Wow. You know, I never thought about this
before, but, like, what do allergens have in common?
And I mean, besides the fact that they're awful
And that's actually a really, really interesting question,
because the little bits and pieces that give you allergies come in
so many different shapes with so many different properties.
Just look at pollen.
Probably the allergen you know the most about.
Turns out *ONE OF* the ways pollen sets off an allergic response is wild.
Pollen is built to instantly wage a kind of chemical warfare.
Basically, wherever it lands, instantly releasing a bunch of gnarly protein
cutting enzymes that, no joke, slice
through the little junctions joining the cells lining your airway.
Why does pollen do this?
The answer there is ridiculous, but we'll get to that later in the video.
For now, the only thing I'll say is
it's honestly understandable that whatever pollen is trying to do
would kick off an immune response.
But there's so many other kinds of allergens that aren't violent attack
platforms.
Surely cutting into your cells isn't a common thing
that sets an allergic reaction into motion?
Right?
Well, according to an incredible new paper that just hit Nature,
maybe that's a decent way of thinking
about the common features between *SOME* allergens.
This incredible research team out of Tsinghua in Beijing
not only managed to build
a really slick cell model to help better understand allergies.
They then use that model to isolate these two gnarly looking proteins
that aggregate together into these massive complexes
that are responsible for allergic reactions caused by a common mold.
The way they pulled off this paper is incredible,
and their findings are awesome.
And it turns out there's a lot of allergens that end up stabbing
tiny little holes in the cells that line your airway.
You know what? Let's go ahead and explore how they do that.
And hey, welcome back to clockwork,
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But anyway, let's get into the research paper we're covering today.
What do I mean when I say this team
managed to uncover a potential common feature for some allergies?
This is a massive study coming out of Tsinghua in Beijing.
First up, this study rocks because the research team that produced it
managed to build a simplified cellular model
for testing how allergies work at the molecular level.
Basically, this model is going to test how epithelial cells interact
with spores from a common mold called Alternaria Alternata
And I'll get into those details in a second.
But, more importantly, building verified in vitro models
like this is an achievement on its own, because scientists can test
so many different variables and still generate clear data.
That's what makes this paper amazing.
We're going to be able
to follow the logic of this research team to a bunch of really cool conclusions.
Ready? Let's go on that journey.
And so when building a model like this, scientists
are going to tune their tests and equipment
to look for a focused set of responses that happen in full organisms.
So let's kick things off by asking, what was this model testing for?
And you know what?
I guess we need to very quickly roll over what allergies are.
And here's the thing.
Allergic reactions are caused by your immune system.
And trying to explain anything that your immune system does
can get astoundingly complicated very quickly.
So I'm going to deeply frustrate every allergist in chat by hitting you
with the most oversimplified explainer for what allergies are.
Ready? Let's go.
Allergies are a kind of inflammation.
The runny nose, the itchy eyes, the sneezing.
That's your immune system flooding an area with fluids, white blood cells
and cute little chemical warfare packages to contain a potential invasion.
Specifically, most allergies come from type two inflammation,
which is mediated by fellahs.
Like your mast cells and eosinophils.
This variety of inflammation probably evolved as a defense
against hardcore invaders like fungi and parasitic worms.
Hence, you know, the really overt response.
Type two inflammation is great to study because it is activated by very specific
molecular signals that scientists can test for when your front line
cells, quote unquote, call in the calvary for an allergic response.
Earlier discoveries have shown there are three big things they do.
First of all, they release a hyper specific alarmin protein called IL 33.
Yes, it is no joke and a protein class called alarmins. More on that later.
Next up, those cells are going to activate a signaling mechanism called MAPK,
which is sometimes turned on
when cells pump a whole bunch of calcium into their cytoplasm.
And finally, those cells are also going to activate a bunch of inflammatory genes
in their DNA,
basically producing a bunch of defense proteins
that can help repel any uninvited guests or call for help.
Specifically, a significant portion of these genes produce proteins
called cytokines and chemokines, which act as more dangerous
signals that activate your immune system or call an immune back up.
A whole mountain of earlier studies has shown that any one of these signals
will activate your immune system, causing special cells to build
and release a very important antibody called IgE.
IgE is eventually used as the activation switch for your allergic goon squad.
So you can think this floppy little doofus the next time you're suffering.
Great job buddy.
We really appreciate what you're doing here.
Now, of course, there is obviously a lot more to allergies than that,
but those are the three main signals that helped guide
the paper we're going to be exploring today.
Before we actually get to that paper, one more layer of background here.
We should probably meet the cells that are ground zero for your allergic reactions.
And you'll meet your airway epithelium.
Now technically allergic reactions can happen in the epithelial cells
lining your eyes and heck, even your skin too.
But this paper focused on the airway.
So you know what we should to. While
all the actual reactions to allergens are pumped out by your immune cells.
These barrier fellas are going to be the ones who raised the alarm
in the first place.
Your airway epithelium is a tightly packed barrier of these little columnar fellows
zooming in.
Their main job is to build really tight junctions with each other and be the
first line of defense against any weird germs that try to break in via your lungs.
Frankly,
their main job is to not be bothered by whatever gunk you just breathed in.
This is what makes allergies so annoying and perplexing.
Type two inflammation in your airways isn't
triggered by an overeager immune system reacting to some random dirt
it just found.
It's *INITIALLY* set off by alarm bells coming from these guys.
So finally getting back to the paper, the experiments done by this team
from Tsinghua University, central to our story, involve
getting a bunch of these barrier cells to comfortably survive
in a more controlled environment, like a warm bath of pink
nutritious cell media inside a petri dish, or whatever.
Once the cell model is established,
we can do whatever we want to these cells, you know, in the name of science.
And you know what the researchers just threw a bunch of mold
extract onto them, highly precise and well calibrated mold extract.
I mean, the research team at Tsinghua University used purified proteins
from a pretty common mold called Alternaria Alternata.
Now, when this... alt little mold isn't bullying tomato leaves, it can set off
some pretty significant allergic responses in anyone who accidentally inhales it.
Spores.
This makes a. alternata a great,
you know, model mold for calibrating these model cells.
And sure enough, when exposed to alternator extract, these model cells
released a bunch of IL-33, boosted all their inflammatory genes,
and sucked up enough calcium to activate their MAPK pathway.
Mold spores cause allergies confirmed! experiment over well done team.
What a cool video, right?
Yeah, no, but of course that's just confirming the model works.
This is Tsinghua University we're talking about.
These teams aren't playing around.
The next step is the actual science part of the paper,
which I am now going to gloss over in a single sentence.
The researchers here carefully filtered the alten area
serum that caused these allergic reactions to the point where they isolated
two individual proteins responsible for activating those allergic signals.
Nice.
And here they are! A pretty small protein and a pretty large protein.
So the researchers named these Aegerolysin- Small and Aegerolysin- large.
Alone they don't look like much.
throw a bunch of these coils into an epithelial cell
and they'll clump together in these little wheel shapes.
And you know what the name really says?
It all.
Turns out when they circle up like this, they basically punch little holes
into the base of our airway epithelium,
which is the start of a really interesting conversation.
Why would these little holes cause an allergic reaction?
And more importantly,
why would "alty" (the mold) here build proteins like this in the first place?
Why are you trying to build pores here, Alternaria?
And right now I think it's important to take a step back
and get a quick big picture look at what a lot of these allergens are doing.
Here's the thing.
Alternaria Alternata spores don't know they're in your airway.
They don't know anything.
They're just randomly floating on the air, hoping to bump into a nice, supple
tomato leaf so they can get to work siring the next generation of moldlings
or whatever you want to call them The minute those spores come into contact
with a little moisture, they're shooting out all the proteins
they need to set down roots.
Complexes like the one made from Aeg-S and Aeg-L, probably are needed to help A. Alternata grab resources from their new host.
They just also happened to kick off an immune response.
To jump back to that original example I used before.
This is actually really similar to why pollen causes an allergic reaction.
It's important to remember what pollen grains are.
They're the--uh-- *boy* part of the plant.
Their entire job is to make their way to the sticky liquid on the stigma
of another plant.
Once pollen hits any kind of dampness at all, it's going to,
you know, shoot its shot.
Throwing out a wave of protein cutting
and growth enzymes in an attempt to build something called a pollen tube.
That's there to ...you know...penetrate the stigma and sire the next generation.
In the case of allergies, you're epithelial cells
just happen to be in the way, and they get all micro-cut up by pollens
initial barrage, despite the fact that those pollen grains
will almost instantly be swept away
by the mucus lining your airway and destroyed by your stomach acid
before they can even think about finishing their pollen tube business.
and yeah, maybe it's a weird way of putting it,
but sometimes these allergic responses happen
because you're getting caught in the crossfire of the circle of life.
Isn't biochemistry super fun?? ...Anyway--
With that super cool.
Tangent aside, let's get back to the real science from this paper.
It's cool that we now have isolated these Aegerolysin
pores as the main thing from alternator extract that causes
allergic reactions, but that doesn't answer our main question here.
How do your epithelial cells know to kick off all these signals
when they're getting... perforated by theAeg-S and Aeg-L pores?
This is the essence of great science.
Teams will try to isolate a few variables inside a living system.
Filter things down to what specifically messes with those variables,
and then test the daylights out of those interactions
to build a mechanistic understanding of what's going on here.
And that's exactly what this team from Tsinghua University did here.
Let's check out the highlights.
Remember, we're looking for three specific signals
to determine that an allergic response is happening.
Let's see how we can modulate those signals.
Model cells that were exposed to a small amount of these Aegerolysin pores
activated two out of the three allergy signals.
They turned on all their inflammatory genes, and they set off this MAPK
pathway, which is kind of technically the same signal, by the way, but whatever.
Meanwhile, the epithelium that got hammered with a huge
concentration of Aeg pores just kind of filled up with water and exploded.
And oh wait, the team from Tsinghua University actually got that on film too.
Nice.
Can I real quick
get some o7's going in the chat for our brave model cells here.
Don't ever forget to show some respect for the quadrillions of individual cells
sacrificed to advance our scientific understanding of how life works.
But, anyway, as they were exploding those cells, experiencing a heavy Aegerolysin
load also released a bunch of that third signal--IL 33-- as a kind of, "help.
I think I'm exploding," message. And with those data points, plus a lot
more we're not covering in this video, we can start to draw some conclusions
about what Aegerolysin pores precisely do to set off an allergic reaction.
Last mile here, folks. Let's put it all together.
To summarize, here's what happens when spores from Alternaria Alternata
hits our airways.
Aegerolysin-S and L form into little pore complexes and perforate
the membrane of our epithelial cells.
This is going to set off a whole cascade of reactions.
First up, calcium ions are going to leak into this epithelial cell
and completely mess up the electrolyte balance in here.
If you've watched any of my videos before,
you know that one of the most important things cells do is actively maintain
a very specific balance of electrolytes in their cytoplasm.
Running those pumps is your largest individual consumer of energy.
Second place isn't even close.
The lion's share of the ATP you generate using food,
energy goes towards running these pumps.
But that's a whole other thing. Anyway--
If that balance gets all out of whack,
it will activate things like this MAPK
signaling pathway and other inflammatory genes.
We tend to talk about cellular events at this level
a little too computationally, and this is a big distraction.
Our epithelial cells don't know they're getting blasted with allergens.
There's no allergy button.
Your body slams down on them and you get hit with a wave of mold spores
or whatever.
Instead, this calcium ion influx triggers an emergency
alert inside your airways that automatically calls in the Calvary.
Nice.
If calcium is there, something bad must be happening.
And that covers two of our three big signals.
Since the MAPK pathway is tied together with the production of these cytokines
and chemokines.
Now if the epithelium just gets hammered with Aeg pores,
then there will be enough holes to allow IL-33 out
into the extracellular space and eventually the bloodstream.
If those cytokines are an alert signal, then IL-33
is a code blue, a Defcon one, whatever you want to call it.
It's a sign for your immune cells to drop everything.
And carpet bomb a region.
That's probably under attack by worms or something.
But if you're deep into biochem here, you know that even though IL-33 doesn't
have the pieces on it necessary to get exported out of cells, normally
it still needs to get cut in order to actually activate the immune system.
Raw IL-33 just isn't going to be able to call in the Calvary.
And this is why I kept bringing up pollen.
Check this out.
The team very specifically pointed out that Alternaria Alternata spores
come with their own protein scissors, a bunch of serine proteases
that are released when they come into contact with water.
They're there to chop up the environment and help
pave the way for alten area spores to set up shop on a new leaf surface.
And here's the thing serine proteases can tend to be a general purpose tool.
They don't care what they're cutting, they're just going to cut
whatever they can for as long as they can.
And previous studies have demonstrated that serine proteases from Alternaia Alternata
specifically can cleave IL 33, thereby activating it... entirely by accident.
And that's the same deal with pollen.
If our eager little soldier here causes enough damage, its proteases can also
activate IL 33 and kick an immune response into overdrive, hence causing allergies.
I should note here that the researchers from Tsinghua University
didn't draw any parallels to pollen in their paper.
Those are just connections I made based on unrelated mechanisms.
Right now, there isn't any evidence that pollen grains release
any kind of pore forming proteins, at least evidence I've seen anyway.
So let's close that tangent for now and bring this thing all the way home.
And I mean, I guess it's cool that we know
the specific proteins from a certain area that induce an allergic reaction.
And it's like, cool
to have a solid understanding of how they kick off that signaling cascade.
But what can we do to confirm
that this could be a general feature for lots of different allergens?
And you know what? That's actually pretty simple.
The researchers isolated similar pore forming proteins from a bunch of different
known allergens and toxins and hurled them at these same model cells.
Incredibly, the cells showed a similar response,
which helps confirm, that it's
these little holes in our epithelial cells that kickstart an allergic reaction.
This is gigantic because it gives a new angle for researchers to take
as we try to understand and build better treatments for allergic responses.
The way we typically talk about allergies is way too broad.
You'll hear folks say that allergies are your immune cells bumping into a protein.
They suddenly decide they don't like setting off an inflammatory cascade.
But studies like this help demonstrate that the immune system
is actively getting called in to deal with very real damage
being done, at least in the case of molds like Alternaria Alternata.
That damage might be mild enough, but A. Alternata's biochemical context
just might over amplify the alert signals originally designed
to help protect you against way more damaging invaders.
In this way, we figured out that some allergens deal
at a kind of micro violence that your body is going to respond to.
Now, potentially, other allergen researchers can screen common pollens
that cause allergic reactions to see if they also leave enough holes
in our epithelial cells to cause an influx of calcium or IL 33 release.
And yeah, anyway, the real magic of this paper is how
it helps us understand that there might actually be common features for allergens,
even if it turns out it's a few common features that are mixed
and matched amongst all allergy causing materials
that still opens the door for better ways to treat and mitigate allergies.
whenever you want to improve the way we treat something,
sometimes it's better to get as close to the source of the problem as possible.
To go upstream of the reaction.
Antihistamines like this only reduce allergies by muting ourselves.
Ability to quote hear the alert chemicals being released by the epithelium.
And that's another drastic oversupply condition.
Don't don't hold me to that.
It would be way better to block those signals
from getting released in the first place if possible, but may be blocking poor
forming proteins ability to make these pores in the first place.
But that's its own can of worms.
For me, this paper was incredible because it managed to put together
so many incredible new insights we've learned about allergic reactions
in the past few years, and managed to shove the science forward by a lot.
This is simultaneously the most frustrating
and most euphoric part about our scientific method.
Our knowledge about the world moves painfully slow but ever forward,
and sometimes a bunch of facts cohere together around a new model,
allowing researchers to crash through a ton of progress all at once.
This is becoming more and more common, as more efficient protocols
and actually useful machine learning supercharge the pace at which biologists
and chemists can find testable hypotheses to chase.
You couldn't pick a more exciting time to be in the life sciences
right now, and I can't wait to keep exploring that with you.
But for now, that's a solid place to leave things.
So all I can say is I really appreciate your time.
Thank you so much for being here. no!
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honestly help me out a lot.
I'm just very curious to see how that plays out in the comments.
Otherwise, I really appreciate your time.
Thank you so much for being here.
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Everyone be well. Thank you so much.