Episode 345: The History of Curare with Matt O'Hara

0:13 [SPEAKER_01]: Hello and welcome back to ACRAC. [SPEAKER_01]: I'm Jed Wolpa and I am really excited for our show today. [SPEAKER_01]: This is a little unusual in a fabulous way. [SPEAKER_01]: I have with me a professor of history, believe it or not. [SPEAKER_01]: And we are going to be talking about the history of curary and of course, therefore all of our neuromuscular blocking drugs.

0:32 [SPEAKER_01]: So I have Matt O'Hara with me. [SPEAKER_01]: He's a professor in the history department at the University of California Santa Cruz. [SPEAKER_01]: He received his PhD in history from UC San Diego and the author of three books, the most relevant is the one we're going to be talking about today, at least relevant to us.

0:47 [SPEAKER_01]: And that's called the Flying Death Poison Plunder and the Quest for a Miracle Medicine in the Amazon. [SPEAKER_01]: And he was named a public scholar by the National Endowment for the Humanities for this book. [SPEAKER_01]: Interestingly, for grad school, he managed teams at broader fund software that helped develop the early adventure games missed and ribbon, which is very cool.

1:05 [SPEAKER_01]: So I am thrilled to have him with me on the show, Matt. [SPEAKER_01]: Welcome to ACRAC. [SPEAKER_02]: Jim, thanks for having me on. [SPEAKER_02]: And I guess thanks for the kind of introduction and also looting to some of it. [SPEAKER_02]: It's really exciting for me to get to share this story with your audience in particular, because obviously there's this intersection with the history of your discipline.

1:24 [SPEAKER_02]: So I'm looking forward to the conversation. [SPEAKER_01]: Yeah, I, you know, I was so glad you reached out and that we're going to get to talk about this because, um, I, so we used to do, unfortunately, we don't anymore, but we used to take our residents out of history of anesthesia, tour, and Boston, and we kind of visited a lot of the original stuff.

1:39 [SPEAKER_01]: But one thing we did not talk about was the history of curary, and of neuromuscular blocking drugs, drugs we use every day. [SPEAKER_01]: So this will be really cool for everybody to get to an idea, because while we use them, and we know how they work, I don't think many of us, if any of us [SPEAKER_01]: really know the details of the history that you have spent a lot of time studying.

1:59 [SPEAKER_01]: So let's start, let me ask you first, just kind of give us a little bit about your background and how you landed on this. [SPEAKER_01]: This is, I've never heard of a history professor studying something so relevant to anesthesiology. [SPEAKER_01]: So how'd you get here? [SPEAKER_02]: Yeah, that's a great question.

2:11 [SPEAKER_02]: So I am a history professor and I've worked on Latin American history for a long time, nothing like this. [SPEAKER_02]: And so I think the easiest way to answer the question is when we're looking around for new projects, a lot of times we're hunting around. [SPEAKER_02]: in the archives.

2:27 [SPEAKER_02]: I mean, most historians are archival rats, and so we don't usually come up with our ideas. [SPEAKER_02]: We usually find them somewhere. [SPEAKER_02]: And so, in my case, I happened, I lived down the road about an hour from UC San Francisco, and I was looking around at the medical school archive.

2:45 [SPEAKER_02]: for a different project that ended up not coming to fruition, and I came across some papers that described the early origins and the kind of transition of cry from the jungle. [SPEAKER_02]: It's used as a hunting poison to the operating room, essentially in about a four or five year period.

3:04 [SPEAKER_02]: And as I dug a little bit deeper into some of the boxes of papers, [SPEAKER_02]: bunch of wild characters started emerging. [SPEAKER_02]: I thought how do I not know this story and I want to know a little bit more So I just kept digging at it and peeling away at the onion and that's how I knew it up here [SPEAKER_01]: very cool and we overlap there too, because I did actually medical school and my residency training at UCSF, very cool place and a lot of really interesting history of anesthesia there, so very interesting that you found this there.

3:30 [SPEAKER_01]: And I think like so many interesting stories, you know, not what you said out to do, but you stumbled on something interesting and it turned out to be really fascinating. [SPEAKER_01]: So let's talk about this exploration story. [SPEAKER_01]: I'm aware a little bit of the just incredibly interesting characters that are involved.

3:45 [SPEAKER_01]: I have [SPEAKER_01]: the book and it's really reads like a novel so it's one of those books that and that you should be committed because I mean in my mind the best history books are books that you wouldn't know were nonfiction and I really think that it reads like an adventure story so let's talk about that what is this exploration story that led to the discovery or at least in discovery in the way we use it of curary.

4:10 [SPEAKER_02]: Yeah, thanks for that. [SPEAKER_02]: And thanks for the kind words about the book. [SPEAKER_02]: I definitely wrote it in a way to try to appeal to a general reader. [SPEAKER_02]: And part of that is that the story itself was speaking through the archive. [SPEAKER_02]: And so I would have thought this is it.

4:24 [SPEAKER_02]: So the most to the extent that people know a little bit about this story. [SPEAKER_02]: So maybe some of your colleagues who know a little bit about anesthesia history might have. [SPEAKER_02]: They recognize that there's a connection to the jungle and so forth. [SPEAKER_02]: And so if people know a little bit about this story, [SPEAKER_02]: It centers on an American couple and an American man, particular Richard Gill.

4:45 [SPEAKER_02]: They had been living in the cloud forest of Eastern Ecuador, starting in the late 1920s and then early 1930s. [SPEAKER_02]: They had been down there working for a rubber company, promptly lost their job in the Great Depression, decided to stay on and try to make a life of it. [SPEAKER_02]: And they became increasingly aware of and then sort of enamored [SPEAKER_02]: that the indigenous peoples that they were starting to encounter had this incredible pharmacopia and traditional medicines, and they also became interested in this poison, the start poison that was used for hunting, that there was actually called Humbi, but the sort of umbrella term for the poison and the Amazon, it was known as Karari.

5:32 [SPEAKER_02]: The key moment in this story is that Gil comes down with a mysterious illness that he could not diagnose initially, he's having tremors, muscle spasms, they kind of come and then they go again, and eventually gets diagnosed as a very difficult case of MS. [SPEAKER_02]: and his neurologist back in D.C., we might talk about him a little bit more later on, tells Gill that if we knew a little bit more about Karare, because some people had dabbled with it, clinically even and certainly in the lab.

6:03 [SPEAKER_02]: If we knew a little bit more about this, it might just help someone like you get back on your feet. [SPEAKER_02]: And so it's a sort of strange counterintuitive thing. [SPEAKER_02]: Gill is nearly paralyzed at this point. [SPEAKER_02]: And his neurologist is telling him, if we knew more about this medicine or the substance that paralyzes, maybe it would help you out.

6:23 [SPEAKER_02]: And so that sense, Gil, on this, what turns out to be a lifelong quest to try to unlock the secrets of cry, he thought this was going to be a triple hitter. [SPEAKER_02]: He was going to cure his own disease. [SPEAKER_02]: He was going to ideally get rich in the process by turning it over to and working with [SPEAKER_02]: And then 30 thought he'd make a name for himself in medicine and science.

6:48 [SPEAKER_02]: As it happens, Gil came from the family of doctors, and he was a med student dropout from, uh, switched to English, and so he always had this sort of monkey on his shoulder that he didn't quite make it in medicine. [SPEAKER_02]: Now this was met in the 1930s that the story starts, yes, it starts in the early 1930s and then really gets heated up in the mid to late 1930s.

7:09 [SPEAKER_01]: Okay, now, was the reasoning for why he was told this might help his condition that [SPEAKER_01]: he was at times couldn't move. [SPEAKER_01]: And so the thought was well, if we relax, you know, if we have this to relax and that maybe that will help you move, I mean, it seems like, as you said, counterintuitive that something that paralyzed is what helps someone who can't move, but where they're thinking of it from a relaxation standpoint.

7:33 [SPEAKER_01]: exactly. [SPEAKER_01]: So that was the initial idea. [SPEAKER_02]: So there had been some tests on kids with what we're called then spastic disease as like cerebral palsy where their muscles were just bound up and tight and corarrate some doctors thought might be a way to alleviate some of those symptoms.

7:51 [SPEAKER_02]: And so that was the general idea. [SPEAKER_02]: Now, as you can spin that out, you can imagine it becomes a really tricky proposition medically because you're going to have to be titrating a dose of this thing, which it turns out varies in potency wildly from batch to batch, just right so that you're getting a certain amount of relaxation if that's even possible without leading to full paralysis.

8:16 [SPEAKER_01]: Yes, and respiratory arrest. [SPEAKER_02]: That turns out to be a problem as well. [SPEAKER_02]: Yeah. [SPEAKER_01]: All right. [SPEAKER_01]: So by the time, you know, he really, you said, this kind of really heats up in the late 1930s. [SPEAKER_01]: And my understanding is that it's not just him.

8:31 [SPEAKER_01]: There's kind of an interesting cast of characters involved in this search. [SPEAKER_01]: So tell us a little bit about that. [SPEAKER_02]: Yeah, that's one of the interesting things about this story is that, on the one hand, it's centers around this one, the American who's trying to save himself and get rich.

8:46 [SPEAKER_02]: But as I began digging a bit into the archive, I realized there's a whole other cast of characters around him. [SPEAKER_02]: That's coming from two things. [SPEAKER_02]: On the one hand, by the time Gil got involved in this story in the mid to late 1930s, [SPEAKER_02]: It turns out that there was actually, he was a bit of a late comer in a certain ways.

9:10 [SPEAKER_02]: There was actually a race going on to try to figure out who could crack the chemical and the botanical riddle of what went into this poison, how did it work, how did it kill in the jungle, how could it be tamed sort of medically. [SPEAKER_02]: So Merck Pharmaceutical, for example, already has a cut-through plant hunter, a Russian immigrant to the U.S. Boris Kruekoff.

9:32 [SPEAKER_02]: who is making trips into the Amazon almost constantly trying to find any kind of planter product that could be turned into a buck back in the U.S., and Merck sets in the loose on trying to figure out [SPEAKER_02]: the plants and some of the chemical properties of Karare. [SPEAKER_02]: So, Krucos, one example, Walter Freeman is the neurologist, psychiatrists who is attending to guild.

9:59 [SPEAKER_02]: He's the one who originally suggests that Karare might be able to help him with his disease. [SPEAKER_02]: So, some of your colleagues might, if the name Walter Freeman rings a bell at all, he's the person who becomes famous initially, but then infamous as the popularizer of the lobotomy in the U.S., where he performs 3500 of them eventually, including the so-called ice-pick variant, the transorbital lobotomy.

10:26 [SPEAKER_02]: So, what you get a sense here is that there is these characters who are obsessive about figuring out how cry could be used, but also, in the case of some of the medical research like Freeman, they're really working on the bleeding edge. [SPEAKER_02]: One of the doctors who initially tries out cry are, you know, I think describes it fairly that clinical research in the 1930s was really the wild west.

10:52 [SPEAKER_02]: If you had an idea, you could more or less try it out. [SPEAKER_01]: right there. [SPEAKER_01]: I think then correct me if I'm wrong, but I this was either in the years before institutional review boards or if they existed they didn't do much. [SPEAKER_02]: Yeah, they didn't do much, and it's also before the moment the FDA really has any teeth.

11:09 [SPEAKER_02]: So sort of right in the middle of this story, there's the famous elixir sulfan-elamide disaster. [SPEAKER_02]: So this is when the early sulfa drugs was perfectly safe and very helpful, but massing it a lot of Tennessee had the idea of putting it into an oral solution that would taste a little bit better and be easier to go down.

11:29 [SPEAKER_02]: and as a solvent to kind of get it to mix, they included diethyl glycol, which is basically radiator fluid, and it led to a hundred deaths around the country. [SPEAKER_02]: And so that begins the moment where there's more attention to labeling and what have you, but even after that incident, when you're doing research, you basically were free to go.

11:51 [SPEAKER_01]: right and so okay so we've got people who are going after this drug or this compound and it's not, I mean presumably they're going into the Amazon and trying to talk to indigenous people who are using it is that right. [SPEAKER_01]: That's right. [SPEAKER_02]: Yeah. [SPEAKER_02]: And Gill had been doing a little bit of that, I guess, who we'd call on an amateur Fnobottonist level in his early years in the Amazon when he was living at this ranch house.

12:22 [SPEAKER_02]: And then he gets the idea that if we could really do this on a more semi-professional scale and bring back a lot more Karrari, this leads to his idea for an expedition return in 1938. [SPEAKER_02]: the Russian plant hunter, Kruchov, he's doing the same in Brazil and other parts of the Amazon, and they're trying to narrow in on this problem of what plants go into this substance, what other substances go into it, how do you extract it, what chemicals are in there and what can we do with it?

12:56 [SPEAKER_01]: And presumably the indigenous tribes were using it in like poison darts, is that right? [SPEAKER_01]: That's right. [SPEAKER_02]: So primarily it's being used in poison darts with so blow guns for hunting small game usually. [SPEAKER_02]: So we're talking about like birds and monkeys, but sometimes bigger things to like tapers and what have you.

13:16 [SPEAKER_01]: And if I understand correctly, there, it wasn't as easy as just like finding an indigenous tribe and saying, hey, let me get some of that curary, right? [SPEAKER_01]: There were different kind of formulations of this, somewhere stronger than others, right? [SPEAKER_01]: So they were trying to find like the right quote, unquote, right mix that they needed that would work for them.

13:34 [SPEAKER_02]: Exactly, and so that's what makes it such a thorny problem is that a it's hard to get and by the time that crew cough it for example is traveling farther up the Amazon in Brazil and looking for this poison. [SPEAKER_02]: Some community aren't producing anymore. [SPEAKER_02]: They're actually starting to hunt with guns and shotguns and so it's a little bit harder to find.

13:56 [SPEAKER_02]: And then it turns out that there's just tons of local variations in how it's produced. [SPEAKER_02]: and what specific plants are going into it. [SPEAKER_02]: So up to the point that I write about in the book, there had been some small samples of Karar that made it out of the Amazon back to labs in France and Britain and people were tinkering with it.

14:18 [SPEAKER_02]: And there's actually sort of a funny story that the alcholoid that it ends up being the key substance in the drug that's used initially in anesthesia was actually isolated from a little tiny sample of Kaurai that was hidden in a tube in the British Museum. [SPEAKER_02]: that was actually 60 years old in 1934 when it was worked on by some British chemists and pharmacologists.

14:47 [SPEAKER_02]: So when those poisons made it back to Europe, they were never linked to any specific recipe or as the botanists put it vouched for with particular plant samples. [SPEAKER_02]: So there's a lot of kind of hunting and pecking and figuring out what works. [SPEAKER_01]: And that story of the bloke dart or the bloke gun in the British Museum was wild when I read it in your book.

15:09 [SPEAKER_01]: I mean, here is, as you said, 60 years old has been sitting there. [SPEAKER_01]: And I think someone like notices a tarry substance and thinks maybe this is your argument. [SPEAKER_01]: Yeah, exactly. [SPEAKER_01]: Yeah. [SPEAKER_01]: And then who would have thought that 60 years later, just sitting there, it would even be active or recoverable, but it turned out it was.

15:27 [SPEAKER_02]: Turns out it was. [SPEAKER_02]: Yeah. [SPEAKER_02]: that Karara can be stable for quite a long time, and that indigenous hunters would occasionally sort of rehydrate it. [SPEAKER_02]: And then it was still totally effective, but certainly not for 60 years. [SPEAKER_02]: And so when this chemist in Britain samples it, he's not sure if it's going to be potent, but indeed he tries it out on some animals, and it's still lethal 65 years after it was collected.

15:57 [SPEAKER_02]: And it wasn't labeled as such in the British Museum. [SPEAKER_02]: It just had a kind of geographically available in 1871 on it. [SPEAKER_01]: that is wild. [SPEAKER_01]: I mean, and especially given that today, 100 almost 100 years later from the time that was discovered and 160, I guess, since it was brought back, we don't have mean, rock your own, for example, is definitely not going to last 60 years out of the refrigerator so that's amazing.

16:23 [SPEAKER_01]: The original was pretty impressive. [SPEAKER_01]: Okay, so what, they brought back some, they found some in this dark, what kind of trials were they doing and trying to, [SPEAKER_01]: hone it down to something that would be useful medically. [SPEAKER_02]: Yeah, so a little bit of backstory to that.

16:38 [SPEAKER_02]: Merck was testing out a bit of poison that it caught from this Russian plant, a hunter, Boris Krukov. [SPEAKER_02]: Prior to Gil's expedition. [SPEAKER_02]: And they tried to dot on some animals and found just really horrific toxic reactions. [SPEAKER_02]: I think there was a histamine response potentially going on.

16:57 [SPEAKER_02]: And the Merck can have said clearly this stuff is not ready for trials and in humans. [SPEAKER_02]: Gil brings back a bunch of poisons in 1938. [SPEAKER_02]: He initially goes to Merck, thinking they're the most obvious partner. [SPEAKER_02]: They try out a little bit of the Gil Poison with similar toxic reactions too.

17:17 [SPEAKER_02]: And so the initial choice that Gil faced was, do I sort of give up on this project, or is there another pathway? [SPEAKER_02]: And the other pathway was testing humans. [SPEAKER_02]: And so he funds an neurologist out in Nebraska, A.E. [SPEAKER_02]: Bennett. [SPEAKER_02]: who has the idea that there have been a little research done on this before that you could take your eye and this gets back to the discussion we were having earlier.

17:43 [SPEAKER_02]: And if you just figured out the right dose, it might help people with these sort of spastic muscle conditions. [SPEAKER_02]: And so he tries it out initially on a group of kids ranging from about 8 to 16, 17 years old, and then Nebraska stay worth a PETA hospital. [SPEAKER_02]: Most of whom it seems like suffer from some form of cerebral palsy.

18:04 [SPEAKER_02]: And he was more or less successful with it. [SPEAKER_02]: He was able to figure out a dose that loosened their muscles. [SPEAKER_02]: didn't lead to respiratory depression, as at least as far as he reported. [SPEAKER_02]: But the problem was, as you and your colleagues know, we didn't last very long.

18:21 [SPEAKER_02]: And so even though this is relatively long acting in this early cry, it, in all of his reports, he noted the same frustrating things. [SPEAKER_02]: These kids were doing better. [SPEAKER_02]: They were getting some physical therapy while they're under the influence of cry, but then he wrote transient fleeting, short acting.

18:40 [SPEAKER_02]: and thought is there's some other way that we can turn, I guess what you might call, that vice of Kaurari into a virtue, and so he tries it out in shock there, but we can talk about that at some point too. [SPEAKER_01]: Pay folks, I just want to take a second to shout out our Rockstar Returning Sponsor True Learn Smart Banks.

18:57 [SPEAKER_01]: I've used True Learn for my residence for years, and it is hands down the best smart bank out there. [SPEAKER_01]: The questions are excellent, and the answers have clear explanations that break down why each choice is correct or incorrect. [SPEAKER_01]: And now you can create flashcards which are a key tool for high quality studying and maximizing test performance.

19:12 [SPEAKER_01]: The education research is clear that space repetition with these kind of tools is the best way to learn and retain information. [SPEAKER_01]: We use their ITE basic and advanced smartpanks for our residents, each with a thousand plus questions, realistic visuals and graphs, and even a calculator that mimics what you have on the exam.

19:26 [SPEAKER_01]: Our residents love it and get great results. [SPEAKER_01]: True learning even has a CMMe smart bank where you can get AMA, PRA, category one credits after you finish training, and an adult cardiac anesthesiology smart bank as well. [SPEAKER_01]: go to trulern.com and use code acquack to get $25 off residency exams, U.S. Emily, and come like smart bank subscriptions of 90 days or longer, and up to 20% off other healthcare exam subscriptions.

19:46 [SPEAKER_01]: We rely on trulern for our test prep, and I recommend you do the same trulern.com and use code acquack. [SPEAKER_01]: Yeah, well, I mean, what's interesting to me is it didn't, and correct me if I'm wrong, but it didn't seem like it occurred to anyone right off the bat that this would be, [SPEAKER_01]: great for surgery, right?

20:05 [SPEAKER_01]: Like that wasn't something that did kind of light bulb went off and they said, Oh, well, a short acting way to keep people from moving, you know, would be great. [SPEAKER_01]: It seems so obvious now because we used it. [SPEAKER_01]: So you make it as like, but it didn't occur back then to the people who were looking at this.

20:18 [SPEAKER_02]: It didn't, which is really interesting. [SPEAKER_02]: And now after the fact, so in some correspondence between this neurologist Bennett and Gill who become sort of collaborators over a number of years, [SPEAKER_02]: They both claimed that early on, they went to squid and some of the other pharmaceutical companies and said, hey, this might be useful in surgery in anesthesia.

20:39 [SPEAKER_02]: And according to Gill, they laughed in his face because it just seemed sort of crazy that you're going to give this poison to someone already undergoing a really dicey medical procedure. [SPEAKER_02]: But it did take a few years before that idea occurred to people and it started being tested in anesthesia and surgery, but there was a sort of intermediate step where Bennett got the idea of that.

21:05 [SPEAKER_02]: Okay, if it's short acting, maybe there's another venue for a short acting drug like that. [SPEAKER_02]: And as it happens, both Freeman and Bennett were sort of on the cutting edge of early shock therapy. [SPEAKER_01]: And shot therapy, meaning like electro-convulsive therapy for depression.

21:22 [SPEAKER_02]: Exactly. [SPEAKER_02]: OK. [SPEAKER_02]: So initially, they're also using it for schizophrenia, but then realized that it's real application was for what they call effective disorders. [SPEAKER_02]: So depression, primarily. [SPEAKER_02]: And they were before ECT, the primary method for shock therapy was to induce similar kinds of convulsions with the chemical metrasal.

21:48 [SPEAKER_02]: And they were having good results in terms of their clinical goals in terms of effective disorders, but the side effects were horrific because the metrosal confulsions were so strong that 30%, 40% of their patients were getting torn muscles dislocated joints. [SPEAKER_02]: vertebra fractures and so most people who are trying it out said we're going way beyond the dunoharm notion and so I'm sorry I've been it had the idea that you could give a kind of prophylactic dose of carara then hit the patient with metrosol and you would get the clinical effect you wanted by dampening the convulsions.

22:31 [SPEAKER_01]: And, of course, that's how we do it today, although we use succinal calling, but for people who don't know, I mean, we may have some folks who are not anesthesiologists listening to this, you know, what we do is we put a turnicate on the foot so that the nerve muscular blocker doesn't get to the foot, and then we give the succinal colon, which paralyzes the entire body except the foot, because it can't get there, because there's no blood flow.

22:54 [SPEAKER_01]: And so then when the seizure happens, you see that it's happening because the foot sees us. [SPEAKER_01]: which the rest of the body doesn't, so you get the brain and you know the brain is happening or at least you get the extra confirmation in addition to the EEG because of the foot. [SPEAKER_01]: So that is, in fact, how we do it now.

23:09 [SPEAKER_01]: We keep the body safe using neuromuscular blocking drugs. [SPEAKER_01]: All right, so this is kind of the entree into surgery and anesthesia. [SPEAKER_01]: Is, okay, here's a [SPEAKER_01]: procedure, not a surgery, but a procedure where we would benefit the patient with benefit from not moving, so it makes sense to do that.

23:26 [SPEAKER_01]: And then how did it get introduced more fully into surgery and anesthesia after that? [SPEAKER_02]: Yeah. [SPEAKER_02]: So I mentioned that both Bennett and Gill at one point later on claim that they have the idea initially, but whether they did or not, it's a little bit unclear, but it certainly didn't lead to its use in anesthesia.

23:49 [SPEAKER_02]: some what standardized corarray extract as into coston and they've developed a pretty decent market for it in its use in shock therapy and then some of these other experimental ideas around cerebral palsy and maybe an MS to alleviate symptoms but they put to work one of their doctors who was in the medical division on the idea of figuring out is there another application for this thing [SPEAKER_02]: And Lewis Wright, it turns out, was trained as an anesthesiologist and started shopping it around to some of his colleagues from the conference circuit, and said, hey, we've got this drug.

24:29 [SPEAKER_02]: You think it could be useful on the anesthesia and do you want to try it out? [SPEAKER_02]: It turns out the initial test go really, really badly. [SPEAKER_02]: One of those is with a manual pepper who was a resident at Bellevue Hospital in 1941. [SPEAKER_02]: He's working under a storied anesthesiologist and re-rovenstein.

24:50 [SPEAKER_02]: Re-rovenstein says, hey, pepper, we've got a little bit of squibs into costron here. [SPEAKER_02]: So, Papua goes down to the lab at the basement of Bellevue Hospital, the lab director promptly says, we can't give you monkeys or two expensive for a new drug. [SPEAKER_02]: Here's a couple of cats.

25:10 [SPEAKER_02]: Papua tries it out in a couple of cats. [SPEAKER_02]: They have a horrible toxic reaction. [SPEAKER_02]: Their respiration craters, they both die pretty quickly. [SPEAKER_02]: He reports this back to Rowan Stein and says, OK, let's try it on to people now. [SPEAKER_02]: And so, Papar gives it to two people, apparently at once, the respiration creators and Papar spends a good chunk of the night keeping them alive.

25:35 [SPEAKER_02]: And it seems like by himself, you know, pressing a couple of breathing bags constantly. [SPEAKER_02]: And so that convinced both of them that maybe in the costume isn't quite ready for anesthesia yet. [SPEAKER_02]: And there's a couple other incidents like that, Stuart Colon, another anesthesiologist, tries it out on some dogs in Iowa, they're going to bronchospasm and it turns out to not be so great.

25:58 [SPEAKER_02]: So it's another year or so before Harold Griffith and Nina Johnson up in Montreal to anesthesiologists try it out on the first surgery, and we can jump into that as well too. [SPEAKER_01]: Yeah, well, I was gonna ask you, and I do want to hear that, but did they, so this thing is lethal, I mean, it was designed, right?

26:17 [SPEAKER_01]: I mean, in the Amazon to be used to kill animals. [SPEAKER_01]: was there an understanding that the way it killed was by stopping respiration or was that thought of as and like because it's clearly in the trials where they were trying it for like cerebral palsy that would be an unwanted side effect.

26:36 [SPEAKER_01]: But was there a point where they thought oh what this is is a total body paralytic that will also stop breathing. [SPEAKER_01]: So that's okay as long as we can breathe for them like did that realization happen at some point? [SPEAKER_02]: Yeah, so that really happens in that next moment when Griffith and Johnson try it out and they're prepared to support respiration.

26:59 [SPEAKER_02]: Bennett, it turns out, had been aware of that as well. [SPEAKER_02]: Some of the early tests with Karara and now we're even going back into the 19th century had made it clear that you could keep an animal alive with artificial respiration. [SPEAKER_02]: It's one of these funny things that knowledge [SPEAKER_02]: You know, almost 100 years prior, it just doesn't circulate perfectly.

27:23 [SPEAKER_02]: And that's one of the things about the emergency, I guess, of a new drug like this, or it's a new application, is that there's this kind of spikiness to the information flow. [SPEAKER_02]: And so it kind of pops up again to benets realizing that if you control respiration, that's a kind of failsafe if he overshoots his dose.

27:43 [SPEAKER_02]: And of course, eventually that's what happens in anesthesia, too. [SPEAKER_02]: Um, so when Griffith and Johnson try it out in Montreal in January of 42, they're prepared to support the patient with breathing with our with our official respiration, but they end up not having to do that on the first try.

27:59 [SPEAKER_01]: They didn't, and why is that? [SPEAKER_01]: They didn't give a large enough dose or whatever. [SPEAKER_02]: Yeah, they were, they're a little bit cautious with the dose. [SPEAKER_02]: And so they just brought the dose up to the amount that the surgeon needed. [SPEAKER_02]: It was, I believe, was an epidemic.

28:10 [SPEAKER_02]: Appendectomy for a young plumber. [SPEAKER_02]: And they thought his tight midsection would be sort of an ideal test case for using, chorari, using a relaxed and alongside, they were using cyclopropane rather than either. [SPEAKER_01]: interesting okay so they gave enough to relax the abdominal muscles but as it turned out not enough to stop breathing and how did they know that was the patient not intubated was the patient intubated but breathing on their own how did they know that they didn't stop the respiration no they he wasn't intubated so they're okay with the breathing but yeah so they were ready to some to put a breathing tube in but didn't have to [SPEAKER_02]: They were ready, and from what I can tell, Griffith and Johnson put kind of looking at each other across the OR, like, they didn't tell the surgeon, they didn't tell anyone in the operating room, they didn't certainly didn't tell the patient that they're about to try out Karrari, and so I think they're quite happy that it went well.

29:01 [SPEAKER_01]: Okay, and did the surgeon, you know, that was the feedback from the surgeon, like, this was way easier than I thought it would be. [SPEAKER_01]: What did you do, or did they just assumed well, maybe it helped? [SPEAKER_02]: No, the surgeon's like, this was soft as death. [SPEAKER_02]: Like, this was one of the easiest procedures of his after say, young career.

29:17 [SPEAKER_02]: I think he was 27 years old, but but no, he immediately commented on this was one of the easiest procedures that I've yet done. [SPEAKER_01]: Interesting. [SPEAKER_01]: Okay. [SPEAKER_01]: So stay with us. [SPEAKER_01]: We'll be right back. [SPEAKER_01]: All right. [SPEAKER_01]: And we're back.

29:33 [SPEAKER_01]: Great. [SPEAKER_01]: So they had this initial success and then how did they follow that up? [SPEAKER_02]: Yeah, so they kind of in rapid succession. [SPEAKER_02]: They did about 25 other cases. [SPEAKER_02]: And in fact, they didn't report this in their initial write-up, which you got to love those mid-20th century.

29:50 [SPEAKER_02]: medical journal articles. [SPEAKER_02]: It was like two and a half pages long. [SPEAKER_02]: You know, it's basically written so that a lay person like me can understand it hand drawn graphs. [SPEAKER_01]: Yeah. [SPEAKER_02]: Exactly. [SPEAKER_02]: So they had an old woman who had interoperable rectal cancer.

30:06 [SPEAKER_02]: And they gave her an intentional overdose. [SPEAKER_02]: They gave her about twice a car that they'd been giving to other patients. [SPEAKER_02]: And [SPEAKER_02]: they immediately had to support her breathing and let it all work that just fine. [SPEAKER_02]: And so that convinced them that, yeah, with intubation, artificial respiration, and then eventually we get to reverse the later on, too.

30:29 [SPEAKER_02]: They weren't reversing. [SPEAKER_02]: Then you could go with the higher dose of [SPEAKER_01]: So they found that with high enough dose, you would, in fact, stop the breathing. [SPEAKER_01]: They supported the breathing either by masking or intubating or whatever they did. [SPEAKER_01]: And then they just had to wait until it wore off.

30:46 [SPEAKER_01]: Yeah. [SPEAKER_01]: And if that because they did not know how to reverse it or they just weren't. [SPEAKER_02]: No, there was already the idea of some a reversal. [SPEAKER_02]: In fact, Bennet was aware of the possibility of reversal with, you know, stigma or pro-stigmund, perhaps back then.

31:02 [SPEAKER_01]: interesting so they must have understood the mechanism at this point in order to know what the reversal would be right they must have known that it was that these compounds were competitively blocking a seat of calling yeah that that was being better understood in the 1930s but again there's this sort of like this uneven flow of information when you get out to the clinical setting [SPEAKER_01]: okay interesting so yes and you know the other thing is that obviously even now it takes I think we often quote 10 years from the time of a new medical discovery until it is put into practice ubiquitously and that's in the age of the internet and if you know easy to find this information so I can only imagine back then how long it must have taken for for this kind of thing to get around.

31:44 [SPEAKER_01]: All right, so they have been figuring this out and then, of course, the other thing that happens in the late 30s into the 40s is World War II. [SPEAKER_01]: So how does that affect this, uh, to story? [SPEAKER_02]: Yeah. [SPEAKER_02]: So a couple things going on with World War II, right?

31:58 [SPEAKER_02]: Well, one is it becomes, um, [SPEAKER_02]: a prime site for the use of muscle relaxants, although the supply of it continues to be a problem because we're talking about just the early years when this complex is sort of getting off the ground. [SPEAKER_02]: So battlefield surgeons are starting to use into cost-rin when they had a available.

32:18 [SPEAKER_02]: And that's also helping diffuse the idea of this new muscle relaxant across the pond to an estates in Britain as well, who start picking up on it. [SPEAKER_01]: interesting okay so it's used ubiquitously and it's used how on the battlefield like what are they using it for? [SPEAKER_02]: Yeah so there's a number of reports of surgeons who are dealing with [SPEAKER_02]: you know injuries or bullet wounds to the midsection and they're using intercostrant to provide relaxation.

32:51 [SPEAKER_02]: There's also some reports of patients who are going into ether convulsions and one doctor uses intercostrant to quiet the ether convulsions and then just allow the surgery to proceed as normal. [SPEAKER_02]: So, you know, there's a lot of kind of improvisation going on. [SPEAKER_01]: Okay, great.

33:10 [SPEAKER_01]: Now, there was an emergency surgery on President Eisenhower, is that right? [SPEAKER_01]: How did, how did, during most of the blockade play into that? [SPEAKER_02]: Yeah. [SPEAKER_02]: So there's a great irony here, too. [SPEAKER_02]: Boris Krueckoff, way back in the 1930s, in thinking about ways that Karare could be used and could be turned into a product.

33:31 [SPEAKER_02]: He wasn't just thinking medically. [SPEAKER_02]: He also had the idea for Karare lace bullets. [SPEAKER_02]: It turns out amazingly that he'd stolen the idea from an article that Richard Gil had published. [SPEAKER_02]: And he and his colleagues wrote to Eisenhower, who was then a major in the army in the Philippines, and said, hey, what do you think about this idea?

33:51 [SPEAKER_02]: We could provide the U.S. word apartment with Karari. [SPEAKER_02]: You'd have the most lethal bullets ever. [SPEAKER_02]: As Krukov put it, he imagined this sort of strange. [SPEAKER_02]: I don't know if you'd call it dystopian or utopian. [SPEAKER_02]: future where there would be no wounded to treat in the hospitals because you just would have died from the car.

34:12 [SPEAKER_02]: It's not the bullet wound. [SPEAKER_02]: So anyway, I shoot down this idea. [SPEAKER_02]: You're like, no, that would violate some ethical principles around hollow tip bullets. [SPEAKER_02]: the wax that's holding the corari into this bullet might melt in the tropical sun. [SPEAKER_02]: It's just not a good idea all the way around.

34:31 [SPEAKER_02]: So ironically, when I is now sitting president in 1956, he undergoes emergency surgery for an obstruction as a pentactor is valid. [SPEAKER_02]: forgetting that. [SPEAKER_02]: And of course, at that point, the car is, is ubiquitous in surgery. [SPEAKER_02]: And so I ends up getting shot with the flying death, even though he shot it down about 20 years earlier.

34:54 [SPEAKER_01]: So I mean, that, what an interesting idea that really goes back to the origin of this, right? [SPEAKER_01]: Of these blowdarts would be to put it on the bullets. [SPEAKER_01]: very interesting and I wonder what would have happened if Eisenhower had embraced this maybe this would be what we did.

35:10 [SPEAKER_01]: I mean, I could have completely changed the war. [SPEAKER_01]: I would have been really interesting. [SPEAKER_01]: All right, so it was used in Eisenhower in the 50s. [SPEAKER_01]: Now, when we think about this time through World War II and into the 50s and it's becoming more and more ubiquitous, is it being, are we now down to what you've used the name and you'll have to say it again.

35:29 [SPEAKER_01]: It's not currary. [SPEAKER_01]: There's a name a brand name maybe. [SPEAKER_01]: Yeah, and it is, uh, is it one now very standardized compound that's used across the country and who owns it, who's now kind of cornered the market on this? [SPEAKER_02]: Yeah, it's a really interesting story.

35:48 [SPEAKER_02]: And frankly, it took me a little while to figure this out. [SPEAKER_02]: Um, so when squib starts marketing this thing, they're calling into costron. [SPEAKER_02]: Initially, it's just a standardized extract. [SPEAKER_02]: of the rare poison, that might include multiple, that almost always included, not a bought plant initially.

36:10 [SPEAKER_02]: over time they start building a production network of sorts that's shipping a lot of the raw poison from Peru actually and primarily it's including one particular vine so it's still an extract and there's still multiple substances in there but that's what they're calling into costron. [SPEAKER_02]: Eventually, so now we're talking about like the mid-1940s, the squib and burrow is welcome, start marketing, and extract of the more or less pure alkaloid de-tubocrarine.

36:43 [SPEAKER_02]: And so by the time we're at Iksurgery in the 50s, he's probably receiving de-tubocrarine extract. [SPEAKER_02]: So it is purified to some extent, then even though in newspaper reports and what have you there, [SPEAKER_01]: OK, and this is purified, but not synthesized in a lab. [SPEAKER_01]: It's purified from this vine in Peru.

37:06 [SPEAKER_02]: Yeah, not not synthesized yet, although the curry had been synthesized, and gallamine and flaxodil are now available. [SPEAKER_02]: Daniel Bovey at Swiss, chemist pharmacologist who had been working in Rome, and Paris had synthesized. [SPEAKER_02]: the first Karrar I substitute, and it also figured out the muscle racks and qualities of sucks as well, but yeah, so this is still being synthesized primarily from, I'm sorry, it is being extracted from a vine in Peru, which is by the 50s and 60s and even into the 70s is happening on a almost quasi-industrial scale.

37:48 [SPEAKER_02]: Interesting. [SPEAKER_02]: Now this vine, do we know the name of the vine? [SPEAKER_02]: Yeah, Condor Dendrum, Tom and Tosum is the scientific name in Kichwa, which was the language. [SPEAKER_02]: Both were Gil was working in Ecuador and also in this part of Peru. [SPEAKER_02]: It was called Anpi Wazca, which meant poison vine.

38:05 [SPEAKER_01]: And do we know is the idea, I mean, ideas the wrong word, but is, do we think that what was going on is this vine was producing this as a defense mechanism? [SPEAKER_01]: Like animals would try to eat the vine and they would get paralyzed. [SPEAKER_02]: Yeah, I think most botanists and ethnobotists think that there is a defense mechanism with these kind of bitter alkaloid substances.

38:25 [SPEAKER_02]: But it's a little bit unclear to be honest, yeah. [SPEAKER_01]: OK, so it was being extracted from this vine and used as a substance in surgery. [SPEAKER_01]: And then there was a study in the mid-50s. [SPEAKER_01]: Let's talk about that with a lot of cases of use, right? [SPEAKER_02]: Yeah, so this gets into what we were talking about a few minutes ago with this kind of explosion in use in a new drug like this.

38:52 [SPEAKER_02]: You get a lot of edgy moments happening. [SPEAKER_02]: So before we get to that steady, there is a [SPEAKER_02]: You know, there's cases where an esitist are questioning whether or not Karare had analgesic properties, whether it blunted awareness at all, which of course we now know is not the case.

39:13 [SPEAKER_02]: In many people knew that back then, but there was some conflicting information. [SPEAKER_02]: And so you have this famous and infamous case of an anesthesiologist in Utah, Scott Smith, [SPEAKER_02]: who was uncertain about this, but then convinced that corari had so silenced the body and the reactions of his patients, which were kids, toddlers, and babies undergone pediatric surgery, that he was just convinced they weren't feeling anything.

39:43 [SPEAKER_02]: And so, at one point, he's giving them Karare alone, and he mentions this to a pharmacologist colleague who says, wait a second, you could be doing, you are likely doing great harm to these kids. [SPEAKER_02]: And so I guess to his credit, Smith says, okay, well, then put me under Karare in nothing out.

40:01 [SPEAKER_02]: So he's one of the early kind of self-experimenting doctors who gets a sense of, well, [SPEAKER_02]: What is going on with awareness? [SPEAKER_02]: And of course, he reports back. [SPEAKER_02]: I felt everything. [SPEAKER_02]: And it was not pleasant at all. [SPEAKER_02]: So there's other instances like this where doctors are saying, okay, wait a second.

40:20 [SPEAKER_02]: We need to be really careful. [SPEAKER_02]: It's a powerful new drug. [SPEAKER_02]: It's saving lives. [SPEAKER_02]: But we've got to be careful in the way that we're using it. [SPEAKER_02]: And so there's this famous study by Beecher and Todd in the mid-1950s, right before I surgery, in fact, [SPEAKER_02]: It's one of the big first big multi-site outcome studies and where they look at about 600,000 surgeries using cry and found according to their quantitative analysis about a six-x increase in mortality.

40:55 [SPEAKER_02]: And so that led Beecher to say that Khrar, we not only need to use it very, very carefully, but my understanding was at Nass General, where he was chief, he discouraged its use. [SPEAKER_02]: But people underneath them were like, no, we've got this figured out. [SPEAKER_02]: It's safe if you do it right.

41:12 [SPEAKER_02]: And so there's in this kind of irony that at this moment where there's some questioning about whether Khrar is safe. [SPEAKER_02]: right after that the sitting president has crore are used on him too. [SPEAKER_01]: Yeah. [SPEAKER_01]: Now, do they have any idea of why they were seeing this increase in mortality was it because people are having like allergic reactions to it was it because they were not securing airways and then people were not breathing.

41:35 [SPEAKER_02]: So I think that was some of the, uh, this led to a bit of a backlash from his, and as colleagues, it said, wait a second, you're, you're analysis might be a little bit off. [SPEAKER_02]: You might not be looking at some confounding variables, but it was a little bit unclear what was the mechanism for this increased mortality rate and, and I, and I don't think they were able to completely tease that out with the data that they had at their disposal.

41:58 [SPEAKER_02]: So it was more of like a signal and a wake-up call. [SPEAKER_02]: You know, incidentally, Phyllis Haroon, who was at UCSF and then did 1940s, had been warning about this prior to the future in Todd's study. [SPEAKER_02]: She said, Karari, we think, is perfectly safe. [SPEAKER_02]: I think she had used it on about a thousand cases without any problems.

42:21 [SPEAKER_02]: But in 46, she started hearing from hospitals around the Bay Area that people were dying [SPEAKER_02]: maybe it's incomplete reversal, maybe it's being that they're basically being left on their own in their recovery room without enough attention. [SPEAKER_02]: So I think those sorts of things are happening as well.

42:40 [SPEAKER_01]: Yeah, you know, we now know that even if someone seems to have their strength back, unless you have a very specific type of computer-generated test that can verify that they do, in fact, have enough strength back. [SPEAKER_01]: You have to reverse because even someone who can breathe and is breathing has some degree or can have some degree of [SPEAKER_01]: weakness in the muscles that protect the airway from for example aspiration and so you're going to with enough patience you're going to see some increase incidence of aspiration pneumonia and complications like that.

43:15 [SPEAKER_01]: So I could absolutely see once you get to those kind of number 600,000 if you're if they're giving these paralletics and then leaving someone in the recovery room who who's breathing but not necessarily strong enough to be safe. [SPEAKER_01]: I absolutely could see that being an issue. [SPEAKER_01]: And then this, when they did this study, were they starting to use informed consent or was this still being done without telling the patients?

43:42 [SPEAKER_02]: So, it's not clear how often patients were being told, once car use becomes standard, right? [SPEAKER_02]: So, you've done about 600,000 cases. [SPEAKER_02]: I think the years of their study were 48 to 52 or something like that. [SPEAKER_02]: Car use is just totally exploded. [SPEAKER_02]: And so, my suspicion is that most patients weren't being told that they're being given car, that doctor's just considered it safe.

44:06 [SPEAKER_02]: by that point. [SPEAKER_02]: However, Beecher of course becomes one of the foundational figures in the development of informed consent about ten years later, and I think that his experience with Karare as a new drug and a new drug that was powerful. [SPEAKER_02]: but also had to be as carefully and was dangerous was foundational to his thinking about patient safety and, you know, and the introduction of new techniques into clinical practice.

44:35 [SPEAKER_01]: For sure. [SPEAKER_01]: All right, so you had mentioned before that there were starting to be some synthetic. [SPEAKER_01]: So let's talk more about that. [SPEAKER_01]: How did the synthetics become more and more prominent of course now? [SPEAKER_01]: That's all we use and what's that story?

44:49 [SPEAKER_02]: Yeah, so as I mentioned, Daniel Boveau is one of the leaders here, and in the mid-1940s and late 1940s, he's working on synthetic versions of what are essentially attempting to mimic the action of D2bicarara in a natural car in this first one is gallamine. [SPEAKER_02]: and marketed as Flaxodil.

45:15 [SPEAKER_02]: And then interestingly, he also is the person who figures out one of the people who figures out the sexual calling has muscle relaxant qualities as well. [SPEAKER_02]: He also does work in his domain. [SPEAKER_02]: So he's a sort of giant in the field and a well deserved Nobel Prize in the 1957.

45:37 [SPEAKER_02]: But one of the interesting things I found about Bove is that he corresponded with Richard Gill and Gill's later years. [SPEAKER_02]: We can potentially return to that story. [SPEAKER_02]: Gill sets up a kind of biotech startup, if you will, in Palo Alto of all places, where he'd moved in the 1940s.

45:56 [SPEAKER_02]: But startup is really the appropriate term here. [SPEAKER_02]: It's basically half of his suburban garage. [SPEAKER_02]: So on this little street in Palo Alto, he's bubbling Karari Poison and trying to extract it in part of his garage. [SPEAKER_02]: But he's trying to stay abreast of the field.

46:13 [SPEAKER_02]: And so in the 50s, he's corresponding with Buffet. [SPEAKER_02]: And one of the interesting things was that they, they, meaning guilt, but they and others, went back and forth on the idea of whether there was some benefit to working with what they called the complex full curary. [SPEAKER_02]: So kind of multi-alcohol.

46:35 [SPEAKER_02]: multi-plant, multi-substance poison that perhaps it might potentiate the the alkaloid in different ways and and both they had some idea that perhaps it did even though he's most famous for his work on narrowing down on a particular alkaloid and then synthesizing it. [SPEAKER_02]: So [SPEAKER_02]: Bovey's work is foundational because this sets up the chain that leads us to our modern substances today.

47:02 [SPEAKER_02]: But it really, my sense is that it took a long time for synthetics to take off. [SPEAKER_02]: There's a really long, dovetail between the natural extracts or the purified versions, detail of the chorarine, and then galamine, and its subsequent synthetic children taking off in practice. [SPEAKER_01]: And so our rock eronium and vec eronium, I guess, first we had panc eronium, but are the eroniums, these are the derivatives or, you know, future generations of yall may.

47:33 [SPEAKER_02]: Exactly, and they're all tipping their hat to, you know, the original name of Karare, of course. [SPEAKER_02]: Yeah, yeah, absolutely. [SPEAKER_02]: Go, no, sorry. [SPEAKER_02]: Get you off. [SPEAKER_02]: Go ahead. [SPEAKER_02]: No, not at that one, right? [SPEAKER_01]: Yeah, no, of course.

47:44 [SPEAKER_01]: No, I was going to say circling back to Gil, right? [SPEAKER_01]: Gil was this character who we talked about from the 30s who at the M.S. [SPEAKER_01]: and was hoping to get a cure and was hoping to become rich and be a foundation. [SPEAKER_01]: So now, when we get to the late 50s, [SPEAKER_01]: Gill is still alive evidently right because you said that bovay is is talking to him.

48:06 [SPEAKER_01]: So how's he doing is he has he achieved any of his goals? [SPEAKER_01]: Yeah, you said he has a he has a half his garage dedicated to this, but is he is he making any money is he house his disease doing what like how's he doing? [SPEAKER_02]: Yeah, so I think what goes on for Gill is that the Ferrari market that he was obviously a big part of getting off their ground A has been taken over by Big Pharma.

48:29 [SPEAKER_02]: So, squib and bro's welcome are the dominant players. [SPEAKER_02]: But it's become such a huge market that someone like him can sort of nibble at the edges and provide their providing a bit of the detail of the carrying. [SPEAKER_02]: extract, which they were, it was almost like a boutique practice, they were arguing that it was somehow more pure than what Squid and Burroughs welcome were producing.

48:53 [SPEAKER_02]: But he's always working to perfect this kind of holy grail of his, which would be a long acting version. [SPEAKER_02]: that you could take orally or as a repository basically self administration that would allow someone like him to have their sentences and so he keeps chasing that through the late 1950s [SPEAKER_02]: He gives some of these tablets to anesthesiologists who later becomes chair of anesthesia at Stanford.

49:20 [SPEAKER_02]: William Neff says, it's amazing how they work. [SPEAKER_02]: I don't know exactly how and he would give some to his buddies after a long day on the golf course or tennis or what have you. [SPEAKER_01]: Like for their solar muscles. [SPEAKER_02]: for their sore muscles and whatnot. [SPEAKER_02]: And so we don't really know that exact chemical composition of this stuff, but they were out there in circulation.

49:40 [SPEAKER_02]: There might still be some old bottles sitting around about to end wood side. [SPEAKER_01]: Interesting. [SPEAKER_01]: All right. [SPEAKER_01]: And the other thing that I wanted to circle back to is these indigenous communities in the Amazon who really were the source of this in the first place, do they enter back into the story in any way?

49:59 [SPEAKER_02]: Yeah, so it's one of the interesting things when I found these materials and was able to connect them back to communities in Peru, parts of Brazil and Ecuador. [SPEAKER_02]: I went back and visited some of these communities on the Boba Nasa River and they weren't aware of this connection to the development of these drugs.

50:19 [SPEAKER_02]: Some elders recalled. [SPEAKER_02]: some of guilt associates making trips down the river and trading with them for Karara. [SPEAKER_02]: But certainly didn't know about the development of NMBs from their own knowledge, essentially. [SPEAKER_02]: And so in that way, it's an example, another example of ways that indigenous knowledge from the Amazon and other parts of the world were sometimes extracted without proper acknowledgement and compensation back to those communities.

50:48 [SPEAKER_02]: And then there's a final interesting return, [SPEAKER_02]: The concept of informed consent, which has a kind of genealogy and connection to the Karari story, is later used by one of the communities that Gil worked in on the Bologna's A River to fight the legal oil extraction in their community.

51:06 [SPEAKER_02]: And this is just in the last 25 years or so. [SPEAKER_02]: They fight back against extraction by a foreign company that was [SPEAKER_02]: searching for oil and doing tests on their territory and they take it all the way to the Inter-American Court of Human Rights, which found that the Ecuadorian government and this foreign oil firm hadn't given free, prior, and informed consent to the community of Sariyaku.

51:35 [SPEAKER_02]: And so they're still fighting for that, you know, for that case, to be appelled. [SPEAKER_02]: But it's an interesting example of the issues of informed consent and the way that they're swirling around this story. [SPEAKER_01]: Interesting. [SPEAKER_01]: Well, that is fascinating. [SPEAKER_01]: And you actually take in some trips to these communities as part of your research.

51:58 [SPEAKER_01]: Are there still communities in the Amazon that are using Curari and like poison darts for hunting or is that pretty much gone by with the way that? [SPEAKER_02]: It's much more limited now. [SPEAKER_02]: There are still some communities that are using, as a primary hunting vehicle, but they tend to be very, very isolated.

52:16 [SPEAKER_02]: So, in most Indigenous communities, including these two communities in Ecuador, as it was, you know, as Kruchov found in the Amazon even in the 1930s. [SPEAKER_02]: Now, it's much more common for people to hunt with shotguns. [SPEAKER_02]: there are still some elders in these communities that know the old recipes and remember in fact their fathers or grandfathers trading corari to gill and associate so there that history is still very much alive but it's evolved okay fascinating alright Matt this has been so interesting any last things we didn't cover that you want to cover before we move on [SPEAKER_02]: There's a little bit of delicious irony that may be only your anesthetist colleagues will appreciate, but murk in some ways, which lost out on the early Karare race and crew coughed the Russian plant under was just furious about this to last day.

53:10 [SPEAKER_02]: You felt like Karare was the thing that got away. [SPEAKER_02]: But I think it's interesting and ironic that Merck ends up making billions of dollars off of Sugaama decks by reversing Kauri, so that's my kind of parting shot on that front. [SPEAKER_01]: Every they made out just fine. [SPEAKER_02]: That's okay.

53:27 [SPEAKER_01]: That is fascinating and and that we've mentioned before that they had figured this out. [SPEAKER_01]: The mechanism out and so new about Neo is taking me as a as a reversal and then obviously Sugaama decks much later and a very different mechanism. [SPEAKER_01]: very interesting. [SPEAKER_01]: All right.

53:45 [SPEAKER_01]: Well, this has been fascinating. [SPEAKER_01]: Let's turn to the part of our show where we make random recommendations. [SPEAKER_01]: What is something you would recommend the audience check out for fun? [SPEAKER_02]: Yeah, I've been reading in a genre that I don't tend to dabble into much, but a couple of great memoirs recently.

53:59 [SPEAKER_02]: One is by the journalist Tom Juneod, and it's a long mouthful title. [SPEAKER_02]: In the days of my youth, I was told what it means to be a man. [SPEAKER_02]: It's drawn from a Led Zeppelin song, if I'm not mistaken, but it's this wonderful meditation about, you know, its father who was the sort of larger than life, almost madman, style figure from the 50s, 60s and 70s.

54:24 [SPEAKER_02]: And so he sort of grappling with this outsized presence in his life, but also coming to grips with some of the damage that came from his dad's life. [SPEAKER_02]: And then maybe on the flip side, there's a really touching memoir by the novelist Geraldine Brooks, called Memorial Days, and she's grappling with a sudden death of her husband, Tony Horvitz, and it's wonderful how it braids together her experience of that moment with also her reckoning of a couple of years later on.

54:58 [SPEAKER_01]: fabulous. [SPEAKER_01]: Those both sound great. [SPEAKER_01]: I'm going to recommend something that is on the total opposite end of the spectrum. [SPEAKER_01]: It is a science fiction fantasy series that is a kind of light and fun. [SPEAKER_01]: Well, light might not be the right word, but certainly not particularly poetic, but it is a lot of fun.

55:15 [SPEAKER_01]: It is called the Dungeon Crawler Carl series, and it is by an author named Matt Diniman. [SPEAKER_01]: several people recommend this to me, my brother, some friends, and I finally got around to it. [SPEAKER_01]: I'm book five of eight. [SPEAKER_01]: They're super fun. [SPEAKER_01]: The concept is that Earth is unbeknownst to Earth, that is part of a huge universe full of intelligent life, and Earth had been marked many, [SPEAKER_01]: one particular system had taken charge of it and the earth had been given a certain number of thousands of years and when that time came up and it comes up right at the start of this book most of life on earth is destroyed is to harvest all the metal and things for this company that owns earth and then the people who are left have a chance to enter into this dungeon with various monsters and things and they have to fight them and they can

56:11 [SPEAKER_01]: progress and it goes on from there. [SPEAKER_01]: So I won't give anything else away, but if anyone has read the solo leveling books, which were initially, I think a manga series and then became novels, it's similar and really, really entertaining, easy fast reads. [SPEAKER_01]: And if you listen to the audio books, they are incredibly well done.

56:32 [SPEAKER_01]: Whoever's reading them has just an incredible talent and they're really fascinating to listen to as well. [SPEAKER_01]: So if you like science fiction fantasy, [SPEAKER_01]: Matt. [SPEAKER_01]: Thanks so much. [SPEAKER_01]: This has been great. [SPEAKER_01]: Thanks for coming on the show.

56:44 [SPEAKER_01]: Chad, thanks a lot. [SPEAKER_01]: It was a fun. [SPEAKER_01]: Thank you. [SPEAKER_01]: All right, hopefully you got as much out of that as I did. [SPEAKER_01]: That was really fantastic. [SPEAKER_01]: Let us know what you thought. [SPEAKER_01]: Go to the website,acrack.com where you can leave a comment.

56:56 [SPEAKER_01]: Others can learn from what you have to say. [SPEAKER_01]: If you are a fan of the show, you can follow us. [SPEAKER_01]: We're on Twitter. [SPEAKER_01]: We are on Facebook. [SPEAKER_01]: We are on Reddit. [SPEAKER_01]: And we are an Instagram. [SPEAKER_01]: I'm AdJ Wolpa on Twitter. [SPEAKER_01]: And we're at Acrack Podcast.

57:12 [SPEAKER_01]: And you can find us on all those other platforms as well. [SPEAKER_01]: If you are a fan of the show, please consider going to Apple Podcasts or wherever you get your podcasts and leaving a comment and a rating, it really helps others find the show. [SPEAKER_01]: If you'd like to support the making of the show, please consider going to patreon.com-acc where you can become a patron of the show.

57:34 [SPEAKER_01]: Even if it's just a dollar or two that you pledge, it makes a big difference and we really appreciate it. [SPEAKER_01]: You can also make donations anytime by going to paypal.me-slashacrack, or looking up J.Wallpa on Venmo. [SPEAKER_01]: Thank you so much to those who have already made donations and become patrons, we really appreciate it.

57:51 [SPEAKER_01]: Thanks as always to our fantastic acrack crew. [SPEAKER_01]: Sonia Aminat is our tech lead, Chitima Ecconti, Rachel Furman, and Mohamed Selab are our production assistants and social media managers. [SPEAKER_01]: Thanks so much for all you do. [SPEAKER_01]: Our original ACRAG Music is by Dr. Dennis Quow.

58:07 [SPEAKER_01]: You can check out his website at studymusicproject.com. [SPEAKER_01]: All right, that is it for today. [SPEAKER_01]: For the ACRAG podcast, I'm Jed Wolpa. [SPEAKER_01]: Thanks for listening. [SPEAKER_01]: Remember what you're doing out there every day is really important and valued.