So, what you're looking at right now is
a bacterial weapon. Technically, this is
a defense platform used to fight off
viral infections already raging inside
bacteria. Regardless, the way this
little bundle of protein and RNA defends
against phase intrusion is so wild to
the point that when the paper describing
the discovery of this complex called
DRT3 hit the PR wire earlier this month,
my little corner of the internet
basically exploded with takes talking
about how one of the central quote
unquote rules in biology had been
violated. And let's kill the clickbait
immediately. That is not what's
happening here. But if you let me take
you through the context real quick,
you'll see that what DRT3 does is
actually far cooler. In a world where it
seemed like you could only build DNA
using another DNA strand or RNA, DRT3
sets off a kind of DNA bomb, assembling
long nonsense fibers of DNA using two
little bits of protein as part of its
template. This machine is a complete
mind blow and an excellent introduction
into the world of fagee defense. In this
video, let's explore how a DNA grenade
can help a bacterial community fend off
the viral horde. No war but the fage
war, folks. Let's explore why.
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But let's jump into the thick of it. For
billions of years, there has been one
endless conflict raging across our whole
biosphere between bacteria and parasitic
bacterial phages like these. This war is
brutal with some estimates suggesting
that a full 25% of all bacterial biomass
is wiped out by phages every day. Now,
of course, that number is hard to
verify, but the important thing to keep
in mind here is that there is a
tremendous amount of pressure for
bacteria of all kinds to defend against
fagee infection, no matter the cost. And
that's been one of the cooler lines of
research for the last 20 years. Turns
out, despite being unisellular, bacteria
have their own kind of internal immune
systems for keeping these phages at bay.
Bacterial phages reproduce by injecting
their genetic material, be it DNA or
RNA, depending on the specific virus,
into host procarots and hijacking their
cellular machinery to build more phages.
So, bacteria have all sorts of defenses
aimed at targeting that viral DNA before
it can complete that hijacking process.
You've probably heard about the most
famous of these defense platforms,
crisper RNA and its cast 9 protein
partner. Bacteria store viral DNA
sequences inside that crisper RNA and
use it to direct the castine protein to
cut down viral DNA before it can do any
damage. And scientists have
re-engineered this system to empower a
new age of DNA editing in the past
decade. It's kind of been one of the
biggest deals in biology honestly. But
there's actually tons of different kinds
of crisper systems and more importantly
a ton of anti-Chrisper weapons developed
by viruses to regain an edge in the
conflict. That's the wild thing about
this fage war. Both sides are constantly
pushing against each other in this kind
of evolutionary arms race. And our
subject today is one of the wilder
defense strategies developed by
bacteria. All the recent hype surrounds
this complex DRT3. And okay, this is a
defense associated reverse
transcriptase. I figure we've set up the
defense part of that name. So, let's
look at the back half of this title.
Reverse transcriptes already rewrote our
understanding of how life works back
when they were discovered in the 70s.
They use an RNA template to generate a
new strand of DNA. Viruses like HIV and
hepatitis B use reverse transcriptases
to smuggle their RNA code into our
genome when we get infected. The gist
here is DRT3 is going to somehow use a
DNA generating process to defend against
attacks from several different classes
of bacteria phasages. And yes, this is a
molecularly accurate rendering of a T1
bacteria phage. They really do use
proteins to build these near crystallin
spaceship looking delivery vehicles for
their predatory DNA sequence. And
instead of having little spaceship legs
you might associate with phages, they
just have this long flexible tail that
spears right into their victim's cell
membranes. But back down to DRT3, let's
focus on how this complex builds a DNA
strand. First off, let's break this
thing down. We're actually looking at a
complex of multiple identical copies of
a DRT3 system. If we zoom in on just one
of them, a complete DRT3 module has an A
and B component as well as a critical
catalytic RNA that partners up with
DRT3A. This core DRT3 system joins with
two other copies to form this little
trimer, which then gets glued buttto
butt with an identical complex to form
the full DRT3 platform, which means
we're working with six identical copies
of the system. But back down to the
individual module, let's look at these
individual components to really sus out
what's happening here. DRT3A is your
classic breadandut defensive reverse
transcriptise. The protein of 3A
stabilizes this non-oding RNA around the
enzyme's active site so that these
letters in that RNA knot can be used as
a template for synthesizing a long
strand of DNA that just repeats the
guanine and thymine or G&T letters of
the genetic code over and over again.
You'll find this a lot with these
defense associated reverse
transcriptases. For emergency reasons,
we need to assemble a whole bunch of DNA
in a whole lot of hurry. So, it doesn't
necessarily matter what information is
being carried inside that DNA. Similar
complexes will assemble DNA strands
randomly or just keep spitting out one
letter over and over. DRT3 is really
special because it can print out a whole
bunch of DNA very quickly using all four
of the DNA letters. While 3A is using
this normal RNA method to spit out a
bunch of GT repeats, 3B is causing all
the drama by adding a complimentary AC
strand with basically no help from
nucleic acids of any kind. This is the
mechanism that blew the molecular
biology internet up earlier this month.
While 3A is building a GT strand, 3B is
almost magically finding a way to
correctly add A's and C's in the correct
sequence very quickly. And if we zoom
all the way into the active site, the
magic comes from these two segments of
3B's protein code. See, one of the
things that makes DNA so amazing is just
how much these individual letters want
to become a polymer. Raw DNA letters are
actually triphosphates, super energy
dense molecules that are eager to pop a
few of these phosphates off and release
a ton of energy in the process. What's
wild is, and I kind of beat this fact to
death, but the RNA version of these
letters is adenazine triphosphate. The
universal energy currency that all cells
use to do basically all the chemistry of
being alive. But if these letters just
bump into each other in the wild, odds
are the angle won't be right for them to
actually join forces. A DNA assembling
enzyme uses complimentary DNA letters to
hold our raw nucleioases at the exact
right angle so they can touch, join the
polymer, and then release a bunch of
energy that pushes the reaction along.
But every enzyme that builds DNA or RNA
like this that we've seen across the
whole tree of life uses complimentary
DNA or RNA to do that building because
complimentary nucleases have this
perfect chemical attraction thanks to
weak hydrogen bonds. T will only get
added to a strand if there's an A to
hold onto it and G will only join if
there's a C ready to help out and vice
versa. But this B module is so clever
because it will use these two sections
of protein, these two amino acid
residues to do that holding. When DRT3
gets activated, it creates this little
perfect pocket where this glutamine
amino acid pokes out two hydrogen
bonding sites that are the exact right
shape to capture an adinine letter which
will start building 3A's contribution to
the DNA double helix. When adanine gets
added on, it's going to shove this chain
along which will create a pocket where
cytosine can use these hydrogen bonds to
join the strand. It is the exact same
chemistry that you get from using
complimentary nucleobases, but it's
these proteins that are providing the
hydrogen bonding sites. C gets added
here. A gets added here. Everything
moves on. Then C, then A, then C, then
A. The way that these hydrogen bonding
sites are spaced means that no matter
what, these letters have to get added on
in this sequential order. C followed by
A followed by C followed by A, which is
just incredible that just this protein
can produce this repeating AC sequence.
And this is going to combine with GT's
more vanilla process producing a GT
strand, which is complimentary to that
CA sequence. And so you get this slick
system where two complimentary strands
of DNA are assembled at the exact same
time in a way that they can find each
other and zip up into a doublestranded
DNA polymer. When activated, DRT3 will
just keep pumping out this full nonsense
repeating double strand of DNA. And in
laboratory conditions, this process has
gone on until the thread is about 2 to
5,000 DNA letters long. And since DRT3
is actually in a big old complex like
this, we have six of these long DNA
threads running all over the place. And
that's very cool. Awesome. We have this
protein that like makes a whole bunch of
DNA in a special way. But I kept calling
this a defense associated reverse
transcriptise. So like a bunch of
questions. How do we know that this is
defense associated? And how on earth can
printing a bunch of DNA defend against a
fage infection? And we're going to
answer those questions and show off some
astonishing tricks that bacteria pull to
fend off the viral horde. But first,
today. But for now, let's jump back into fage defense. First up, let's zero in on
the more pressing question. How can
DRT3's DNA bomb strategy defend against
fagee infection? I don't think repeating
the same four letters over and over and
over again is going to produce any
usable protein. So like what's happening
here? Now this is the part where things
get tricky because based on just the
tests done in this paper, it's actually
hard to know precisely how DRT3 fits
into an antiviral response. Best guess
right now is that DRT3 works like its
cousin DRT9, which probably activates a
similar DNA bomb strategy in order to
soak up critical proteins produced by
another class of bacteria. The team
behind the paper also alluded to this,
where you can make the argument that the
bacteria wielding DRT3 are using DNA
like a literal net or sponge to tie up
and trap viral proteins. Out here in the
media space, we talk a lot about how
easy it is to break DNA molecules. But
one of the superpowers that's made DNA
kind of like the storage medium for all
life is the fact that DNA is an
incredibly stable polymer, provided you
don't expose them to extreme forces or
radiation or reactive oxygen species or
whatever. So it could be strong enough
to sort of gum up the works and
sequester viral proteins once they've
been detected. Our immune system
actually uses DNA in this way. You've
got white blood cells called neutrfils
which straight up blast pathogens with a
sticky glob of their own DNA called a
neutrfil extracellular trap or net.
Nice. But you could also think of DRT3
as a kind of asset denial platform.
Fages invade in order to steal resources
from their host bacteria. And spewing
out this much DNA very quickly sucks up
a ton of energy and spare DNA letters,
making it hard for the virus to assemble
more of itself. And if that seems like a
weird strategy based on what we've seen
so far, keep in mind that bacteria have
two main concerns when they find out
they've been infected. First of all,
one, they're probably going to die, and
two, they're probably going to be turned
into a bomb that kills all their friends
nearby. Therefore, some of these
antiviral responses are actually meant
to completely destroy the bacteria from
the inside before the phages can steal
any more resources and build more
phages. It is an incredible
communityoriented response that helps
keep the whole species alive while
sacrificing the individual, which may be
surprising if you think about bacteria
as selfish individuals only. And okay,
that's cool, but I think we skipped this
step. Why do we feel justified in giving
DRT3 the defensive reverse transcriptise
label? Just how do we know that this is
a defense protein and how would it
interact with other defensive tools like
crisper? For me, this highlights one of
the most important contributions made by
this paper. The team here managed to
isolate a single fage protein ST61 that
provably activates the DRT3 system by
itself. This is huge because it helps
prove that DRT3 is a defense weapon and
it also demonstrates where DRT3 fits
into the antiviral response. If DRT3 is
set off by a fage coded protein, that
means it only activates once we've hit
the point of no return after the fage
DNA has gained a foothold inside the
host bacteria. I need to repeat this
point because it is critical. It isn't
fage DNA that activates DRT3. It is a
fully synthesized fagee protein. Most
bacterial phages are just shoving
predatory DNA sequences into their
victims. So encountering a fagee protein
means it's already game over. Crisper
and other DNA destroying systems are
like the frontline defense for bacteria.
They snip and destroy predatory DNA
before it can completely take over the
cell. If crisper can neutralize fage DNA
before it gets to critical bacterial
proteins, the bacteria might survive.
However, if that frontline defense
fails, there really isn't any turning
back. This viral DNA is so good at
hijacking bacterial systems that once it
starts taking over, our victim here has
as little as 5 minutes to react before
its metabolism is irreversibly shut
down. and repurposed for viral
production. It's that fast. That's what
makes a system like DRT3 so powerful. It
is an incredibly fast defense system
that sits outside the genome and can't
really be stopped once the party starts.
One of the more evil things some phages
do is hang out and wait a little once
they've basically killed off their
host's metabolism. Without replication
and maintenance, the bacterial DNA will
degrade over time, breaking back down
into raw nucleotides, which the viral
machinery will just repurpose into
making more viruses. But the virus can
do that if DRT3 is over here competing
for those same nucleotides and
effectively denying this fagee a clear
path to assembling new viruses. Still,
without further study, it's hard to say
precisely what making all this DNA would
do to defend against fage infection. And
since the whole like violating the
central dogma thing is just a product of
the internet hype cycle, that can leave
us with a deeply unsatisfying conclusion
to this video. But like come on folks,
you know me. Longtime clock watchers
know exactly what's coming. This is
always the best part of the video. Let's
add some more context and see how this
asset denial thing would actually play
out. Get this. The PI who led this DRT3
discovery also worked with the team that
2 years ago absolutely nailed both the
structure and precise job performed by
one of DRT3's cousins. Let's
contextualize this around a fully formed
defensive response. Meet DRT 2, folks.
This defense platform is much smaller
than DRT3, but wow does this thing ever
punch above its weight. The way that
DRT2 weaponizes DNA in response to fagee
infection is jaw-dropping. And I have
been dying to tell you about it ever
since this paper dropped in 2024. So
y'all, let's put this all together and
see exactly how you can arrest a viral
takeover even after you've passed this
point of no return. Like DRT3, this is a
reverse transcriptise. But when this one
activates, it uses this circular RNA to
continuously pump out a repeating DNA
strand that kind of loops back on itself
and becomes double stranded. What's
different here is that we're catalyzing
a long circular RNA to encode actual
repeating information. What DRT2 does is
assemble a fully ready to produce gene
out of thin air that hijacks the
bacteria's own machinery to produce a
recursive mRNA. This repetitive DNA code
ends up being around 120 letters long.
But again, they really pack a punch.
Every repeat has a spot for the
bacterial RNA polymerase to bind as well
as the instructions to start making a
protein. You know, the start code on.
But critically, it has zero stop
instructions. Basically, RNA polymerase
will get stuck on here and just keep
printing out a repeating mRNA sequence
potentially endlessly. And sure enough,
that mRNA is going to find its way to a
ribosome and trap it in an endless open
reading frame of its own. The ribosome
is going to be stuck here, unable to
stop building this, a completely useless
little accordion protein chain that's
just the same helical bundle strung
together over and over again without end
until the bacteria starves to death or
this long repeating nonsense protein
causes fatal amounts of damage by
gumming up the works nearby. So again, a
circular RNA attached to a reverse
transcriptase makes a repetitive
sequence of DNA which makes an endlessly
repetitive mRNA which makes an endlessly
repetitive nonsense protein. By setting
off this little chain reaction, DRT2 has
effectively halted the bacteria's
metabolism on its own very quickly.
Whether by trapping all of the
bacteria's RNA polymerases and ribosomes
in endless reading frames, or by this
useless protein getting tangled up in
the rest of the bacteria's metabolic
machinery, no matter what, DRT2 halts
everything much faster than the invading
viral DNA can. Again, DRT2 exists as a
kind of self-destruct system bacteria
use to protect their community when they
realize they're about to get zombified
by a fagee infection. This is such a
beautiful uno reverse card in my view. I
mean, this bacteria is effectively
saying, "Oh, hey, you want to steal my
stuff and use it to kill my friends?
Jokes's on you, loser. I'll steal my own
stuff and build a bomb out of nonsense.
Good luck breaking this accordion cable
thing down into the base amino acids you
need to build more fages, loser." It's
like the Philly sports fan response to
fage infection. I'm serious. This might
be one of my favorite things I've
learned about in bacteriology. DRT2
races to destroy this bacteria's
metabolism by just endlessly repeating
the same 120word code over and over. And
since that code repeats the start codeon
and RNA polymerase binding site over and
over again, it's possible that multiple
polymerases and ribosomes are getting
stuck on these DRT2 DNA repeats, which
would rapidly soak up all these
bacterial resources before the viral DNA
could reach a critical mass. And really
the only like super minor issue with
this DRT2 paper is how the team here
couldn't find a specific trigger that
activates this nonsense cascade after
fagee infection. But that's just another
detail that makes the DRT3 paper even
cooler since the team here managed to
isolate this single fage protein that
provably sets DRT3 off. So despite the
fact that we instantly killed that
clickbait about the central dogma of
molecular biology being violated today,
we instead saw how bacteria can cleverly
hide these unstoppable DNA bombs in
their cytoplasm as a last line of
defense against fagee infection, which
for me is a way cooler payoff. This is
incredible to me because why should it
matter to a single bacteria if its
community gets infected if it is already
guaranteed to die? Game's over for them
already. It shouldn't matter, right? But
these defensive reverse transcriptases
work because they help limit the spread
of phages and keep the community alive.
Systems like DRT3 and DRT2 floored me
when I first learned about them. We are
only able to be multisellular because
our individual cells will sacrifice
themselves without question if things
start to go wrong. It's a process called
apoptosis and it is critical for keeping
the whole multisellular operation alive.
And to me, it is so incredible to see
other systems that work like that kind
of altruism operating at the single cell
level. The way we've uncovered the
mechanics of our biochemical world
created a narrative that was very
focused on selfish actions and
individualistic survival in the mid to
late 20th century. Since then, we've
uncovered more and more about how
community-based life is at all levels.
If bacterial populations didn't work
together and have this self-sacrifice
system in place, this constant
overwhelming pressure from fages could
have wiped out that whole kingdom long
ago. Instead, somehow, incredibly,
bacteria and their fage predators are
caught in a kind of balance that
produces incredible systems like DRT3
and DRT2 that have helped us completely
rebalance our understanding of what it
means to be alive in the first place.
Sure, the overhype of DRT3 rewriting the
rules of life itself is fun if you don't
want to pay attention, but the real
mechanics of these defense platforms and
their place in the anti-age arsenal are
far more interesting. It is a beautiful
last stand made by a dying individual to
deny resources to the monster about to
kill it. The brave last stand at the end
of a zombie movie, except it's a real
thing that happens in real life billions
to trillions of times a day. That's why
I love putting the effort into
understanding the real details in
molecular biology. It's so much more
meaningful to see how the base chemical
rules of evolution can generate
something that looks like altruism even
at the single cell level. And it helps
me contextualize the weird amalgamation
of trillions of cells that I have
emerged from. Life just works. That's
all it can do. And the more we learn,
the more it appears that life works best
when we're working together. Either way,
that's a good place to put a bow on
this. I really appreciate your time.
Thanks so much for exploring this with
me.
And hey, thanks so much for making it to
the end of the video. If you liked this,
it really helps a lot if you could like,
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But hey, let's be real. You've already
done the most impactful thing you could
by making it to the point where you're
hearing these words specifically. And
what I mean is just watching the video
all the way through. If there's a
creator you really like, making sure you
watch a video stem to Stern is honestly
the best possible way you can support
them in the current meta. Now, this was
kind of a breaking news situation, so I
tried to shoehorn this video in before
the one that it was actually planned.
So, we haven't seen any payoff to the
question I asked y'all in the last
video. That said, uh what's your
favorite pepper? I just want to get a
quick temperature check from y'all here.
Either way, that's a good spot to close
out. Thanks for being here with me right
in this moment. I really appreciate your
time, and as always, I like to leave you
with peace, love, and open reading
frames. Everyone, be well. Thank you so
much.
Jokes's on you, loser. I'll steal my own
stuff and build a bomb out of nonsense.