Chapter 19: Viruses

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All right, I want you to try and picture something for us.

Okay, I'm ready.

Imagine a biological agent that is so unbelievably small that for decades, scientists were absolutely convinced it was a liquid.

Like a poison.

Right, like a ghost in the machine.

Yeah.

I mean, it doesn't eat, it doesn't breathe, it doesn't grow.

You take this thing to put it in a jar, it will just sit there unchanging for a thousand years.

Yeah.

It is

essentially a crystal.

Just a static object.

Exactly.

But, and here's the crazy part, if you drop that exact same crystal onto a living cell, it suddenly wakes up, it breaks in, it hijacks the host machinery, and it turns that cell into a factor.

to make millions of copies of itself.

It really does sound like science fiction, you know, like a microscopic nanobot or something.

It does.

But it's not fiction.

It's biology.

Welcome back to The Deep Dive.

Today, we are cracking open Chapter 19 of Campbell Biology, 12th edition, and we are going to tackle the ultimate masters of the biological gray area.

We're talking about viruses.

It's such a massive topic.

And honestly, it's the kind of topic that forces you to rethink pretty much everything you've ever learned about what it actually means.

And it's a topic that forces you to rethink pretty much everything you've ever learned about what it actually means.

That really is the big philosophical question, isn't it?

Because we've spent all this time in our previous deep dives defining life.

You know, you need cells, you need metabolism, you need to be able to reproduce on your own, and then viruses just come along and, well, they break every single one of those rules.

They really do.

They are the ultimate rule breakers of the natural world.

So here is our mission for today's deep dive.

We are going to completely deconstruct the virus using the material from Chapter 19.

We're going to guide you through the detective story of how scientists even found these things in the first place, which, to be honest, is kind of a comedy of errors involving invisible enemies.

Very much so.

Yeah.

And then we'll look at their structure, which is terrifyingly simple.

We will break down the actual heist, like mechanically, how they hijack a cell.

We'll get into the permanent nature of things like HIV.

And then we're going to end with something that's even simpler and, frankly, scarier than viruses.

Oh, prions, the absolute stuff of nightmares.

Exactly.

Yeah.

But let's start with that hook, that whole are they alive debate, because I feel like I learned in grade school that viruses are emphatically not alive.

But then when you actually see them evolve and attack, they sure act like they are.

Yeah.

It's the debate that just never really ends in biology.

You kind of have to look at the history of it to understand why.

When early microbiologists first started hunting these things, they didn't think they were creatures at all.

They actually thought they were just biologicals.

They thought they were biological chemicals, just poisons.

Which is where the actual name comes from, right?

Right.

Exactly.

The Latin root for the word virus literally just means poison.

They couldn't see a creature under their microscopes, so they just observed the effect.

And the effect was death and disease.

But as we learn more over the years, the pendulum sort of swung the other way.

People started saying, well, OK, maybe they are just the simplest possible form of life.

But the textbook points out there's a pretty massive catch to that.

A huge catch.

Because to be considered alive in the

biological sense, you need to be able to reproduce.

You need your own metabolism.

You have to be able to process energy.

And viruses just can't do any of that.

So if I have, say, a test tube full of the flu virus and I just leave it sitting on my desk.

It does absolutely nothing.

It is completely biologically inert.

It's just complex chemistry sitting in a tube.

It cannot replicate itself.

It cannot generate ATP for energy.

It is totally static.

Right.

Until it touches a living cell.

Right.

Until it enters a host.

And then suddenly it borrows the host's metabolism.

It uses the host's ribosomes to make its own proteins.

It steals the host's energy.

The textbook actually uses a specific phrase for this, right?

A borrowed life.

Yes.

They lead a kind of borrowed life.

They exist in this really shady, fuzzy gray area right between actual life forms and just complex chemicals.

That's just so unsettling.

Because it suggests that for you and me, life isn't just a simple binary switch like you're either on or off, alive or dead.

It's more of a spectrum.

And viruses are hovering right there on the edge.

Exactly.

And because they sit on that edge and because they are so incredibly simple, they were remarkably hard to discover.

Which brings us perfectly to the discovery story in Concept 19 .1.

I really love this part of the chapter because it highlights how scientific inquiry actually works.

It's basically just people stumbling around in the dark, testing things until they bump into the truth.

Let's take you all the way back to 1883.

Right.

We're in Germany with a scientist named Adolf Mayer.

Yes.

Mayer.

And he is studying...

Tobacco plants.

Now, you have to remember, tobacco was a massive cash crop.

So if something was messing with the harvest, it was a huge economic deal.

And something was definitely messing with it.

It was tobacco mosaic disease.

It gets that name because it causes the tobacco leaves to develop this really distinct, mottled mosaic pattern of light and dark green spots.

Plus, it heavily stunts the growth of the plant.

The infected plants just look terrible.

So Mayer puts on his detective hat.

He takes a sick plant.

He grinds up the diseased leaves to extract the sap.

And then he just rubs that infected sap directly onto a healthy plant.

It's a classic, straightforward transmission experiment.

And just as you'd expect, the healthy plant gets sick.

So Mayer says, aha, it's contagious.

Right.

And in 1883, if you find something that's contagious, you immediately assume it has to be a bacterium.

They knew about bacteria at this point.

They had microscopes.

So Mayer takes that infectious sap, puts it out of his best microscope, and he starts looking for the germ.

What does he find?

Absolutely nothing.

He sees no bacteria at all.

So what was his conclusion?

Did he think he had discovered some kind of invisible ghost?

No, because he was a rational, methodical scientist.

He looked at the evidence and concluded that the pathogen must still be a bacterium, but one that was just unusually small, like so tiny that it was beyond the resolution of his microscope.

Which is a totally fair hypothesis, given what he knew.

But of course, he was wrong.

He was definitely wrong.

But that tiny bacteria hypothesis actually held up, for about a decade.

Until we move over to Russia in 1893, to a scientist named Dmitry Ivanovsky, he decides to rigorously test Mayer's tiny bacteria theory.

And he does this using a porcelain filter.

I want to emphasize this for you listening, because the equipment here is key.

Yeah, this was a critical piece of technology at the time.

It was a filter made out of unglazed porcelain.

And the pores in this porcelain were so incredibly microscopic that even the smallest known bacteria could not be found.

And so he decided to use a porcelain filter.

And so he it was originally designed to purify water.

If you pour water full of bacteria through this porcelain, the bacteria get trapped on top, and completely sterile, safe water drips out the bottom.

So Ivanovsky has a brilliant thought.

He thinks, okay, I'll take this infected tobacco plant sap and pour it through the porcelain filter.

If Mayer is right, and the disease is caused by a tiny bacterium, the bacteria will get stuck in the filter and the clear sap coming out the bottom will be turned into a porcelain filter.

And so he decided to use a porcelain filter.

And so he totally harmless.

Precisely.

It's a great experimental design.

So he runs the sap through the filter.

He takes the filtered liquid, which by all known science should be completely sterile, and he rubs it onto a healthy tobacco plant.

And the plant gets sick anyway.

The plant gets sick.

That must have been so infuriating for him.

Oh, I'm sure it was baffling because it essentially meant one of two things.

Either these bacteria were impossibly, unimaginably smaller than any cell could theoretically be, or...

Or it wasn't a bacteria at all, which leads to the other theory, right?

Maybe it was a toxin.

That was the logical next step.

Maybe the bacteria were getting caught in the filter, but they were secreting some kind of chemical poison.

And that liquid poison was small enough to wash right through the porcelain pores.

So Ivanowski is sort of stuck.

He knows the sap is infectious.

He knows whatever is causing it is tiny, but he still kind of clings to the idea that it's bacterial in origin.

And that sets the stage for a Dutch botanist named Martinus Bejerink.

Bejerink is...

Arguably the real hero of this particular story.

He is the one who tackles that toxin theory head on.

He realized something very fundamental.

If the disease agent were just a chemical toxin, just a poison, it would dilute over time.

Walk us through the logic of that.

How did he prove it wasn't diluting?

Think about it this way.

Imagine you have a cup of chemical poison.

You pour it on a plant.

That plant gets sick.

Then you take a tiny drop of sap from that sick plant and put it on a second plant.

Then a drop from the second plant gets sick.

On to a third plant.

By the time you get to the 10th plant, that original drop of poison would be so incredibly diluted that it wouldn't have any effect at all.

But that is not what happened in Bejerink's experiments.

Not at all.

The disease was just as potent, just as aggressive on the 10th plant as it was on the very first plant.

That proved definitively that the infectious agent wasn't a static chemical.

It was replicating.

It was actively making more of itself inside the host plant.

Okay, so it replicates.

That rules out a simple chemical toxin.

So no, it's significantly smaller than any bacteria.

Right.

And here is the real kicker of Bejerink's work.

He tried to culture this agent in a test tube.

Now, you can easily grow bacteria in a petri dish with nutrient agar.

You just give them food and they multiply.

But this mysterious agent, nothing.

It absolutely refused to grow or multiply unless it was inside a living host cell.

So Bejerink puts all these clues together.

It's not a standard bacteria.

It's not a chemical toxin.

It is something entirely unprecedented.

He called it contagium vivum fluidum, which translates to contagious living fluid.

He basically conceptualized the very idea of a virus, a replicating infectious particle that is much smaller and much simpler than a cell.

He is credited with voicing the concept of a virus.

But even with that brilliant deduction, they still couldn't actually see the thing.

No, the technology just wasn't there yet.

They wouldn't actually see a virus for another 40 years.

But before they could see it, 1935, an American scientist named Wendell Stanley finally proved what it physically was.

And he didn't do it with a microscope.

He did it using chemistry.

Right.

He crystallized it.

Yes.

He took the infectious agent, the tobacco mosaic virus or TMV, and he managed to crystallize the particle.

Now, for someone listening who might not be a chemist, why is crystallizing it such a massive mic drop moment in biology?

Because cells simply do not crystallize.

You cannot take a mouse or a bacterial cell or a human skin cell and crystallize it.

You cannot take a mouse or a bacterial cell or a human skin cell and crystallize it.

You cannot take a mouse or a bacterial cell and turn it into a neat geometric crystal.

Cells are wet, messy, incredibly complex bags of dynamic fluid and machinery.

Crystals, on the other hand, are highly ordered, repetitive, static structures.

Pure chemicals crystallize.

Minerals crystallize.

Purified proteins crystallize.

Living biological cells do not.

So just by the sheer act of turning it into a crystal, Stanley proved it.

It wasn't a cellular creature at all.

It was a particle.

Exactly.

That was the pivotal moment, where the line between biology and chemistry became completely blurred.

And then, shortly after Stanley's work, scientists invented the electron microscope, and we could finally actually look at these things.

And what we saw is weird.

So let's transition into concept 19 .1 and talk about the actual physical structure of viruses.

If you are used to studying cells, you know, these massive, beautiful, complex, miniature cities with a nucleus and mitochondria and a complex cytoskeleton, a virus looks incredibly barren.

It's like a minimalist apartment with, almost no furniture.

It is surprisingly, almost aggressively simple.

It really is.

A virus is, at its absolute core, basically just two things.

It is genetic code and a box to put that code in.

Code in a container.

That's it.

That's it.

The textbook defines a virus as an infectious particle consisting of nucleic acid enclosed in a protein coat.

And occasionally, some of them have a membranous envelope around that coat.

But the fundamental core is just those two basic components.

Let's talk about the scale of these things first.

Because we've used the word small a lot, but small is highly relative.

We say bacteria are small.

How much smaller are viruses compared to bacteria?

Oh, significantly smaller.

Think about a ribosome.

A ribosome is a tiny molecular machine found inside our cells that manufactures proteins.

It's just a tiny speck floating inside a cell.

The tiniest viruses are actually smaller than a single ribosome.

They're only about 20 nanometers across.

Whoa.

So just to visualize that, if an average animal cell was the size of, say, a massive football stadium.

If the cell is a whole stadium, a typical virus is maybe the size of a soccer ball sitting right on the 50 yard line or maybe a marble.

That is an absurdly small scale.

No wonder they slipped right through Ivanowski's porcelain filter.

Exactly.

OK, so let's look inside that tiny box.

Let's talk about the genome, the code.

Now, you and I, we're used to our own human DNA.

It's double stranded.

It's massive.

It contains tens of thousands of genes.

Viruses, I assume, are quite a bit simpler.

They are simpler and they are incredibly chaotic.

They basically break every established rule of genetics.

In our cellular world, the golden rule is that double stranded DNA is the master blueprint, period.

But viruses, they don't care about that rule at all.

A viral genome can be double stranded DNA, sure.

But it can also be single stranded DNA or it can be double stranded RNA or a single stranded RNA.

Wait, they just use whatever type of nucleic acid they want.

Pretty much.

In fact, viruses are formally classified based on what specific type of genetic material makes up their genome.

And regardless of the type, their genomes usually consist of just a single linear or circular molecule of a nucleic acid.

And how many genes are we talking about here?

Because a human has what, around 20 ,000 genes?

A bacteria might have a few thousand genes, but a virus, some of the smallest viruses have only three genes in their entire genome.

Three.

Just three genes.

How can you conquer a host of three genes?

Because those three genes are incredibly efficient.

They basically just say, build the box and copy the code.

They pack super light because they don't need to carry all the heavy metabolic machinery required to actually live.

They just plan to steal all that machinery from the host cell.

That makes sense.

OK, so that's the code.

Now let's talk about the box itself, the shell.

The text calls this the capsid.

Right.

The protein shell that perfectly encloses the viral genome is called the capsid.

And it is built from a large number of individual protein subunits, which are called capsomeres.

Capsomeres.

Got it.

And Campbell Biology has this great visual breakdown, figure 19 .3, that illustrates the different shapes these capsids can take.

Because they aren't all just simple spheres.

They form these fascinating geometric shapes as a solution to a structural problem, right?

Like, how do I build a sturdy container using the absolute minimum amount of genetic code?

Exactly.

They have to be mathematically efficient.

And the text outlines three main categories of viral shapes.

First, you have the helical virus.

Tobacco mosaic virus is the classic example of this.

Imagine taking a bunch of identical protein groups and stacking them in a tight spiral, kind of like a spiral staircase.

It forms this rigid, hollow, rod -shaped tube.

And the viral RNA is just neatly coiled around inside that tube.

So it looks a bit like a microscopic protein straw.

That's a great way to picture it.

Next, you have the icosahedral virus.

This is the shape of an adenovirus, which is a common virus that causes respiratory infections in humans.

An icosahedron is a polyhedron with exactly 20 identical triangular faces.

It looks exactly like a 20 -sided die from Dungeons and Dragons.

It really does.

And the reason they use that specific shape instead of, say, a perfect smooth sphere is because an icosahedron is the most mathematically efficient way to build a closed, near -spherical shell out of identical flat protein subunits.

In the case of the adenovirus, it's made of exactly 252 identical protein molecules.

It's structural perfection achieved with minimal genetic instructions.

It's beautiful in a sterile sort of way.

And then, well, then we have the third category, the ones that genuinely give me the creeps, the complex irises.

Ah, yes, the bacteriophages, or phages for short.

Even that name is aggressive.

Bacteriophages?

It translates directly to bacteria eater.

These are viruses that specifically target and infect bacterial cells.

And they do not look like simple straws or 20 -sided dice.

They look exactly the same.

Exactly like the Apollo lunar lander.

They really do.

I'm looking at figure 19 .3 right now, and it is uncanny.

You have this complex icosahedral head sitting at the very top, which acts as the vault holding the DNA.

Then below that, there's this rigid tail sheath.

It looks like a long mechanical neck.

And at the bottom, there are these spindly tail fibers that look exactly like jointed spider legs.

It is, for all intents and purposes, a microscopic mechanical syringe.

When a phage attacks, those spider legs land perfectly on the surface of a bacteria.

And that tail sheath actually contract.

It physically scrunches down like a spring.

And it drives a hollow tube straight through the thick bacterial cell wall, forcibly injecting its DNA into the host.

It is terrifyingly industrial.

It's a literal machine.

It is a molecular machine perfectly evolved for injection.

Now, some viruses have one more structural layer outside the capsid, an envelope.

Right.

This is particularly common in animal viruses like the influenza virus.

The virus will cloak its protein capsid in a membranous envelope.

But here is the really sneaky part.

It is not a viral membrane.

It is derived directly from the host cell's own membranes.

Wait, explain how that works.

When the newly formed virus is preparing to leave the infected cell, it actually wraps itself up at a piece of the host cell's own plasma membrane.

It essentially steals the host's skin as it exits.

So it's wearing a disguise.

It is a disguise, yes.

But it actively modifies that stolen membrane.

Before it leaves, the virus studs the outside of that stolen membrane with specific viral proteins called glycoproteins.

So it's like putting on a stolen security card uniform, but then you pin your own special badge onto the lapel.

Exactly.

And that badge is what allows you to unlock the next door you encounter.

The envelope provides camouflage, but those glycoproteins act as the key card to infect the next host cell.

That is brilliantly sinister.

OK, so we've established the components.

We have the code, we have the capsid container, and sometimes we have the crystal and envelope.

Now, let's talk about the actual crime.

Let's move to concept 19 .2, viral replication.

How does this inert, static crystal actually manage to take over a living, breathing cell?

It is a hostile takeover through and through.

The textbook refers to viruses as obligate intracellular parasites, which means they are absolutely obligated to be inside a cell to do anything parasitic.

But the process always starts with access.

A virus can't just infect any random cell it bumps into.

It has what we call a specific host range.

This is the classic lock and key concept, right?

Precisely.

The virus has those surface proteins, the keys, and they have to fit perfectly into specific receptor molecules on the outside of a potential host cell, the locks.

If the key doesn't fit the lock, the virus just harmlessly bounces off.

So that's the biological reason why my dog can't catch the measles from me.

Exactly.

The measles virus has a very specific key that only fits a specific lock found on human cells.

It simply doesn't fit the molecular locks on dog cells.

So we say its host range is extremely narrow.

Other viruses, like the West Nile virus, possess more of a master key.

They can successfully open locks found in mosquitoes, birds, horses, and humans.

They have a very broad host range.

OK, so let's say the virus finds the right lock.

The key fits.

It enters the cell.

What happens next?

Once it's in, it initiates the general replicative cycle.

It's essentially a four -step process.

Entry, reprogramming, assembly, and exit.

Let's break down that second step, reprogramming.

Because I think this is where that borrowed life concept really hits home.

Once the viral genome is inside and the capsid is stripped away, the host cell is essentially doomed.

The viral DNA or RNA acts like a brand new overriding set of orders from corporate headquarters.

It ruthlessly commands the host cell to completely stop whatever normal functions it was doing and to redirect all its efforts into copying the viral genome and manufacturing viral capsid proteins.

Then the host cell just obeys.

It doesn't fight back.

At a mechanical level, it really has no choice.

The viral code is just read by the cell's machinery like any other code.

The host cell innocently provides all the free nucleotides for DNA synthesis.

It provides all the necessary enzymes.

It provides the ribosomes to make the proteins.

It provides all the ATP energy.

The virus brings literally nothing to the table except the blueprints.

The host provides all the labor and all the raw materials.

It really is a factory takeover.

It's like someone breaking into a car factory and saying, stop making sedans.

We're only making tanks now.

That's a perfect analogy.

And once all those new tank parts are manufactured, thousands of copies of the viral genome, thousands of individual capsid proteins, they enter the assembly phase.

Do they need some kind of specialized cellular machine to put all those pieces together?

No.

And this is the really beautiful physics driven part of the process.

The viral components are shaped in such a specific way that they spontaneously self assemble.

It's thermodynamics, like microscopic magnets just napping into their lowest energy configuration.

You could theoretically just mix purified viral RNA and capsomeres in a test tube, and they would spontaneously form intact infectious viruses.

Wow.

And then once they are assembled, they exit the cell.

Right.

And usually that mass exodus physically destroys the host cell.

OK, so that gives us the broad general idea.

But the textbook spends a very significant amount of time detailing how those lunar lander viruses of the bacteriophages do this.

And phages have two very different, very distinct strategies for replicating the lytic cycle and the lysogenic cycle.

I have to admit, I always get the names of these two mixed up.

It's very common to mix them up.

The easiest way to keep them straight is to think of their ultimate goals.

The lytic cycle is an immediate explosion.

The lysogenic cycle is a patient squatter.

OK, let's start with the explosion.

The lytic cycle.

Lysis literally means to break or burst, right?

Exactly.

Let's look at a phage named T4.

The text uses T4 as the classic example of a phage that uses the lytic cycle.

We call a phage that only uses this cycle a virulent phage.

So T4 lands on an E.

coli bacteria, uses its tail to puncture the wall and injects its DNA.

Almost immediately, it goes to all out war.

One of the very first things the phage DNA does is command the cell to produce an enzyme that actively hydrolyzes or chops up the host bacteria's own circular DNA chromosome.

Deliberately destroys the bacteria's hard drive right out of the gate.

Completely shreds it.

The bacteria is now just an empty zombie shell.

It has no instructions of its own left.

So the phage machinery completely takes over.

It pumps out viral genomes.

It synthesizes viral proteins and it undergoes that spontaneous self -assembly we talked about.

Finally, the phage directs the cell to produce a specific enzyme that damages the bacterial cell wall from the inside because the wall is compromised.

Osmosis causes water to rush into the cell.

The cell swells up and boom, it lexes.

It literally bursts open.

Yes.

Releasing somewhere between 100 to 200 completely new, fully assembled phages that immediately float off to hunt down other healthy bacteria.

That is incredibly aggressive.

It's a total smash and grab operation.

It is highly effective, but it has a major strategic flaw.

It kills the host immediately.

And from an evolutionary standpoint, that's not always the smartest strategy.

If you rapidly kill all the available hosts in your environment, you run out of factories and your viral lineage dies out, too.

So that's where the patient squatter comes in.

The lysogenic cycle.

Right.

Some phages are capable of using both the lytic and lysogenic cycles.

We call these temperate phages.

The textbook uses a phage called Lambda as the primary example here.

In the lysogenic cycle, the Lambda phage injects its DNA into the bacteria just like before, but then it stops.

It does not destroy the host's DNA.

Instead, the viral DNA forms a circle and then physically splices itself.

It integrates itself directly into the bacterial chromosome.

Wait, it just cuts and pastes its own genetic code into the bacterial genome?

Yes.

And once the viral DNA is officially integrated into the bacterial chromosome, it gets a new name.

It is now called a prophage.

It has become a silent, hidden part of the bacteria's own genetic identity.

But doesn't that prophage immediately start making viral parts and make the bacteria sick?

No.

That is the brilliant trick of the lysogenic cycle.

One specific gene on that prophage codes for a repressor protein.

And that repressor protein actively shuts down the expression of almost all the other

genes.

It keeps the virus totally quiet so the bacteria doesn't know it's infected.

It just lives its normal bacterial life.

It eats, it grows, and most importantly, it divides.

And when a bacteria divides?

It faithfully copies its entire chromosome.

And because the prophage is part of that chromosome now, the bacteria silently copies the viral DNA right along with it, passing it on to both daughter cells.

So the bacteria is unknowingly acting as a cloning facility for the virus.

Exactly.

A single infected cell can rapidly divide and give rise to a massive population of bacteria, every single one of them carrying this silent sleeper agent tucked away in their DNA.

But obviously the virus doesn't want to stay asleep forever.

Right.

It eventually has to get out.

Right.

It's waiting for a specific signal to wake up.

Usually that trigger is an environmental stressor.

Things like high energy radiation or exposure to certain toxic chemicals.

Basically, the prophage detects a signal that says the host cell is in serious trouble.

It might die.

It's like realizing the ship you're hiding on is sinking.

So it's time to find a lifeboat.

That's a perfect way to put it.

When that environmental distress signal hits, the prophage actively excises itself.

It cuts itself back out of the bacterial chromosome and immediately switches over to the aggressive lytic cycle.

It rapidly builds the new phages, bursts the cell and escapes before the host dies of other causes.

I have to say, for a simple piece of genetic code, that is an incredibly sophisticated logic gate.

Hide and multiply quietly.

When times are good, smash and grab when times are bad.

It's a masterpiece of natural selection.

Speaking of natural selection, bacteria have been dealing with these phage attacks for billions of years.

Surely they haven't just accepted their fate as viral factories.

They must have evolved some defenses.

Oh, absolutely.

It's a classic ongoing evolutionary arms race.

And the textbook outlines a few major ways bacteria fight back.

The first is just straightforward natural selection.

Because bacterial populations reproduce so quickly,

mutations happen often.

If a bacteria happens to experience a random mutation that slightly changes the physical shape of its surface receptor proteins.

And the virus's key no longer fits the lock.

Exactly.

The phage lands, but it can't attach.

The bacteria survives and passes that mutated resistant receptor onto its offspring.

The second major defense is internal.

Bacteria produce things called restriction enzymes.

I always loved that name.

It sounds like a bouncer at a club.

And that's exactly how they function.

These are cellular enzymes that constantly patrol the inside of the bacterium.

Their entire job is to look for foreign, unrecognized DNA.

If a phage injects its DNA, the restriction enzymes identify it as foreign and physically cut it up.

They restrict the ability of the phage to infect the cell.

But wait, if these enzymes just swim around cutting up DNA, how do they know not to cut up the bacteria's own DNA?

That's the clever part.

The bacteria's own chromosomal DNA is methylated, meaning it has these tiny chemical methyl groups attached to it at specific locations.

Those methyl groups act like VIP passes that tell the restriction enzymes do not cut.

The incoming phage DNA doesn't have those markers, so snip.

That's elegant.

But the absolute coolest bacterial defense, and honestly, the one that has completely revolutionized modern human genetics, is the CRISPR system.

Ah, yes, the CRISPR -Cas system.

This is, without exaggeration, the bacterial equivalent of an adaptive immune system.

It actually gives the bacteria a memory of past infections.

I really want to take our time explaining this, because everyone hears the word CRISPR on the news all the time as this futuristic gene editing tool.

But the textbook shows us where it actually comes from in nature.

Right.

Nature invented it first.

In the bacterial genome, there is a specific region called the CRISPR region.

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, which is a mouthful, but essentially it's a section of DNA made up of repetitive sequences.

But the key is what lies between those repeats.

There are unique stretches of DNA called spacers.

Scientists analyzing these spacers realize something mind -blowing.

Those spacer sequences precisely match the DNA of known bacteriophages.

So they are like genetic trophies or mugshots.

Exactly like mugshots.

Here's how it works.

If a bacterial cell somehow survives a phage infection, a complex of bacterial proteins will actually snip out a small piece of the defeated viral DNA and physically file it away in the CRISPR region of its own chromosome.

It's logging the attacker's fingerprint.

Remember this guy.

OK, so the bacteria now have a permanent record of the attacker in its own DNA.

What happens if that exact same type of phage tries to attack again?

This is where the defense mechanism kicks in.

If the bacteria is attacked again, it transcribes that specific CRISPR spacer DNA into a strand of RNA.

That RNA molecule is essentially a wanted poster.

It links up with a specialized protein called a Cas protein.

Cas9 is the most famous one.

The Cas protein is a nucleus.

It's a pair of molecular scissors designed to cut DNA.

So the RNA wanted poster guides the scissors to the target.

Yes.

The Cas RNA complex floats around inside the cell.

The RNA guide is looking for any invading DNA that perfectly complements its own sequence.

If the phage injects its DNA, the RNA guide binds to it.

And the moment that perfect binding occurs, it triggers the Cas protein to clamp down and physically cut the invading phage DNA, destroying it before it can hijack the cell.

Snip virus neutralized.

It is a programmable, highly targeted weapon.

The bacteria is literally using a piece of the virus's own historical code to identify and destroy it in real time.

That is just it's mind blowing.

We normally think of immunity as this complex thing involving white blood cells and antibodies and lymph nodes.

But here you have a single microscopic bacterial cell with a genetic filing cabinet of enemies and a pair of RNA guided scissors.

It's one of the most elegant defense mechanisms in biology.

OK.

Let's pivot.

Let's leave the microscopic world of bacteria and talk about viruses that infect us.

Animal viruses.

Because while we do have complex immune systems, animal viruses have evolved some incredibly nasty tricks to get around them.

We briefly touched on the envelope earlier.

Right.

The viral envelope completely changes the rules of engagement.

In the bacterial world, the phage has to mechanically drill a hole through a tough, rigid cell wall.

But in animals, our cells don't have rigid walls.

We just have a soft, squishy fluid plasma membrane.

Enveloped viruses, like the influenza virus, don't need to drill.

They use those viral glycoproteins to bind to our cell receptors and then their stolen envelope simply fuses directly with our plasma membrane.

The virus just melts right into the cell.

And the way they exit is different, too, right?

They don't always use the lytic explosion.

No.

Many enveloped animal viruses use a process called budding.

Instead of bursting the cell, the newly assembled virus pushes gently against the inside of the host's plasma membrane.

It pushes and pushes until it creates a little outward bubble.

Eventually, that bubble pinches off, wrapping the virus in the host's membrane as it leaves.

And because it just pinches off, the host cell actually survives the exit.

Often, yes.

The host cell might be damaged or depleted, but it doesn't instantly explode, which means that infected cell can remain alive and function as a continuous churning virus factory, budding off new viruses for quite a while.

But the textbook emphasizes that the absolute biggest complication with animal viruses and the reason things like H .H.

B .V.

are so uniquely devastating comes down to their genetic material, specifically the ones that use RNA.

Yes, the RNA complication.

This is a massive biological hurdle.

You see, normal cellular machinery in humans, animals, plants is strictly built to follow the central dogma of molecular biology.

DNA makes RNA and RNA makes protein.

We have plenty of enzymes like RNA polymerase designed to read a DNA template and transcribe it into RNA.

Right.

Transcription.

Right.

But normal host cells do not possess any enzymes that can read an RNA sequence and use it to synthesize more RNA.

We simply do not have a biological photocopier for RNA.

So if a virus like the flu, which has an RNA genome, enters a human cell,

how does it manage to replicate its code if the host lacks the machinery?

It has to bring its own tools.

The viral genome itself actually codes for a specialized viral enzyme, an RNA dependent RNA polymerase.

The virus brings the genetic instructions to build the exact tool that the host cell is missing.

So once inside, the host ribosomes read the viral RNA, build the viral polymerase, and then that viral polymerase goes to work copying the viral RNA genome.

So the virus essentially says, oh, you don't have the machinery to copy me.

That's fine.

I brought the blueprints for my own machinery.

Exactly.

But the absolute most complex, rule breaking manifestation of this RNA problem is found in class six viruses, the retroviruses.

This is where we talk about HIV, human immunodeficiency virus.

Yes.

HIV is the quintessential retrovirus.

The prefix retro means backwards.

And these viruses literally reverse the standard flow of genetic information.

Instead of going from DNA to RNA, retroviruses go from RNA backwards to DNA.

Which, based on everything we learned in previous chapters, shouldn't even be structurally possible.

It shouldn't be.

But again, they bring a specialized tool.

Retroviruses come equipped with a unique viral enzyme called reverse transcriptase.

The name pretty much says it all.

It performs transcription, but in reverse.

Exactly.

If you look at Figure 19 .8 in the text, it outlines the HIV replicative cycle in detail.

HIV is enveloped.

It has specific glycoproteins that bind to receptors on certain human white blood cells.

It fuses with the membrane and releases its capsid into the cell.

The capsid degrades, releasing the viral RNA and that reverse transcriptase enzyme.

OK, I'm following.

Then the reverse transcriptase immediately gets to work.

It reads the single -stranded viral RNA and it synthesizes a complementary strand of DNA.

Then it synthesizes a second DNA, strand complementary to the first.

So now, floating in the cytoplasm of the host cell, you have a newly minted piece of double -stranded viral DNA.

It literally turned its working copy back into a master blueprint.

Yes.

And here is where it gets truly insidious.

That newly formed double -stranded viral DNA travels into the host cell's nucleus and it actively integrates itself directly into the host's chromosomal DNA.

OK, wait, that sounds exactly like what the prophage does in bacteria during the lysogenic cycle.

It is very similar, but there is one critical, terrifying difference.

In bacteria, we saw that the prophage eventually excises itself.

It leaves the bacterial chromosome to initiate the phyrolytic cycle.

But in retroviruses, this integrated viral DNA, which we call a provirus, never leaves.

Never.

It just stays there.

Never.

It is a permanent, permanent resident of that cell's genome.

If a person is infected with HIV, that viral genetic code is seamlessly stitched into the DNA of their white blood cells for the rest of their life.

Every single time that host cell divides, the provirus is faithfully copied along with it.

And the host cell just, it just reads the provirus like it's a normal human gene.

The host cell's machinery cannot tell the difference.

The host's own RNA polymerase binds to the provirus DNA, transcribes it into mRNA, and that mRNA is used both to translate new viral proteins and to serve as the new RNA genomes for the next generation of viruses.

They assemble, they bud off the white blood cell, and they go infect more cells.

Perfectly explains why HIV is so incredibly difficult to cure.

We can develop drugs that kill the active virus floating in the bloodstream, but we can't just go in and scrub the blueprint out of the DNA of the patient's own living cells.

Exactly.

It hides inside the library itself.

It becomes part of the host.

That is just terrifyingly permanent.

It really is.

So let's zoom out for a second.

We've talked about phages, RNA viruses, retroviruses.

Looking at all this insane variety, a huge question comes up.

Where do these things even come from?

Did viruses exist before the first cells evolved?

Like, did life start with viruses?

It's a great question, but the virus first hypothesis has largely been discarded by modern biologists because, as we keep saying, viruses are obligate intracellular parasites.

They absolutely require a host cell's complex machinery, rhizomes, ATP enzymes to reproduce.

If there are no cells around, there is no way for a virus to replicate or sustain itself.

Right.

A parasite can't exist before its host exists.

So the cell must have come first.

The current scientific consensus is that viruses actually evolved after the first primitive cells appeared.

So if they came from cells, what are they?

The leading hypothesis is that viruses originated from naked bits of cellular nucleic acids that somehow gained the ability to move from one cell to another.

Think about what we call mobile genetic elements.

You mean the plasmids?

We talked about those in the genetics chapters.

Exactly.

Plasmids are small, circular, independent loops of DNA found in bacteria and yeast.

They replicate in cells.

They replicate separately from the main chromosome.

And crucially, they can be physically transferred between different cells.

Then you also have transposons.

The jumping genes.

Right.

Transposons are DNA segments that can literally cut and paste themselves to entirely different locations within a cell's genome.

Plasmids, transposons and viruses all share this fundamental characteristic.

They are mobile genetic elements.

So the idea is that millions of years ago, some of these jumping genes or plasmids managed to wrap themselves up in a basic protein coat and figured out how to leave the cell entirely and enter a new one.

That's the most widely accepted model.

A virus is basically a rogue plasmid or transposon that put on a protein spacesuit so it could survive the journey between cells.

The discovery of giant viruses like the Mimivirus, which actually contains some genes previously thought to only exist in cellular life, further blurs the lines and supports this evolutionary link.

That makes them sound even more like rogue computer code.

Like a tiny software glitch that figured out how to email itself to other computers.

It is a very, very apt analogy.

OK, let's talk about the real world impact.

Let's move into concept 19 .3.

Viruses as pathogens.

We all know viruses make us sick.

We've all had the flu or cold.

But biologically, how do they actually cause the symptoms we feel?

The mechanism of damage really varies depending on the specific virus.

Sometimes the damage is very direct.

As we saw with the myelitic cycle, the virus fills the cell until it melts.

That physically kills the host tissue.

Other viruses cause infected cells to alter their internal structures, like causing lysosomes to release their hydrolytic enzymes.

And the lysosome is basically the cell's stomach full of digestive acids.

So if it breaks open, the cell essentially digests itself from the inside out.

Correct.

Furthermore, some viruses direct the cell to produce viral proteins that are themselves highly toxic.

But, and this is a really important point to understand about viral illnesses, a lot of the time the suffering and the symptoms you experience aren't actually caused directly by the virus itself.

They are caused by you.

By our own immune system.

Yes.

The fever, the intense body aches, the systemic inflammation that is the body's scorched earth defense policy.

Your immune system detects the viral intruder and deliberately turns up the body's thermostat to try and cook the virus out or at least slow down its replication.

You feel absolutely terrible, but those symptoms are actually evidence that your defenses are actively fighting the war.

And whether you fully recover from that war, really depends on where the battle was fought, right?

The tissue type matters.

This is crucial.

If you get a common cold, the rhinovirus attacks the respiratory epithelium, the cells lining your respiratory tract.

Now, those epithelial cells naturally divide and replace themselves very rapidly.

So even if the virus kills a bunch of them, your body just manufactures new ones.

The tissue repairs itself and you recover completely.

But other tissues don't have that regenerative ability.

Exactly.

Take the polio virus.

Polio specifically

targets and destroys mature nerve cells in the central nervous system.

And mature nerve cells typically do not divide.

They do not replace themselves.

So if the polio virus kills a motor neuron, that neuron is gone forever.

That is why polio causes permanent paralysis.

The virus irreversibly destroys the body's electrical hardware.

And the body has no mechanism to build new hardware.

Which perfectly highlights why prevention is the only truly viable strategy against many viral diseases.

Yeah.

Talking about vaccines.

Vaccines are arguably the greatest medical intervention in human history.

The textbook formally defines a vaccine as a harmless variant or derivative of a pathogen that stimulates the immune system to mount defenses against the harmful pathogen.

I always think of it as a fire drill for your immune system.

That's exactly what it is.

You are showing your immune system the enemy's uniform without actually putting them in danger.

You inject a harmless piece of the viral capsid or a deactivated version of the virus.

The immune system inspects it, memorizes its exact shape and takes the time to build highly specific antibodies.

So later on, if the real dangerous virus ever enters your body, the security team is already armed, trained and waiting at the door.

They neutralize it before it can establish an infection.

Now, we absolutely have to mention antibiotics here, because despite decades of public health messaging, people still get this fundamentally wrong.

Please.

Yes.

Let's make this crystal clear.

Antibiotics kill bacteria.

They do this by specifically targeting bacterial machinery like enzymes that bacteria use to replicate.

Or pathways they use to build their cell walls.

Viruses, as we have discussed at length today, do not possess any of those things.

They don't have a cell wall to target.

Exactly.

So taking a bacterial antibiotic like penicillin for a viral infection like the flu or a cold is mathematically useless.

It's like trying to kill a ghost with a mousetrap.

It does absolutely nothing to the virus, but it will indiscriminately wipe out all the healthy, beneficial bacteria living in your gut.

Just don't do it.

Okay.

So dealing with known viruses using vaccines is one thing, but the textbook has an entire section dedicated to emerging viruses.

These are the ones that seem to just pop out of nowhere and dominate the news.

Ebola, Zika, SARS, H1N1.

Why does this keep happening?

How do new viruses just appear?

It definitely feels sudden to the public, but biologically it is a highly predictable process.

The text outlines three primary processes that contribute to the emergence of viral diseases.

Let's go through them.

Cause number one, mutation.

This is a huge factor, particularly for RNA viruses.

Remember how we talked about RNA viruses needing their own viral RNA polymerase enzyme to copy their genome?

Yeah, the one they bring with them.

Well, that viral enzyme is notoriously sloppy.

It does not proofread its work.

Meaning it makes typos when copying the genetic code?

Constantly.

Human DNA polymerase has a built in delete key.

If it inserts the wrong nucleotide, it catches it and fixes it.

Viral RNA polymerase doesn't have a delete key.

So every single time the flu virus runs, replicates, it is generating countless microscopic genetic errors mutations.

Most do nothing, but some slightly change the shape of the virus's surface proteins.

This rapid mutation rate is precisely why you need a brand new flu shot every single year.

The influenza virus you encounter in 2024 is genetically distinct from the one that circulated in 2023.

OK, cause number two for emerging viruses, dissemination.

This is a factor of human geography.

Sometimes a viral disease isn't actually new.

It might have existed for decades.

In a very small, highly isolated human population, say a remote village.

But it stayed contained.

However, in the modern world, with global air travel, international trade, blood transfusions and urbanization, a virus can move from a remote, isolated jungle community to the subway systems of New York City in under 24 hours.

The virus didn't change.

Its geographic reach did.

And that leads to cause number three.

And the text notes, this is by far the biggest source of new human viral diseases.

Zoonosis.

The spread of existing viruses from animals to humans.

It is estimated that about three quarters of new human diseases originate in animals.

The text calls the animal population the natural reservoir for the virus.

Right.

The virus circulates harmlessly or with mild symptoms within a population of bats or pigs or birds.

But then the virus undergoes a random mutation that allows it to bind to human cell receptors or a human comes into unusually close contact with the infected animal, perhaps through deforestation or farming or butchering, and the virus successfully jumps the species barrier.

The textbook uses the 2009 H1N1 outbreak as the ultimate case study for this, right?

It was like a perfect storm of zoonosis.

It was.

The 2009 H1N1 virus, which was commonly called the swine flu, was essentially a viral chimera.

When researchers sequenced its genome, they found it contained genetic sequences from an avian or bird flu virus, a classic human flu virus, and two different swine or pig flu viruses.

How does that even happen?

How do four different viruses combine?

It happens when a single host animal, in this case likely a pig, gets infected by multiple different flu viruses at the exact same time.

The viruses all enter the same cell.

They all dismantle their genomes to replicate.

And during the chaotic assembly process, the viral RNA segments get mixed up and repackaged together.

It's called viral reassortment.

The result was a totally novel Frankenvirus that the human immune system

had absolutely zero prior exposure to.

And because no one had immunity, it spread rapidly across the entire globe, which is the literal definition of a pandemic.

An epidemic is a general localized outbreak, but a pandemic is a global epidemic.

Precisely.

Now, before we get to the final horror of the chapter, we have to briefly talk about plants.

Because as humans, we tend to ignore plant pathology, but viral diseases in plants are economically devastating.

We're talking billions of dollars in agricultural losses every year.

Absolutely massive impact.

The text references figure nineteen point twelve here to show the visual symptoms.

When a plant has a viral infection, you'll see severely bleached or brown spots on the leaves, severely stunted growth and damaged, distorted flowers or roots.

But from a mechanical perspective, infecting a plant is totally different than infecting an animal.

The animal cells just have a soft membrane.

Plant cells are surrounded by a thick, rigid cell wall made of cellulose.

It's like a medieval fortress.

A virus can't just use its envelope to fuse and melt in.

Exactly.

Plant viruses require a physical breach in that fortress wall, and they generally spread through two major transmission routes, horizontal and vertical.

OK, horizontal transmission means the virus is coming from an external source, right?

Yes, the plant is infected from the outside.

But because of the cell wall, the virus usually needs a vector to penetrate the armor.

This is very often an insect, like an aphid, that bites through the plant's epidermis to feed on the sap, injecting the virus in the process.

Or very commonly, it's caused by human agriculture.

If a gardener uses pruning shears to clip a diseased plant and then immediately uses those same shears to clip a healthy plant, they are physically cutting through the cell wall and inoculating the healthy plant with the virus.

That makes sense.

And vertical transmission.

I assume that means it's passed down from the parent plant?

Inherited, yes.

A plant can inherit a viral infection vertically from a parent.

This can happen through a sexual propagation, like if you take a cutting from an infected plant to grow a new one, or it can be passed down via infected seeds.

The new plant is essentially born already harboring the virus.

OK, but once the virus actually gets inside a single plant cell, how does it spread to the rest of the plant?

Because plants are rigid.

They don't have a circulating bloodstream like we do to carry the virus around.

They don't have blood, but they have a very specific cellular infrastructure called plasmodesmata.

Oh, I remember those from the early cell chapters.

Right.

Plasmodesmata are the microscopic cytoplasmic channels that physically connect adjacent plant cells through their cell walls.

Think of them as tiny secret tunnels connecting the individual rooms of the plant castle.

The viral genomes and sometimes fully assembled viral particles can actually thread themselves right through these plasmodesmata, creeping steadily from one cell to the next, slowly spreading the infection throughout the entire plant structure.

It's slow, but it's incredibly thorough.

Very thorough.

All right.

We have covered a massive spectrum today.

We have the shape -shifting RNA animal viruses, the mechanical lunar lander phages,

the permanent genome altering retroviruses.

And honestly, just when I thought I finally understood the baseline rules, the rule that you absolutely need some kind of genetic code, whether it's DNA or RNA, to be an infectious agent, the final pages of the chapter throw a massive curveball.

Yes, the prion.

This genuinely breaks my brain.

It absolutely should, because prions are not viruses.

They are not bacteria.

They do not have a DNA genome.

They don't have an RNA genome.

What on earth are they?

They are proteins, just proteins.

How can a single protein be infectious?

A protein is just a folded up macromolecule.

It's like telling me that a spoon is contagious.

It is incredibly counterintuitive.

A prion is a specific, misfolded form of a protein that is normally found in the brain cells of various animal species, including humans.

We all have normal prion proteins in our brains.

We don't fully understand their exact biological function yet, but they are there and they are folded into a normal, healthy shape.

OK, I have normal proteins.

So how did the disease start?

Sometimes a misfolded version of that protein, a rogue prion, manages to enter the body.

The most common route is through consuming infected food like infected beef.

This rogue, misfolded prion travels to the brain and enters a brain cell.

And here's the terrifying mechanism.

When that misfolded prion physically contacts a normal, healthy prion protein, it somehow induces the normal protein to spontaneously change its shape.

Wait, it just touches it and converts it.

It flips it.

It acts like a mold or a template.

It forces the normal protein to refold itself into the abnormal robe shape.

Yeah.

And now you have two prions.

It's like a chain reaction, a chain reaction of bad origami.

That is a brilliant way to describe it.

The two misfolded prions go on to touch two more normal proteins, flipping them.

Now you have four, then eight, then 16.

And as these misfolded proteins multiply, they don't just float around.

They aggregate.

They clump tightly together to form dense cellular complexes or plaques.

And these massive protein clumps severely interfere with normal cellular functions and eventually cause the brain cell to die.

And as millions of brain cells die, it physically degrades the brain tissue.

It literally turns the brain into a sponge, right?

Which is why they call these diseases spongiform encephalopathy.

Exactly.

Mad cow disease is the most famous example in paddle.

In humans, it's known as Creutzfeldt -Jakob disease.

And the textbook points out two specific characteristics that make prion diseases absolutely uniquely terrifying to public health officials.

First is the incubation period.

Crayons act incredibly slowly.

It can take a decade, ten full years or more between the time the prion enters your body and the time you show the first symptoms of brain degeneration.

By the time a patient actually gets sick, they have absolutely no idea what specific burger they ate a decade ago that caused it.

It makes epidemiological tracking almost impossible.

That's terrifying.

And what's the second thing?

They are virtually indestructible.

Indestructible.

How?

It's just a protein.

Normal proteins denature when you heat them.

When you cook meat, the high heat breaks down the bacterial structures and destroys any viral capsids.

That's why cooking makes food safe.

But prions are remarkably stable.

Standard cooking temperatures and even standard hospital sterilization procedures do not destroy them.

You cannot simply cook or boil them away.

Once a piece of meat is infected with prions, there's essentially no standard way to make it safe for consumption.

Wow.

That completely explains why the outbreak of mad cow disease in the UK in the 1990s caused such a massive international panic because it fundamentally challenged the central dogma of biology

even more aggressively than viruses did.

It proved that a naked protein completely devoid of any genetic code could transmit a lethal disease.

It was a paradigm shift in biology.

It was a stark reminder that biology isn't just about life and DNA.

It is fundamentally about molecular structure.

Structure dictates function.

And sometimes that function is exponential destruction.

We have covered a truly massive amount of ground today.

From Adolph Mayer staring at mottled tobacco leaves in 1883 to the high -tech RNA -guided warfare of the CRISPR system to the silent, slow -moving threat of indestructible prions.

It is a dense, heavy chapter, but it is absolutely essential for understanding modern biology and medicine.

If there is one core foundational takeaway that our listeners should carry with them from this deep dive into Chapter 19, what do you think it is?

I think it comes back to that idea of the gray area.

Human beings intrinsically like to categorize things neatly.

Alive versus dead, animal versus mineral, safe versus dangerous.

Viruses sit perfectly right in the middle of all our neat categories.

They utilize the exact same universal genetic code that we do, A, C, T, G.

But they completely strip away all the cellular complexity.

They are biology's minimalist hackers.

And precisely because they use the same fundamental code that we do, studying them, has been the perfect key to understanding our own biology.

Most of what we know about how human DNA replication and transcription works, we discovered by watching viruses actively steal and manipulate those processes.

So they are our most dangerous enemies, but they are also our most revealing teachers.

Exactly.

They force us to look in the mirror.

Which brings me to a final, slightly provocative thought to leave you all with.

We've talked about how retroviruses, like HIV, permanently integrate their DNA into our human chromosomes.

But the evolutionary scale of this virus is staggering.

Scientists have sequenced the entire human genome, and they estimate that up to 8 % of our human DNA is entirely made up of ancient viral remnants.

Over millions of years, retroviruses infected our ancestors, integrated their pro -viruses into sperm or egg cells, and those viral genes were passed down to us.

In fact, one of the crucial genes that allows human embryos to form a placenta, the synctin gene, is actually derived from an ancient viral envelope protein.

So the question isn't just if our virus is alive, the real question might be how much of what we consider human is actually just domesticated virus.

That is a thought that will keep you up at night.

It definitely will.

And with that, we are going to close the book on Chapter 19.

It's been a great discussion.

Don't forget to wash your hands, everyone.

Always good advice.

Thank you so much for exploring the gray area with us.

From all of us here, a warm thank you from the Last Minute Lecture team.

Catch you on the next deep dive.