This is penicillin — possibly the most famous antibiotic of all time. Most histories of penicillin focus on Alexander Fleming — the scientist whose accidental experiment on the penicillium mold eventually led to the antibiotic. And we’ll definitely get into his story, but I’m more curious about how penicillin took over as the miracle antibiotic of the twentieth century. How it made it from the lab bench and into the pharmacy. So in this video, we’ll look at what Fleming actually did, how labs across the world ramped up penicillin production, and we’ll look at something I didn’t expect before researching for this video: how the rise of penicillin created the modern American pharmaceutical industry. The story starts in London, near Paddington station. The year was 1900, and a microbiologist named Almroth Edward Wright was trying to expand his new Inoculation Department at St. Mary’s Hospital. Wright was the real deal — he developed the first vaccine against typhoid fever in 1895. And his lab would be all about vaccines, antiseptics, anything that could treat infectious disease. And in 1906 he brought on a 25 year old Scottish research assistant named Alexander Fleming. Fleming spent his first few years at St. Mary’s resarching another antimicrobial we’ve talked about already — Salvarsan, the anti-syphilis drug, which came out in 1909. But then World War 1 kicked up, and some of the St. Mary’s hospital staff went over to France where they did some really cool research on wound infections. At this point in medical history, germ theory is pretty well established, so most doctors would treat a battlefield wound with an antiseptic to prevent infection. But over the course of World War 1, Wright and Fleming noticed that that antiseptics ran the risk of killing off too many of the patients’ white blood cells, which actually /encourages/ infection. So after the war ends, Fleming goes back to St. Mary’s and decides to look for other substances that might treat infections too. This is when we hear a familiar story… but not /the/ familiar story. In November 1921, Fleming came to work with a cold. And so he did what anyone would do in that situation and put some of his drippy, mucousy snot on a Petri dish full of bacteria. Now, I looked everywhere for documentation about /why/ he decided to do this and couldn’t find anything, just that it /did/ happen. So as far as I could tell, he was just following his curiosity in the moment. He left out the dish with snot on it, and came back to it two weeks later, when of course, a bunch of bacteria had grown on the dish. /Except/ for in the places where he put his mucus. He thought, huh, that’s interesting, and decided to repeat the experiment with a bunch of other bodily fluids to see if the same thing would happen. Fleming and his assistant tested saliva, blood, semen, pus. They tested fluids from different plants and animals and other biological liquids like egg whites and milk. And all of them had some degree of antibacterial effect when they were put in a dish full of bacteria. Fleming reasoned that something in these fluids killed the bacteria, and called that chemical lysozyme — lyso or lyse, meaning to break open a cell (it’s actually the same etymology for Lysol), and zyme meaning an enzyme, like a catalyst. Fleming looked for lysozyme in a ton of different materials, but he never had much success killing bacteria that caused disease with them. So it wasn’t super exciting clinically. Nevertheless, Fleming kept looking for sources of lysozyme for years. And that’s when we hear the famous story. Traditionally the story says that Fleming left out some samples of staphylococci before going on vacation in August 1928. At some point during his vacation, one of his samples had somehow been contaminated by a green fungus — maybe it came in through a window, maybe it floated up from the lab downstairs that was studying molds. We don’t really know, but it was a warm summer, so both the mold and the bacteria had good conditions for growth. When Fleming came back from vacation, he noticed that there was a ring around the fungus without any visible staphylococcus. So he reasoned that the fungus, a member of genus Penicillium, excreted some kind of chemical that lysed the staph. And in a March 1929 paper, he names this antibiotic chemical penicillin. Science history is made, he gets the Nobel Prize, and they all live happily ever after, the end. Just kidding. I say this all the time on the channel, but when stories in science history are cute and tidy, they’re probably leaving out some context. And I got two main things with this story: First thing: while Fleming named penicillin, he wasn’t the first to notice penicillium’s antibacterial effects. Like I mentioned in the first episode of the antibiotics series, the ancient Egyptians used molds against infections millenia before Fleming. And even more recent scientists like John Tyndall described antibacterial effects of a mold in 1876. Joseph Lister had as well, including the properties of penicillium. Not trying to take anything away from Fleming, just trying to add some extra context. Point number two, there are some inconsistencies in the traditional story. And the most important one has to do with how staph and penicillin actually work. Staphylococcus is a Gram positive bacteria, which means that it stains purple when it’s hit with a special dye. And it does that thanks to a thick, outer cell wall made of a tough material called peptidoglycan. At the molecular level, it looks something like this. Those long rectangles are different sugars, which are the glycans. And those circular chains there are peptides. And those peptides are joined together through cross links, which make the cell wall extra strong. Now, this structure is constantly being repaired and rebuilt, especially when the bacteria are replicating. And that process happens thanks to a few enzymes and chemical ingredients. One of which is called transpeptidase. It facilitates the cross linking of those peptides in the cell wall, hence trans-peptid-ase . Here’s where penicillin comes in. It has something called a beta-lactam ring in it, this guy here. Beta-lactam is a compound that binds to transpeptidase. And if the enzyme is bound, it can’t catalyze its reaction. It can’t do the cross linking in the cell wall. And without peptidoglycan’s cross links you can’t make new cell walls, so you can’t make new bacteria. And existing cell walls get so weak that they collapse. Fleming and his assistant, Stuart Craddock, later found that penicillin could prevent the growth of streptococcus, another gram positive bacteria. But it was less effective at killing the germ that causes typhus, which is a gram negative bacteria. That’s because Gram negative bacteria are built differently — they have a thin cell membrane outer layer, then a thin cell wall, then another cell membrane. It’s a cell wall oreo. Beta-lactams drugs can pretty readily diffuse through a Gram positive bacteria’s cell wall where it can exert its effect. But that extra cell membrane on Gram negative bacteria keep them from crossing through. There are some pores where drugs /could/ get into gram negative bacteria, but they still never let /that/ much in. So beta-lactams like penicillin are way more effective on gram positive bacteria than gram negative bacteria. So coming back to Fleming’s original report, he said that he covered a dish with bacteria, left it out, and said it “was obviously undergoing lysis. He thought the mold actively killed the bacteria like it was a lysozyme. But over the decades, historians of science have questioned that. They think the mold would’ve needed to be in the dish before the bacteria were plated to see that ring of absent staph like Fleming did. There are some other inconsistencies with the story too. Like in some retellings, Fleming says he left the petri dish out for 2 weeks, and sometimes he says 5 weeks. And the whole part about the mold coming in through the window probably isn’t true either — it turns out they rarely opened the window. But it was a hot summer, so who knows, maybe they made an exception. Either way, he maintained that penicillium ended up in the dish by accident. Alright, so what’s the deal? Was Fleming P-hacking or up to something dubious? Probably not. It was 6 months from the first time he noticed penicillin to publication date. And nobody knew how significant the finding would be for over a decade. So Fleming probably just forgot the details. HIs big practical takeaway was more for microbiologists than doctors. See, back then, scientists believed that influenza might be caused by a bacteria called Bacillus influenzae — it’s not, go watch my video about the Spanish Flu to hear that story. But long story short, this bacillus tended to show up alongside pathogens like streptococcus and staphylococcus — both of which are Gram positive and treated by penicillin, while B. influenzae is Gram negative and not as affected by penicillin. Therefore, Fleming was able to use penicillin to kill off the gram positive bacteria, and isolate Bacillus influenzae. So in the final portion of his most important research paper ever, Fleming says “Guys! This penicillin stuff is gonna be huge. We’ll be able to isolate this one microbe with it.”. Bit of an understatement. Understandably, there was nothing in that original paper that made it seem that this chemical would change the world. Fleming and his assistant never managed to purify penicillin very well — they couldn’t get it higher than a 1% concentration. And penicillin was tricky to work with. It would evaporate and leave a sticky, ineffective syrup. And while they did test penicillin for safety in lab animals, they never tried to treat bacterial infections in animals. Fleming’s penicillin paper came in 1929 and by 1935, the German company IG Farben came out with sulfanilamide, giving the world a useful tool against germs like staph and strep — the same pathogens Fleming tested. And so, the penicillin research sat on the shelf for years. Like the One Ring sitting at the bottom of the stream. Until it was picked up by the most unlikely creature imaginable. This is Howard Florey, an Australian who spent most of his career in the UK, mostly at Oxford. In the late 1920s, Florey was curious about why certain bacteria couldn’t infect the wall of the gastrointestinal tract. And one of the suggestions was that the GI tract had a higher concentration of lysozyme than other tissues. So he took extracts from different animal and human bodily fluids and tested them for antibacterial properties. A lot like Fleming did in 1922. He published his findings in 1930, and while he didnt find anything groundbreaking, this research got him familiar with Fleming’s work. A few years go by, and in 1935, Florey goes back to his alma mater of Oxford where he became the director of the Dunn School of Pathology. He’s still really excited by lysozyme research, and being a director would give him a unique opportunity to build his own team. One of his first hires was Ernst Chain, a Jewish chemist who grew up in Berlin but became an English citizen in 1933 right as the Nazis were taking over Germany. In 1936 they hired a 25 year old biochemist named Norman Heatley — he’ll become very important later on. Then there was a brilliant chemist named Edward Penley Abraham. He was able to isolate lysozyme in 1937. And Over the years, they also hired physicians, epidemiologists, microbiologists — all kinds of experts from other fields. And this was totally by design. Florey wanted an interdisciplinary team to bring different ideas to the table. And this panned out to be a very good strategy. And they spent the first few years focusing on the chemical structure of lysozyme, but after a while, Florey and Chain start thinking about a new project — they wanted to do a big survey of the antibacterial properties of different substances made by microbes — making them true antibiotics. It would be a long term project that would hopefully get years of funding. So the team started their project with a literature search, like you should. And in 1937, Chain came across Fleming’s original paper about penicillin. This gave the team the idea that penicillin might be a special subtype of lysozyme. This wasn’t a eureka moment, no lightbulb over someone’s head, just, huh, this is interesting science. We should look into it. So in 1938, Chain and his team started trying to isolate penicillin from the penicillium mold, and they did, but it took massive amounts of mold juice just to get a little bit of penicillin. They was going through mold faster than they could get it. And this is where Heatley, our biochemist, comes in. He played around with a few different techniques for growing penicillium in the lab, but ultimately settled on growing the mold in good old agar. This stuff is like really firm vegetable gel. He found that penicillium grew well in shallow, wide vessels filled with 1 and a half centimeters of agar. And he started growing the mold /everywhere/ — after a little bit their whole lab was covered in dishes of moldy agar. He also comes up with a more standardized way of measuring penicillin’s potency by looking at the size of the ring around the mold — a bigger ring meant a stronger antibacterial effect. And this is when the lab started to realize that this chemical is really good at keeping bacteria in check. But at this point. Florey and the team don’t think theyre going to revolutionize medicine. Actually quite the oppiosite. Florey is quoted as saying ‘I don’t think that the idea of helping suffering humanity ever entered our minds’. It really seemed like these boys were just a bunch of nerds following their curiosity. Either way, by summer of 1939 things were looking hopeful. The lab was making penicillin and learning more and more about how it worked, but there was a problem. They were nearly out of money. Florey was able to get a little bit of cash from the UK’s Medical Research Council, but he knew he needed more, so he applied for a grant from the Rockefeller Foundation which he got by March 1940. And they had some stuff they needed to do with this cash. Their first order of business: make a more potent mold (and more of it), extract a more pure penicillin from the mold, and safety test it in animals. Heatley was making progress on the first part. He’d figured out how to grow a hundred times the penicillin from the molds in his little mad-scientist mold farms. He also made progress on purification and was able to increase concentration substantially. It wasn’t good enough for manufacture yet, but it was at least good enough for Chain to do some experiments. And while he still didn’t know exactly what the drug was, Chain was pretty sure that penicillin at least wasn’t an enzyme or protein. As a bonus, they also learned that penicillin was excreted in the urine and stayed nearly as potent. This was good news considering how rare this stuff was. Now it was time for more robust safety testing. They get a bunch of test mice and infect them with either Streptococcus pyogènes, staphylococcus aureus, or an anaerobic microbe called Clostridium septique. They separate some mice into the control group and some into an experimental group. Then they gave the experimental group shot after shot of penicillin, but they didn’t know how much to give them. They knew the mice tolerated small doses well, but they didn’t know the therapeutic index yet — the range of dosage where the drug is effective but not harmful. They also needed to figure out the best timing between injections of penicillin. Their goal was to “keep up an inhibitory concentration of the substance in the tissues of the body throughout the period of treatment by repeated subcutaneous injections”. A fancy way of saying “we’ll figure it out when we get there”. At the end, all 25 of the strep mice died if untreated, while only 1 out of 25 died in the group given penicillin. All 24 of the staph mice died if untreated, only 3 out of 24 died in the penicillin group. Finally, all 25 of the Clostridium control mice died while only 1 died in the penicillin group. They published their results in The Lancet in August 1940 as “Penicillin as a chemotherapeutic agent” and made it clear they had something new and useful on their hands. “The results are clear cut, and show that penicillin is active in vivo against at least three of the organisms inhibited in vitro”. This stuff doesn’t just make rings in a pétri dish, it’s gonna be useful in real bodies. To me, this is the moment when our group of nerds turn into a lab of superheroes saving the world. Around then, they also brought on two microbiologists from Oxford, Arthur Duncan Gardner and Jena Orr-Ewing. They’d work on figuring out how penicillin actually worked on a cellular level. But if the Dunn Lab was ever going to do trials on a human they would need a lot more penicillin. And at this point, Heatley is doing everything he can — like he even repurposed bedpans from the hospital to grow mold. So that summer, Florey starts talking to a few UK pharma reps to see if they’d help ramp up penicillin production. But for whatever reason, they didn’t strike a deal, and Florey had to keep penicillin production in house. It took them /months/ of production and all the labs resources, but by Christmas Day 1940 they had finally made enough penicillin to treat a systemic human infection. They gave some to a junior doctor named Charles Fletcher, who worked at the infirmary at Oxford. And on January 17, 1941, a woman with terminal cancer agreed to try it out. They weren’t trying to cure her cancer, just seeing if she’d tolerate the antibiotic. Their first shot was an injection of a hundred milligrams of penicillin, and it didn not go well at first. While the lab had figured out methods for increasing the concentration of penicillin in the mold, they had also increased the amount of contaminants. This first injection was less than 5% pure penicillin, and the volunteer developed a fever and what they called “rigor”. Fortunately, she tolerated the second injection much better. Their first test for /effectiveness/ came about a month later. A few months prior, a 48 year old policeman named Albert Alexander cut himself while doing yard work, and over the next few months had developed a life threatening infection with both Staph and Strep bacteria. He was admitted to the Infirmary where he was treated with sulfa drugs, but the infection kept spreading. So on February 12, 1941, he received an injection of 200 milligrams of 5% penicillin, and continued to get injections over the next 5 days. And for those 5 days, it seemed to be working. This was, to quote Fletcher “the nearest I ever came to seeing a miracle”. Unfortunately, there wasn’t enough penicillin to finish the treatment. They even collected and tried recycling penicillin from the man’s urine, but they finally ran out, and the man succumbed to the infection and died on March 15, 1941. The whole thing was both encouraging and heartbreaking at the same time. They were so close to saving a life, but were limited by resources. If they wanted to do further trials and save a life, they would need to figure out how to ramp up production. But how? At this point, the UK was fully involved in World War 2. The Dunn Lab did ask UK-based drug companies to help expand penicillin production, but they were mostly tied up with the war effort. So Florey and Heatley went to the United States — a country that hadn’t entered the war yet. A colleague got them in touch with a mold expert named Charles Thom at the US Department of Agriculture. The Oxford scientists needed to farm and harvest some penicillin, and the USDA had the tools and expertise to do exactly that. Thom got them in touch with the Northern Regional Research Laboratory in the town of Peoria, Illinois — what’s often just called The Northern Lab And thus the Penicillin Project was born. They had three main goals: find the strains of penicillium that make the most penicillin, develop a protocol for growing the mold more efficiently at scale, and improve the fermentation process that grew the molds so they could get more pure penicillin. As “The Miracle Cure” by William Rosen put it “In traditional agricultural terminology, they were looking for better seeds, better soil, and better cultivation and harvesting”. It’s a great book by the way, I’ll link to it down in the description. Goal number one, find a more efficient growing method. Norman Heatley decided to stay in the US to teach the Northern Lab scientists his methods for growing the mold. And right away, the scientists realized they could improve penicillin yields by using lactose instead of sucrose in the growth medium. But the real advancement came when they decided to add a byproduct of corn fermentation called corn steep liquor. When mixed with sugar and a few other ingredients, it increased penicillin’s antibacterial abilities a thousand times. Also, there’s something so American about the solution being corn. The other thing — Heatley was growing mold in shallow dishes, which is really inefficient. Even when they stacked all those flat dishes on top of one another, they were wasting a ton of space. So the Northern Lab scientists used these big tanks that they’d aerate and stir with a big mechanical stir bar — they called it deep tank fermentation, which looks like it fits in at microbrewery or something. Now they just had to find a more productive version of penicillin. In the summer of 1942, a lab assistant named Mary Hunt went to a local farmer’s market and found a cantaloupe covered in a Penicillium mold. When she brought it back to the lab, it turned out this strain had 200 times the penicillin compared to Fleming’s penicillium. After they treated it with radiation, they eventually got a mold that produced a thousand times more penicillin than the original mold. Fun dinner party fact: that random strain of cantaloupe mold is the source for most penicillin in the world today.... And also the scientists ate the cantaloupe after they picked the mold off. While the Northern Lab is ramping up production, our scientists back at Oxford were trying to figure out the chemical structure of penicillin. Because a solid chemical understanding would let drug manufacturers make penicillin in a standardized lab instead of the big fermentation tanks. This would make the final product more controlled and consistent. They noticed that when penicillin was broken down, each of those pieces was a crystal. So Chain started working with a brilliant young scientist named Dorothy Crowfoot, later Crowfoot Hodgkin. Crowfoot was an expert on an equally young technique called X-ray crystallography. And over the course of the 1940s, used it to find the beta-lactam structure of penicillin along with other things like vitamin B12 and insulin. At this point it’s fall of 1942, and some UK based drug companies had started making penicillin, which luckily, would be enough for the Dunn lab to continue research. But to get enough penicillin production to treat humans, they would ultimately need the United States. And of course, ramping up production wouldn’t be cheap, so we need to talk about government contracts and the pharmaceutical industry. And don’t worry, it’s not gonna be as morally egregious as you might be thinking. Our timelines start to overlap a little bit here, so let’s rewind a little. In 1941 while Heatley was doing science with the Northern Lab, Florey was taking care of finances. He started by talking to pharmaceutical companies including Merck, Squibb and Eli Lilly, who had actually done some penicillin research of their own. Unfortunately, he wasn’t able to make a deal because there wasn’t a ton of data showing that penicillin was safe and effective yet. There was one more company who seemed interested — a small chemical company who mostly made flavorings and citric acid up until that point, but were interested in moving into pharmaceuticals. That company was Pfizer. But they didn’t take a deal at first either. So alright, the drug companies don’t want to play, what about government funding? The United States had recently started the Office of Scientific Research and Development, or OSRD, as a way to fund medical and scientific research related to national defense. Florey was long time friends with the chairman of the medical division of the OSRD, a pharmacologist named Alfred Newton Richards. So they meet up, and Florey tells Richards about their research with penicillin, and Richards is into it. No, it doesn’t have the strongest clinical data to support it yet, but he saw a lot of potential. Plus, there was the human element — Richards already trusted Florey. So in August of 1941, Richards promised he’d recommend that the board give them a grant. Hopefully Florey would get funding from the US government and Richards would get a successful project, and probably end up with a bigger budget next year. Then Richards gets the reps from four drug companies together: Merck, Lederle, Squibb, and Pfizer, and basically says “I’m not making you, but it would be really great and patriotic of you guys to support this. And maybe we can pay you, we’ll see”. This was a very different initiative for the US. This wouldn’t be a government contract like when Lockheed makes airplanes for the military, it would be more like a research partnership. The federal government had sponsored medical research since the 1880s, but it was always performed by another government agency. Go check out my video about the plague in San Francisco for a good example of that. The US government hadn’t partnered with private businesses at this scale ever before. And in October 1941, the penicillin committee got together for the first time. It was made up of government people, but also reps from companies like Pfizer and Merck. They talked about what they might do, but the tone was very casual. At first it’s like “ohh who wants to be in charge of making a kilogram of penicillin for clinical trials?”. Super chill… but then Pearl Harbor happens. And their /next/ meeting was much more serious. Now, at this point in the scientific timeline, the Northern Lab had just figured out the corn liquor thing, so they were much more hopeful for large scale production. And a few scientists at the USDA ended up patenting parts of the production process and licensing them out for free to the drug companies. As a quick side note: the Oxford scientists never patented anything, so they didn’t get rich off penicillin. Fame, yes, but fortune no. So now, those initially hesitant drug companies were on board. They agreed to research penicillin and share their results within the committee. But /just/ within the committee. The OSRD (Office of Science Research and Development) were real tight with what information got out to the public. They didn’t want people to get their hopes up and think this miracle drug was freely available when drug companies could still barely make any. Like only 22 approved doctors would get any penicillin to test, and they were only allowed to test it on specific conditions: staph, strep, and pneumococci infections that didn’t respond to sulfonamides. But despite their best efforts, word got out about penicillin. In March 1942, a woman named Anne Miller was admitted to a hospital in New Haven Connecticut with a severe streptococcal infection due to a miscarriage. Her doctors tried sulfa drugs and even surgery, but nothing worked. But just by chance, one of the other patients in the hospital was friends with Howard Florey. So Anne’s doctor asked the patient if he could ask Florey for some penicillin. At this point, Norman Heatley was working for Merck over in New Jersey. So Florey called Heatley who got Merck to send over a vial of 5.5 grams of penicillin. This was about half of the United States’ entire supply of penicillin at the time. And getting the antibiotic to this woman in Connecticut was such a big deal that it required approval from the National Research Council in Washington and an escort by a state trooper. Miller got her first dose of penicillin on Saturday afternoon, and by Monday her temperature was back to normal. She became the first person to have their life saved by penicillin and lived another 57 years. But penicillin’s even bigger breakout moment came a few months later. On November 28 1942, there was this big fire at the Cocoanut Grove nightclub in Boston. Most of the survivors got rushed to Massachusetts General Hospital, where they were given sulfa drugs at first, but then Merck came through with 32 liters of penicillin broth. Not refined penicillin, but literal tanks of penicillium mold culture. This would be enough to give patients a really small dose of penicillin every few hours. And whether penicillin actually made a huge difference, the Boston Globe sang its praises in the December 2, 1942 issue. Then on February 8 the next year,, Time Magazine published an article calling penicillin “the wonder drug of 1943”. Penicillin was officially in the public consciousness. Penicillin got so popular so quickly that people started writing letters to President Roosevelt asking for it. All while there’s still an extremely limited supply. Some civilians would be able to get penicillin on a case by case basis, but there was only enough to treat a few hundred patients in the first half of 1943. So penicillin was prioritized for soldiers. With World War 2 still going, penicillin became a strategic advantage, allowing soldiers to survive infections. So in June 1943, penicillin production came under the umbrella of the War Production Board. And they start the Penicillin Producers Industry Advisory Committee and decide that partnering with American chemical manufacturers is their best strategy for increasing production. They looked into over a hundred companies before giving contracts to about 20. My sources had different numbers for this and I couldn't find a full list of the companies chosen, but it was between 17 and 21. On the list for sure though were Merck, Pfizer, Squibb, Eli Lilly, and Abbot Labs. The WRB agreed to pay each firm 200 dollars per million units made and prioritized raw materials for the companies involved. And on first glance, this seems like a sweet deal, but the economics complicated things a bit. Each of these drug companies was just one of many in the market for penicillin. And collectively, they were flooding the market with literally /trillions/ of units of supply. Greater supply with no change in demand lowers the price, and with drug companies cranking out tons of penicillin, the final good would be super cheap after the war. Sure enough, the new price came to $20 per million units in 1943, then $6 in 1945 and eventually in 1949, ten cents. Penicillin was never anyone’s blockbuster. Future antibiotics would be, which we’ll talk about in the tetracycline video, but penicillin was a special case. But here’s the thing. Ten cents per million units when we’re talking about hundreds of trillions of units is still a /lot/ of money. So long term, getting a WRB contract was a big payoff. For context, before the penicillin project, there were hundreds of tiny pharmaceutical companies in the US, none of which had huge market shares. But after the project, there were 15 companies that made 90 percent of the industry’s profits. 17 of the top 20 companies were firm who got government contracts to make penicillin. According to models by sociologist Peter Younkin, being awarded OSRD contract was equivalent to a getting a 5 million dollar head start in profits compared to other pharma companies. And of coure, the pharma industry as a whole grew from this injection of cash too. According to a 1934 report published by the National Bureau of Economic Research, the pharma industry was the 16th most profitable industry in the wholesale and retail group in the US in the 1920s. It was behind industries like furniture, automobiles, and men’s clothing. Only a few decades later, pharmaceuticals were the number one most profitable industry in the country. This is a little bit of a weird statistic though. Like prior to the 1920s, pharma companies were usually counted under the umbrella of /chemical/ companies, so it hasn’t always been measured consistently. And of course, the introduction of penicillin wasn’t the only thing that changed in the US after the war. This is a story for another time, but employee sponsored health insurance exploded in popularity after the war. And everything from drug research and development, to production and distribution were all changing, as were global demographics and prevalence of certain diseases. But the broader point stands: the pharma industry got really big after penicillin. And there were plenty more antibiotics to come. Conclusion: The Problems with Penicillin A quick review of the timeline: in 1941, we knew that penicillin could beat bacterial infections but we couldn’t produce enough to save a single human life. By 1943, we had enough to supply an active military. And by 1945, you could get penicillin in your local pharmacy. According to a 2017 article in The Journal of Emerging Infectious DIseases: “Its detection completely changed the process of drug discovery, its large-scale production transformed the pharmaceutical industry, and its clinical use changed forever the therapy for infectious diseases”. But just like every antibacterial we’ve talked about in this series, once the drug got more widespread use, the more problems started popping up. First, allergies. I found papers published in 1943 talking about allergic reactions to penicillin in some of the first soldiers who got the drug — basically as soon as penicillin got out there we saw penicillin allergies. And these days, penicillin allergies are some of the most common allergies to medications. So obviously, it’s not a miracle cure for everyone. Second, bacteria became resistant to penicillin and other beta-lactam drugs really quickly. Like penicillin started rolling out to a few folks in 1942, and by the end of the year, scientists had documented penicillin-resistance strains of staphylococcus aureus in the hospitalized setting. By the end of the 1960s, over 80% of staph aureus infections were resistant to penicillin. Luckily, we’ve found more beta-lactam antibiotics since then, like there were the cephalosporins which started rolling out in the 1950s, or ampicillin in 1963, and amoxicillin in 1972, but bacteria quickly evolved resistance to each of them. Like you’ve probably heard gnarly stories of MRSA before — methicillin-resistant staphylococcus aureus. I’m gonna dediucate an entire video in this series to talk the history of resistance, so we’ll wait for that one. But the most immediate concern in the 1940s was the one major bacteria that penicillin /couldn’t/ treat: Mycobacterium tuberculosis. Luckily, a little lab in New Jersey would find their own wonder drug, not in a moldy fruit, but in the ground. Next up, streptomycin.