This Podcast Will Kill You - Ep 153 Alpha-Gal Syndrome: A tick bite gone bad

Episode Date: October 1, 2024

One day, you’re enjoying a beautiful hike through the tall grass. A few months later, you find yourself in anaphylaxis from a post-hike hamburger. The culprit: a tick bite. In this much-requested episode, we take on alpha-gal syndrome, the red meat allergy triggered by the bite of a tick. Sometimes science is stranger than fiction. How exactly does an encounter with a tiny arachnid cause your throat to swell up and your skin break out into hives hours after eating red meat? Is it all red meat? Is it all ticks? How on earth did anyone even make this connection in the first place? Those are just a few of the questions we answer in this action-packed episode that has us venturing into surprising topics, like primate evolution, ancient epidemics, and cancer treatments. Tune in for all this and more.Support this podcast by shopping our latest sponsor deals and promotions at this link: https://bit.ly/3WwtIAu See omnystudio.com/listener for privacy information.

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Get 50% off your first two orders plus free shipping with code this podcast 50. Terms and Conditions Apply. Visit blueapron.com slash terms for more information. I'm Clayton Eckerd. In 2022, I was the lead of ABC's The Bachelor. But here's the thing. Bachelor fans hated him. If I could press a button and rewind it all I would.

That's when his life took a disturbing turn. A one-night stand would end in a courtroom. The media is here. this case has gone viral. The dating contract. Agree to date me, but I'm also suing you. This is unlike anything I've ever seen before. I'm Stephanie Young.

Listen to Love Trapped on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. I'm Amanda Knox, and in the new podcast, Doubt, the case of Lucy Letby, we unpack the story of an unimaginable tragedy that gripped the UK in 2023. But what if we didn't get the whole story? 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 Letby on the IHeartRadio app, Apple Podcasts, or wherever you get your podcasts.

Hi, my name is Winnie, and I'm an ecologist. In the summer of 2018, my husband and I moved to Northeast Missouri for his job. In early August, we decided to go for a hike at a nearby conservation area. We had about a mile left in the hike when we heard rustling in the brush beneath some big oak trees. It turned out to be a red-tailed hawk with a broken wing. In order to bring the bird to the nearest wildlife veterinarian located in Columbia, Missouri, we needed to get the bird to our car. So my husband gave me his overshirt.

While he distracted the hawk, I tossed it. the shirt over the bird's head to calm it down, and we safely carried the bird back to our car. It was like a 90-minute drive to Missou Veterinary Hospital, and before long, we noticed that our feet and our ankles were really itchy. About halfway to Columbia, we had to stop for gas, so that's when I pulled down my sock, and I saw what looked like thousands of tiny grains of sand moving across my ankles. At the time, I was convinced that these were chiggers. With very few options for how to remove them, we continued on our mission to get the hawk to the veterinary hospital. The staff stabilized and treated the animal, and we drove back home.

After that day in 2018, my husband and I avoided areas that were chigger prone, particularly between April and September when they're the worst. We also used repellent sprays, and we treated our clothes. and shoes with permethrin to deter sugars. It's worth noting that we had also been warned about lone star ticks. These are really common in Missouri, and they're common even in urban and suburban areas, and they're also really aggressive feeders. So we were really careful not to get any ticks, and it turns out that sugar treatment and

tick treatment for clothes and repellents, they're the same thing. One evening in October of 2022, we made a meal with hamburger. It was noteworthy because we didn't eat much meat, and it was a special treat for us. Later that night, I woke up violently ill, and I was certain that I had gotten food poisoning. At some point, while I was dry heating into a bucket, I realized that my ankles and my palms were insanely itchy and covered in hives. The hives quickly spread to my torso, legs, arms, and scalp. I was struggling to breathe, and I remember feeling that numb feeling in my entire body. You know the feeling when you get Novacane at the dentist?

It was like that, but everywhere. I wasn't thinking entirely clearly, but I do remember taking two Benadryl, waiting about five minutes, panicking, and then taking two more Benadryl. While I waited for the hives to go away, I remember trying to figure out how and why food poisoning could cause hives. The next day, I arranged to see an allergist. He sent off a bunch of blood tests, and one of them came back positive. It was for AlphaGal. As an ecologist, I knew about AlphaGal. I had friends with AlphaGal. I have coworkers with AlphaGal. It's something that we're aware of in the ecology world, at least in Missouri. But I do remember being really angry. I was angry because my husband and I had been so careful not to get any ticks or chiggers since that first incident in 28.

But then I remembered. I remembered those chiggers. And in hindsight, they had to have been seed ticks or tick larvae. We probably had walked into a bed of these seed ticks and we were probably bitten by hundreds of them. Also, it wasn't until the doctor told me the results of those tests that I realized a lot of the last four years really just sort of fell into place. You see, sometimes I had noticed that my ankles and my arms would get really itchy for no apparent. reason. In hindsight, it was usually after I had like jello or soup that was made with beef broth. Fast forward to the present. In 2023, we moved to Minnesota. As an ecologist, I like to keep an eye out for all sorts of different organisms. And I note how their ranges are changing. Just last month, I found a lone star tick on my dog. Neither she nor I have been to Missouri for over a year.

So those little ticks, those little lone star ticks, they are more. moving their way north. Winnie, thank you so much for sharing your story with us. We really appreciate it. And like, my gosh, what a strange thing this is. I know. Thank you so much for being willing to go through all of that with us and with all of our listeners. We really appreciate it. Yeah. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. And today we're getting real weird. Really weird. Really weird. because we're talking about alpha-gal syndrome, aka red meat allergy. As given to you by the bite of a tick.

By the bite of a tick. It's so weird, Aaron. Yep. It is very bizarre. It feels like something out of a sci-fi novel that's like, you know, near future. And the world is about to collapse because climate change and farming and whatever. And so then a rogue science. introduces this thing into ticks that causes everyone to be vegetarian. Yeah, you get the,

you get the drift. I liked it a lot. I would watch that movie, honestly. I would, yeah, I would absolutely watch that movie and probably fall asleep halfway, but that's my, that's my jam. Yeah, it's, I'm really excited for it. It's going to be a really fun episode. Yeah, I have so many, it's so weird. It's so weird. Yeah. And we'll get, we'll get into all of that weirdness. We will. business later on. But first, we've got some other business to take care of. We do. It's quarantine time as always. It is. What are we drinking this week? We're drinking gal pal. You know, just your little gal pal. Just a little gal pal. You're out of gal pal. It's a delicious beverage. Of course, it is made with none other than beef eater gin. Yeah. Not sponsored. Not sponsored, but we can't,

We can't pass up that name, that branding. As well as passion fruit and lemon lime soda. It's a really refreshing gin Bev. Yeah. Galpal is great. Yeah. And check it out because we'll be posting the recipe for Galpal, the quarantini, as well as Galpal, the placebo rita on our website, this podcast will kill you.

com and all over our social media channels. So if you're not following us there, you really should be because we're coming out with some pretty stellar content, if we do say so ourselves. And we do. We do say so ourselves pretty much every week. We do. If you check out our website, you will also find a lot of other really great content that we tell you about every single week, including transcripts from all of our episodes,

which I believe you can now find as well on Apple Podcasts. Speaking of Apple Podcasts, are you subscribed? Because you should be to make sure that you're helping support the show. It really helps us to double check that you are. and haven't accidentally been unsubscribed, which happened to me, in fact, from our own podcast. And anyways, back to our website. You can find transcripts. You can find merch. We have a whole bunch of merch. We have new merch and we have a few items left from some of our old merch. So if you wanted to get your hands on things that you thought we were out of, double check because we might

just have it there. Limited stock. Uh-huh. We've also got links to to Bloodmobile, who does the music for all of our episodes. We've got a goodreads list. We've got a bookshop.org affiliate account. We have the sources from all of our episodes. Oh, my goodness. This podcast will kill you.com. Check it out. I don't think we have any other business, do we. No. Okay. Well, then let's get started because I feel like we have a lot of ground to cover when it comes to this bizarre thing called Alpha-Gal Syndrome. We do. We do. Let's get into it right after this break. Dinner shows up every night, whether you're prepared for it or not.

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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. at O'Keefscompan.com slash this podcast and code this podcast at checkout. In 2023, a story gripped the UK, evoking horror and disbelief. The nurse who should have been in charge of caring for tiny babies is now the most prolific child killer in modern British history. Everyone thought they knew how it ended. A verdict,

a villain, a nurse named Lucy Leppie. Lucy Letby has been found guilty. But what if we didn't get the whole story. The moment you look at the whole picture, the case collapses. I'm Amanda Knox, and in the new podcast, Doubt the case of Lucy Letby, we follow the evidence and hear from the people that lived in, to ask what really happened when the world decided who Lucy Lettby was. No voicing of any skepticism or doubt. It'll cause so much harm at every single level of the British establishment of this is wrong. Listen to Doubt, the case of Lucy Lettby, on the I Radio app, Apple Podcasts, or wherever you get your podcasts. Alpha Gal Syndrome is, at its core, a food allergy.

And allergies are a hypersensitivity response to a very specific thing. Most allergies usually are a hypersensitive response to a protein. So that right there is the first of so many places where the story of alpha-gal syndrome is so much weirder than just a food allergy. Because in this case, it's an allergy to a specific sugar, alpha-gal. And alpha-gal, of course, has a much more complicated chemical name. It's galactose alpha-13 galactose. It's really hard to search for because I didn't want to have to put in the little alpha sign every time I searched. Actually, I never thought about if you just type alpha, does Google also recognize alpha as the word alpha, you know?

Probably. I don't know. I don't know enough about SEO or whatever. Anyways. Oh, gosh, no. In any case, Galactos Alpha-13 Galactos, Alpha-Gal. So this is a short sugar. It's a ligosaccharide.

It's just a couple of sugar molecules linked together in a specific way. And Alpha-Gal syndrome is when people develop an allergy to this particular. sugar. And like we already mentioned, this food allergy is also different than most food allergies because it develops after an initial exposure, not to a food, but to a tick. So I figured to understand the story of alpha-gal, to understand this weird food allergy, we first have to kind of take a step back and understand allergies more generally, like how do allergies, food allergies, usually work. So an allergy at its core, like I said, is a hypersensitivity reaction, which basically means it's your body overdoing it in response to some kind of exposure, and that exposure is

usually a protein. So in the case of food allergies, it's proteins that we eat. And adverse reactions to foods can come in a lot of different types and flavors. We already covered this season, celiac disease, which is an adverse food reaction to specific proteins in gluten. Some types of adverse reactions are classified as allergies, and these are usually what are called IGE-mediated allergies. And IGE-mediated allergies are the types of allergies that you probably think of if you think of a food allergy. You probably think of, most classically, peanuts. So someone who's allergic to peanuts. Peanuts might develop hives and then throat swelling and then anaphylaxis, difficulty breathing,

after exposure to peanuts. At its core, what's happening here is that our body is mistaking a food protein, like a peanut protein, for a pathogen, and then mounting an immune response to this perceived threat. But it's doing that in a weird way by making these antibodies called IgE antibodies. to understand allergies, we then also have to understand what the heck is an IgE antibody. Can I ask a question real quick? Please. Why proteins?

Ooh, good question. I don't have an exact answer to that, except that proteins tend to be more immunogenic. Okay. So it's similar with, like, vaccines. Yeah. A lot of times if we try and develop a vaccine against genes, just carbohydrates or sugars that we could also target on the outside of a pathogen, that doesn't tend to last as long. So we usually then link it to a protein, like, for example, tetanistoxoid.

Yeah. And then we'll link carbohydrates to that protein to generate a better immune response. But I don't know why proteins tend to be more immunogenic. Yeah. It's a good question. It's interesting. Okay. Yeah. And so I feel like maybe this is jumping ahead. But you said that when you are exposed to something that triggers this IGE response, the IGE response is because your body is thinking that this is a pathogen. But this response is kind of out of control and really bad. Yeah. And can be much worse for you than a pathogen than a potential pathogen could be. Totally.

Yeah. So I don't know what my question. question is there? Why would that happen? Why would that be an evolved response? Yeah. This is a great question. Like, why did allergies evolve is a bigger question than I can. Maybe that'll be something that we address in the R2-parter. A hundred percent. But what part of your question is getting at is like why IGE, like, why is this response so weird? So let's talk about what IGE is and why the response with IGE antibodies can be so. severe. So antibodies, I feel like we've talked a lot about on this podcast in various time points,

but antibodies are one of our immune systems ways of having a very specific response. So antibodies are the things that we make, say, for example, when we get a vaccine, to then be able to specifically target and fight off one particular, say, virus or something, right? Our antibodies can very precisely identify one particular protein, for example. or carbohydrate sugar on a particular virus. And then when we're exposed to that, again, our antibodies bind to those antigens that they can identify and they act like a flag. They alert our immune system. Hey, come over here. I found something that shouldn't be here, right? And then we do our immune response thing. Most of the time when we talk about antibodies,

or at least on this podcast when we have, we haven't mentioned the different types. But in vaccines and those kinds of antibody responses, our body is usually making IGM and IGG antibodies. There's other ones that are like in the context of our guts and our mucosal membranes called IGA. And then there's IGE antibodies. And these are created in the same basic way as all of our other antibodies in response to one particular protein. They're very, very specific. and it's our B cells, the same cells, that are making these antibodies. It's thought that evolutionarily this antibody response, IGE, evolved mostly to respond to parasites and protozoan pathogens and maybe even venoms like snake venom.

And what IGE does is it doesn't just serve as a flag the way that something like IgG does. IgE is an antibody that hangs out attached to some of our other immune cells, like called masked cells and our basophils. That part's less important. But basically, IGE is attached. It's not free floating. It's attached to these other white blood cells. And when they find the antigen that they're targeted for, they grab onto it.

And what that does is it triggers these cells that they're attached to to kind of almost burst open and spew forth a ton of highly reactive, super inflammatory stuff. Really quick, all of a sudden. It's like a boom, immune response. Rather than like a flag, hey guys, everyone come over and then that response takes some time. Right. It's kind of like scorched earth policy. Exactly. Yes. It's like something's here. Blah! Just destroy it all. A little reactive maybe, like, let's take a moment. Let's breathe. Let's just see, do we need to do this? Are there less extreme responses that we can come up with? No, apparently not. IGE is like my toddler last night when I told me needed to come out of the bath.

It's like, 100%. So in a food allergy, like a peanut allergy, our body is inappropriately recognizing a peanut protein. and then it's mounting weirdly this IGE response to it. That process is called sensitization. That has to happen first. You have to be exposed to something. Your body does kind of a weird thing by deciding that it's going to make IGE antibodies against that protein.

And our immune system doesn't ever forget things. So it holds on to those IGE antibodies, just waiting in the wings. And then the next time that we eat a peanut, those antibodies are already there, and they're like, we found the invader! And they do their scorched earth thing. They bind to that peanut protein. All of those mass cells expel tons of inflammatory material, and then you have the symptoms of that allergic reaction.

And that is what we see in alpha-gal syndrome, except for a few pretty important details. So again, alpha-gal, it's a sugar, a carbohydrate, and already that's a little. bit weird. We're mounting a massive immune response to an oligocaccharide. Why is this particular sugar so immunogenic? Well, it turns out that this particular sugar is found pretty universally attached to proteins and lipids on cell membranes of, it seems like most all, many, many different types of cells throughout the body of pretty much every mammal except for humans and apes and old world monkeys. Oh yeah, we'll get into it. I know. I cannot wait. I know, Erin, that you're going to get into a lot more detail about Alpha-Gal and the antibodies that we make against Alpha-Gal

from an evolutionary context. But just for some context on Al-Fa-Gal. So we do not make this sugar in our bodies. we happen to make from infancy antibodies against this particular alpha-gal sugar. The same way that people who, like me, our blood group O, make antibodies against the A and B sugars that make blood groups A, B, and O that are attached to our red blood cells. So the antibodies that we make and have circulating around us are IgG antibodies. I like to think of them as like normal ones, even though they're all normal. That's a terrible descriptor. But you know what I mean?

They're just like free floating. They're not doing much. Right. We can eat all the bacon that we want, and it doesn't trigger any kind of immune response, even though we have these IgG antibodies floating around. Now, we cannot take a pig heart and transplant it into a human body. It so happens that this particular sugar is one of the major barriers to transplantation of animal organs into humans.

But we can eat bacon, be exposed to it through our guts, and do just fine. Unless we can't. Enter the tick. Oh, gosh. Yep. It's so weird. It's so weird. So when I talked about how food allergies work, the first step that I went through was

sensitization, right? There has to be a period of sensitization where our body sees. these antigens and goes, ooh, something's weird here, I'm going to make antibodies against it. And in alpha-gal syndrome, that sensitization to alpha-gal, it doesn't happen from food. It happens from a tick bite. Ticks, of course, are our little six-to-eight-legged, depending on life stages, blood-feeding friends. These are obligate blood feeders throughout their whole life cycle, and they have to be.

to stay attached for a pretty long time, like hours to days in order to get a full blood meal. And while they do this, just like our friend The Leach, they spit a whole bunch of their saliva into our bodies to help with things like anticoagulation and anesthetizing us so that we don't notice them and we're not bothered by them. It can hang out for a long time. Tick saliva is kind of a magical substance. Same way Leach saliva is, right? Exactly. And I feel like tick saliva, I know people are working on it, but I do feel like there are some amazing opportunities in tick spit. I agree. I was reading about like the sialome, they call it, the saliva microbiome. So cool.

I love it. I love when there's a new word for microbiome for a different part of a different area. A different area. So what happens in alpha-gal syndrome is that during blood feeding, some species of tick, some species of tick, somehow some way, introduce alpha-gal into our bodies directly into our bloodstream or our lymphatics while they're blood-feeding. And for some people, this triggers that sensitization, the development of those IgE antibodies against that specific sugar alpha-gal. That is how sensitization happens. Often, but not always, when people develop alpha-gal, they report. like one specific tick bite that they had a more severe local reaction to. So they'll get like a

large red welt that's super itchy and this reaction will last like a lot longer or be a lot more extreme than other tick bites that they might have had in the past. And then what happens is that on re-exposure to alpha-gal, like the next time that somebody eats bacon, because alpha-gal is all over any meat products that you're eating, now their body has all of this IG. waiting and it goes, whoa, whoa, whoa, this is that highly virulent pathogen I have to respond to. It binds to it. Those mast cells degranulate. They release all of their super inflammatory stuff and you get this massive immune response, aka allergy. That's how Alphagal works. Well, Aaron, I have a few questions here. Well, Aaron, I thought that you might.

Okay. We know that this is multiple tick species all over the world. All over the world. All over the world. It's happening. And so it's clearly not related to certain tick species or like tick phylogeny. Yeah. It was surprising to me how many different genera of ticks, like totally unrelated species of ticks across the whole globe, can end up causing this. Right. Which suggests like can any tick be a culprit? in this can can any tick induce this allergy so where is like what is the trigger from the tick yeah that's a great question it's the trigger is alpha gal yeah question is where is this alpha gal right is it coming from a previous blood meal does that mean but i also couldn't find i did a little bit of digging and i couldn't find any relationship between life stage of the tick that bit someone and because you would

think okay now i'm just getting nitty gritty but Let me. When ticks are first born or when ticks first hatch from their little eggs, they haven't eaten. They haven't taken any blood meals. And so those larvae, if they bite you and they do bite you, like the seed ticks, will that still induce alpha-gal response? It can. Exactly. So like what the heck is going on? Right. So that's the question is what the heck is going on? Where is this alpha-gal coming from? For a long time, we really didn't know. Like you said, was it coming from a previous blood meal that like just was still there? And so the, that's the, tick spit a little bit into us? Was it something that's in the tick? It seems like it is coming from the ticks themselves. There was a paper. The call is coming from inside the house. It doesn't really work in this context, but.

We try, though. We try. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands. Hand's hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands

creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way. Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for decades by people who wash their hands constantly 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'Keef's company.com slash this podcast and code this podcast at checkout.

In 2023, a story gripped the UK, evoking horror and disbelief. The nurse who should have been in charge of caring for tiny babies is now the most prolific child killer in modern British history. Everyone thought they knew how it ended. A verdict? A villain. A nurse named Lucy Leppie. Lucy Lepe has been found guilty. But what if we didn't get the whole story? The moment you look at the whole picture, the case collapses. I'm Amanda Knox.

And in the new podcast, Doubt, the case of Lucy Letby, we follow the evidence and hear from the people that lived it. To ask what really happened when the world decided who Lucy Lettby was. No voicing of any skepticism or doubt. It'll cause so much harm at every single level of the British establishment of this is wrong. Listen to Doubt, the case of Lucy Letby on the Iheart Radio app, Apple Podcasts, or wherever you get your podcasts. I'm Clayton Eckerd, and in 2022, I was the lead of ABC's The Bachelor.

Unfortunately, it didn't go according to plan. He became the first Bachelor to ever have his final rose rejected. The internet turned on him. If I could press a button and rewind it all I would. But what happened to Clayton after the show made even bigger headlines. It began as a one-night stand and ended in a courtroom, with Clayton at the center of a very strange paternity scandal. The media is here. This case has gone viral. The dating contract. Agree to date me, but I'm also suing you. Please search for it. This is unlike anything I've ever seen

before. I'm Stephanie Young. This is Love Trapped. This season, an epic battle of he said she said, and the search for accountability in a sea of lies. Listen to Love Trapped on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. There was a paper from 2019 in Frontiers and Immunology that found evidence of alpha-gal in ticks, even ticks that had not fed on other mammals, like ticks that were fed on human blood. And they weren't able to find alpha-gal in unfed ticks. So it was only after at least partial blood feeding that they were able to find alpha-gal that was reactive to these anti-alphalgal antibodies. And they found this in multiple different tick species, including the one that most commonly

causes alpha-gal syndrome in the U.S. Amblyoma Americatum. Now, what's really weird is that we still don't know how the tick is making this alpha-gal, because ticks don't have the enzyme, just like humans don't have the enzyme that other mammals use to make alpha-gal. Ticks don't have that enzyme. So what that means is that there has to be either some other chemical, pathway that they're using to make alpha-gal? Or is it one of their microbes? Is it something in the tick microbiome, like say a commensal or another pathogen, like a rickettsia or something,

that is making alpha-gal inside the tick, and then it gets into the salivary glands, and then the tick is spitting it into us? That level, we don't know. So, like, we know it's coming from the tick. We know it's coming from tick saliva, but we don't know how the ticks are making it. And why? Like, why are ticks making this weird sugar? Like, what? Why, why does anyone make this weird sugar? Because, so I spent a lot of time. I was hoping you would answer that question, Aaron. Well, no, I mean, the question that I, that I am trying to answer is why don't we make it? But instead, I never really considered, why would we? Why would we? Yeah. Why do we? I don't know. So it's very, very weird. And like we mentioned, there's a lot of different tick species.

that can cause this. In the U.S., Amblyoma Americanum is the most common in Australia. It's exodes holocyclists, also called the paralysis tick. We have to do tick paralysis in a future episode. Yeah, we do. We do. But also things like exodes, ricinous, uh, rificephalus Bursa, hyaloma species, like so many different species across again, the entire globe, North America, South America, Australia, Europe, Africa, everywhere. Yeah, like, see, and and you shall find red meat allergy from tick bites. Yep. Including in some species, like exoduscapularis, people have found alpha-gal in the saliva,

but we have yet so far to see alpha-gal syndrome develop in people after exoduscapularis bites, as far as we know. Asterisk, who knows what will happen? But what does actually alpha-gal syndrome look like? We haven't even talked about what the symptoms are. Aside from being like, allergy. And it turns out that this also gets. a little bit weirder than just your typical, quote-unquote, food allergy. Of course. Of course.

So the symptoms of alpha-gast syndrome can, of course, vary. But they often start with GI symptoms that might include things like abdominal pain, nausea, or vomiting. They can also include skin symptoms, like hives or what are called urticaria. And hives, if anyone has never had them or never seen them. They're a very classic allergy association. They're these like red, irregularly shaped, slightly raised, kind of puffy-looking welts that you can get kind of anywhere across your whole body. They can be big. They can be little. There can be a combination of different sizes. And they're usually super, super itchy hives are. And then you can also get angioedema, which means swelling edema, swelling of the face, especially the lips and the mouth. And then the most

severe reaction is anaphylaxis. And we think of anaphylaxis as that not being able to breathe, right? Airway constriction because of swelling and edema. But anaphylaxis is actually a widespread widespread widespread respiratory response. It's not local to just the respiratory system. So what's happening in anaphylaxis is widespread vasodilation of blood vessels and then constriction of your respiratory system of like your bronchials. And that can lead to hypotension, so low blood pressure and eventually shock and death. Anaphylaxis is very, very scary and a serious emergency. And a pretty high proportion, something like 60% or some studies cite even more people,

report very severe reactions, including anaphylaxis with alpha-gal syndrome. And so this, those suite of symptoms there are, found in other food allergies, in alpha-gal is just delayed. Yeah, that's the other weird thing that sets alpha-gal apart from most other food allergies, is that these symptoms usually develop hours, three to six hours after exposure to the allergen in question, which is mammal meat, usually. Not minutes, and most other food allergies happen after a matter of minutes and peak even in like 10 to 20 minutes after exposure.

So I knew you were going to ask. I asked, why the heck is there this delay? Yeah. Unsurprisingly, we don't entirely know. But it's thought that it's not necessarily something like weird about alpha-gal or this allergy in specific, but it's just a delay in the circulation of this antigen. So the sugar itself, alpha-gal, it's not just like a free-floating sugar. It's not like a carbohydrate that's like, you know, what makes up your breads or something.

These are sugars that are attached to proteins and lipids. They're glycoproteins and glycolipids. And so they enter the system. They enter your body a little bit more slowly. But we can see really quick onset reactions in someone with alpha-gal syndrome if they're exposed to alpha-gal via the bloodstream. And this we saw in the case of cytuximab, which is an antibody, a monoclonal antibody. I think you'll probably talk about it, Aaron, that happens. to have some alpha-gal on it or in it in that medication.

And people who were exposed to that, who they didn't know that they had alpha-gal, but they did, their response was much more rapid on the order of minutes and peaked within 20 minutes, which is more like what we'd expect with other food allergies. Okay. It's so weird, Erin. So I want to like just like reframe it again as like, okay, so what are we actually talking about? What is alpha-gal syndrome overall? alpha-gal syndrome is just like a food allergy, except that it's a tick bite and not a food that

causes that initial sensitization. It's a sugar and not a protein that you're reacting to. It's a delayed, like three to six hours later allergic response rather than an immediate one. And it often can develop later in life, but it can develop at any point. in life. And most food allergies develop during childhood after just a few exposures rather than like a lifetime of being able to tolerate it and now all of a sudden you can't. Oh, and just so that I don't forget, re-exposure to ticks, like getting more tick bites after you've already developed alpha-gal syndrome seems to heighten the sensitivity even more so that people have renewed worse reactions or are like never able to tolerate meat again. Whereas if people,

can not get any tick bites for a number of years, they might be then eventually able to tolerate meat again at some point in the future. Right. Okay. Okay, I have a few questions. Great. Give them to me. Are there other carbohydrates that trigger food allergies in people? It's a great question. I tried to find some more like specific details on this. Not really that I can see. There certainly can be carbohydrates that you have adverse reactions to, but an IGE mediated allergy response like this, no, this is pretty unique. Okay. And then another question is if every tick has the potential, more or less, I know some more than others, has the potential to cause alpha-gal syndrome, does every person then have the capacity to develop alpha-gal syndrome? I love your question,

Darren. Such a good one. No idea. We have no idea what it is. is about one person versus another that predicts why someone would develop alpha-gal syndrome after exposure to a tick and another person wouldn't. Like same tick could bite two people. One could develop it and one could not. Why? We don't know. And what's really weird too is that a lot of times like with allergies, food allergies and respiratory allergies, we often see this kind of like triad. It's called an atopic triad where you have like allergies, asthma, eczema. These are all kind of things that share similar immunologic pathways. And so you might expect that someone with one food allergy is more predisposed to have other food allergies because, again, it's this like

hypersensitivity response. But a lot of times people with alpha-gal syndrome don't have any other allergies. They don't have any other food allergies. They don't have any other respiratory allergies. So it's like we really don't know right now. Like why? Why? Yeah. Right. Who? We don't know. Oh, it's just, it's so weird. Like, what? Is it just that it's this, the alpha gal is coming into your body in a weird way? Like through a tick bite? It's a weird way for sure. But like, is every amblyoma, Americanaum tick bite doing that? Probably, maybe. We think it's probably a threshold thing. Like maybe everyone develops some degree of these IgE antibodies, but not everyone is going to then have alpha gal syndrome, like respond in this severe way to, you know, to, you know, exposure to alpha-gal in their meat. Because there is also degrees, right? Alpha-gal is a sugar on so many mammalian products, not just meat. It's also found in dairy at lower levels, but most people don't have reactions to dairy, and some people do. It's also found in things like gelatin, which means that it's in a lot of pharmaceuticals. And so for some people, there's a really wide

range of stuff that they now can't tolerate. And for other people, they can tolerate all of those things just fine. And it's really only like bacon or like pork product or like red meat, like beef. And so it's a really like wide variation. And so there's probably a lot that's like thresholds. Like how much IGE do you have? How much did you make? How recent was it? You know, all of that kind of stuff. I remember talking with someone who had alpha-gal syndrome and they could eat cured meats, but not like a hamburger. Interesting. Yeah. And is that just volume? Like when you eat a hamburger, do you just eat a lot more of it than you do with a cured meat? I don't know. Or somehow the carbohydrate more degraded in cured meat. It's like I... Exactly. Right. I do. I don't know. I don't know either. There's a lot. It's so, it's so, so, so interesting. So... Oh, yeah. Aaron, tell me. Everything. Like, I know you're going to talk about this sugar. Like, where did it come from? Why did it come from? Why do some mammals make it?

Why do we not make it anymore? How did this come to be? And then also like, how did we figure this out? Because, yeah. You know what I did not realize is how recently we figured it out? Because I feel like when we were in Panama, it was the thing. Everyone had it. Everyone had it.

Yeah. Yeah. But it was like very new at the time. Yeah. Yeah. Yeah. Let's get into some of these questions. Okay.

Take a quick break and then we'll begin. Aaron, like you mentioned, we learned about this, I think, pretty recently. Yeah. The first time that I learned about the fact that you could become allergic to red meat following a tick bite, I was so confused. Like, I had no idea. I think it was 2013, and I had just started fieldwork in Panama for my PhD research on ticks and climate change.

And for all of you listeners out there right now, I'm wearing my Smithsonian t-shirt that has little larval tics all over. it. I love it so much. Actually, they have eight legs, so they must not be larvae, even though they look like larvae. No, I think they're They're big. They're big, but they look, I don't know. Some look like there's an adult. I think it's nymphs. Also, okay, anyway, we don't need to get into it. She's wearing a tick shirt, guys. She dressed for the occasion. It's one of my favorite shirts. But yeah, so in 2013, a professor who was also in Panama reached out to me and was like, oh, I heard you're working on ticks. Have you heard of a red meat out? following a tick bite. I have it. A few other researchers who have spent a lot of time doing field work in this area also have it. And it could be a cool project. And I didn't end up pursuing it as a

project because probably I was scared of like the immunology aspect of it. But over the, I probably should have. But over the next few years that I worked there, every field season, people would come up to me and say, oh, I just got diagnosed with this red meat allergy. I ate a hamburger and nearly died. Yep. Or hey, I think my allergy is getting better. I can eat salami now. Like there are so many people, Aaron. It definitely seems like Central Panama is a hotspot, but maybe

it's just that everywhere is sort of a hot spot for red meat allergy. But it really was like a lot of people. The people that we hung out with like got bit by a lot of ticks. Let's be honest, we all dead. Yeah, exactly. I mean, yeah, thousands and thousands I would catch every day. Yeah.

So anyway, but every time I learned of someone new who had developed the allergy, I would do some like like Google Scholaring to try to answer the three main questions that I had. What the heck is going on in this allergy? How the heck did people discover the connection to tick bites and why the heck does this happen? Yeah. And so Aaron, you just took us through the first question. And so I'm going to try to take on those other two, starting with the how. Like how was alpha-gal syndrome first recognized? So the syndrome itself has no doubt been around for longer than people have recognized it. That professor that I mentioned

had developed it, I believe, in the early 1990s. And there is apparently unpublished work from the state of Georgia in the late 1980s that mentioned the potential of a red meat allergy in association with tick bites. But it took a series of kind of unusual events at opposite ends of the earth for the connection to be made between tick bite and red meat allergy. On the one end of the Earth was Dr. Cheryl Van Noonan, an immunologist who was working at an allergy clinic in Sydney, Australia. She noticed what seemed like an unusual number of people coming to the clinic complaining that they had recently developed an allergy to red meat with a delayed onset of symptoms that involved things like tongue swelling, throat constriction, respiratory distress, and all the other sort of

suite of symptoms that you mentioned. What's an unusual number, you might ask? Like, when did this start to stand out? So between 2003 and 2007, 25 patients, seven men, 18 women, reported this allergy. And I'm sure that she and her collaborators ruled out many other potential causes, but ticks seemed like a strong possibility from the beginning, with 24 of the 25 patients reporting a history of having bad local reaction to tick bites. And the areas, like the regions where these patients resided were known to be, quote unquote, endemically infested with several tick species. In 2007, Van Noonan authored an abstract, the first academic publication, linking the red meat allergy to a tick bite from the tick exodes holocyclists.

While Van Noon was drawing her own conclusions down under, other researchers in the U.S. were on a different trail, but one that would lead them to the same strange allergic reaction. In 2004, trials were underway to test a cancer drug called cetexamab. Sootoximab. Satuximab. No wonder I didn't recognize it, and you first said it because I've only read it and I didn't try to say it in my head. But they were testing this cancer drug to see if it was safe for FDA approval. But researchers were noticing that in some patients, this medication was causing a hypersensitivity reaction.

particularly those patients residing in a handful of states in the southern U.S. The reactions could be quite severe, pretty quick onset, anaphylaxis, that would have you on the floor and had even resulted in death for a few. So the pressure was on to find out what was causing this. Researchers Christine Chung, Thomas Platz Mills, Scott Commons, and others were tasked with solving the problem, and they quickly narrowed in on an IGE response to a carbohydrate antigen called AlphaGal. So that answered one question they had, which was like what were people's immune systems reacting to with this drug? But it still left an important one unanswered.

What was triggering this reaction? Like why AlphaGal? The first clue came from AlphaGal itself. As you mentioned, Aaron, this antigen is found in tissues of non-primate, mammals and some primate mammals with some notable exceptions like humans, apes, and old world monkeys. And so the researchers thought that maybe we should look for patients who have had allergic reactions to beef and then map where they live. And the story goes, according to the radio lab episode on this, that the researchers then took out their map of beef reactions and compared it to as many other

maps that they could find, just like overlaying other distribution maps, you know, other disease maps, other, like all sorts of environmental exposures, whatever. And one map in particular stuck out, which was the distribution of Rocky Mountain spotted fever cases. Could this allergy be triggered by a tick bite? They interviewed the patients with the beef allergy, confirmed to be IgE antibodies to alpha gal, and found that more than 80% of them had been bitten by a tick before experiencing symptoms.

This finding, combined with the report from all the first of the fact that. Australia was more or less the solid proof that they needed to suggest that tick bites were triggering an allergy to red meat, specifically the alpha-gal antigen. And fascinatingly, it was different tick species and on opposite ends of the world. And also just like found around the same time. I think that part is also amazing. It's so, so, so weird that it happened, especially like the cetucamab thing and then the figuring that out and the like Australia thing, like to do it all, it's so weird, like the, right, serendipitous, I guess. Erin, I feel like I need to throw in this well actually here.

So, this is not for you. But the tick species that you mentioned that is thought to be primarily responsible for alpha-gal syndrome here in the U.S. is the lone star tick, amblyoma Americanum, which actually very, very rarely transmits the causative agent of Rocky Mountain spotted fever. And so the fact that the maps line up, for Rocky Mountain Spotted Fever and Alpha Gow, it really just seems coincidental to some degree. It might just be overlapping distributions of the Rocky Mountain spotted fever ticks.

Right. Yeah, or tick and, yeah. But I was just like, wait, that doesn't, that, like, am I understanding? Similar distributions of all of those tick species. Yeah. But anyway, I had, I am sorry, I had to. But once those reports came out, first Van Noonan in 2007 and then Commons and Platt's Mills in 2008. Platz Mills, by the way, developed the red meat allergy during this research

through a tick bite. But it seemed like following these reports, the allergy was everywhere. All you had to do was look. France, Spain, Germany, Switzerland, Sweden, South Korea, Japan, Central America, South Africa, and more every year worldwide distribution. Yeah. The fact that this stranger-than-fiction allergy to red meat triggered by a tick bite was discovered on two different continents across the globe within a few years of each other is pretty incredible. Is it coincidence? Maybe.

But is it serendipitous? Maybe. But some of the researchers have also hypothesized that exposure to ticks has been steadily on the rise over the past few decades in some regions where the allergy is common as a result of increasing numbers of mammalian hosts like bandicoots in affected regions of Australia. and white-tailed deer in the southeastern U.S., in addition to habitat encroachment. So we're basically just like more, we're encountering ticks more readily. Classic.

And more ticks are there to encounter. Exactly. Yeah. And as for what the future may hold, I'll leave that to you, Aaron, except to say that as the climate continues to change impacting the range of tick species as we continue to encroach into these habitats, I'm sure we'll just see more and more of this allergy. develop. The ticks are just trying to save us all from eating too much meat. Yeah. Thank you, ticks. We appreciate you. Yeah. But for now, let's turn back in time to get at the second question

that I mentioned at the top of this. Like, why the heck does this happen evolutionarily? So like you mentioned, Aaron, humans react to alpha-gal because we don't produce it ourselves. And so we recognize it as non-self and we attack it. Pretty standard issue, immune stuff, right? Yeah. And that inability to produce alpha-gal makes us outliers among mammals. Of all mammal species, catarines, which includes old-world monkeys and apes, including humans, are the only ones who can't make alpha-gal, who don't make alpha-gal. That means that other primates like New World monkeys, lemurs, loruses, and tarceres, not to mention cows, pigs, dogs, mice, etc., all produce alpha-gal. We also continuously circulate antibodies against it.

Alpha-gal is, in fact, the most abundant natural antibody in humans, making up about 1% of immunoglobulance. That's so bizarre, Aaron. It's so bizarre. And so it seems like this kind of a big deal. Yeah. And so what makes us different? Like, why?

Why us? Or why not us, rather? And that's the question that researchers have been trying to figure out for decades now. Looking at which species make alpha-gal and which species don't, two things stand out. Number one, since the ability to produce this is so widespread among mammals, including both placental and marsupial mammals, it's clear that catarines once produced alpha-gal like all other mammals and lost the ability at some point. Okay. And number two, that point was around 28 million years ago before the old world monkeys

and apes diverged. Okay. That makes sense. What happened 28 million years ago to cause such a big shift, resulting in both the loss of the ability to make alpha-gal and the production of antibodies against it? Right. And like did that happen like all of a sudden or was it? Yeah.

Because all, you're saying all catarines make antibodies against alpha-gal? Yes. Okay. Right. So what happened? Yeah. How does a deadly disease sound? Well, sounds like, sounds like right up our alley is how it's time. Right up our alley. This carbohydrate will kill you. Some researchers, namely Yuri Galili, who has done a tremendous amount of work on Alphagal, have proposed that around 28 million years or so ago, a highly virulent pathogen or pathogens, I've seen. airborne enveloped viruses suggested and also sepsis-causing bacteria suggested. Some pathogen swept through old-world primates on the Eurasia-Africa landmass, killing those who produced alpha-gal and sparing the very few who didn't, who would over the next generations increase in number. And there seems to be some debate as to the cause or causes, like was it a pathogen, was it a climate, was it a mix of both? But there does seem to be a sharp decline.

in old world primate populations during this time, almost leading to extinction, like overall, but I think also extinction of certain species. But why would not producing alpha-gal help protect you from severe infection or death? That's where things get super interesting. Because it turns out that mammals aren't the only species to produce alpha-gal. In fact, some viruses, bacteria, and parasites do. Or they bind to. host-produced alpha-gal to gain entry into their host cells. E. coli species of clobesiala, plasmodium species, some of which cause malaria and humans, mycopalasma, causative agent of tuberculosis, salmonella, tropanosoma, leish mania, sea-diff, mosquito-borne viruses. I mean, a lot of pathogens

either produce or use alpha-gal in some capacity. And also microbes that aren't pathogenic to us. For instance, some members of our gut microbiome may produce alpha-gal, which triggers this constantly elevated antibody response, which could then protect us from things like malaria. And some people are looking at this in terms of an actual mechanism for how we can shape our gut microbiome to boost our immune system, like adding in more bacteria that produce alpha-gal as a way to raise those antibody levels and neutralize any invading malaria parasites. What? It's so cool. Because they're, does seem to be this association between gut microbiome, alpha-gal production, anti-gal antibodies, and then malaria susceptibility. And so I love it because I'm like, oh, is this the first time that

I've actually seen the microbiome, like a mechanism for the microbiome instead of just like. It's functional, right? It's not just like what are these bacteria. It's like what is the function of this and how is that interacting with our? It's direct links instead of there's an association, which is also really important, but at the same time, it's exciting to see like this sort of concrete pathway of logic. Yes, love it. Alpha-gal can also provide some insight into blood types and disease. People who have type B or type A-B blood seem to be less susceptible to Al-Gal's syndrome because the B, like me, because that B antigen that they produce is very similar apparently structurally to alpha-gal. And so their bodies see it as more like self. And so they're

not as liable to attack it. Yeah. I've heard too that you have more specific anti-gal proteins, anti-alphagal proteins, whereas people who are O or A have like less specific ones that bind to maybe B and alpha-gal are just a little bit messier. It's messy. It's just a little more efficient. Yeah. There you go. Yeah. Painting with a broad brush. But researchers have also genetically engineered mice to knock out the alpha-gal producing gene and found some fascinating results, with knockout mice being more protected against some pathogens like SynV virus or Cyndibus virus and less protected against others like Herpes Symplex type 2. Huh. Yeah. Interesting. And then there's the genetic engineering of pigs to not produce.

Alpha-Gal, so-called gal-safe pigs, which I love, because it makes them not only safe to consume for people with alpha-gal syndrome, but also it opens the doors for xenotransplantation, transplanting pig organs into humans, which, as you mentioned, Erin, previously could not be done in part because, or in major part, because of this alpha-gal carbohydrate. Yeah. It's wild that this particular carbohydrate, like this little sugar, is that important. I know. Right?

Like, it was one of the major, I mean, it still is one of the major barriers to animal organ, like, transplant into humans. And so now with the development of these pigs, like, it's so, it's so fascinating, Aaron. I think the thing that surprised me the most about doing this episode is that I had never heard of AlphaGal before 2013. and I since then have never heard about it outside of the context of alpha-gal syndrome. Same. But this is one of the most important components of like our life of our immune system in terms of anti-gal in terms of other animals. And it just plays so many more roles than preventing you from eating meat.

Right. Than just alpha-gal syndrome, which is also very like interesting and important and cool. Yeah. It's wild. The other big takeaway from this, I think, and that it's very obvious is that the story of alpha-gal is still very much unfolding. And the tick-borne allergy is really just a part of it. Yeah.

I mean, I was going down so many rabbit holes in terms of autoimmune diseases in alpha-gal, whether there are people who do produce alpha-gal and how they respond to different pathogens, because it really is just like a simple frame-shift mutation. Right. So we still have the gene. It's just like is non-function. It just doesn't work. Yeah.

Right. And then blood types and association with different diseases. Let's do an episode on that. I mean, but every answer that I found or every partial answer that I found just led to a million more questions. And so now I'll end this with a question for you, Aaron, which is where are we today with Alpha-Gal syndrome? Oh, I can't wait to tell you all about it right after this break. To the CDC in the U.S., there were over 110,000 cases of Alpha-Gal reported between 2010 and 2020. And most of those are the latter half of that 12 years.

Okay. Which is somehow both way more than I expected, but also likely a gross underestimate, because Alpha-Gal syndrome is not a notifiable disease. And the estimates of prevalence globally really, really range. And I think will likely change drastically over time and not just because numbers are actually changing. But the estimates that I saw right now in places where we have prevalence estimates range between in Germany four cases per 100,000 people to 13 cases per 100,000 people in Virginia, which is a part of the U.S. that has a higher number of cases than a lot of other parts of the U.S. And 113 per 100,000 people in the Sydney Basin in Australia.

Wow. Okay. Right? So like really big variation. And a lot of that has to do with both tick species and where those ticks exist, how much people are interacting with ticks, right? Like if you're in a big city, you're not probably going to be interacting with ticks as much as if you're in a more rural area, et cetera. But also where are we looking?

Like where are we looking for this? Because like we said, if you're looking for it, you'll find it. And cases are on the rise without a doubt. For example, in the U.S., in 2017, there were just over 13,000 new cases diagnosed. There were nearly 19,000 cases diagnosed in 2021. Wow. Yeah. And what's really mind-blowing is that in studies where they have looked at, like, larger populations,

just like checking for people who might have IG. those allergy-associated antibodies against alpha-gal. In some populations, they found up to 20% of people who had IgE antibodies against Al-Fagal. But by no means does that mean that all of those people have Al-Gal syndrome. So there's still a really big open question of like, what is that threshold? Like how much IGE do you have to have? And why are some people reacting and developing Al-Fagal syndrome? and some people aren't.

Do levels of IGE correspond directly with that allergic response? Or can some people have like two people have the same levels of IGEE and one person has anaphylaxis and the other person does not react whatsoever? Yeah, it's a great question. It does seem to be that the levels do matter in terms of what your response is. Okay. There still isn't a very clear like, for example, diagnostic threshold of like, okay, this is the value which you have alpha-gouf syndrome versus.

this is the value where you don't, that is still a little bit like up for debate, it seems like. Okay. Yeah. But it does seem to correspond where higher levels, more response. And like repeat tick bite, those levels go up. Mm-hmm. And like you mentioned, Aaron, as with all, I think, ever of our vector-borne disease episodes, there's a lot that is probably contributing to this rise in incidents and prevalence.

This includes things like changes in the distribution of ticks. In the U.S. especially increases in things like deer populations and other mammal populations and other parts of the globe that are really great hosts for ticks. But also our exposures to ticks, things like land use change, deforestation, blah, blah, blah, climate change, everything that changes the way that we interact with ticks and other tick hosts is going to affect any kind of tick-borne disease, including Alpha-Gal. Yeah. But also things like getting better at recognizing and diagnosing this because one of the things that we, I always try and talk about like, well, where's the current research or where's the research going? And for a disease like AlphaGal that is still so brand new in the scheme of what medicine understands about this disease to begin with, like we just figured out this existed a couple decades ago, not even like 20 years ago. So we're still very much. writing that story of like where do we go with alpha-gau syndrome from here. And right now, we need people to know that it exists because a recent survey by the CDC from 2022 found that 42% of health care providers in their particular study hadn't heard of alpha-gau syndrome. They didn't know about it. Wow. And I will say that that was just a survey of primary care

providers. So it was like pediatricians, internists and family practice physicians, and then NPs and PAs. And rates of knowledge are probably much higher among, say, allergists or even GI specialists that people might get referred to for their GI symptoms. But that is still a pretty important knowledge gap to kind of highlight. Absolutely. We've talked a lot on this podcast about like delays in diagnosis and things like that. And these are very severe reactions. So this is like pretty significant. Yeah. Yeah. So I think that's one of the biggest areas of like how to make everyone know about it.

Maybe make a podcast for example. Maybe you can help. The solution. And in truth, there is so much that is still unknown in terms of what is the next big research area. It's everything. Like, why do some people mount this response and others don't? What really is that IGE threshold and what's causing it in some people? What other treatment options might exist besides just never eating any kind of mammalian meat again?

How can we desensitize people like we might do for other food allergies? Can we do that? Is it just avoidance of tick bites or is there anything else? What are all the different tick species that can cause this? How many have we not yet discovered? How is it going to change with things like climate change? How are these ticks making alpha-gal to begin with? Right, right.

There are so many different questions and different opportunities for research into this from so many perspectives to make it super integrative research. It's a really incredibly open field with a lot of opportunity to understand too, like something that is so universal in across mammals except for a handful of our cousins. Mm-hmm. It's, yeah, it is really, really an interesting disease and such a weird and wacky mechanism. Mm-hmm. I also am dying to know everyone who's listening. Like, had you heard of alpha-gal syndrome? Because I never know with things like this if it's like everyone knows about it at least a little bit,

or if we really are just that weird where, like, we've been talking about it. since like 2013 because so many people in Panama had it. Right. And like it's not that normal. And there was that radio lab episode so many years ago. But like, how, had you heard of this? How much did you know about this? Right.

I really want to know. Do you have this? Do you have this? Because we have had a lot of people reach out to say, I am allergic to red meat, thanks to a tick bite. What's going on here? And how long did it take to get diagnosed? Because it seems like there's a pretty big gap in diagnosis.

But yeah, I have so many more questions. Aaron. I think that we all do. And so let's direct people to the best source of where they can try to answer those questions, which is- They can answer our questions for us. A million sources. I truly do have like a million sources here. I want to shout out just a few. So there's one by Commons and Platz Mills from 2009 that goes into sort of anaphylaxis syndromes relating to alpha-gal. then there are a couple of interesting papers about sort of the evolutionary significance of alpha-gal, one by Galilee from 2019, as well as a handful of many more, actually. And this paper goes into how viruses may have led to the loss of alpha-gal production

and the rise in alpha-gal antibodies. And then there's a paper by Rodriguez and Welsh from 2013, no relation, as far as I'm aware, titled Possible Role of a Cell Surface Carbohydrate in Evolution of Resistance to Viase, viral infections in old world primates. And there's so many more, including the paper on this pig that's been on the pigs that have been engineered to not produce alpha-gal. Amazing. And a paper about how dogs can actually develop alpha-gal syndrome possibly. What? Even though they make alpha-gal? Yeah, I found a paper from 2019 about how tick bites can induce anti-alphagal antibodies in dogs. Wow. Wow. Really strange.

It is really wild. I also had quite a lot of papers for this episode. Probably some of the same ones, Erin, that you read and mentioned some of the early reports from 2009 from Van Noonan, as well as an early one from Commons at all from 2009 in Journal of Allergy and Clinical Immunology. The one from Van Noonan was in the Medical Journal of Australia. I also had update ones from both of those authors. There's like so many. The really interesting, paper from 2019 was by Chris Bell at all in Frontiers and Immunology. That was discovery of alpha-gal containing antigens in North American tick species believed to induce red meat allergy. That one was super interesting. And then I had a bunch as well about allergies and allergic

responses in general, if you want more details on like how food allergies work and IGEE and all of that kind of stuff. As always, we'll post the list of our sources from this episode and every one of our episodes on our website. This podcast will kill you.com. Right under the episodes tab, you can find it there. Thank you again so much, Winnie, for sharing your story with us. We appreciate it. So, so much. We really, really do.

Thank you. Thank you also to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Tom Brifogel and Leanna Squalachi for our amazing audio mixing. Thank you to Exactly Right Network and everybody there. And thank you to you listeners. We hope that you enjoyed this and are like, wait, what? Wait, what? If you have questions, I'm sure you do, send them our way.

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