SYMHC Classics: Penicillin

This 2022 episode covers the development of penicillin, which started – but definitely did not end – with the chance discovery of some mold in a petri dish. See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Speaker 00

  This is an iHeart Podcast. Guaranteed Human.

• 0:04Speaker 01

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• 0:33Tracy V. Wilson?

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• 1:16Tracy V. Wilson?

  Robert, Mick, Bill and Jessa strut back down memory lane for season two, sharing lessons on life, love and loss. These are the kind of insights that only come from experience. So tune in to Silver Linings with The Old Gays on the iHeart Radio app, Apple Podcasts, or wherever you get your podcasts. Workplace chaos, we've all been there. Deadlines are slipping, projects are piling up, and suddenly you realize the missing piece is the right person. That's when you say, this is a job for sponsored jobs. With Indeed Sponsored Jobs, your job post gets a boost so you can connect with quality candidates faster. In fact, sponsored jobs posted directly on Indeed are 95% more likely to report a hire than non-sponsored jobs.

• 1:59Tracy V. Wilson?

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• 2:15Tracy V. Wilson?

  Happy Saturday. After this week's episodes on Dorothy Crowfoot Hodgkin, including her work determining the structure of penicillin, today's Saturday classic is on the discovery of penicillin.

• 2:26Holly Frey?

  This episode originally came out on September 5th, 2022. Enjoy.

• 2:34Holly Frey?

  Welcome to Stuff You Missed in History Class, a production of iHeartRadio.

• 2:45Tracy V. Wilson?

  Hello and welcome to the podcast. I'm Tracy V. Wilson.

• 2:48Holly Frey?

  And I'm Holly Frey.

• 2:50Tracy V. Wilson?

  Holly, when you were a kid, did you learn the story of penicillin?

• 2:56Holly Frey?

  I feel like I didn't get it until later.

• 2:59Tracy V. Wilson?

  Okay. Do you remember what you learned?

• 3:02Holly Frey?

  You know, accidental grew on mold because there was a rumor at our school that you could make your own antibiotics in your bedroom.

• 3:10Tracy V. Wilson?

  Well, we'll talk about something similar to that.

• 3:15Holly Frey?

  And you better believe my crafty little brain was like, could I? Could I start a little apothecary out of my closet?

• 3:24Tracy V. Wilson?

  Maybe. So I, like a lot of people, learned this very basic story about Alexander Fleming leaving a Petri dish out and it getting contaminated 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. 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 Abby, which we actually read on the show recently.

• 4:09Tracy V. Wilson?

  And Abby mentioned that after World War II, there was a penicillin recycling project. And I was like, I need to know more about this.

• 4:20Holly Frey?

  Yes.

• 4:22Tracy V. Wilson?

  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 phrase like mold broth bothers you, maybe this is not the episode. For you.

• 4:39Holly Frey?

  That's your punk band, Mold Broth.

• 4:41Tracy V. Wilson?

  Yeah, Mold Broth. We're 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.

• 4:56Holly Frey?

  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.

• 5:22Tracy V. Wilson?

  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. The vast majority of these treatments involved using mold to make a topical preparation for wounds. So this included using moldy soybeans in China and moldy bread in Egypt and cheese mold in Greece, with all of those dating back roughly 3,000 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 2,000 years ago, people in northern Africa consumed something

• 6:05Tracy V. Wilson?

  that contained enough tetracycline to leave evidence of that on their bones. Tetracycline actually comes from bacteria, not from mold, but the bacteria in question form these branching filaments that look enough like a fungus that it was classified as a fungus for a really long time.

• 6:24Holly Frey?

  In more recent times, herbalists and apothecaries in Europe described medicinal mold preparations all through the 17th and 18th centuries. And researchers looking into the historical use of mold in the 20th century, found that a lot of folk 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.

• 7:04Tracy V. Wilson?

  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."

• 7:40Holly Frey?

  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 19th century to describe this antagonistic effect that microorganisms could have on one another.

• 8:02Tracy V. Wilson?

  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 filtrate made from penicillium glaucom as early as 1877. Around the same time, there were other doctors and scientists experimenting with whether penicillium mold killed other microorganisms 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

• 8:43Tracy V. Wilson?

  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 were not necessarily complete.

• 8:57Holly Frey?

  You cannot replicate and experiment to test it if you don't really know what went down.

• 9:02Tracy V. Wilson?

  Right.

• 9:04Holly Frey?

  The early 20th century saw the development of the first drugs that killed specific bacteria. In the 1870s, German physician Paul Ehrlich had noticed that chemical dyes changed the color of some bacteria and not others. This was a precursor to the Gram 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. Ehrlich started to wonder if it was also possible to discover a substance that killed some bacteria, but not others.

• 9:38Tracy V. Wilson?

  In 1909, researchers in Ehrlich's lab discovered that the arsenic compound arsenamine killed the bacteria that caused syphilis. This drug was marketed as Salversan, and it was also known as 606 because it was the 606th preparation that had been tested in Ehrlich's lab as part of this project. Salversan 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. Ehrlich 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.

• 10:23Holly Frey?

  Ehrlich's lab had been systematically testing one arsenic compound after another when it developed Salversan. On the other hand, Alexander Fleming's discovery of penicillin a little less than 20 years later was an accident. He was interested in the antimicrobial properties of the body's own fluids and secretions. He coined the term lysosome 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 Petri dish

• 11:08Holly Frey?

  had sat there forgotten in some clutter for a couple of weeks before he made the discovery.

• 11:14Tracy V. Wilson?

  His discovery of penicillin had some similarities. This time, he was studying staph bacteria. And all of his petri dishes were supposed to be in an incubator when he left for a two-week vacation in 1928. One of them, though, was apparently left on a lab bench by accident. When he got back to the office on September 3rd, he noticed the misplaced petri dish that had been contaminated with mold, and the area around the mold, he saw colonies of staph bacteria that were dying.

• 11:48Holly Frey?

  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 petri dish was left out on a bench. If it had gone into the incubator like it was supposed to, the staph bacteria would have flourished, but the temperature would have been wrong for the mold to grow.

• 12:13Tracy V. Wilson?

  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 petri 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 in the British Journal of Experimental Pathology in June of 1929, he made it sound as though he routinely left his staph 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

• 12:58Tracy V. Wilson?

  later corrected that identification to "Penicillium notatum."

• 13:03Holly Frey?

  That June 1929 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 filtrate because writing "mold broth filtrate" over and over was apparently cumbersome. He did some basic toxicity tests in small mammals by injecting them with this filtrate, 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.

• 13:39Tracy V. Wilson?

  He did test penicillin's activity against various microbes in a Petri dish, including Staphylococcus, Streptococcus, and Pneumococcus, as well as what was described at the time as Bacillus influenzae and Bacillus diphtheriae. Penicillin was particularly effective against all the pyogenic cocki, so the ones that ended with caucus in that list. But it wasn't as effective against the bacilli. So if he had a Petri dish that was growing both staph bacteria and Bacillus influenzae, he could use penicillin to kill only the staph, leaving that bacillus culture in place. Side note, today bacillus influenzae is known as Haemophilus influenzae.

• 14:24Tracy V. Wilson?

  It got the influenza moniker when people thought that it caused influenza, which it does not. Influenza is caused by a virus.

• 14:34Holly Frey?

  Just to keep things a little confusing for everybody.

• 14:37Tracy V. Wilson?

  That was one of the things about reading this paper was then needing to go and look like, what do they call that now? I don't think that's what they call that now.

• 14:45Holly Frey?

  Fleming didn't really have the skills or expertise to try to extract this filtrate 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 1931.

• 15:13Tracy V. Wilson?

  We'll talk about how it did become a medicine after a sponsor break.

• 15:20Speaker 04

  First thought is like, wow, how are we going to do all this?

• 15:23Tracy V. Wilson?

  Hey, everybody, it's Tracy from Stuff You Missed in History Class. That's Alan Goya, a planning engineer at AT&T. He's talking about Intuit Dome, home of the Los Angeles Clippers, where every seat, screen, phone, and transaction is connected with AT&T fiber and 5G, defining the fan's experience. And Alan's master plan made it all possible.

• 15:43Speaker 04

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• 15:51Tracy V. Wilson?

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• 15:57Speaker 05

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• 16:03Tracy V. Wilson?

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• 16:07Speaker 05

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• 16:14Tracy V. Wilson?

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• 17:27Speaker 06

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• 17:53Speaker 06

  We're talking new buffalo sauce, honey mustard, sweet and sour, and even a whole new option too, the new special savory sauce, which is only available for a limited time at participating US restaurants. I mean, you need to taste it all for yourself. This new chicken nugget, reinvented based on real feedback, is made with 100% white meat chicken and is now better than ever. You gotta try the new Burger King chicken nuggets and sauces today.

• 18:21Tracy V. Wilson?

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• 19:05Tracy V. Wilson?

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• 19:39Tracy V. Wilson?

  When Alexander Fleming was working with penicillin at the end of the 1920s, he was mostly approaching it as something that 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 1930.

• 20:05Tracy V. Wilson?

  As well as to treat a minor who had an infected scratch on his cornea. But Payne 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.

• 20:22Holly Frey?

  Meanwhile, in 1932, German bacteriologist Gerhard Domack was studying a red dye that hadn't been an effective antibacterial in a Petri dish, but turned out to treat strep infections in mice and staph infections in rabbits. This dye was developed into the drug Protonzel, the first sulfa drug and the first drug used to treat and prevent a range of bacterial infections in humans. Unlike Salversin, which was primarily used to treat syphilis, Protonzel could treat a variety of gram-positive bacteria.

• 20:55Tracy V. Wilson?

  Domack was awarded the Nobel Prize in Physiology or Medicine for this work in 1939, 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 Karl von Ostrowski in 1935. Domack 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 II, and he never actually got the monetary award.

• 21:35Holly Frey?

  As a side note, we mentioned Paul Ehrlich earlier in the episode. The street in Frankfurt where his institute was located was named after him, but it was renamed after the Nazis came to power because he was Jewish. Ehrlich was no longer living at this point. He had died after a stroke in 1915.

• 21:53Tracy V. Wilson?

  So the same year that Domack 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.

• 22:07Tracy V. Wilson?

  There had been a Department of Pathology at Oxford for decades, but this school was almost brand new. It had opened in 1935 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 Florrie had been appointed professor of pathology, and the research team he recruited included Ernst Chain, who was a Jewish biochemist who had fled to the UK from Germany after the Nazi party came to power.

• 22:40Holly Frey?

  Florrie, Chain, and others at Oxford had been inspired by Domac's success with sulfa drugs, and in 1938, they started studying the enzyme lysozyme, which Alexander Fleming had discovered. Chain also found Fleming's earlier paper on the antimicrobial effects of penicillium mold, and Oxford already had a sample of Fleming's mold on hand. The team started working with it in 1939.

• 23:05Tracy V. Wilson?

  Fleming and his team at St. Mary's had been mostly working with small amounts of mold in a petri dish. Florrie and Chain, on the other hand, were 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 bedpans 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 whatever vessels they could scrounge up: jars and food tins,

• 23:50Tracy V. Wilson?

  milk churns, fuel cans, all kinds of things.

• 23:56Holly Frey?

  I love that it's a little hodgepodgey.

• 23:58Tracy V. Wilson?

  It's very hodgepodgey.

• 24:00Holly Frey?

  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 Callow, Claire Inea, Betty Cook, Peggy Gardner, Megan Lancaster, and Patricia McKegney, and they were nicknamed the Penicillin Girls. Norman Healy 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.

• 24:31Tracy V. Wilson?

  And on May 25th, 1939, almost exactly 10 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.

• 25:01Holly Frey?

  Other tests on animals followed, including studies on rats and cats. They tested penicillin's efficacy against multiple bacteria. In addition to strep and staph, there was Clostridium septicum, which can cause Gas Gangrene. And penicillin was dramatically effective against all of them, with little to no toxicity to their test subjects. In August of 1940, Chain, Florrie, Heatley, and others published "Penicillin as a Chemotherapeutic Agent" in the journal The Lancet, detailing the basic findings of their research.

• 25:37Tracy V. Wilson?

  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 in injuries that had seemed really superficial. People like Ignat Semmelweis and Joseph Lister had advocated for things like handwashing 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,

• 26:22Tracy V. Wilson?

  and often there just was not much that could be done about it. Celfa 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.

• 26:40Holly Frey?

  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 at war. Germany had invaded Poland on September 1st, 1939, 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.

• 27:22Holly Frey?

  The team eventually used 700 of these vessels to produce about 500 liters of mold broth every week.

• 27:29Tracy V. Wilson?

  But this was a slow and cumbersome and kind of fiddly process. Even with all 700 vessels in use, it took about four weeks to make enough penicillin to treat one human patient. And it took months for all 700 of those vessels to be ready. At the end of 1940, only about 90 of them were all set and had been seeded with mold spores.

• 27:56Holly Frey?

  The first attempt to treat a person with penicillin made from all of this mold started on February 12th, 1941. 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. In 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.

• 28:32Tracy V. Wilson?

  Alexander showed promising signs of recovery within 24 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 penicillin out of it and then reuse it. So the body excretes penicillin really rapidly, and roughly 70% of it comes out in the urine unchanged. It could be more or less than that. I saw numbers that were literally from 1% to 99%. 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.

• 29:14Holly Frey?

  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. He died on March 15, 1941.

• 29:33Tracy V. Wilson?

  So it was clear that making enough penicillin to do a clinical trial was going to be a huge challenge. With all this effort, they had not made enough to successfully treat even one patient. Although focusing on treating children would have allowed the team to use smaller doses, at this point, the priority was really confirming that 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 sick soldiers to return to duty faster.

• 30:10Holly Frey?

  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.

• 30:31Tracy V. Wilson?

  Flory 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 losing 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.

• 31:02Holly Frey?

  Why does everybody on this, on this transport smell weird?

• 31:07Tracy V. Wilson?

  Smells a little musty.

• 31:09Holly Frey?

  In 1941, Florrie 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.

• 31:32Speaker 06

  Okay, chicken nugget fans, I've got huge news. The new Burger King Chicken Nuggets just dropped, and they are the crispiest, the juiciest, and the tastiest chicken nuggets ever at Burger King. Burger King heard that a lot of you didn't like the old chicken nuggets, so they got to work and reinvented them. To go along with the new chicken nuggets, a lot of the sauces were reinvented too, because better chicken nuggets deserve better sauces. We're talking new buffalo sauce, honey mustard, sweet and sour, and even a whole new option too, the new special savory sauce, which is only available for a limited time at participating US restaurants. I mean, you need to taste it all for yourself. This

• 32:15Speaker 06

  new chicken nugget, reinvented, based on real feedback, is made with 100% white meat chicken and is now better than ever. You gotta try the new Burger King Chicken Nuggets and sauces today.

• 32:28Tracy V. Wilson?

  For any small business owner, there's a moment when you realize the next hire could be the difference between staying busy and actually growing. The challenge is finding the right person without wasting time sorting through candidates who aren't the right fit. That's where Indeed Sponsored Jobs comes in. When workplace chaos hits and you need someone who can step in and make a difference, this is a job for Sponsored Jobs. It helps put your job in front of candidates To match the criteria that matter most to you, whether that's skills, experience, certifications, or location. And you're certainly not alone in using Indeed. Join the 3.3 million employers worldwide that use Indeed to connect with quality talent that fits their needs. That's millions of businesses turning to Indeed to help solve hiring challenges and find people

• 33:13Tracy V. Wilson?

  who can help drive results. Spend less time searching and more time actually interviewing candidates who check all your boxes. Less stress, less time, more results. Get your $75 sponsored job credit today at indeed.com/podcast. Terms and conditions apply. Hiring now, then this is a job for Indeed sponsored jobs.

• 33:40Speaker 07

  Livright, publishers of John U. Bacon's New York Times bestseller, The Gales of November, a chronicle of the S. S. Edmund Fitzgerald's 1975 shipwreck. Never has it been told better than by Mr. Bacon in this colorful book, writes John J. Miller of The Wall Street Journal, while author Hampton Sides proclaims that it's destined to be a classic. The Gales of November, now in paperback.

• 34:09Tracy V. Wilson?

  Guess who's back in the house? The old gays return for season two of Silver Linings, their hit podcast from iHeart's Ruby Studio in partnership with ViiV Healthcare. Just wait until you hear what hosts Robert McBill and Jesay have in store this time around. They strut back down memory lane, navigating life, love, loss, and everything that shaped them along the way. And as usual, someone just might break into song. From leather bars to bathhouses, dance floors to drag brunch, nothing stays off limits. These are the kinds of insights that can only come from experience, so listen to your elders, honey, and discover the silver linings you can take with you. All sass, zero filter, and decades of perspective from four friends proving that queer joy

• 34:54Tracy V. Wilson?

  only gets better with age on the podcast that never gets old. Listen to Silver Linings, available on the iHeart Radio app, Apple Podcasts, or wherever you get your podcasts.

• 35:14Tracy V. Wilson?

  In June of 1941, Howard Florrie and Norman Heatley took a series of flights to get from the UK to the 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.

• 35:52Holly Frey?

  As Florrie 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. Florrie 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 concerns 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.

• 36:31Tracy V. Wilson?

  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 Chain argued that penicillin was their work and it deserved to be protected, Chain 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. Chain 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 Florrie. Since the whole purpose of this trip was to try to get manufacturing started, and Heatley

• 37:16Tracy V. Wilson?

  was the person who had been focused on manufacturing, like, it makes sense that Heatley would be the person to go. 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.

• 37:31Holly Frey?

  The US had passed the Lend-Lease Act in March of 1941, 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 manufacture of penicillin seemed to fall under that definition, but Florrie 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.

• 38:02Tracy V. Wilson?

  They had a series of meetings and disappointments and kind of stops and starts. And then Florrie and Heatley wound up at the Department of Agriculture's Northern Regional Research Laboratory, or NRRL, in Peoria, Illinois, which already had a fermentation division, which was very handy since they grew penicillin by fermenting. 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 of 1941.

• 38:34Holly Frey?

  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 10 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.

• 39:01Tracy V. Wilson?

  Those vessels in 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 their finding a different strain of penicillium mold that would grow really well while submerged, and also produce 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.

• 39:41Tracy V. Wilson?

  They eventually, though, found a sample growing on a moldy cantaloupe that worked really well. This find is usually credited to lab assistant Mary Kay Hunt, who was nicknamed Moldy Mary. She had found this cantaloupe not in some far-reaching place brought back by the Army Transportation Corps, but at a local Peoria fruit market. The strain of the mold, Penicillium chrysogenum, was about 100 times more productive than the other strains they tried.

• 40:12Holly Frey?

  Even as the research lab figured out ways to increase the yield of penicillium mold, they still needed pharmaceutical or chemical manufacturers to actually get a penicillin drug into production. A group of pharmaceutical companies and the federal government met in October of 1941 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.

• 40:51Tracy V. Wilson?

  It was also going to be really tricky. John L. Smith from Pfizer 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 assay 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 57 different research contracts related to it. The War Production Board also worked with 25 different companies to scale up production of penicillin. They narrowed it down to those 25

• 41:36Tracy V. Wilson?

  after investigating more than 175 different companies to determine whether they were suitable or not.

• 41:43Holly Frey?

  The first patient in the US to be treated with penicillin was 33-year-old Anne Miller, who had developed septicaemia after a pregnancy loss. Her treatment started on March 14, 1942, and it required half the penicillin that was in existence in the US at that point.

• 42:02Tracy V. Wilson?

  Also, in 1942, 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 write-up about it in The Times. This article didn't actually mention Florrie 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 Florrie didn't want to talk to the press and also didn't want the rest of the Oxford team to talk to the press. This is really starting the ball rolling on this being just Alexander Fleming's own

• 42:47Tracy V. Wilson?

  work and nobody else's.

• 42:49Holly Frey?

  The fact that all of this was happening during World War II 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 believed that information about how to make it, or samples of the mold itself, should

• 43:30Holly Frey?

  not be shared, not with Germany and not with any countries likely to cooperate with Germany.

• 43:37Tracy V. Wilson?

  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 penicillin being produced was going to be reserved almost exclusively for military use.

• 44:05Tracy V. Wilson?

  At the same time, there 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 10, 1943, Julius A. Vogel, who was the plant physician at a steel plant in Pennsylvania, figured out how to make penicillin in his kitchen.

• 44:37Holly Frey?

  See, my plan as a kid was not completely off the rails.

• 44:42Tracy V. Wilson?

  Not completely off, no.

• 44:43Holly Frey?

  Because I had the knowledge of a plant physician. 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 8, 1943, they reported that they had found a way to make a topical treatment by soaking a gauze pad in 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-infused gauze. Vogel's wife, Eunice, was a big part of this process, making the

• 45:26Holly Frey?

  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.

• 45:40Tracy V. Wilson?

  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 11th, 1943, 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 at

• 46:22Tracy V. Wilson?

  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.

• 46:32Holly Frey?

  Yet another ethical conundrum arose after Florrie and Chain traveled to northern Africa in 1943 to test penicillin on wounded soldiers and realized that it was also effective against gonorrhea. Before this point, penicillin had been envisioned as something that would save the lives of soldiers who had been seriously injured in battle or had contracted a serious illness like bacterial pneumonia. But gonorrhea, 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

• 47:13Holly Frey?

  who had gonorrhea back into peak condition, rather than treating seriously injured soldiers who were going to be sent back home.

• 47:21Tracy V. Wilson?

  Most supplies were not limited for that much longer, though. Pfizer's first plant for the commercial production of penicillin opened in Brooklyn, New York on March 1st, 1944. 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 15th of 1944.

• 48:00Holly Frey?

  By this point, pharmaceutical companies in the US were 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. 21 billion units of the drug had been made in 1943, and in 1945, it had jumped to 6.8 trillion. In March of 1945, the US was able to lift rationing restrictions on penicillin and make it commercially available to the public.

• 48:38Tracy V. Wilson?

  After the liberation of Paris in 1944, 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 1945, the team collected urine from patients to reclaim the penicillin in it. So if a patient was being treated with penicillin, their bed was marked with a placard to note that their urine should be collected. Patients who were 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.

• 49:21Tracy V. Wilson?

  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.

• 49:33Holly Frey?

  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 as the war was going on.

• 50:06Tracy V. Wilson?

  Alexander Fleming, Ernst Boris Chain, and Howard Walter Florrie were jointly awarded the Nobel Prize in Physiology or Medicine in 1945. That same year, the chemical structure of penicillin was confirmed by Dorothy Crawford Hodgkin, and that paved the way for synthetic forms of penicillin.

• 50:27Holly Frey?

  Penicillin's effect on medicine was massive, and many other antibiotics followed. Streptomycin, which was the first truly effective treatment for tuberculosis, was developed in 1943. We have covered that and the controversy around who should be credited with discovering it on the podcast in 2013.

• 50:47Tracy V. Wilson?

  This is an enormous advance in medicine, but by the 1950s, some bacteria were already becoming resistant to penicillin, including some strains of staph 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 penicillin 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

• 51:32Tracy V. Wilson?

  drug, make them resistant."

• 51:35Holly Frey?

  This is, obviously, still a problem. You've 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 1940s and the 1960s, along with the widespread use of antibiotics in agriculture. In 2014, 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.

• 52:08Tracy V. Wilson?

  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.

• 52:18Holly Frey?

  We're living through it.

• 52:24Tracy V. Wilson?

  Thanks so much for joining us on this Saturday. If you'd like to send us a note, our email address is [email protected]. And you can subscribe to the show on the iHeartRadio app, Apple Podcasts, or wherever you listen to your favorite shows.

• 52:46Tracy V. Wilson?

  Whether you're calling the wise women in your life, video calling your girlfriends across the country, or checking in on someone who always knows how to make you smile, staying connected matters. Those small conversations, shared laughs, and quick hellos are what keep relationships strong even when life gets busy. Some of the most life-giving conversations start with just a phone call. That's why AT&T guarantees the network you can rely on, so you can focus on the moments and people that matter most. That's the AT&T Guarantee. AT&T: Connecting changes everything. Terms and conditions apply. Visit ATT.com/guarantee for details.

• 53:24Speaker 07

  Livrite, publishers of John U. Bacon's New York Times bestseller, The Gales of November, a chronicle of the S.S. Edmund Fitzgerald's 1975 shipwreck. "Never has it been told better than by Mr. Bacon in this colorful book," writes John J. Miller of The Wall Street Journal, while author Hampton Sides proclaims that it's destined to be a classic. The Gales of November, now in paperback.

• 53:51Tracy V. Wilson?

  Long hours, work deadlines, family commitments. You give so much to everyone else. Isn't it time to invest in yourself? The University of Arizona Global Campus is built for working adults with flexible online degree programs designed to fit your life. Your previous education, training, and eligible experience may even help you earn college credit. At UAGC, you can take one accelerated course at a time, helping you move toward your goals in five- and six-week class formats. Visit UAGC.edu today. A rare disease diagnosis can change your life, but it doesn't have to define your future. In season seven of Untold Stories: Life with a Severe Autoimmune Condition, host Martine

• 54:32Holly Frey?

  continues the conversation with people living with MG, CIDP, and the broader rare disease community, exploring what comes after diagnosis through stories of hope, progress, and connection. Produced by Ruby Studio in partnership with Argenx. Listen on the iHeart Radio app, Apple Podcasts, or wherever you get your podcasts.

• 54:52Speaker 00

  This is an iHeart Podcast. Guaranteed human.