Ep 29 Aspirin the Wonder Drug: Crossover w/ IDOP

00:00:30
Speaker 1: Hi, I'm Aaron Welsh and I'm Aaron Oman Updyke.

00:00:41
Speaker 2: And I met.

00:00:42
Speaker 3: Yes, and this is this podcast will Kill You crossover style.

00:00:47
Speaker 2: With in Defensive Plants. Yes.

00:00:51
Speaker 3: Yes, And this week, even though our past episodes have primarily focused on poisons, we're doing something a little bit different.

00:01:01
Speaker 4: A little bit healthier.

00:01:03
Speaker 2: I mean, yeah, it could be a poison if you took enough of it.

00:01:06
Speaker 4: Well, that's true.

00:01:07
Speaker 3: I mean that's that was the lesson we learned in poisons, I guess.

00:01:10
Speaker 4: Yeah.

00:01:11
Speaker 3: But this week we are talking all about aspirin, and in particular willow and some of the other plants that produce some of the primary components that are made or that are used to make aspirin.

00:01:25
Speaker 4: Yeah.

00:01:26
Speaker 2: This was an exciting one because it's something that I was introduced to early on when I was starting to learn about plants, and something we all kind of took advantage of. And a shout out to my friend who started putting willow bark in his tea and then realized he was bruising really bad. There was a steep learning curve when we figured out that this was around. Wow, So this is a this is like a hearkening back to my early days of plant obsessiveness.

00:01:50
Speaker 4: So you're like first flirtation with plant. Yeah yeah, how fun cool?

00:01:55
Speaker 3: Wow. Okay, So to celebrate aspirin, we are drinking.

00:02:02
Speaker 4: Our quarantine named Pain in the Aspirin.

00:02:06
Speaker 2: Yeah, there we go.

00:02:08
Speaker 3: Excellent, And what is in pain and the Aspirin?

00:02:12
Speaker 4: We've got rum lemon juice and time Simple syrup.

00:02:18
Speaker 3: It's really delicious.

00:02:20
Speaker 4: Keep it simple. It's quite tast there.

00:02:23
Speaker 1: Yeah, and we will will post the recipe for this quarantini as well as the non alcoholic Placebrita on all of our social media plate pages including Twitter, TPWKY and Facebook and Instagram, This podcast will Kill You and.

00:02:39
Speaker 4: Our website This Podcast will Kill You dot com.

00:02:41
Speaker 3: So I'm I'm really excited about the history of aspirin because it reaches back so much farther than I thought, and it also has associations or connections with a lot of other things that we have already talked about in different areas of the podcast. So be excited. All right, So this week we're talking about aspirin, and because this is a crossover with you, Matt, we're not just talking about aspirin, but also the plant it comes from, which is the willow and some of the other species of plants. And let me tell you, willow and humans go way way back. In fact, they go so far back that we can't even say for certain when people started using willow bark as a medicine, or if it was even Homo sapiens that used it first. Ooh, because willow bark was actually found in a Neanderthal burial site in Iraq dating back to sixty one thousand BCE.

00:04:02
Speaker 4: Are you serious.

00:04:03
Speaker 3: Yes, we can't and we don't know for sure obviously, or people don't know for sure why it was there, whether it was included intentionally or had been used for I don't know, some sort of ritualistic purpose, or maybe it was just a random tossome you know, things in there. Super cool. So what do historical texts tell us? Something called the or you are third?

00:04:27
Speaker 2: Three?

00:04:28
Speaker 3: I don't know. Tablet.

00:04:30
Speaker 2: I read it, it's cool, it's fine.

00:04:32
Speaker 4: Oh yeah, the Earth three.

00:04:35
Speaker 3: So this tablet dates back to three thousand BCE from ancient Sumeria, and it includes some of the earliest known references to willow as a treatment. And you probably or maybe not remember me talking about the Ebers Ebers Papyrus, which is that. Yeah, that medical text from ancient Egypt, and it was written around fifteen thirty four BCE, but it contained information that much much older, so some sections had been copied from documents that were at least a thousand years older. Wow, Jesus and Egyptologists have gone through the over one hundred and sixty remedies listed in this papyrus to try to identify the ingredients, and they've really only been successful in about twenty percent of those. But one of those is willow hmmmm, the plant that makes aspirin. It also includes another salaic lit producing tree in its list of remedies, the myrtle. Anyway, Okay, I did not know that. Yeah, I don't know what that is.

00:05:37
Speaker 2: So there's a lot of them. It's all good.

00:05:41
Speaker 3: According to this papyrus, you should mix together willow either ground up barker leaves, figs, beer, and dates.

00:05:48
Speaker 2: That's odd combination. Sounds good, could be tasty.

00:05:51
Speaker 4: I'd drink it.

00:05:52
Speaker 3: I think that's for a cough. And if you have muscle aches or arthritis, you were supposed to have applied a willow salve to the affected area, but that may not have worked depending on how much you put on yourself. But in any case, by the time that ebers Papyrus was written, the willow was well known as an effective treatment for various aches and pains and fevers and whatnot. And that makes it one of the oldest, if not the oldest, effective plant based treatments that we know of, dating back so many tens of thousands of years.

00:06:25
Speaker 2: That's really neat. Yeah, and it like the Neanderthal thing, it's like it just begs that question of how the heck did any species figure that out? At some point?

00:06:35
Speaker 3: Yeah, d right, Well, and one of the things that you know, probably perpetuated its reputation as this legitimate medicine besides the fact that it actually worked, was just how widespread it was. So they were all over the prehistoric world. So if you were an ancient human or hominid trying out some new treatments for your sore too or whatever, you might have run into willow as a possible relief provider.

00:07:03
Speaker 2: Yeah, And it's interesting to think about where they grow today and how you know, quote unquote weedy they can be. It's usually along some sort of riparian area near a body of water, disturbed areas places where humans would frequent, and they re sprout after you cut them, So it's one of those things that would have been ever present.

00:07:21
Speaker 3: Yeah, yeah, exactly, It's like kind of makes sense, but also it still blows my mind that it would be so old. So the ancient use of willow as a pain reliever has ample support throughout the ancient world. We've got Hippocrates, of course, using it for an effective analgesic for childbirth and also to reduce fevers, and ancient Roman physicians or scholars also wrote about using it to treat pain. Ancient Chinese texts show that it was used as a medicine by the sixth century CE. It was also used by people living in southern Africa and by Native Americans before Columbus. By around two hundred c e. Willow was basically as common a remedy as aspirin is today. But then mysteriously willow just kind of falls by the wayside and much of Europe and its importance is a medicinal plant there wouldn't be recognized again until the seventeen hundreds. Weird, Yeah, it just kind of disappears, Okay, but what happens in the seventeen hundreds, Let me set the scene.

00:08:24
Speaker 4: I just want to say, how excited your facebooks right now.

00:08:27
Speaker 2: There's a lot of enthusiasm for the drum roll here.

00:08:30
Speaker 3: Yeah, okay. So you are a fifty six year old man, a reverend, living in Chipping Norton, a sizable town in England. It's the seventeen hundreds, mid seventeen hundreds, to be exact. It's a gorgeous day outside. The sun is shining, birds are calling, and there's a gentle breeze whispering through the willow trees. On days like today, it's your habit to take a stroll around your proper maybe stopping for a bit, for a little sit and think. And one of your favorite places to sit and think is underneath the willow trees that line the creek on your property. Today, as you contemplate your next sermon, perhaps you absent mindedly take a piece of willow bark and pop it into your mouth. Yeah naturally, I sorry, that's exactly what an Oxfordshire accent would sound like.

00:09:27
Speaker 2: Yeah, you nailed it.

00:09:31
Speaker 3: The bitterness of this bark is shocking, and the gears in your mind start turning. This bitter bark is reminding you of another medicinal plant which is effective for treating fevers, but is in super high demand, almost impossible to get any idea what that could be.

00:09:48
Speaker 4: Is it that myrtle thing you were talking about?

00:09:51
Speaker 3: Uh huh think outside aspirin.

00:09:54
Speaker 4: This is a Matt question.

00:09:56
Speaker 2: Yeah, and I'm embarrassing myself here that something in the Carrott family. I don't know.

00:10:03
Speaker 3: This is something that hearkens back to first season TPWKY quinine yep, Yeahona tree yes. So. So the Sinchona tree, which is where we get quinine, was super it was there was a monopoly on it basically, and you could not get it, which was really problematic because tons of people were suffering from malaria. So there were a lot of efforts to try to find cheaper alternatives or at least available alternatives to the Sanhona tree bark. So when Reverend Stone and this really happened, by the way, this whole sequence of events I've just described, when he tasted that bark, he immediately saw the potential for it as a substitute for the Sinchona bark. Huh, and he wanted to pursue this. So the first thing he did was he set up a bunch of willow bark to dry, and while that was drying, he searched the library for any info on the willow bark as in effective treatment. He didn't find anything, probably because he was looking in more recent books.

00:11:12
Speaker 2: Control f hadn't been invented yet.

00:11:21
Speaker 3: Fortunately he wasn't dissuaded by this, and so he ground up his dried willow bark and started looking around for some malaria sufferers to volunteer for treatment. And he administered the powdered bark every four hours to these volunteers in increasing doses until he reached one that appeared to work. The fevers disappeared, word got around and his taally of cured patients grew larger. So then Reverend Stone sent this letter describing his discovery and subsequent experiments to the head of the Royal Society, and the discovery within that letter gained traction very slowly, unfortunately, and Reverend Stone died before its importance would be recognized.

00:12:04
Speaker 2: Bummer.

00:12:06
Speaker 3: So, while his curiosity helped to bring willow to the forefront of plant based medicine again, he wasn't entirely correct either though in how it worked. So as we discussed in the Malaria episode Quinine, which is found in sanchoona Bark actually attacks the parasite itself that causes malaria, while Willow Bark just relieves the symptoms, doesn't actually treat the disease.

00:12:28
Speaker 2: Yeah.

00:12:28
Speaker 4: I was going to say, he didn't need anybody, no, no, he just made they're suffering. Yeah.

00:12:35
Speaker 3: Well, and in some ways that made his discovery all the more important, because this was a remedy that you could use to treat all kinds of aches and fevers, not just malaria.

00:12:44
Speaker 4: Very true, I.

00:12:45
Speaker 2: Was going to say, I mean, that's one of the most common things I hear people talking about, is how the heck do people figure this stuff out? And there's a first hand account of this tastes like this, it's gross, let's see.

00:12:56
Speaker 3: Yeah, yeah, I think that's a really interesting the whole. It illustrates exactly how early humans might have done it too, Like this tastes like this, that thing does this, so this could be like that as well. So from the time that Reverend Stones, whose first name is Edward by the way, from the time that Reverend Stones's letter got published in Philosophical Transactions in seventeen sixty three, so it's quite a long time ago to the early eighteen hundreds, willow had started to be widely used as a cheap alternative to sinchona bark, and during this time the field of chemistry had really started to ramp up, so there was motivation to isolate active compounds and different remedies so that you could do things like regulate dose, increase concentrations, and try to make synthetic versions so that you could reduce the cost. It's all about the money, It's.

00:13:49
Speaker 4: All about the Benjamin were the equivalent of that time period.

00:13:56
Speaker 3: By nineteen twenty, things like stric nine, caffeine, morphine, and quinine had been isolated and it was only a matter of time before willow got the same treatment. Progress to isolate the active ingredient in willow bark was made in teeny tiny increments, so first you started with impure lumps, or then maybe you got a few grams isolated from a kilo of bark. But eventually the methods were refined and more could be obtained, and this is when a name was given to the substance, first salacin, after salx, which is the Latin name for willow, and then salsilic acid. And during this time so willow is not the only plant that produces this compound. And so during this time, another apothecary chemist was working on a pet project of his own, trying to isolate the active ingredient in the meadow sweet flower spirea spiria how you say it, spiria ol maria so metasweet was thought to have pain relieving qualities, so he decided to make a tincture, which then was used by another guy to experimentally treat volunteers for fever and pain. Long story short, it was found to be effective, and this guy was like, everyone, listen up, I found something totally new and amazing and actually, oh okay, yeah, it is just sal selic acid. This is nothing new here, but it kind of did you know really cement sala silic acid's reputation as a pain reliever and fever reliever. So after salasilic acid had been isolated, physicians prescribed it to patients, but people didn't really love taking it. It was acid sal salic acid, super acidic. It would hurt their mouths and stomachs, and they didn't really want to take it again. So something had to give. A guy named Charles Gerhardt tried to reduce the acidity of sala silic acid by adding acetyl chloride, and when he did that, he got out an impure and crude version of acetyl salicelic acid, which is what is in our aspirin pills today.

00:16:01
Speaker 2: Boom.

00:16:02
Speaker 3: So then Gerhardt's work was picked up by somebody else, and then this incremental progress just continued to you know, happen. Just a couple of things remained, though, before aspirin could actually become the power house medicine that we see it as today. First money, Second justification. If someone was going to invest time and energy into synthesizing this compound, they had to be convinced that it was actually medically important, and that justification would come in eighteen seventy four in the form of a pretty carefully done study on the effectiveness of sallasin in treating rheumatic fever. The study was published in the journal The Lancet, and that seemed to be the push that salison needed to gain widespread and immediate recognition. So the cost of salason went way high, and doctors everywhere started publishing their own findings. So this led to more widescale trials of both salasin and salsalic acid and then seeing what else it could do. Okay, for the next segment of the history of aspirin, we'll see how a German die making company set the groundwork for creating the multi billion dollar pharmaceutical industry that is that it is today. Yes, this is the story of Beyer.

00:17:14
Speaker 4: I love it.

00:17:17
Speaker 3: During the eighteen hundreds, when all of these different medicinal compounds were being isolated and purified and prescribed, physicians would sell them by their chemical names, which were often really complicated and hard to remember. And by the late eighteen hundreds there were just too many names to remember. So some guy had the brilliant idea, It really was a brilliant idea of renaming a chemical to something memorable and then patenting the production method. And this was genius because a doctor could then more easily remember and spell the name tailanol, for instance, compared to acetaminifin or paracetamol or paracetamol. But at this time pharmacies were legally obligated to follow a doctor's prescription to the letter, So if he had written acetaminifin, any generic acetaminifin could be given. But if he had written thilanol, only thilanol could be given so that.

00:18:16
Speaker 4: These people could make bank yep.

00:18:19
Speaker 2: Tricky, tricky.

00:18:20
Speaker 4: Yeah.

00:18:21
Speaker 3: And so you could see how this naming and patenting system would appeal to many of these chemical producing companies, many of which switched to focus solely on development and production of these medical compounds or renaming other chemicals and finding unique ways to make them. And so this is how Bayer, which started out as a die making company, found itself leading the pharmaceutical industry. Wow, but what is the actual story of aspirin, Not of willow or salsilic acid, but aspirin capital a trademark. Salsilic acid was on a long list of chemicals to try to improve on Beyer's list, and because it had clear medical benefits and Bear would really clean up if they could find a way to lessen its nasty side effects. But when beer chemist Felix Hoffmann found a way to efficiently make a cetyl salsilic acid which didn't have the painful side effects of salsilic acid, the head of development, Heinrich Dresser, refused to test it in clinical trials. What because he was like, ah, salsilic acid it enfeebled the heart and this chemical will be no different, yea. So he stopped all the work on it, and instead he shifted his focus to diacetyl morphine aka heroin Great Cool, which, by the way, was its trademarked name. Did you know that it was a trademarked name heroin? Yeah? Huh Wow I didn't know that.

00:19:51
Speaker 2: Yeah either.

00:19:52
Speaker 3: Yeah. So another guy, Arthur Eichingrin, who was another chemist at Beer, he was not happy with this is to abandon a cetyl selic acetyl celic. I hate the same acetyl sal silic acid. So he took matters into his own hands and he went behind Dresser's back to conduct a bunch of drug trials, all of which, of course, were successful. The only hurdle left was deciding on a name for the new drug. So spire from spyriea, the genus name of meadow sweet as an and as a nod to acetylation A and in just to make it easier to say and remember. So that's how you get aspirin.

00:20:33
Speaker 2: Wow. I appreciate that so much more now, thank you.

00:20:38
Speaker 3: So Aspirin, the wonder drug produced by Bayer, would be officially launched in eighteen ninety nine.

00:20:44
Speaker 4: Was that its tagline aspir the wonder drug.

00:20:47
Speaker 3: No, that was my tagline for it.

00:20:49
Speaker 2: You are missing out on the marketing gig.

00:20:53
Speaker 3: After its launch, aspirn kind of just slipped quietly onto the market, and to push along red cognition, Beher sent packages of aspirin to doctors all over the world, encouraging them to try it out and publish your findings. And they did. The drug worked, I mean, and it's it is hard to overstate just how much it worked and how many applications it seemed to have and also virtually no side effects at least at this point, sales of aspirin shot through the roof. And even though Germany wouldn't issue a patent for aspirin, arguing that it had been isolated before the US and Britain would, so then Beher had this monopoly on two of the biggest markets for aspirin in the world. And even if they didn't own the rights to the patent in the rest of the world, they did own the name, which was super catchy anyway. But at the time, the US medical field was very much against patent drugs, which they felt either couldn't be trusted or could be trusted. But then should be available to everyone at a low cost. So it's kind of hard to imagine that that was ever the mindset, considering how just how much has changed and things are, yeah, how things are today? Okay, So then Beyer had to figure out how to get into the US market and firmly establish itself so that when their brand trademark wore off, they would still be the aspirin of choice for consumers. And in a monumental law case, Beyer's patent for Aspirena was deemed invalid in the UK, and it seemed like things were headed in that direction for the US as well. They had until late February nineteen seventeen to cement the brand name and image of aspirin in the minds of the public before their patent expired, so they went on the offensive. They were pushing aspirin on physicians everywhere, which, of course the American Medical Association hated at the time, and in an effort to reduce the sneaky advertising and promotion of drugs that contained either no medicine or harmful substances like heroin and cocaine, a law was passed restricting promotion of a patent drug just to the name of the company and the name of the drug. That's it. You could just say, this is the name of the company, this is the name of.

00:23:04
Speaker 4: The drug, so you can't say, like what it does or.

00:23:07
Speaker 3: Nope not at the time, weird interesting and only non trademark drugs called by their generic names could be included in the in the official US pharmacopeia.

00:23:17
Speaker 4: Oh yeah, that's still like we only learn non trade names. That's what's on the us MLA tests and everything.

00:23:24
Speaker 3: Which makes sense.

00:23:25
Speaker 2: Yeah.

00:23:26
Speaker 3: Yeah, all of this trademark patent advertising controversy is going down in the early nineteen hundreds, and guess what happens in nineteen fourteen.

00:23:36
Speaker 4: Oh, Titanic No.

00:23:38
Speaker 3: Nineteen twelve.

00:23:39
Speaker 2: I actually knew that.

00:23:42
Speaker 4: Defenestration of progue.

00:23:44
Speaker 2: Oh my god, the dustbel.

00:23:49
Speaker 3: What was the dust ball? Actually i'm reading it.

00:23:52
Speaker 4: Yeah, yeah, grapes of wrath.

00:23:55
Speaker 3: Okay, all right, Well, World War one is what happens. And so with this outbreak of war, citizens of the UK were like, we're not supporting Beyer. This is a German company. But that was easier said than done. First off, large scale manufacturing of a cetyl sala silk acid was logistically difficult, and many chemical companies had switched to making you know, like wartime things explosives, poisons, whatevers, and doctors were still prescribing aspirin capital a rather than a setyl salad silk acid. So Beher was still making a killing. And they also were making mustard gas, so they were also making a chemical that was doing killing.

00:24:39
Speaker 2: Yeah, it's a fine line, as we've learned.

00:24:45
Speaker 3: So yeah, so Behar was still making a killing. But that was only until the British government's Board of Trade nullified the trademark on Aspirn's name and it made it public property.

00:24:55
Speaker 4: Yeah, because now it's just aspin lower case.

00:24:58
Speaker 2: Yes, I never put in the other day.

00:25:00
Speaker 3: Yeah, okay, maybe you'll remember some other things that happened during World War One that are relevant to the podcast.

00:25:10
Speaker 4: Like the nineteen eighteen flu for example.

00:25:12
Speaker 3: Well, yes, precisely get one, even though early rumors went around saying that Bayer made aspirin was actually responsible for spreading the flu because it was a German company, right, But soon people got over that and were popping pills like crazy, which actually recent studies suggest may have actually led to excess death due to influenza, particularly in those age groups that were the hardest hit. There's a really interesting paper on that.

00:25:39
Speaker 2: Yeah.

00:25:40
Speaker 3: So, after World War One, though, the aspirin market became a free for all, and tons of different companies began producing and packaging aspirin which they could sell under that name. Finally, advertising got out of control, and soon aspron was claimed to cure all kinds of things, even if there was no evidence for them. But it was effective in a few of the claims, so namely reducing fevers, pain, whatever. And somehow aspirin companies had to distinguish themselves above the rest, and they came up with really bizarre and creative solutions. Certain ones didn't nauseate, some were stronger than the rest, Some had caffeine, some had calcium. And then there was this revolutionary idea which aspirin in soluble form. Hello alca celter mornings ah oh don draper.

00:26:31
Speaker 2: Hence it works.

00:26:33
Speaker 3: This was a new age for pharmaceutical advertising in many ways. All of a sudden, people or companies were taking out billboards, radio ads, newspaper ads, and it was free for all. And as is usually the case in things like this, the legality or regulations for this type of advertising lagged far behind the advertisements themselves. Many of these companies were making outrageous or at the very least exaggerated claims, and the biggest repercussions they faced were just like, oh, slap on the wrist, that's it okay. During the nineteen thirties, the history of aspirin, or at least the history of Beher starts to take a dark turn. The company that had really established itself as a giant due to aspirin had survived World War One despite losing its trademarks and patent rights in many countries, and in the late nineteen twenties, the head of Beher, Karl Duisburg I don't know how you say his last name, teamed up with a bunch of other German pharmaceutical and chemical manufacturers to basically create a monopoly over the drug market.

00:27:38
Speaker 4: Cool, great, guys.

00:27:40
Speaker 3: Yeah, it would be known as ig Farbin and it would play a pivotal role in World War two. War and genocide are expensive and that money has to come from somewhere. So when in February of nineteen thirty three, Hitler demanded financial support from this new monopoly, and they gave it to him. In fact, ig Farben would essentially bankroll the entire Nazi Party, providing an endless source of wealth to fund the war and Holocaust.

00:28:09
Speaker 4: I did not know that.

00:28:11
Speaker 3: Yeah, So, if Beyer had not been the one to produce aspirin, it's possible that the company would have stayed in the chemical dye business, never growing to the point where it could almost single handedly support the Nazis.

00:28:24
Speaker 2: That's a terrible what if, right, right?

00:28:28
Speaker 3: Yeah, And of course it didn't just support the Nazis, but also became directly involved, starting with the arianization of its workforce and ending with the production of the zyklon B gas used in the gas chambers and concentration camps, and also directly financing and managing some of those camps.

00:28:48
Speaker 2: Well, that's despicable.

00:28:50
Speaker 3: It also financed the human experiments conducted by Nazi doctors and scientists that resulted in death and torture for that thousands and thousands of people.

00:29:02
Speaker 4: Jesus Christ. Yeah.

00:29:03
Speaker 3: Even the developer of a cetylsal silic acid at Bayer, so Arthur Eichngrin. So this is the guy who was like, no, we're not going to toss this drug aside. We want to keep working on this so he was Jewish, and he noticed that he had begun to be written out of history. His name would start was erased from the different history books at Bayer, and not just for aspirin, for many of the chemicals that he isolated as well. And also he was sent to a concentration camp. So he miraculously survived, and a few years after his release he published a work on the history of aspern where he said, actually, I was very crucial for the drugs development, and yet his role in the history of aspirin would be ignored for over fifty years to the early two thousands. Wow okay. So at the end actually of World War two, twenty three senior executives from ig Farban would be tried at the Nuremberg trials and thirteen would be acquitted. Wow yeah, okay, so I G Farban didn't survive the war intact, but Bayer did and continued to produce aspirin at high rates. After World War Two, the aspirin market had continued to grow, and many other brands had taken big chunks out of Beyer's profits. They had to come up with something else, not just another way to package or advertise aspirin something else entirely. They went back through their development records and found a chemical by the name of n acetyl para aminophenol which appeared to be an analgesic but with some nasty side effects. So they revisited this chemical, which they called acetaminifin. Oh yeah, and didn't find any of the side effects that it had that had halted its earlier development. Boom, new drug created, perfect done.

00:30:49
Speaker 4: I had no idea that Beyer also made chilanow mm hmm.

00:30:54
Speaker 3: They called it panadal, So this was they called it acetaminifin, and then in the UK it became known as paracetamol and its brand name was Panadal, And so it was like it flew off the shelves because this was this non stomach irritating aspirin alternative, and so aspirn kind of just started to slip out of the you know, leading place in the market, and in the US, cedamnifin of course would be tailanol, and ibuprofen was not far behind, and so by the nineteen sixties the trio of aspirin a cedamnifin slash paracetamol and ibuprofen dominated the over the counter analgesic market, and ASPIRN continued to slip until the nineteen eighties, and it took a major blow when the link between aspirin and Ray's syndrome was discovered. So just when things were looking pretty grim for aspirin, its renaissance would begin. Through all of this history of aspirin that I've talked about so far, and there's a lot of history there, sorry about its mechanism of action was still unknown.

00:32:04
Speaker 2: No one knew how it worked.

00:32:06
Speaker 3: Yeah, it's funny because there wasn't much interest in finding out the mechanism of action until nineteen fifty eight when a dude, a chemist named Henry Collier, decided to play around with it. And over the next decade or so, Collier, along with pharmacologist Priscilla Piper and John Vain, they worked together, sometimes separately, sometimes on the same project to uncover the mysteries of ASPERN. And I'm not going to go into the whole thing, but essentially what happened is that John Vain made the final leap and he and Piper would publish the results in Nature, where it became one of the most cited papers of all time. Cool, and I think Vain won a Noble or was awarded a Nobel Prize for his work on pharmacology. Understanding the three main effects of aspirin, so pain reduction, inflammation reduction, and reducing the ability of blood to clot did more than just solve a scientific mystery. It also held huge implications for the uses of aspirin. One of these beings that in small doses aspron had this effect on the body's clotting ability. So in the second half of the twentieth century and through to today, of course, heart disease is a leading cause of death in many industrialized countries such as the US and parts of Europe, and this anti clouding ability of aspirin also meant it could be used as a possible heart attack preventative. And despite many successful trials, this idea was slow to gain traction, but by the mid nineteen eighties it was finally accepted, which meant new branding and campaigning. So yeah, back to the whole aspirin advertising situation. But this is really where my story of aspirin leaves off and where I think you pick it up, Aaron, So tell me how does aspirn work and what is it good?

00:33:57
Speaker 4: Is it bad.

00:33:57
Speaker 3: What does it do for you?

00:34:00
Speaker 4: Let's talk about it. We'll take a quick break, Fir, I just took another ten milligrams of phenolphyrine HCl, so it should be good. So, as we heard from Aaron Ardy, the main compound that's found in willow bark is solicen. So listen, this compound itself actually doesn't do very much. It becomes salistilic acid in your body, so your body actually breaks it down and metabolizes it to produce salicilic acid. But solicin itself is what's called a pro drug, meaning by itself it doesn't have any mechanism really, but in your body you metabolize it into salicilic acid. Salicilic acid. As you heard from Aarin, I'm not going to talk a ton about because it's not the interesting part of the story. It is still used today pharmaceutically. It's in a lot of skincare products.

00:35:28
Speaker 3: Yeah.

00:35:28
Speaker 4: I've used it, Yeah, I use it every night.

00:35:31
Speaker 2: Yeah, and now that I think about it, I see it show up on labels a lot. Yeah.

00:35:35
Speaker 4: Yeah. So it's a really common acid that's still used in skincare products, acne products, things like that. But to take it for its anti inflammatory properties, like you mentioned, has a lot of side effects, especially really bad gastro intestinal side effects. So the development of aspirin acetylsalicilic acid was massive because it has much less of the side effect. So how do these things actually work? It turns out all of salicylic acid and acetyl salicelic acid have basically the same mechanism of action. But before we can talk about that, we have to first talk about inflammation. Your immune system has mechanisms by which it stimulates inflammation, and even though we usually think of inflammation as something bad, it's actually a really important part of the healing process. So if you imagine, for example, that you get a tear in your muscle, that tear is damage to actual muscle cells, right, So your body has to have a way to jump into gear to repair that tear and to fix or make new muscle cells. So the way that it does that is via inflammation. Your cells release a number of different compounds that signal to other cells like, hey, we've got like some messed up muscle cells over here. We need to fix this, And then whatever cells are needed can come to the aid and actually stop the bleeding or fight off infection or whatever needs to get done. Cool. Yeah, Okay, so this is something like really fun, just like general pathology that everyone gets to learn today. There are four main components of inflammation, redness, swelling, heat, and pain. Okay, yeah, so if you imagine a cut, you can imagine that all of those things will happen. If you get a cut, you'll get redness around the cut. You'll get swelling because you're getting fluid and stuff that's coming to there. It might be warm to the touch and it hurts.

00:37:41
Speaker 3: It's just like when I cut my finger when I was doing night cheese, night.

00:37:45
Speaker 2: Cheese, night cheese. Yeah, typical night cheese.

00:37:49
Speaker 4: And it turns out that there's kind of one main pathway by which your body actually makes a lot of the molecules that are involved in this inflammatory response. So if we can block this one main pathway, or even just one part of this main pathway, we can reduce inflammation substantially. Okay, because although inflammation is a normal response, it sometimes can get out of control, right.

00:38:16
Speaker 3: Right, But so where is that line?

00:38:21
Speaker 4: That's a great question, and it's totally not clear. So, like if you tear a muscle, like do playing soccer or something like that. It's actually not clear that taking anti inflammatories has an actual benefit because in that case, inflammation is needed to actually repair that muscle tear right, But then at what point is there too much inflammation which is actually inhibiting the process of repair. We don't in medicine have a very good answer to that. If you have a fever that's very, very high, like one hundred and four, one hundred and five, you definitely need something to bring that fever down because your brain is going to start to melt.

00:38:57
Speaker 2: PG.

00:38:59
Speaker 3: Can I put in a plug for a book really quick? Yeah, called Why We Get Sick? Oh yeah, and yeah, like that's one of the chapters they talk about inflammation response and when they don't talk about when is too much, but they do talk about sort of the acts of anti inflammatories and how it might be counterproductive to the healing process.

00:39:17
Speaker 4: Yeah. Yeah, it's a really interesting like there's a lot of drugs on the market to counteract the inflammatory response, and yet this inflammatory response is also entirely necessary to fight off infection and to Yeah.

00:39:31
Speaker 2: So when I be fevering as a kid and my mom would be like, I'm not giving it to you. Yet you got to fight this for a little bit. She was actually doing me probably a little bit of around a good I mean within reason.

00:39:42
Speaker 3: The thing is, we, like as humans and as other animals have, we've evolved these responses to pain, to infection, to injury, and so it's kind of interesting to say, like when do we start stopping these responses and is that actually productive?

00:39:57
Speaker 4: Yeah?

00:39:57
Speaker 3: Yeah, it's a great question, Darwini and medicine.

00:40:01
Speaker 4: So that main inflammatory pathway is called the aracadonic acid pathway.

00:40:08
Speaker 2: I like that name.

00:40:09
Speaker 4: It's good. It's a good name. It sounds fancy. So a rackadonic acid is actually made from uh, it's made from phospholipids that are in your cell membrane. So you can make it in pretty much everywhere, pretty much almost every cell. You can make a rackatonic acid, which can then be used to make a whole host of different markers of inflammation. And there are two main enzymes that break down a rackotonic acid into all of these active metabolites, cyclo oxygenase or COX and lipoxygenase, which I don't think we ever shortened locks.

00:40:49
Speaker 3: Locks.

00:40:53
Speaker 4: Okay, so everyone's still with me, Yeah, Okay, good, All right, So I'm actually not going to talk about locks lipoxygenase that we're going to ignore that for now because it's not that important in the story of aspirin. So, as it turns out, cyclooxygenase or cocks of which there are several different forms of this enzyme, can turn a rackaedonic acid into a number of different compounds, prostaglandins, which there's a whole bunch of different prostaglandins, and thromboxanes. Prostaglandins are molecules that are really important in mediating a lot of different parts of the inflammatory response. Redness, which prostaglandins can help with vasodilation, which we have talked a lot about vasodilation in other diseases causing redness and rashes, fever which is also via vasodilation, and pain. So there are prostaglandins that actually sensitize your nerve cells to pain that now you feel pain. WHOA, it's pretty cool.

00:42:03
Speaker 2: Wow.

00:42:04
Speaker 4: So those are prostaglandins. Those are all made via a cox enzyme from a rackodonic acid. You can also with other cox enzymes make thromboxanes. The word thrombis means clot and a thrombocyte is a platelet. Platelets are the blood cells in your body that are responsible largely for clotting. You need to have platelets in order for when you get cut to not bleed out everywhere, right right, Thanks platelets, thank you, You should thank your platelets. So one thromboxane, especially thromboxane A two. It is produced by activated platelets via COX from a rackodonic acid. And what it does is it helps to aggregate other platelets and activate more platelets to actually form a clot So, the more thromboxane you have, the more clotting that you're gonna get. The less thromboxane you have, the less clotting you're gonna get. Sound good, yeah, excellent. Thromboxanes are also important in vasoconstriction because you can imagine if you're bleeding out, if you can constrict blood vessels, even if you can't clot them all the way, if they're smaller, less blood is flowing to that area.

00:43:25
Speaker 2: M h okay makes sense.

00:43:27
Speaker 4: Okay, So where do all of these salicylates, salicilic acid, acetosalicilic acid, Where do these fit in? It turns out their mechanism is to inhibit cyclooxygenase COXS. So what that means is that aspirin binds to the cox enzyme and blocks the action of it. So you cannot form thromboxanes or prostaglandins from a rackodonic acid. Therefore, you have less inflammation if you have less prostaglandins, and you have less clotting if you have less throumbox sis.

00:44:05
Speaker 2: Hm hmm, fascinating.

00:44:07
Speaker 3: It makes sense.

00:44:08
Speaker 4: It gets better, It gets better. Okay.

00:44:12
Speaker 2: I just like being able to draw the line between the dots, like oh okay, yeah, okay.

00:44:18
Speaker 4: So, like you said, Aaron, aspirin is well, you didn't say this exactly, but I'm gonna just keep going on on what you said. There's kind of three big drugs that we think about when you think about over the counter pain relievers. Thailanol or acetaminifin, hyboprofen, and aspirin. These are drugs that we call N SAIDs, although thailan all is kind of not really an inset. We'll talk about it. N said means non steroidal anti inflammatory. That just means that it can reduce inflammation, but it's not steroids. Yeah, yeah, which is.

00:44:55
Speaker 2: A good thing.

00:44:56
Speaker 4: Right. Yeah. So the mechanism of action of iboprofen is very similar to aspirin. It also blocks cox it cox blocks.

00:45:11
Speaker 2: Wow, that was funny.

00:45:16
Speaker 4: But the reason why you may have heard of doctors recommending that you take aspirin and not ibiprofen to prevent something like heart disease is because aspirin binds irreversibly to the cox enzyme. Really, yes, So what that means is that if you have, for example, a platelet, once aspirin binds to the cox in that platelet, for the life of that platelet, it will not be activated and it will not form a clot. Wow.

00:45:56
Speaker 3: So okay, question first of all, why how does it bind irreversibly and why does ibuprofen not?

00:46:05
Speaker 4: So ibuprofen binds in a different place, and it just it binds reversibly, so it can be out competed and it can fall off essentially.

00:46:15
Speaker 3: Okay.

00:46:15
Speaker 4: So I'm not a biochemist, so that's the most detail I can give you. Okay, But aspirin binds and doesn't let go. It binds really tightly and it completely blocks the action of cycloxygenase.

00:46:27
Speaker 3: How long does a platelet live?

00:46:29
Speaker 4: Eight to nine days? So glad you asked.

00:46:34
Speaker 2: Thirty years later.

00:46:36
Speaker 4: So, yeah, so baby aspirin, which is just a low dose of aspirin. For a while, like you were saying in the eighties, nineties, even early two thousands, it was like, everybody take baby aspirin every day. It'll reduce your risk of heart attack. It's not recommended that everybody take it. However, in some people who have had a prem i or myocardial infection, they do recommend that those people take it because it does reduce your risk of further clot formation, and it also reduces overall inflammation, and it does so irreversibly. So you would have to take a ton more ibiprofen. You'd have to take ibiprofen like every four hours because it wears off, whereas aspin you can take just eighty one milligrams once a day, and that's going to bind up any platelets that are not yet bound to aspirin.

00:47:35
Speaker 2: Awesome, that's so coral. Yeah, real, it's thrilling.

00:47:41
Speaker 4: There are very few things that I remember from like original biokem, and this is one of them because I think it is just so so fascinating. Oh, I love it. So that's how it works. You have aspirin that binds irreversibly to COX. It blocks the activation of platelets. It does so for the whole life of that platelet. If you don't have activated platelets, you don't have clot formation. If you don't have clot formation, you don't occlude your arteries. If you don't occlude your arteries, you don't have a heart attack.

00:48:14
Speaker 3: Boom so one, two, three, four. I don't know how many steps there were, but there was a lot.

00:48:19
Speaker 2: But I understood it. And that's a lot for any medical text or journey.

00:48:23
Speaker 3: Yeah.

00:48:25
Speaker 4: So ibuprofen, which is another end said, it's another nonsteroidal anti inflammatory. It works very similarly, but again it is reversible, so it's not going to have that same long lasting effects. Thailanol or acetaminifin or paracetamol has a million names, is not quite the same. It Actually it's not entirely clear yet how thailanol really works. We think that it binds COX, but it does not do so in your peripheral body, but it might do so in your brain. So thilanol is technically an anti inflammatory. It does not have anti inflammatory properties. It does have analgesic properties, so it will reduce pain because it works on your nervous system and it will reduce fever. So it's what we call an anti pyretic. Okay, so really quickly, I guess we can just talk about like when you would actually use aspirin. I don't know, do you want to talk about that?

00:49:25
Speaker 3: Yeah?

00:49:27
Speaker 4: So, like I said, there is some evidence that for certain populations, aspirin in small doses can be used to lower the risk of future myocardial friction or heart disease. There's also some evidence that it can be effective in lowering the risk of some cancers, especially colorectal cancer. And this has to do not so much with its effects on clotting and throw boxinges, but on its inflammatory anti inflammatory effects, because a number of cancer's processes, and we're sort of of learning this more and more, are associated with prolonged inflammation. So if you think of something like something like ul sort of colitis, which is a very high risk for colorectal cancer, is an inflammatory bowel disease. So you have constant inflammation in the colon and that puts you at risk for developing cancer. If you can reduce the inflammation, you can potentially reduce the risk of cancer. That's the thought.

00:50:30
Speaker 2: So does that go back to what you had told me a couple of weekends back where anytime you get a situation where cells are constantly being asked to replenish themselves, you always run the risk of irregularities and cell division and thus cancer. Exactly, blow beautifully mind blown.

00:50:50
Speaker 4: Now, I also want to say, I'm going to give you two disclaimers. Number One, baby aspirin is called baby aspirin because it's eighty one milligrams of dose rather than three hundred and twenty five, which is like grown have aspirin, regular aspirin, like aspirin you.

00:51:09
Speaker 2: Would take for a headache, adult aspirin.

00:51:12
Speaker 4: It does not mean that you should give baby aspirin to a baby because.

00:51:19
Speaker 2: Bad naming.

00:51:20
Speaker 4: Yeah, it's a terrible name for some reason. And it's not clear why this happens. If you give aspirin to children under basically under teenagers, it can cause a very very serious disease called rehea syndrome, which you mentioned aaron, which can lead to encephalopathy, which is swelling of your brain, liver failure, and death.

00:51:42
Speaker 2: Ugh.

00:51:43
Speaker 4: It's not clear why this happens, but that's why in general, the recommendation is never ever give children aspirin. If they have a fever, you give them thailan all or maybe motrin, which is ibuprofen.

00:51:54
Speaker 2: Oh wow, so that explains the Thailand. Okay that my childhood makes a little bit more.

00:51:59
Speaker 4: My mom was, yeah, don't give babies aspirin.

00:52:03
Speaker 2: Thanks mom.

00:52:05
Speaker 4: Uh. And the other caveat that I want to make is that the evidence of the effectiveness of long term aspirin treatments is still quite mixed. It's not clear that every single human is going to benefit, and it is absolutely not the recommendation that every adult needs to be taking baby aspirin. So to be clear, I am not yet a doctor who can make those kinds of recommendations. So I am not suggesting that everyone go out and start taking a baby aspirin. But some people who have certain risk factors might benefit from talking to doctors to figure out because it is very cool. It's a very cool drug, and for a lot of people it really does work.

00:52:50
Speaker 2: Yeah, so do your homework.

00:52:52
Speaker 4: Talk to a doctor. Man. So yeah, that's uh, that's the mechanism of aspirin.

00:53:00
Speaker 2: Yeah, and I was not expecting to understand it.

00:53:02
Speaker 4: And I do you have no idea how that makes me because I was like, oh, this is so biokim.

00:53:09
Speaker 3: But yeah, that was really cool.

00:53:11
Speaker 4: Oh good, I liked it. Yeah, okay, So Matt, hey, what's up with the willow plant?

00:53:43
Speaker 3: Yeah? Why does it have sal silic acid?

00:53:46
Speaker 2: This was super exciting. So when you messaged me and said, hey, can we do this instead of what we were planning for a future episode of spoilers, I was like sure, And then I googled it and I was like, oh, yeah, we definitely have to do this because my job with these crossovers is usually sitting here and going like, well, plants don't want anything to eat them, and they want to kill you for trying or hurt you really bad. And this time it's going to be really different. So we've unlocked, or at least for me, unlocked a whole new world with the big Caveat obviously that I'm not a plant pathologist. I do not understand genetics to any serious degree, So I apologize if I offend anyone right out of the gates, but we'll do this as best as we can. Salicylic acid in plants is fascinating because it has sort of multi purposes. It does get involved in defense, but not in the context of what we've talked about in the past with you know, keeping herbivores at bay. It's more about defense against a bad ex stresses, so environmental stresses like drought, heavy metal tolerance, heat, and osmotic stress, as well as some pathogens. So it does defend against bad things, but not in the context of like a deer or a caterpillar. It's more about viruses and different things that can get in and fungi that can infect a plant and cause a lot of damage.

00:55:06
Speaker 3: It's so cool because it's like the way humans I do is aspirin.

00:55:10
Speaker 2: Yeah, exactly, And the overlaps here kind of gave me goosebumps because we often treat them. You know, our two walks of life is so radically alien and foreign, but we're a jumble of cells, each with their own sort of functions. And the deeper I dug, the more the similarities started to get kind of eerie, with mitochondria and stuff which I don't fully understand. But then there's the other side of it, the hormone side, where it's involved in a lot of regulation of different processes from flowering to sinessence. Yeah, we'll get there. But this was a really interesting dive and it made my job so much cooler this time around than to just say, yeah, they just don't want to get eaten. But the amazing thing is is I had always associated it with willa. Like I said, it was one of the first times I'd learned about like what was going on with plant chemistry and how that's been co opted by humans. And you mentioned the bitter taste, and I have a really funny picture of my friend Steve chewing on willow branches after we learn this, just making an awful face. But it's found in different levels and a wide variety of plant species. This is something that plants are dealing with quite a bit, and it might have something to do with this defense response and some of the regulatory functions. But the levels is what's most interesting. Is they found upwards of one hundredfold difference in what's produced not only among organs within plants, but among different plants WHOA I don't know. I tried really hard to figure out why willow especially. It could have just been that we are closely associated with willows. They have a deep historical ties to our society and our cultures, or it just could be that they're producing a lot more of it. I don't know, so if anyone does know, please let me know because I would really like to know that. But it has been recognized as sort of the signal mediating plant response to stresses, but also sort of regulatory function from a hormone standpoint, so it's a phenolic compound. I do think that even though you get it as salacin plants will turn it into salasilic acid. I just don't know if that involves any sort of extraction. But from the defense side of things, there's a lot of papers on this, and what's fascinating is what we know about salasilic acid in plants is still largely up in the air. There's a lot of unknowns, but we know it from studying mostly economic important species, so tobacco comes up a lot in this research, as well as rabidopsis, which is the model plant system for understanding like genes and stuff like that, so it's there. It's in a lot of different things, but one of the main functions in defense is that it's regulating like local disease resistance mechanisms and also like a systemic acquired resistance or the ESSAAR response. And there's a lot of pathways involved in this. I'm only going to mention a few of them. But what ends up happening is that it helps recognize an invading pathogen and then it mounts this effective defensive response, which is split between sort of this cognitive pathogen encoded effects protein, which is essentially an effector triggered an effector triggered immunity, which then leads into what they call a hyper sensitive response. And if you've ever seen a leaf that looks really blotchy with a lot of necrotic tissue on it, you're seeing the hyper sensitive response in action. So a few plant hives, yeah, plant hives, But think about plants as sort of these compartmental organisms. They're not like us with a lot. I mean, they are connected, but they're modular. You can break off pieces, and plants, oftentimes with their immune response, want to isolate it just by knocking out that entire section of their tissue. If you just kill it off, it's gone, and there's evidence that it's This comes into play here, so after some sort of infection is detected, a few hours after even the unoculated portions of the plant will also sort of start to take up increased levels of the genes that start the systematic acquired resistance pathway, So that's more of the long lasting thing. So there's both timeframes getting involved here, an immediate response where they start killing off and trying to localize it, and then okay, we have to protect the rest of the tissues and this is where celicilic acid comes into play. Yeah, So the biggest evidence that we have for its role really comes from studying plants that are deficient in these genes and the ability to produce it. So it's the mutants that tell us really what's going on. But it's a key signaling component involved in this, and so it accumulates in high levels around the sites of infection. But then after a decent amount of time it varies from species to species, you'll see it starting to turn up in uninfected systemic tissues. So they have discovered that even by inoculating the plant or applying it with aspirin essentially they powder it up or put it in there in some form, they can actually get those genes to start playing a role and turn those on in the plant. So they know it's signaling they know there's something about this that's saying, hey, we have an issue here. We have to get going. And then the best part is it doesn't end there. It gets even crazier as you go on. So after pathogen infection, there's a big component of reactive oxygen species in here, and that is really fascinating because, as we'll learn later and some of the other functions of salicylic acid, the relationship between these two things is extremely complicated. So what they're finding is that the relationship between salicylic acid and cell death and H two two is that peroxide. Yeah, yeah, and peroxide has led to this idea that the defenses are regulated by some sort of oxidative cell death loop, which is pretty strange to think about. But what ends up happening is peroxide increases following there's some sort of infection, and then it activates salicylic acid synthesis. So they have peroxide sitting in the cells and that says, okay, we have to start making salicylic acid. So then as sellicylic acid starts to increase, they begin to work with these reactive oxygen species that are generated during a second phase of the cell death response, and that potentiates more peroxide production, and then that in turn activates the synthesis of mores salicylic acid and cell death, and then it just becomes this like self amplifying loop.

01:01:19
Speaker 4: My god, this is very similar to how neutrophils kill bacteria in our bodies.

01:01:25
Speaker 2: Really, yes, so the immune response, despite being a modular system, is there's a lot.

01:01:30
Speaker 4: Of overhast overlap.

01:01:31
Speaker 2: Yeah, that's bizarre, so cool. Yeah, so they think it's broad spectrum. This isn't specific, although the tobacco mesaic virus probably has allowed us to understand it in its most intense form. So all of this taken together supports the sort of this contention or hypothesis that salacilic acid may be a signal that translocates from the infection site to other areas of the plant. However, there's also plenty of lines of evidence mixed in there that I don't fully understand that it's not a long distance signal. So really, what we can say at this point is that either slicilic acid is not a long distance signal, or that all it takes is very small amounts of it within the infected leaves to kind of put in this systematic sort of response induction within the plant.

01:02:18
Speaker 4: So it's almost like salicilic acid in plants is acting the way that prostaglandins do in humans to like go around and tell other parts of the plant like, hey, we've got an infection.

01:02:30
Speaker 2: Over here, right, And again, the mechanisms by which that's working they don't know, but it is there's something going on there with when that is perceived in the plant, it's it's immune systems are kicked on. Cool And what's even cooler is that I didn't get into the weeds with this, but there is a way that this becomes volatilized in the form of methylsilicylate and which is a volatile aster, which means it comes airborne, and that can actually signal neighboring plants to kick in with the same response without having experienced the virulent pathogens stop it. Yeah, which is what bonkers. And it's one of those things that we're really only now starting to appreciate is that these aren't static organisms sitting there. And I don't think this is altruism at work. I just think it's if you can detect some sort of signal in your environment that maybe not everything's Okay, you're probably better off in the long run.

01:03:25
Speaker 4: Yeah, or maybe you could recruit help or something.

01:03:27
Speaker 2: Like, yeah, exactly, and any that's a whole new realm of understanding in the world of what plants are doing, especially to one another.

01:03:35
Speaker 4: They're gossiping about us that they're doing.

01:03:37
Speaker 3: It's just like the happening.

01:03:38
Speaker 2: Guys. If we can bring that up every time I'm around, I'd be really happy. Where's John Luguizoma. But outside of the defense and dealing with these sorts of things, there's a lot of evidence that this functions as a hormone in regulating processes such as seed germination, vegetative growth, photosynthesis, respiration, thermogenesis which is the production of heat that you didn't know plants could do that, flower formation, seed production, senescence, and a type of cell death that is not associated with the hypersensitive response. This is a super important compound in plants.

01:04:19
Speaker 4: I'm trying to think of a single hormone in humans that can do that many things.

01:04:25
Speaker 3: And are chronologists let us know.

01:04:27
Speaker 2: These effects are probably more indirect they think, because sollicilic acid alters the synthesis of other signaling hormones and other important hormones like jasmonic acid, ethylene, and oxen so to start with seed germination. This is one of those things where the dose varies. So they found that when low doses of salicylic acid have been applied to a Rabidopsis seeds, it promotes the synthesis of proteins and enzymes that are essential for germination and mobilization or degradation of seed proteins accumulated during seed saturation. So it basically gets rid of the proteins that teleseed to not germinate, and it helps turn the genes on that say, let's start getting this game.

01:05:09
Speaker 4: Let's do this.

01:05:10
Speaker 2: Yeah, let's get to show on the roya. But then there's also evidence that in higher doses it actually shuts that down and says, don't germany here, which actually could come into play there and that they're not so sure of why, but it could be that have something to do with that whole oxidative stress issue there. Yeah. It also is involved in photosynthesis, which is arguably the most important reaction on the planets.

01:05:36
Speaker 4: That's a play biologist. Yeah, well that also, Yeah.

01:05:41
Speaker 2: But one of the cooler things in photosynthesis is that what they found is that it's really important in the plant when it's protecting photosynthesis against a specific type of herbicide which steals electrons from the photosystem pathways.

01:06:00
Speaker 3: It gets there's an herbicide that steals electrons.

01:06:05
Speaker 2: Yeah, there's an electron stealing herbicide.

01:06:07
Speaker 3: Is that it's catchphrase? I steal electrons, I hope.

01:06:10
Speaker 2: So use of this herbicide and seeing how salicylic acid turns on to protect the plant against this herbicide also gave us insights into what the actual biological evolutionary function of this could be going on within the leaf itself. That's wild and that's all about detoxifying those reactive oxygen species. Wow, yeah, pretty bonkers. It can also induce stomatol closure, which is again goes back to sort of that defense against drought stress. So stomata are pores on the surface of the leaf and stems that regulate the passage of CO two and oxygen inside and outside, but also water, and as you can imagine, if things are getting really hot, plants are going to want to shut those so they don't lose water. But then again they can't keep gas exchange going on and therefore can't photosynthesize you know, most of the money going into this research is figuring out how to make better crops that can deal with the stressors of climate change, mostly drought in this context. So solicilic acid is being studied to an intense degree in Stoll model closure, which again just for the listeners to follow that path if they so decide. So in growth, plants got to grow, right, It's little studied compared to the other hormones because the other hormones, as we mentioned, are having a more direct effect, but solicylic acid is having interactions with those. So there's growth stimulating effects that have been found in soybean and cammomeal, which it's interesting that camomile was thrown into the mix there, but they found it to enhance cell division and they think this might be related indirectly through changes in hormonal status or by the improvement of photosynth photosynthesis, transpiration, and Stow model conductance. So some of the stuff we already just talked about is coming into play when plants are starting to actively divide and grow. Now here's where things get super interesting, at least for me, because flowering, at least in andreosperms or the flowering plants. Is one of the most vital things to any sort of sexual organism or sexually reproducing organism. And we've known about this actually for a very long time because slicilic acid has been showing to promote flower bud formation in callus tissue. So not even where flower buds are supposed to form when they nick a tobacco plant and create this callus tissue, if you apply salicylic acid to it, you can actually get flower buds to form, which is weird, but that tells you that something really important is going on there.

01:08:39
Speaker 4: Yeah, so I have a question. Okay, that's usually your line here. Are there are plants that do not produce salicilic acid probably? Yeah, Like, it seems like it's kind of a big deal in all the parts of plant.

01:08:56
Speaker 2: I would assume that the levels are there in some sort of background amount, but the fact that it's involved in all of these things are telling me that every plant is probably dealing with it on some level.

01:09:07
Speaker 4: Wow, that's so weird.

01:09:09
Speaker 2: But think about it from the perspective of a researcher. Are you going to get funding for a plant that has some sort of economic importance to humanity or some obscure little weed sitting in a ditch or along a trail somewhere in the woods. So the unknowns here vastly outweigh the nones. And so thinking about the ways that we've discovered slicelic acid to work in just important species and in mutant varieties, there's probably a myriad laundry laundry lists of different things that could be going on another plant. Wow, And I'm going to talk about one of those right now, because this was the most mind blowing thing to me. If I said sorromatum gutatam to you, what would that? What would that elicit?

01:09:53
Speaker 4: Absolutely?

01:09:54
Speaker 3: Yeah, got nothing.

01:09:55
Speaker 2: That's what I was hoping for. Just a little chuckle. That's a giant eroid called the voodoo. And if you think of the titan arum that gets a lot of press, that giant smelly corpse flower that blooms every once in a while, it's one of those. It's a close relative of those. And one of the most amazing things about this family of plants is that they are thermogenic. They produce their own heat. So in fact, there's a philodendron species that does this to a degree that it's metabolic process during that is comparable to that of a hummingbird, which is the highest metabolic activity of any vertebrate animal. What so it is converged on a similar strategy, what same similar metabolic processes at least to that of a hummingbird to produce heat and its giant inflorescence.

01:10:45
Speaker 4: And are they producing heat to seem more like an actual dead body?

01:10:48
Speaker 2: There is elements of that, but part of that corpse element is the smell and what they think with the heat, part of it is that it volati volatilizes that scent and makes it spread a lot further than it would otherwise. Yeah, that is so cool. And then then more temperate species, there's also the element of attracting pollinators. So right now as we're recording this, it's early March and it's cold outside, but plants like skunk cabbage, which is a cousin of this, are emerging. They produce heat which helps get their scent out, but it also is believed to attract pollinators. So what few insects are able to emerge at this time? Want a nice warm place to sit and stay? Why not a hot inflorescence?

01:11:31
Speaker 3: God, that is so cool.

01:11:34
Speaker 2: Yeah, so when they studied the voodoo lily, which you can actually purchase one of these plants that are a pretty common house plant. You probably don't want it hanging around in your house when it comes time to bloom, unless you are weird like me. But when they looked at this, they found that right as the inflorescence is emerging and starting to produce its heat, they found about a hundredfold increase in salicylic acid right as the onset of the heat process starts within the organ called the spadex, which is a very phallic central terminal length of tissue where the flowers are arranged around.

01:12:10
Speaker 4: But length of tissue, yes.

01:12:15
Speaker 2: And so what salicylic acid does is it stimulates thermogenesis primarily by increasing the activity of the alternative respiratory pathway within the mitochondria of the plant. So it switches from a plant metabolism to something way more like an animal metabolism.

01:12:33
Speaker 3: My god, that's so cool, yeah, god.

01:12:36
Speaker 2: And so it enhances the capacity of this alternative respiratory pathway by inducing the expression of alternative oxidase, which is the terminal electronic sceptor of the of the alternative respiratory pathway. So here we're seeing again, you're doing something that's going to create a lot of reactive oxygen stuff, and why not co opt the organ of the hormone that's already there, already being produced. And that's what's fascinating to me about plants and just evolution in general, is you see, it's not denovo it's not these new things happening. It's a retooling of systems that are already in place.

01:13:13
Speaker 4: Yeah, in this it's inducing these oxygenase enzymes, and then you put it into humans, now it's blocking these oxygenase enzymes. Oh my god.

01:13:23
Speaker 2: And so this dual function is just mind blowing to me, and I think it lends to a lot of the confusion and the contradictory results is we study this one pathway we got this, and we studied another and it's doing the exact opposite. Well, it's both both. And how plants are doing this opens that whole new set of questions as to what is going on with signaling and sort of the mainframe of a plant. How do they regulate this without a central nervous system per se. Fascinating, that is so cool. So to wrap this all up, we'll talk about sinessence, which is essentially the programmed reduction or death of the plant. You see this more in temperate species or if you live in the tropic anytime the dry season comes around. Sin essence is the dying back of tissues, and you don't just kill the tissue. You do it in a way in which you could probably extract some of what you invested in this. So it's involved in the decline in photosynthetic activity, which is also characterized by an increase in reactive in those reactive oxygen species due to a loss in the antioxidant capacity of the leaf at that time. So you have a die back of the photosynthetic machinery, but you also are taking away antioxidant pigments at the same time, which would normally protect against those So it's like, okay, we need to do this. It's almost like the crossing guard. A lot of crap is going on, but salasilic acid seems to be there to say we're not going to let the byproducts of this process damage us in any way.

01:14:48
Speaker 3: Wow, that's so cool.

01:14:51
Speaker 2: Boom boom. So this was a whole new adventure for me. And again I apologize, I'm not a plant pathologist. I'm not a genetic if I butchered any of this. The point is that defense comes in many forms, and in this case, it's environmental stressors, it's pathogens, it's not herbivery outright, you know, this isn't something you'd want to go and poison someone with or could poison someone with, although we learned you can, you can. But it's also a really important plant hormone in regulating some of the most essential, arguably the most essential processes within plants itself.

01:15:26
Speaker 3: Yeah, dude, Yeah, this was much more massive, I think than than I think we all realized it was going to be.

01:15:33
Speaker 4: Yeah, I had no idea.

01:15:35
Speaker 2: This was, I mean massive and kind of overwhelming, but in a good way because I remember early on getting into this again learning about salicilic acid, and it's a lot. But it's amazing that we've been able to unpack as much as we have about it.

01:15:48
Speaker 3: M hm cool. Okay, Well, that's that's aspirin, that's val so, that's seal silic acid.

01:15:56
Speaker 4: That's a wrap.

01:15:57
Speaker 2: Thanks, plants.

01:15:58
Speaker 3: Should we do source? Yeah, let's okay, So I'll start. I read a book called Aspirin, The Remarkable Story of a Wonder Drug by Diarmond Jeffries, and I just have to say this was one of the most exciting, engrossing books I've read on medicine and history ever. Go read it. Another book I read was called Dragon's Blood and Willow Bark by Tony Mount and this was about remedies and medicine in the Middle Ages. And then I read an article about how aspirin might have been used or might have led to excess mortality during the nineteen eighteen flu. So we'll post all.

01:16:41
Speaker 2: Of that excellent If you want to look up some of the stuff that I talked about, obviously I will send links. There is a few papers that really helped me with this. One is salsilic acid a multifaceted hormone to combat disease by vlot at all. There is salsilic acid and disease resistance in plants by dinner at all. And there is systemic acquired resistance by ryals at all. And I'm just gonna have to send you the rest. But those were really good ones in terms of giving enough background that a dumb dumb like me could understand.

01:17:16
Speaker 3: You're not a dumb dumb met definitely not.

01:17:18
Speaker 2: In this context. I feel like.

01:17:20
Speaker 4: One we will post a list of all of our sources on our website, this podcast will Kill You dot com. You can find all of the sources that we used in this episode and every episode.

01:17:31
Speaker 3: And we also have a good Reads list where we keep track of the books that we cite in our in our episodes, and anyone can add to that list. So if you know that, yeah, so if you feel like you that there's a particular book that you really enjoy about disease, added to the list. Fiction, nonfiction, whatever. And so it's been really fun to sort of for me to go through and look at them because I see so many that I'm like, oh my god, I want to read that. Oh I want to read that. Oh that looks so cool. Oh that looks so cool. So thank you for adding this neat.

01:18:03
Speaker 4: Thank you Matt for coming on today.

01:18:06
Speaker 2: Yeah, thank you both for having me. It is always a blast to not only research these episodes, but to record them. I really appreciate the opportunity.

01:18:13
Speaker 4: We love it. It's so fun, so much fun.

01:18:16
Speaker 3: And thank you to everyone who's listening. We really appreciate you taking the time to tune in.

01:18:24
Speaker 4: It's the best. And thank you to blood Mobile for the music in this episode, In every episode.

01:18:29
Speaker 3: And until next time wash your hands

01:18:32
Speaker 4: You feelthy animals.