This Podcast Will Kill You - Ep 95 Tetanus: An inhuman calamity!

Episode Date: April 26, 2022

[CW: Firsthand account includes description of the death of an infant. Skip approximately first 3 min to avoid.]What comes to mind when you hear the word tetanus? For many people, it’s probably the horrible thought of stepping on a rusty nail or the every-so-often Tdap booster you get at your doctor’s office. Thanks to the wide availability of this incredibly effective vaccine, not many of us have an image of what an infection with tetanus actually looks like or how deadly it can be. But that’s not the case everywhere, especially in places with limited access to these life-saving vaccines. In this episode, we take you through the biology of the spore-forming, soil-dwelling, obligately anaerobic, Gram positive Clostridium tetani and the powerful paralytic neurotoxins it produces. We then venture into the history of this pathogen, a history that includes a tour through early medical texts and a discussion of the origins of epidemiology as viewed through the context of neonatal tetanus in the American South. We round out the episode by reviewing where tetanus still poses a substantial threat today and highlighting some very exciting ways this deadly pathogen may be used to treat cancer! Tune in to gain a newfound respect for this incredible microbe! See omnystudio.com/listener for privacy information.

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This is a job for Indeed Sponsored Jobs. Hey, everyone. We're including a content warning for the firsthand account that we're about to read. which includes a description of the death of an infant. To skip this, jump ahead about three minutes. Mrs. Cyril, Orchard Street, age 24, was delivered of her third child on Friday morning, September 2, 1859.

It was a male child, fine and apparently healthy in every respect. From Friday till Wednesday, all was well. The cord separated on Tuesday, the fifth day. On Wednesday, the child was restless, cried, and kicked. On Thursday, the mother reported that he cried all day, could not open his mouth, could not suck, and frequently stretched, and was stiff. The next day, Friday, I saw him. Every few minutes he appeared as if struck by an electric shock. Every muscle was thrown into distorted action.

I will not attempt to describe. This drawing tells the wrinkled forehead, the elevated brow, the closed eye, the dilated nostril. the rigid masseter, the fixed jaw, the closed mouth, the corrugated lips, the bubbling saliva, the retracted head, the shortened neck, the starting cervical muscles, the turgid veins, the arched spine, the raised chest, the troubled breathing, the catching diaphragm, the heaving, the separated arm, the squared elbow, the bent wrist, the clenched fingers, the incurved thumb, the extended and separated legs, the bent down toes, the livid surface, the whole figure, rigid as wood, a pitiful sight. The paroxysm was renewed by a slight noise, the gentlest touch,

A placid interval of a few minutes succeeded, and then another fit followed. On examining the child, the umbilicus was seen prominent, at least half an inch long, red, and showing an unhealthy, separating surface. The umbilicus continued to discharge. Emaciation rapidly advanced. The skin assumed a brownish hue and hung in shriveled folds of leathery texture. Peace and pang perceived. sued their sickening interchange.

The child gradually became more feeble, and on the 10th day of the disease, and the 15th of his existence, he sank by degrees exhausted. It was really difficult to read. Absolutely horrible. Yeah. And thank goodness there's a vaccine. Mm-hmm. Yeah.

That was from an 1860 case description of. of tetanus in phantom, aka neonatal tetanus or tetanus. Yep. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. And I'm sure you all know by now the subject of today's episode. Yeah.

Tetanus. It's a vaccine preventable disease that we haven't covered yet, which is exciting. Yep. And it's obviously going to be difficult. at times because it's a really truly horrible disease. I mean, absolutely horrific, devastating, awful. Yeah. Yeah.

But there's going to be a lot of very interesting biology. I know there's going to be some fascinating history that I can't wait to learn about. And I have some thrilling things to talk about in the current events section. Like, I am really excited. Yeah. Ooh, I'm so intrigued. So shall we, you know, get started on the important things? Of course. Of course we should. What time is it?

Quarantine time. It is. And this week, we are drinking the rusty nail, which just so happens to be an actual cocktail. It's a real drink. It is. It has scotch and brambouy. And I think that's it. And we're going to find a way to make the non-alcoholic version, our placebo-rita. Yeah, it's going to be an interesting one to make a placebo rita for, but, you know, I think that it might not bear too much resemblance to a scotch and a scotch-based lique. But I think that's okay as long as it's delicious, right? I trust in you, Erin. Okay, thank you. And we'll post the full recipe for this quarantini and non-acolic placebo rita on our website, this podcast will kill you.com. on our website, this podcast will kill you.com.

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So today we're talking about another Clostridium species, Clostridium tetani. We've covered this genus before, of course, in our botulism episode. And then I mentioned it again in our C-DIF episode, although C-DIF was reclassified as Clostridioides. But anyways, today it's Clostridium. Clostridium tetanai is an incredibly widespread and hardy little bacterium. It's a rod-shaped gram-positive spore-forming bacteria. that when it's making its little spores, if you look at it under a microscope,

looks like a little matchstick or like a tennis racket. It's kind of cute. Oh. Because it makes its little spore at the end. It's like, weoom, boop, and pops off. Oh, interesting. Uh-huh. And like its cousin, Clostridium botulinum, this is an anaerobic bacterium,

which means it likes to grow without any oxygen. But because it's a spore former, these spores are. incredibly hearty. They're very resistant to heat, to cold, to antiseptics, to oxygen. And so this is a bacterium that persists in the environment across the globe. It makes its home in the soil. But Clostridium tetanai can also thrive in the intestines of various animals, including humans. I found that so interesting. And what is it doing there? Like, is it just a part of your gut microbiota? Are there any sort of negative effects? Or is it just really hanging out? As far as I know, at least, they just hang out. I'll be honest, I didn't do a lot of digging into

what they're doing in our guts. Okay. Yeah. But as this is a soil bacterium, and as this is, this podcast will kill you and we're talking about the disease caused by Clostridium-Tetanai, people are exposed through the soil, kind of, in general. Usually, exposure to this bacterium tends to be from wounds, especially deep wounds or puncture wounds, that come into contact with anything contaminated with this bacterium, which again can live almost anywhere. So this can be anything from rusty nails to fence posts, thorns from a tree, even potentially bites if they are contaminated, really any kind of deep wound because those kind of wounds

have pretty limited exposure to air, which means limited exposure to oxygen. And so as tissue death occurs deep within that wound, the environment can become very anoxic, which can allow for tetanai spores that are present in the soil that contaminated that wound to germinate and grow. Interesting. Yeah. I have a really dumb question. Okay. Anorobic environment, meaning there's no oxygen. Mm-hmm. There's oxygen carried by your blood. If you're bleeding, is that an anaerobic environment? It's a great question. So, no. If you have active blood flow to an area, then that tissue is not going to become very anoxic. What can happen in deep puncture wounds is that the tissue can die like deep within. And so once you have dead tissue, that tissue is not being supplied by your blood supply very well. So that is why it can become anoxic. But that's a really good question.

It's not a dumb question at all. That is okay. Yeah. I'm fascinated. Yeah. That's why it's, in theory, any wound can become contaminated with Clostridium tetanai. But not every wound is going to be as susceptible to actually harboring a active tetanus generating infection, if that makes sense. Now, I'll talk a lot in this episode about neonatal tetanus, and the firsthand account that you heard was a description of neonatal tetanus. This is a, it's the same as regular tetanus in kind of what it does to the body, but neonatal Tetanus is often classified as specific because it happens with contamination of the umbilical stump. So the umbilical cord that's left when a baby is born. That's just kind of an open area that can very

easily become contaminated. And the base of that is dead and dying tissue because that's what's normally supposed to happen with an umbilical cord. And so that's why it's a place that's very easily. And then, of course, babies have almost no immune system. So that helps as well. Right, right. So that's kind of how we get exposed. And just like with Clostridium botulinum and Clostridioides difficile, the story here is not the bacterium itself. It's also not the spores of this bacterium. The story of tetanus is the story of the toxins that this newly germinated bacterium can release within our body. So let's talk about them. Yeah, these toxins are, can I read a quote real quick, actually? Can I interject a quote? Okay. Yes, please do.

I was hoping I was going to be able to use it somewhere. Quote, an amount of tetanus, botulinus, or dysentery toxin, weighing no more than the ink in the period. at the end of this sentence, presumably Times New Roman 12, would be enough to kill 30 grown people, an ounce could kill 30 million tons of living matter, half a pound would be more than enough to destroy the entire human population of the world. I'm not sure when this was written, but I think it probably would still be sufficient. I love, okay, I feel like I remember you reading that quote in our botulism episode. I feel like I did, Two? Whoopsie. I'm pretty sure you did. No, it's not a whoopsie. I'm really glad that you said that

again because I was trying to classify like how much because the numbers that we're going to talk about are so small. And I was really worried that you were going to ask me to be able to. And I'm really glad you just did it for me. Oh, why? How about that? All right. So let's talk about those incredibly terrifying potent toxins, shall we? Let's do it. So exotoxins are proteins that bacteria make that can disperse throughout our body and cause an effect. We've talked about them a lot on this podcast. The toxin in Clostridium tetanai is the causative agent of tetanus, not the bacteria themselves. This toxin, the tetanis toxin, tetan as a side note, it actually produces two different toxins. One is called tetanolycin and the other tetanospasmin.

Tetanolicycin, we don't really understand, at least from what I read, like maybe it helps establish an infection or something like that. But tetanospasmin is tetanistoxin. So that's what we're going to talk about today. So this tetanus toxin is a neurotoxin, just like botulinum produced from claustridium botulinum. And so it specifically binds to our nerves and affects our nervous system. Let's recap what we learned in our botulism episode, shall we? Mm-hmm. Then we can do some compare contrast.

My favorite. I was so looking forward to this. I know. I actually just took some notes. Like I copy-pasted some notes from my, that's going to be great. It's a recap. Botulinum toxin blocks the release. of acetylcholine at our peripheral nerve synapses, if that sounds familiar.

Mm-hmm. So what that results in is a flaccid paralysis, meaning a limp paralysis. Because the signals from our brain don't ever actually make it all the way to our muscles. So your muscles are paralyzed in this flaccid, limp state rather than a contracted state. that happens when this botulinum toxin binds to our nerve cells at the neuromuscular junction, which is the junction between our nerves and the muscles that they innervate, and then blocks the release of the transmitters at that junction. Okay.

Tetanus toxin does the exact same thing. It blocks the release of neurotransmitters in a synapse, in a junction. but it does it in the inhibitory interneurons within our spinal cord. I'll explain. But the bottom line is that tetanus toxin has the exact opposite clinical effect. It causes a spastic paralysis or muscles that are paralyzed in a rigid or contracted state. So let's go through the steps, shall we? Yeah.

What happens in the case of tetanus toxin is it binds actually to our nerve cells in the same exact place as botulinum toxin. It binds to our nerve cells at the neuromuscular junction, the MMJ, and it is internalized in those cells at the same place as botulinum. But while botulinum toxin acts, it exerts its effects right there at the neuromuscular junction, blocking the release of acetylcholine. What tetanus toxin does, instead of acting right where it enters our cells, is it actually travels retrograde along our nerve axon a la like rabies virus. Oh, yeah. Okay. If that sounds familiar. It travels all the way up our nerve axons, like from the muscle in your jaw, for example, all the way up the nerve into our central nervous system, where the nerve came from.

and then it enters the space in between. It travels through that inter-synaptic space inside our central nervous system and enters another set of neurons in our spinal cord. And there it blocks the release of neurotransmitters, the same way that botulinum does. But it just so happens that the neurons that it enters in our spinal cord are the inhibitory neurons. that primarily release neurotransmitters whose primary job is to inhibit or block the firing of our motor neurons. Okay. And so if they can't do their job, then all those motor neurons are going,

shoe, shoe, and then that's where you get the rigidity and spasms. Exactly. You just read my next line. It's perfect. So exactly. If you can't inhibit the inhibitors, then your motor neurons are getting signals from your brain like rapid fire, which leads to this intense muscle rigidity, this spasm. Okay, I have a question about wound location and course of disease and stuff like that. So the classic picture that I have of someone with tetanus, and I'll talk about this actual picture later on is like someone who is completely every single muscle is rigid. Yeah.

Does that happen all the time? Does it happen in stages? For instance, if you have a wound on your hand, does that mean that the hand will become rigid first? Such a good question. In general, the course of tetanus is the same always. And in general, the course is that the muscle. that tend to be affected first are the facial nerves. So the muscles that are in your face, like your jaw and your neck and your head. And then it tends to travel kind of downward and then

affect your trunk and your limbs, etc. Why is that? That's a great question. I don't know and I don't think that we fully know. So the nerve pathways to our facial muscles are a lot shorter, like the distance from the central nervous system to those muscles, it is a lot shorter, but it doesn't matter where you get exposed, if that makes sense. So say you get a wound on your foot, that tetanus toxin makes it in, makes it to your central nervous system, and it seems to be that it's still the head and neck first and then the rest of the body after that. It is really interesting. I don't fully know why. So bizarre. I know. It is really, really interesting. Huh. Yeah. And the same was true for botulism, where it often went from the head down.

Right. Yeah. Yeah. So that is kind of how this toxin works. In general, the incubation period, the time from when you are first exposed to when these symptoms, start. It's quite variable. Most sources on average, say like three to 14 days, some say seven to 10. It really can just depend on where you get exposed, whether you're talking about an infant versus an adult, things like that. And like I said, the symptoms do tend to follow this general progression. So they often start with this neck stiffness, difficulty opening the mouth. And then that progress. to the classic name for tetanus, which is lock jaw. And that is from the spasm of the muscles of chewing, the muscles of the jaw, that spasm shut. And then that continues to progress.

There is a kind of characteristic facial posture called rhesus sardonicus. Oh. And it's this really awful facial expression that's a very pronounced closed mouth, teeth-beared, grimace because all of the muscles of your face are just rigidly contracted. At this point, the muscles of swallowing are very likely affected, so there's going to be some degree of dysphasia or difficulty swallowing. And as it continues to progress, the muscles of the trunk can become affected. And this can lead to a rigid posturing that's known as epithotonous, which is, again, really, really awful if you see pictures of it. But it's this very

rigid, arched back with head jutted back because all the muscles of your spine, like along your spine, become contracted. At this point, because of all of this contraction of all of these muscles, the chest wall is not very compliant. So that means that you can't breathe very well because the muscles between your ribs and your back, they're kind of in spasm. So it can be really difficult to take in air. Oh, my goodness. Yeah. There can also be kind of convulsions that happen similar to seizures that can happen on top of this generalized increase in muscle tone. So these spasms can look a lot like seizures. But if these spasms affect muscles like the larynx of the throat, then they can lead to airway obstruction, which can be life-threatening. And one of the papers I wanted to read a quote from,

because I think it kind of sums up just how awful this really is. They said, after this description of all of these symptoms, quote, consciousness is preserved, making tetanus a truly dreadful disease. Oh, no. Yeah. Yeah. So it's a really horrible disease. Yeah. To say the least. To say the least. And you can imagine there are a lot of different ways that people can end up dying from tetanus. And just like with botulinum, while there is treatment for the effects of tetanus toxin, we have tetanus IgG, like antibody. treatment. The treatment, the main function is to bind and neutralize any of this toxin that hasn't

yet bound into the central nervous system. But this can only do so much because once tetanus toxin is bound and internalized into our nerve cells, there's nothing that we can do about it. It's permanent until our nerves essentially regenerate, which is what has to happen. Those nerve terminals have to actually, you know, remake themselves to be able to then resend the signals that they need to send to inhibit muscle contraction. So if you don't get that early enough, it's... Right. Yeah.

Yeah. Tetnis toxin doesn't kill any of the nerve cells, which I think is really important. But the neurons still do have to kind of remake those synapses in order. order to be able to work again properly. So you're not having to make entirely new nerves or anything like that, but you can't stop the effects of the toxin that have already been integrated into our cells. Right. So on top of using treatments like the, you know, tetanus antibodies, you also have to treat the source of infection. So antibiotics or wound debreedment, if there is some kind of active wound that's still making more tetanus toxin. But really the most important thing in terms

of treatment is supportive care and sedation. And one thing that's really interesting, although incredibly depressing still, is that after the advent of mechanical ventilation, so like being able to intubate someone and breathe for them while this process is taking place in their body, This obviously helps keep people alive because they usually would die from respiratory failure with tetanus. But since we have invented that, we have found that tetanus wreaks even more havoc on the body than we realized. While botcholinum really only affects the motor nerves, because tetanus goes into our central nervous system, it causes a lot of autonomic instability as well that we didn't realize until we had mechanical ventilator. to keep people alive long enough to see that process, if that makes sense. And so it can cause a lot of, you know, blood pressure variation.

It can cause heart rates to go really, really high and then drop really, really low because it basically is blocking your autonomic nervous system from being able to send signals appropriately. So it's a very difficult disease to treat with supportive treatment, though it's not impossible. It's absolutely possible. It's just really complicated. Jeez. And so because of that, mortality rates for people who are unvaccinated who have never been vaccinated can still vary really widely.

One source that I read estimated anywhere from 10 to 60 percent mortality for neonatal tetanus. And of course, neonatal tetanus happens when babies are too young to be vaccinated. So in adults, the mortality rate can vary from 8 to 50 percent, I read, and it increases with age. So it's a very complicated disease to treat, but it is entirely preventable, which is amazing. Yeah, truly. It really is. We have an incredibly effective vaccine that has very long-lasting. immunity. And it is, I think, the cheapest vaccine to ever have been produced is one thing that I

read, which is, yeah, I love that. And it's been around for a really long time. So that's the good news that we'll get to end this episode later with at least some happy news because of the vaccine. So that's the biology of tetanus, Erin. It is just as maybe more horrifying than I anticipated it would be. Yeah, I know. It really, it really is. Yeah. Yeah. I have a question for you, Erin. Mm-hmm. How on earth did this process evolve? Oh. Because, okay, here's the thing, Erin. Yeah. Yeah. You mentioned up at the top just how potent this toxin is. Right. Right? It's, it is so potent. I didn't even know this until researching. But getting infected with tetanus, getting infected with Clostridium tetanai and then surviving an infection does not provide you with immunity. Because the tetanus toxin is so potent that just the tiniest amount of it causes incredible symptoms, but not enough to produce antibodies that we actually make enough of to then produce immunity. Whereas we know that we produce immunity because we have a great vaccine.

And, I mean, that's incredible. And one source that I read said that the toxin may constitute 5% of the weight of this organism. So they're making a ton of this toxin. It is so bizarre. And I'm not certain that I have a satisfying answer, but I want to, like, get into it with you. So let's take a quick break and then I'll get started. I can't wait. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keeffe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented,

and absorbs quickly. A little goes a long way. that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works. O'Keefs is my hand cream of choice in these dry Colorado winters when it feels like my skin is always on the verge of cracking. It keeps them soft and smooth, no matter how harsh it is outside. We're offering our listeners 15% off their first order of O'Keefs. Just visit o'Keefscom.com slash this podcast and code this podcast at checkout. Success starts with your

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Bults are tight. Now your plans refined. Run a smoother business when you're all the line. Do that with Acrobat. Learn more at Adobe.com slash do that with Acrobat. I found the history of Tetanus to be so interesting for a number of reasons. First, it checks a lot of the boxes for a classic TPWKY episode. Tetanus is an infamous disease.

There are plenty of ancient descriptions. of course, war, you know, plays a role, gets a mention. And also we get to talk about the golden age of germ theory. Yeah. All that good stuff. Second, we've covered a couple of related pathogens before, as you mentioned. And so it was kind of fun to compare the evolutionary histories or human histories of these, especially with Clostridium Botulinum. Yeah. And third, there are parts of the history of tetanus that I feel provided an opportunity to think about how perceptions of a disease, especially who is most likely to get that disease, can really find their way into how these diseases are written about historically. And I think that's good to keep in mind as we

try to read between the lines and understand like how people were observing disease and why. So let's get started. I love it. Where did tetanus come from? Great question. Wish I had an answer. I can tell you where the word tetanus came from, which is the Greek verb, Tannotan, meaning to stretch. But from what I can tell, we don't really know where this pathogen originated in the world,

and when it spread around the world, because it is, like, globally distrachian. Did its global distribution predate wide-scale travel by humans? Maybe. Maybe? Maybe. It's a mysterious little pathogen. We do know, though, that humans have been exposed to tetanus for at least most, if not all, of written history, and probably have been for all of our prehistory as well. But we'll get to that in a second, because first, I want to talk about some aspect.

of tetanus ecology and evolution. So like I said, we don't know where geographically tetanus emerged, but we do know that it doesn't really seem to change all that much. Its genome is highly conserved, which is actually, I think, something that we've seen for a few other spore formers, which I think is cool. Yeah, anthrax, right? Anthrax especially, yeah. Botchilinum, Clostridium botulinum is less stable, but anyway, the plasmid carrying the tetanus toxin gene is more variable, but the gene itself is not. Is very stable.

Yeah. Yeah. Which doesn't make sense. That's so interesting though, because like with botulism, there's more than a few different like types of the toxin. But with tetanus, it's really just tetanus toxin. Yeah. And with the botulatum toxin, it's found in many different strains of claustridium.

Whereas, yeah, the tetanus neurotoxin only in Clostradium tetanai. Yeah. And like you said, these two neurotoxins are structurally and functionally similar, but they seem to have followed different evolutionary pathways. And I think it's really cool to look at the ecology of these bacteria to see, like, maybe why that might be, or why these different characteristics of these two, bacterial species, why they contribute to the patterns that we see in disease, in outbreaks,

and sporadic cases, stuff like that. So both Clostridium tetanai and Clostridium botulinum are anaerobic, soil dwelling, and they produce this deadly and potent neurotoxin. But why? Why do they do this? Right. Why are you the way you are with the title of our botulism episode, because we were like, why, why, why? And we talked about how. And we talked about how, Clostridium botulin will be picked up by a dabbling duck or something. And then the toxin will kill the bird. That carcass becomes a great anaerobic replicating ground for the bacteria. And also a great source of environmental contamination as other animals either nibble on the corpse or around the corpse or in like, you know, the more dabbling ducks than the soil, whatever.

Right. Right. I remember that a lot. Yeah. It was a very cool thing to visualize. Like, oh, that's why this exists. And so having this deadly neurotoxin is key to the life cycle of clostridium bochalinum. By killing its host, it can now contaminate a big chunk of the environment and spread to other hosts. And the tetanus toxin isn't too much different, really. It's a potent neurotoxin that can kill its host, but one key difference is that the bocholinum neurotoxin can survive ingestion, and that's like how it creates disease, while the tetanus neurotoxin cannot. And this difference is why we see outbreaks in botulism in nature and in food poisoning outbreaks, whereas we mostly see isolated sporadic cases in tetanus.

Whoa. Uh-huh. So it makes even less sense. It makes even less sense, but it also does, it does make. sense to a degree, right? So this is likely a costly toxin to make. It has to help the bacteria. It has to help Clostradium tetanai to survive, to be transmitted, to help it complete its life cycle in some way. I mean, these are soil-dwelling microbes, so they don't necessarily need hosts to live, to proliferate. But it would be great if a host came along with a little cut on their foot and picked up some tetanus spores, tetanis spores.

And then that host, after it died, became another great breeding ground for more contamination. So it might be a combination of the fact that this is a very useful tool for the bacteria and also their spore formers. Yeah. So I don't know. The whole gut thing, that's just so interesting. I know. Because I feel like that was such a big part of the botulinum story where, you know, then you eat it and then you continue it, etc. And so to know that that's not part of the story here is really interesting.

Yeah. I mean, I feel like the story makes sense still. Like the toxin plays an important role, but it is. isn't as satisfying. Yeah. Nearly as satisfying. Right. And maybe that's the lesson.

Is that like evolution doesn't always tell a satisfying story? Doesn't always make sense. Yeah. It doesn't always make sense. It doesn't follow logic. It's just, it just is what it is sometimes. That being said, if anyone listening is like, wait, no, I know why this happens. Or you have a paper where you can show me exactly because I spent hours and hours on Google Scholar

trying to find out the evolutionary ecology of this neurotoxin, please shoot us an email. Yeah. I would love to read it. We have so many more questions. Yeah. But the good thing about this relatively non-exciting or maybe not satisfying evolutionary history and the super stable genome of clostridine tetanai is that this means that the vaccine is very widely and highly effective.

And we don't have to worry about the emergence of strong. that the vaccine doesn't protect you against, which is good because this disease is horrible, absolutely horrible. Tetanus causes this dramatic, visually dramatic and deadly infection. And so it should come as no surprise that it has been mentioned in so many ancient texts. All of them. All of them. It's really back-to-back classic TPWKY with trachoma and chlamydia last episode.

and now this. So we're going to run through these ancient medical texts again for tennis. So we've got the Edwin Smith surgical papyrus written around 1,500 BCE, that mentions it. The ancient Indian physician Sushruda from around 600 BCE made a possible reference to it. Early Chinese medical text from around 400 to 200 BCE described it. And of course we've got the Hippocratic texts from around the 400s BCE. Yep. Yep. Hippocrates and other contributors to the text because it wasn't just Hippocrates actually wrote quite extensively about tetanus, both the local and systemic forms, and included some very colorful descriptions of the disease. Quote, a man who was struck from behind by a sharp dart a little below the neck had a wound which did not look serious because it did not go deep. But sometime later, when the point had been extracted, the patient was seized with backward bending convulsions like those of opishtonus.

His jaws were locked, and any liquid that he attempted to swallow was returned through his nostril. He died on the second day. Oh, goodness. And if you're looking for treatments, the Hippocratic texts have got you covered. Fat bird soup, vapor baths, cold water baths, pepper, hell-bore, and of course you have to throw in some bloodletting. Of course. Of course.

And over the next hundreds of years, nothing really changed for tetanus. 700 years after the Hippocratic texts, Eritus of Cappadocia added his thoughts on the disease, and you can really tell how badly he felt as a physician completely unable to help his patients. Quote, an inhuman calamity. An incredible sight, a spectacle painful even to the beholder, an incurable malady. He listed treatment after treatment, frankincense, the hair of a poly, fleabane, turpentine, etc. And this variety just kind of goes to show, again, that nothing seemed to help. Classic tetanus, like what you would see in an adult human, wasn't the only thing that these ancient physicians noticed.

There was also mentions of equine tetanus and neonatal tetanus, which was sometimes called trismus and not necessarily recognized to be the same thing as tetanus for hundreds of years. Interesting. From these ancient texts, I'm going to skip way ahead until the 1800s, kind of like I did also for chlamydia slash trachoma, because not very much happened in terms of tetanus until that time. I mean, yeah, sure, there were additional descriptions of it and case reports and shifting hypotheses as to what caused the disease. But overall, the way that it was characterized in the Hippocratic text didn't change much. A tiny injury, like one instance I read from the bite of a tame sparrow in the 1700s.

Whoa. I know. There's a lot to take in in that sentence. Yeah, there really is. But this tiny injury could lead to a horrifically. painful infection that was ultimately fatal a lot of the time with no reliable effective treatments. Right. Even in 1892, when doctors had slightly better tools to help with feeding and muscle relaxation, the mortality rate was 80% after four days. Yeah. For much of human history,

Tettinus remained a sporadic disease, except in a few instances or populations. And one of these was, of course, soldiers or during times of war for all the usual reasons of basically not having access to sanitation, an increase in both small and large wounds, etc. There's a famous painting, this is the picture of tetanus I mentioned, that you've probably seen depicting a soldier in a violent, rigid spasm from tetanus infection. And I'm going to post this probably for like the announcement release post for this episode on our social media. That was painted in 1809 by surgeon and artist Sir Charles Bell. It's titled Tetanus following gunshot wounds. And guess where the soldier got those gunshot wounds? During the Napoleonic Wars. I mean, again, Napoleon. It's just so many parallels.

Yeah. Specifically, if you're interested, the Battle of Karuna. I distinctly remember seeing that painting for the first time in like my high school biology textbook or something and being so fascinated but also terrified by it. Yeah. Like I couldn't believe it was a real thing. Yeah. Yeah. And soldiers, of course, weren't the only ones that were disproportionately affected by this

pathogen. In the mid-1800s, several doctors in the American South became interested in what they called Trismus Nessensium, which would later be called neonatal tetanus. And they remarked that it was, quote, no uncommon disease among infants born to enslaved people in the South. I want to take a minute to talk about neonatal tetanus in the American South before the Civil War, because I think it's important for several reasons. First, it gives us an opportunity to see how much the established knowledge about a disease is so dependent on who's looking and especially whom they're looking at. Second, neonatal tetanus is, I think, a really clear example of how differently medicine was

practiced, how medical stats were collected, and whom those stats represented between the American North and the Confederate South. And third, I think it highlights the beginning of a shift in medicine overall, from heroic medicine, so-called heroic medicine, to preventative care. I love it. Okay. So, neonatal tetanus, as you described, Aaron, and as our firsthand account, so vividly and horribly described, is when the umbilical stump gets infected with the tetanus pathogen. It's tightly linked to access to sanitation and hygiene practices following delivery, and it is,

like adult tetanus incredibly horrific and deadly. Those are not even adequate adjectives. No. And inhuman calamity. Yeah. Maybe we could borrow that phrase from Eritus. Before the U.S. Civil War, inslavers would frequently employ doctors to monitor the health of enslaved people, not out of the goodness of their hearts, of course, but to protect

their financial interests. These southern doctors began to notice high rates of neonatal tetanus in the infants born to enslaved people. And when I say high rates, I mean very high. Some doctors estimated that up to two-thirds of the deaths among these infants were due to neonatal tetanus. Oh, man. Yeah.

Because of this, neonatal tetanus was labeled by many doctors, especially those in the north, as a disease of the South, or more specifically a disease of enslaved black people. but was it especially so? We don't really have any good way of knowing, considering that statistics weren't widely used at the time, but it almost certainly wasn't. There may have been a few things that contributed to the high rates observed by Southern doctors. For instance, there were some postnatal practices,

such as using cow dung or charcoal to wrap the cut umbilical cord that could have increased exposure, and some of those practices are still used today in various places, and they are associated with higher rates of neonatal tetanus. But it was also probably a matter of visibility. Neonatal tetanus was certainly present in the north, but northern doctors probably didn't see it as much, because unlike the Southern doctors who wrote about neonatal tetanus, northern doctors didn't treat nearly as many people living in conditions that put them at risk for the infection. Mostly, they would work at hospitals.

And so if someone came into the hospital, maybe then they would see them. But they didn't travel as widely into as varied urban and more rural centers the way that Southern doctors could do. People who were living with a lack of access to sanitation, people living in poverty, etc. Northern doctors weren't getting paid to treat these people, unlike Southern doctors. In addition, Southern doctors, especially those that were employed by enslaved. Slavers were much more likely to encounter cases of neonatal tetanus than their northern counterparts

since it was midwives that mostly attended the birthing and postnatal care in the north. And another big difference was that the Southern doctors tended to keep more detailed records of the people they treated. Not because they were inherently more meticulous, but again, because it was more a matter of business and economics. And slavers wanted to know which diseases were contributing to the most death and disability, or in their eyes, lost profit. And this informed, to some degree, which diseases were given priority for study. Neonatal tetanus garnered a substantial amount of interest in the mid-1800s in the southern U.S. because it contributed so highly to infant mortality among babies born to enslaved people. and several doctors started to try to understand why that was.

Dr. Marion Sims, infamous so-called father of modern gynecology, I can't resist like an opportunity to dismarian Sims or at least call him out for being someone who absolutely tortured so many, an untold number of enslaved black women. Yeah, Marian Sims was one of the doctors who tried to say, oh, I know the cause of neonatal tetanus. And he thought it had to do with the formation of the skull. He said, you should put the baby. People were obsessed with skull shape for decades.

Too long. He said, you know, if you put the baby in a crib, you should make sure there are lots of pillows around the baby and position the baby very carefully so that the skull could grow properly. Oh, dear. Uh-huh. Oh, no. And one of his horrifying treatments involved drilling a hole in the baby's skull. No. No.

No. No. Yeah. And there was no evidence, of course, to support his hypotheses. And a couple of other doctors, fortunately, were around to pick apart his arguments. William Baldwin, a physician who graduated med school, Transylvania University in Lexington, Kentucky, at age 19. Wow. Yeah.

I mean, it was the 1850s, 1840s. He wrote that Sims was wrong and that the disease was more common among enslaved people, not because of how they laid an infant in a crib, but because of living conditions and lack of access to sanitation. He didn't agree with Sims' and others' claims that there was a racial disposition to disease, but instead thought it was living in an environment that led to greater exposure, which is pretty like incredible to hear or like more forward thinking than I anticipated considering this was the 1850s. But I feel like that was, you know, malaria, et cetera. Yeah.

People knew of this environmental. Yeah, myasma. Yeah, exactly. Yeah. So I think I think that was definitely part of it. But I also think he might have been ahead of his time with this next quote because he suggested that it was, quote, a great. rain of dust or sand or other particle of foreign substance, however small, may be lodged in the delicate granulations of the ambilicus just after the detachment of the cord.

There you go. So there it's, I mean, that's not, that's not wrong, really. No. No, it's exactly what it is. I found that fascinating. And Baldwin wasn't alone. Another physician named John M. Watson from Tennessee took up the charge and further dismissed Sims in 1859, like kind of harshly and directly, I appreciated it. He too believed that

it was irritation of the wound and suggested that instead of Sims' barbaric skull drilling practice, people should try for simply cleaning the wound, having a more sanitary environment overall, basically practicing preventative medicine, which was not in fashion at the time. Instead, doctors tended to practice heroic medicine, which I talked a bit about in the antibiotics episode. Essentially, it was a way of practicing medicine through intervention only. Your patient came in, sick, and you thought, okay, how can I stop this? You made your patient sweat, purge, bleed, get a fever, be freezing cold, whatever, to shock their body back into balance. Medicine was about activity and treatment rather than prevention. The concept of cleanliness and sanitation as a method of disease

prevention was a fairly new one in some degree. Yes, there was a miasma theory, but in terms of like Semmelweis and Lister, you know, like all of those sanitation, it was starting to come around. But most doctors thought the cleaning a wound, that doesn't make you a doctor, saw a off a gangrenous limb in five seconds, that sure did. But the tide was turning, from heroic medicine to preventative medicine, partially because of germ theory and also partially because of people like Lister and Semmelweis. And also partially because the emerging field of epidemiology allowed people to see wide-scale patterns of disease and how interventions such as handwashing or ventilation affected the spread of disease. But the origin story of epidemiology is more complex

than the classic story of John Snow and his cholera maps. One of my favorite things about this podcast is that we are wrong sometimes and we read more. Like we get to learn new stuff all of the time. Every day. Every day. And that makes us, I think, both look back and go, oh, my goodness. I didn't know that. I said that wrong. I didn't understand the context for this. And part of me is like, oh, I wish I could go back in time. But another part really likes to observe the fact that we are learning and growing. Yeah. And this is one of those instances. Epidemiology didn't come about because of John Snow and his cholera maps. Of course, they played a role. But it's more complicated story than that. So we've talked about how tropical medicine as a field was largely created during the huge period of colonialism in the late 1800s, right, to help the imperialist to, quote, conquer an area. In a similar way, epidemiology developed out of colonialism, out of slavery, out of war, when doctors were incentivized to study and treat populations rather than individuals that they may not have otherwise. these circumstances provided doctors the opportunity to see disease on a scale that they hadn't before, moving through army hospitals, prison camps, ships, etc. You and I learned the story of epidemiology, and we've told the story of epidemiology as one of the early epidemiologists of John Snow and the Broad Street pump. But you and I, as well as the royal we, those. who are also in the field of public health,

we haven't fully or ever acknowledged the people who made up those maps, who are mentioned in those early studies of the spread of the disease simply as cases. And many of these people were disenfranchised. They had no consent or knowledge of their involvement. And this theme, this new exploration of the origins of epidemiology, is the subject of next week's bonus episode, as well as the topic of a new book by Dr. Jim Downs,

who is my expert guest for next week. I cannot wait. I am thrilled to be chatting with Dr. Downs, who is a professor of history at Gettysburg College, about his latest book called Maladies of Empire, how colonialism, slavery, and war transformed medicine. I am super excited, for this conversation, so mark your calendars.

I can't wait. Okay, but for now, let's get back to the history of tetanus. Moving into the second half of the 1800s, tetanus was still very much present, but it would soon meet its match, first in the form of antitoxin and then in the form of a vaccine. In 1884, Carlo and Raton took pus

from the skin lesion of an infected human's face, who later died of tetanus, and injected it into a rabbit, which began showing signs of tetanus, confirming the presence of the pathogen in that lesion. And so, like, the story of the microbiology of tetanus began. Later that same year, a guy named Arthur Nicolier injected soil samples into animals who also developed tetanus symptoms. He isolated a rod-shaped bacillus from these animals and hypothesized that the bacteria produced a toxin resembling strychnine in its action. which we should add to our future topics. It's on our list.

Okay, good. But he didn't isolate the organism in pure culture. That would be done by Shabasa Burro Kitasato in 1889 from a fatal case of a soldier in Berlin. Does his name sound familiar to you? A little bit, yeah. Diphtheria episode. Thieria, makes sense. So Kitasado and Emil von Bering worked closely together on a diphtheria.

anti-toxin. Von Bering got the first Nobel Prize in medicine in 2001 for the work that they did, and Kitasato did not. Anyway, with this pure culture of Clostridium tetanai, Kitasato was able to see that it was indeed a toxin produced by the bacteria that caused some of the symptoms, which spurred him on to look for other toxin-producing bacteria, including the one that causes diphtheria. Kitasato and Von Bering's on producing antitoxin for tetanus and diphtheria is, I mean, essentially that started the field of serum therapy. Wow. And this was great.

Having an antitoxin was revolutionary in a number of ways, but it wasn't perfect, right? You have to administer it early on for it to be effective. And in the case of tetanus, you had to keep the wound clean. Yeah. And both of those things were pretty difficult if you were like a soldier at, you know, high exposure risk. Right. And we have some numbers to back that up to.

Oh, dear. It's not that bad. I mean, it's bad to begin with and then it gets better. Okay. In 1808, so pre-germ theory, pre-Tetness antitoxin, pre-vaccine, the rate of tetanus was 12.5 per 1,000 in soldiers. And the author of this didn't say which soldiers and where. Okay.

But in the first months of World War I, that dropped to eight per 1,000 wounded, still high. Yeah. And then as wound care and antitoxin delivery improved, it dropped further to 1.5 per 1,000. Okay. And by the time the U.S. entered the war, it was down to 0.16 per 1,000. Wow. Okay. Great.

That's pretty cool. Yeah. Interestingly, tidbit here, where you were fighting, like physically, played a role in your tetanus really. risk. Fields that had been fertilized with manure over long periods of time had more tetanus and led to the misconception that horses were the reservoirs for the bacteria. Interesting. But really, it can be carried, like you said, in all kinds of animals and humans like rats, chickens, cows, horses, I'm sure many, many other animals. Yeah. But further declines in tetanus were in the future

and not just for soldiers, but for everyone. The tetanus vaccine was developed in 1924 by Gaston Ramon, and widespread vaccination meant a drastic drop in tetanus wherever the vaccine was available. Soldiers in World War II experienced tetanus at a rate of 0.04 per 1,000. Wow. Yeah, and I think there was, I saw a stat that like no one who was vaccinated got tetanus. Wow. And neonatal tetanus rates also dropped as researchers realized that vaccination during pregnancy offered some protection to the newborn.

That's the most amazing and my favorite thing. Yes, it's so important. It is so important. And these drops in tetanus continued throughout the 20th century and into the 21st. But not, I'm guessing, as much as they should have. So, yeah, this is kind of just like a quick little scoot through the 20th century. on my end, but I'm curious to know, Erin, where we stand today when it comes to tennis. I can't wait to tell you right after this break.

So in the U.S., we'll start here, from 2009 to 2017, only 264 cases and 19 deaths were reported from Tetan. Wow. I know. That's pretty major. Yeah. Across the globe, while the decrease in cases overall is still very impressive, unsurprisingly, we still do have a ways to go. The World Health Organization estimated in 2018, which is the latest data that they have as of today, that in 2018, 25,000 newborns died from neonatal tetanus. 25,000 worldwide.

What? And as depressing as that number is, that is an 88% reduction from cases in the year 2000 and a 96% reduction from cases in the 1980s. Oh, my goodness. I know. I had no idea just how widespread tetanus was, even as recently as the 1990s. No? For example, a paper from 2001 estimated 800,000 to 1 million deaths worldwide from tetanus every year,

including over half a million from neonatal tetanus. That's 2001 paper estimated. And another paper from 2007. which was talking about data from the 90s, estimated that up to 5% of maternal mortality was due to tetanus and 14% of neonatal mortality was due to tetanus. The scale of this disease, I had no idea. I cannot, I mean, I can't even formulate a sentence.

I know. I feel very much the same. So we have come an incredibly long way. The World Health Organization, who tracks data on vaccinations as well as cases, estimated that worldwide in 2019, 86% of children were covered by DTP3, which is the three doses of vaccine in the first year of life. Okay. So 86% of children. And I want to take a minute to emphasize here just how preventable this disease really is. Vaccination generally starts at two months old, and it's a series of three shots initially and then a booster around kindergarten,

and then boosters every 10 years or so to maintain immunity. But like you mentioned, Aaron, vaccination during pregnancy also confers protection against neonatal tetanus, And it's been estimated vaccination during pregnancy to reduce mortality from neonatal tetanist by 94%. That's incredible. It's amazing. So we have the capacity to protect people from this disease. But a really important thing is that this is a continual struggle, or at least it's a continual process. because this is not a human-specific disease that, for example, like smallpox, if you can

interrupt the chain of transmission between humans for long enough, you can eliminate the disease. You can't do that with this because it's environmental pathogen that has always, like you said, Aaron, and likely always will be in our environment. So it is a process of continual protection through these incredibly efficacious, incredibly safe vaccines. And as we have seen, for example, in the COVID pandemic, things that drastically alter the global landscape pose really big challenges to vaccination. So you know how I said in 2019, 86% of children were covered by DPT3? Well, in 2020, that number had gone down to 83%. So an estimated 23 million children under the age of one did not receive their basic vaccination.

vaccines in 2020, and the number of completely unvaccinated children globally increased by nearly 3.4 million in that year alone. So we're not done yet. No. We're never done. We're never. But I want to end this episode on some really high notes and also just like keep bragging about the tetanus vaccine. It's fantastic. Yeah. And really the tetanus toxoid. So the, the tetanus vaccine is a toxoid vaccine. A toxoid is just an inactivated toxin, right? And the toxin is a protein. So it's easy. It's cheap to produce. And this tetanist toxoid that is easy to produce, that is cheap, that is very immunogenic to our immune system, is used to make a whole bunch of other vaccines, like our pneumococcal vaccine, our meningococcal vaccine, HIV, all of these vaccines are made by

conjugating or combining things like sugars, polysaccharides, to the tetanistoxoid protein to induce a better protective immunity against these other diseases as well. That is just so cool. Isn't it beautiful? And on top of that, the other reason that tetanistoxoid makes for such a good vaccine is that it's really shelf-stable. It doesn't have to be frozen or frozen. refrigerated. It's stable at room temperature for months. So it's really transportable even to

remote areas that don't have access to refrigeration. That's fantastic. There's more, Erin. Literally not 10 minutes before we were going to record. I was eating dinner and I was Googling because I remember a very long time ago, you were like, hey, did you see this news article about something that we were going to record. And never had it crossed my mind to Google, like, news articles about whatever we were talking about. And ever since then, and that was a long time ago, now I always, like the last thing that I do before I wrap up my research is I Google, like Tetanus, and I press the news button on Google. Oh, I love it. So I did that while I was eating dinner right before we recorded.

And lo and behold, this paper was published, one. week ago, a group out of Albert Einstein College of Medicine published a study in science translational medicine that used a combination of listeria monocytogenes, which is a bacteria that will cover eventually. We haven't, right? No. Okay. So a combination of this bacteria and tetanus toxoid to treat pancreatic cancer.

Incredible. I know. Essentially, briefly, they injected mice that had pancreatic cancer that had also been vaccinated for tetanus, like before they got cancer, with a listeria that had been engineered to have the tetanus toxoid protein. And for whatever fascinating reason has to do with listeria, it preferentially congregates in these cancer. cells, I think because the immune system wipes it out in other places. And then the mouse's immune system has a bunch of antibodies that recognize the tetanus toxoid because they were vaccinated. And so, boom, they end up attacking the cancer that has these bacteria that have this toxoid protein. What? That's amazing. And also, first of all, that's fantastic news for pancreatic cancer. I know. But secondly, I feel like that could be a model for many other types of cancer treatment. Exactly. Yeah. Oh, so cool. I know. These mice had their pancreatic tumors decrease in size by 80% and metastases decreased by 87%. And they lived 40% longer than untreated mice. It's in mice. But like, this is a big deal. It's a big deal. So that's a high note to end on and I will absolutely link that paper.

Cool. Yeah. So tetanus is a horrible disease, but we have a vaccine, and it is awesome. I love that. Yeah. Yeah. Sources? Sources?

I have a large number of sources for this episode. I'm going to shout out three right now and put the rest on our website. One is called No Uncommon Disease by Sally McMillan. Another is called an essay on the history of Lockjaw by William Shalian. And the last one I'll shout out is called the population structure of Clostridium tetanide deduced from its pan genome. And that is by Chapeton Montes et all from 2019. I had just a few papers for this episode. I really enjoyed actually a 1994 paper called The Mechanism of Action of Tetanus and Botulinum Neurotoxins.

It was pretty thorough. And then a 2019 botulinum and tetanus neurotoxins kind of an update. A few other papers on the epidemiology as well as links to the World Health Organization and the CDC surveillance. And then that awesome paper that just came out in March of 2022 was titled Listeria delivers tetanus toxoid protein to pink. tumors and induces cancer cell death in mice. So it really tells you the whole study. And we'll post the list of these sources and every source from every one of our episodes on our website. This podcast will kill you.com. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to the exactly right network.

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