DazeBlog

Look at this.

These two mushrooms right here, as well as those two over there, are known as destroying angels.

And just one of them, just one of them, contains enough alpha-Amanitin to kill you.

So it rained here a lot last week, and that meant that mushrooms were sprouting up everywhere.

Together with a trained mushroom hunter, and I emphasize trained, we found the deadly mushrooms we were looking for.

And by the way, these mushrooms, there's no antidote for them.

But that might be changing soon.

These are Destroying Angels.

They're white, they're ghostly, they're beautiful and it belongs to the Amanita family of mushrooms.

That also includes the extremely toxic death caps as well as the also extremely toxic Fool’s Mushroom.

Now, roughly 90% of all mushroom fatalities globally worldwide are caused by a single class of chemical compounds called cyclopeptides.

And the most toxic cyclopeptide is called Alpha Amanitin or AMA for short.

So when we were out in the field, Annie told me to smell the death caps a few days after and oh God, that is awful.

I mean, it smells like a dead body.

I've never smelled a dead body, so I don't know.

But it smells like death and decay.

Just one death cap or destroying angel can contain 10 milligrams of AMA which is plenty to kill most adults, and don't worry, this is not actually AMA, it's just baking soda.

AMA stops protein synthesis.

It prevents cells from making protein.

And when they can't do that, they die.

But protein synthesis is not immediately mission critical like say breathing is, so AMA is actually a relatively slow acting toxin.

I read a case study once where a woman ate some death caps, went to the hospital, got a bunch of medical care, and then ultimately died.

But it took two weeks for the mushrooms to kill her.

Now that said, they can also kill you a lot faster, a few days to a week.

And AMA is also heat stable, which means that even if you cook the mushrooms, they are still just as toxic as they were raw and will happily kill you without batting an eye.

Warm garlicy death.

And no, these are obviously not amanitin mushrooms.

Do you think I would eat a poisonous mushroom just for a YouTube video?

Come on!

They're death caps.

I'm just kidding.

Unfortunately, there is no antidote for amanitin poisoning, until now.

We will talk about this paper but first we should talk about what an antidote even is.

And the name kind of clues you in anti something, right?

Maybe it's an anti-poison.

Okay, but what is a poison?

Poisons are a type of toxin.

Toxin is an umbrella term.

It basically means any substance that's bad for you in relatively small quantities.

Now, if a creature like a spider or a snake injects a toxin into you, then that toxin is called venom.

If, on the other hand, the toxin seeps through your skin and into your blood or you eat something toxic, then that toxin is called a poison.

Either way, toxins tend to target a specific function in your body, and antidotes are chemicals that block or reverse the action of a specific toxin.

For example, cyanide.

Cyanide poisons you by binding to an iron containing co-factor in an enzyme called cytochrome oxidase.

And normally cytochrome oxidase catalyzes the reduction of oxygen to water, which allows your body to make ATP, which is the energy carrier of the cell.

No cytochrome oxidase means no ATP, which means no energy, which means your cells die very quickly.

Depending on whether you inhale the cyanide, or whether you ingest it, you could die in minutes to hours.

Now the antidote for cyanide poisoning is called hydroxocobalamin.

To a cyanide molecule, hydroxycobalamin looks a lot like cytochrome oxidase and in fact, the cyanide actually prefers binding to hydroxycobalamin which is the antidote, remember, over cytochrome oxidase which is the very essential enzyme in your body that it normally targets.

Now, when cyanide does bind to hydroxycobalamin, the resulting molecule is cyanocobalamin which is also known as vitamin B-12.

Vitamin B-12 is obviously totally non-toxic and you just pee it right out.

Hence an antidote to cyanide poisoning, if you give it fast enough.

Another example, Narcan, also known as naloxone is the antidote for an opioid overdose.

Now this right here is the mu opioid receptor which I've drawn as a cat because it sounds like meow but not because of any biological similarity whatsoever.

Anyway, mu opioid receptor with fentanyl bound to it.

When you administer Narcan, Narcan comes in, it binds to the mu opioid receptor which kicks out anything that was there, including fentanyl.

This basically turns off the effects of the opioid.

But there is one important thing to be aware of.

Some opioids can hang out in your brain longer than Narcan does, and that means that it's possible for a person to relapse even after receiving a dose of Narcan and waking up.

So if you are ever in the position where you have to administer Narcan, it is a good idea to call 911 just to be safe.

Antidotes are very specific to their toxin so hydroxocobalamin is not gonna do anything for you if you've overdosed on opioids and Narcan is not gonna save your life if you've ingested cyanide.

As you can probably guess, it's a lot easier to develop an antidote to a toxin if you know at least something about how the toxin works.

And it was very hard to know how the toxin worked before the invention of toxicology and science, rational thought.

Starting in the 1930s, antidote development really kicked into high gear.

And the classic example of this is the development of something called British anti-Lewisite.

Now, as you might guess, that is an antidote for something called Lewisite which was also known as the Dew of Death.

The Dew of Death was a chemical weapon developed near the end of World War I, but never actually used in World War I. Dew isn't very deadly, though I don't know.

I mean, it's not the greatest nickname.

Anyway, to this day, we still don't actually know exactly how Lewisite works but scientists think that what happens is it gets inside you and then it releases trivalent arsenic which then does toxic things inside your body.

That's the fuzzy part.

I don't know if you could tell, but that's the fuzzy part.

Chemists knew that arsenic loves thiol groups, SH groups.

So they started testing molecules that had them in their structure, and they eventually found this guy, British anti-Lewisite.

BAL scoops up arsenic forming this cyclic arsenic compound that importantly is non-toxic, and that's how it antidotes the dew of death.

Okay, now let's get back to mushrooms which means getting back to this paper.

This was published in May of 2023 and it reports an antidote to death cap mushrooms or actually any mushroom that contains alpha amanitin.

The cool thing is that this method could be used theoretically against any toxin.

And in fact, in 2019 the researchers used this same method to create an antidote against box jellyfish venom.

I have never been bitten by a box jellyfish or I guess stung is the right word, and I hope to never be.

So here's how the method works.

The researchers used CRISPR to find proteins that if they were disabled, made cells resistant to AMA.

So one of the proteins they came up with is called oligosaccharyltransferase complex B and it turns out that AMA needs OSTB to get inside your cells.

So the idea is that if you can inhibit OSTB, then you can prevent AMA from getting into your cells which prevents it from killing you.

So to inhibit OSTB, you need a molecule that's gonna jam itself into the active site of the protein.

But how do you know where the active site is?

Luckily there are chemists, called x-ray crystallographers who devote their entire careers to figuring out the exact 3D structures of proteins and lots of other molecules and then putting that information on the internet for completely free.

And you right now can go download it without giving your firstborn, your bank account information or even your email address.

You can just, right now, you can go do it.

What are you even still doing?

Just go.

It's Protein Data Bank, go download stuff.

So I downloaded OSTB and here is the active site.

Question is, how do you design a molecule that's gonna fit in this active site and jam it up?

If you enjoy masochism, you might do it from scratch using biochemistry intuition which means looking at the enzyme and guessing what the molecule should look like.

So for example, the enzyme has a carbonyl group sticking out here, you think, okay maybe I'll need a hydroxyl group here to hydrogen bond to it, and if the enzyme has an amine group here, maybe I'll need a carboxyl group on my molecule.

Doing it this way would honestly be like trying to do a puzzle, but instead of your usual puzzle, the pieces would be flexible.

You could use each more than once and the whole thing would be in three dimensions and not two.

And even if you did manage to successfully complete this puzzle, there is no guarantee that the molecule you make would actually be safe to put into a human.

Years of work just to fail in the FDA approval process.

But there is another way, and it's actually pretty genius.

Instead of starting with empty space and building up from there, you start with a list of all molecules that are currently approved as drugs by the FDA.

By doing that, you are essentially guaranteeing that if you do find a molecule that inhibits OSTB, it does not have to go through a lengthy approval process.

Doctors can basically start prescribing it tomorrow.

Problem is the list of FDA approved drugs is over 3000 molecules long.

If you wanted to test how well each of these different molecules inhibits OSTB in the lab, it would be obscenely expensive.

Ordering 3000 different molecules, plus enough of the protein to test all 3000 samples.

We are talking thousands, maybe tens of thousands of dollars for a single experiment.

But there's another way.

You can use the free structure of OSTB, which you can download online as well as this software that's also free.

You can virtually put every single molecule on the FDA list into OSTB's active site and see how well it fits.

And that is exactly what the researchers did.

Now look, I need to say that using software to predict the results of an experiment is not the same thing as actually doing the experiment.

But in this case, it is a great way to narrow down the list of molecules you need to test from 3000 to say 30 ish.

The researchers ended up testing 24 different molecules and the one they found with the most anecdotal power was Indocyanine Green.

Indocyanine Green is a medical dye used to visualize stuff inside your body.

It's injected and then it shows up clearly on scans.

It's FDA approved and has been used for years.

So the researchers tested it as an antidote to AMA poisoning in mice.

And what they found was that Indocyanine Green cut the fatality rate roughly in half only when administered up to four hours after exposure to the toxin.

And that's still pretty impressive.

And remember, because this drug is already FDA approved, doctors can start prescribing it tomorrow.

If you eat wild mushrooms and you start to feel bad, call poison control.

It's free, it's confidential and the best part is you get to chat with a toxicologist which I personally always enjoy.

Hopefully some effects will be in there.

Hopefully I'm just not like maniacally laughing alone in my living room.

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