1 00:00:02,440 --> 00:00:06,480 Speaker 1: Happy Saturday. After this week's episodes on Dorothy Crowfoot Hodgkin, 2 00:00:06,760 --> 00:00:10,840 Speaker 1: including our work determining the structure of penicillin, Today's Saturday 3 00:00:10,880 --> 00:00:15,200 Speaker 1: Classic is on the discovery of penicillin. This episode originally 4 00:00:15,200 --> 00:00:21,959 Speaker 1: came out on September fifth, twenty twenty two. Enjoy Welcome 5 00:00:22,000 --> 00:00:32,519 Speaker 1: to Stuff You Missed in History Class, a production of iHeartRadio. Hello, 6 00:00:32,640 --> 00:00:35,839 Speaker 1: and welcome to the podcast. I'm Tracy V. Wilson and 7 00:00:35,920 --> 00:00:38,680 Speaker 1: I'm Holly Frye. Holly, When you were a kid, did 8 00:00:38,680 --> 00:00:44,120 Speaker 1: you learn the story of penicillin? I feel like I 9 00:00:44,159 --> 00:00:47,879 Speaker 1: didn't get it until later. Okay, do you remember what 10 00:00:47,920 --> 00:00:52,680 Speaker 1: you learned? You know, accidental grew on mold because there 11 00:00:52,720 --> 00:00:54,680 Speaker 1: was a rumor at our school that you could make 12 00:00:54,720 --> 00:01:01,320 Speaker 1: your own antibiotics in your bedroom. Well about something similar 13 00:01:01,360 --> 00:01:05,160 Speaker 1: to that, and you better believe my crafty little brain 14 00:01:05,360 --> 00:01:07,720 Speaker 1: was like, could I could I start a little apothecary 15 00:01:07,800 --> 00:01:14,280 Speaker 1: out of my closet? Uh? Maybe so, I, like a 16 00:01:14,319 --> 00:01:17,640 Speaker 1: lot of people learned this very basic story about Alexander 17 00:01:17,680 --> 00:01:20,880 Speaker 1: Fleming leaving a Petrie dish out and it getting contaminated 18 00:01:20,920 --> 00:01:23,240 Speaker 1: with mold, and then it's just sort of presented as 19 00:01:23,440 --> 00:01:29,000 Speaker 1: voila penicillin. He did it all by himself. That is 20 00:01:29,240 --> 00:01:35,279 Speaker 1: not remotely accurate. Like the petri dish and mold part, 21 00:01:35,520 --> 00:01:38,280 Speaker 1: that part kind of accurate. At least we'll talk more 22 00:01:38,280 --> 00:01:41,760 Speaker 1: about it. But like it was not suddenly he had 23 00:01:41,800 --> 00:01:47,000 Speaker 1: invented penicillin by himself at all. Uh. So that's one 24 00:01:47,040 --> 00:01:49,760 Speaker 1: of the things we're going to talk about in today's episode. Also, though, 25 00:01:49,760 --> 00:01:53,920 Speaker 1: this was just inspired by an email from listener Abby, 26 00:01:54,000 --> 00:01:57,200 Speaker 1: which we actually read on the show recently, and Abby 27 00:01:57,320 --> 00:02:02,600 Speaker 1: mentioned that after World War Two there was a penicillin 28 00:02:02,680 --> 00:02:06,640 Speaker 1: recycling project and I was like, I need to know 29 00:02:06,800 --> 00:02:10,360 Speaker 1: more about this, yes, uh, And I didn't talk about 30 00:02:10,360 --> 00:02:13,040 Speaker 1: it a lot in that listener mail segment because it 31 00:02:13,080 --> 00:02:16,360 Speaker 1: is gross. So just as a heads up, there is 32 00:02:16,440 --> 00:02:19,880 Speaker 1: a lot of mold in this episode, and if a 33 00:02:19,960 --> 00:02:23,480 Speaker 1: phrase like mold broth bothers you, maybe this is not 34 00:02:23,600 --> 00:02:29,160 Speaker 1: the episode for you. That's your punk band mold broth, Yeah, 35 00:02:29,240 --> 00:02:32,360 Speaker 1: mold broth. We're also just there's a lot of bodily fluids. 36 00:02:32,400 --> 00:02:36,640 Speaker 1: There's also some animal testing just you know, I know 37 00:02:36,960 --> 00:02:40,840 Speaker 1: people can be squeamish about particular things. Just a heads 38 00:02:40,919 --> 00:02:44,280 Speaker 1: up on all of that. So, like we just said, 39 00:02:44,400 --> 00:02:48,600 Speaker 1: the development of penicillin started but definitely did not end 40 00:02:48,960 --> 00:02:52,520 Speaker 1: with the chance discovery of some mold in a petri dish. 41 00:02:52,720 --> 00:02:55,160 Speaker 1: We're gonna get back to that. But the discovery of 42 00:02:55,200 --> 00:02:58,880 Speaker 1: a seemingly miraculous treatment made from mold peak the interest 43 00:02:58,960 --> 00:03:02,960 Speaker 1: of medical historians who started looking for earlier uses of 44 00:03:03,040 --> 00:03:06,280 Speaker 1: mold as a treatment for wounds or diseases, and it 45 00:03:06,320 --> 00:03:09,320 Speaker 1: turned out there were actually a lot of them. Yeah, 46 00:03:09,360 --> 00:03:12,119 Speaker 1: the people who had been using these obviously already knew 47 00:03:12,120 --> 00:03:16,200 Speaker 1: about them, but there had not really been a systemic 48 00:03:16,360 --> 00:03:20,920 Speaker 1: historical look at it. The vast majority of these treatments 49 00:03:21,000 --> 00:03:25,080 Speaker 1: involved using mold to make a topical preparation for wounds, 50 00:03:25,760 --> 00:03:29,520 Speaker 1: so this included using moldy soybeans in China, and moldy 51 00:03:29,560 --> 00:03:33,040 Speaker 1: bread in Egypt, and cheese mold in Greece, with all 52 00:03:33,080 --> 00:03:36,560 Speaker 1: of those dating back roughly three thousand years or more. 53 00:03:37,480 --> 00:03:41,040 Speaker 1: Aboriginal and indigenous peoples all around the world have used 54 00:03:41,120 --> 00:03:45,720 Speaker 1: molds medicinally as well. There's also some evidence that more 55 00:03:45,760 --> 00:03:50,760 Speaker 1: than two thousand years ago, people in northern Africa consumed 56 00:03:51,360 --> 00:03:56,480 Speaker 1: something that contained enough tetracycline to leave evidence of that 57 00:03:56,680 --> 00:04:02,360 Speaker 1: on their bones. Tetracycline actually comes from bacteria, not from mold, 58 00:04:02,440 --> 00:04:06,320 Speaker 1: but the bacteria in question form these branching filaments that 59 00:04:06,360 --> 00:04:08,960 Speaker 1: look enough like a fungus that it was classified as 60 00:04:08,960 --> 00:04:12,640 Speaker 1: a fungus for a really long time. In more recent times, 61 00:04:12,680 --> 00:04:17,320 Speaker 1: herbalists and apothecaries in Europe described medicinal mold preparations all 62 00:04:17,360 --> 00:04:21,679 Speaker 1: through the seventeenth and eighteenth centuries, and researchers looking into 63 00:04:21,720 --> 00:04:24,840 Speaker 1: the historical use of mold in the twentieth century found 64 00:04:24,880 --> 00:04:28,160 Speaker 1: that a lot of folk remedies using mold were still around. 65 00:04:28,839 --> 00:04:32,400 Speaker 1: One biochemist described traveling through Europe and finding that each 66 00:04:32,520 --> 00:04:35,520 Speaker 1: home had a moldy loaf of bread stored in the 67 00:04:35,600 --> 00:04:38,760 Speaker 1: kitchen rafters, which would be used to prepare dressings for 68 00:04:38,880 --> 00:04:43,880 Speaker 1: cuts or other wounds. Other oral accounts described people intentionally 69 00:04:43,920 --> 00:04:47,760 Speaker 1: growing mold on oranges or other fruit or substances, or 70 00:04:47,800 --> 00:04:51,320 Speaker 1: collecting it from meat as it was being cured. We 71 00:04:51,400 --> 00:04:54,320 Speaker 1: don't really have a lot of detail about how effective 72 00:04:54,360 --> 00:04:58,080 Speaker 1: these treatments actually were. There weren't clinical studies or things 73 00:04:58,120 --> 00:05:01,800 Speaker 1: like that to reference. But there are so many different 74 00:05:01,839 --> 00:05:05,599 Speaker 1: medicinal uses for molds to treat infections in so many 75 00:05:05,600 --> 00:05:08,760 Speaker 1: different parts of the world that some medical historians have 76 00:05:08,839 --> 00:05:12,160 Speaker 1: concluded that at least some of them probably did have 77 00:05:12,240 --> 00:05:16,680 Speaker 1: some real antimicrobial efficacy. Some of the folks that were 78 00:05:16,720 --> 00:05:20,960 Speaker 1: interviewed about their folk remedies after penicillin was developed and 79 00:05:21,000 --> 00:05:23,480 Speaker 1: they learned that penicillin was made out of mold, they 80 00:05:23,480 --> 00:05:25,560 Speaker 1: were kind of like, oh, yeah, We've been doing that forever. 81 00:05:27,520 --> 00:05:32,760 Speaker 1: And by the time Fleming spotted that contaminated culture plate, 82 00:05:32,920 --> 00:05:36,920 Speaker 1: it was already established that various bacteria, molds, and other 83 00:05:37,080 --> 00:05:42,000 Speaker 1: organisms could inhibit one another's growth. The term antibiosis was 84 00:05:42,080 --> 00:05:44,800 Speaker 1: coined by the end of the nineteenth century to describe 85 00:05:44,920 --> 00:05:48,680 Speaker 1: this antagonistic effect that microorganisms could have on one another, 86 00:05:49,560 --> 00:05:53,040 Speaker 1: and there may have even been some work with penicillium 87 00:05:53,120 --> 00:05:58,360 Speaker 1: mold specifically before Fleming made his discovery. Joseph Lister may 88 00:05:58,400 --> 00:06:01,800 Speaker 1: have successfully treated a paya with a filtrate made from 89 00:06:02,040 --> 00:06:06,360 Speaker 1: Penicillium glaucum as early as eighteen seventy seven. Around the 90 00:06:06,400 --> 00:06:10,400 Speaker 1: same time, there were other doctors and scientists experimenting with 91 00:06:10,440 --> 00:06:16,479 Speaker 1: whether penicillium mold killed other microorganisms in a lab. None 92 00:06:16,560 --> 00:06:20,120 Speaker 1: of this is totally certain, though, the taxonomy for molds 93 00:06:20,160 --> 00:06:23,320 Speaker 1: and other fungi was not very robust yet, and the 94 00:06:23,360 --> 00:06:26,840 Speaker 1: people who were doing this work were not experts in mycology. 95 00:06:27,520 --> 00:06:31,120 Speaker 1: It's possible that they were working with totally different molds 96 00:06:31,160 --> 00:06:34,720 Speaker 1: that they were just calling penicillium. And then aside from that, 97 00:06:34,800 --> 00:06:38,159 Speaker 1: none of them published a thorough description of their work, 98 00:06:38,400 --> 00:06:41,080 Speaker 1: so a lot of this conclusion is based on notes 99 00:06:41,680 --> 00:06:47,240 Speaker 1: which were not necessarily complete. You cannot replicate an experiment 100 00:06:47,320 --> 00:06:49,240 Speaker 1: to test it if you don't really know what went 101 00:06:49,320 --> 00:06:54,080 Speaker 1: down right. The early twentieth century saw the development of 102 00:06:54,080 --> 00:06:58,400 Speaker 1: the first drugs that killed specific bacteria. In the eighteen seventies, 103 00:06:58,480 --> 00:07:02,119 Speaker 1: German physician Paul Erleck had noticed that chemical dyes changed 104 00:07:02,120 --> 00:07:06,240 Speaker 1: the color of some bacteria and not others. This was 105 00:07:06,240 --> 00:07:09,000 Speaker 1: a precursor to the gram staining method that is still 106 00:07:09,080 --> 00:07:13,400 Speaker 1: used today to broadly classify bacteria as GRAM positive and 107 00:07:13,480 --> 00:07:16,720 Speaker 1: gram negative based on how they respond to the stain. 108 00:07:17,760 --> 00:07:20,480 Speaker 1: Erlick started to wonder if it was also possible to 109 00:07:20,520 --> 00:07:24,440 Speaker 1: discover a substance that killed some bacteria but not others. 110 00:07:25,160 --> 00:07:28,760 Speaker 1: In nineteen oh nine, researchers in Erlick's lab discovered that 111 00:07:28,800 --> 00:07:33,880 Speaker 1: the arsenic compound arsphenamine killed the bacteria that cause syphilis. 112 00:07:34,400 --> 00:07:37,679 Speaker 1: This drug was marketed as saliversan and it was also 113 00:07:37,760 --> 00:07:40,160 Speaker 1: known as six oh six because it was the six 114 00:07:40,320 --> 00:07:44,040 Speaker 1: hundred and sixth preparation that had been tested in Erlick's 115 00:07:44,080 --> 00:07:47,160 Speaker 1: lab As part of this project. Salversan was found to 116 00:07:47,240 --> 00:07:51,200 Speaker 1: be effective against other infectious diseases as well. This was 117 00:07:51,280 --> 00:07:54,800 Speaker 1: really the first effective treatment for syphilis and the first 118 00:07:55,000 --> 00:08:00,120 Speaker 1: modern antimicrobial compound. Erlick described this use of a chem 119 00:08:00,440 --> 00:08:03,520 Speaker 1: to kill cells in the body using the word chemotherapy, 120 00:08:03,960 --> 00:08:07,040 Speaker 1: and he coined the term magic bullet to describe the 121 00:08:07,080 --> 00:08:12,520 Speaker 1: drug's ability to target pathogens. Rlick's lab had been systematically 122 00:08:12,560 --> 00:08:16,400 Speaker 1: testing one arsenic compound after another when it developed Salversen. 123 00:08:17,200 --> 00:08:20,600 Speaker 1: On the other hand, Alexander Fleming's discovery of penicillin a 124 00:08:20,640 --> 00:08:24,240 Speaker 1: little less than twenty years later, was an accident. He 125 00:08:24,360 --> 00:08:27,920 Speaker 1: was interested in the antimicrobial properties of the body's own 126 00:08:28,000 --> 00:08:32,600 Speaker 1: fluids and secretions. He coined the term lysizyme to describe 127 00:08:32,600 --> 00:08:35,960 Speaker 1: a substance in things like mucus, tears, and saliva that 128 00:08:36,080 --> 00:08:40,559 Speaker 1: seemed to inhibit bacterial growth. He reportedly made this discovery 129 00:08:40,679 --> 00:08:43,560 Speaker 1: when he had a cold. He cultured his own mucus 130 00:08:43,600 --> 00:08:46,200 Speaker 1: in a petri dish and then later discovered that the 131 00:08:46,280 --> 00:08:51,120 Speaker 1: area around the mucus wasn't growing bacteria. In some versions 132 00:08:51,160 --> 00:08:54,560 Speaker 1: of this story, his office was perpetually untidy, and this 133 00:08:54,679 --> 00:08:57,960 Speaker 1: Petrie dish had sat there forgotten in some clutter for 134 00:08:58,000 --> 00:09:00,480 Speaker 1: a couple of weeks before he made the disas discovery. 135 00:09:01,440 --> 00:09:05,880 Speaker 1: His discovery of penicillin had some similarities. This time, he 136 00:09:06,040 --> 00:09:10,200 Speaker 1: was studying staff bacteria, and all of his Petrie dishes 137 00:09:10,200 --> 00:09:13,320 Speaker 1: were supposed to be in an incubator when he left 138 00:09:13,360 --> 00:09:16,800 Speaker 1: for a two week vacation in nineteen twenty eight. One 139 00:09:16,840 --> 00:09:19,880 Speaker 1: of them, though, was apparently left on a lab bench 140 00:09:20,000 --> 00:09:22,920 Speaker 1: by accident. When he got back to the office on 141 00:09:22,960 --> 00:09:27,120 Speaker 1: September third, he noticed the misplaced Petrie dish that had 142 00:09:27,120 --> 00:09:30,680 Speaker 1: been contaminated with mold, and the area around the mold 143 00:09:30,840 --> 00:09:35,360 Speaker 1: he saw colonies of staff bacteria that were dying. We 144 00:09:35,480 --> 00:09:40,000 Speaker 1: don't know exactly where the mold contamination came from. One 145 00:09:40,040 --> 00:09:43,800 Speaker 1: possibility is an open window, and another is a mycology 146 00:09:43,880 --> 00:09:47,240 Speaker 1: lab that was in the same building. And this discovery 147 00:09:47,440 --> 00:09:50,280 Speaker 1: was only possible because the petrie dish was left out 148 00:09:50,320 --> 00:09:53,079 Speaker 1: on a bench. If it had gone into the incubator 149 00:09:53,120 --> 00:09:56,719 Speaker 1: like it was supposed to, the staff bacteria would have flourished, 150 00:09:56,760 --> 00:09:58,880 Speaker 1: but the temperature would have been wrong for the mold 151 00:09:58,920 --> 00:10:03,520 Speaker 1: to grow beyond this. Other details are really hazy. Fleming 152 00:10:03,600 --> 00:10:06,480 Speaker 1: did not take careful notes about exactly what he was 153 00:10:06,600 --> 00:10:09,520 Speaker 1: looking at when either he or one of his assistants 154 00:10:09,720 --> 00:10:14,520 Speaker 1: spotted this patri dish. His later descriptions about exactly how 155 00:10:14,559 --> 00:10:17,480 Speaker 1: the mold and the bacteria were interacting with one another 156 00:10:17,520 --> 00:10:21,280 Speaker 1: could be contradictory. When he published his discovery in the 157 00:10:21,320 --> 00:10:25,679 Speaker 1: British Journal of Experimental Pathology in June of nineteen twenty nine, 158 00:10:25,760 --> 00:10:28,960 Speaker 1: he made it sound as though he routinely left his 159 00:10:29,040 --> 00:10:32,280 Speaker 1: staff culture on plates on the bench for extended periods, 160 00:10:32,920 --> 00:10:35,800 Speaker 1: rather than that often repeated story that this was one 161 00:10:35,840 --> 00:10:39,560 Speaker 1: that was forgotten while he was on vacation. He also 162 00:10:39,760 --> 00:10:44,880 Speaker 1: described the mold as most resembling Penicillium rubrum, and other 163 00:10:44,960 --> 00:10:50,800 Speaker 1: researchers later corrected that identification to Penicillium notatum. That June 164 00:10:50,920 --> 00:10:55,000 Speaker 1: nineteen twenty nine paper describes various experiments Fleming and his 165 00:10:55,120 --> 00:10:57,880 Speaker 1: colleagues did with a filtrate made from the broth the 166 00:10:57,920 --> 00:11:01,520 Speaker 1: mold was growing in. He coined the term penicillin to 167 00:11:01,559 --> 00:11:05,800 Speaker 1: describe this filtrate because writing quote mold broth filtrate over 168 00:11:05,840 --> 00:11:10,120 Speaker 1: and over was apparently cumbersome. He did some basic toxicity 169 00:11:10,160 --> 00:11:13,400 Speaker 1: tests in small mammals by injecting them with this filtrate, 170 00:11:13,760 --> 00:11:16,440 Speaker 1: and it did not seem to be toxic. But he 171 00:11:16,480 --> 00:11:19,360 Speaker 1: doesn't seem to have tried injecting animals with one of 172 00:11:19,360 --> 00:11:22,360 Speaker 1: the bacteria that he knew penicillin killed in a petrie 173 00:11:22,400 --> 00:11:25,000 Speaker 1: dish to see if that worked in a living body 174 00:11:25,040 --> 00:11:30,640 Speaker 1: as well. He did test penicillin's activity against various microbes 175 00:11:30,720 --> 00:11:36,400 Speaker 1: in a petrie dish, including Staphylococcus, streptococcus, and Newmacoccus, as 176 00:11:36,440 --> 00:11:39,199 Speaker 1: well as what was described at the time as Bacillus 177 00:11:39,280 --> 00:11:46,240 Speaker 1: influenzae and Basillis diphtheria. Penicillin was particularly effective against all 178 00:11:46,320 --> 00:11:49,800 Speaker 1: the piogenic cacci, so the ones that ended with caucus 179 00:11:50,040 --> 00:11:53,680 Speaker 1: and that list, but it wasn't as effective against the basilla. 180 00:11:53,920 --> 00:11:56,600 Speaker 1: So if he had a petrie dish that was growing 181 00:11:56,679 --> 00:12:01,640 Speaker 1: both staff bacteria and Basillis influenza, he could use penicillin 182 00:12:01,760 --> 00:12:06,200 Speaker 1: to kill only the staff, leaving that Basillis culture in place. 183 00:12:06,960 --> 00:12:11,880 Speaker 1: Side note. Today Basillis influenzae is known as Hemophilis influenzae. 184 00:12:12,000 --> 00:12:15,440 Speaker 1: It got the influenzae Moniker when people thought that it 185 00:12:15,559 --> 00:12:19,839 Speaker 1: caused influenza, which it does not. Influenza is caused by 186 00:12:19,880 --> 00:12:24,120 Speaker 1: a virus. Just to keep things a little confusing for everybody. 187 00:12:24,880 --> 00:12:26,760 Speaker 1: That was one of the things about reading this paper 188 00:12:26,880 --> 00:12:28,480 Speaker 1: was then needing to go and look like, what do 189 00:12:28,600 --> 00:12:30,640 Speaker 1: they call that now? I don't think that's what they 190 00:12:30,720 --> 00:12:34,880 Speaker 1: call that now. Fleming didn't really have the skills or 191 00:12:34,920 --> 00:12:39,640 Speaker 1: expertise to try to extract this filtrate into a usable medicine. 192 00:12:39,679 --> 00:12:43,440 Speaker 1: His research students, Stuart Kradack and Frederick Ridley both worked 193 00:12:43,440 --> 00:12:45,599 Speaker 1: on this, and both of them were credited at the 194 00:12:45,679 --> 00:12:49,280 Speaker 1: end of the published paper. Fleming also sent samples of 195 00:12:49,320 --> 00:12:52,240 Speaker 1: the mold to anyone who asked for it, but he 196 00:12:52,360 --> 00:12:56,400 Speaker 1: didn't really make any headway into turning penicillin into a medicine, 197 00:12:56,440 --> 00:12:59,200 Speaker 1: and he stopped working with it in nineteen thirty one. 198 00:13:00,200 --> 00:13:03,120 Speaker 1: We'll talk about how it did become a medicine after 199 00:13:03,160 --> 00:13:16,040 Speaker 1: a sponsor break. When Alexander Fleming was working with penicillin 200 00:13:16,080 --> 00:13:18,600 Speaker 1: at the end of the nineteen twenties, he was mostly 201 00:13:18,679 --> 00:13:22,520 Speaker 1: approaching it as something that would have uses in a laboratory, 202 00:13:22,720 --> 00:13:26,120 Speaker 1: such as using it to isolate different cultures from one 203 00:13:26,200 --> 00:13:30,120 Speaker 1: another depending on whether they were sensitive to penicillin. One 204 00:13:30,120 --> 00:13:33,760 Speaker 1: of his students, Cecil George Pain, does seem to have 205 00:13:33,800 --> 00:13:38,760 Speaker 1: successfully used penicillin to cure eye infections in newborns in 206 00:13:38,880 --> 00:13:41,920 Speaker 1: nineteen thirty as well as to treat a miner who 207 00:13:42,000 --> 00:13:46,080 Speaker 1: had an infected scratch on his cornea. But Pain did 208 00:13:46,120 --> 00:13:49,840 Speaker 1: not publish anything about this success, and he also does 209 00:13:49,920 --> 00:13:53,360 Speaker 1: not seem to have realized until much later that he 210 00:13:53,440 --> 00:13:57,959 Speaker 1: had been looking at something that could have revolutionized medicine. Meanwhile, 211 00:13:58,080 --> 00:14:02,160 Speaker 1: in nineteen thirty two, German bactiter peiologist Gerhard Domac was 212 00:14:02,200 --> 00:14:06,240 Speaker 1: studying a red dye that hadn't been an effective antibacterial 213 00:14:06,280 --> 00:14:09,120 Speaker 1: in a petri dish, but turned out to treat strep 214 00:14:09,160 --> 00:14:13,880 Speaker 1: infections in mice and staff infections in rabbits. This die 215 00:14:13,960 --> 00:14:17,480 Speaker 1: was developed into the drug protonsil, the first sulfa drug 216 00:14:17,480 --> 00:14:19,960 Speaker 1: and the first drug used to treat and prevent a 217 00:14:20,120 --> 00:14:24,680 Speaker 1: range of bacterial infections in humans. Unlike Salversen, which was 218 00:14:24,720 --> 00:14:28,359 Speaker 1: primarily used to treat syphilists, Protonsil could treat a variety 219 00:14:28,480 --> 00:14:33,720 Speaker 1: of Gram positive bacteria. Domac was awarded the Nobel Prize 220 00:14:33,720 --> 00:14:37,560 Speaker 1: in Physiology or Medicine for this work in nineteen thirty nine, 221 00:14:37,640 --> 00:14:41,400 Speaker 1: but the Nazi Party had forbidden Germans to accept the 222 00:14:41,440 --> 00:14:45,520 Speaker 1: Nobel Prize. This was because the Nobel Peace Prize had 223 00:14:45,600 --> 00:14:50,160 Speaker 1: previously been awarded to German pacifist Carl von Ossietsky in 224 00:14:50,280 --> 00:14:56,040 Speaker 1: nineteen thirty five. Domac accepted the prize anyway. Afterward, he 225 00:14:56,120 --> 00:14:59,240 Speaker 1: was arrested by the Gestapo and forced to write to 226 00:14:59,280 --> 00:15:02,920 Speaker 1: the Nobel Committe rejecting the prize. He wasn't able to 227 00:15:02,960 --> 00:15:06,080 Speaker 1: get his medal for having won the Nobel Prize until 228 00:15:06,120 --> 00:15:07,840 Speaker 1: after the end of World War Two, and he never 229 00:15:07,840 --> 00:15:11,560 Speaker 1: actually got the monetary award. As a side note, we 230 00:15:11,680 --> 00:15:15,320 Speaker 1: mentioned Paul Erlick earlier in the episode. The street in 231 00:15:15,440 --> 00:15:18,640 Speaker 1: Frankfurt where his institute was located was named after him, 232 00:15:19,040 --> 00:15:21,560 Speaker 1: but it was renamed after the Nazis came to power 233 00:15:21,680 --> 00:15:25,080 Speaker 1: because he was Jewish. Erlick was no longer living at 234 00:15:25,080 --> 00:15:28,200 Speaker 1: this point. He had died after a stroke in nineteen fifteen. 235 00:15:29,080 --> 00:15:31,800 Speaker 1: So the same year that Dolmach was awarded the Nobel 236 00:15:31,840 --> 00:15:35,720 Speaker 1: Prize for developing the first sulfa drug, researchers at the 237 00:15:35,760 --> 00:15:39,880 Speaker 1: Sir William Dunn School of Pathology at Oxford University started 238 00:15:40,040 --> 00:15:45,160 Speaker 1: studying penicillin. There had been a Department of Pathology at 239 00:15:45,200 --> 00:15:49,280 Speaker 1: Oxford for decades, but this school was almost brand new. 240 00:15:49,360 --> 00:15:52,359 Speaker 1: It had opened in nineteen thirty five after the university 241 00:15:52,440 --> 00:15:55,760 Speaker 1: received funds from the estate of the late Sir William Dunn, 242 00:15:56,200 --> 00:16:00,400 Speaker 1: which is what funded the new school. Australian pathologist Howard 243 00:16:00,440 --> 00:16:04,560 Speaker 1: Walter Florey had been appointed Professor of Pathology, and the 244 00:16:04,680 --> 00:16:08,280 Speaker 1: research team he recruited included Ernst Chane, who was a 245 00:16:08,480 --> 00:16:11,720 Speaker 1: Jewish biochemist who had fled to the UK from Germany 246 00:16:11,880 --> 00:16:15,840 Speaker 1: after the Nazi Party came to power. Flory, Chain and 247 00:16:15,920 --> 00:16:19,160 Speaker 1: others at Oxford had been inspired by Domok's success with 248 00:16:19,200 --> 00:16:22,400 Speaker 1: sulfa drugs, and in nineteen thirty eight they started studying 249 00:16:22,400 --> 00:16:27,480 Speaker 1: the enzyme lyszyme, which Alexander Fleming had discovered. Chain also 250 00:16:27,520 --> 00:16:31,960 Speaker 1: found Fleming's earlier paper on the antimicrobial effects of penicillium mold, 251 00:16:32,320 --> 00:16:35,800 Speaker 1: and Oxford already had a sample of Fleming's mold on hand. 252 00:16:36,480 --> 00:16:39,960 Speaker 1: The team started working with it in nineteen thirty nine. 253 00:16:40,120 --> 00:16:43,160 Speaker 1: Fleming and his team at Saint Mary's had been mostly 254 00:16:43,240 --> 00:16:46,480 Speaker 1: working with small amounts of mold and a Patriot dish 255 00:16:46,760 --> 00:16:49,040 Speaker 1: Flori and Chane on the other hand, were trying to 256 00:16:49,200 --> 00:16:52,480 Speaker 1: extract enough of the active substance to test whether it 257 00:16:52,520 --> 00:16:56,080 Speaker 1: could be used as a medicine. Even though they were 258 00:16:56,080 --> 00:16:59,600 Speaker 1: going to start with mice, which are very small, this 259 00:16:59,640 --> 00:17:03,520 Speaker 1: record wired a lot of mold, so much more mold 260 00:17:03,960 --> 00:17:08,600 Speaker 1: than Fleming had been working with. Hospital bedpans turned out 261 00:17:08,640 --> 00:17:11,240 Speaker 1: to be just about the right size and shape to 262 00:17:11,359 --> 00:17:14,399 Speaker 1: grow this mold in, but most of the ones on 263 00:17:14,480 --> 00:17:18,080 Speaker 1: hand were needed by hospital patients, so the team at 264 00:17:18,080 --> 00:17:23,480 Speaker 1: Oxford started repurposing whatever vessels they could scrounge up, jars 265 00:17:23,640 --> 00:17:29,240 Speaker 1: and food tens, milk churns, fuel cans, all kinds of things. 266 00:17:30,440 --> 00:17:34,520 Speaker 1: I love that it's a little hodgepodgy. It's very hodgepodgy. 267 00:17:34,680 --> 00:17:37,920 Speaker 1: It was also really a team effort. Over the course 268 00:17:37,960 --> 00:17:40,520 Speaker 1: of the project, six women were paid two pounds a 269 00:17:40,520 --> 00:17:44,560 Speaker 1: week to tend to the fermenting mold. They were Ruth Callo, 270 00:17:44,760 --> 00:17:50,320 Speaker 1: Claire Niant, Betty Cook, Peggy Gardner, Meghan Lancaster, and Patricia mckagney, 271 00:17:50,640 --> 00:17:55,200 Speaker 1: and they were nicknamed the Penicillin Girls. Norman Heatley developed 272 00:17:55,240 --> 00:17:58,200 Speaker 1: a method to extract penicillin from the mold broth into 273 00:17:58,280 --> 00:18:03,240 Speaker 1: ammial acetate and then back into water Edward Abraham developed 274 00:18:03,280 --> 00:18:07,359 Speaker 1: techniques to purify it, and on May twenty fifth, nineteen 275 00:18:07,480 --> 00:18:11,879 Speaker 1: thirty nine, almost exactly ten years after the British Journal 276 00:18:11,920 --> 00:18:16,840 Speaker 1: of Experimental Pathology received Fleming's paper on penicillin, they conducted 277 00:18:16,880 --> 00:18:21,399 Speaker 1: an experiment involving eight mice. All eight of the mice 278 00:18:21,440 --> 00:18:25,359 Speaker 1: were injected with Streptococcus bacteria, then four of the mice 279 00:18:25,400 --> 00:18:28,960 Speaker 1: were injected with penicillin and the other four were left untreated. 280 00:18:29,760 --> 00:18:33,600 Speaker 1: The four untreated mice died, but the other four who 281 00:18:33,640 --> 00:18:38,880 Speaker 1: got penicillin all survived. Other tests on animals followed, including 282 00:18:38,920 --> 00:18:43,600 Speaker 1: studies on rats and cats. They tested penicillin's efficacy against 283 00:18:43,720 --> 00:18:47,520 Speaker 1: multiple bacteria. In addition to Strep and staff, there was 284 00:18:47,600 --> 00:18:52,440 Speaker 1: Claustridium septicum, which can cause gas gangreen and penicillin was 285 00:18:52,520 --> 00:18:55,639 Speaker 1: dramatically effective against all of them, with little to no 286 00:18:55,800 --> 00:19:00,200 Speaker 1: toxicity to their test subjects. In August of nineteen ten, 287 00:19:00,280 --> 00:19:04,920 Speaker 1: forty Chain, Flory, Heatley, and others published Penicillin as a 288 00:19:05,000 --> 00:19:09,920 Speaker 1: chemotherapeutic agent in the journal Blancet, detailing the basic findings 289 00:19:09,960 --> 00:19:14,040 Speaker 1: of their research. It was clear from this work that 290 00:19:14,160 --> 00:19:18,639 Speaker 1: penicillin could potentially be a life saving drug for human beings, 291 00:19:19,400 --> 00:19:21,960 Speaker 1: and at this point, aside from the medicines we have 292 00:19:22,040 --> 00:19:25,400 Speaker 1: talked about in this episode, there just weren't many effective 293 00:19:25,440 --> 00:19:30,160 Speaker 1: options to treat bacterial infections. That meant that minor illnesses 294 00:19:30,240 --> 00:19:33,639 Speaker 1: like strep throat could lead to much more serious problems 295 00:19:33,720 --> 00:19:38,520 Speaker 1: like rheumatic fever. Life threatening infections could develop in injuries 296 00:19:38,560 --> 00:19:43,359 Speaker 1: that had seemed really superficial. People like Ignot Celeweiss and 297 00:19:43,520 --> 00:19:47,400 Speaker 1: Joseph Lister had advocated for things like hand washing and 298 00:19:47,480 --> 00:19:50,639 Speaker 1: sterile surgical techniques to cut down on the likelihood that 299 00:19:50,680 --> 00:19:54,320 Speaker 1: a person would contract an infection during childbirth or surgery, 300 00:19:54,920 --> 00:19:58,359 Speaker 1: but infections could still happen, and often there just was 301 00:19:58,480 --> 00:20:02,080 Speaker 1: not much that could be done a it SELFA drugs 302 00:20:02,119 --> 00:20:06,080 Speaker 1: had been a huge step forward in providing broadly effective 303 00:20:06,119 --> 00:20:09,200 Speaker 1: treatments for bacterial infections, but a lot of people were 304 00:20:09,240 --> 00:20:12,200 Speaker 1: allergic to them, and most of them could also cause 305 00:20:12,200 --> 00:20:16,240 Speaker 1: a range of unpleasant side effects. So figuring out whether 306 00:20:16,280 --> 00:20:19,280 Speaker 1: penicillin could be a usable drug in people and not 307 00:20:19,359 --> 00:20:22,959 Speaker 1: just small mammals was a huge priority, and since people 308 00:20:23,160 --> 00:20:26,440 Speaker 1: are significantly bigger than mice, that meant that the team 309 00:20:26,480 --> 00:20:29,600 Speaker 1: needed to grow a lot more mold. But at this 310 00:20:29,720 --> 00:20:33,600 Speaker 1: point the UK was a war. Germany had invaded Poland 311 00:20:33,640 --> 00:20:36,960 Speaker 1: on September first, nineteen thirty nine, and both the UK 312 00:20:37,160 --> 00:20:40,080 Speaker 1: and France had declared war on Germany two days later. 313 00:20:40,920 --> 00:20:43,480 Speaker 1: That meant that a lot of equipment and materials were 314 00:20:43,520 --> 00:20:46,679 Speaker 1: now dedicated to the war effort. For the sake of 315 00:20:46,720 --> 00:20:51,000 Speaker 1: time and expense, Norman Heatlely designed a flat, rectangular pottery 316 00:20:51,040 --> 00:20:54,359 Speaker 1: vessel with a spout that was stackable and glazed on 317 00:20:54,400 --> 00:20:58,320 Speaker 1: the inside to make it watertight. The team eventually used 318 00:20:58,440 --> 00:21:01,639 Speaker 1: seven hundred of these vessels to produce about five hundred 319 00:21:01,720 --> 00:21:05,520 Speaker 1: liters of mold broth every week, but this was a 320 00:21:05,600 --> 00:21:10,439 Speaker 1: slow and cumbersome and kind of fiddly processed. Even with 321 00:21:10,680 --> 00:21:14,439 Speaker 1: all seven hundred vessels in use, it took about four 322 00:21:14,480 --> 00:21:18,560 Speaker 1: weeks to make enough penicillin to treat one human patient, 323 00:21:19,240 --> 00:21:22,400 Speaker 1: and it took months for all seven hundred of those 324 00:21:22,480 --> 00:21:25,560 Speaker 1: vessels to be ready. At the end of nineteen forty 325 00:21:25,680 --> 00:21:28,479 Speaker 1: only about ninety of them were all set and had 326 00:21:28,520 --> 00:21:32,480 Speaker 1: been seeded with moldsbores. The first attempt to treat a 327 00:21:32,520 --> 00:21:36,080 Speaker 1: person with penicillin made from all of this mold started 328 00:21:36,080 --> 00:21:41,000 Speaker 1: on February twelfth, nineteen forty one. That patient was Albert Alexander, 329 00:21:41,119 --> 00:21:45,920 Speaker 1: and there are multiple conflicting descriptions of how he became injured. 330 00:21:46,800 --> 00:21:50,520 Speaker 1: In some accounts, he cut himself shaving. In others, he 331 00:21:50,600 --> 00:21:54,800 Speaker 1: scratched himself while pruning roses. In still others, he was 332 00:21:54,880 --> 00:21:58,560 Speaker 1: injured in a bombing during the blitz. But regardless of 333 00:21:58,600 --> 00:22:01,800 Speaker 1: the cause, it is documented that he had a very 334 00:22:01,840 --> 00:22:05,399 Speaker 1: serious infection that was certain to be fatal if left untreated. 335 00:22:06,560 --> 00:22:11,000 Speaker 1: Alexander showed promising signs of recovery within twenty four hours 336 00:22:11,000 --> 00:22:15,640 Speaker 1: of being treated with penicillin, but because so little penicillin 337 00:22:15,760 --> 00:22:18,280 Speaker 1: had been made at this point, they had to collect 338 00:22:18,320 --> 00:22:21,479 Speaker 1: his urine and extract the penicillin out of it and 339 00:22:21,520 --> 00:22:26,560 Speaker 1: then reuse it. So the body excretes penicillin really rapidly, 340 00:22:27,040 --> 00:22:29,760 Speaker 1: and roughly seventy percent of it comes out in the 341 00:22:29,880 --> 00:22:33,000 Speaker 1: urine unchanged. It could be more or less than that. 342 00:22:33,119 --> 00:22:35,560 Speaker 1: I saw numbers that were literally from one percent to 343 00:22:35,680 --> 00:22:40,480 Speaker 1: ninety nine percent. It's possible to recover half or more 344 00:22:40,560 --> 00:22:44,240 Speaker 1: of that excreted penicillin using the same basic method that 345 00:22:44,359 --> 00:22:46,840 Speaker 1: was used to extract it from the mold broth in 346 00:22:46,960 --> 00:22:50,760 Speaker 1: the first place. Even with the penicillin that had been 347 00:22:50,800 --> 00:22:54,520 Speaker 1: reclaimed from his urine, there wasn't enough to totally cure 348 00:22:54,640 --> 00:22:59,480 Speaker 1: Alexander's infection. Eventually, the team had given him all of 349 00:22:59,480 --> 00:23:02,679 Speaker 1: the pennacilin they had, and after they ran out, his 350 00:23:02,760 --> 00:23:07,720 Speaker 1: infection returned. He died on March fifteenth, nineteen forty one. 351 00:23:08,080 --> 00:23:11,000 Speaker 1: So it was clear that making enough penicillin to do 352 00:23:11,119 --> 00:23:14,400 Speaker 1: a clinical trial was going to be a huge challenge. 353 00:23:15,000 --> 00:23:16,919 Speaker 1: With all this effort, they had not made enough to 354 00:23:16,960 --> 00:23:21,960 Speaker 1: successfully treat even one patient, Although focusing on treating children 355 00:23:22,080 --> 00:23:24,919 Speaker 1: would have allowed the team to use smaller doses, at 356 00:23:24,920 --> 00:23:28,600 Speaker 1: this point, the priority was really confirming that penicillin worked 357 00:23:28,680 --> 00:23:32,800 Speaker 1: in adults, and then if it did, supplying Allied troops 358 00:23:32,840 --> 00:23:36,840 Speaker 1: with it. Infections were a major major cause of death 359 00:23:36,880 --> 00:23:41,120 Speaker 1: for wounded soldiers, and effective treatments for bacterial illnesses could 360 00:23:41,119 --> 00:23:45,520 Speaker 1: also allow six soldiers to return to duty faster, but 361 00:23:45,560 --> 00:23:48,679 Speaker 1: the prospects for doing that in the UK were grim. 362 00:23:49,240 --> 00:23:52,119 Speaker 1: Although there were British companies that were interested in working 363 00:23:52,119 --> 00:23:56,600 Speaker 1: with penicillin, most were dedicated to critical wartime work involving 364 00:23:56,680 --> 00:23:59,439 Speaker 1: drugs and other chemicals that were already known to have 365 00:23:59,520 --> 00:24:03,640 Speaker 1: a use. Plus, British factories were at risk of being 366 00:24:03,720 --> 00:24:08,639 Speaker 1: bombed or otherwise attacked. Flori and his team also understood 367 00:24:08,680 --> 00:24:12,320 Speaker 1: that if Britain were invaded, they might need to destroy 368 00:24:12,359 --> 00:24:15,440 Speaker 1: their research work to prevent it from being captured by 369 00:24:15,520 --> 00:24:19,639 Speaker 1: the Germans. But they were also really unwilling to risk 370 00:24:19,880 --> 00:24:25,560 Speaker 1: losing their penicillium mold entirely. Norman Heatly suggested that several 371 00:24:25,600 --> 00:24:30,199 Speaker 1: of them intentionally rub mold into their coats so that 372 00:24:30,240 --> 00:24:33,000 Speaker 1: if they had to flee, they could just wear their 373 00:24:33,040 --> 00:24:39,320 Speaker 1: samples with them undetected. Why does everybody a miss on 374 00:24:39,359 --> 00:24:44,160 Speaker 1: this transport smelt weird? Smells a little musty. In nineteen 375 00:24:44,240 --> 00:24:47,440 Speaker 1: forty one, Flori and Heatly went to the United States 376 00:24:47,520 --> 00:24:51,240 Speaker 1: to try to find pharmaceutical companies that could help whek 377 00:24:51,280 --> 00:24:53,800 Speaker 1: in the UK didn't stop at this point or in 378 00:24:53,880 --> 00:24:57,439 Speaker 1: other countries that had started experimenting with penicillium, but the 379 00:24:57,520 --> 00:25:00,919 Speaker 1: focus on mass producing penicillin shift did to the US, 380 00:25:01,320 --> 00:25:03,919 Speaker 1: and we'll talk more about that. After a sponsor break 381 00:25:13,400 --> 00:25:16,359 Speaker 1: in June of nineteen forty one, Howard Flory and Norman 382 00:25:16,440 --> 00:25:19,480 Speaker 1: Heatley took a series of flights to get from the 383 00:25:19,600 --> 00:25:22,880 Speaker 1: UK to the US. These flights were paid for by 384 00:25:22,880 --> 00:25:26,159 Speaker 1: the Rockefeller Foundation, which had also done some of the 385 00:25:26,200 --> 00:25:30,880 Speaker 1: funding for their research. When they left, they had treated 386 00:25:30,960 --> 00:25:35,720 Speaker 1: a total of six patients with penicillin, in addition to 387 00:25:35,760 --> 00:25:40,119 Speaker 1: Albert Alexander. One other patient had died, but that patient 388 00:25:40,200 --> 00:25:44,119 Speaker 1: died of a ruptured aneurysm, not of the infection that 389 00:25:44,160 --> 00:25:49,240 Speaker 1: the penicillin was treating. There was just not enough penicillin 390 00:25:49,320 --> 00:25:53,320 Speaker 1: to treat more people than that. As Flory and Heatley 391 00:25:53,400 --> 00:25:56,840 Speaker 1: were preparing to go, the Oxford team was preparing and 392 00:25:56,960 --> 00:25:59,800 Speaker 1: freeze drying as much penicillin as possible for them to 393 00:25:59,840 --> 00:26:03,879 Speaker 1: take with them. Flori was also finishing a second paper 394 00:26:04,000 --> 00:26:07,639 Speaker 1: titled Further Observations on Penicillin, which went on to be 395 00:26:07,680 --> 00:26:11,719 Speaker 1: published that August. There had been a lot of debate 396 00:26:11,800 --> 00:26:14,840 Speaker 1: about whether to publish this paper. On the one hand, 397 00:26:14,920 --> 00:26:18,240 Speaker 1: it contained a lot of information that could save people's lives, 398 00:26:18,480 --> 00:26:21,640 Speaker 1: but on the other hand, there were concerns about Germany 399 00:26:21,760 --> 00:26:25,159 Speaker 1: or its allies producing penicillin, which could provide them with 400 00:26:25,200 --> 00:26:28,360 Speaker 1: an advantage in the war, and that paper would give 401 00:26:28,400 --> 00:26:31,119 Speaker 1: them a lot more information to do it. There were 402 00:26:31,160 --> 00:26:35,840 Speaker 1: similar debates among the Oxford team about whether to patent penicillin. 403 00:26:36,600 --> 00:26:39,679 Speaker 1: A lot of them found the idea of patenting any 404 00:26:40,000 --> 00:26:44,040 Speaker 1: medicine to be just appalling. While Ernst Chane argued that 405 00:26:44,080 --> 00:26:47,800 Speaker 1: penicillin was their work and it deserved to be protected. 406 00:26:48,720 --> 00:26:52,400 Speaker 1: Chaine also thought that their ongoing struggles to get enough 407 00:26:52,440 --> 00:26:55,840 Speaker 1: funding for their work would be totally resolved if it 408 00:26:55,880 --> 00:26:59,719 Speaker 1: could just be paid for through licensing fees from a patent. 409 00:27:00,480 --> 00:27:03,960 Speaker 1: Chain was also deeply disappointed by not being part of 410 00:27:04,000 --> 00:27:06,160 Speaker 1: this trip to the United States, and this is something 411 00:27:06,200 --> 00:27:09,240 Speaker 1: that seems to have caused a huge rift between him 412 00:27:09,760 --> 00:27:12,760 Speaker 1: and Flory. Since the whole purpose of this trip was 413 00:27:12,760 --> 00:27:15,520 Speaker 1: to try to get manufacturing started, and Heatlely was the 414 00:27:15,560 --> 00:27:18,360 Speaker 1: person who had been focused on manufacturing like it makes 415 00:27:18,400 --> 00:27:21,640 Speaker 1: sense that Heatly would be the person to go. They 416 00:27:21,680 --> 00:27:24,600 Speaker 1: also wanted to minimize the number of people going for 417 00:27:24,600 --> 00:27:27,840 Speaker 1: the sake of secrecy. The decision made sense, but Chain 418 00:27:27,920 --> 00:27:31,080 Speaker 1: seems to have been incredibly upset by it. The US 419 00:27:31,119 --> 00:27:33,919 Speaker 1: had passed the Lend Lease Act in March of nineteen 420 00:27:33,960 --> 00:27:37,520 Speaker 1: forty one, which established a framework for the United States 421 00:27:37,560 --> 00:27:42,639 Speaker 1: to provide the allies with things like weapons, vehicles, materials, machinery, 422 00:27:42,680 --> 00:27:46,480 Speaker 1: and facilities that would promote the defense of the United States. 423 00:27:47,320 --> 00:27:51,480 Speaker 1: The manufacture of penicillin seemed to fall under that definition, 424 00:27:51,920 --> 00:27:54,199 Speaker 1: but Flory and heat Ly still had to find a 425 00:27:54,200 --> 00:27:57,919 Speaker 1: pharmaceutical company that had the interest and the ability to 426 00:27:57,960 --> 00:28:01,600 Speaker 1: try to produce penicillin on a commercial scale. They had 427 00:28:01,600 --> 00:28:04,400 Speaker 1: a series of meetings and disappointments and kind of stops 428 00:28:04,440 --> 00:28:07,640 Speaker 1: and starts, and then Flory and Heatly wound up at 429 00:28:07,640 --> 00:28:13,760 Speaker 1: the Department of Agriculture's Northern Regional Research Laboratory were NRRL 430 00:28:14,200 --> 00:28:18,200 Speaker 1: in Peoria, Illinois, which already had a fermentation division, which 431 00:28:18,240 --> 00:28:23,400 Speaker 1: was very handy since they grew penicillin by fermenting. Researchers 432 00:28:23,520 --> 00:28:27,560 Speaker 1: there started working on finding ways to grow penicillium mold 433 00:28:27,800 --> 00:28:30,399 Speaker 1: a lot faster than it had been They started on 434 00:28:30,400 --> 00:28:33,919 Speaker 1: that work in July of nineteen forty one. This was 435 00:28:33,960 --> 00:28:38,160 Speaker 1: a multi step process. At Oxford, researchers had been growing 436 00:28:38,200 --> 00:28:42,040 Speaker 1: the mold in a broth in flat rectangular pottery vessels. 437 00:28:42,680 --> 00:28:46,080 Speaker 1: In Illinois, researchers figured out that growing it in corn 438 00:28:46,160 --> 00:28:51,440 Speaker 1: steep liquor yielded about ten times more penicillin. This was 439 00:28:51,520 --> 00:28:54,719 Speaker 1: convenient because corn steep liquor is a byproduct of the 440 00:28:54,720 --> 00:28:57,920 Speaker 1: wet milling process, and people were already trying to find 441 00:28:57,920 --> 00:29:01,560 Speaker 1: a practical use for it. Those vessels in Oxford were 442 00:29:01,560 --> 00:29:05,000 Speaker 1: also rectangular and flat because the mold was essentially growing 443 00:29:05,240 --> 00:29:09,120 Speaker 1: as a flat surface layer, and researchers in Peoria thought 444 00:29:09,160 --> 00:29:11,760 Speaker 1: it would be more efficient to grow the mold in 445 00:29:11,840 --> 00:29:16,920 Speaker 1: a submerged medium, but this also required they're finding a 446 00:29:17,000 --> 00:29:21,080 Speaker 1: different strain of penicillium mold that would grow really well 447 00:29:21,160 --> 00:29:26,680 Speaker 1: while submerged and also produced the antimicrobial substance that they need, 448 00:29:26,720 --> 00:29:29,640 Speaker 1: because not all of the penicillium strains really did that 449 00:29:29,800 --> 00:29:34,840 Speaker 1: very well. This involved gathering mold from all over the world, 450 00:29:34,880 --> 00:29:37,840 Speaker 1: which they did with the help of the Army Transportation Corps, 451 00:29:37,840 --> 00:29:42,080 Speaker 1: and they tested all these samples in the lab. They eventually, though, 452 00:29:42,240 --> 00:29:46,320 Speaker 1: found a sample growing on a moldy cantelope that worked 453 00:29:46,360 --> 00:29:50,720 Speaker 1: really well. This find is usually credited to lab assistant 454 00:29:50,800 --> 00:29:54,840 Speaker 1: Mary kay Hunt, who was nicknamed Moldy Mary. She had 455 00:29:54,920 --> 00:29:58,360 Speaker 1: found this cantelope not in some far reaching place brought 456 00:29:58,400 --> 00:30:00,880 Speaker 1: back by the Army Transportation Corp, but at a local 457 00:30:00,920 --> 00:30:06,240 Speaker 1: Peoria fruit market. The strain of the mold, Penicillium chrysogenome, 458 00:30:06,360 --> 00:30:09,880 Speaker 1: was about one hundred times more productive than the other 459 00:30:10,040 --> 00:30:14,000 Speaker 1: strains they tried. Even as the research lab figured out 460 00:30:14,000 --> 00:30:17,720 Speaker 1: ways to increase the yield of penicillium mold. They still 461 00:30:17,840 --> 00:30:22,160 Speaker 1: needed pharmaceutical or chemical manufacturers to actually get a penicillin 462 00:30:22,240 --> 00:30:26,280 Speaker 1: drug into production. A group of pharmaceutical companies and the 463 00:30:26,280 --> 00:30:29,800 Speaker 1: federal government met in October of nineteen forty one to 464 00:30:29,880 --> 00:30:34,800 Speaker 1: coordinate both the production process and information sharing. The goal 465 00:30:35,080 --> 00:30:38,960 Speaker 1: was to first produce enough penicillin for clinical trials, and then, 466 00:30:39,440 --> 00:30:42,680 Speaker 1: if those were successful, to scale up production to make 467 00:30:42,720 --> 00:30:46,120 Speaker 1: as much as could be needed for Allied troops. This 468 00:30:46,280 --> 00:30:50,560 Speaker 1: was a huge and really unprecedented level of cooperation. It 469 00:30:50,680 --> 00:30:53,680 Speaker 1: was also going to be really tricky. John L. Smith 470 00:30:53,760 --> 00:30:56,640 Speaker 1: from Pfizer had this to say about it, quote, the 471 00:30:56,720 --> 00:31:01,080 Speaker 1: mold is as temperamental as an opera singer. The yields 472 00:31:01,080 --> 00:31:05,280 Speaker 1: are low, the isolation is difficult, the extraction is murder, 473 00:31:05,640 --> 00:31:11,560 Speaker 1: the purification invites disaster, and the assay is unsatisfactory. So 474 00:31:11,600 --> 00:31:15,760 Speaker 1: the Office of Science, Research and Development helped coordinate information 475 00:31:15,920 --> 00:31:20,080 Speaker 1: sharing about methods and techniques to do this successfully. Along 476 00:31:20,120 --> 00:31:25,000 Speaker 1: with managing fifty seven different research contracts related to it, 477 00:31:25,840 --> 00:31:29,960 Speaker 1: the War Production Board also worked with twenty five different 478 00:31:30,000 --> 00:31:34,160 Speaker 1: companies to scale up production of penicillin. They narrowed it 479 00:31:34,200 --> 00:31:37,239 Speaker 1: down to those twenty five after investigating more than one 480 00:31:37,360 --> 00:31:40,440 Speaker 1: hundred and seventy five different companies to determine whether they 481 00:31:40,480 --> 00:31:43,720 Speaker 1: were suitable or not. The first patient in the US 482 00:31:43,800 --> 00:31:46,400 Speaker 1: to be treated with penicillin was thirty three year old 483 00:31:46,480 --> 00:31:50,720 Speaker 1: Anne Miller, who had developed septocemia after a pregnancy loss. 484 00:31:51,440 --> 00:31:54,840 Speaker 1: Her treatment started on March fourteenth, nineteen forty two, and 485 00:31:54,920 --> 00:31:58,959 Speaker 1: it required half the penicillin that was in existence in 486 00:31:59,000 --> 00:32:02,840 Speaker 1: the US at that point. Also in nineteen forty two, 487 00:32:02,920 --> 00:32:06,600 Speaker 1: back in the UK, Alexander Fleming got some penicillin from 488 00:32:06,600 --> 00:32:10,040 Speaker 1: the Oxford group, which was still at work, used that 489 00:32:10,120 --> 00:32:12,440 Speaker 1: to treat one of his patients, and when that treatment 490 00:32:12,480 --> 00:32:15,280 Speaker 1: was successful, he got a huge write up about it 491 00:32:15,320 --> 00:32:19,880 Speaker 1: in The Times. This article didn't actually mention Flory or 492 00:32:19,920 --> 00:32:23,040 Speaker 1: any of the other researchers at the Oxford team, though, 493 00:32:23,280 --> 00:32:26,800 Speaker 1: and this really started to build the perception that penicillin 494 00:32:27,320 --> 00:32:32,400 Speaker 1: was solely Fleming's work. Fleming also seemed willing to take 495 00:32:32,440 --> 00:32:35,080 Speaker 1: that credit, and Flory didn't want to talk to the 496 00:32:35,120 --> 00:32:37,840 Speaker 1: press and also didn't want the rest of the Oxford 497 00:32:37,920 --> 00:32:42,080 Speaker 1: team to talk to the press, just really starting the 498 00:32:42,080 --> 00:32:46,480 Speaker 1: ball rolling on this being just Alexander Fleming's own work 499 00:32:46,560 --> 00:32:49,840 Speaker 1: and nobody else's. The fact that all of this was 500 00:32:49,880 --> 00:32:53,080 Speaker 1: happening during World War Two came along with a number 501 00:32:53,080 --> 00:32:56,920 Speaker 1: of ethical dilemmas. One that we referenced earlier was how 502 00:32:57,000 --> 00:33:01,400 Speaker 1: careful researchers should be about making sure information about penicillin 503 00:33:01,800 --> 00:33:06,240 Speaker 1: and penicillin production wasn't available to Germany or its allies. 504 00:33:07,280 --> 00:33:10,920 Speaker 1: Doctors and medical ethicists generally agreed that if a patient 505 00:33:10,960 --> 00:33:14,880 Speaker 1: needed penicillin and the penicillin was available, they could have it, 506 00:33:15,120 --> 00:33:18,280 Speaker 1: regardless of their nationality or what army they fought for. 507 00:33:19,480 --> 00:33:23,880 Speaker 1: But since access to penicillin could also create a military advantage, 508 00:33:23,920 --> 00:33:27,160 Speaker 1: people also believed that information about how to make it 509 00:33:27,800 --> 00:33:30,760 Speaker 1: or samples of the mold itself should not be shared, 510 00:33:31,120 --> 00:33:34,160 Speaker 1: not with Germany and not with any countries likely to 511 00:33:34,240 --> 00:33:39,160 Speaker 1: cooperate with Germany. There are a lot of articles discussing whether, 512 00:33:39,360 --> 00:33:42,600 Speaker 1: in fact, somebody in Germany did or did not receive 513 00:33:42,640 --> 00:33:46,360 Speaker 1: one of Fleming's samples way earlier in this whole story, 514 00:33:46,400 --> 00:33:51,800 Speaker 1: before the hostilities started. Within the US, another ethical issue 515 00:33:51,880 --> 00:33:56,240 Speaker 1: was access to penicillin, because once clinical trials were complete, 516 00:33:56,360 --> 00:34:00,000 Speaker 1: the penicillin being produced was going to be reserved almost 517 00:34:00,000 --> 00:34:05,120 Speaker 1: most exclusively for military use. At the same time, there 518 00:34:05,120 --> 00:34:08,480 Speaker 1: were definitely going to be civilians whose lives would be 519 00:34:08,600 --> 00:34:12,960 Speaker 1: lost without it. Doctor Chester Keefer was responsible for rationing 520 00:34:13,120 --> 00:34:18,120 Speaker 1: penicillin to civilians and was absolutely inundated with requests for it. 521 00:34:18,960 --> 00:34:22,120 Speaker 1: This led some people to figure out ways to make 522 00:34:22,160 --> 00:34:27,000 Speaker 1: their own penicillin. For example, on November tenth, nineteen forty three, 523 00:34:27,120 --> 00:34:30,319 Speaker 1: Julius A. Vogel, who was the plant physician at a 524 00:34:30,400 --> 00:34:34,200 Speaker 1: steel plant in Pennsylvania, figured out how to make penicillin 525 00:34:34,280 --> 00:34:38,239 Speaker 1: in his kitchen. See my plan as a kid was 526 00:34:38,280 --> 00:34:43,799 Speaker 1: not completely not now because I had the knowledge of 527 00:34:43,840 --> 00:34:48,120 Speaker 1: a plant physition. Vogel based his work on an earlier 528 00:34:48,200 --> 00:34:52,319 Speaker 1: discovery by George Robinson and James Wallace at Singer Laboratory 529 00:34:52,360 --> 00:34:57,200 Speaker 1: at Allegheny General Hospital in Pittsburgh, Pennsylvania. On October eighth, 530 00:34:57,320 --> 00:35:00,399 Speaker 1: nineteen forty three, they reported that they had found away 531 00:35:00,440 --> 00:35:03,200 Speaker 1: to make a topical treatment by soaking a gauze pad 532 00:35:03,239 --> 00:35:06,319 Speaker 1: and penicillium mold and then letting it grow in a 533 00:35:06,360 --> 00:35:10,440 Speaker 1: petrie dish for four or five days. Vogel, who had 534 00:35:10,440 --> 00:35:13,640 Speaker 1: been disabled following a serious infection in his knee as 535 00:35:13,680 --> 00:35:16,919 Speaker 1: a child, built on this to turn his kitchen into 536 00:35:16,960 --> 00:35:23,200 Speaker 1: a miniature factory for treating similarly mold infused gauze. Vogel's wife, Eunice, 537 00:35:23,320 --> 00:35:25,760 Speaker 1: was a big part of this process, making the augur 538 00:35:25,840 --> 00:35:29,759 Speaker 1: for the petrie dishes and sterilizing the equipment between batches. 539 00:35:30,800 --> 00:35:33,080 Speaker 1: As you can imagine, all of this required a lot 540 00:35:33,120 --> 00:35:35,920 Speaker 1: of careful planning to keep a steady supply of mold 541 00:35:36,280 --> 00:35:40,360 Speaker 1: that was the right age to produce penicillin. Yeah, Vogel 542 00:35:40,400 --> 00:35:44,600 Speaker 1: talked a lot about how if penicillin had existed when 543 00:35:44,600 --> 00:35:48,560 Speaker 1: he was a child, he probably would not have almost 544 00:35:48,760 --> 00:35:52,680 Speaker 1: died and then had like a disability that affected him 545 00:35:52,680 --> 00:35:56,400 Speaker 1: for the rest of his life. Vogel presented his development 546 00:35:56,600 --> 00:36:00,000 Speaker 1: at the Department of Industrial Research on November eleventh night, 547 00:36:00,000 --> 00:36:03,520 Speaker 1: eighteen forty three, and he got a lot of criticism 548 00:36:03,560 --> 00:36:06,359 Speaker 1: from the research community and from the companies that were 549 00:36:06,440 --> 00:36:12,480 Speaker 1: working on mass producing penicillin. There were some understandable concerns 550 00:36:12,560 --> 00:36:15,640 Speaker 1: about the potential for penicillin made at home to be 551 00:36:15,760 --> 00:36:20,960 Speaker 1: contaminated in some way, but Vogel reportedly used these gauze 552 00:36:20,960 --> 00:36:25,120 Speaker 1: pads at steel mills all over the area, treating workers 553 00:36:25,160 --> 00:36:28,360 Speaker 1: who had on the job accidents and otherwise would have 554 00:36:28,440 --> 00:36:32,120 Speaker 1: just not had access to any antibiotics at all. Yet 555 00:36:32,160 --> 00:36:36,319 Speaker 1: another ethical conundrum arose after Flory and Chain traveled to 556 00:36:36,400 --> 00:36:40,160 Speaker 1: Northern Africa in nineteen forty three to test penicillin on 557 00:36:40,280 --> 00:36:45,400 Speaker 1: wounded soldiers and realized that it was also effective against gonorrhea. 558 00:36:46,239 --> 00:36:49,320 Speaker 1: Before this point, penicillin had been envisioned as something that 559 00:36:49,360 --> 00:36:52,000 Speaker 1: would save the lives of soldiers who had been seriously 560 00:36:52,000 --> 00:36:55,640 Speaker 1: injured in battle or had contracted a serious illness like 561 00:36:55,760 --> 00:37:00,520 Speaker 1: bacterial pneumonia, but gonorrhea, especially in its early set stages, 562 00:37:00,880 --> 00:37:04,640 Speaker 1: is more of a nuisance. Winston Churchill reportedly said that 563 00:37:04,680 --> 00:37:08,799 Speaker 1: penicillin should be used for the quote best military advantage, 564 00:37:09,200 --> 00:37:12,359 Speaker 1: which meant when supplies were limited, getting soldiers who had 565 00:37:12,360 --> 00:37:17,000 Speaker 1: gonorrhea back into peak condition, rather than treating seriously injured 566 00:37:17,000 --> 00:37:20,359 Speaker 1: soldiers who were going to be sent back home. Those 567 00:37:20,560 --> 00:37:24,759 Speaker 1: supplies were not limited for that much longer, though. Pfizer's 568 00:37:24,840 --> 00:37:28,840 Speaker 1: first plant for the commercial production of penicillin opened in Brooklyn, 569 00:37:28,920 --> 00:37:32,960 Speaker 1: New York, on March first, nineteen forty four. By that point, 570 00:37:33,000 --> 00:37:37,840 Speaker 1: clinical trials had showed that penicillin was clearly beneficial against 571 00:37:37,920 --> 00:37:42,719 Speaker 1: a range of pathogenic bacteria. Refinements to the production process 572 00:37:42,920 --> 00:37:46,120 Speaker 1: and to the mold itself using things like X rays 573 00:37:46,200 --> 00:37:52,160 Speaker 1: and UV light continued to increase the yield. Meanwhile, Alexander Fleming, 574 00:37:52,640 --> 00:37:54,840 Speaker 1: who wasn't involved with any of this, was on the 575 00:37:54,840 --> 00:37:57,960 Speaker 1: cover of Time magazine on May fifteenth of nineteen forty four. 576 00:37:59,040 --> 00:38:02,400 Speaker 1: By this point, pharmaceutical companies in the US were trying 577 00:38:02,400 --> 00:38:05,400 Speaker 1: to produce enough penicillin to meet the needs of the 578 00:38:05,440 --> 00:38:09,480 Speaker 1: D Day invasion. Propaganda posters were hung on the walls 579 00:38:09,520 --> 00:38:13,080 Speaker 1: of penicillin factories reminding workers that they were doing it 580 00:38:13,160 --> 00:38:16,720 Speaker 1: for the troops, and production of penicillin in the US 581 00:38:16,840 --> 00:38:21,440 Speaker 1: expanded rapidly. Twenty one billion units of the drug had 582 00:38:21,480 --> 00:38:24,640 Speaker 1: been made in nineteen forty three, and in nineteen forty 583 00:38:24,680 --> 00:38:29,160 Speaker 1: five it had jumped to six point eight trillion. In 584 00:38:29,239 --> 00:38:31,920 Speaker 1: March of nineteen forty five, the US was able to 585 00:38:32,000 --> 00:38:36,160 Speaker 1: lift rationing restrictions on penicillin and make it commercially available 586 00:38:36,200 --> 00:38:39,880 Speaker 1: to the public. After the liberation of Paris in nineteen 587 00:38:39,960 --> 00:38:44,640 Speaker 1: forty four, American military hospitals throughout France started trying to 588 00:38:44,800 --> 00:38:49,560 Speaker 1: extend the supply of penicillin in the country, which is 589 00:38:49,600 --> 00:38:55,400 Speaker 1: what inspired this episode. The French Military Penicillin Team was established, 590 00:38:55,440 --> 00:38:58,680 Speaker 1: and starting in January of nineteen forty five, the team 591 00:38:58,920 --> 00:39:03,200 Speaker 1: collected urine from patients to reclaim the penicillin in it. 592 00:39:03,760 --> 00:39:06,439 Speaker 1: So if a patient was being treated with penicillin, their 593 00:39:06,480 --> 00:39:08,920 Speaker 1: bed was marked with a placard to note that their 594 00:39:09,080 --> 00:39:12,480 Speaker 1: urine should be collected. Patients who were well enough to 595 00:39:12,480 --> 00:39:15,320 Speaker 1: get up and go to the bathroom themselves were instructed 596 00:39:15,360 --> 00:39:18,279 Speaker 1: to urinate in flasks that were just left around the 597 00:39:18,320 --> 00:39:23,000 Speaker 1: wards for that purpose. Officials were understandably a little concerned 598 00:39:23,040 --> 00:39:26,399 Speaker 1: that these flasks that people were peeing into could themselves 599 00:39:26,480 --> 00:39:30,120 Speaker 1: become a source of infection, so the penicillin team collected 600 00:39:30,160 --> 00:39:34,960 Speaker 1: them all twice a day. After the war, manufacturing methods 601 00:39:34,960 --> 00:39:37,480 Speaker 1: for penicillin that had been developed in the US were 602 00:39:37,480 --> 00:39:41,160 Speaker 1: introduced in the UK, which meant that the same researchers 603 00:39:41,200 --> 00:39:44,440 Speaker 1: who had originally developed the drug had to pay licensing 604 00:39:44,480 --> 00:39:49,040 Speaker 1: fees to access American methods to produce it. Although penicillin 605 00:39:49,160 --> 00:39:53,000 Speaker 1: itself had not been patented, some of the manufacturing methods 606 00:39:53,120 --> 00:39:57,319 Speaker 1: had been. New Penicillin factories were also established around the 607 00:39:57,320 --> 00:40:01,440 Speaker 1: world as nations started making their own supply or expanded 608 00:40:01,480 --> 00:40:03,839 Speaker 1: production from research that they had been doing as the 609 00:40:03,840 --> 00:40:08,360 Speaker 1: war was going on. Alexander Fleming Ernst Boris Chain and 610 00:40:08,440 --> 00:40:12,279 Speaker 1: Howard Walter Florey were jointly awarded the Nobel Prize in 611 00:40:12,320 --> 00:40:17,040 Speaker 1: Physiology or Medicine in nineteen forty five. That same year, 612 00:40:17,239 --> 00:40:22,160 Speaker 1: the chemical structure of penicillin was confirmed by Dorothy Crowfoot Hodgkin, 613 00:40:22,600 --> 00:40:25,920 Speaker 1: and that paved the way for synthetic forms of penicillin. 614 00:40:26,520 --> 00:40:33,200 Speaker 1: Penicillin's effect on medicine was massive, and many other antibiotics followed. Streptomycin, 615 00:40:33,239 --> 00:40:36,520 Speaker 1: which was the first truly effective treatment for tuberculosis, was 616 00:40:36,560 --> 00:40:39,960 Speaker 1: developed in nineteen forty three. We have covered that and 617 00:40:40,040 --> 00:40:42,880 Speaker 1: the controversy around who should be credited with discovering it 618 00:40:43,280 --> 00:40:47,200 Speaker 1: on the podcast in twenty thirteen. This is an enormous 619 00:40:47,320 --> 00:40:51,839 Speaker 1: advance in medicine. But by the nineteen fifties, some bacteria 620 00:40:51,920 --> 00:40:57,120 Speaker 1: were already becoming resistant to penicillin, including some strains of 621 00:40:57,200 --> 00:41:01,400 Speaker 1: staff bacteria, and this was something that fled had foreseen, 622 00:41:01,719 --> 00:41:04,560 Speaker 1: and he warned about it in his Nobel Prize address 623 00:41:04,680 --> 00:41:08,759 Speaker 1: quote that is not difficult to make microbes resistant to 624 00:41:08,800 --> 00:41:12,839 Speaker 1: penicillin in the laboratory by exposing them to concentrations not 625 00:41:12,920 --> 00:41:16,320 Speaker 1: sufficient to kill them. And the same thing has occasionally 626 00:41:16,360 --> 00:41:20,360 Speaker 1: happened in the body. The time may come when penicillin 627 00:41:20,440 --> 00:41:23,520 Speaker 1: can be bought by anyone in the shops. Then there 628 00:41:23,600 --> 00:41:27,200 Speaker 1: is the danger that the ignorant man may easily underdose 629 00:41:27,280 --> 00:41:31,440 Speaker 1: himself and by exposing his microbes to non lethal quantities 630 00:41:31,480 --> 00:41:36,479 Speaker 1: of the drug, make them resistant. This is obviously still 631 00:41:36,520 --> 00:41:39,480 Speaker 1: a problem. You've probably heard about it in your day 632 00:41:39,520 --> 00:41:42,359 Speaker 1: to day life at some point, and it's compounded by 633 00:41:42,360 --> 00:41:45,400 Speaker 1: the fact that most antibiotics in use today were developed 634 00:41:45,400 --> 00:41:48,880 Speaker 1: between the nineteen forties and the nineteen sixties, along with 635 00:41:48,920 --> 00:41:53,400 Speaker 1: the widespread use of antibiotics in agriculture. In twenty fourteen, 636 00:41:53,440 --> 00:41:56,280 Speaker 1: the World Health Organization warned that the world is nearing 637 00:41:56,320 --> 00:42:00,560 Speaker 1: the point of a post antibiotic era and currently describes 638 00:42:00,560 --> 00:42:04,760 Speaker 1: antibiotic resistance as one of the biggest threats to global health, 639 00:42:05,080 --> 00:42:10,440 Speaker 1: food security, and development. Yeah, the use of penicillin and 640 00:42:10,600 --> 00:42:13,720 Speaker 1: other antibiotics after the discovery and sort of the golden 641 00:42:13,760 --> 00:42:18,280 Speaker 1: age of antibiotics be a whole other episode. We're living 642 00:42:18,440 --> 00:42:26,480 Speaker 1: through it. Thanks so much for joining us on this Saturday. 643 00:42:26,640 --> 00:42:28,400 Speaker 1: If you'd like to send us a note, our email 644 00:42:28,440 --> 00:42:33,160 Speaker 1: addresses History Podcast at iHeartRadio dot com, and you can 645 00:42:33,160 --> 00:42:36,640 Speaker 1: subscribe to the show on the iHeartRadio app. Apple podcasts, 646 00:42:36,760 --> 00:42:38,880 Speaker 1: or wherever you listen to your favorite shows.