Hi. My name is Winnie and I'm an ecologist. In the summer of twenty eighteen, 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 the shirt over the bird's head to calmb it down, and we safely carried the bird back to our car. It was like a ninety minute drive to Missoo 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 twenty eighteen, 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 chiggers. 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 chigger treatment and tick treatment for clothes and repellents, they're the same thing. One evening in October of twenty twenty two, 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 novacine. At the dentist it was like that, but everywhere. I wasn't thinking entirely clearly, but I do remember taking to 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 Alpha gal. As an ecologist, I knew about Alpha Gal. I had friends with Alpha Gal, I have coworkers with Alpha gal. 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 twenty eighteen. 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 I'd noticed that my ankles in 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 twenty twenty three, we moved to Minnesota. As an ecologist, i'd 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 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 yeah 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 Erin Allman Updike.
And this is this podcast will kill you.
And today we're getting real 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.
Yeah, it is. 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 is farming and whatever, and so then a rogue scientist introduces this thing into ticks that causes everyone to be vegetarian. Yeah, you get the you get the.
Right, I got it. 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 gonna 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 business later on, but first we've got some other business to take care of.
We do. It's quarantiney time as always. So what are we drinking this week? We're drinking gal Pal, you know, just Pal, gal Pal, you're out the gal Pal. It's a delicious beverage. Of course, it is made with none other than Beef Eater Gin Yeah sponsored.
Not sponsored, but you know, we can't. We can't pass up that that name, that branding.
As well as passion fruit and lemon lime soda. It's a really refreshing gin bev.
Yeah, gal pales great. Yeah, and check it out because we'll be posting the recipe for gal Pal the Quarantini as well as Galpal the Place Barta on our website. This podcast will kill you dot 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 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
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I don't think we have any other business do 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 alphagal syndrome.
We do, we do, we do. Let's get into it right after this break. 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 hyper sensitive response to a protein. So that right there is the first of so many places where the story of alphagal syndrome is so much weirder than just a food allergy, because in this case, it's an allergy to a specific sugar. Alpha gal an alpha gal of course,
has a much more complicated chemical name. It's galactose alpha one three 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 it does, and I don't know enough about seo or whatever. Any Oh, gosh, no, In any case, galactose alpha one three galactose alpha GAL. So this is a short sugar, it's a aligosach ride. 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 seliac 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 ig e 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 m hm. So someone who's allergic to 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. So to understand allergies, we then also have to understand what the heck is an IgE ant a body?
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 iminogenic. Okay, So it's similar with like vaccines. A lot of times, if we try and develop a vaccine against 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, tetnos toxoid, 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 iminogenic. Yeah, it's a good question.
It's interesting. Okay, Yeah, and so I feel like maybe this is jumping ahead. Okay, you said 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 is
why why would that happen? Like why why would that be an evolved response?
Yeah, it's a great question, like why did allergies evolve?
Is a bigger question than I can maybe not only something that we address in the R two parter, but.
What 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, but 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 responds. 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 mass cells and our basofyls. 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 anigen 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, Wow, I just 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 ig.
Is like my toddler last night when I told me we needed to come out of the bath, Like yeah. 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 prod the invader and they do their scorz ter 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 alphagau syndrome, except for a few pretty important details. M H. 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 oligosaccharide.
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 old monkeys. Oh yeah, we'll get into it. I know, I cannot wait. I know, Aaron, 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 alphagel. So we do not make this sugar in our bodies. We happen to make from infancy and to bodies against this particular alphag sugar the same way that people who like me are blood group oh 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 anti bodies 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 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 alphagau syndrome, that's 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 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 leech, they spit a whole bunch of their saliva into our bodies to help with things like anti coagulation 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. Saliva is right exactly, and I feel like saliva. I know people are working on it, but I do feel like there are some amazing opportunities in tickspit.
I agree. I was reading about like the sia loam. They call it the saliva microbiome. I love it.
I love when there's a new word for microbiome for a different part of a different area, but different area.
So what happens in alpha gau syndrome is that during blood feeding, 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 ig e anna bodies against that specific sugar alphagal. 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 IgE waiting and it goes whoa wha whoa, this is that highly varulent pathogen. I have to respond to it, binds to it. Those mast cells de granulate, they release all of their super inflammatory stuff, and you get this massive immune response aka allergy. That's that's how alpha that 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. The worst is happening yep, and so it's clearly not related to certain tick species or like tick phylogeny.
Yeah, it's 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? And 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 coming from? 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 when 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. So those larva, 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 alphagal coming from? For a long time, we really didn't know, like you said, was it coming from a previous blood meal that just was still there and so the ticks 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 is coming from inside the house that doesn't really work in this context, but.
Though we try.
There was a paper from twenty nineteen 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 alphagal antibodies, and they found this in multiple different ticks species, including the one that most commonly causes alphagal syndrome in the US Ambloma americanum. 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 GL, 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 gl or is it one of their microbes? Is it something in the tick microbiome, like say a commensal or another pathogen like a ricketsia or something that is making alpha gal inside the tick and then it gets into the salary glands and then the tick is spinning
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? What why?
Why does anyone make this weird sugar? Because so I spent a lot of.
The time you would answer that questionarion.
No, I mean the question that I am trying to answer is why don't we make it? But I never really considered why would we?
Why would we? Yeah? Why do we? Don't know?
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 US, Amblioma americanum is the most common. In Australia, it's Exodees holocyclists, also called the paralysis tick. We have to do tick paralysis in we do, but also things like Exode's risinous rifycephalous Bursa hyaloma species, like so many different species across again the entire globe, North America, South America, Australia, Europe, Africa, everywhere.
Yeah, you shall find, yes, resideolergy from tick bites yep.
Including in some species like Exodi scapularis. People have found alpha gal in the saliva, but we have yet so far to see alphagau syndrome develop in people after Exodia scapularis bites as far we know astrisk, who knows what will happen, But what does actually alphagal 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 alphagal 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 weltz 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 so 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 an edema. But anaphylaxis is actually a widespread 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 bronchioles, 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 sixty percent or some studies site even more people report very severe reactions including anaphylaxis with AlphaGo syndrome.
And so this those suite of symptoms there are found in other food allergies in alphagal is just delayed.
Yeah. That's the other weird thing that's like alphagal 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 ten to twenty minutes after exposure. So I knew you were gonna 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 alphagal or this allergy in specific, but it's just a delay in the circulation of this anigen. So the sugar itself alphagal 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 on set reactions in someone with alphagou syndrome if they're exposed to alphagal via the bloodstream. And this we saw in the case of setuximab, which is an antibody, a monoclonal antibody. I think you'll probably talk about it erin uh huh, that happens to have some alphagl on it or in it in that medication, and people who were exposed to that, who they didn't
know that they had alphagal but they did. Their response was much more rapid, on the order of minutes and peaked within twenty minutes, which is more like what we would expect with other food allergies. Okay, it's so weird, Aaron, So I want to like just like reframe it again as like, Okay, so what are we actually talking about? What is alphagau syndrome? Overall? Alphagal 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 developed 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 alphagal syndrome seems to heighten the sensitivity even more so that people have renewed worse reactions or are like never able to tolerate me to 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 try 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 alphagal syndrome, does every person then have the capacity to develop alphagal syndrome?
I love your question, Darren, such a good one. No idea, We have no idea what it is about one person versus another that predict why someone would develop alphagau 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, eggzema. 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 alphagau 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 it we really don't know right now, Like why why?
Yeah?
Right?
Who?
We don't know.
Ah, 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 it's a weird way for sure, But like is every amblioma americanom 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 alphagal syndrome, like respond in this severe way to 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 gl syndrome and they could eat cured meats, but not like a hamburger.
Interesting, Yeah, 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 you get more degraded in cured meats, like exactly right, I do. I don't know.
I don't know either. There's a lot. It's so, so, so so interesting. So yeah, Aaron, tell me m everything, like what I know you're going to talk about this sugar, Like where 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 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, but it was like very new at the time.
Yeah.
Yeah, let's get into some of these questions and 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 thirteen and I had just started fieldwork in Panama for my PhD research on tics and climate change, and also for all of you listeners out there. Right now, I'm wearing my Smithsonian T shirt that has little larval ticks all over it. I love it so much. Actually, they have eight legs, so they must not be larvae.
Even though they don't like the nymphs or adults. They're big.
They're big, but they look I don't know. Some look like there's an adults. I think it's nymphs. Also, Okay, anyway, we don't need to get into it.
She's wearing a tick shirt, guys the occasion.
It's one of my favorite shirts. But yeah, So in twenty thirteen, a professor who was also in Panama reached out to me and was like, oh, I heard you're working on tics. Have you heard of a red meat allergy following a tick bite?
I have it.
A few other researchers who have spent a lot of time doing fieldwork in this area have also had 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 erin 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 that we hung out with, like got bit by a lot of ticks. Let's be we all did.
Yeah exactly, Yeah, I mean yeah, thousands and thousands I would catch every day.
Yeah.
So anyway, but every time I learned if someone knew who had developed the allergy, I would do some like light 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 Aarin, 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 nineteen nineties. And there is apparently unpublished work from the State of Georgia in the late nineteen eighties that mention 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 doctor Cheryl van Nonan, 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 suite of symptoms that you mentioned, what's an unusual number you might ask, like, when did this
start to stand out? So between two thousand and three and two thousand and seven, twenty five patients, seven men,
eighteen women reported this allergy. And I'm sure that she and her collaborators ruled up many other potential causes, but ticks seemed like a strong possibility from the beginning, with twenty four of the twenty five 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 two thousand and seven, 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 Nounan was drawing her own conclusions down under, other researchers in the US were on a different trail, but one that would lead them to the same strange allergic reaction. In two thousand and four, trials were underway to test a cancer drug called Texa mab aaron texmab se tuxamab.
No wonder, I didn't recognize it when 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 US. 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 Plats, 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 alphagaw. 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 alpha gw Right. The first clue came from alpha gul 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 over laying other distribution maps, you know, other disease maps, 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 eighty percent of them had been
bitten by a tick before experiencing symptoms. This finding, combined with the report from 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 tuxamap 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.
Aaron, I feel like I need to throw in this well actually here so please, this is not for you, but the tick species that you mentioned that has thought to be primarily responsible for alpha gal syndrome here in the US is the lone star tick Ambloma 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 spotted fever and alpha gal it really
just seems coincidental to some degree. It might just be overlapping distributions of the Rocky Mountain spotted fever ticks yeah or tick and yeah, but I was just like, wait, that doesn't.
Like, in my understanding, 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 two thousand and seven, and then Commons and Plats Mills in two thousand and eight. Plots 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 us in
addition to habitat encroachment. So we're basically just like more, we're encountering ticks more readily, classic and more tis ticks are there to encounter exactly.
Yeah.
And as for what the future may hold, I'll leave that to you Arin, except to say that as the climate continues to change, impacting the range of ticks 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
gl 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 gl. That means that other primates like New World monkeys, lemurs, lorises, and tarsiars, 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 one percent of immunoglobulence.
That's so bizarre.
It's so bizarre, and so it seems like this kind of a big deal. 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 alphagal 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 twenty eight million years ago, before the Old World monkeys and apes diverged.
Okay, that makes sense.
What happened twenty eight 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 did that happen like all of a set in or was it?
Yeah?
Because all using all catarines make antibodies against alpha gl.
Yes, okay, right, so what happened?
Yeah?
How does a deadly disease sound?
Oh? It sounds like sounds like right up our alleys.
Right up our alley. This carbohydrate will kill you. Some researchers, namely Uri Galilee, who has done a tremendous amount of work on alpha gal, have proposed that around twenty eight million years or so ago, a highly virulent pathogen or pathogens I've seen airborne envelope viruses suggested, and also sepsis causing bacteria suggested. Some pathogen swept through Old World primates on the Eurasia Africa land mass, 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 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 ALPHAGL
help protect you from severe infection or death? That's where things get super interesting, Okay, because it turns out that mammals aren't the only species to produce ALPHAGL. In fact, some viruses, bacteria, and parasites do, or they bind to host produced ALPHAGL to gain entry into their host cells. Ecoli species of Clebsiella, Plasmodium species, some of which cause malaria and humans, Micolplasma causative agent of tuberculosis, Salmonella, trepanosoma,
leish Mania, sea diff mosquito borne viruses. I mean, a lot of pathogens either produce or use ALPHAGL in some capacity, and also microbes that aren't pathogenic to us. For instance, some members of our gut microbiome may produce alphagal, which triggers this constantly elevated anti body 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. Why it's so cool because there does seem to be this association between gut microbiome, alpha gall 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. Yeah, for the microbiome kind of just sational.
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 alpha gl 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 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 into maybe B and alpha gown like are just a little bit messier.
It's massy. It's just a little more efficient.
Yeah, there you go.
Yeah, painting with the broadbrush. 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 sinv virus or syndibis virus and less protected against others like herpie simplex type two.
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 zeno transplantation, transplanting pig organs into humans, which, as you mentioned aarin previously could not be done in part because or in major part because of this alpha gala carbohydrate.
Ye 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 it's so it's so fascinating, Aran.
I think the thing that surprised me the most about doing this episode is that I had never heard of alpha gal before twenty thirteen, and I since then have never heard about it outside of the context of alphagal syndrome. Same, but this is one of the most important components of our life, of our immune system in terms of anti gall, in terms of other animals, and it just plays so many more roles than preventing you from eating meat.
Right than just alphagal 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 is very obvious, is that the story of alpha gal is still very much unfolding, and the tickboarn allergy is really just a part of it. Yeah, I mean, I was going down so many rabbit holes in terms of autoimmune diseases and 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. We still have the gene. It's just like is non It's just should work 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. According to the CDC in the US, there were over one hundred and ten thousand cases of alpha gau reported between twenty ten and twenty twenty two, and most of those are the latter half of that twelve years, Okay, which is somehow both way more than I expected, but also likely a gross underestimate because alpha gaul 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 one hundred thousand people to thirteen cases per one hundred thousand people in Virginia, which is a part of the US that has a higher number of cases than a lot of parts of the US, and one hundred and thirteen per one hundred thousand 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 US in twenty seventeen, there were just over thirteen thousand new cases diagnosed. There were nearly nineteen thousand cases diagnosed in twenty twenty one.
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 IgE those allergy associate antibodies against alpha gal. In some populations, they found up to twenty percent of people who had IgE antibodies against alpha GL. But by no means does that mean that all of those people have alphagal 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 alphagal 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 IgE 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 alphagal 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. And like you mentioned Aaron, as with all I think ever of our vector born 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 US, 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 born disease, including alpha glah,
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 alpha gal 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 twenty years ago, so we're still very much writing that story of like where do we go
with alphagau syndrome from here? And right now we need people to know that it exists because a recent survey by the CDC from twenty twenty two found that forty two percent of healthcare providers in their particular study hadn't heard of alphagau 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.
Maybe you can help a solution.
And in truth, there is 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. Like 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.
Except for us and a handful of our cousins. H. It's yeah, it is really really an interesting disease and
such a weird and wacky mechanism. I also am dying to know everyone who's listening, had you heard of alpha GAO 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 twenty thirteen 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 arin.
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 they can answer our questions for us a million sources. I truly do have like million sources here. I want to shout out just a few. So there's one by Commons and Plats Mills from two thousand and nine 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 GL one by Gillilee from twenty nineteen, as well as a handful of many more. Actually, and this paper goes into how viruses may have led to the loss of alpha gl production and the rise in alpha gal antibodies.
And then there's a paper by Rodriguez and Welsh from twenty thirteen no relation as far as I'm aware, titled possible role of a cell surface carbohydrate and evolution of resistance to 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 gl amazing, and a paper about how dogs can actually develop alphagal syndrome possibly.
What even though they make alpha gal.
Yeah, I found a paper from twenty nineteen about how tick bites can induce anti alpha gal antibodies in dogs. Woow, really strange.
It is really wild. I also had quite a lot of papers for this episode, probably some of the same ones Aaron that you read and mentioned. Some of the early reports from like two thousand and nine from Van Noonan as well as an early one from commons at all from two thousand and nine in Journal of Allergy and Clinical Immunology. The one from Van Nounin 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 twenty nineteen 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 IgE 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 dot com ran 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.
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Yeah we do. Well. Until next time, wash your hands
You filthy animals.