In 2023, there was a grim changing of
the guard that not a lot of folks
noticed. After a brutal, terrifying
2-year reign, CO 19 relinquished its
title as the deadliest pathogen in the
world. And rather than some new, even
more horrific contender taking over the
crown, CO simply gave the belt back to
the all-time deadliest single pathogen
known to science. And off the dome, can
you guess which one? It's this guy,
mcoacterium tuberculosis, which is wild,
right? I mean, outside of history books
and Red Dead Redemption 2, how many of
us have even heard of TB in the 21st
century? More importantly, how has a
disease like tuberculosis managed to
persist and haunt us for effectively all
of human history? Other pathogens either
burn bright and fade away or have
effectively been wiped off the map by
civilizational advancement. And the
answer to this question just reveals so
much because tuberculosis here is such
an effective human pathogen because it
takes things so terribly slow. It turns
out that playing the slow game for the
last 9,000 years minimum has allowed TB
to adapt its way to becoming a nearly
unstoppable force in human history. Even
though tuberculosis has been essentially
curable and on the table to be made
irrelevant for the last 70 years, this
ancient human predator has managed to
conform to the shape of civilization
itself to ensure that it can persist as
our single deadliest enemy of all time.
Today, I want to explore the biochemical
foundations of what makes tuberculosis
so deadly and so difficult to beat. TB
has some of the most incredible tools at
its disposal, hacking into the base
mechanics of our immune system to ensure
that it will always have a place to
survive. It's time to discover the
methodical, tireless adaptations of the
White Death, and come face to face with
the diabolical strategies deployed by
our first true nemesis as a species.
It's TB time, y'all. Turns out it's
always TB time. Let's get into it.
series. But let's get into TB itself, right? The success of TB is a story that
relies on timing and subturfuge. Sure,
if you know TB, you know TB is an
infection of the lungs. But like most
other truly successful human pathogens,
TB is really an infection of your immune
system itself, mcoacteria like TB are
absolute tanks at the molecular level.
And this high defense simply buys
tuberculosis enough time to hack into
and disrupt the cells holding the front
lines of your defensive perimeter.
Tuberculosis isn't looking for anything
but a place to survive. And this video
is structured around how TB sidesteps
your immune system at every stage of the
immune response. To fully understand
this, we're actually focused on one
small aspect of the TB infection story,
a concept called immune evasion. I'm
going to basically follow the structure
of this absolute banger of a review
Nature put out a few years ago, and make
sure you check that out along with other
sources in the description of this
video. So, we're only going to explore a
handful of different mechanisms that
quickly take us through some of the big
moments of early TB infection and how
tuberculosis seems to have an answer to
every single immune weapon we have for
it. But, let's go ahead and jump right
in. Starting with a quick overview of
the structure of the bacteria that
causes tuberculosis. Meet your enemy.
This is mcoacterium tuberculosis. If you
want to understand how a bacteria like
this has managed to kill more people
than uh basically any other outside
force, we first need a quick primer on
how TB is built different from other
proarots. While most pathogens play for
efficiency and speed, TB and other
mcoacteria use the exact opposite
strategy here, sacrificing speed for the
single-sellled equivalent of high
defense. TB grows painfully slow. On
average, completing a single cell
division once a day. But make no
mistake, that slow division is still a
blistering pace considering how many
complex components TB needs to grow
every time it divides. Here, let's zoom
into the molecular level so you can see
exactly what I'm talking about. This is
an atomic view of a full microacterial
envelope. Every layer here serves a key
purpose and it all adds up to making TB
hardy and resilient. By comparison, most
human cells have just this single lipid
billayer surrounding them with a dusting
of extracellular matrix. But TB has two
different membranes that sandwich a
dense forest of structural sugars.
Miccoacterium tuberculosis is about 60%
fats and oils by weight. And most of
that weight is used to build the top and
bottom layers of this thick almost
resiny outer envelope. Up top we have
these exotic and complex micolic acids
which are held up by branching chains of
arabino galactan. That arabino galactin
grows out of this strong winding mesh of
pepidoglycin down here which is one of
TB's main defensive structures. And now
if you pull back to take in the whole
envelope you'll see that there's all
sorts of proteins embedded in the wax of
the micromembrane and beyond. We're
going to come back to this view a lot
because this whole membrane plays a
crucial role in making TB so effective.
Why though? Because TB's thick cell wall
here forces the bacteria to divide slow.
That's a critical disadvantage when the
only place you can survive is the
incredibly hostile environment of the
human lungs. So to overcome that
disadvantage and have the best chances
of survival, tuberculosis works smarter
instead of harder. Effectively, every
single molecular piece of TB has some
sort of side job disrupting the human
immune system. We're going to watch most
of these pieces here do something to
delay and obfiscate your immune system's
response to a TB infection. By playing
it smart, TB can buy itself enough time
to establish a proper colony and
guarantee its chances of survival. But
let's see how that plays out. TB is
going to land somewhere on the inner
surface of your lungs, probably. Now,
this is an incredibly hostile
environment, and most other pathogens
are going to try and overwhelm your
defenses by dividing as much as
possible. We already know that TB can't
do that. So, it's going to wait and let
your immune system make the first move
here. In all likelihood, once it hits
the inner surface of your lungs, TB is
going to encounter this squishy fella.
Meet one of your billions of alvolar
macrofasages. He's a frontline member of
your immune defense force. But unlike
the stolen cold killers in your immune
army, think like neutrfils and dendritic
cells, alvolar macrofasages are
basically like trained seagulls. They
roam around gobbling up whatever garbage
they can find, taking anything that
looks dangerous back to better armed
members of team immunity. And as we head
deeper into the molecular biology of
what powers this, I really do want to
encourage you to check out my guy Fi the
Neutrfil's video on tuberculosis if you
want to get a better sense of the cell
biology of what's about to go down.
Frankly, all of you should be subscribed
to Fi if you aren't already, but that's
neither here or there. I'm just super
excited that molecular biology YouTube
is getting stronger by the minute, it
seems. Anyway, our cellular seagull here
is going to encounter and devour these
TB invaders. And while this is standard,
it's also exactly what TB wants. TB is
not here to infect your lungs. It's here
to infect this alvolola macrofase
specifically. When this macrofase eats
TB, it engulfs the bacteria in this
little circular pocket called a
fagazone. This is supposed to protect
your immune cells from the pathogen, but
it also gives TB a nice little house,
buying it all the time it's going to
need to do everything else. Again, TB
has to be efficient here. And so, the
moment it gets engulfed inside these
macrofasages, it is going to pump all
sorts of attack proteins into the
cytoplasm of our poor, dumb,
unsuspecting macrofase. The precise
mechanism here is still hazy, but let me
highlight two wild things that happen to
these immune cells from the jump. So
zooming all the way in here, somehow
alvolar macrofasages that ingest TB
overproduce a transcription factor
called NRF2, which binds to all sorts of
genes in the macrofasages nuclei. NRF2
is a normal response for macrofasages
that helps them calm down and not
literally explode when they eat anything
super dangerous. But somehow ingesting
tuberculosis causes the NRF2 signal to
continue way longer than normal, which
among other things prevents this
macroofage from self-destructing once it
realizes how much trouble it is in,
which basically guarantees that TB is
going to have a house no matter what
happens. Meanwhile, and this is way more
evil, TB somehow tricks infected
macrofasages into turning out a bunch of
this protein, tricetropolin, which
everyone else just calls TTP. So that's
what we're just calling it from now on.
Cool. This guy is going to bind to mRNA
signals coming out of the nucleus and
it's going to recruit this big old pair
of molecular scissors to destroy that
mRNA. Now, if you go back to watch my
videos about the central dogma, you know
that nothing actually happens in your
cells unless there's mRNA signals
getting into the wider cytoplasm. No
mrna, no protein, no protein, no work.
And the crazy thing here is that TTP, at
least in tuberculosis's case, seems to
be targeted. The TTP produced by
infected macrofasages specifically
silences the production of critical
immune response proteins like INOS, TNF
alpha and interlucans 12 and 23. And
just for simplicity sake, once those
immune factors are silenced, that's kind
of the whole ballgame here, y'all. In
short, these two small hacks are about
buying tuberculosis enough time to break
out the big guns. Turning up TTP
production is going to keep our alvolar
macrofase from mounting a more robust
defense quickly enough, while NRF2 will
disarm the alvolar macroofage's
emergency counter measures once it
realizes just how much trouble it's in.
This is what is so jaw-dropping about
tuberculosis. From the instant it
arrives inside this fagazome, it is
producing dozens of little responses all
at once, just trying to buy as much time
as possible to make up for its glacial
pace of division. By overcoming this
massive disadvantage, TB has evolved
into a staggeringly effective molecular
sniper. Tuberculosis doesn't get second
chances, so it makes every microscond
count. And I really want you to wrap
your head around how effective TB is. So
check out how it stacks up compared to
other pathogens. To do that, let's talk
about something called infectious dose.
Infectious dose is just the measurement
of how many individual pathogens it
takes to establish an infection inside
of a host. These numbers are always
fuzzy, but researchers have gotten good
at sort of narrowing it down for things
that are very contagious. Typically,
bacteria aren't very good at this. One
of the most common infections comes from
staff bacteria, and it's going to take
at least a 100,000 individual staff
bacteriums to set up shop in whatever
place they're causing an infection.
Salmonella, another way worse bacteria,
is a little bit better at this. And
their infectious dose, sits at a little
bit over 10,000 individual bacteriums.
Viruses are a little bit more specific
and therefore for a lot of them it takes
way fewer individuals. Influenza is a
great example where it only takes about
2,000 individual influenza particles to
give you, you know, the flu. And then we
get to things like norovirus, a
devastatingly contagious scourge on your
gastrointestinal system. I've seen some
papers describe norovirus as the perfect
human pathogen. And the infectious dose
for norovirus is pretty wild. On the
high end, it can be 100 individual viral
particles, but some estimates have put
it as low as 18 individual viruses being
enough to establish infection, which is
why if you even come close to this
stuff, you need to wash your hands super
thoroughly. And again, all of these are
considered highly contagious, right? And
this chart gives us a pretty solid idea
of what the range is when it comes to
how infectious a bacteria or virus can
be. But where does TB fall in on this
chart? And here's the plot twist, folks.
TB isn't even on this chart. Norovirus
comes the closest, but it really can't
hold a candle to the king. TB's
infectious dose has been estimated to be
as low as three individual basil. Not
tens of thousands or thousands like
other bacteria, not even double digits
like the most infectious virus we know
of. Three, which for me is the most bone
chilling aspect of TB. It is just that
good at establishing a beach head that
even the smallest exposure can lead to
latent infection. And yeah, this is just
the tip of the iceberg. TB's adaptations
to surviving inside the immune system
are only going to get more wild from
here. And all this adaptation has
allowed TB to conform to not only our
immune system, but the system of human
society itself. To better understand how
tuberculosis has integrated itself into,
you know, 100% of the human story, I
really think you should check out this
episode's entry into the Clockwork Book
Globe, which is Everything is
Tuberculosis by John Green. Honestly,
the title really takes care of
everything here. John Green does a
really solid job of putting a coherent
narrative line out of the thousands of
little ways tuberculosis has shaped the
world we live in today. This book
definitely leans more into the
historical angle than the science. And
furthermore, I feel like I need to do a
quick bias check by reminding you that
this channel kind of only exists because
of a Vlog Brothers grant I received a
few years back, but whatever. Either
way, Everything is tuberculosis is a
strong historical read, but as a biochem
degenerate, I wanted a little more
immunology in there. The everything was
beautiful, but I could have used some
more tuberculosis. We'll give it a
respectable 4.5 clocks out of five, and
then I'll sink months of my life into
making a video that explores the biochem
that I feel like I'm missing. Oh,
speaking of which, let's get back to
that video. And so, yeah, we're a third
of the way into this thing, and we're
only just starting to get into the big
guns. TB has that small edge, but how
will it leverage that advantage to
become irrefutable? And so, welcome to
part two. We've slowed down this alvolar
macrofase and now tuberculosis is going
to completely defang it. TB's initial
slowdown really shouldn't matter because
no matter what when these macroofasages
ingest anything they'll automatically
set to work destroying it just in case.
Fortress TB is just a naked membrane
right now. But immediately this alvolola
macroofage is going to recruit a bunch
of antimicrobial workers to obliterate
anything inside this fagazone just in
case. And there's two major weapons that
most of your innate immune cells utilize
when they want to destroy anything
potentially dangerous inside these
fagosomes. First up, there's the VATP
ace, which is basically ATP synthes, but
in reverse. You might know ATP synthes
as the chemical motor that effectively
powers everything you do by allowing
protons to turn a turbine that presses
ATP together, which acts as like the
energy currency your cells use. Vatpace
is just the reverse of that chemical
reaction. It uses ATP to push protons
through a membrane in the opposite
direction, which means it can use
cellular energy to acidify any cellular
compartment it wants to, which is great
considering that a sufficiently acidic
environment is pretty good for
destroying, you know, most living
things. However, that might not be
enough. And so cells will also recruit
this incredible complex to your
fagosomes. This is NADPH oxidase. And
without getting too complicated with it,
what this thing basically does is it
takes electrons away from NADPH, moves
them on up this electron transport chain
in order to produce reactive oxygen
species inside the fagosome. If you go
back to an old video I did about
chlorophyll, you'll know that reactive
oxygen species are incredibly
destructive forces in a cellular
context, which is why our immune cells
use NADPH oxidase as kind of like a
metabolic death rate to purge even the
hardiest pathogens they happen to
ingest. And of course, TB has an answer
for this. Firmly entrenched in its
little membrane pocket, TB will now work
to make its new home unassalable. To
protect against our antimicrobial
weapons, TB will produce a bunch of
factors. First up, it's got one TBD, a
powerful ant acid. This will soak up all
the damage produced by the V8pace. And
at the same time, TB will pump out a
powerful antioxidant peroxidase/catalase
enzyme that will act as a kind of shield
wall against the cellular death rays
produced by NADPH oxidase. And TB is not
done here because it will make proteins
that bind to our VATP ace before they
even get moved to the faggosome. Another
protein PBE2 blocks the priming pin of
NADPH oxidase right here, completely
disarming one of our best weapons. And
with those two major moves, amongst
others, Fortress TB is now effectively
impenetrable, which means TB finally has
time to secure its position. In
addition, all these blocking moves
increase the metabolic stress on our
macroofage and hinder its ability to
throw in the towel and activate
apoptosis. With TB's shelter fully
secured, the white death will now shift
to start the process of resource
extraction from this doomed macroofage.
Again, bacteria just don't infect us for
fun. For the most part, critters like TB
are just looking for a place where they
can survive and scrunch up food for long
enough to secure their next generation.
So the point of all this subtrifuge is
also to squeeze resources out of this
alviola macroofage. It's now time to
transform fortress TB from a protective
shell into an offensive weapons
platform. Every single molecular piece
of tuberculosis feels like a weapon at
this point because one of the microlids
in TB's outer envelope, which I'm just
going to call PDM, is going to start
invading the fagosal membrane,
disrupting the heck out of it. At the
same time, TB is going to be pumping out
proteins like ESXH here, which impairs
the machinery that immune cells will use
to patch holes in the fagosome once it
gets damaged. This creates handy
openings that TB can use to sneak in all
sorts of sabotaging proteins into our
soontobe doomed macroofage. And TB pumps
out a ton of different attacks and
modifiers during the stage. But let's
focus on the evilst one I know about.
Going back to the very top of the TB
micromembrane, there's this nutrient
channel embedded throughout the
micromembrane layer. This one is called
CPNT. And while the core of this fella
is just there to provide a highway for
TB to absorb nutrients, the tail end of
this thing kind of dangles out beyond
the membrane. This nub tethered to CPNT
is way better studied and it has its own
name. It's called TNT or the
tuberculosis necrotizing toxin. Huh,
sounds ominous. With Fortress TB fully
secured, tuberculosis will start
snipping off TNT and letting it run
rampant in the host's cytoplasm. And
like I said, TNT is a deeply messed up
microbial weapon. A label like that
might make you think that TNT is a bomb
or something, but TNT is actually a tiny
pair of scissors, specifically adapted
to slice one key molecule, NAD+. NAD+ is
a key intermediary in the Kreb cycle.
And breaking it will cause our infected
macrofase to start to starve as its
metabolism legitimately starts breaking
down. But that's no big deal because our
macrofage will just overproduce more
NAD+ in response. We can get through
that. No big deal. Which TB will then
readily absorb and store internally so
it gets surplus metabolic intermediates
for free. Dang. And now finally, all
that success is going to make Fortress
TB feel pretty crowded now that it's had
time to grow a substantial colony in
there. So it's time to move out and take
over a larger part of this alviolar
macrofase. Eventually, all that PIM is
going to disrupt the fagosome enough to
shatter the walls of Fortress TB,
allowing the bacteria to access all the
resources in the wider cytoplasm. But
while this alvolar macroofage is
effectively powerless to stop what's
coming, it's not supposed to be working
alone either. The whole time all this
takeover happens, our immune system is
supposed to be breaking out the big
guns. And indeed, by the time TB has
achieved a cytolic breakout, this
macroofage is showing pretty visible and
obvious signs of stress, and other
immune cells have definitely stopped in
to try and help. Which gets us to the
final layer of immune evasion. TB also
has enough chemical tricks to disrupt
our adaptive immune system, which
prevents even our most brilliant and
powerful weapons from controlling this
ever larger TB outbreak. Again, this
video is coming outside of a larger and
more foundational series on the immune
system. So, we're going to end up
skipping a lot of the immune story here
to focus on the better studied aspects
of TB's immune counters. But in short,
when the primary immune response isn't
enough to contain an encroaching germ,
your frontline fagicites will take
pieces of the invader back to immune HQ,
which is one of your lymph nodes, by the
way, to activate your disease fighting
big guns. You've got boss level cells
like these, called T-C cells and B
cells, which can recognize threats and
help coordinate a response overwhelming
enough to cut into the heart of even the
most overwhelming infestations. I have
been yapping for ages about TB wanting
to buy time. Well, this is the event TB
is trying to push back as much as
possible. An overwhelming adaptive
immune response too early in the game
will bulldoze Fortress TB without
breaking a sweat. And so TB's most
important wave of attacks is all about
delaying that adaptive TE-C cell
response as much as possible. Let's
check out a small sample of TB
strategies here. The key to activating
the adaptive immune system is
identifying the threat. Your frontline
cells will chop up little surface
proteins from whatever the invader is.
Attach them to this crucial complex
called the major hystocompatibility
complex and then shove those onto
adaptive immune cells like this T- cell
receptor to get the real response
rolling. For reasons that would take too
long to explain, this is one of the best
superpowers we have as a species. And TB
has been with us for long enough that
it's evolved some tools to disrupt this
identification step. from the jump.
We've already talked about a bunch of TB
tools that have side jobs jamming the
adaptive immune response. Remember PDM
from earlier? Turns out this waxy little
fella gums up the works when dendritic
cells try to present antigens to immune
command. At the same time, this ESX
protein is going to disrupt antigen
processing and presentation in dendritic
cells. And it also causes enough damage
that certain tea cells actually will
have a hard time recognizing infected
macrofasages. But those are nothing
compared to TB's final trump card, decoy
antigens. No, for real, we're talking
about actual subtuge. There's two ways
that tuberculosis can play the decoy
game here. The first is illustrated by
this chaperone protein, Growel L2. At
some point during the infection cycle,
TB will send a small army of protein
cutting enzymes to clip a small piece
off of Growl2, yeating this larger
portion into the host cytoplasm. Clipped
Growl2 doesn't activate the immune
system nearly as well as the fulllength
version. So these little nubs act like
chaff to confuse and confound the
adaptive immune system. And there's even
evidence to suggest that this clip grow
2 actually interferes with host
mitochondrial effectiveness, which is
just bonus damage TB can do to again
delay and obiscate this immune response.
But then here's something even wilder.
Up top in the outer micromembrane yet
again is an assembly protein that we're
just going to call a 85b. TB will start
out with a ton of this protein and wait
long enough to guarantee that a
dendritic cell has picked it up to bring
it back to headquarters. Now, your
immune cells think they're going to have
an easy time identifying TB with an
antigen as solid as a 85b. But get this,
tuberculosis downregulates a 85b shortly
after it gets picked up. For real, it
just straight up removes this protein
from the rotation. By the time the
immune systems big guns return hunting
for a big bad pathogen with the A85B ID
card, they're effectively blind to the
raging TB fire that's actually blazing
here. I'm serious. It's like an actual
4D chess move from a bacteria, y'all.
And here's the thing. At this point, all
of these counters are going to start to
compound. Like, one thing I've glossed
over is how all these anti-immune
weapons are also causing actual damage
while they block various defenses. Like
this is a period of serious metabolic
distress for our poor infected alvolar
macrofase. And with the local TB
population now getting out of hand. And
with all these individual basil
releasing TNT, mind you, eventually the
metabolism of our hero here grinds to a
halt, killing the cell in a brutal
process called necrosis. Our once proud
cellular seagull is now, well, a pile of
inert goo. And sure enough, this is
exactly what TB wants. This wad of
cellular material is a great place to
store and harvest nutrients and an even
better barrier against stronger immune
responses. More and more immune cells
are going to stop by and try to clean
this up, which is going to add more
metabolic stress to the entire area. And
it's going to allow themselves to also
get infected by TB, repeating the whole
video all over again. And if TB could
have its way, things would continue like
this forever. But eventually, your
immune system catches wise and mounts
one last desperate defense. TB may think
hiding inside this ball of corpses is a
brilliant defensive play, but we can
take advantage of this barrier, too.
Your immune cells will recognize this
rapidly expanding ball of necrotic
tissue as an imminent threat and begin
to rapidly surround it and wall it off.
This structure is called a granuloma.
Inside the ball of cells, TB still
reigns supreme. All of our immune
weapons just cannot get through this
goo. Which means that TB is in here
controlling what machinery it can to
release immune suppressing proteins
while simultaneously tricking unlucky
macrofasages into accumulating as many
libits as possible which TB will use as
fun little caches of food. And here's
the thing, granulomaas honestly can
eventually work by becoming so tightly
packed that they prevent oxygen from
getting to the bacterial core. When all
else fails, seal these dorks up and
starve them out, right? But of course,
TB can respond to this by entering
stasis, allowing itself to survive long
term. Maintaining a granuloma like this
takes a lot of energy. And should your
immune system ever take a big enough hit
that it can't keep maintaining its hold
here, the granuloma can rupture,
allowing TB to wage a wider war that far
too often results in death. Granulomaas
and stasis are also the final ultimate
trump card that make tuberculosis such a
difficult pathogen for doctors to treat.
With alvolar macrofasages moving toward
immune managers in the interstitial lung
tissue, granulomaas tend to form in a
few different deep nooks and crannies
inside your lungs, which means that it's
even harder for antibiotics to actually
get to TB in the first place. You need a
strong enough dose that an antibiotic
molecule can penetrate all the way into
that lung intimid. And then it's got to
make it through dozens of layers of very
tightly packed immune cells, you know,
without killing them. And then somehow
make it through the thick, heavily
defended mcoacterial envelope, micro
membrane, and so on. When TBL enters
stasis, this membrane actually becomes
even more packed somehow and harder to
penetrate. Plus, since TB divides
unevenly, some members of a TB colony
will be more asleep than others. So, you
have to figure out a way to treat all
levels of TB activity kind of at the
same time. Folks are therefore forced to
take several different hardcore
antibiotics at the same time for months,
maybe even years, just to ensure that
the local TB population gets completely
eradicated. Because remember, if even
three three of these fellas survive,
that's enough to start this party all
over again. This is tuberculosis's final
most brutal weapon. If you catch TB
these days, congratulations. your
full-time job just became fighting this
disease. And the reality is we are at a
stage of civilization where the vast
majority of folks simply cannot afford
that fight. And a lot of treatment
regimens are forced to get administered
imperfectly. This has allowed our old
nemesis to evolve new forms that resist
multiple classes of antibiotic which
makes treatment all the more difficult.
And because we've given TB the
opportunity to evolve drug resistance,
fighting this disease has become so much
harder. Which is why instead of
accepting a sponsor on this video, I'd
like to use this segment to encourage
y'all to check out the work being done
over at tbfighters.org.
TB Fighters are an incredible group of
volunteers organizing around actionable
steps folks can take to help build a new
front line in the war on tuberculosis.
They've done brilliant work affecting
real change in public health around
tuberculosis specifically and are
currently in the trenches fighting for
the restoration of public health funding
here in America. Every single action
counts right now. So, I'd love it if you
went over to tbfighters.org/action
and got involved. Feel free to visit
Partners in Health as well to get
involved on the broader global health
stage, but let's get focused and finish
this video. We've explored how TB
pacifies, disarms, and disrupts every
layer of your immune system. We
understand that TB has to play things
smart like this so it can overcome how
slowly it grows thanks to a stacked
defense. The incredible thing about TB
is that these same adaptations to our
immune system work as incredible
adaptations to human civilization
itself. Other germs can get borderline
eradicated while TB has been able to
survive into the 21st century despite
incredible efforts to push it out of the
West entirely. Again, check out
Everything is tuberculosis to get a
better understanding of how that all
plays out. But it is just so important
to remember how TB got this good at
infecting us. And so the main thing I
want you to take away from this video is
an understanding of how deeply our true
enemies conform to and adapt with us. TB
is as resilient as it is because it has
to be. It always has to overwhelm us
from basically nothing. Therefore, it's
super important to contextualize how TB
developed all these tools to solve its
human problem because TB is not some
grim force of nature purpose-built to
prey upon us. And I think the historical
record is actually the best place to
find the context we need. Let me put it
like this. While most diseases eb and
flow, tuberculosis has been in the
written historical record for just over
3,000 years. Meanwhile, there's strong
archaeological evidence of TB infections
dating back to around 20,000 years ago.
And the earliest strong decent evidence
for mcoacterial infection comes from the
Horn of Africa around 70,000 years ago.
But then it gets deeper. There is a
controversial study focusing on fossil
remains from 510,000 years ago that has
evidence of a TB- like infection. And
TB's genome is unvaried enough that we
can pinpoint a moment around 3 million
years ago where tuberculosis's ancestors
were infecting early hominids. Which
means, in short, that there is a
possibility that tuberculosis' lineage
has been haunting us for longer than
we've been homo sapiens, which helps me
make sense of TB's staggering arsenal.
Of course, tuberculosis can counter all
of our defenses. TB co-evolved with us
across an unfathomable stretch of our
story. TB might play things slow, but it
plays to win in a way that very few
diseases or other forces of nature can
even come close to. Which is why I think
it's so important you've taken the time
to understand this fella a little
better. In so many ways, tuberculosis is
our first true nemesis as a species. It
is a subtle and somehow omnipresent
force constantly pushing back against us
and robbing an uncountable number of
people of their full life potential.
There's a lot of ways to think about our
current moment, but for me, the last, I
don't know, decade or so have been a
pretty heavy-handed reminder of just how
much we are in the middle of history. We
have come incredibly far, but the
science of molecular biology is only 70
years old at this point. We've
established strong foundations for
eradicating TB. But the economic
structures that we have built and
maintained also serve as kind of a cage
that prevents us from delivering TB
treatments where they need to be the
most. While that's changing, it's at a
slow, stumbling, and deeply human pace.
And so, I once again want to greatly
encourage you to check out
tbfighters.org and partners in health so
you can join the struggle to grind the
white death into the dust bin of
history. Our real enemies like
mcoacterium tuberculosis stay with us
because we give them the cracks they
need to survive. TB has adapted to every
nook and cranny made by us for longer
than we have even been people. That's
the science that pushed me to make this
video. What's that falconer line? The
past is never finished. It's never even
passed. I am astonished practically
every day by the staggering inbetweeness
of this moment of history. Our
scientific progress is genuinely
accelerating. And yet, we still find
ourselves haunted by horrors that prayed
upon ancestors so distant they would not
even recognize who we are now. In so
many ways, life on this earth is a
constant, neverending evolutionary arms
race. By sticking it out for this video
about TB, I hope you have a deeper
understanding of just how long and just
how hard our nemeses have been working
just to stick with us. And that's not a
depressing note to leave on. TB works
hard, but I know we can work harder.
We've done it before and we'll do it
again. But now you have a richer
understanding of the stakes. That's a
good start for me. I really appreciate
your time. Thank you so much.
[Music]
And hey, as always, thank you so much
for sticking to the end of this video.
If you like this video, please consider
supporting us over at Patreon. I'm about
to go through a big revamp over on
Patreon.
So, check us out there if you want early
access to everything that's coming.
Otherwise, another great way you can
support us is by going over to watch
clockwork.com and signing up for our
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bringing back to more regular
production. And of course, I've said it
a bunch towards the end of the video,
but I would love it if you checked out
the work being done over at
tbfighters.org. Otherwise, I want to
make this sign off quick because there's
a lot more awesome videos on the way. If
you enjoyed this video, it would mean a
lot to me if you liked and subscribed.
just to keep the algorithm gods happy.
Otherwise, I would also love it if you
checked us out over at Patreon because
I'm about to start really revamping what
we're doing over there. We're going to
have a lot more interesting tiers within
the next month. Now, of course, I left a
lot of this video on the cutting room
floor. There might be enough here to do
a kind of part two. So, if you really
want to hear me disjointedly act about
immunology for another I'm looking at 35
minutes basically. Uh, you know, comment
below. You got to get real loud about
that in the comments. But otherwise,
just hang tight because season 4 of
Clockwork will focus entirely on
immunology. First, we have to finish the
central dogma and then get through sort
of the foundations of metabolism before
we have enough foundational work to
tackle one of the most difficult
concepts in molecular biology.
Otherwise, thank you so much for
listening this far. This is genuinely
one of the best possible things you can
do to support this channel. I really
appreciate your time and as always, I
like to leave you with peace, love, and
strong antigens. Everyone be well. Thank
you so much.