Speaker 1: Welcome back to thrilling threads. If you are joining us
for the first time, strap in because we are about
to pull on a loose thread of reality and see
just how far it unravels.
Speaker 2: And today that thread is all about speed.
Speaker 1: Oh, it's about speed, specifically the terrifying, exhilarating velocity of
scientific evolution.
Speaker 2: It's moving faster than most of us can actually comprehend.
We tend to think of scientific breakthroughs as these distinct
finish lines. You run the marathon, you break the tape,
you pop the champagne, and you're done. You solve the
problem exactly.
Speaker 1: We have this historical narrative where we think, okay, we
map the human genome, check done, or we invented the Internet. Finished.
But in the world of biotechnology, a breakthrough isn't a
finish line. It's barely even the warm up.
Speaker 2: It's a starting gun.
Speaker 1: It is a starting gun, and the race that starts
after that gun goes off. That is where the real
story happens.
Speaker 2: And nowhere is that truer than in the story of
gene editing. We are going to be talking about a
tool that has i mean, effectively redefined what it means
to be human in the last decade.
Speaker 1: It really has.
Speaker 2: But more importantly, we are talking about why that tool,
which we all think of as the absolute cutting edge,
is already being treated as legacy technology by the very
people who built it.
Speaker 1: We are talking, of course about Crisper, the heavyweight champion
of biotech, the celebrity, the heavy hitter, the celebrity of
the molecular world.
Speaker 2: For sure, it really is. I mean, it went from
being a theoretical mechanism something we just observed in bacteria
and argued about in you know, obscure journals, to a
functional tool for curing a living, breathing human infant in
just over a decade.
Speaker 1: A decade.
Speaker 2: That's just that is light speed in the world of medicine.
Usually that process takes thirty, forty, maybe fifty years.
Speaker 1: It's absolutely mind betting. I mean, we are talking about
a tool that allows to literally cut and paste DNA.
It sounds like science fiction, but it is science fact.
Speaker 2: It is.
Speaker 1: But and here is the twist, And this is why
I was so excited to record this specific episode. The
very people who pioneered Crisper, the people who hold the patents,
the people who won the accolades, They aren't sitting around
polishing their trophies.
Speaker 2: No, they're certainly not. In fact, they're the ones most
critically analyzing their own creation. They see the flaws more
clearly than anyone.
Speaker 1: They're already looking for its replacement. Yeah, they are already saying, Okay,
Crisper is great, but what's next, what's version two point zero.
It's not just about editing genes anymore. It's about reverse
engineering life itself with a level of precision we didn't
think was possible even five years ago.
Speaker 2: And that brings us to our source material for today.
We are taking a look at a fascinating field trip
to the Broad Institute in Cambridge, Massachusetts. This is arguably
the epicenter of genomic research right now. It is the
Yankees of biotech, if you.
Speaker 1: Will, that's a good way to put it.
Speaker 2: And central to this story is a figure named feng Zeng.
Speaker 1: Feng Zeng. Now, if you follow biotech, you know this name.
He is a giant. But if you don't, let me
just paint a picture. This guy is a titan in
the field. He's won the National Medal of Technology and Innovation.
He's a core member at the Broad Institute, but his
reputation isn't just smart guy. His reputation is that he's
the guy who doesn't just want to solve the puzzle.
He wants to build a better puzzle solver.
Speaker 2: That's a great way to put it. He is a
tool builder. He's an engineer at heart who happens to
work with biology, and.
Speaker 1: Our mission today on Thrilling Threads is to pull apart
the threads of his newest discovery. It's a system with
a very cool name, Tiger. Tiger tigr like the animal,
but cooler because it's an acronym exactly.
Speaker 2: And we're going to find out why Tiger might just
make Crisper look like the opening act to the main event.
Speaker 1: Which is a bold claim considering Crisper is currently curing
diseases in living people, a very bold claim. But before
we get to the Tiger, we have to understand the man.
Let's unpack thing Zang because his origin story, it really
it explains everything of about how he approaches biology.
Speaker 2: It really does.
Speaker 1: He didn't start as a biology kid, did he. He
wasn't out there with a butterfly net or a microscope
looking upond water.
Speaker 2: No, not at all. And this is so critical to
understanding his success thing. Sang's parents were computer scientists, so
just imagine that household environment, logic, code systems, debugging. As
a preteen, he wasn't out catching frogs or looking at
leaves under a magnifying glass. He was taking apart PCs.
Speaker 1: I love that image. Just a kid surrounded by motherboards,
circuit boards and hard drives.
Speaker 2: He was stripping them down to see how they worked,
and then using the parts to build new, better computers.
He had an engineer's brain from day one. He sees
the world as a series of components that can be assembled, disassembled,
and reassembled.
Speaker 1: He understands modularity.
Speaker 2: Yes, exactly, the idea that you can swap out one
part for a better one without having to rebuild the
entire system.
Speaker 1: So how does a computer hardware kid end up rewriting
the code of life? I mean, how do you make
that leap from sel licon to carbon.
Speaker 2: Well, the story is it happened in seventh grade. It's
such a specific pivotal moment. He went to a Saturday
enrichment class.
Speaker 1: It's always the Saturday classes. That's what the magic happens,
the extra credit life, it really is.
Speaker 2: And the topic was molecular biology. They showed a film
you can probably picture it, one of those classic nineties
educational films about the inner workings of the cell.
Speaker 1: With the like the animated ribosomes chugging along a strand
of RNA.
Speaker 2: That's the one and for zaying the light bulb didn't
just turn on, it exploded. He had this epiphany that
biology is just a different kind of operating system.
Speaker 1: Okay, let's pause on that, because that is a profound
shift for a seventh grader. Most kids see biology as
squishy stuff, you know, dissections, plants. He saw it his software.
Speaker 2: It is profound because he realized that DNA is just code.
It's the kernel of the operating system and the proteins.
The proteins are the hardware. They're the chips, the processors,
the physical machinery that carries out the instructions for the code.
The cell is the machine, and.
Speaker 1: The logic follows perfectly. If you change the code the DNA,
you change the output of the machine.
Speaker 2: That is such a programmer mindset. Oh the program is glitching.
Let me check the source code. Oh there's a bug
in line four hundred, Let me just fix that.
Speaker 1: You don't just treat the symptom of the glitch, you
go to the source.
Speaker 2: And rewrite it exactly. And that realization moved him from
soldering sirpit boards to tinkering with the building blocks of life.
He realized that if you can learn the language of
the code, you can program us sell to do something
different than what it was programmed to do by nature.
Speaker 1: He stops seeing disease as a tragedy and started seeing
it as a syntax error.
Speaker 2: That's a great line. It really reframes the whole problem.
A syntax error can be fixed, it can be debugged.
Speaker 1: And he didn't wait until his PhD to start, right.
He was doing this stuff early, very early.
Speaker 2: By high school, he was already volunteering at a gene
therapy lab. And this is where he started working with
something that's now a staple in every biology lab GFP.
Speaker 1: GFP green fluorescent protein, the glowing jellyfish protein.
Speaker 2: Right, it comes from the jellyfish Aquaria victoria. In nature,
it makes the jellyfish glow this eerie green color under
certain light. But for a molecular biologist, it's a tracking device.
It's a biological flashlight.
Speaker 1: So break that down for us, how do you use
a jellyfish protein to track things in a human cell
or a mouse.
Speaker 2: Well, think about a virus or a cancer cell. They're
invisible to the naked eye. You can't just watch them moving.
Speaker 1: Through a body, right, they're too small.
Speaker 2: But if you take the gene for that glowing protein,
the actual sequence of DNA that says make this green
glowing thing, and you attach it to the virus's DNA
or the cancer cells DNA.
Speaker 1: You're tagging it. It's like putting a neon vest on
a construction worker, so you can see them in the dark.
Speaker 2: Precisely. The cell reads its own DNA, sees this new
glow green instruction, and it just it manufactures the protein,
so the cell literally glows green under a special light.
Speaker 1: So Zang used this during his undergen at Harvard right
to track the flu he did.
Speaker 2: He used it to track how the influenza virus enters cells.
He literally lit up the path of the virus as
it infected a cell. He could watch it happen in
real time.
Speaker 1: That is incredibly cool. It's like putting a GPS tracker
ond the bad guys in a movie, so you can
see where they're going on the map.
Speaker 2: There is a great example from the source material about
cancer research. Using this imagine, you want to know how
a cancer metastasizes, how it spreads from say the lung
to the brain, A hugely important question.
Speaker 1: It's one of the biggest questions. So you put the
gfpgene into a cancer cell, put that cell in a mouse,
and then you just you look. You can use imaging
technology to see the mouse's body. Wherever you see a
tiny green light, that's where the cancer has spread.
Speaker 2: That visualization is so powerful. It takes the abstract concept
of disease progression and makes it visible data it does.
Speaker 1: And this seems to establish his whole philosophy, doesn't it.
Speaker 2: It really does.
Speaker 1: He finds a tool in nature, like the jellyfish glow,
he figures out how it works, understands its mechanism, and
then he applies it to see things to solve a
problem that was previously invisible or unsolvable.
Speaker 2: And that's the core of it. It's the distinction between
basic science and applied science. Right, Let's break that down,
because I feel like those terms get thrown around a
lot in academia, but they really matter here.
Speaker 1: They do. So applied science is when you have a
specific goal. I want to build a better rocket engine.
I want to cure this specific flu You are playing
existing knowledge to solve a defined problem.
Speaker 2: You're building something you have a blueprint exactly. Basic science
is just curiosity. It's asking how does this weird bacteria
in a hot spring work? Why does this jellyfish glow?
You aren't trying to sell a product, You're just trying
to understand the universe.
Speaker 1: But Zaying sits right in the middle, doesn't he He's
straddling that fence.
Speaker 2: He does. He does the basic science. He pokes at
bacteria and viruses just to see what they do. But
he always has that engineer's eye. He's always thinking, Okay,
this is a cool mechanism, but what tool could this become.
Speaker 1: He's looking for the API of nature, the application programming interface,
the part you can plug into.
Speaker 2: That is a perfect analogy for his mindset, which leads
us perfectly to the tool that made him famous, the
Big One, Crisper.
Speaker 1: The Big One. Now we've covered Crisper on other shows,
but we need to set the stage here to understand
why we might need an upgrade because to the average person,
to me, Crisper already sounds like magic. Why fix what
isn't broken?
Speaker 2: Well, it's a great question. And first it's so important
to remember where crisper came from. We didn't invent it.
It wasn't designed in a lab by humans to cure
human diseases.
Speaker 1: Right.
Speaker 2: It is a bacterial immune system.
Speaker 1: It's how bacteria fight the flu.
Speaker 2: Essentially, yes, bacteria get attacked by viruses too. We call
them bacterio phages or just phages, and crisper is the
bacteria's defense mechanism. It's a way to find and chop
up the DNA of an attacking virus. It's ancient molecular warfare.
Speaker 1: And the mechanism is often described as molecular scissors. That's
the go to.
Speaker 2: Analogis that's the classic one. You have two main parts.
You have a snippet of RNA which acts like a
tour guide or maybe a.
Speaker 1: Bounty hunter, I like bellonder.
Speaker 2: It has a wanted poster of the bad DNA, the
sequence of the virus's DNA. It floats around the cell
and it leads a protein, usually one called CAST nine,
to that specific spot in the DNA, and then CAST
nine clamps down and just cuts it.
Speaker 1: Cuggy paste or really just cut, primarily cut. The pace
part is what the cell tries to do afterward to
repair the damage, which is a whole other complicated story.
Speaker 2: Now we have to acknowledge the Nobel winners Emmanuel Sharp
Pontier and Jennifer Dobna, who did the foundational work on
this mechanism. Absolutely, they discovered how the system works, but
Fingzang's specific contribution was crucial. He was the one who
proved you could take this entire system out of a
bacteria and make it work in eukaryotic cells. Eukaryokase, that's us,
that's us, that's mice, that's plants, anything with a cell nucleus.
That was the game changer. Going from prokaryotes to eukaryotes
is like going from a simple calculator to a supercomputer.
Speaker 1: That's what turned it from a biological curiosity into a
medical revolution. Fat a doubt, and speaking of revolution, the
source material mentions a milestone from twenty twenty five. This
is in science fiction anymore. This is recent history.
Speaker 2: It's absolutely stunning. In twenty twenty five, Crisper was used
to rewrite the DNA of a living infant to treat
a devastating liver condition.
Speaker 1: Just pause and think about that for a second. We
rewrote the source code of a living human being to
save its life. That is some Star Trek level medicine.
Speaker 2: It is miraculous, it really is, and it worked incredibly well.
But then here's the butt that drives people like Feng Zang.
It's not perfect. In fact, for an engineer, it's messy.
It's version one point zero.
Speaker 1: Okay, So why if we can cure a liver condition
in an infant, why do we need an upgrade? What's
wrong with Crisper?
Speaker 2: Several things? First, let's talk about that liver condition. Why
was it a liver condition?
Speaker 1: Is it because the liver is just easier to get to?
Speaker 2: Exactly? This is what researchers call the liver bias.
Speaker 1: The liver bias sounds like a band name, but I'm
guessing it's about physiology.
Speaker 2: It is. Think about how we deliver these gene editing tools.
We usually package them inside a viral vector, basically a
hollowed out virus that acts like a delivery.
Speaker 1: Truck, right an AAV or something usually.
Speaker 2: In a Dano associated mirus. Yeah, we inject that truck
into the blookstream now the blood circulates, where does the
blood get filtered?
Speaker 1: The liver.
Speaker 2: The liver. The liver is the body's detox center. It
is designed to catch foreign things floating in the blood.
Anatomy Wise, the liver has these massive holes in its
blood vessels called fenestrations. It's like a biological sieve.
Speaker 1: So the viral vectors just naturally get trapped there.
Speaker 2: They fall right in. So it's not that we chose
the liver because we love the liver. It's that the
liver is where the package naturally gets delivered.
Speaker 1: So if you want to treat the liver, nature helps you.
But what if you want to treat the brain or
the heart or muscle tissue.
Speaker 2: The liver is hoarding all the medicine. It's a huge
delivery problem. Imitation number one.
Speaker 1: Okay, what's number two? You mentioned bluntness earlier.
Speaker 2: Yes, the cut itself, the original and most famous crisper
protein CAS nine cuts straight across both strands of the DNA.
It snaps the latter in half. That's a blunt end cut.
Speaker 1: And why is that bad? A cut is a cut,
isn't it?
Speaker 2: Because the cell goes into absolute panic mode? Oh no,
my DNA is broken. This is an emergency. It rushes
to glue the ends back together using a process called
non homologous end joining, and that sounds messy. It is
the messiest. It's quick and dirty. The cell often jams
in random letters or deletes a few just to get
the two strands reconnected. It prioritizes connection over accuracy, so.
Speaker 1: It's like using duct tape to fix a ripped masterpiece painting.
Speaker 2: It is. It's great if your goal is just to
break a gene, say a gene that's producing a toxic protein.
Breaking it stops it from working. But if your goal
is to fix a typo, to precisely change one letter
to another, blunt cuts are very, very risky.
Speaker 1: You might fix the original TYPEO, but introduce three new
errors in the process.
Speaker 2: You absolutely could, which could be even worse. And the
third problem is size right right, You mentioned that size
is a huge issue. Molecularly speaking, CAS nine is a
big protein. It's a complex piece of machinery. The viral
vectors we used to deliver it, those AAVs are tiny.
They have a very small cargo capacity.
Speaker 1: It's like trying to move a grand piano in a Mini.
Speaker 2: Cooper exactly If the CAS nine protein itself takes up
the whole trunk, you have no room for the other
stuff you need, like the guide RNA that tells it
where to go, or regulatory switches to turn the system
on and off at the right time. It's physically difficult
to package it all up.
Speaker 1: So Zang, being the engineer, looks at this and says, Okay,
Version one point zero is great. It's a proof of concept.
But it's too big, it's a bit messy, and it
gets stuck in the liver. I need to make version
two point zero.
Speaker 2: He actually had an intermediate step, an upgrade called cast
one bay. It was smaller, it only needed one RNA
guide instead of two, and it made jagged, sticky cuts,
which are much better for precisely inserting new DNA.
Speaker 1: So that was like version one point five.
Speaker 2: It was. It was an optimization. But even that wasn't enough.
He wanted something radically different, something that solved all the
problems at once.
Speaker 1: And this is where the story gets really thrilling, because
to find the next big thing, he didn't look forward
into the future of synthetic biology. He went back to nature.
He went back to the drawing board.
Speaker 2: He did he started mining genomes again. He went digging
through these massive public databases of genetic sequences from all
corners of.
Speaker 1: Life, looking for another paris.
Speaker 2: Looking for another tool. And he found a new set
of genes. But he didn't find them in bacteria this time,
which is where Crisper was found. He found them prominently
in transposons and viruses in bad guys. Well biology is messy,
bad guy is relative. But yes, he found these genes
and mobile genetic elements, things that jump around the genome.
And he named this new system tiger.
Speaker 1: TIGER which stands for let me check my notes here,
tandem inners based guide RNA.
Speaker 2: That's the one.
Speaker 1: Okay, break that name down for us. What does it
look like? Structurally?
Speaker 2: It looks a lot like Crisper on the surface. It's
these long stretches of repetitive DNA with these unique non
repeating guide snippets in between each repeat. Tandem repeats with
innerspace guides.
Speaker 1: So the organization is similar, but the context is completely
different because of where you found it.
Speaker 2: Completely different. And this is the central mystery, right, Why
would a virus or a transposon, which is like a
jumping gene, why would they carry around a pair of scissors.
Speaker 1: It seems counterintuitive.
Speaker 2: It's a huge question. Viruses are usually minimalists. They want
to travel light. Their whole goal is just to get
into a cell and replicate as efficiently as possible. Why
carry a heavy, complex gene editing system. That's extra baggage.
Speaker 1: So what's the theory? Why do they have it?
Speaker 2: The leading theory is biological warfare. It's an evolutionary arms race.
Speaker 1: I love an arms race theory.
Speaker 2: Think about it. Viruses infect bacteria. Bacteria try to kill
viruses with their crisper system right defense. So maybe viruses
evolved tie as a counter attack, a countermeasure. Maybe they
use it to cut open the bacteria's genome and insert
themselves like a burglar cutting a hole in a security fence.
Speaker 1: Or what if the bacteria is steal the tiger from
the virus to use it back against other viruses.
Speaker 2: Exactly, it's a constant back and forth of stealing weapons
and developing defenses over billions of years. It's this incredible
invisible war happening all around.
Speaker 1: Us and humans. We are just swooping in at the
very last second of evolutionary time, seeing these weapons lying
on the battlefield and saying, hey, I bet I could
use that to cure Alzheimer's.
Speaker 2: We are the ultimate scavengers. Ooh, nice sword.
Speaker 1: I'll take that truly. But okay, let's get into the
specs of this new weapon. Why is Tiger potentially better
than Crisper? What's the technical smack down here?
Speaker 2: Yeah, let's do the stats Tiger versus Crisper.
Speaker 1: Give me the tail of the tape.
Speaker 2: Okay, First major advantage the mechanism of the cut. Unlike Crisper,
Tiger appears to read both sides of the DNA double helix.
Speaker 1: Both sides. Okay, Why does that matter so much?
Speaker 2: We think of it like a security check Crisper or
cast nine. It checks one id, it binds to one
strand of the DNA. If the sequence matches its guide,
it cuts. But sometimes other parts of the genome look
similar enough to fool it. There might be a sequence
that's only one or two letters different, and Crisper might
accidentally cut there. That leads to off target effects.
Speaker 1: Which is the nightmare scenario in medicine. You're trying to
fix one gene and you accidentally break another, potentially vital.
Speaker 2: One correct Taiger by reading both strands acts like a
two factor authentication. It asks does the left strand match
my guide? Yes? Okay? Now does the right strand match
my guide? Yes? Only then does it act the double
check a double check, and this potential for a double
check means it could be significantly more accurate, more precise.
It ensures you were cutting exactly where you want to
cut and nowhere else.
Speaker 1: Okay. So that's a huge upgrade in safety and precision.
What's the next advantage?
Speaker 2: The second advantage is what they call the wind. When
Crisper opens up the DNA to make an edit, it
creates a little bubble, an unwound section of DNA that's
about five to eight genetic letters wide. That sounds tiny
in our world, yes, but in the molecular world, where
a single letter can cause a disease, it's actually kind
of wide. If you are trying to change just one letter,
say to fix the single letter mutation that causes sickle
cell anemia, having eight other letters exposed is risky.
Speaker 1: It's like trying to erase a single typo in a
book with the giant, clumsy eraser. You might smudge the
words next to it.
Speaker 2: That's a great analogy. You fix the A, but you
accidentally delete the G next to it. Tager seems to
open a much smaller window. This potentially allows for single
letter precision. We are talking about the ability to change
an A to a T without touching anything else. It
is truly surgical.
Speaker 1: And the third and perhaps the most critical advantage you
hinted at before, size Tiger is more compact, much more compact,
so it fits through the doggy door.
Speaker 2: It fits through the doggy door. We're back to our
car analogy. It fits in the Mini Cooper with plenty
of room to.
Speaker 1: Spare, and that changes everything regarding where we can use
it in the body.
Speaker 2: It's the key that could unlock everything beyond.
Speaker 1: The liver before we get to where we can use it,
which I know is the exciting part about the brain.
I want to talk about how they figure this stuff
out because the source material takes us inside the lab
at the Broad Institute, and it's this fascinating mix of
being incredibly mundane and yet totally science fiction at the
same time.
Speaker 2: It really is a study in contrasts. It demystifies that
whole Ivory Tower idea of science.
Speaker 1: Yeah, there's this FedEx moment described in the piece walk
us through that because it's wild.
Speaker 2: So imagine you are a researcher on Zeng's team. You've
identified a genetic mutation and a patient that you want
to target. Your first step isn't in a wet lab
with beakers.
Speaker 1: It's at a computer.
Speaker 2: It's at a computer. You sit down and you design
an RNA sequence that perfectly matches that mutation. You are
basically typing code ATCG.
Speaker 1: Okay, so I'm just typing it out on a screen.
Speaker 2: You're typing out. Then you open a website a commercial vendor.
You paste your sequence into a box, you put in
your credit card info. The customer RNA sequence costs about twenty.
Speaker 1: Dollars twenty bucks, I spend more lunch sometimes right.
Speaker 2: You hit by, and a few days later, a FedEx
envelope arrives at the lab. Inside is a tiny plastic
tube with your custom guide RNA freeze dried into a
little white powder.
Speaker 1: That is just it's wild. You are ordering the fundamental
building blocks of life online like it's a pair of
sneakers from Zappos.
Speaker 2: It highlights how accessible the tools of this revolution have become.
The hard part isn't getting the materials anymore. The hard
part is the design, the knowledge, the understanding of what
to order. But the logistics it's just online shopping.
Speaker 1: The commoditization of synthetic biology.
Speaker 2: It's one of the biggest, quietest stories of our time.
Speaker 1: But then you have the machinery. Once the FedEx package arrives,
the work gets physical and the description of the centrifuge
is blew my mind.
Speaker 2: Oh yes, this is where we leave the Pewter kid
world and enter the industrial biology world. To test these systems,
they need to concentrate their viral vectors. They grow the
virus in huge vats of cells. But then they need
to separate the tiny virus particles from all the cell
debris and liquid.
Speaker 1: They need to purify their fleet of delivery trucks exactly.
Speaker 2: To do that, they have to spin them down. And
we are not talking about a salad spinner here. We
are talking about ultracentrifuges spinning at one hundred thousand times
the force of gravity.
Speaker 1: One hundred thousand gs. I mean, what does that even mean?
A fighter pilot might pull what nine g's and pass out?
Speaker 2: Right? This is orders of magnitude beyond that. The interviewer
in the source who is a marine scientist, tried to
compare it to the crushing pressure at the bottom of
the ocean, but the host at the broad laughed and said, no, no,
this is exponentially higher than that.
Speaker 1: So what would happen to a person at one hundred
thousand g's.
Speaker 2: If a human were somehow inside that centrifuge rotor, they
wouldn't just be crushed. The structural integrity of your cells
would fail. You're heavy proteins would separate from your lipids,
which would separate from the water. You would be, as
the host put it, smushed, just liquified into your component parts,
perfectly layered based on density.
Speaker 1: It's a terrifying amount of power just sitting there on
a lab bench, and yet.
Speaker 2: The virus survives because it is so small and has
such a dense crystalline structure, it can withstand forces that
would obliterate us. It's a reminder of how different the
physics of the microscopic world are.
Speaker 1: And then there are the sequencers, which are the other
side of the coin.
Speaker 2: The sequencers are the eyes of the entire operation. We
used to spend years and literally billions of dollars to
sequence the first human genome.
Speaker 1: I remember that being a huge international project it was.
Speaker 2: Now they have machines that look like office printers that
can sequence a whole human genome, all three billion base
pairs in a single day.
Speaker 1: One day.
Speaker 2: Its industrial scale biology, and that speed is what allows
Zang's team to test Tegger so quickly. They can have
an idea in the morning, order the parts, build the system,
put it into Ea Coli bacteria, purify the protein, put
it into human cells in a petri dish, and then
sequence those cells the next day to see exactly what
edits were made. So they get feedback almost instantly, almost instantly.
It's the fail fast learn fast model of Silicon Valley
apply to evolution itself.
Speaker 1: And that iteration is what leads to the future. So
let's talk about the implications. Yeah, because if Tiger is
smaller and more precise, what does that unlock. You mentioned
the brain earlier, and.
Speaker 2: This is the holy grail, moving beyond the liver. As
we discussed, the nervous system is notoriously difficult to treat.
The cells your neurons, they don't divide, so the repair
mechanisms we rely on in other tissues are weak or
non existent.
Speaker 1: And there's the blood brain barrier.
Speaker 2: The blood brain barrier, it's like a fortress wall around
the brain that keeps out most large molecules to protect it.
It's great for keeping out toxins, but it's terrible for
getting in medicine.
Speaker 1: But Tiger, being smaller, could sneak in.
Speaker 2: Because it is so compact, it is much easier to
package into a delivery vehicle, like a specific engineered AAV
that has been designed to be able to cross the
blood brain barrier. This just it opens the door for
treating a whole class of neurodegenerative diseases.
Speaker 1: Okay, let's get specific. What diseases are we talking about.
Speaker 2: We are talking about things like als lou Gerrigg's disease.
We're talking about Huntington's disease, Parkinson's and the biggest one of.
Speaker 1: All, Alzheimer's diseases that we have for all of human
history been essentially helpless.
Speaker 2: Against exactly right now. For Alzheimer's, we mostly treat symptoms.
We try to clear out the amyloid plaque, or we
try to give drugs to slow down the memory loss,
but we're not fixing the root cause.
Speaker 1: They're managing the declined.
Speaker 2: They're managing the decline. But if you could go in
and edit the genetic risk factors like the apoe four gene,
which is a major risk factor for Alzheimer's, if you
could reverse the mutation.
Speaker 1: And that's a key phrase. You just used reverse mutation.
That's different from what we discussed before.
Speaker 2: Yes, this is the ultimate goal of precision gene editing.
It's not just cutting a gene to break it, which
is what we do when we want to stop a
bad protein from being made, but actually rewriting the error,
correcting the typo.
Speaker 1: Explain the difference with an example.
Speaker 2: Okay, a perfect example is Huntington's disease. It's caused by
a genetic stutter in one gene. The code repeats itself
too many times cag cagcag over and over. Current Christper
therapies might try to just cut that whole gene to
silence it, but that gene might be doing something else
important in the cell. If you break it, you might
cause other problems.
Speaker 1: Right, you lose it.
Speaker 2: Normal function With reverse mutation using a precise tool like Tiger,
the goal is to go in and snip out just
the extra repeats. You turn the stutter back into a
clear sentence.
Speaker 1: You're not deleting a corrupted file. You're actually fixing the
code inside the file so it runs perfectly. Again.
Speaker 2: That's it exactly. It is restoring function rather than just
managing dysfunction. It's the difference between being curative and being palliative.
Speaker 1: And it all comes back to Zaying's core philosophy about nature.
I loved his quote about this in the Source. He said,
nature is very wise.
Speaker 2: Nature has been innovating for billions of years. That is
the engineer's humility. He realizes that he doesn't need to
invent the solution from scratch. He doesn't need to be
smarter than four billion years of evolution.
Speaker 1: The virus needed a way to cut DNA to survive,
the bacteria needed a way to block it to survive.
The solution is almost certainly already out there. We just
have to find it.
Speaker 2: Our job is to go and learn to be the
student of nature, not just the master of it, to
be a really good scavenger on that ancient battlefield.
Speaker 1: I want to touch on the human element here before
we wrap up. Yeah, because despite all this, the nobel
of a work, the immense pressure, the potential to cure
Alzheimer's Fangsang seems remarkably grounded.
Speaker 2: He does. He talks about the thrill of everyday lab work.
He's not just in it for the big gala dinners
or the awards. He genuinely loves the process. He likes
seeing the cells change color. He likes the pipette in
his hand.
Speaker 1: There was a beautiful moment in the Source where he
described the feeling of discovery.
Speaker 2: Yes, he said that when you find an answer to
a question no one has ever asked before, when you
see that data pop up on the screen for the
first time, for a brief moment, you are the only
person in the universe who knows that specific secret of
how life works.
Speaker 1: That gives me chills, the only person in the universe.
Speaker 2: It's a profound intimacy with reality. You have peaked behind
the curtain. And I think that feeling, that pure curiosity
is what drives him. It's that same feeling of the
seventh grader taking apart the computer just scaled up to
the machinery of life itself.
Speaker 1: And his optimism is infectious. I mean, he treats biology
like broken code, and if it's just code, it can
be debugged. It implies that sickness isn't a destiny, it's
just a glitch in the system.
Speaker 2: That is a very powerful and hopeful worldview. It shifts
the entire narrative from coping with disease to solving disease.
It's an engineer's approach to human suffering.
Speaker 1: So what does this all mean? We've gone from a
kid taking apart PCs in his bedroom to a man
who might be on the verge of handing us the
keys to the human mind. We are moving from a
world of treating symptoms to a world of debugging the
source code of humanity.
Speaker 2: It raises huge, huge questions. We are getting very, very
good at the debugging part, but tools are agnostic. A
scalpel can be used for healing or for harming. It
doesn't know the difference between fixing and changing right.
Speaker 1: And Tiger seems to be the next level of that,
a sharper, smaller, more accessible scalpel. But it leaves me
with a thought and I want our listeners to really
chew on this one. If Tiger works as well as predicted,
if we can edit single letters of DNA in the
brain with ease, where does the debugging stop and the
enhancing begin.
Speaker 2: That is the line we're going to have to draw
as a society, and it's a very blurry one. Because
if you can fix a gene for Alzheimer's to restore memory,
can you also tweak a gene for memory retention in
a healthy person to give them a photographic memory?
Speaker 1: Exactly? If the tool is that precise and that easy
to deliver, the temptation will be immense. The line between
therapy and enhancement could vanish.
Speaker 2: It brings us right back to the start. The breakthrough
is just the starting gun. We're inventing these incredibly powerful
tools faster than we are inventing the ethics and the
wisdom to handle them.
Speaker 1: So here is my question to you listening right now.
If you could change one line of code in your
own genetic makeup, race a family illness, sharpen as sense,
maybe change a trait you've always struggled with, would you
trust yourself to make that edit? It's a tough question,
or is some code better left unread?
Speaker 2: A fascinating question. I think many of us would say
yes to the cure for a terrible disease, but would
we be able to say no to the upgrade to
making ourselves better than.
Speaker 1: A Well, we want to hear from you. Leave a comment,
tell us your stance. Would you tiger your own genome?
What's the line for you?
Speaker 2: I'm very curious to see what people say me too.
Speaker 1: Thanks for joining us on this journey into the microscopic,
and thanks for listening to thrilling threads. Until next time,
keep pulling on those threats. You never know what you'll find.