Ep 153 Alpha-Gal Syndrome: A tick bite gone bad

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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 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 Mizzou 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 trigger-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 Novocaine 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 2018.

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 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 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 Erin 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 AlphaGal 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.

It is very bizarre.

It feels like something out of a sci-fi novel that's 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 scientist introduces this thing into ticks that causes everyone to be vegetarian.

Yeah, you get the

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 uh, I'm really excited for it.

It's going to be a really really fun episode.

Yeah, I have so many.

It's so weird.

It's so weird.

Yeah.

And we'll get into all of that weirdness

later on.

But first, we've got some other business to take care of.

We do.

It's quarantining time, as always.

So what are we drinking this week?

We're drinking Gal Pal.

You know, just your little Gal Pal.

Gal Pal.

You're also a Gal Pal.

It's a delicious beverage.

Of course, it is made with none other than Beef Eater gin.

Not sponsored.

Not sponsored, but

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.

Gal pal is.

It's great.

Yeah.

And check it out because we'll be posting the recipe for Gal Pal, the quarantini, as well as gal pal, the placebarita on our website, this podcastwillkillyou.com, and all over our social media channels.

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And we do.

We do say so ourselves pretty much every week.

We do.

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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, we do.

Let's get into it right after this break.

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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 alpha13 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.

And I don't know enough about SEO or whatever.

Anyway.

Oh, gosh, no.

In any case, galactose alpha 1, 3, galactose alpha gal so this is a short sugar it's a oligosaccharide 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 AlphaGal, 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 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 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 be more immunogenic.

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, tetanus 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 immunogenic.

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, 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

and can be much worse for you than a a pathogen, than a potential pathogen could be.

Totally.

Potentially.

Yeah.

So

I don't know what my question is there.

Why would that happen?

Like, why, 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 our two-parter.

100%.

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 immucosal 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 mast 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 him he needed to come out of the bath.

Yeah.

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 thing.

They bind to that peanut protein.

All of those mast 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 are 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 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 AlphaGal and the antibodies that we make against alpha-gal from an evolutionary context.

But just for some context on alpha-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, are 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, Erin.

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 AlphaGal syndrome, that sensitization to AlphaGal, it doesn't happen from food.

It happens from a tick bite.

Ticks, of course, are our little six to 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 anticoagulation and anesthetizing us so that we don't notice them and we're not bothered by them.

can hang out for a long time.

Tick saliva is kind of a magical substance.

Same way lynch 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 siolome, 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, 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 IgE 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 alpha gal works.

Well, Erin, I have a few questions here.

Well, Erin, I thought that you might.

Okay.

We know that this is multiple tick species all over the world.

That

this is happening.

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 in this?

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.

The 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 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, 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 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

coming from inside the house.

It doesn't really work in this context, but

we try, though.

We try.

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There was a paper from 2019 in Frontiers in 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-alpha gal 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 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-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, Erin.

Well, no, I mean, the question 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?

Yeah.

I don't know.

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 amblyoma americanum is the most common in australia it's exodes holocyclis also called the paralysis tick we have to do tick paralysis and if you drive we do we do

but also things like exodes ricinus uh rifficephalus bursa hyaloma species like so many different species across again the entire globe, North America, South America, Australia, Europe, Africa, everywhere where there is tick and you shall find

red meat allergy from tick bites.

Yep, including in some species like Exodes scapularis, people have found alpha-gal in the saliva, but we have yet so far to see alpha-gal syndrome develop in people after exodes scapularis 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 Gal 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 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 60% or some studies cite even more people report very severe reactions, including anaphylaxis with AlphaGal syndrome.

And so this, those suite of symptoms there are found in other food allergies.

In alpha gal, it's just delayed.

Yeah, that's the other weird thing that sets 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 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, 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 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 cetuximab, 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 AlphaGal, 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 would expect with other food allergies.

Okay.

It's so weird, Aaron.

So I want to like just reframe it again as like, okay, so what are we actually talking about?

What is AlphaGal 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 develop during childhood after just a few exposures rather than like 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 Gao 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 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.

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 amblyoma Americanum 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 AlphaGal 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.

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 is somehow the carbohydrate 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, oh, yeah.

Aaron, tell me

everything.

Like, 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 is how recently we figured it out.

Cause I feel like when we were in Panama, it was the thing.

Everyone, everyone had it.

Everyone had had it.

Everyone had it.

Yeah.

Yeah.

But it was like very new at the time.

Yeah.

Yeah.

Let's let's get into some of this, these questions and take a quick break and then we'll begin.

Erin, like you mentioned, we learned about this, I think, pretty recently.

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 field work 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 ticks all over it.

I love it so much.

Actually, they have eight legs, so they must not be larvae, even though they look like they're not.

No, I think they're nymphs or adults.

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'll take that 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 allergy following a tick bite?

I have it.

A few other researchers who have spent a lot of time doing field work in this area have 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 hotspot 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 did.

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 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, 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 AlphaGal 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 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 Dr.

Cheryl Van Noonen, 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 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 Noonen authored an abstract, the first academic publication, linking the red meat allergy to a tick bite from the tick Ixodes holocyclis.

While Van Noonen 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

ceteximab.

Ceteximab.

Cetuximab.

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 Platts-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 alpha-gal.

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-gal?

Right.

The first clue came from alpha-gal itself.

As you mentioned, Erin, 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 Radiolab 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 AlphaGal, and found that more than 80% 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 satuximab thing and then the figuring that out and the like Australia thing.

Like to do it all, it's so weird.

Like the serendipitous, I guess.

Erin, 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 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 gal, it really just seems coincidental to some degree.

It might just be overlapping distributions of the Rocky Mountain spotted fever ticks

or tick and yeah.

But I was just like, wait, that doesn't

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 Noonen in 2007 and then Commons and Platts Mills in 2008.

Platz Mills, by the way, developed the red 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

are there to encounter.

Exactly.

Yeah.

And as for what the future may hold, I'll leave that to you, Erin, 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, lorises, and tarsiers, 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 immunoglobulins.

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 this 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, what happened?

Yeah.

How does a deadly disease sound?

Well, sounds like, sounds like right up our alley is how it is.

Right up our alley.

This carbohydrate will kill you.

Some researchers, namely Yuri Galili, who has done a tremendous amount of work on alpha-gal, 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 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 Klebsiella, Plasmodium species, some of which cause malaria in humans, mycoplasma, causative agent of tuberculosis, salmonella, trypanosoma, leishmania, C.

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 there 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 yeah for the microbiome instead of just 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

AlphaGal can also provide some insight into blood types in disease.

People who have type B or type AB blood seem to be less susceptible to alpha-gal 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-alpha-gal proteins, whereas people who are O or A

have like less specific ones that bind to maybe B and alpha-gal and like a 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 syndbis virus, and less protected against others like herpes simplex 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.

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, Aaron.

I think the thing that surprised me the most about doing this episode is that I had never heard of alpha gal 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 is very obvious, is that the story of AlphaGal 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 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.

So we still have the gene.

It's just like, is not exposed to it.

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, Erin, 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 110,000 cases of AlphaGal reported between 2010 and 2022.

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 AlphaGal 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 US 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 IgE, those allergy-associated antibodies against alpha-gal, in some populations, they found up to 20% of people who who had IgE antibodies against AlphaGal.

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 Alpha-Gal 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 Alpha Gauss 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, Erin, as with all, I think ever of our vector-borne disease episodes, there's a lot that is probably contributing to this rise in incidence 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 in 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.

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 AlphaGal 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 healthcare 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.

Maybe we can help.

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 AlphaGal 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, 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.

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, like, had you heard of Alfegao 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 Radiolab 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, Erin.

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

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 Galile 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 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-alpha-gal antibodies in dogs.

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 like 2009 from Van Noonen,

as well as an early one from Commons et al.

from 2009 in Journal of Allergy and Clinical Immunology.

The one from Van Noonen 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 et al.

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 podcastwillkillyou.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 Breifogel and Liana 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?

Do you have questions?

I'm sure you do.

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Well, until next time, wash your hands.

You filthy animals.

Be honest, how many tabs do you have open right now?

Too many?

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Every week, we scour the internet to bring you deep dives that explain how the digital world connects and divides us all.

Everyone's cooped up in their house.

I will talk to this robot.

If you're a truly engaged activist, the government already has data on you.

Driverless cars are going to mess up in ways that humans wouldn't.

Listen to Close All Tabs, wherever you get your podcasts.

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