew penicillin by fromenting. Researchers there started working on finding ways to grow penicillium mold. A lot faster than it had been. They started on that work in July. This was a multi step process. At Oxford, researchers had been growing the mold in a broth in flat, rectangular pottery vessels. In Illinois, researchers figured out that growing it in corn steep liquor yielded about ten times more penicillin. This was convenient because corn steep liquor is a byproduct of the wet milling process and people were already trying to find a practical use for it. Those vessels and Oxford were also rectangular and flat, because the mold was essentially growing as a flat surface layer, and researchers in Peoria thought it would be more efficient to grow the mold in a submerged medium, but this also required they're finding a different strain of penicillium mold that would grow really well while submerged and also produced the antimicrobial substance that they need, because not all of the penicillium strains really did that very well. This involved gathering mold from all over the world, which they did with the help of the Army Transportation Corps, and they tested all these samples in the lab. They Eventually, though, found a sample growing on a moldy cantelope that worked really well. This find is usually credited to lab assistant Mary kay Hunt, who was nicknamed Moldy Mary. She had found this cantelope not in some far reaching place brought back by the Army Transportation Corp, but at a local Peoria fruit market. The strain of the mold, Penicillium chrysogenum, was about a hundred times more productive than the other strains they tried. Even as the research lab figured out ways to increase the yield of penicillium mold, they still needed pharmaceutical or chemical manufact ers to actually get a penicillin drug into production. A group of pharmaceutical companies and the federal government met in October of to coordinate both the production process and information sharing. The goal was to first produce enough penicillin for clinical trials, and then, if those were successful, to scale up production to make as much as could be needed for Allied troops. This was a huge and really unprecedented level of cooperation that was also gonna be really tricky. John L. Smith from Fieser had this to say about it, quote, the mold is as temperamental as an opera singer. The yields are low, the isolation is difficult, the extraction is murder, the purification invites disaster, and the essay is unsatisfactory. So the Office of Science, Research and Development helped coordinate information sharing about methods and techniques to do this successfully. Along with managing fifty seven different research contracts related to it, The War Production Board also worked with twenty five different companies to scale up production of penicillin. They narrowed it down to those twenty five after investigating more than a hundred seventy five different companies to determine whether they were suitable or not. The first patient in the US to be treated with penicillin was thirty three year old and Miller, who had developed septicemia after a pregnancy loss. Her treatment started on March fourteenth, ninety two, and it required half the penicillin that was in existence in the US at that point. Also in nineteen forty two, back in the UK, Alexander Fleming got some penicillin from the Oxford Group, which was still at work, used that to treat one of his patients, and when that treatment was successful, he got a huge right up about it in the times. This article didn't actually mention Floory or any of the other researchers at the Oxford team, though, and this really started to build the perception that penicillin was solely Fleming's work. Fleming also seemed willing to take that credit, and Flory didn't want to talk to the press and also didn't want the rest of the Oxford team to talk to the press, just really starting the ball rolling on this being just Alexander Fleming's own work and nobody else's. The fact that all of this was happening during World War Two came along with a number of ethical dilemmas. One that we referenced earlier was how careful researchers should be about making sure information about penicillin and penicillin production wasn't available to Germany or its allies. Doctors and medical ethicists generally agreed that if a patient needed penicillin and the penicillin was available, they could have it, regardless of their nationality or what army they fought for. But since access to penicillin could also create a military advantage, people also believe that information about how to make it or samples of the mold itself should not be shared, not with Germany, and not with any countries likely to cooperate with Germany. There are a lot of articles discussing whether, in fact somebody in Germany did or did not receive one of Fleming's samples way earlier in this whole story, before the hostilities started. Within the US, another ethical issue was access to penicillin, because once clinical trials were complete, the penicillian being produced was going to be reserved almost exclusively for military use. At the same time, they were definitely going to be civilians whose lives would be lost without it. Dr Chester Kiefer was responsible for rationing penicillin to civilians and was absolutely inundated with requests for it. This led some people to figure out ways to make their own penicillin. For example, on November tenth three, Julius A. Vogel, who was the plants physician at a steel plant in Pennsylvania, figured out how to make penicillin in his kitchen see my plan as a kid was not completely because I had the knowledge of a plant position. Vogel based his work on an earlier discovery by George Robinson and James Wallace at Singer Laboratory at Allegheny General Hospital in Pittsburgh, Pennsylvania. On October eighth, n they reported that they had found a way to make a topical treatment by soaking a gauze pad and penicillium mold and then letting it grow in a petri dish for four or five days. Vogel, who had been disabled following a serious infection in his knee as a child, built on this to turn his kitchen into a miniature factory for treating similarly mold and few used gauze. Vogel's wife, Unice, was a big part of this process, making the auger for the petri dishes and sterilizing the equipment between batches. As you can imagine, all of this required a lot of careful planning to keep a steady supply of mold that was the right age to produce penicillin. Yeah, Vogel talked a lot about how if penicillin had existed when he was a child, he probably would not have almost died and then had like a disability that affected him for the rest of his life. Vogel presented his development at the Department of Industrial Research on November eleven, and he got a lot of criticism from the research community and from the companies that were working on mass producing penicillin. There were some understandable concerns about the potential for penicillin made at home to be contaminated in some way, but Vogel reportedly used these gauze pads that steel mills all over the area, treating workers who had on the job accidents and otherwise would have just not had access to any antibiotics at all. Yet another ethical conundrum arose after Floory and Chain traveled to Northern Africa in ninety three to test penicillin on wounded soldiers and realized that it was also effective against gonaihea. Before this point, penicillin had been envisioned as something that would save the lives of soldiers who had been seriously entered in battle or had contracted a serious illness like bacterial pneumonia, but gonahea, especially in its early stages, is more of a nuisance. Winston Churchill reportedly said that penicillin should be used for the quote best military advantage, which meant when supplies were limited, getting soldiers who had gonaha back into peak condition, rather than treating seriously injured soldiers who were going to be sent back home. I supplies were not limited for that much longer, though. Fiser's first plant for the commercial production of penicillin opened in Brooklyn, New York, on March first, nineteen. By that point, clinical trials had showed that penicillin was clearly beneficial against a range of pathogenic bacteria. Refinements to the production process and to the mold itself using things like X rays and UV light continued to increase the yield. Meanwhile, Alexander Fleming, who wasn't involved with any of this, was on the cover of Time magazine on May fifteenth. By this point, pharmaceutical companies in the U s we're trying to produce enough penicillin to meet the needs of the D Day invasion. Propaganda posters were hung on the walls of penicillin factories reminding workers that they were doing it for the troops, and production of penicillin in the US expanded rapidly. Twenty one billion units of the drug had been made in nineteen forty three, and in nineteen forty five it had jumped to six point eight trillion. In March of nineteen forty five, the US was able to lift rationing restrictions on penicillin and make it commercially available to the public. After the liberation of Paris in nineteen forty four, American military hospitals throughout France started trying to extend the supply of penicillin in the country, which is what inspired this episode. The French military Penicillin Team was established, and starting in January of nineteen forty five, the team collected urine from patients to reclaim the penicillin in it. So if a patient was being treated with penicillin, their bed was barked with a placard to note that their urine should be collected. Patients who are well enough to get up and go to the bathroom themselves were instructed to urinate in flasks that were just left around the wards for that purpose. Officials were understandably a little concerned that these flasks that people were peeing into could themselves become a source of infection, so the penicillin team collected them all twice a day. After the war, manufacturing methods for penicillin that had been developed in the US were introduced in the UK, which meant that the same researchers who had originally developed the drug had to pay licensing fees to access American methods to produce it. Although penicillin itself had not been patented, some of the manufacturing methods had been new. Penicillin factories were also established around the world as nations started making their own supply or expanded production from research that they had been doing is the war was going on. Alexander Fleming, Earnsports Chain, and Howard Walter Floory were jointly awarded the Nobel Prize in Physiology or Medicine in that same year. The chemical structure of penicillin was confirmed by Dorothy Crowfort Hodgkin, and that paved the way for synthetic forms of penicillin. Penicillin's effect on medicine was massive, and many other antibiotics followed. Stripped a mic in, which was the first truly effective treatment for tuberculosis, was developed in nineteen three. We have covered that and the controversy around who should be credited with discovering it on the podcast in This is an enormous advance in medicine, but by the nineteen fifties, some bacteria were already becoming resistant to penicillin, including some strains of staff bacteria and This was something that Fleming had foreseen, and he warned about it in his Nobel Prize address, quote, it is not difficult to make microbes resistant to penicillin in the laboratory by exposing them to concentrations not sufficient to kill them, and the same thing has occasionally happened in the body. The time may come when penicilla and can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non lethal quantities of the drug, make them resistant. This is obviously still a problem. You have probably heard about it in your day to day life at some point, and it's compounded by the fact that most antibiotics in use today were developed between the nineteen forties and the nineteen sixties, along with the widespread use of antibiotics in agriculture. In the World Health Organization warned that the world is nearing the point of a post antibiotic era and currently describes antibiotic resistance as one of the biggest threats to global health, food security, and development. Yeah the use of penicillin after and other antibiotics after the discovery and sort of the Golden Age of antibiotics could be a whole other episode. We're living through it. You have listener mail for us I do. I have listener mail from Susan, and Susan says, hello, I just finished listening to your episode on hypertension. I enjoy your podcasts, and I wanted to say thank you for that episode. Like Tracy, I have to monitor my BP at home and so appreciated a detailed history of the condition. I did not realize that dogs could be affected by hypertension until one of my dogs was diagnosed with a heart murmur. When he went in for his e k G, his BP was to ten. The vet said their readings should be like ours, when twenty is normal. My sweet Baron has been on medication since then and it has worked wonders. My other dog, Ramona, recently had to have hers checked. Hers was one fourteen, so she's good. I've always appreciated the work that vets and vet texts do, but I can't imagine what it takes to read blood pressure on a dog. I've attached pictures of the baby's Ramona is pictured with cuttles the resident boss Lady. I was fortunate enough to travel to Europe the summer. Having listened to your episode on Margaret Cavendish, I made sure to see your tomb at Westminster Abbey picture attached. My day job is middle school science teacher, but I'm a history buff and very much enjoy listening to your podcast. Thank you for all you do season. Thank you so much for this email. Season. One of the things that crossed my mind in the many, many, many minutes that I have spent taking my own blood pressure at home is could my cats have high blood pressure? How would we even find that out? I'm just gonna say probably the answer is yes, if it can also occur in dogs. Thank you so much for the email and the dog pictures and the picture of Margaret Cavendish's tomb. I don't remember if I looked up pictures of that when I was researching that episode, but it was more ornate than I had it in my head. So thank you for all of that. If you would like to send us a note about the sereny other podcast or history podcast that I heart radio dot com. IM in all over social media and missed in history. That's where you'll find our Facebook, Twitter, Pinterest, and Instagram and you can subscribe to our show, um I heart Radio app, or wherever else you'd like to get your podcasts. Stuff you Missed in History Class is a production of I heart Radio. 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