This Podcast Will Kill You - Ep 55 Rocky Mountain spotted fever: The tick must be destroyed!

Episode Date: August 4, 2020

Despite what its name might suggest, the story of Rocky Mountain spotted fever (RMSF) takes us far beyond the jagged, snow-capped peaks of the western range. From the Bitterroot Valley to southeastern Brazil, it is a story filled with equal parts tragedy and discovery, as the researchers desperate for answers fall victim to the very disease they seek to prevent. In this episode, we dive into the dark past of this deadly disease, first exploring the biology of the teeny tiny organism that wreaks such devastation. As always, we follow that up by tracing the history surrounding this much-feared infection and its role in the creation of one of the world’s leading infectious disease laboratories. Finally, we end with the current status of RMSF, which (spoilers) isn’t as bleak as you might think, thanks once again to antibiotics. Tune in to hear why we’ve been excited to research this episode since the very beginning of the podcast. See omnystudio.com/listener for privacy information.

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Listen to the Sixth Bureau on the IHeartRadio app, Apple Podcasts, or wherever you get your podcasts. I'm Amanda Knox, and in the new podcast, doubt the case of Lucy Lettby, we unpack the story of an unimaginable tragedy that gripped the UK in 2023. But what if we didn't get the whole story? Evidence has been made to fit.

The moment you look at the whole picture, the case collapsed. What if the truth was disguised by a story we chose to believe. Oh my God, I think she might be innocent. Listen to doubt the case of Lucy Lettby on the IHeartRadio app, Apple Podcasts, or wherever you get your podcasts. On July 19th, during dinner, announcement was made of the departure of Sister Rogers after an illness of eight days. This was the beginning of a great time of sorrow for Beth Abara and for me. A strange kind of fever had broken out amongst us, and most of those living in Beth Barra had it in more or less a serious form.

My doctor was much worried, for the usual treatment for fever gave little relief. Of those who left us, Sister Rogers was the first, but not the last. Next came Catherine Seidel, and it seemed almost impossible that only a few short weeks before she had traveled south with us. Her husband missed her, sadly, and it was only a few days later that he returned from a visit to Bethania, oppressed by the feeling of utter weariness, which we were learning to recognize as the first symptom of the disease. He did not seem very ill at first, but when hope was expressed for his recovery, he shook his head. And so it was. And then my Martin. Perhaps because of his unremitting efforts for others, he was seriously ill from the first. He

saw what was coming. His pain was intense, as it always was in the earlier stages of the fever. His request was, Stay by me and hold my hand, hold it tight. And when the fever mounted, when the terrible red splotches broke out on his body, when delirium came, he still felt my presence and was quieted as I held his hand in mine, spoke gently to him, or saying some of our best-loved hymns. Then he became unconscious of pain or weariness, but we were still hand in hand when the call came that took him back to the eternal home.

Others were laid to rest beside him, but I was seen. stunned and rebellious and nothing seemed to matter much. The fever that took Martin from me persisted until late in the fall, though with decreasing violence, and we heard that it was prevalent in many parts of North Carolina and Virginia. Yeah, that's a sad story. It's really sad. So that is from an account from 1759, and I found it in a paper referenced in a book that I read. The paper is titled a 1759 spotted fever epidemic in North Carolina. Before we go any further, it's debated. The whole purpose of this paper is to say,

this might be an instance of spotted fever or Rocky Mountain spotted fever. It's not certainty. But I liked the account so much that I wanted to read it. It was a really good account. Right? It's heartbreaking. By everything that you, that was in that account, it certainly could be Rocky Mountain spotted fever. There are a few things that are like, as we'll talk about, that seem a little bit off to me.

I mean, the fact that like, was it contagious? It seemed to be strike all at once, but it's not contagious. Anyway. So, yeah. Okay. Maybe we should. Maybe we should pump the brakes. Yeah.

Because, Erin, what are we? This is, this podcast will kill you. I'm Erin Welsh. And I'm Erin Elman Updike. Welcome. Wow, we did that all weird and backwards. Yeah, that was backwards, but we're professionals. Oh, totally. We've done this before. We've done this before. 50, oh, I lost count already. This is 55 or 6? No. Yeah. I thought it was 52. too. Antibiotics was last week. Oh gosh.

Well, this week, we are covering Rocky Mountain Spotted Fever or Rickettsia, Rickettsia. Yes, Spotted Fever Group Rickettsia. I am very excited about this episode, Aaron. I didn't start out that way, but I've come around. And now I'm thrilled. I have known that this was going to be a great episode since we literally decided to make a podcast. Okay. Oh, okay.

Can I guess the two reasons why? Okay. Yeah, please guess them. Are there two reasons why, first of all? No, but please guess them. Okay, number one is because of the quarantini name. So what's our quarantini name, Aaron? Nice segue, Aaron.

Oh my God, we're being so obnoxious. Okay. Our quarantini is cold as the rocky mountain spotted fever. That's the most clever name that we could come up with. It's so good. We came up with that quarantini literally the same moment that we came up with a podcast idea. Yeah. It was on our list that very first day.

Original. At the picnic of like what are we or at the barbecue. Yeah. Exactly. What are the quarantini names? So in this quarantini, of course you have to have Coors Light, not sponsored. Because the logo is cold as the Rockies, just in case anyone has forgotten. And we'll basically, we're making a shandy out of it, okay?

Yeah. Super simple. Summertime. Delicious. We'll post a full recipe for that quarantini as well as a non-alcoholic placebo Verita on our website, this podcast will kill you.com, and all of our social media channels. Yes, we will. So, Aaron, what's the second reason that you knew I was going to be excited about this episode?

Because we get to tell the story of Brett, possibly having Rocky Mountain spotted fever. Genuinely forgot about that. I mean, I didn't forget about that. I just, I forgot that aspect of it. I keep remembering it. It's an informative moment of our friendship. Oh, it absolutely was. I will never forget the moment.

Okay. I just meant I forgot that we were going to get the opportunity to talk about it. Oh, right, right, right. Okay, so why did you think it was going to be such a great episode from the very beginning of the podcast? Mostly the quarantini name. Oh, yeah. Yeah. Yeah.

Excellent. But as I was researching for this episode, I, yeah. you know, I also was having a really busy week and I was like, oh gosh, I have to do research. But then the very first paper that I came across to do research for this episode, the first line of the biology section, I was like, oh, this is going to be a good one. Erin, I had to Google two words in the first sentence. What were they? Festidious and pleomorphic. Oh.

Yeah. It's a good sentence. I'll read it to you later. Also, I have to say that the book that I read, the very first line of the chapter, so you know how chapters start with like a quote from whatever? It literally, it made me go, oh, this is going to be good. And I put it in my notes. Look at us both. We are the same person.

Oh, man. Oh, my gosh. That's really funny. So do we get to just like, you know, do the episode now or do we have business? We've got new merch coming out soon. Yeah, keep an eye out for that. We're very excited. It's literally the most exciting thing.

We love it. Yeah. Love is not a strong enough word. What's a stronger emotion? Really love. Okay, I don't think we have any other business to attend to, Erin. So let's take a short break and then get into the biology of this. Oh my gosh, let's do it.

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and how one man's ambition and mistakes opened its fault of secrets. Listen to the Sixth Bureau on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. Okay, so here it goes. Rickettsia Rickettsiai is a fastidious, small, pleomorphic gram-negative coxobacillus. Okay.

Okay. So, I feel, okay, that description, it's why people don't like reading scientific papers. Oh, for sure. And I, the reason that it made me excited for this episode is because I was like, I really like that this is how, if you read that, you'd be like, snooze, I don't want to learn anymore. So now I'm going to take that and make it a lot more exciting and tell you why you should be excited about Ricketts. Riketiae, okay? Oh, yes, please. So here's what that boring sentence means. We're talking today about a very, very tiny, like so tiny that it lives inside of our cells, bacterium that is very difficult to grow in medium. And the reason it's difficult to grow is because it lives inside of cells. Is that the festidious part? That's what fastidious means, yep. Okay. When you're talking about fastidious organisms. Okay. And the pleomorphic part means that not every single coxobacillus, not every single cell looks exactly like every other. So they kind of, when you look at them stained

inside of another animal cell, they look like a bunch of little, little and bigger dots, if that makes sense. Okay. Why? That's a really good question. that I don't know because they divide the same way that anything else divides, right? Like just by fishing. That's fascinating. All right. So let's get into the disease that Rickettsia-Riketzii causes. Rocky Mountain Spotted Fever.

So this is a tick-borne disease. Okay. Woo-woo. We get excited about these. So humans get infected. Humans are essentially dead-end hosts, okay? So we're not part of the normal life cycle necessarily of this pathogen. But humans get infected when we are bitten by an infected tick.

Specifically in a number of different species, but most commonly in most of the U.S., it's dermacenter variabilis. That's the dog tick, the American dog tick. But there's also the. Rocky Mountain Wood Tick, Dermacenter Andersoniae. Mm-hmm. Those live in the Rocky Mountains in Canada. The brown dog tick,

Riffacephalis sanguinisis. No. Riposephalus sanguineus. Riffasephalus sanguinius in Mexico. And of course, Aaron, amblyoma, Kianense. Or Amblyoma Mixedum. I was waiting for you to go, correct, correct, correct me. as I got corrected at an academic conference, yes, it is now amblyomachian and say species complex.

Okay, great. And that's in, is that throughout Central America, that species complex? Yes, Central, yeah, Central and South America. All right. So now we also know where this disease is found, right? This is a disease of the new world, essentially. So North America, Central America, and then down into South America. Okay.

And like many other tick-borne diseases, in order to get infected, the tick does have to be attached for a relatively long period of time, usually a minimum of four to six hours, but sometimes up to 24 hours. And the reason that the tick has to be attached for a long period of time is because although these bacteria are already in the salivary glands of the tick, when they're in the tick, I'm getting excited. When they're in the tick, they're basically not in a virulent state. Right. So then they have to bite a host, and then something happens within the salivary glands of the tick to reactivate these bacteria and make them virulent, make them able to actually infect our cells. It's so... Amazing and weird.

Don't know how it happens. And it also like, oh my gosh, yeah. Yeah. You're right. This is a thrilling, a thrilling disease. Absolutely thrilling. Okay. That is, I didn't know that either before researching this.

And I think that's just super fascinating. Okay. So then you have activation. It gets somehow becomes virulent again. And then it will exit the salivary glands and then enter. underneath our skin. Okay? So then because we know that this is a life cycle, right? How does the tick then get infected? How do we end up with infected ticks? As it turns out, there's two ways that a tick can become infected. One, one is the way that we know of ticks getting infected

from past tick-borne disease episodes. And that is that a tick takes a bite of an infected host and then in that blood meal, they suck up some bacteria. Okay? And then those bacteria go on to replicate. And like many tick-borne diseases, once a tick is infected, they remain infected for their entire life. So even if they get infected as a larvae, then when they transition to a nymph, they remain infected. When they transition to an adult, they remain infected.

But here's where it gets interested. I know where you're going I know you do. Infected female ticks transmit transovarially and lay infected eggs. So you can have larval tick bombs that burst out

already full of rickettsia just waiting to infect their first blood meal host. Let's put an asterisk on this. Oh, great. Well, I actually have a question for you about this. Okay. Because my understanding from what I read, and you are much more of an expert, if you guys didn't know listeners, by the way, Erin literally did her PhD research on Rickettsias in Central America. On pathogens in ticks in Central America, which happens to be a lot of Rickettsias.

Do you hear her trying to asterisk her way out of that? Well, I'm not an expert. Okay. So my question is, my understanding is that for humans, it's really only adult ticks that go on to infect humans. Is that just behavioral? Is that just because these tick species don't tend to bite us unless they're adults? Or is that something to do with infectious dose? What is, why is that?

I don't, I mean, honestly, I don't know. possibly behavioral. I mean, so different tick species will have different host preferences overall. So like this tick species might like, you know, deer and mammals more. And this tick species might like reptiles more. But even within a tick species, you see a lot of differences in terms of like what they like to feed on at different stages. And so there's a trend that's not 100%, but there is. is a trend where as you go to the older life stages, so like from larva to nymph to adult,

the host range narrows. And part of that is like a mate-seeking phenomenon. Because if you're trying to find a mate, you want to be like, all right, I want to get on this horse because I know that other, you know, tics, adult ticks of my species are going to be on this horse. But like, you might not be like, oh, or maybe that squirrel or maybe that monkey or maybe that sloth. Like, you're going to be focused in. Right. Because, anyway. So it might be behavioral.

As far as the bacterial load overall across the life stages, that might be a factor. But another factor might be that as you're in a, if you're an adult tick, you've taken two blood meals. And so just the chance that you have acquired the pathogen is greater than if you have taken just one blood meal as a nymphal tick. Right. That makes sense. Yeah. But the asterisk that I want to add to the transovarial transmission is that it's fairly rare for rickettsia rickettsiae. Like it doesn't happen all that often.

And actually the rickettsie rickettsiae negatively affects the reproductive output of the tick, the female tick. Oh, yeah. So that's, I mean, good news in a way. So if you look at horizontal transmission, so getting it from an infected animal versus transovarial. transmission or vertical transmission getting it from mom. It's much less likely to get it from mom. Oh. And then the third way that might be possible is co-feeding. Oh, does co-feeding mean the same thing for ticks as it does for kissing bugs? Probably. They're like two bugs feeding close to one another and then they, oh, what does it mean for kissing bugs? Sometimes the adult kissing bugs will come back to the nest and then the nymphs will

feed on the adult, like, from their blood meal. Beautiful and horrifying. Yeah, it is. That's my aesthetic. Literal lifeblood. Co-feeding. So then if you have, say, an infected adult feeding very close by to another uninfected nymph, then they could...

That's fascinating. Oh, yeah. That happens with tick-borne encephalitis viruses. as well, I think occasionally. You do get co-feeding events. And this is really important when you have co-current stages existing or emerging. So if you have larvae that are emerging at the same time as nymphs. Yeah.

Then, yeah. Very cool. Well, that was very fascinating. Okay, so now we understand fully the transmission dynamics of this bacterium. So let's talk about what happened. if you get infected, okay? What are the symptoms? It starts with, Erin, wait for it,

with a fever. Oh! Okay. So in general, the incubation period after you get infected is about seven days on average. It can range from about two to 14. And the first symptom is often a rather sudden onset of fever. pretty substantial malaise and body aches and very commonly a headache, which very often people will

describe as the quote, worst headache they've ever had is what one paper said. Interesting. I will say in med school we don't learn Rocky Mountain spotted fever as the worst headache you've ever had. You learn that for a brain bleed, but that's okay. The point is it's a very severe headache. It's not just like I feel a little dehydrated. headache. It's like a bad headache. Okay. Okay. You can have a lot of other pretty non-specific

symptoms as well, things like anorexia because your stomach doesn't feel good. Anorexia, meaning you just don't want to eat, not like an eating disorder. Nausea vomiting, abdominal pain is fairly common. So especially early on in the course of this disease, it's very potentially easy to mistake it for a kind of viral syndrome. Okay. You feel crappy, but it's very non-specific. And then comes the third of what's often called the classic clinical triad of Rocky Mountain Spotted Fever. There's actually two different triads, which I think is silly, depending on what paper you read. Okay. Within two weeks of a tick bite, almost always, in like 80 to 90 to 90s. 90% of cases, you see this third symptom, and that is the spots of Rocky Mountain spotted fever.

There we go. It's a rash. This rash starts out as small, what are called macules, which just means flat red spots, little ones, maybe like less than the size of your pinky nail. and these tend to start on your wrists and your ankles. They're a blanching rash. It doesn't itch usually. It doesn't hurt. So if you press on them, then the color would drain from them. Oh, that's what a blanching rash. Wow.

Yeah. Cool. New word. New word. Then this rash, which starts on your ankles, will begin to spread. It will spread up approximately, like up your arms and up your legs to your trunk, but it also spreads down, down to your palms and your souls. Which you may remember from our episode on syphilis is a very uncommon place to have a rash. The palms of your hands and the

souls of your feet really don't get rashes except in a few infectious diseases. Okay, it was syphilis, Ciphyllus, hand, foot, mouth. Cuxacchi virus. And Rocky Mountain Spotted Fever? Rocky Mountain Spotted Fever. Is that it? That's it. There are, you know, you could get fungal infections on your palms or souls.

You could get contact dermatitis and things. But in terms of infectious diseases, those are the three big ones. And it would be all like both hands, both feet. Both hands, both feet, exactly. Yeah. But it's not itchy. Not itchy usually. And not painful.

Not painful. Well, that's nice. Yeah. Well, not really. I spoke to you soon. He spoke to you soon. Okay. So this rash is now spreading.

By the end of about a week of having this rash, the rash becomes raised. So it's now what we call maculopopular. So it has red flat spots with little dots raised bumps in the middle. And then in the center of these lesions, you can sometimes get patiquia, which are little pinpoint purple spots that usually are a sign that you're having some kind of issues with your blood clotting. And so that is kind of the general course of disease. It doesn't sound that bad, right? Well, that was a leading question. I mean, it doesn't though, right? It's like headache, fever, you're feeling crappy, you get a rash. But then as it turns out, this

disease is about, okay, without treatment and before we had treatment for it, it was on average about 25% fatal. But that fatality rate ranged a lot from about 20% to maybe up to 85% depending on where geographically you got infected. Yep. So this is a highly fatal illness. Right. If you're average, if your lower level is still over, what did you say? 25%. Yeah. If the average is 25%, that's, I mean, think about the other ones that we've had that have been 25%.

Right. It's not that many. Exactly. That's a huge case fatality rate. Yeah. So the question is, what are you dying from? Right. You've got a rash.

How is this killing you? Well, I feel like the. the tiki or whatever, the blood clotting issue, that might be an indication? Yeah, so that's one sign. So let's talk about kind of the actual pathophysiology of how this makes you sick. What's going on when you have this rash? Okay. So this is a tick-borne disease.

So like many other tick-borne diseases, when that tick spits the bacteria underneath your skin, those bacteria travel through your lymphatic system to end up in their host. cells. And even though this is a bacterium, it acts a little bit more like a virus in that it has to invade our cells. It's an intracellular bacteria in order to replicate. It does not have the machinery to replicate outside of a host cell, much like a virus. Isn't there some sort of, like, isn't it thought that Rickettsia are, might be closely related to mitochondria? Yes, I believe so. They think that mitochondria came from something, whether a precursor to Rickettsia or something similar, because they're like, yep, yes. I just think that's so cool.

Oh, it's so cool. It's so cool. Their genomes are tiny. Okay. So in the case of Rickettsia, Rickettsia, the cells that they invade, the cells that they replicate in are our vascular endothelium. are the cells that line our blood vessels, okay? The inside lining of our blood vessels. Okay. Do you see where we're going with this? I mean, yeah, unfortunately. So what happens when they enter our cells and start to replicate? They do a very good job replicating. They replicate by fission. They also have these ways of moving from cell to cell to cell without necessarily damaging our cells directly as they move from cell to cell. so they can kind of just spread along your blood vessels, just jumping from cell to cell to cell.

And because they're in your blood vessels, they are literally anywhere and everywhere in your body, because everywhere needs blood, right? Mm-hmm. And then they start to cause direct damage to the cells that they infect. And they do this in a few different ways. One is free radical induced injury, which I feel like we're experts on now, after our radiation episode. Okay.

And then they also release a number of different enzymes that cause damage to these cells. So if you are damaging the cells that line your blood vessels, what do you think is going to happen to the fluid that is supposed to be in your blood vessels? Well, it's going to create a little leaky pipeline. A little leaky pipeline, Aaron, exactly. Okay. So this cell damage causes exactly that. Not Frank Hemorrhage, okay?

They're not, like, it's not gross enough damage that you're going to be bleeding out necessarily. Who's Frank Hemorrhage? I'm sorry. Oh, did you like that? I really did. So not actual hemorrhage. But this damage does cause increase in the permeability of that membrane, essentially. So that means you're going to get fluid, plasma leaking out.

This is going to also cause you to lose protein because as you damage that membrane, proteins are usually kept in your blood vessel in part by a charge differences. So you mess up that membrane. You mess up those charges. So then protein can leak out more easily, which then just draws more liquid out with it. Okay. So it's like this cascading horrible positive feedback loop. Exactly. And let's talk about positive feedback loops, okay? Because like we talked about in the radiation episode, when you have this free radical damage that happens to these cells, our body mounts a response to that, right? And that's an inflammatory response. And in responding to that, part of what our body does to try and, you know, fight off the inflammation and damage that's caused by things like free radicals and these enzymes.

is that they will vasodilate our blood vessels in order to get more white blood cells to the areas that they need to be to try and fix this damage. That vasodilation means you have more flow, which means you have more vascular permeability, which means you have more leakage. So this will eventually lead to edema,

so swelling outside liquid outside of our blood vessels, and eventually hypovolemia, where you don't have enough volume in your blood vessels. On top of that, if it happens to be important organs like your brain or your lungs that get involved in this, this is called a vasculitis where you have inflammation of your blood vessels, if it's somewhere like your brain or your lungs, you don't have a lot of good lymphatic drainage to drain that fluid away. So you have pressure that builds up because of that in that interstitial space.

So what's interesting about this is that none of the papers that I read really clearly outlined what the exact cause of death tends to be in Rocky Mountain Spotted Fever. But it is essentially organ failure. What organ it is that ends up failing kind of just depends on what organ happens to be the most affected. A very large proportion of people have hepatomegaly on necropsy or on autopsy after they've passed. So your liver is very commonly involved, at least in fatal cases. Many people also have renal failure, so kidneys might fail. Your lungs can certainly be involved, so you could die maybe just from not being able to breathe from respiratory failure because of all the

fluid around your lungs. But there's not like a one single thing that tends to be the ultimate cause of death necessarily. But pathophysiologically, we know that it's this diffuse vascular damage that leads to hypovalemia, so not enough volume and eventual shock. So, yeah. Terrible. Really, really terrible.

Another thing that I did want to point out that I think. think is really, really important about this disease is that the mortality rates, still today, it's non-trivial. It usually hovers around 5% even with treatment, and there is very good treatment for this. Doxycycline, a few days worth clears infection. But delays in diagnosis are strongly associated with poor outcomes. So not getting to a doctor fast enough or a doctor failing to make the correct diagnosis or get the treatment initiated quickly is very strongly associated with a vastly increased risk of death. And especially in the U.S., this disproportionately affects black individuals. And, you know, there was a limited amount of discussion in the papers that I

read as to why exactly that is, whether it's, you know, people not seeking care and things like that. But my guess, and some of the papers also said this, is that we are really bad at diagnosing rashes on black skin. It's a huge issue. When you Google pictures of this, I haven't seen a single picture of Rocky Mountain Spotted Fever on a black-skinned person. Yeah. Yeah, I came across that as well in the research and how it's like historically, it's been like that as well. Yeah. And I mean, it's not just for this, but this is a very fatal disease that's also very treatable if you diagnose it properly. And so the thing is, we don't have good tests, like laboratory tests to diagnose this. It's a clinical diagnosis, which means you make that diagnosis based on history and

physical findings, including a rash. So if we don't know what a rash is supposed to look like, because no one's taking pictures of it, no one's, you know, it's not in our textbooks, etc., then people are dying unnecessarily, which is a huge, huge failure of the medical system. So, absolutely. So, yeah, that's the biology of Rocky Mountain spotted fever. Well, it's a terrible disease. And that is, that's a point that I saw made in a lot of different papers in terms of, like, how important this disease is and how overlooked it tends to be, despite the fact

that things like landscape change and climate change are going to greatly shift our exposure, our risk, you know? Yeah. And I mean, it's the kind of case where it directly results in, like, people dying, you know. But it is, it's a difficult thing because it is so rare. And I think that, you know, we'll talk later about where you see this geographically, but I think a lot of people maybe don't know or don't know to think of it. you know, when they're kind of listing their differentials in their head, it could easily

look like a viral illness. It's like, oh, you've got a fever and a headache and you're feeling crappy, you know? Well, and in the history section, I don't talk much about like the name itself, but if you look at so many different rickettsial diseases, they tend to have, particularly the arthropod-born ones, they tend to have location-specific names. And so in one place, it's, It's Rocky Mountain Spotted Fever in another place. It's something else. And so you have like all over the world, you know, different species of pathogenic rickettsia called, called by different names. And that has created a lot of confusion, particularly with Rocky Mountain Spotted Fever since we're talking about it.

Like, yes, it occurs in the Rockies and the Western states. But the Eastern Seaboard is like, bam. South America. Bam. Right. Central America. Bam. Like, it's there, too.

And so there was a huge push at one point to just call it spotted fever or spotted fever group Rquetteziae, but that never really caught on. So our MSF is what it is. Yeah. So, well, tell me more, Erin, about this history. How did we get here? Where did this thing come from? Okay, I cannot wait.

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Listen to the Sixth Bureau on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. Erin, you started off biology with a quote, and I laughed because I'm starting off history with a quote. I love it. You started off with the quote from the first paper you read, and I'm starting off with that quote from the book from the very beginning. Perfect.

Here we go. The unwritten history of the investigative. work in connection with Rocky Mountain Spotted Fever, if written, would read like a romance. Right? I want to read it. Can you see why I was like, what? What is this? Okay.

So, yeah, I mean, why is that? Yeah. Hopefully I'll tell you. Hopefully I'll do a good enough job that you'll understand what that quote means. I'm not sure that I do. Anyway. So, I mean, and I, before researching this, I didn't know there's quite a bit of, like, lore or fame or infamy around Rocky Mountain Spotted Fever Research. There was a movie called Greenlight, starring Errol Flynn from 1937, and one of the subplots, it tells the story of the researchers involved on the Rocky Mountain Spotted Fever Project.

What? Yeah. And the disease itself plays a major role in the 1947 movie Driftwood. I haven't seen either of these, so I can't vouch for their accuracy or how much romance they have in them or whatever. But I have now read about the history of Rocky Mountain Spotted Fever, especially the history of its research, and that does contain a fair amount of drama and romance. to start the story, we don't have to go all that far back, actually. So the firsthand account that I read in the beginning of the episode, as I mentioned, is from 1759. But like I said, it's not 100% accepted to be Rocky Mountain Spotted Fever. In any case, there were likely cases of RMSF, Rocky Mountain Spotted Fever, scattered throughout the Americas for hundreds of years at least. But the real story begins only in the late 1800s. We don't have written records for anything earlier.

Yeah. So around this time, starting in maybe the 1860s or the 1870s, a mysterious illness was seeming to pop up in the Bitterroot Valley in Montana. So this, if you can picture Montana in your head, go to the far, far west, kind of the southwestern part of the state. Okay. If you know where Missoula is, it's like the very north end of the valley. I don't know where that is, but I can picture Montana.

Okay. So this valley, the Bitterroot Valley, runs about 95 miles long, and it's sandwiched in between the Bitterroot Mountains and the Sapphire Range with the Bitterroot River winding its way through the valley. Historically, the Salish tribe of the Flathead Nation lived in Bitterroot Valley, and while the region experienced some settlement throughout the 1800s, Lewis and Clark passed through in 1805, it lagged behind other parts of the West. But then, the discovery of gold in California and then the increasing number of Mormon settlements in Utah eventually led to people striking out to

find a piece of land of their own. And in the second half of the 19th century, Montana grew enormously in popularity. The Bitterroot Valley in the second half of the 1800s in particular was super popular because it had these ample resources for lumber and fertile farmland for livestock and apple orchards were really popular. And as you can guess, the increasing number of white settlers meant that more land had to be found. So what was the natural solution to this problem?

Genocide? Well, at least forceful removal. So the government removed the Salish for whom this was their ancestral home. Of course. And so in the 1870s, with the Salish driven out, the land of the Bitterroop was ripe for clear-cutting and apple farming. And it was also apparently ripe for the emergence of a seemingly new tick-borne disease. All this clear-cutting to make room for orchards and farms led to proliferation of scrub habitat. which was great for sheep grazing, but also great for mice and other small mammals,

which happened to be excellent blood meal host for ticks. The first case of what we now know was Rocky Mountain spotted fever that we can trace back for sure occurred in 1873 in Montana. Consequences, man. Consequences for our actions. And this case was not a one-off. So from that first case, more followed, and not just in Montana. Colorado, Oregon, Idaho, Wyoming, a lot of other places grew aware and wary of the disease, rightfully so.

And I have to include another side note here. So for a while, it was thought that the Salish Indians had warned the incoming white settlers of Rocky Mountain spotted fever by saying certain canyons in the spring in the bitter root were full of evil spirits. but this is no longer thought to be in relation to the disease. Oh, okay. So rather what, at least in this book, it was thought that the disease probably wasn't super prevalent before the white settlers clear-cut the land and allowed for the super proliferation of ticks. And so anyway, with this alarming rise of an extremely fatal disease combined with like the

daughter and son-in-law of the Montana governor dying of the disease, the state fear that they would lose out on prospective land buyers because of this pesky fatal illness. And so they told the Montana State Board of Health to do something. And that's exactly what they did. Starting in 1902 by appointing two young pathologists named Lewis Wilson and William Chowning to see what they could figure out about the disease. And that same spring, a bacteriologist named Earl Strain suggested a connection between the disease and a tick bite because he was there touring to kind of see, oh, you know, like what can I figure out about this disease?

And he visited someone who had Rocky Mountain Spotted Fever and noticed a tick embedded in the genitals of the sick person. Very interesting that he just happened to see a tick because almost certainly, if that person was suffering from Rocky Mountain spotted fever, and they happened to have a tick. That tick was not, in fact, the perpetrator of their illness. I think it speaks to the high levels of infestation around the bitter root at the time. Right. No, but I mean that's – and that would explain why, you know, you had such a huge increase in cases if –

Oh, yeah. You know, you were just getting bit left and right. Mm-hmm. And genitals. Well, and if you think about, like, the occupations, of people who were settling in the Bitterroot at this time, you're outdoors. Right. You're outdoors, especially during that time of year.

And so it's almost unavoidable. Yeah. Yeah. So William and Chowning took note of Strains' observation when they were planning their research season, which they had to do basically right away because Rocky Mountain Spotted Fever season is actually pretty short, which is great news if you're at risk for the disease. but a little bit challenging if you're researching it.

The joys of fieldwork. And they covered their bases. They performed autopsies. They did epidemiological surveys, lab studies. And what they found was concerning. Between 1895 and 1902, there were 88 cases in the Bitterroot Valley with 64 deaths. Wow. So it's a 72.7 mortality rate.

And they concluded that it was not contagious from person to person and not a result of melted snow water, which was the leading hypothesis at the time. Okay. Well, a good thing. Right? It would be hard to avoid melting snow water. Yeah. Melted snow water. And so they suspected instead that it was caused by a protozoan that they had found in some of the tick samples that they had dissected and stuck under a microscope. Interesting. And so by the end of this first season of their research, they had a nice little disease ecology cycle all laid out. The wood ticks transmitted the protozoan to humans, and ground squirrels, aka gophers, were the disease reservoirs. This was an untested hypothesis, but that didn't stop reports of it in the news because people were hungry for information about it.

We were like, we want to know how to protect ourselves. But just knowing or thinking that ticks were responsible for the disease didn't really do that much because ticks were absolutely. everywhere in the spring, in the Bitterroot. And so the only way to avoid them would be to not live or work there, which is not the solution that the state was looking for. And the only practical step in their eyes, which wasn't really practical at all, was to eliminate the ticks themselves or the gophers that were thought to be the hosts. Oh, gosh. So in the spring of 1904, the residents of the Bitterroot took this to heart. They burned and they burned, vegetation and they set out poison grain to kill the gophers,

which actually killed a lot of game animals, game birds and other animals. And they also got a bunch of sheep to eat the grass, the tall grass that they thought was the ticks habitat. Oh, dear. But it's nearly impossible to get rid of ticks. You need possums, Aaron. We need possums.

Just set loose the possums. Just kidding. Don't do that. I feel like maybe we shouldn't gamble, throw the ecological die in that way. So the next best thing, though, is just to remove a tick as soon as you saw it attached, right? And people were encouraged to treat it like a snake bite, like a venomous snake bite, dab some carbolic acid on the side of the bite right away. So then people had a lot of acid burns, accidental spills, infections, et cetera.

I mean, basically the bottom line is that, you know, though these efforts had led to some fundamental knowledge being gained, the application to prevention simply wasn't there. Right. And so more help was called in in the form of Charles Wardell Stiles. Does that name sound familiar to you? Yeah, it sounds very familiar. What else did he do? Hookworm. Oh, that's right, Aaron.

He discovered or identified the second species of hookworm in the Americas. Yeah. And I think he played a role in, I don't remember, but I think he played a role in determining that it was the cause of the widespread anemia in the South. And he's Harry Stiles' great grandpa. Exactly. Exactly. I'm so hip.

Just dropping those names. Oh, my God. Okay. So, anyway, so Stiles set out to basically test the ground squirrel, tick protozoan life cycle that Wilson and Chowning had laid out. He was enthusiastic about the hypothesis early on, but he was a little bit close-minded when it came to any challenge to the accepted dogma of the time. Which was, and this is news to me, but apparently for a while it was believed that that arthropods could transmit protozoa but were not capable of transmitting bacteria other than accidentally.

Like a fly could accidentally, I don't know, give you an infection. Right, because like they stepped in poop or something. Exactly. But mosquitoes and ticks and whatever weren't capable of actually completing the life cycle. I don't know why. That's so interesting. Yeah. So when he searched for this supposed protozoan in the ticks and the blood of the victims, he came up empty-handed again and again. But instead of saying, you know, well, the ticks may have something to do with it, but the protozoan probably doesn't, he openly refuted and dismissed the existing hypothesis.

Oh, dear. And he was started to say like, oh, you know what, these people are, these residents are overreacted. Ticks aren't involved. It's probably snow melt all along. And it's in a way, this contemptuous criticism actually was beneficial for the research of Rocky Mountain Spotted Fever because it drew such attention from other researchers, including a pathologist from the University of Chicago named Howard Taylor Ricketts. Ricketts. Ricketts. Hmm, Ricketts. Ricketts set up a correspondence with Chowning saying that he believed their hypothesis had gotten unfair treatment by styles.

And Chowning was like, I agree. Also, I've been doing some side experiments in my spare time, including a little bit of medicalized torture. Oh, great. So he had obtained, quote, consent from two people to attach ticks to them, which had been feeding on a man who died of Rocky Mountain spotted fever. Oh. They both got sick with a disease and recovered.

And so Chowning was like, must be ticks. So anyway, Ricketts, when he told Ricketts about this, Ricketts just didn't acknowledge it, apparently. He didn't denounce him, but he didn't acknowledge it. And he was like, I'm going to do my own research. And so he went to Montana. Okay. But the state had no money to give him. And so he and Wilson and Chowning had to find their own way to pay.

So they, like, cobbled together a bunch of resources. And in 1906, Ricketts set up a laboratory in a tent on the grounds of the Northern Pacific Hospital in Missoula. So he was just, like, in a tent. And that spring and summer proved very productive for Ricketts and another researcher named Walter King, who joined in on the research. But it must be said that this wasn't a super collaborative. project. Each one of these men for the most part, maybe, you know, Chowning and Wilson worked together, but like Ricketts and King were very much like, this is my project and I want to do it my way. And I want research and I want publication priority and I want blah, blah, blah.

So anyway. And so first they found, Ricketts and King found that they could cause the disease in a guinea pig by injecting serum into the animal. And they could sustain the infection by alternating infecting a guinea pig and then a monkey and then a guinea pig and then a monkey, which then enabled year-round research. Okay, that makes sense. Yeah. Then at the very end of the spotted fever season, both Ricketts and King demonstrated that ticks can cause infection. And they did this by attaching a tick to a guinea pig and then disease resulted. Ah. And this was a super exciting finding.

but it came at just the wrong time for them because it was the end of the season and soon there would be no more ticks to be found. Back in Chicago and Washington, Ricketts and King tried to keep these tick experiments going by advertising in Montana papers for anyone who could find a tick, a live tick, to send it their way.

At one point they offered a financial incentive of $10 in gold for anyone who could find. could deliver 50 or more live ticks. Oh my gosh. Citizen science. But they never got any. They had to wait until the spring. Okay.

And mid-April 1907 saw the first victim, a 26-year-old lumberman whose family refused to allow Ricketts to draw any blood. Ricketts was peeved about this. And so he asked the Secretary of the State Board of Health to do something about it. And so he drew up an official looking document saying that the fact that the federal. family must cooperate with the investigation. And then he told Ricketts, hey, don't let anyone get too close to look at this because in truth, I have no authority to issue it. So, you know. Oh my gosh. And people wonder why there's deeply rooted mistrust in the medical establishment and research. And the government and research and authority. Yeah. Oh, my goodness.

So anyway, in 1907, Ricketts concentrated on finding out the pathology of the infection in ticks, still without knowing what the causative agent was. And he determined that a small proportion of female ticks could transmit the pathogen to their offspring. So larval ticks could be infectious. Awesome. Which is a great finding. And then in January of 1909, he seemed to finally hit the jackpot when he published a paper in which he described the teeny tiny, bishops. Coxibacillus, that was the causative agent of Rocky Mountain Spotted Fever. He had detected ample amounts of the bacteria in eggs of infected females, and while he was

unable to culture the bacteria, he was confident in his finding. Yeah. Yeah. It's, I mean, it's pretty cool. And his achievements, like, people were psyched about this. I guess he had done, I mean, he had done microbiological research. He had done ecological research. He had done some medical research.

And so his achievements won him praise and opportunities left and right, and even the state of Montana recognized his work by writing in a bill in 1909 that would fund a bunch of his research on Racky Mountain Spotted Fever over the next couple of years. Unfortunately, though, the funds were suspended when the state realized that they had allocated more money than they were going to collect in revenue. And so Ricketts' work was put on hold. Oh, man. And even though his colleagues in Montana encouraged him to stick around, to get private funds to bridge the gap, Ricketts was like, no, I've got so many opportunities here. I'm going to Mexico to solve the question of another spotted fever-like disease, typhus.

Ah. So then he went on to Mexico City. but it was only after he arrived in Mexico City in December of 1909 when he learned that the big puzzle pieces of typhus had already been put together. The vector. Animal model. You know, it was a lot of the stuff that had drawn him to study it was already discovered, identified, done.

But he gamely stayed on and tried to figure out the causative agent, which he suspected might be very similar to Rocky Mountain Spotted Fever. So then in early 1911, Ricketts got word that it finally looked like the Montana funds were coming through. And he was super happy, but he was not incredibly eager to leave despite, you know, he was working under very dangerous conditions. There was like no protection against typhus. In his letters to his friends, he wrote like, my wife is very upset with him. me. She's very scared for me. Like, if she knew what I was doing, she'd be feeling me to come back.

And, but he, he wanted to see the project through to the end. And so just as Tick season was starting in Montana, just as he was like trying to get up there, he came down with typhus and died on May 3rd, 1910 at the age of 39. No. Yeah. His death was a huge huge blow to spotted fever research, and it also established a very tragic pattern. If the first decade of the 1900s was characterized mostly by research on the causative agent and medical treatments for Rocky Mountain spotted fever, the second decade looked towards the tick for answers. By the late 19th century, when the focus on Rocky Mountain spotted fever was heating up, entomology and medicine were two-timore.

totally different fields, particularly in North America. Research combining the two was conducted only rarely, such as with like yellow fever research in Panama, for instance. Largely, entomologists played the role of helping combat agricultural pest arthropods or doing like academic foundational biology research. And medical doctors and researchers dealt with human diseases, how it worked in the body, how to control it, and there often wasn't a lot of opportunity for overlap. Rocky Mountain spotted fever, however, required a full understanding of the vector tics ecology, like its life cycle, hosts, behavior, et cetera, as well as the characteristics of the disease, bacteria, pathogenesis, et cetera. And you might instinctively

think that public health researchers or physicians and entomologists working together would be the best way to make progress. But then maybe you forgot about ego. After Ricketts met his untimely end, there was maybe a bit of a vacuum in the Rocky Mountain spotted fever research arena in Montana. The head, the secretary of the state public health department, whose name was Tuttle, appointed a physician named McClintick to continue work on the project. But then when he arrived, he found an entomologist named Robert Cooley had rudely started on a bunch of control efforts on his own. And neither was willing to cede any ground for publication priority or research area.

And apparently neither was willing to work together. Oh, my gosh. I know. Just get over yourselves. Get over it. So the physician McClintick believes. because it's a human disease, it's a physician or a public health problem. And then entomologist was like, no, it's a tick transmitted disease. So that calls for a tick control expert. No, it's all of these

just work together. Ugh. I know. Oh, it's just like goes on and on. The sparring over funds, it's actually spilled over to the federal level and resulted in Cooley, the entomologist, losing support for his work. Oh, my goodness. So then McClintick, who was the physician was like, all right, I'm gearing up to do some tick work, setting up giant vats to dip the livestock in, to try to prevent tick infestations on livestock, and I'm going to initiate a massive project to identify the reservoir of the bacterium. But that second project was mostly just destroying all small wild mammals, like pine squirrels, yellow belly chipmunks, woodrats, woodchucks, weasels, badger, and of course the infamous gopher.

Cool, cool, cool, cool, cool, cool, cool, cool, cool. That's not the way you do it, by the way, to control ticks. That doesn't work. And so while he was able to rule out several of the species as playing a major role in the infection cycle, such as Badgers, he had a hard time finding a single smoking gun species responsible for the disease. And he would never find it because he died of Rocky Mountain spotted fever in 1912. Oh, my God.

Just a year after starting his research in Montana. Oh, that's sad. It's really sad. Once again, spotted fever research in Montana was left without a leader. Maybe this was an opportunity for a fresh start to bring together physician and entomologist. I have a feeling it's not going to happen, Aaron. No, it didn't happen. The budget and the land would be split.

The north part of the valley went to the U.S. Bureau of Entomology with Cooley in charge, and the south part of the valley would be designated as U.S. public. health service land. Kind of an interesting way to do it, huh? Isn't it so fascinating? Who did better? Well, great question. So the entomologists on the north side of the valley were set on just livestock

dipping and basically taking a cattle, submerging them into a caricide or a pesticide to kill the ticks. And so these entomologists were like, all right, this is the key. Killing small rodents, that's wasted effort. And the public health folks, on the other hand, were like, no, we're going to dip and kill small mammals and also not allow cattle to feed in the western, on the western side of the river, which was the only side that was infected, by the way. Oh. Yeah. And so whether the dipping was actually effective was called into question as well.

So from 1913 to 1918, the number of ticks supposedly declined 80 to 90%, while the number of cases had been reduced from 11 to 3. But these numbers are far from conclusive. Like 11 to 3 is super... Could just be seasonal variation or whatever. Exactly. Exactly. And eradication, which was the promised end of these projects, was not on the horizon. The tick must be destroyed.

killing small animals wasn't doing it, dipping cattle wasn't doing it, maybe a vaccine could work. By the way, that's our title. The tick must be destroyed. Before Ricketts died, he published his preliminary findings of this bacterium, but the debate continued with still the protozoan leading the pack. Gosh. I know. psychologist S. Burt, Walbach. Like, Wolbachia. Oh, that's exciting. Yeah. He decided to give it a shot. And he also observed teeny tiny bacteria-like things in the ticks, their eggs, and the blood of humans and animals that had spotted fever. But he wasn't sure that they were actually bacteria because he was like, it doesn't make sense. They live entirely within the cells of the animals. So this has got to be some new kind of microorganism, somewhere in between protozoa and bacteria.

I mean, you're not wrong. He's not wrong. Like, and even though he was pretty certain he had discovered the causative agent, which he called Dermacentrozenousinus Rickettsi, others weren't convinced, chiefly because he was unable to culture the organism in media in a lab. Of course he was. And he was like, he was like, listen. I understand that these postulates are important, but like we have to evolve. Like we're learning new

things. Maybe we should look at different criteria. Yeah. He was right. He was right. But then the discovery of the causative agent of typhus forced researchers to accept that these intracellular microbes might actually be real and maybe a new type of microbial life, or at least a new version of what we've already seen. And eventually the name that Wolbach had given for the spotted fever bacterium was changed to Rickettsia rickettsiae, giving rise to a whole new genus of pathogenic intracellular bacteria. Cool. So by the 1920s, the causative agent of Rocky Mountain spotted fever had been discovered and the life cycle had been outlined. But this knowledge didn't translate into live saved yet again. Rather, the incidence of the incident of the

disease as well as its mortality seemed to be on the rise. For instance, in 1921, all 11 cases of Rocky Mountain Spotted Fever died. Land prices reflected this. They were dropping from $125 per acre to $15 per acre in some places. Also, $15 per acre can you even imagine. We should have bought, Aaron. We really missed out. We did. And tourism obviously plummeted. No one wanted to go to a place where you could catch spotted fever. And 100% of you would die. Yeah.

And matters were only made worse when the first state bacteriologist, Arthur McCrae, died of Rocky Mountain spotted fever in 1919. Oh my gosh. Aaron, how many people are going to die from this? There's more. Okay. So panic. Was that an all-time high? So the state finally acquiesced to providing funds to create a laboratory whose main focus was to stop the problem of spotted fever.

The, quote, schoolhouse lab was established in an abandoned schoolhouse a couple of miles from Hamilton, Montana, in the Bitterroot Valley. There, lab and ecological facilities were built or cobbled together, where researchers could actually do the work that they had been doing in their spare time. time in makeshift tents and distant university labs for years. And to head this new research venture, two people were appointed, physician Roscoe Spencer and entomologist Ralph Parker. Parker. I, all right. Another physician and another entomologist. Are they going to work together this time? Well, this is where the romance comes in. Just kidding. Oh. At first, the old-time rivalry between these two professions seemed like it was going to rear its ugly head yet again. And they were like, oh, you know, before they arrived in Montana, it was like, oh, what about publication priority?

What about this? What about that? But then they met in person. And they were like, let's work together. All of our research will be published jointly. Isn't that nice? That is how you do it. That's how you do it.

So Parker, the entomologist, he had set his sights on big picture ecological studies, like huge, what are we, how do we find out the links between ticks and these animals and spotted fever and the behavior and seasonality and all of these like just the most fun questions, right? And Spencer is like, I'm going to do a vaccine. And so there had been some research by Hideo Noguchi at the Rockefeller Institute that was promising. in terms of spotted fever vaccines. And in 1923, Noguchi had declared that he had developed an effective vaccine. It just needed to be tested in humans. So who better to volunteer than some of the laboratory staff at the schoolhouse lab in Hamilton? For sure.

Where incidence of the disease was disturbingly high. The vaccine was not without side effects, but it seemed to be effective and at least reducing the severity of illness, if exposed to the disease. All right. But because the efficacy of Noguchi's vaccine remained doubtful, Spencer, the physician involved in the project, continued his own work on a vaccine.

Work which ended up being delayed because tularemia, another disease, started popping up in the Bitterroot Valley. Oh my gosh. This does not make me want to visit this part of Montana. Oh my gosh. What? I mean... First of all,

Okay. That was not the image I was trying to portray with this history, and I feel now very bad about it, because it is absolutely beautiful. And yes, there are ticks, but we know a lot more about Rocky Mountain spotted fever. We know a lot more about how to protect ourselves. And if there's ever an area where the physicians are probably keyed into... Yeah, that makes sense. Signs and symptoms.

You would get doxycycline. if you walked in and said I had a fever. You're like, I went hiking in the bitter route. Here's some doxycycline. Just kidding. You don't give it prophylactically. But anyway. So, okay, tularemia popped up.

Both Spencer and Parker, the heads of the project, became ill. And they wouldn't be the last to fall during this work. No, Erin, I don't know if my heart can take this. I'm so sorry. You said romance. This is not that. I think it was like romance meant in the way that was like tragedy. Oh, yeah, those are two different categories of film.

I don't know, are they? I think a tragic movie could be romantic at the same time and vice versa. Romeo and Juliet. Yeah, I don't like that one. Well. Anyways. Regardless. Let's learn more about the fallen researchers.

Okay. Student research assistant William Gettinger died in 1922 of spotted fever. Field assistant George Henry Cowan, who had worked for over a decade on the disease, died in 1924. And another student researcher named Albert Curley died in 1928 of spotted fever. In 1925 alone, six people working at the schoolhouse labs became infected with either spotted fever or tularemia. Oh, my goodness. The schoolhouse lab was notoriously and deservedly so an incredibly dangerous place to work because there was no biocontainment facilities.

And spotted fever-ridden ticks were crawling all over the place. Oh, no. Like they would have rabbits that they would infect, and then the ticks would just be like, your tick falls off and then it could go and get up on a lab worker. Dogs wandered in and out, bringing ticks with them. I mean, they didn't have the best facilities. Right, right. Part of it was funds.

Like, there's a lesson here, and it's about funding disease research. As usual. There's a famous book called Microb Hunters by Paul DeKrieff that tells the romantic and swashbuckling tales of, like, early microbiologists and, well, microbe hunters. And it includes the story of the Rocky Mountain Spotted Fever researchers, which enraged the rest of the rest of the rest of the rest of the, residents of the bitter root because it portrayed them all as like cowering in their cabins, hiding from this dreaded disease. But, I mean, people were rightfully scared of spotted fever. And so when Spencer rolled out testing of his vaccine in 1925, people, like both workers at

the lab as well as residents eagerly volunteered. And it seemed effective in at least reducing the duration and severity of the illness. Okay. So overall, like retrospective studies showed that vaccinated people had a 75% lower fatality rate than those who were unvaccinated. What? That's amazing. Yeah. Yeah. So, you know. But the hazardous working conditions remained a concern. And so the state finally put together funds to build new facilities. But where should they go? Should they move to Missoula where the University of Montana was located? But maybe that was too far. from the field, and so we should keep it close to Hamilton. And so it was decided that it would

be built on the east side of the river in Hamilton, which had always been spotted fever-free. Oh, no. This caused quite a bit of a stir as people became concerned that the disease would become established on the east side, or that infected ticks would escape, or children playing in the yards of the lab would get infected, but tons of special precautions were put in place, including like a moat and heavy-duty sterilization procedures. Wow. And work began. Ultimately, the residents of Hamilton warmed to the lab, and they would occasionally, like,

lead out-of-town visitors through the building. And then that became problematic because the researchers were like, you're putting yourselves at risk. We need to shut this down. Like, you need to sign in. you need to have somebody supervising this. So, but anyway, the availability of a vaccine also allayed some of these fears. But the vaccine was not a permanent solution because in order to make it,

researchers had to collect or rear thousands of ticks, get them infected, and then grind them up, and then turn that into a vaccine. Oh, that's what they were using. Okay. Mm-hmm. And there wasn't much work that had been done on streamlining the production process. And nor would there probably be since the market for the vaccine was relatively, like, low only in the western states. Yeah. Or was it?

So, throughout the 1930s, a mysterious typhus-like illness was noted along the eastern seaboard of the U.S. as well as in Brazil, and it seemed to be associated with a tick bite. And while initially it was thought to be a disease distinct from spotted fever, like doctors would say, oh, I would say this is supposed. spotted fever if I were in Montana. Ah. But ultimately, microbiological research showed it to be one and the same. And this development was pretty crucial since it came around the same time as the Great Depression was sinking its teeth into everything. Oh.

Including scientific research funding. So funding for the Rocky Mountain Laboratory was threatened. And in response to this, one person, one researcher replied, quote, and I'm including this quote because I think it's relevant to today and always. If the government should discontinue this activity in the light of our present knowledge, the person's responsible for such action would, in my opinion, be morally responsible for the deaths which will occur as a result of the lack of material. I may add that only a few days ago, a request was received from the army for a large quantity of

material to be used for the protection of its forces in the field. So. Sounds strangely familiar in our current climate. And that's all I'm going to say about that. It's like the government doesn't want to fund this anymore, but yet they want it. So anyway, fortunately, you know, maybe this is cause for optimism. The funds were preserved. The lab stayed in place.

And actually some civilian conservation corps, CCC camps, which was like part of the whole, you know, Roosevelt's New Deal, were established in the bitter route to help collect ticks and to do this research for vaccine productions. They had tons of people coming in to work there, which was actually also a problem because there wasn't enough vaccine to vaccinate the newly arrived workers. Oh, my. Anyway. So until the mid-1930s, research at the spotted fever lab in Hamilton had focused on just that, hence its name, which is the spotted fever lab, maybe some dips into tularemia. But developments in the mid-1930s would greatly expand its role and give it the name Rocky Mountain Laboratory. But that, like, Rocky Mountain Labs is still a thing today. Oh, yeah.

These are its roots. Yeah, I never knew that. And when you said Rocky Mountain Labs earlier, I was like, I never would have, I don't know how I never would have made a connection between Rocky Mountain Spotted Fever and Rocky Mountain Labs. I never made that connection before. Oh my gosh. And it's, it's so wild because like that's always been like, well, throughout my PhD, I was like, oh, that's my dream place to work. I want to work on Rickettsias in RMO in RML. Yeah. In beautiful Hamilton. And but like, I do. didn't know any part of this history. And I also didn't know the incredible significance that this lab has had, like, not only on Rocky Mountain spotted fever research, but as we're about to find out, even more research. Oh, tell me. Okay. So in 1936, a researcher at Rocky Mountain Laboratory named Harold Cox had been experimenting with different ways to grow Rickettsiae outside of ticks.

because he was like, I want to put together a better method of vaccine production. One day, he ran out of the tissue that he had been using mid-experiment, and rather than scrapping the whole thing, he reached for some yoke-sack that he had put in the fridge. You have that just like around. I guess. Well, they were doing like egg membrane, whatever stuff. Right, right. And the next day, he found it teeming with Rickettsiae.

And he was like, oh my gosh, what? He wrote to everyone, people were super skeptical, and then they saw it in person, and they were like, are you kidding me? Good job. Good job. And this accidental discovery had huge implications, but not just for spotted fever research, but other rickettsial diseases. And I know that, like, we haven't done a typhus episode, but, like, typhus is really bad. Yeah.

I mean, you talk about one of the big killers. of especially like, you know, wartime and any sort of like civil unrest areas. Like, typhus was massive. Yeah. So it's still around. It's still massive. Yeah. Yeah.

So typhus was a huge one. And so spotted fever, yeah, across the U.S. and interest central in South America, incidents of it ran pretty low. Of course it was very deadly. And so that was a huge cause for concern. Right. But of even more interest was this. the big killer typhus.

Yeah. Especially as World War II began and as U.S. soldiers began to be stationed in regions where it was endemic. Cox's Yolk-Sak method provided a cost-efficient way to produce the volume of vaccines that had long been sought after. Huh. This discovery turned Rocky Mountain Laboratory into a national vaccine factory for typhus and yellow fever and others during.

World War II. Like, it turned into just pumping out vaccines. Wow, I did not know that. And it played such a hugely important role during World War II that there were armed guards, like, from, you know, armed forces. There, around the clock 24-7 to make sure that, like, nothing happened to the lab. In old Hamilton, Montana, like, tiny town. So anyway, super cool. And then while at Rocky Mountain laboratory, Cox also developed the complement fixation test, which allowed for diagnosis of rickettsial diseases. Wow. That's a big deal.

That's a very big deal. So, Rocky Mountain Lab. Rocky Mountain Lab. The discovery of antibiotics that were effective against rickettsial diseases in the 1940s and the 1950s, they took some of the urgency out of the preventative or treatment research programs for spotted fever. Researchers could now focus on understanding the physiology of Riketia and the microbiology of these, like, bizarre, tiny bacteria. And the miracle of antibiotics, as we had discussed a few episodes ago, led to this unfortunate decline in some of the more

fundamental medical entomology research that had been the hallmark of the Rocky Mountain laboratory in its early decades. With the combination, of a vaccine and antibiotics, fear of spotted fever declined throughout the 50s and the 60s, despite the fact that it continued to pop up in new locations and with increasing incidents. Like it, if you look at a chart of the cases over time, it's like increasing, increasing in the late 1800s, early 1900s, and then plummets. And then throughout the 60s and 70s, it's like on the rise. Oh, just wait, Aaron. Just do wait.

I'm very interested. Okay. And then budget cuts in the 1970s eliminated the medical entomology research program at Rocky Mountain Lab. And I don't know if it's back up or not. I should have checked that. And the tick collection was shipped to the Smithsonian.

Work on Rickettsia continued, and Rocky Mountain Laboratories is still a hugely important site of research in general. as we mentioned. And a few more pieces of the spotted fever puzzle fell into place during this time. For instance, the recent resurgence in cases in the 1970s was traced to the encroachment of humans into previously wooded areas, a la lime disease. Surprise, surprise. And most interestingly, the longstanding mystery of why the east side of the Bitterroot River remained protected from the west side.

side was solved. Okay. By Willie Bergdorfer. Bergdorferi! Of our Lyme disease episode, Porelia Bergdorferi. What? Okay. You don't know. So I'm so excited that I get to tell you this.

Oh, I'm so excited too because I really was expecting this story to go and then they built a lab and then released infected ticks and now they're everywhere. Like that's 100% what I expected. So that's not what I had. happened. And here's why. So he discovered that on the east side of the river, he was doing a bunch of microbiology assays of these ticks, and he discovered that they were infected with rickettsia, but it was a non-pathogenic one. And the rickettsia in those ticks prevented rickettsia-Rickettsia, the pathogenic one from colonizing the ticks. Interference phenomenon. Okay. Oh my God, I'm getting

like chills. I know. I know. So researchers had long made the observation that animals freely passed from the east side to the west side of the river. Animals are found on both sides. Like, it didn't make sense. Right. So if a tick that is infected with this non-pathogenic rickcia bites an animal that is infected with spotted fever, rickettsiae, rickettsiae. That spotted fever can't establish in that tick. Right. Because the other bacteria is just already there. And so, and this bacteria also has better transovarial transmission.

So it will not hurt the tick as it's passed from female tick to eggs. This is so interesting, Aaron. tick biology is so amazing it really is very cool it's so amazing that is so bizarre so this this interference phenomenon people have like it's been discussed this type of thing we've talked about it with with walbachia and like yeah maybe we haven't but like we've referenced it at least or alluded to it in terms of like finding certain microbes that can prevent pathogenic ones from establishing in a vector we talked about it with dengue fever oh yeah yeah yeah So anyway, Bergdorfer.

Yeah. So even though Rocky Mountain Spotted Fever has been heavily studied for over 100 years, there's still a lot that we don't know about it, particularly when it comes to the disease reservoirs, strain differences, geographic differences, climate change, like the list goes on and on and on. Seasonality. Fortunately, for researchers now, it's a lot safer than it used to be to study. and I repeat again, I hope, hope I haven't discouraged anyone from visiting the Bitterroot Valley because you definitely should do so. It's gorgeous. It's amazing. And anyway. And you could go see

Rocky Mountain Labs. And you could go see the infamous, the famous, the amazing Rocky Mountain Labs. Okay. Well, Erin, tell me what's going on with Rocky Mountain Sputtle. did fever today. Oh, I'm really thrilled, too, after that history. We'll take one quick break first. I'm going to start off, not where I expected to start off, because I want to ask you questions, Erin. Okay. Okay. I want to start off with a vaccine. We don't have one, Erin. No. There is none. The one that they had developed, the Parker Spencer vaccine, that was used, I don't know how, like, it's not been used for several decades now. Yeah. And I think ultimately it caused some side effects and possibly infection in some people. That makes sense if they were just grinding up ticks, then that would that would do that. It seems like Rickettsiae in general are a tricky bunch to make. vaccines for? Yeah, I don't know. I don't know, but we don't have a vaccine. Honestly, from what it

sounds like, and I'm sure that this is the case, it's largely just because of a lack of funding and a lack of interest, not just from like a research standpoint, but from a pharmaceutical standpoint. there are not enough cases essentially per year to produce a vaccine. It's not like financially viable for better or for worse. It is true that patients who survive infection do mount a very good and long-lasting immune response. And we've also identified a number of the surface protein antigens. So it's certainly theoretically possible to develop a vaccine. But when you, you know, I usually use Google Scholar. That's my preferred search website for finding my papers.

And when you search Rocky Mountain Spot of Fever vaccine, the first entire page of results, there is not a single paper from past 1990 on that page. So, yep. And some of them are from 1925. They're probably some of the ones referenced in your book. Oh my gosh. Parker Spencer. Right. But that doesn't mean that no one's doing research on it. I did find a recent paper that was looking at and did develop an effective wholesale vaccine that they tested in

dogs. I will link to it, but like I wouldn't read that paper again. It was very depressing. They killed a lot of dogs. Oh my God. Yeah. But they made a vaccine. Oh. So anyways, that's the the current research, let's talk about the epidemiology. Okay. Yes. All right. So in the United States, Rocky Mountain Spotted Fever has been a nationally notifiable disease since the 1920s. Since 2010, they've been calling it a different name and therefore reporting it a little bit differently. It's now reported as spotted fever rickettsiosis. And the reason is, we don't have a good way to differentiate the clinical syndrome that is caused by rickettsia rickettsia from the clinical syndromes that are caused by a number of other rickettsial pathogens, including rickettsia

parker eye, which we briefly said those words earlier, rickettsial pox, and a few others. So kind of, that's the background, I think, to keep in mind as I'm going to talk about these numbers because this gets really interesting, okay? Okay. So let's talk about, you said that cases were increasing, you know, through the late 1990s, or through the late 1900s, right, after that drop off. Well, if you look at the graphs of cases since the year 2000, it's terrifying. It is.

It's an exponential growth curve, which everyone is now very, very. familiar with. We've all seen a lot of those these days. Okay. The number of cases has increased steadily just about every year. 2018 was a little better than 2017, but in 2017 there were over 6,000 cases reported, and that's up from under 500 in the year 2000. What? Okay. That's, like, and I'm so embarrassed because this is literally what I did my PhD on. But I didn't, you did it in Panama. Okay. It's fine.

Okay. You didn't need to know these numbers. So, but here's the question. We're seeing these huge increases in cases. How many of these are the very deadly Rocky Mountain spotted fever versus other rickettsia? And it's really hard to say. And also, how much of it is, are we getting better at recognizing it? Are we getting better at reporting it?

Or are there an increased in infection? I think this is me thinking, but also like based on what I read, it's likely a combination of both as usual. But the increase is so large over such a short period of time. Like we're talking 20 years, right? From 2000, you have under 500 cases to over 6,000 in 17 years. That's massive. And this is a disease that's been notifiable since the 1920s. Yeah.

And our diagnostic tools are not much better today than they were 20 years ago. Okay. The case fatality rate has drastically, dramatically decreased since the 1940s, since the introduction of tetracycline's for treatment. So in clinical reviews, like worldwide, even after tetracycline's were introduced for treatment, case fatality rates still usually are about 5 to 10%, usually around 5%. But the current case fatality rate in the U.S., according to surveillance data, is as low as 0.5%. What? That's excellent.

It is excellent, but it bears the question, is this Rocky Mountain spotted fever or is this something else? So let's look in other parts of the world. what's going on there? Well, turns out that's hard to do. There's not very good surveillance data for much of the rest of the world, but I did find some really good data for Mexico. So in Mexico, throughout the 2000s, the incidence of disease has also been increasing, also dramatically. I don't have an exact number. However, unlike in the U.S., the case fatality rate has also been increasing rather than decreasing. Really? The aggregate case fatality rate has been between 14 to 18 percent, depending on the region of Mexico, but in some years, the case fatality rate has been as high as

40 percent. Ooh. So then I think, you know, there's a lot of questions as to what, what is this? Does this mean that we're looking at different diseases or does it just mean that we're looking at drastic differences in lack of availability of good diagnostic tests, delays in reaching a doctor to get diagnosis or to get treatment? Another issue is that a large proportion of cases, not just in Mexico, but in Mexico and also in the U.S. are in children because kids are running around outside, getting bitten by ticks. And usually tetracyclines aren't. aren't used as treatment for children because it can permanently damage and discolor your teeth. So a lot of physicians might be hesitant to prescribe doxycycline for kids, but it turns out that

for Rocky Mountain Spotted Fever, it's a short enough course that it doesn't actually increase the risk of tooth discoloration, but maybe you don't know that. And so then a kid is delayed in getting the appropriate treatment or receives the wrong kind of treatment. And so than you have an increase in case fatality rate. But overall, it's less than 1% of spotted fever group rickettsioses that are reported in the United States are actually lab confirmed. Okay. So it's all based on the triad of.

Yeah, exactly. Oh, and the other triad piece is often tick exposure. So some people say the triad is fever, rash, tick exposure, or history of tick exposure versus fever headache and rash. But not everyone reports tick exposure, right? And that doesn't mean that they weren't exposed. They just might never have known it. Comforting thought.

Yeah. So that's spotted fever group rickettsiosis. Rocky Mountain spotted fever today. We never told Brett's story. Okay, okay, now we need to tell Brett's story. Cast your mind back to 2013, 2013, 2014. 2014. The summer.

The summer of 2014. Okay, listen. The rainy season in Panama. Everyone. June. As we mentioned, Aaron Welsh did her research on tick-borne disease in Panama. That was what her thesis was on.

Our lab is a disease ecology lab. We studied tick and other vector-borne diseases, okay? My focus in particular, well, my focus was the general ecology of ticks and their pathogens as it related to the climate gradient across the isthmus and seasonality and different animals and blah, blah, blah. But, you know, in all the research proposals I ever wrote during my PhD, I always mentioned Rickettsia Rickettsia I. Of course.

Because it is present there and it is a cause for concern. So you want to understand where they are, what the ticks are, and you want to increase awareness of a tick bite and a rash and a fever and a possible headache. So June of 2014, Brett, my now husband, and I flew back from Panama after my first field season down there to California to stay with family for a short time. And on the plane ride back, he started feeling crappy, okay? He felt unwell. We made it back to my brother's house. And I believe he had a fever, but I'm sure we didn't have a thermometer. But he felt sick. Like he just really didn't feel good. And I was like, gosh, like, I hope he didn't come down with something, you know. But he had no respiratory symptoms.

He wasn't coughing. He didn't have, you know, like sore throat, any of the normal kind of things I would associate with flu or a cold. He just felt achy. He felt unwell. He had a headache, a fever. And this lasted for a couple of days. And then he went to the bathroom. Is he going to be...

Did you tell him that you were going to tell the story? Yes, I told him. Don't worry. He goes, I knew as soon as you said you were doing Rocky Mountain Spotted Fever. He's like, I've been waiting for this for three years and it's finally here. So then he came out of the bathroom and he said, I just, I pulled something off of my, the top of my butt crack. And he said, what? And he was like, yeah, it was like there was a bunch of blood and some black stuff. And I said, what? And then I grabbed his arms and on his wrists was a rash, a red, blanching,

macular rash that did not hurt and did not itch. And oh, he also had one on his legs that he hadn't even fully noticed up to this point. Okay. Brett. And then he said, I pulled this thing off the top of my butt. I saw it. I squished it. There was blood and then black things. And I went, and I threw it in the toilet. And I flushed. And I said, you just flushed a tick. You have a ricketia. You need to, first of all, go to the doctor. And second of all, I can't believe that you threw the tick in the toilet. I was devastated. Oh, we all were.

Our whole lab knows this story. He's also probably going to be like, you told it entirely incorrectly, but I didn't. This is how it happened. Yeah. This is the myth, as I know it now at this point. It's legendary status. It was classic. I mean, as soon as, and I can't, I will say, I can't remember if he had the rash before

he pulled a tick off or if if I didn't see the rash until after he told me about pulling the tick off. But as soon as he told me about that, I looked and he had this rash and I was like, I knew that it was. I was like, this is either Rickettsia Rickettsiae, and you're going to die or it's a lesser one, but either way you need to go get treatment. And he wouldn't listen to me until we went to go visit his parents. And I had to tell his mother and she's the one who forced him to go to the doctor and get treatment because he wouldn't listen to me. So thank you, Chris, because otherwise he might be dead. So he went to the doctor and he said that the doctor, like he told the doctor that he thought

he had Rocky Mountain Spotted fever and this is why. And then apparently the doctor like went and took his phone and then came back in with his phone and was like, well, we could do a test, but I think I should just give you some antibiotics. And Brett was like, yep. And he was better in a couple of days. Well, I am very glad that Brett was better. I'm still puzzling over where you picked it up because you had just been scuba diving or something.

We had been at Koiba. So it could have been Koiba because we had hiked around that a little bit. But it also could have just been in Gamboa because we went up to the ridge or whatever. Oh, well, yeah. We'll never know because he threw the tick in the toilet. Even yesterday when I told him we were going to tell this story on the podcast, he was like, I should have just thrown it in the trash. I know. I know, Brett.

Like, you had killed it dead and good. Like, it could have been like my entire dissertation right there. Right? Like, at least that's a case report. We could have been co-authors, Aaron. We could still be co-authors on a paper. Yeah. Whoops. I know.

Okay. Don't tell Brian. So that's our story. That's our story. You know, Aaron, this, I feel like it lived up to my expectations, my hype for this episode. I had a great time. Me too. I feel like it was back to our roots in a way. Yes, it really did. It felt good. It felt good. I was a little bit afraid to do something that was like very close to my PhD.

And then I realized it doesn't have anything to do with my PhD. Well, sources? Sources, yes. I mostly used a book called Rocky Mountain Spotted Fever, History of a 20th century disease by Victoria Hardin, which told the complete story. It was great. And then a couple of papers. and I will include those on our references page on our website.

I read through a number of fun papers about the biology and a few good ones on the epidemiology. We'll post all of our sources on our website. This podcast will kill you.com under the episodes tab. You can find all of our sources for this and every single one of our episodes. Yeah. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. And thank you, everyone, for listening.

Yes, thank you. We hope that you enjoyed this one as much as we enjoyed talking about it. We really enjoyed this one, so we hope that you guys did too. Well, with that, until next time, wash your hands. You filthy animals. This is Special Agent Regal, Special Agent Bradley Hall. In 2018, the FBI took down a ring of spies working for China's Ministry of State Security, one of the most mysterious intelligence agencies in the world.

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