Chapter 33: Prions

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Welcome back to The Deep Dive.

It is so great to have you with us again.

It's good to be here.

Today, we are cracking open a book that has, I think it's fair to say, saved the skin of many, medical students for decades.

Clinical microbiology made ridiculously simple.

Oh, absolutely a classic.

We're looking at the ninth edition, but we are not starting at the beginning.

We're not doing the basics of gram staining or, you know, the structure of a bacterial cell wall.

No, no, we're fast forwarding.

We're fast forwarding.

We are skipping past, what, hundreds of pages on bacteria, viruses, fungi, parasites, and we are landing in a section that well, it feels like it belongs in a different genre of book entirely.

It really does.

We're looking at part five.

Yeah.

And the authors who usually stick to very, you know, very clinical titles for this section, they call it very strange critters.

Very strange critters.

I mean, it sounds less like a medical text and more like a sci -fi anthology from the 70s or something.

Right.

It immediately tells you you're not in Kansas anymore.

And specifically, we are deep diving into chapter 33.

The title of the chapter is just one word,

prions.

And that brevity is so deceptive because while the title is short, the implications of this chapter, they basically challenge everything you learn in the previous 32 chapters.

How so?

Well, if you've been building this mental model of how infectious disease works, you know, a bug gets in, it multiplies, causes damage.

This chapter is here to just smash that model to pieces.

That is exactly the vibe I get just from looking at the visual aids in this chapter.

We're going to be breaking down the diagrams here.

And I have to say, the visual language is, it's just so distinct.

We are not looking at Petri dishes.

We are looking at these stark diagrams of brains, jagged lightning bolts, and lists that casually include words like cannibalism and death.

It is dramatic, but I think that drama serves a very specific purpose for learning.

Okay.

The whole mission for this deep dive really is to decode those visuals.

We need to look at the headers, the diagrams, the list to understand why prions are classified as these strange critters to understand why they aren't bacteria.

They aren't viruses and they aren't fungi.

Exactly.

So let's start right there.

The strange critter hook.

I'm looking at the first major section header in the text, the infectious agent and etiology.

Okay.

Now, usually when I see infectious agent, my brain is primed.

I'm expecting the text to introduce an organism, you know, a little guy with a nucleus, or at the very least, some DNA, some genetic material of some kind.

Right.

But here the source material gives us a diagram and the key, it doesn't show an organism at all.

No, it doesn't.

And this is the first big hurdle every single student has to clear to understand this topic.

We're not dealing with life, not dealing with life.

We're dealing with a molecule, specifically a protein, just a protein, just a protein, no DNA, no RNA, no cell membrane, no metabolism, nothing that we associate with being alive.

That's why the text flags them as very strange.

It's a profound difference.

It is.

In the entire rest of the book, the enemy is a living thing, or at least a genetic entity, like a virus that hijacks living things.

Here, the enemy is.

It's a building block.

It's so hard to wrap my head around that.

How can a protein be infectious?

I think of proteins as the bricks that build the house.

I don't think of a brick as something that can, you know, catch a cold or give me a disease.

And that is the perfect intuition to have, because it highlights just how bizarre this is.

To understand it, we really have to look at the tale of two prions that this central diagram presents.

Okay.

If you look at the legend, the key, at the bottom left of the main diagram, the text identifies two very distinct characters in this story.

Right.

Let's paint this picture for you if you're listening.

We have two symbols on the key.

The first one is labeled PRP, with a Now look at how the artist has drawn this.

What does it look like to you?

It looks organized.

It's drawn as a tight vertical coil, almost like a little spring or a helix.

It looks stable, neat.

Exactly.

It represents structure and order.

And the nomenclature here is key.

PRP stands for prion protein.

Pretty straightforward.

Okay.

And the superscript C stands for cellular or common.

This is the critical takeaway from the text.

PRP is the normal protein.

So it's supposed to be there.

It is.

You have this in your brain right now.

I have it in mine.

It's just sitting on the surface of your nerve cells, minding its own business, doing its job.

Okay.

So PRPC is the civilian.

It's the good guy.

It's part of the normal architecture.

Yes.

But then right below it, in the key, we have the villain.

The text labels this one PRP, but with a superscript SC PRPSC.

And visually, this is just a stark, stark contrast.

It really is.

The artist didn't draw a nice neat coil here.

It looks like a clump.

It's squiggly.

It's messy.

It's tangled.

It looks like a piece of yarn that a cat got to.

That visual disorder is the entire point.

PRPSC is the abnormal form.

The superscript SC technically stands for Scrapey, which is a prion disease found in sheep.

That's historically where this was first characterized.

But for our purposes and for the student who's trying to just memorize this, you can just think of Screamdy as the scrambled version.

Scrambled.

I like that.

So we have the coil, which is the good PRPC and the scrambled clump, the bad PRPSC.

Perfect.

Now the core mystery of this chapter and the thing that makes it a strange critter is how you get from one to the other.

The diagram has this central interaction,

a big arrow connecting the healthy state to the diseased state.

And this is where we have to be so precise with our language, just like the text is.

Read the caption that goes with that arrow.

What is the mechanism it's describing?

The text says PRPSC spreads protein structure change to host PRPC.

Spreads protein structure change.

Note what is missing from that sentence.

What's missing?

It does not say the bad protein reproduces.

It doesn't say it replicates or divides or lays eggs.

It says it spreads chain.

It converts.

This is what we often call the zombie effect in microbiology, even though the textbook is, of course, more formal.

A zombie effect.

Think about a zombie movie.

When a zombie bites a human,

the zombie doesn't get pregnant and have a little zombie baby.

The human becomes a zombie.

That is a terrifyingly helpful analogy.

Okay.

So the scrambled clump, the PRPSC, it physically bumps into a nice normal coil, a PRPC.

And just by touching it, it somehow convinces the coil to unravel and scramble itself?

Essentially, yes.

It acts as a template.

It induces a conformational change.

The good protein refolds into the bad shape.

And now instead of one scrambled protein, you have two.

And those two then go and find two more coils.

Exactly.

It's a chain reaction.

It's exponential.

You start with one single misfolded protein and it just cascades through the brain, converting the host's own normal biology into this pathological toxic form.

And the diagram shows us the result of this.

I mean, we see the bad proteins accumulating.

The drawing shows the brain filling up with these little worm -like squiggles.

And those squiggles represent the amyloid plaques, these clumps of essentially protein garbage that the body can't break down or get rid of.

But the diagram adds another visual element that I think is crucial for the student to notice.

It's not just the squiggles.

No, it's not.

It's the lightning bolts.

Yes, the lightning bolts.

It's very dramatic.

Yellow jagged bolts shooting out of the brain.

It looks like something out of a comic book, a superhero origin story or something.

It does, but it's brilliant visual shorthand.

It answers the question, so what?

So what if my proteins are clumping up?

The lightning bolts represent the neurological dysfunction,

the misfiring neurons,

the cell death, the clumping physically destroys the architecture of the brain.

It literally creates holes in the tissue.

Holes?

Yeah.

That's why we call these diseases spongiform encephalopathies.

The brain ends up looking like a sponge under a microscope, full of voids.

So the lightning bolts are the visual shorthand for catastrophic brain damage.

Correct, and not just mild damage.

We're talking catastrophic electrical functional failure of the central nervous system.

Okay, so we understand the who.

It's these two proteins.

We understand the how.

It's the zombie conversion.

Now we need to look at the where, as in where does the first zombie come from?

Right, the inciting incident.

Because the diagram is very specifically divided into two columns, we have this pink background on the left and a blue background on the right.

This is the study framework.

If you are a student staring at this page,

this split is how you organize your knowledge.

This is your mental filing cabinet.

So two different paths to the same disaster.

Exactly.

Let's start with the left side, the pink column.

The header is infectious pion disease.

The text also calls this exogenous, meaning it comes from outside the body.

Right, you are introducing the bad agent, the PRPSC, into a system that was previously perfectly healthy.

And the diagram gives us a text box here with three specific sources.

And I have to be honest, this list is, it's wild.

It's not your typical transmitted by coughing and sneezing list.

No, this is unique to prions, very specific routes of transmission.

Let's go through them.

Number one, eating infected beef.

This is the dietary link.

This is the one that made all the headlines in 90s.

Mad cow disease.

Mad cow disease or bovine spongiform encephalopathy.

The concept is straightforward.

The cow has the disease.

Its brain and spinal cord tissue are full of PRPSC.

You then eat a burger or some other product made from that contaminated tissue.

But hold on, this is what always confuses me.

And I think the text implies this question.

Why does that work?

We eat bacteria all the time, but we cook our food, right?

If I cook a burger, I kill the ecorlae.

I kill the salmonella.

Why doesn't the heat from the grill kill the prion?

And that brings us right back to the strange critter definition.

If this were a bacterium, heat would denature its proteins, explode its cell wall, it would die.

But PRPSC is just a protein shape.

It's not alive.

And it is an incredibly, incredibly stable shape.

So you can't kill it because it's not alive to begin with.

Exactly.

You can cook that burger until it is well done.

You can cook until it's charcoal.

And that fundamental misfolded protein structure might still remain intact.

It survives the heat.

It survives your stomach acid.

It survives your digestive enzymes.

It gets absorbed into your system and eventually somehow finds its way to your brain.

That is deeply, deeply unsettling.

It's like eating a poison that is immune to destruction.

It is a level of resilience that is almost unheard of in biology.

Okay, moving down the list.

Source number two.

And this is the one that I think makes this chapter stick in everyone's mind forever.

Cannibalism.

Yes.

It is quite the bullet point to see in a clinical summary, isn't it?

It's just sitting there, right between infected beef and surgical instruments.

Cannibalism.

It refers to a very specific and tragic historical context that is actually foundational to all of prion science.

The Kuru epidemic among the four people of Papua New Guinea.

And the mechanism here is the same as the beef, right?

Just more direct.

Biologically, yes, identical.

It was a result of mortuary rituals where the brain tissue of deceased relatives was consumed as a sign of respect.

Oh, wow.

But if the deceased person had the disease, then the person consuming that tissue was ingesting a massive dose of PRPSC.

It really reinforces the idea that you are what you eat in the most horrific way possible.

It's the most direct transmission route you can imagine.

It is essentially a high dose inoculation.

And it proves definitively that the species barrier isn't an issue here.

Human to human transmission is brutally efficient if the infectious tissue is ingested.

And then we have number three on the list,

contaminated surgical instruments.

This is the medical risk.

The fancy word for it is iatrogenic, which just means caused by the doctor or caused by a medical procedure.

But this goes back to the stability thing again, right?

Because hospitals wash their tools.

They have autoclaves.

They steam clean everything at incredibly high temperatures and pressures.

They do.

But standard sterilization protocols, the temperatures and times that are more than enough to kill bacteria and viruses,

historically were not enough to fully denature prions.

They would just stick to the metal.

That is the scariest part of this for me.

You can put a scalpel through a machine that is designed to kill everything known to man.

And this, the shape, this prion comes out the other side, still zombified.

Exactly.

So imagine a scenario.

A neurosurgeon operates on a patient who has an undiagnosed case of Kreuzfeldt -Jakob disease or CJD.

The instruments get covered in the prion.

They wash them.

They autoclave them according to standard procedure.

They think they're sterile.

And then they use those same instruments on the next patient.

They are, in effect, planting the seed.

They are mechanically inoculating the next patient's brain.

This is why modern protocols for neurosurgery are so incredibly aggressive when CJD is even suspected.

In many cases, the instruments are just quarantined or destroyed.

You don't take the chance.

So whether it's a hamburger, a funeral ritual, or a contaminated scalpel, the left side of this diagram, the pink side, is all about the bad protein getting in from the outside.

Correct.

An external invasion.

Now contrast that with the right side, the blue column.

Inherited prion disease.

This is where the story completely shifts.

We aren't eating anything here.

We aren't being exposed to anything.

So what's the trigger?

The text box says,

mutation in PRPC gene is presumed to favor spontaneous change in protein structure to PRPSC.

Let's break that sentence down.

Mutation in the gene.

This is endogenous.

It comes from within your own DNA.

So you're born with a kind of a sabotage code, a self -destruct sequence.

That's a good way to think about it.

You were born with a genetic blueprint that makes your normal coil protein, your PRPC,

just a little bit unstable.

Unstable how?

Imagine building a chair where one leg is just a millimeter too short.

It stands up.

Most of the time it's fine.

But it's always a little bit wobbly.

It's inherently less stable than a perfectly built chair.

And if you wait long enough, or if someone sits on it just the right way.

Exactly.

Eventually, purely by chance, or thermodynamics, or just bad luck, it slips.

It snaps.

One of those unstable proteins spontaneously flips from the coil shape into the scrambled shape.

And once that one protein flips, the game is over.

The chain reaction starts.

The first zombie is now in the house.

And it goes and finds all the other proteins, even the ones that were holding up okay, and it converts them one by one.

That, to me, is the brilliance of this diagram.

You have these two completely different starting lines.

One is, I ate a bad burger.

The other is, I have a bad gene.

But if you look at the bottom of the columns, they merge.

They flow into the exact same picture, the same brain full of squiggles and lightning bolts.

That is the key conceptual anchor for the student.

The etiology, the cause, is different.

One is acquired, one is genetic.

But the pathogenesis,

the mechanism of disease, and the clinical presentation, the result are identical.

The brain doesn't care how the first zombie got there.

Not at all.

Once the conversion process starts, the relentless destruction is exactly the same.

And that destruction leads us to the box at the bottom center of the page, the clinical presentation box.

We've seen the lightning bolts in the brain diagram, and now we have the list of what that actually looks like in a human patient.

And it's a grim list.

This is not a disease of subtle, quiet symptoms.

It's a list of four items.

Item one, dementia.

And we really need to clarify what this means in this context.

When we say dementia here, we are not talking about the slow, gradual memory loss you might see over many years in an elderly relative with Alzheimer's.

No, no.

In prion disease, this is almost always a rapidly progressive dementia.

How rapid are we talking?

We're talking months, sometimes weeks.

It is a catastrophic,

terrifyingly fast unraveling of cognitive function.

Confusion, memory loss, profound personality changes.

The lightning bolts are scrambling the neural circuits that make you you.

Okay.

Then item two on the list, ataxia.

For any listener who hasn't looked at a neurology textbook in a while, ataxia refers to a loss of coordination.

It's usually a sign that the cerebellum, the part of the brain that coordinates movement, is being destroyed.

What does that actually look like in a person?

It looks like a lack of order in every movement.

You try to walk and you stumble and sway.

You look like you're drunk.

You try to reach for a cup of coffee and your hand overshoots it or shakes uncontrollably.

It's not that the muscles are weak.

It's that the brain can't control where the limbs are going in space.

You're losing your mind with the dementia and you're losing control of your body with the ataxia at the same time.

Simultaneously and rapidly, yes.

Item three, and this is the one I really want to focus on because I feel like it connects so perfectly to the visuals in the diagram,

myoclonic jerks.

Myo meaning muscle, clonic meaning rhythmic jerking.

These are sudden involuntary muscle spasms.

Very often, they're brought on by a sudden stimulus like a loud noise.

They're like exaggerated startle responses.

See, this is where I think that lightning bolt in the diagram becomes a powerful mnemonic.

When I see a lightning bolt, I think zap.

I think of an electrical shock.

That is a perfect way to remember it.

That is exactly what's happening.

The brain's electrical system is short -circuiting.

So if you're sitting in an exam and you read the words myoclonic jerks, you should immediately visualize those yellow lightning bolts shooting out of the brain in the diagram.

Absolutely.

It represents that explosive, uncontrolled electrical misfiring.

It's a very, very high -yield association for any test.

And then the list ends with item four, just one word, death.

It's a harsh way to end a clinical list, but it is brutally accurate.

Prion diseases are, as of now,

universally and progressively fatal.

There's no cure.

There is no off switch for that zombie conversion once it begins.

That sense of finality is really emphasized by the other visual aid here, the table provided in the source material.

We have an image of a table that is largely empty in this preview, but the headers are all visible.

And the headers tell you exactly what you need to know to study this.

The headers are the roadmap.

They tell you what questions to ask.

So we have disease, which would be things like Kuru or CJD.

We have typical syndromes, which we just discussed.

We have etiology.

And then there's this last one, duration of illness before death.

That last header is just chilling, isn't it?

Duration of illness before death.

It's not recovery time or prognosis?

No.

It implies that the only real variable between these different named prion diseases like Kuru versus CJD versus something like fatal familial insomnia is speed.

How long does it take?

Six months, one year, 18 months, but the destination is fixed.

And that etiology header in the table?

That's the book checking to see if you paid attention to the pink and blue columns in the main diagram.

Is the disease infectious from the outside or is it inherited from your own genes that that's how you categorize them?

There is one last header on the page sitting all by itself down at the very bottom, treatment.

It looks almost lonely down there, doesn't it?

A single word.

Given everything we've just said, the death bullet point on the symptoms list, the duration before death header in the table.

What can we assume about this section of the chapter?

We can assume it is very, very short and very frustrating for a clinician to read and to live.

The treatment is supportive.

It's palliative.

We can give medications to try to reduce the severity of the myoclonic jerks.

We can help with the anxiety and agitation, but we cannot stop the underlying process.

We don't have a protein untwister.

Not yet.

And that brings us full circle back to why this is a strange critter.

Antibionics work because they target bacterial machinery that our cells don't have.

Antivirals work because they target enzymes specific to viral replication.

But how do you target a misfolded protein shape without harming the billions of normal, correctly folded proteins that the patient needs to survive?

That's the problem.

That is the grand challenge of prion disease.

It's a heavy chapter.

I mean, it's probably only one or two pages in the book, but it packs such a punch.

It does.

It absolutely forces you to rethink the very definition of an infectious agent.

So let's wrap this up with a final recap.

If you are a student listening to this, maybe driving to an exam right now, what are the three essential things you need to lock into your brain from chapter 33?

Okay.

Number one, the agent.

It is a protein, not a bug.

Remember the two forms.

PRPC is the normal coil.

BRPSC is the infectious scrambled cump.

Got it.

Number two.

The mechanism.

It is conversion, not reproduction.

Remember the zombie effect.

It's not multiplying.

It's spreading a structural change, a misfold from one protein to the next.

Right.

Conversion, not reproduction.

And number three.

The visuals.

Use the diagram.

Remember the two paths, infectious, which is the pink column, and inherited the blue column and how they merge into the same disastrous outcome.

And remember the lightning bolts.

The lightning bolt.

If you see lightning bolts on a question, or if you read about myoclonic jerks, you should think dementia.

You think rapid progression.

You should think prions.

And maybe, just maybe, think about how well done you want your next burger.

A little caution never hurts, though thankfully the risk is exceedingly low these days due to changes in farming practices.

Thank you so much for guiding us through the very strange critters of part five.

This was fascinating, if a little terrifying.

It was a pleasure to decode it with you.

It's a really important topic.

And to you, the listener, thank you for sticking with us on this one.

Good luck with your studies.

Keep those proteins folded the right way.

And we will see you on the next Deep Dive.