This Podcast Will Kill You - Ep 29 Aspirin the Wonder Drug: Crossover w/ IDOP

Episode Date: June 11, 2019

On this very special crossover episode with our friend Matt Candeias from In Defense of Plants, we’re switching things up from poison to remedy, focusing on the plant-derived wonder drug, aspirin! We cover the ancient use of salicylic acid-containing willow bark to relieve pain and fevers and then reveal how such a harsh compound was transformed into a useable pharmaceutical. We also delve into what happens in your body when you pop an aspirin and discuss why on earth so many plants make this incredible compound. Spoiler - it’s not just a wonder drug for humans. See omnystudio.com/listener for privacy information.

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Contact dealer for details. Offer ends 3-2. Hi, I'm Aaron Welsh. And I'm Aaron Elman Updike. And I'm Matt. Yay. Yes, and this is, this podcast will kill you. Crossover style with.

In defensive plants. Yes. Yay. And this one. week, even though our past episodes have primarily focused on poisons, we're doing something a little bit different. A little bit healthier? I mean, it could be a poison if you took enough of it. Well, that's true. I mean, that's, that was the lesson we learned in poisons, I guess. Yeah. 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. Yeah. 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 like a harkening back to my... my early days of plant obsessiveness. You're like first flirtation with plants. Yeah, yeah. How fun. Cool. Wow. Okay.

So to celebrate aspirin, we are drinking our quarantini named Pain in the Aspirin. Yeah. There we go. Excellent. And what is in Pain in the Aspirin? We've got rum, lemon juice, and thy simple syrup. It's really delicious. Keeping it simple.

It's quite tasty. Some good botanical families in there. Yeah. Yeah. And we will post the recipe for this quarantini as well as the non-alcoholic placebo ita on all of our social media pages, including Twitter, TPWKY, and Facebook and Instagram, This Podcast Will Kill You. And our website, This Podcast Will Kill You.com.

So 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. Snap. Because Willow Bark was actually found in a Neanderthal burial site in Iraq dating back to 60,000 BCE. Are you serious? Yes. 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, toss some, you know, things in there. Super cool. So what do historical texts tell us? Something called the Ur-U-R-R-3? I don't know. Tablet. I read it. It's cool.

It's fine. Oh, yeah. The Earth 3. The Earth 3. So this tablet dates back to 3,000 B.C.E from ancient Sumer. area, 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, Ebers, Papyrus. Yeah. Just that, yeah, that medical text from ancient Egypt. And it was written around 1534 BCE, but it contained information

that was 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 160 remedies listed in this papyrus to try to identify the ingredients. And they've really only been successful in about 20% of those. But one of those is willow. Hmm. The plant that makes aspirin. It also includes another salicillot producing tree in its list of remedies, the myrtle.

Anyway, okay. I did not know that. Yeah. I don't even know what that is. There's a lot of them. It's all good. According to this papyrus, you should mix together willow, either ground up bark or leaves, figs, beer, and dates. Odd combination.

Sounds good. Could be tasty. I drink it. 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 Eber's papyrus was written, the willow was well-known. 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. That's really neat. Yeah. And the Neanderthal thing, it's like, it just begs that question of how the heck did any species figure that out at some point. Yeah, dude. 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 toe or whatever, you might have run into Willow as a possible relief provider. 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 resprout after you cut them. So it's one of those things that would have been ever present. Yeah. Yeah, exactly. So 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 6th century

CE. It was also used by people living in Southern Africa and by Native Americans before Columbus. By around 200 CE, Willow was basically as common a remedy as aspirin is today. Huh. But then, mysteriously, Willow just kind of falls by the wayside in much of Europe. And its importance as a medicinal plant there wouldn't be recognized again until the 1700s. Weird. Yeah. It just kind of disappears.

Okay. But what happens in the 1700s? Let me set the scene. I just want to say how excited your face was right now. There's a lot of enthusiasm for the drum roll here. Yeah. Okay. So you are a 56-year-old.

old man, a reverent, living in Chipping Norton, a sizable town in England. It's the 1700s, mid-1700s, 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 property, 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 lined the creek on your property. Today, as you contemplate your next sermon, perhaps, you absentmindedly take a piece of willow bark and pop it into your mouth. Naturally, eh?

Sorry. I think that's exactly what an Oxfordshire accent would sound like. Yeah. Yeah, you nailed it. 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?

Is it that myrtle thing you were talking about? Uh-uh. Think outside aspirin. This is a mat question. Yeah, and I'm embarrassing myself here that... Something in the carrot family, I don't know. This is something that harkens back to first season, TPWKY. Quineine!

Yep. The cinchona tree. Yes. So the cinchona tree, which is where we get quinine, was super, 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 Sinchona 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 an effective treatment. He didn't find anything, probably because he was looking in more recent books. Control F. Hadn't been invented yet. That was funny. 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 tally of cured patients grew larger. So then Reverend Stone sent this letter describing his discovery in 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. Bummer. 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 Santonabark, actually attacks the parasite itself that causes malaria, while Willow Bark just relieves the symptoms, doesn't actually treat the disease. Yeah, I was going to say, he didn't hear anybody. No, no. He just made their fever better. Ease their suffering.

Yeah. 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. Very true. I 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 firsthand account of this tastes like this. Yeah.

It's gross. Let's see. 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 Stone's letter got published in philosophical transactions in 1763, so that was quite a long time ago, to the early 1800s, Willow had started to be widely used as a cheap alternative to Sanchona Bark. And during this time, the field of chemistry had really started to ramp up. So there was motivation to isolate active compounds in 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 all about the Benjamin. Or the equivalent of that time period. By 1920, things like strychnine, caffeine, morphine, 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, salison, after salix, which is the Latin name for willow, and then salicylic acid. And during this time, so willow is not the only plant that produces this compound. Nope. 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. Spira? Spiria.

Spiria. Is that how you say it? Spiria. Olmaria. So Meadow Sweet 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 salicylic acid. This is nothing new here. But it kind of did, you know, really cement salicylic acid's reputation as a pain reliever and fever reliever. So after salisylic acid had been isolated, physicians prescribed it to patients, but people didn't really love taking it.

It was acid. Salisylic 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 salicylic acid by adding acetylaclyde, and when he did that, he got out an impure and crude version of acetylacilic acid, which is what is in our aspirin pills today.

Boom. 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 powerhouse 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 1874 in the form of a pretty carefully done study on the effectiveness of Salison 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 wide spread and immediate recognition. So the cost of Salison went way high, and doctors everywhere started publishing their own findings. So this led to more wide-scale trials of both salicin and salic acid, and then seeing what else it could do. Okay, so for the next segment of the history of aspirin, we'll see how a German dye-making company set the groundwork for creating the multi-billion dollar pharmaceutical industry that it is today. Yes. This is the story of Bayer. I love it. During the 1800s, 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 1800s, 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 Tylenol, for instance, compared to acetaminopin. Or paracetamol. Or paracetamol. And at this time, pharmacies were legally obligated to follow a doctor's prescription to the letter. So if he had written acetaminopin, any generic acetaminopin could be given. but if he had written Tylenol, only Tylenol could be given. Ah, so then these people could make bank.

Yep. Tricky, tricky. Yeah. And so you could see how this naming and patenting system would appeal to many of these chemical producing companies, many of which switch 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 dye-making, company found itself leading the pharmaceutical industry.

Wow. But what is the actual story of aspirin? Not of Willow or a salicylic acid, but aspirin capital A, trademark. Salosilic acid was on a long list of chemicals to try to improve on Bayer's list, because it had clear medical benefits and Bayer would really clean up if they could find a way to lessen its nasty side effects. But when Bayer chemist Felix Hoffman found a way to efficiently make a way to efficiently make acetylacilic acid, which didn't have the painful side effects of salicylic acid,

the head of development, Heinrich Dresser, refused to test it in clinical trials. What? Because he was like, oh, salicylic acid, it enfeebled the heart, and this chemical will be no different. What a turd. Yeah, what a turd. So he stopped all the work on it. And instead, he shifted his focus to diacetylmorphine, aka. a heroin.

Great. Which, by the way, was its trademarked name. Did you know that? No. It was a trademarked name. Heroin? Yeah. Huh.

Wow. I didn't know that. Yeah. Yeah. So another guy, Arthur Eichengren, who was another chemist at Bayer, he was not happy with this decision to abandon acetylacalic. Acetylac... I hate this word.

Third time's a charm. Acetylsilic acid. So he took matters into his own. hands, and you went behind Dresor'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 Spireia, the genus name of Meadow Suite, 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. Wow. I appreciate that so much more now. Thank you. So aspirin the wonder drug, produced by Bayer, would be officially launched in 1899. Was that its tagline, Aspirin the Wonder Drug? No, that was my tagline for it. You are missing out on the marketing gig.

After its launch, aspirin kind of just slipped quietly onto the market. And to push along recognition, Bayer 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 U.S. and Britain would. So then Bayer had this monopoly on two of the biggest markets for aspirin. 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 U.S. 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 Bayer had to figure out how to get into the U.S. 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, Bayer's patent for aspirin was deemed invalid in the U.K., and it seemed like things were headed in that direction for the U.S. as well. They had until late February 1917 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 the drug. So you can't say like what it does or? Nope, not at the time. Weird. Interesting.

And only non-trademark drugs called by their generic names could be included in the official US pharmacopia. Oh yeah. That's still like we only learn non-trade names. That's what's on the USMLE tests and everything. Really? Which makes sense. Huh.

Yeah. Yeah. All of this trademark patent advertising controversy is going down in the early 1900s. And guess what happens in 1914? Titanic. No. 1912. I actually knew that.

The de-fenestration of Prague. Oh, my God. The Dust Bowl? What was the Dust Bowl, actually? It's like in the late 20s, I think. Grapes of wrath. Okay. All right.

Well, World War I is what happens. And so with this outbreak of war, citizens of the UK were like, we're not supporting Bayer. This is a German company. Oh. But that was easier said than done. First off, large-scale manufacturing of acetyl cellic acid was logistically difficult, and many chemical companies had switched to making, you know, like wartime things, explosives, poisons, whatever. Rations. And doctors were still prescribing aspirin capital A rather than acetylacilic acid. So Bayer was still making a killing. and they also were making mustard gas.

So they were also making a chemical that was doing killing. Yeah. It's a fine line, as we've learned. So, yeah, so Bear was still making a killing, but that was only until the British government's Board of Trade nullified the trademark on aspirin's name, and it made it public property. Yeah, because now it's just aspirin, lowercase, eh? Yes.

I never put two and two together there. Yeah. Okay. Maybe you'll remember some other things that happened during World War I that are relevant to the podcast. Like the 1918 flu, for example? 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. Yeah. So after World War I, 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 aspirin 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 kept up with, you know, 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 Alka-Seltzer mornings. Oh. Oh. Don Draper. Hence it works. 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 a free-for-all. And as is usually the case and things like this, the legality or regulations for this type of advertising lagged far behind the advertisements themselves. Yeah. Many of these companies were making outrageous or at the very least, exactly. exaggerated claims, and the biggest repercussions they faced were just like, oh, slap on the wrist. That's it. Okay. During the 1930s, the history of aspirin, or at least the history of Bayer, starts to take a dark turn.

Oh. The company that had really established itself as a giant due to aspirin had survived World War I, despite losing its trademarks and patent rights in many countries. And in the late 1920s, the head of Bayer, Karl Dewesburg, I don't know how you see, say's last name, teamed up with a bunch of other German pharmaceutical and chemical manufacturers to basically create a monopoly over the drug market. Cool. Great guys. It would be known as IG Farben, and it would play a pivotal role in World World War II. War and genocide are expensive, and that money has to come from somewhere.

So when in February of 1933, 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. I did not know that. Yeah. So if Bayer 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. That's a terrible what-if. Right? Right? Yeah. And of course it didn't just support the Nazis, but also became directly involved, starting with the arionization of its workforce, and ending with the production of the Zyclan B gas used in the gas chambers and concentration camps, and also directly financing and managing some of those camps.

Well, that's despicable. It also financed the human experiments conducted by Nazi doctors and scientists that resulted in death and torture for thousands and thousands of people. Jesus Christ. Yeah. Even the developer of acetylacilic acid at Bayer. So Arthur Eichengren, 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.

Yeah. So he was Jewish and he noticed that he had begun to be written out of history. His name 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 aspirin 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 50 years to the early 2000s. Wow. Okay. So at the end, actually, of World War II, 23 senior executives from IG Farben would be tried at the Nuremberg trials, and 13 would be acquitted. Wow. Yeah. Okay, so I.G. Farben didn't survive the war intact, but Beyer did and continued to produce

aspirin at high rates. After World War II, the aspirin market had continued to grow, and many other brands had taken big chunks out of Bayer'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 paraaminophenol, which appeared to be an analgesic, but with some nasty side effects. So they revisited this chemical, which they called acetaminophen. Oh. Hey now. I know that. 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.

I had no idea that Bayer also made Tylenol. Mm-hmm. They called it Panadol. So this was, they called it acetaminopin, and then in the UK, it became known as paracetamol, and its brand name was Panadol. And so it was like, it flew off the shelves because this was this non-stomachythoritating aspirin alternative. And so aspirin kind of just started to slip out of the, you know, leading place in the market. And in the U.S., acetaminopin, of course, would be Tylenol, and ibuprofen was not far behind. And so by the 1960s, the trio of aspirin acetaminopin slash paracetamol and ibuprofen dominated the over-the-counter analgesic market. And aspirin continued to slip until the 1980s, 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 that. Its mechanism of action was still unknown. No one knew how it worked. Yeah. It's funny because there wasn't much interest in finding out the mechanism of action until 1958, 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 Pollyard.

Piper and John Vane, they worked together sometimes separately, sometimes on the same project to uncover the mysteries of aspirin. And I'm not going to go into the whole thing, but essentially what happened is that John Vane 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 Vane won a Nobel 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 being that in small doses, aspirin had this effect on the body's clotting ability. So in the second half of the 20th century, and through to today, of course, heart disease is a leading cause of death in many industrialized countries, such as the U.S. and parts of Europe. And this anti-clodding 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-1980s, it was finally accepted, which meant new branding and campaigning.

Bring in the marketers. Yeah. Back to the whole aspirin advertising situation. But this is really where my story of aspirin leaves off and where I think, you know, you pick it up, Erin. So tell me, how does aspirin work? And what is it good? Is it bad? What does it do for you? Okay, let's talk about it. We'll take a quick break first. I have to peece so bad. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients so there's no meal planning and no extra grocery trip. There, assemble and

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the main compound that's found in Willow Bark is Salison. Solicin. This compound itself actually doesn't do very much. It becomes salicylic acid in your body. So your body actually breaks it down and metabolizes it to produce salicylic acid. But Salicylic 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 salicylic acid. salicylic acid, as you heard from Aaron, 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.

Yeah, I've used it. Yeah, I use it every night. Yeah, now that I think about it, I see it show up on labels a lot. Yeah, 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 gastrointestinal side effects. So the development of aspirin, acetylalicic acid, was massive because it has much less of the

side effects. So how do these things actually work? It turns out all of salicylic acid and acetyl salicylic 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 some 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. It's just like when I cut my finger when I was doing night cheese. Night cheese. Night cheese. Yeah. Typical night cheese. 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 the main pathway, we can reduce inflammation substantially.

Okay. Because although inflammation is a normal response, it sometimes can get out of control, right? Right. But so where is that line? That's a great question. And it's totally not clear. So like if you tear a muscle, like doing 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. 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 104, 105, you definitely need something to bring that fever down because your brain is going to start to melt. Pitchie. 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 it, not, 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. Yeah. Yeah. It's a really interesting, like we, 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. So when I'd be fever and 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 round of good. I mean, within reason. The thing is we like as humans and as as other 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? Yeah. Yeah. It's a great question. Darwinian medicine. So that main inflammatory pathway, is called the arachadonic acid pathway. I like that name. It's good. It's a good name.

It sounds fancy. So, arachidonic acid is actually made from, 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 arachadonic 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 arachidonic acid into all of these active metabolites, cyclooxygenase or cox and lypoxygenase, which I don't think we ever shorten. Locks. Locks.

The old cox and locks. Okay. So everyone's still with me? Yeah. Okay, good. All right. So I'm actually not going to talk about locks. Lipoxygenase.

Get rid of 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 cox, of which there are several different forms of this enzyme, can turn arachidonic acid into a number of different compounds. Prostaglandins, which there's a whole bunch of different prostaglandins, and thromboxanes. Prostoglandins are molecules that are really important. in mediating a lot of different parts of the inflammatory response. Redness, which prostate glandants can help with vasodilation,

which we have talked a lot about visodilation in other diseases causing redness and rashes. Fever, which is also via vasodilation, and pain. So there are prostaglandins that actually sanitize your nerve cells to pain, so that now you feel pain. Whoa. It's pretty cool. Wow. So those are prostaglandins.

Those are all made via a Cox enzyme from arachidonic acid. You can also, with other Cox enzymes, make thromboxanes. The word thrombus means clot, and a thrombosite 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. get cut to not bleed out everywhere. Right. Thanks, platelets.

Thank you. You should thank your platelets. So one thromboxane, especially thromboxane A2, it is produced by activated platelets via Cox from arachidonic 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 going to get, the less thromboxane you have, the less clotting you're going to get. Sound good?

Yeah. Excellent. Thromboxanes are also important in vasoconstriction, because you can imagine if you're bleeding out, if you can constrictive blood vessels, even if you can't clot them all the way, if they're smaller, less blood is flowing to that area. Okay. Makes sense. Okay. So where do all of the? these salicyllate, salicylic acid, acetyl salicylic acid, where do these fit in? It turns out

their mechanism is to inhibit cyclooxygenase. Oh, Cox. Whoa. 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 arachidonic acid. Therefore, you have less inflammation. if you have less prostaglandins, and you have less clotting if you have less thrombocytes. Hmm. Fascinating. Makes sense. It gets better.

It gets better. Okay. I just like being able to draw the line between the dots clearly. I'm like, oh, okay. Yeah. Okay. So like you said, Aaron, aspirin is, well, you didn't say this exactly, but I'm going to just keep going on what you said earlier. There's kind of three big drugs that we think.

think about when you think about over-the-counter pain relievers, Tylenol or acetaminopin, ibuprofen, and aspirin. These are drugs that we call ensigns, although Tylenol is kind of not really an insid. We'll talk about it. Ensed means non-steroidal anti-inflammatory. That just means that it can reduce inflammation, but it's not steroids. Yeah. Yeah.

Which is probably a good thing, right? Yeah. So the mechanism of action of ibuprofen is very similar to aspirin. It also blocks cox. It cox blocks. Wow, that was funny. I had to be done. But the reason why you may have heard of doctors recommending that you take aspirin and not ibuprofen 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. So, okay, question. First of all, how does it bind irreversibly and why does ibuprofen not?

So ibuprofen binds in a different place and it just binds reversibly. So it can be outcompeted and it can fall off essentially. Okay. I'm not a biochemist, so that's the most detail I can give you. But aspirin binds and doesn't let go. It binds really tightly and it completely blocks the action of. psychooxygenase. How long does a platelet live? Eight to nine days. So glad you asked. 30 years later. So, yeah, so baby aspirin, which is just a low dose of aspirin, for a while, like you were saying, in the 80s, 90s, even early 2000s, it was like, everybody, take baby aspirin every day. It'll reduce your risk of heart attack. It's not recommendations. It's not.

that everybody take it. However, in some people who have had a previous MI or myocardial infarction, 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 ibuprofen. You'd have to take ibuprofen like every four hours because it wears off. whereas aspirin you can take just 81 milligrams once a day. And that's going to bind up any platelets that are not yet bound to aspirin. Awesome. That's so cool.

Yeah, that's really rare. It's thrilling. There are very few things that I remember from like original biochem, 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 acclude your arteries. If you don't acclute your arteries, you don't have a heart attack. Boom. Simple. One, two, three, four. I don't know how many steps there were. There was a lot.

But I understood it. And that's a lot for any. medical texture jerky. Yeah. So ibuprofen, which is another n-sed, it's another non-steroidal anti-inflammatory. It works very similarly, but again, it is reversible. So it's not going to have that same long-lasting effects. Tylenol, or acetaminopin or paracetamol, has a million names, is not quite the same. It actually, it's not entirely clear yet how Tylenol really works. We think that it binds cocks, but it does not do so in your peripheral body, but it might do so in your brain. So Tylenol isn't 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 antipyretic. 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? Yeah. 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 infarction 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 thromboxanes,

but on its inflammatory, anti-inflammatory effects, because a number of cancer's processes, and we're sort of learning this more and more, are associated with prolonged inflammation. So if you think of something like, something like ulcerative 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. So does that go back to what you had told me a couple weekends back where anytime you get

a situation where cells are constantly being asked to replenish themselves, you always run the risk of irregularities in cell division and thus cancer. Exactly. Beautiful. Mind blown. 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 81 milligrams of dose rather than 325, which is like grown of aspirin, regular aspirin.

Like aspirin you would take for a headache. Adalt aspirin. It does not mean that you should give baby aspirin. to a baby because... Bad naming. Yeah, it's a terrible name. For some reason, and it's not clear why this happens, if you give aspirin to children, basically under teenagers,

it can cause a very, very serious disease called Reyes Syndrome, which you mentioned, Aaron, which can lead to encephalopathy, which is swelling of your brain, liver failure, and death. It's not clear why this happens, but that's why it, In general, the recommendation is never, ever give children aspirin. If they have a fever, you give them Tylenol or maybe Motrin, which is ibuprofen. Oh, wow. That explains the Tylenol.

Okay. My childhood makes a little bit more. My mom was listening. Yeah. Don't give babies aspirin. Thanks, Mom. 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's, It is very cool. It's a very cool drug. And for a lot of people, it really does work. Yeah. So do your homework.

Talk to a doctor, man. So yeah, that's the mechanism of aspirin. Isn't it cool? Dang, yeah. And I was not expecting to understand it, and I do. You have no idea how happy that makes me. Because I was like, oh, this is so biochem. Yeah, that was really cool.

Oh, good. I liked it. Yeah. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's Working Hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way. moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for decades by people who wash their hands constantly

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What's up with the willow plant? Yeah. Why does it have salicylic acid? This was super exciting. So when you message me and said, hey, can we do this instead of what we were planning for a future episode? No 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. Salicilic 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 keeping herbivores at bay. It's more about defense against abiotic stress.

So environmental stresses like drought, heavy metal tolerance, heat, and osmotic stress, as well as some pathogens. 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. It's so cool because it's like the way humans use aspirin. 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 were a jumble of cells, each with their own sort of functions. And the deeper I dug, the more of 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 senescence. 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 with willow. Like I said, it was one of the first times I'd learn 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 a hundredfold difference in what's produced, not only among organs within plants, but among different plants. 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 salic implants will turn it into salicylic 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 salicylic acid,

plants is still largely up in the air. There's a lot of unknowns, but we know it from studying mostly economic and 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 S-A-R 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 effector protein, which is essentially an effector-triggered immunity, which then leads into what they call a hypersensitive 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 hypersensitive response in action. So a few... It's like 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 ununoculated portions of the plant will also sort of start to take up increased levels of the genes that will 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 salicylic acid comes into play.

Huh. Oh. Yeah. So the biggest evidence that we have for its role really comes from studying plants that are deficient in these genes and their ability to produce it. So it's the mutants that tell us really what's going on. That's really cool. 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 speech. 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 in 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 H2O2, is that peroxide? Yeah, hydrogen peroxide. 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 cellicic 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 more salicylic acid and cell death, and then it just becomes this like self-amplifying loop. Oh my God. This is very similar to how neutrophils kill bacteria in our bodies. Really? Yes. So the immune response despite being a modular system is, there's a lot of overlap there's a lot of overlap, yeah. That's bizarre. That's so cool. Yeah. So they think it's broad spectrum. This isn't specific, although the tobacco

mosaic 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 salicylic 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 salicylic 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. So it's almost like salicylic 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 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, its 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, this becomes volatileized by, in the form of methylsilate, and which is a volatile astor, which means it comes airborne, and that can actually signal neighboring plants to kick in with the same response

without having experienced the virulent pathogen. Stop it. Yeah. Which is 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. Yeah, or maybe you could recruit help or something like that. Yeah, exactly. And that's a whole new realm of understanding in the world of what plants are doing, especially to one another. They're gossiping about us. That's what they're doing. It's just like the happening, guys.

If we can bring that up every time I'm around, I'd be really happy. Where's John Luguizama? 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. Bet 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. Wow.

This is a super important compound in plants. I'm trying to think of a single hormone in humans that, can do that many things. Endocrinologist, let us know. These effects are probably more indirect, I think, because salicylic 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 Arabidopsis seeds, it promotes the synthesis of proteins and enzymes that are essential. essential for germination and mobilization or degradation of seed proteins accumulated during seed maturation. So it basically gets rid of the proteins that tell the seed to not germinate and it helps turn the genes on that say, let's start getting this game. Let's do this thing. Let's get to show on the road. But then there's also evidence that in higher doses, it actually shuts that down and says,

don't germinate here, which actually could come into play there. And they're not so sure of why, but it could be that have something to do with that whole oxidative stress issue there. Wow. Yeah. It also is involved in photosynthesis, which is arguably the most important reaction on the planets. That's a play biologist right there. But also, yeah. That's true.

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. There's a pestle. There's an herbicide that steals electrons? Yeah, there's an electron stealing herbicide. What? Is that its catchphrase?

I steal electrons? I hope 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's 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 stomato 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 CO2 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 salicylic acid is being studied to an intense degree in stomotocl 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 salicylic acid is having interactions with those. So there's growth stimulating effects that have been found in soybean and chamomile, 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 photosynthesis, transpiration, and stomatoconductance. 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 angiosperms 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 salicylic acid has been showing to promote flower bud formation in callous tissue. So not even where flower buds are supposed to form. What? When they nick a tobacco plant and create this callous tissue, if you apply salicylic acid to it, you can actually get flower buds to form.

What? Which is weird. But that tells you that something really important is going on there. Yeah. So I have a question. Okay. That's usually your line area. Are there, there are plants that do not produce salicylic acid?

Probably, yeah. Like, it seems like it's kind of a big deal in all the parts of plant. 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. Wow. Wow, that's so weird. 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 knowns. And so thinking about the ways that we've discovered salicylic acid to work in just important species and in mutant varieties, there's probably a myriad laundry lists of different things that could be going on in other plants. 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 soromatum gutatum to you, what would that elicit? Absolutely nothing.

Yeah, I got nothing. That's what I was hoping for, just a little chuckle. That's a giant aeroid called the voodoo lily. And if you think of the titanarum that gets a lot of press, that giant smelly corpse, 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. That's so cool. In fact, there's a philodendron species that does this to a degree that its 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? Similar metabolic processes, at least, to that of a hummingbird to produce heat and its giant inflorescence. And are they producing heat to seem more like an actual dead body?

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 volatizes that scent and makes it spread a lot further than it would otherwise. Wow. Yeah. That is so cool. 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. It's cold as heck. 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? Oh my God, that is so cool. 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, like, length of tissue where the flowers are arranged around. Length of tissue. Yes.

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. Oh my God, that is so cool. Yeah. 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 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-op 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 de novo. It's not these new things happening. It's a retooling of systems that are already in place. 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. 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 act opposite. Well, it's both. It's 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 senescence, which is essentially the programmed reduction or death of the plant. You see this more in tempered species or if you live in the tropics, anytime there's the the dry season comes around, senescence 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 those reactive oxygen species due to a loss in the antioxidant capacity of the leaf at that time.

So you have a dieback of the photosynthetic machinery, but you also are taking away antioxidant pigments. at the same time, which would normally protect against those. Right. 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 salicylic acid seems to be there to say, we're not going to let the byproducts of this process damage us in any way. Wow.

That's so cool. 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 geneticist. 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 herbivory 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. Yeah. Dude.

Yeah, this was much more massive, I think. then I think we all realized it was going to be. I had no idea. 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 salicylic acid. And it's a lot, but it's amazing that we've been able to unpack as much as we have about it. Mm-hmm.

Cool. Okay. Well, that's aspirin. That's al-Aspirin. That's whillic acid. That's a wrap. Thanks, plants. Should we do sources?

Yeah, let's. Okay. So I'll start. I read a book called Aspirin, the Remarkable Story of a Wonder Drug by DeArmond Jeffries. And I just have to say this was one of the most exciting and grossing 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 1918 flu. So we'll post all 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 salicylic acid, a multifaceted hormone to combat disease by Vlot at all. There is salicylic acid and disease resistance in plants by Derner at all. And there is systemic acquired resistance by Rials at all. And I'm just going to 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. You're not a dumb, dumb, Matt. Definitely not. In this context, I feel like one. We will post a list of all of our sources on our website. This podcast will kill you.com. you can find all of the sources that we used in this episode and every episode.

And we also have a Goodreads list where we keep track of the books that we cite in our episodes. And anyone can add to that list. Oh, I didn't know that. Yeah. So if you feel like you, that there's a particular book that you really enjoy about disease, add it to the list, fiction, nonfiction, whatever. And so it's been really fun 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. Thank you, Matt, for coming on today. 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. We love it. It's so fun. It's so much fun. And thank you to everyone who's listening. We really appreciate you taking the time to tune in. It's the best. And thank you to Bloodwell. for the music in this episode and every episode. And until next time, wash your hands. You filthy animals.

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