WEBVTT 00:00:00.000 --> 00:00:03.240 Okay, so today we're diving deep into something 00:00:03.240 --> 00:00:07.759 pretty incredible. Yeah, this one is, it's a 00:00:07.759 --> 00:00:10.679 big one. It is, it's penicillin. Penicillin, 00:00:10.820 --> 00:00:13.220 that's right. Yeah, and I think what makes this 00:00:13.220 --> 00:00:15.539 one so interesting is, you gave me all this great 00:00:15.539 --> 00:00:17.920 material to look at, and it's everything from 00:00:17.920 --> 00:00:20.730 like the, you know, the. the sort of accidental 00:00:20.730 --> 00:00:24.210 discovery to the manufacturing process and the 00:00:24.210 --> 00:00:27.230 regulation and the economic impact. I mean, it's 00:00:27.230 --> 00:00:30.030 a lot. It's the whole picture. Yeah, it's the 00:00:30.030 --> 00:00:32.950 whole thing. And so we're going to try to distill 00:00:32.950 --> 00:00:36.990 all that down to the good stuff, all the really 00:00:36.990 --> 00:00:39.450 cool, the really interesting stuff. Yeah. And 00:00:39.450 --> 00:00:41.229 really what's amazing about this is this is like 00:00:41.229 --> 00:00:44.409 a fundamental shift in how we treated diseases. 00:00:44.429 --> 00:00:46.729 Yeah. Before this, bacterial infections were 00:00:46.729 --> 00:00:48.509 like the number one killer, and this was like 00:00:48.509 --> 00:00:50.759 a huge So let's start right at the beginning 00:00:50.759 --> 00:00:52.880 with the historical origins of this. How did 00:00:52.880 --> 00:00:55.299 this all come about? Well, so it all starts in 00:00:55.299 --> 00:00:59.280 1928 with a guy named Alexander Fleming. And 00:00:59.280 --> 00:01:02.560 he was a professor at St. Mary's Hospital in 00:01:02.560 --> 00:01:05.780 London. And what he was doing was he was working 00:01:05.780 --> 00:01:08.939 with cultures of Staphylococcus, which is a very 00:01:08.939 --> 00:01:13.379 common bacteria. And as the story goes, one of 00:01:13.379 --> 00:01:16.359 his petri dishes accidentally got contaminated 00:01:16.359 --> 00:01:19.920 by mold. by a mold called penicillium notatum. 00:01:21.340 --> 00:01:24.480 He didn't just toss it out, though. He noticed 00:01:24.480 --> 00:01:26.579 something really interesting was happening. Lucky 00:01:26.579 --> 00:01:30.060 break. It was. Yeah, it was a huge break. He 00:01:30.060 --> 00:01:32.780 noticed that around the mold, the staphylococcus 00:01:32.780 --> 00:01:35.599 wasn't growing. It had inhibited the growth of 00:01:35.599 --> 00:01:37.719 the bacteria. So that must have been an interesting 00:01:37.719 --> 00:01:39.680 thing to see. Hold on a second. Yeah, yeah. I 00:01:39.680 --> 00:01:41.859 mean, this is a huge moment in medical history. 00:01:41.879 --> 00:01:44.040 Yeah. Like this is something that could change 00:01:44.040 --> 00:01:46.180 everything. And he kind of reasoned that the 00:01:46.180 --> 00:01:49.640 fungus must be producing something that was antagonistic 00:01:49.640 --> 00:01:52.299 to the bacteria, to the germs. Right. And so 00:01:52.299 --> 00:01:55.760 he followed up on this. And in 1929, he published 00:01:55.760 --> 00:01:57.840 a paper in the British Journal of Experimental 00:01:57.840 --> 00:02:01.900 Pathology. And in that initial report, he suggested 00:02:01.900 --> 00:02:05.609 that this substance might be useful for treating 00:02:05.609 --> 00:02:07.409 infections from microbes that were susceptible 00:02:07.409 --> 00:02:09.509 to it. OK, so right away, he saw that there was 00:02:09.509 --> 00:02:11.389 a therapeutic potential. That's right. Yeah, 00:02:11.389 --> 00:02:13.849 yeah. For this mold, basically. And in fact, 00:02:14.509 --> 00:02:17.310 he continued to use penicillin in his lab himself 00:02:17.310 --> 00:02:20.250 to distinguish between different types of bacteria 00:02:20.250 --> 00:02:22.490 to kind of help him isolate different things. 00:02:22.509 --> 00:02:24.509 OK. It was almost like a tool for him. Interesting. 00:02:24.689 --> 00:02:27.569 OK. But there was a little bit of a quiet period, 00:02:27.590 --> 00:02:30.349 I think, after this initial allocation. Yeah, 00:02:30.349 --> 00:02:33.710 you're absolutely right. for several years after 00:02:33.710 --> 00:02:36.849 that 1929 publication, there wasn't a lot of 00:02:36.849 --> 00:02:39.710 attention paid to penicillin. Huh. It kind of 00:02:39.710 --> 00:02:42.770 languished on the sidelines for a few years. 00:02:42.830 --> 00:02:45.090 Why? You know, that's a really good question. 00:02:45.210 --> 00:02:47.030 Yeah, it's surprising. I mean, it sounds like 00:02:47.030 --> 00:02:49.469 such a breakthrough. Yeah. Why do you think that 00:02:49.469 --> 00:02:52.370 was the case? Well, I think there's a number 00:02:52.370 --> 00:02:54.930 of factors probably at play here. Maybe the scientific 00:02:54.930 --> 00:02:57.310 community wasn't totally convinced by the findings. 00:02:57.990 --> 00:03:00.169 Maybe the research efforts were focused on other 00:03:00.169 --> 00:03:03.210 avenues. But it wasn't until the later successes 00:03:03.210 --> 00:03:07.009 of sulfonamide drugs that people really started 00:03:07.009 --> 00:03:10.330 to think about chemotherapy in a big way, which 00:03:10.330 --> 00:03:12.289 is the use of chemicals to treat infections. 00:03:12.610 --> 00:03:17.330 And so it was the success of those drugs that 00:03:17.400 --> 00:03:19.599 kind of open the door again for penicillin. So 00:03:19.599 --> 00:03:22.280 it sounds like the success of one scientific 00:03:22.280 --> 00:03:26.020 advance kind of paves the way. Right. For others. 00:03:26.180 --> 00:03:28.520 Right. It opens people's minds to a new possibility. 00:03:28.580 --> 00:03:30.780 OK. And they start thinking in that direction. 00:03:30.780 --> 00:03:33.039 Right. And so then fast forward a few years to 00:03:33.039 --> 00:03:35.539 the late 1930s. We have a researcher at Oxford 00:03:35.539 --> 00:03:39.099 University named Ernst Chain. OK. And he stumbles 00:03:39.099 --> 00:03:43.780 across Fleming's 1929 paper. Aha. And he's immediately 00:03:43.780 --> 00:03:47.870 intrigued. Wow. And he proposes to his supervisor, 00:03:48.110 --> 00:03:50.629 Howard Flory, this idea of, hey, let's try and 00:03:50.629 --> 00:03:52.509 isolate this active compound. Let's see what's 00:03:52.509 --> 00:03:53.710 going on here. Let's see what we can do with 00:03:53.710 --> 00:03:55.849 this. And what's interesting is that they actually 00:03:55.849 --> 00:03:58.650 had Fleming's original strain of penicillium 00:03:58.650 --> 00:04:02.250 at Oxford. Wow. So they had the ingredient right 00:04:02.250 --> 00:04:05.330 there. Wow, that's amazing. So by 1939, Flory 00:04:05.330 --> 00:04:09.210 had assembled a research team. OK. And one very 00:04:09.210 --> 00:04:11.009 important member of that team was a guy named 00:04:11.009 --> 00:04:14.500 Norman Heatley. Okay. And he was a fungal expert. 00:04:14.520 --> 00:04:17.199 Okay. And he was really crucial because he developed 00:04:17.199 --> 00:04:21.060 a way to grow penicillium in much larger quantities. 00:04:21.319 --> 00:04:23.160 Okay. So you're taking it out of the petri dish, 00:04:23.360 --> 00:04:25.420 you're scaling it up. Right. You know, you can't 00:04:25.420 --> 00:04:27.160 treat people with petri dishes, you want something 00:04:27.160 --> 00:04:30.060 more. Right. And there's this funny little historical 00:04:30.060 --> 00:04:33.259 side note that his contract was nearing its end 00:04:33.259 --> 00:04:36.540 and the outbreak of World War II actually prevented 00:04:36.540 --> 00:04:39.560 him from taking another job in Stockholm. Wow. 00:04:39.800 --> 00:04:42.680 So he stayed on at Oxford and continued this 00:04:42.680 --> 00:04:45.019 really important work. Wow. Yeah. Well, I mean, 00:04:45.079 --> 00:04:47.279 that's a reminder that history really does turn 00:04:47.279 --> 00:04:50.660 on these very small events. It does. It's just, 00:04:50.699 --> 00:04:52.600 it's wild. The things that happen that can change 00:04:52.600 --> 00:04:55.199 the course of history. Yeah. So while he was 00:04:55.199 --> 00:04:58.420 doing that, Ernst Chain was tackling the incredibly 00:04:58.420 --> 00:05:01.560 difficult task of purifying the penicillin from 00:05:01.560 --> 00:05:05.240 the malt extract. Okay. And you know, he eventually 00:05:05.240 --> 00:05:07.639 succeeded in isolating a much more concentrated 00:05:07.639 --> 00:05:10.120 form of the drug. So then they could actually 00:05:10.120 --> 00:05:12.819 start doing animal trials. And that was really 00:05:12.819 --> 00:05:14.300 important to see if this stuff could actually 00:05:14.300 --> 00:05:18.939 fight infections in living organisms. So Flory 00:05:18.939 --> 00:05:22.319 oversaw these experiments and they took mice 00:05:22.319 --> 00:05:25.800 that were infected with streptococcus, a very 00:05:25.800 --> 00:05:28.500 virulent strain of streptococcus. And they treated 00:05:28.500 --> 00:05:31.879 some of them with penicillin. And the results 00:05:31.879 --> 00:05:37.019 were really dramatic. The treated mice survived. 00:05:37.279 --> 00:05:40.899 and the untreated mice all died. Wow. So that's 00:05:40.899 --> 00:05:43.300 an incredible moment for them to see. Yeah. I 00:05:43.300 --> 00:05:45.199 mean, one of the sources says that Chain himself 00:05:45.199 --> 00:05:49.139 called it a miracle. Wow. It was a huge breakthrough. 00:05:49.279 --> 00:05:51.980 Yeah. So they followed up on that with the publication 00:05:51.980 --> 00:05:56.959 in The Lancet in 1940, in August of 1940. And 00:05:56.959 --> 00:06:00.120 in that paper, They detailed the production and 00:06:00.120 --> 00:06:02.920 purification of penicillin and then their experimental 00:06:02.920 --> 00:06:04.899 use against, you know, these different bacteria 00:06:04.899 --> 00:06:07.240 streptococcus and staphylococcus and Clostridium. 00:06:07.579 --> 00:06:09.579 Okay. So now the world's really on notice. Yeah, 00:06:09.579 --> 00:06:11.060 the world is starting to pay attention. Yeah. 00:06:11.079 --> 00:06:12.639 And it's really important to connect this back 00:06:12.639 --> 00:06:14.819 to this earlier idea of a magic bullet, right? 00:06:15.000 --> 00:06:17.040 This was championed by a guy named Paul Ehrlich. 00:06:17.279 --> 00:06:21.519 Okay. And it was really this idea that there 00:06:21.519 --> 00:06:25.560 could be some chemical agent that could selectively 00:06:25.560 --> 00:06:28.930 kill microorganisms. without being toxic to the 00:06:28.930 --> 00:06:32.290 host. Right, so just target the bad stuff. Exactly. 00:06:32.430 --> 00:06:34.970 And leave the good stuff alone. Exactly. And 00:06:34.970 --> 00:06:36.990 Ehrlich, he actually coined the term chemotherapy. 00:06:37.149 --> 00:06:39.910 Okay. And he had achieved a breakthrough himself 00:06:39.910 --> 00:06:43.269 with Salverson to treat syphilis. Okay. But progress 00:06:43.269 --> 00:06:45.350 in finding these other magic bullets was really 00:06:45.350 --> 00:06:48.689 slow until penicillin came along. Okay. And so, 00:06:48.689 --> 00:06:50.509 you know, Flemming's discovery really, really 00:06:50.509 --> 00:06:54.139 kind of brings that vision. much closer to reality. 00:06:54.500 --> 00:06:56.420 Yeah. Okay. So penicillin is starting to look 00:06:56.420 --> 00:06:59.860 like this magic bullet that everyone's been searching 00:06:59.860 --> 00:07:03.899 for. Let's talk about its clinical use and how 00:07:03.899 --> 00:07:06.639 significant it was therapeutically. Initially, 00:07:07.560 --> 00:07:10.259 as Fleming himself had suggested, the hope was 00:07:10.259 --> 00:07:13.699 to treat infections with these specific microbes 00:07:13.699 --> 00:07:16.029 that were susceptible to it. That's right. Yeah, 00:07:16.449 --> 00:07:18.449 and early animal studies showed that it was really 00:07:18.449 --> 00:07:20.449 effective against common bacteria that caused 00:07:20.449 --> 00:07:23.970 lots of serious infections. Right. And it quickly 00:07:23.970 --> 00:07:26.410 became clear that penicillin was superior to 00:07:26.410 --> 00:07:28.129 those sulfonamide drugs that we were talking 00:07:28.129 --> 00:07:30.769 about. Yeah. In a lot of ways. Really? Yeah. 00:07:30.930 --> 00:07:34.230 So this really was a new era of chemotherapy. 00:07:35.920 --> 00:07:38.920 This is particularly important for diseases that 00:07:38.920 --> 00:07:41.579 weren't affected by the sulfonamides. Things 00:07:41.579 --> 00:07:43.959 like certain forms of pneumonia, staphylococcus 00:07:43.959 --> 00:07:48.660 infections. And there was initially hope that 00:07:48.660 --> 00:07:51.000 penicillin would be effective against tuberculosis 00:07:51.000 --> 00:07:53.980 and leprosy and malaria, but that wasn't totally 00:07:53.980 --> 00:07:57.740 realized. But it did have this huge impact on 00:07:57.740 --> 00:08:00.500 other infections. So this is really the beginning 00:08:00.500 --> 00:08:02.899 of what we think of as the antibiotic revolution. 00:08:03.079 --> 00:08:05.420 Exactly. It's the beginning of that. Yeah. Penicillin 00:08:05.420 --> 00:08:07.360 was effective against all these different bacteria. 00:08:07.360 --> 00:08:10.800 Right. Infections. And that led to a huge decrease 00:08:10.800 --> 00:08:13.339 in mortality and morbidity. Right. From things 00:08:13.339 --> 00:08:15.540 that had previously been life threatening. So 00:08:15.540 --> 00:08:17.899 this really changed medicine. Yeah. And then 00:08:17.899 --> 00:08:20.959 later. the discovery of other antibiotics like 00:08:20.959 --> 00:08:25.040 streptomycin just further expanded that ability 00:08:25.040 --> 00:08:28.939 to treat infections. Yeah, okay. So penicillin's 00:08:28.939 --> 00:08:32.860 great. It is. But of course like with any drug 00:08:32.860 --> 00:08:36.659 there are some potential drawbacks. Right. And 00:08:36.659 --> 00:08:38.720 one thing we do need to talk about is penicillin 00:08:38.720 --> 00:08:41.019 allergy. Right, so penicillin has saved countless 00:08:41.019 --> 00:08:44.240 lives. Yes. But it's also true that penicillin 00:08:44.240 --> 00:08:46.980 allergy is a thing. Right. It's a real concern. 00:08:47.080 --> 00:08:49.940 It's a real concern. Yeah. And your source mentions 00:08:49.940 --> 00:08:53.879 that for some oral conditions, alternative antibiotics 00:08:53.879 --> 00:08:57.679 like azithromycin and cephaloxin are often prescribed 00:08:57.679 --> 00:08:59.820 for people who have a penicillin allergy. Right. 00:09:00.139 --> 00:09:02.379 But there's a warning there for cephaloxin. Oh. 00:09:02.480 --> 00:09:04.399 Because it can also cause a reaction in people 00:09:04.399 --> 00:09:06.860 who have a severe penicillin allergy. OK. So 00:09:06.860 --> 00:09:08.940 it's not always a straightforward substitution. 00:09:09.559 --> 00:09:11.679 Gotcha. Yeah. So you have to be really careful. 00:09:11.879 --> 00:09:16.700 Yeah. And what's interesting is that There's 00:09:16.700 --> 00:09:18.740 a growing understanding now about the importance 00:09:18.740 --> 00:09:22.500 of accurate penicillin allergy assessment, because 00:09:22.500 --> 00:09:25.480 research, especially in pregnant women, has shown 00:09:25.480 --> 00:09:27.460 that a lot of people who think they have a penicillin 00:09:27.460 --> 00:09:31.860 allergy don't actually have a true allergy. So 00:09:31.860 --> 00:09:35.000 allergy evaluations, including skin testing. 00:09:35.149 --> 00:09:37.990 can actually lead to what's called delabeling. 00:09:38.110 --> 00:09:40.230 Which means that they can actually be treated 00:09:40.230 --> 00:09:42.950 with penicillin or first line alternatives like 00:09:42.950 --> 00:09:48.090 cefazolin. And that avoids the potential downsides 00:09:48.090 --> 00:09:51.039 of using broader spectrum antibiotics. which 00:09:51.039 --> 00:09:53.460 can sometimes be less effective. And they also 00:09:53.460 --> 00:09:56.019 contribute more to antibiotic resistance. Right, 00:09:56.279 --> 00:09:58.879 so basically, if you think you're allergic to 00:09:58.879 --> 00:10:00.779 penicillin, it's probably a good idea to actually 00:10:00.779 --> 00:10:03.200 get that checked out. Yeah, absolutely, because 00:10:03.200 --> 00:10:06.240 you might not be. And that can change your treatment 00:10:06.240 --> 00:10:09.299 options. Yeah. OK, let's talk about the manufacturing 00:10:09.299 --> 00:10:11.779 process. Obviously, this is a huge breakthrough. 00:10:12.379 --> 00:10:15.100 But initially, they're working with these small 00:10:15.100 --> 00:10:18.299 -scale lab productions. How do they scale this 00:10:18.299 --> 00:10:20.470 up? Right, so initially they were using what's 00:10:20.470 --> 00:10:23.370 called surface culture of the mold. Okay. So 00:10:23.370 --> 00:10:27.629 they would grow the mold in flasks or bottles 00:10:27.629 --> 00:10:32.610 with a nutrient -rich broth. Okay. But, you know, 00:10:32.710 --> 00:10:34.309 obviously you can't treat millions of people 00:10:34.309 --> 00:10:36.529 with flasks and bottles. Right. So then World 00:10:36.529 --> 00:10:39.909 War II comes along. Okay. And there's this huge 00:10:39.909 --> 00:10:42.490 need for penicillin. Right. And that really drives 00:10:42.490 --> 00:10:46.149 the development of large -scale production techniques. 00:10:46.210 --> 00:10:48.570 Okay. And so that's where deep tank fermentation 00:10:48.570 --> 00:10:51.450 comes in. OK. So what is deep tank fermentation? 00:10:51.690 --> 00:10:53.750 It's a game changer. Yeah. It's a huge advancement. 00:10:53.830 --> 00:10:57.850 OK. So Pfizer, a company that had actually pioneered 00:10:57.850 --> 00:11:00.970 these submerged fermentation techniques for citric 00:11:00.970 --> 00:11:04.990 acid production in World War I, they recognize 00:11:04.990 --> 00:11:08.509 that you could use this technique to grow penicillium 00:11:08.509 --> 00:11:12.690 in large vats. Oh, it's not a huge vein. Huge 00:11:12.690 --> 00:11:15.370 vats, yeah. And so there was this big debate. 00:11:15.549 --> 00:11:18.269 internally at Pfizer about whether to invest 00:11:18.269 --> 00:11:22.450 in this or not. It was a big gamble, but ultimately 00:11:22.450 --> 00:11:26.370 the leadership decided to go for it. And in the 00:11:26.370 --> 00:11:29.909 autumn of 1943, they bought a repurposed ice 00:11:29.909 --> 00:11:33.629 factory in Brooklyn and turned it into the world's 00:11:33.629 --> 00:11:37.090 first deep culture penicillin production plant. 00:11:37.480 --> 00:11:39.700 Wow, so they're really going all in on this. 00:11:39.820 --> 00:11:42.080 Yeah, they're going all in. That's really something. 00:11:42.480 --> 00:11:45.080 OK, so just to clarify here, we're talking about 00:11:45.080 --> 00:11:48.059 a fungus that's producing penicillin. Right. 00:11:48.519 --> 00:11:51.840 And it's primarily penicillium chrysogenum. Right. 00:11:52.600 --> 00:11:54.799 Although the initial discovery was with penicillium 00:11:54.799 --> 00:11:56.860 notatum. Right, different species, but yeah. 00:11:56.860 --> 00:11:59.860 Different species, but yeah. But the basic principle 00:11:59.860 --> 00:12:02.639 here is that you're interfering with the metabolism 00:12:02.639 --> 00:12:05.759 of the microorganism that's causing the infection. 00:12:05.779 --> 00:12:08.700 Right. So that says chemotherapy. Okay. Yeah, 00:12:08.840 --> 00:12:11.279 so how does deep tank fermentation work? I mean, 00:12:11.539 --> 00:12:14.539 yeah, so then practice so basically you're you're 00:12:14.539 --> 00:12:18.120 growing huge volumes of The penicillium mold 00:12:18.120 --> 00:12:20.299 okay in these big tanks that are filled with 00:12:20.299 --> 00:12:23.539 a nutrient medium a liquid nutrient medium And 00:12:23.539 --> 00:12:25.899 you're controlling things like temperature oxygen 00:12:25.899 --> 00:12:29.600 levels pH right to really maximize penicillin 00:12:29.600 --> 00:12:32.529 production, okay? And of course, modern production 00:12:32.529 --> 00:12:35.350 methods have become even more refined. One of 00:12:35.350 --> 00:12:37.889 your sources talks about hydrosobic adsorption. 00:12:38.850 --> 00:12:41.570 So basically, you're directly adsorbing the penicillin 00:12:41.570 --> 00:12:44.970 from the broth using these selective hydrophobic 00:12:44.970 --> 00:12:47.990 resins. OK, so what is hydrophobic? Hydrophobic 00:12:47.990 --> 00:12:50.889 means that it repels water. So it's attracted 00:12:50.889 --> 00:12:53.909 to things that are not water. And so the penicillin 00:12:53.909 --> 00:12:58.039 molecule is one of those things. The efficiency 00:12:58.039 --> 00:13:01.259 of this process is also affected by the pH of 00:13:01.259 --> 00:13:04.720 the solution. So lower pH levels actually improve 00:13:04.720 --> 00:13:07.740 adsorption because they increase the neutral 00:13:07.740 --> 00:13:10.480 form of penicillin, which binds more readily 00:13:10.480 --> 00:13:13.539 to the resin. But you can't go too low because 00:13:13.539 --> 00:13:15.159 then you can actually degrade the penicillin 00:13:15.159 --> 00:13:17.740 molecule. So you have to kind of find this sweet 00:13:17.740 --> 00:13:21.399 spot around pH 4. Interesting. So it's a really 00:13:21.399 --> 00:13:23.679 delicate process. It is. It's very precisely 00:13:23.679 --> 00:13:29.080 controlled. We're taking this from this moldy 00:13:29.080 --> 00:13:32.759 Petri dish to this really sophisticated chemical 00:13:32.759 --> 00:13:36.059 engineering. Yeah. Wow. Yeah, it's a huge leap. 00:13:36.279 --> 00:13:37.899 OK, so now we've got to make sure that all this 00:13:37.899 --> 00:13:40.379 stuff is, you know. done right. Right. So what 00:13:40.379 --> 00:13:42.559 are the quality control measures? Right. So there's 00:13:42.559 --> 00:13:44.320 this thing called good manufacturing practices. 00:13:44.440 --> 00:13:48.299 Okay. Or GMP. GMP. Yeah. And the FDA has these 00:13:48.299 --> 00:13:51.480 regulations that cover current good manufacturing 00:13:51.480 --> 00:13:54.139 practice for finished pharmaceuticals. Okay. 00:13:54.720 --> 00:13:57.340 And this includes making sure that all the equipment 00:13:57.659 --> 00:14:00.700 and the utensils that are used are clean and 00:14:00.700 --> 00:14:02.620 properly maintained. Right. So you don't have 00:14:02.620 --> 00:14:04.399 any contamination. Right. You don't want to mess 00:14:04.399 --> 00:14:06.019 this up. Right. Yeah. You don't want anything 00:14:06.019 --> 00:14:10.080 to compromise the safety or the identity or the 00:14:10.080 --> 00:14:12.500 strength or the quality or the purity of the 00:14:12.500 --> 00:14:14.519 drug. Right. So you've got to have these written 00:14:14.519 --> 00:14:17.340 procedures for all the steps in the process, 00:14:18.019 --> 00:14:20.230 including cleaning and maintenance. OK. And you've 00:14:20.230 --> 00:14:22.370 got to retain reserve samples from each batch. 00:14:22.490 --> 00:14:24.529 OK. And you've got to have these comprehensive 00:14:24.529 --> 00:14:27.149 master production and control records. Right. 00:14:27.269 --> 00:14:29.230 So that you can trace everything back. OK. If 00:14:29.230 --> 00:14:31.129 there's a problem. So even though, you know, 00:14:31.149 --> 00:14:33.809 this is an early drug. Right. They're still following. 00:14:33.909 --> 00:14:36.269 Oh, yeah. The same. Oh, yeah. The regulations 00:14:36.269 --> 00:14:40.730 are rigorous standards. Super strict. Yeah. OK, 00:14:40.750 --> 00:14:44.269 let's talk about the regulatory journey of penicillin. 00:14:44.309 --> 00:14:47.129 OK. You know, obviously, its initial use kind 00:14:47.129 --> 00:14:51.000 of predates the modern drug approval frameworks 00:14:51.000 --> 00:14:53.120 that we have today. Right. So it was introduced 00:14:53.120 --> 00:14:55.559 and used widely before we had all these really 00:14:55.559 --> 00:14:57.779 stringent new drug application requirements. 00:14:57.779 --> 00:15:02.320 OK. Similar to acetaminophen. OK. But the urgency 00:15:02.320 --> 00:15:05.879 of wartime probably really played a role in its 00:15:05.879 --> 00:15:09.019 initial adoption and distribution. Yeah. I mean, 00:15:09.080 --> 00:15:11.759 they needed it on the battlefields. Right. Yeah. 00:15:11.759 --> 00:15:14.539 So that likely expedited its use and distribution. 00:15:14.820 --> 00:15:16.830 Right. So they kind of had to. Yeah, they had 00:15:16.830 --> 00:15:19.330 to cut through some red tape, I'm sure. What 00:15:19.330 --> 00:15:22.129 about patents and global access? Right, so that's 00:15:22.129 --> 00:15:24.809 a really interesting aspect of this story. Britain 00:15:24.809 --> 00:15:27.769 made a decision not to heavily patent penicillin. 00:15:28.049 --> 00:15:31.509 Really? Yeah. And this was a policy choice to 00:15:31.509 --> 00:15:33.950 ensure that there was wide access to the drug 00:15:33.950 --> 00:15:37.110 during the war. They wanted to make sure that 00:15:37.110 --> 00:15:40.019 everyone who needed it could get it. And this 00:15:40.019 --> 00:15:42.779 actually contrasts with their later approach 00:15:42.779 --> 00:15:45.179 to cephalosporin. Oh. Where they were much more 00:15:45.179 --> 00:15:47.720 aggressive about patenting. Oh, interesting. 00:15:47.860 --> 00:15:49.820 Yeah. So it's an interesting sort of ethical 00:15:49.820 --> 00:15:52.799 consideration. Yeah. There. Yeah, for sure. Yeah. 00:15:53.659 --> 00:15:57.159 But obviously, over time, you know, the production 00:15:57.159 --> 00:16:00.019 and distribution of penicillin became subject 00:16:00.019 --> 00:16:03.779 to more regulatory oversight. Oh, yeah. As these 00:16:03.779 --> 00:16:06.799 national and international bodies emerged and, 00:16:06.799 --> 00:16:09.580 you know, pharmaceutical quality standards became 00:16:09.580 --> 00:16:12.539 more formalized. Penicillin production was subject 00:16:12.539 --> 00:16:16.500 to all of that. Now, did you come across any 00:16:16.500 --> 00:16:23.600 specific legal challenges or controversies? Not 00:16:23.600 --> 00:16:26.299 in the way that you see with some other pharmaceutical. 00:16:26.460 --> 00:16:28.899 There weren't any big legal battles. Gotcha. 00:16:29.720 --> 00:16:33.820 But the principles of GMP would have applied 00:16:33.820 --> 00:16:37.789 to penicillin as well. OK. So let's talk about 00:16:37.789 --> 00:16:40.889 the economic impact. OK. You know, initially, 00:16:41.470 --> 00:16:43.850 the demand must have been huge. Oh, yeah. I mean, 00:16:43.929 --> 00:16:46.190 this was a miracle drug. Yeah. And there was 00:16:46.190 --> 00:16:48.830 very limited supply. Yeah. So the demand totally 00:16:48.830 --> 00:16:50.750 outstripped the supply. Yeah. And the prices 00:16:50.750 --> 00:16:54.210 were probably really high at first. OK. But then 00:16:54.210 --> 00:16:56.590 the development of deep tank fermentation, that 00:16:56.590 --> 00:16:58.730 really changed things. That changed everything. 00:16:58.730 --> 00:17:01.820 Right. Yeah. Suddenly, they could produce. Much 00:17:01.820 --> 00:17:04.960 more. The supply went up, and the prices came 00:17:04.960 --> 00:17:07.900 down. And as production methods became more widespread, 00:17:08.539 --> 00:17:11.279 and the initial patents expired, there was more 00:17:11.279 --> 00:17:13.460 competition. More companies started making it. 00:17:13.720 --> 00:17:16.539 And so the prices went down even further. OK, 00:17:16.680 --> 00:17:18.759 so it's sort of the same thing you see with like 00:17:18.759 --> 00:17:22.119 aspirin. Exactly. Branded versus generic. Yeah, 00:17:22.160 --> 00:17:26.140 OK. And penicillin has played a role in global 00:17:26.140 --> 00:17:29.059 health initiatives as well. Yeah. Yeah. Making 00:17:29.059 --> 00:17:31.079 it more accessible in various countries. Yeah. 00:17:31.259 --> 00:17:33.839 It's been really important for improving health 00:17:33.839 --> 00:17:37.000 care outcomes. Yeah. Worldwide. Yeah. Treating 00:17:37.000 --> 00:17:39.000 infectious diseases, reducing complications. 00:17:39.220 --> 00:17:41.660 Yeah. And that's had a positive impact on health 00:17:41.660 --> 00:17:44.619 care costs. Yeah. OK. So it's been a game changer. 00:17:44.720 --> 00:17:46.460 It's been a game changer. Yeah. I mean, let's 00:17:46.460 --> 00:17:48.700 talk about the cultural influence of penicillin. 00:17:48.740 --> 00:17:50.940 OK. I mean, people were calling it a miracle 00:17:50.940 --> 00:17:53.019 drug. It was a miracle drug. Yeah. You know, 00:17:53.259 --> 00:17:58.019 this is a huge. shift in in how people thought 00:17:58.019 --> 00:18:02.700 about treating infectious diseases You know suddenly 00:18:02.700 --> 00:18:05.740 there was hope right before there was often despair 00:18:05.740 --> 00:18:09.200 Yeah, yeah, and it's had a huge impact on life 00:18:09.200 --> 00:18:11.279 expectancy huge impact because it's eliminated 00:18:11.279 --> 00:18:14.119 so many of these bacterial infections that used 00:18:14.119 --> 00:18:17.599 to kill people Yeah, so so penicillin has really 00:18:17.599 --> 00:18:19.970 yeah change the world. Just change the world. 00:18:20.210 --> 00:18:22.690 In so many ways. Yeah. But there's a downside 00:18:22.690 --> 00:18:25.450 too, and that's antibiotic resistance. Right. 00:18:25.970 --> 00:18:28.809 So how did that happen? So the widespread use 00:18:28.809 --> 00:18:31.509 of penicillin and other antibiotics has led to 00:18:31.509 --> 00:18:35.369 the evolution of bacterial resistance. OK. Basically, 00:18:35.490 --> 00:18:37.869 the bacteria have adapted. Yeah. They've found 00:18:37.869 --> 00:18:40.950 ways to survive in the presence of these drugs. 00:18:41.150 --> 00:18:44.250 OK. And how do they do that? So there are a few 00:18:44.250 --> 00:18:47.779 different mechanisms. OK. One is. limiting the 00:18:47.779 --> 00:18:50.759 uptake of the antibiotic into the bacterial cell. 00:18:51.440 --> 00:18:54.700 Another is modifying the target site, so the 00:18:54.700 --> 00:18:57.559 antibiotic can't bind to it. Another is producing 00:18:57.559 --> 00:19:00.619 enzymes that inactivate the antibiotic, and another 00:19:00.619 --> 00:19:04.519 is actively pumping the drug out. of the cell, 00:19:05.059 --> 00:19:08.099 and that's called efflux. Efflux, okay. And so 00:19:08.099 --> 00:19:10.359 do different types of bacteria use different? 00:19:10.359 --> 00:19:13.519 They do. Mechanisms. The gram -negative bacteria 00:19:13.519 --> 00:19:16.859 often use all four of those mechanisms. Gram 00:19:16.859 --> 00:19:19.460 -positive bacteria less commonly limit the uptake. 00:19:19.519 --> 00:19:23.640 Okay. But yeah, so it's really an arms race between 00:19:23.640 --> 00:19:25.950 us and the bacteria. Yeah. Yeah. So what can 00:19:25.950 --> 00:19:28.109 we do? Well, the important thing is the antibiotic 00:19:28.109 --> 00:19:31.789 stewardship. OK. So using these drugs responsibly, 00:19:32.009 --> 00:19:35.069 carefully, not overusing them, making sure that 00:19:35.069 --> 00:19:37.950 we're using the right drug for the right infection. 00:19:38.349 --> 00:19:40.950 Yeah. OK. Wow. Well, this has been a really amazing 00:19:40.950 --> 00:19:43.369 story. It is an amazing story. Yeah. You know, 00:19:43.529 --> 00:19:46.150 going from this accidental discovery to this. 00:19:46.329 --> 00:19:49.150 that's changed the world. Yeah, it's a testament 00:19:49.150 --> 00:19:52.329 to scientific curiosity collaboration. Yeah. 00:19:52.549 --> 00:19:54.769 And the impact of medical innovation. For sure. 00:19:55.109 --> 00:19:58.150 For sure. And it's amazing to think that, you 00:19:58.150 --> 00:20:00.890 know, this seemingly accidental event could have 00:20:00.890 --> 00:20:03.569 such huge consequences. It is, yeah. You know, 00:20:03.869 --> 00:20:07.990 reshaping medicine and industry and just the 00:20:07.990 --> 00:20:10.670 way we think about life itself. Yeah. So it really 00:20:10.670 --> 00:20:13.190 makes you think, you know, as we reflect on this. 00:20:14.220 --> 00:20:17.839 how can we learn from penicillin's history to 00:20:17.839 --> 00:20:21.000 address this growing challenge of antibiotic 00:20:21.000 --> 00:20:23.759 resistance? How can we make sure that future 00:20:23.759 --> 00:20:26.599 generations can still benefit from these drugs? 00:20:27.319 --> 00:20:30.599 What role will new discoveries play? And what 00:20:30.599 --> 00:20:32.759 role will responsible antibiotic stewardship 00:20:32.759 --> 00:20:35.200 play? These are all really important questions 00:20:35.200 --> 00:20:36.859 to think about. Yeah, some food for thought. 00:20:37.619 --> 00:20:38.259 Yeah, for sure.