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0:00CRISPR is one of the biggest biotech game
changers of all time, right up there with
0:05figuring out the structure of DNA in the
first place. In a little over a decade,
0:09scientists went from wondering if this
gene editing tool could even work in
0:13humans to rewriting a living infant's DNA
to administer a life saving treatment.
0:19But CRISPR didn't start with a grand plan
to solve genetic disorders. It started with
0:24a curiosity about how bacterial immune
systems worked. A scientist named Feng
0:29Zhang was one of the people studying
an element of those immune systems,
0:32and he would use what he learned to help
pioneer CRISPR gene editing in human cells.
0:38But apparently he was just getting started
because Zhang is back in the lab studying
0:43another seemingly niche area of molecular biology
that may have even bigger implications. It's a
0:51set of genes called TIGR that are found in
some viruses and single-celled organisms,
0:56and they may be an even more powerful tool
than CRISPR for certain kinds of gene editing.
1:02And that sounds like a story big enough to
tell in person. And that's why we created
1:07a new series called SciShow Field
Trips. Each episode we get out of
1:10the studio and we visit a lab where
cutting edge science is happening.
1:15Our good friend Jaida Elcock
talked to Zhang in Boston,
1:18and she has the scoop on a scientist
who reverse engineers life itself.
1:28Thanks, Hank. On any given day, you might
find Feng Zhang meeting with colleagues to
1:32discuss data in a lecture hall, teaching at MIT
or right here at the Broad Institute in Cambridge,
1:37Massachusetts. Although he's won countless
awards, including the National Medal of
1:41Technology and Innovation, he still
loves the thrill of everyday lab work.
1:45You can actually see with your eyes how something
is changing, or how a cell or an animal is
1:52behaving. Sometimes maybe you make an observation
that's not exactly related to the original
1:58question, but it can sort of inspire you to think
about something new. And oftentimes in science is
2:06the least expected result that really inspires
you to come up with something novel and new.
2:12Zhang's work often falls under what's
called basic science or basic research.
2:16This tends to mean figuring out
how stuff works at a fundamental
2:19level without an immediate application,
like a blockbuster drug or a new kind
2:23of rocket engine. But Zhang usually has a
vision of where such things could lead.
2:27When we are trying to do research, we have
some hypotheses. So, for example, we want
2:32to know if there is a system in a bacteria that
might be able to recognize DNA, or maybe it can
2:40recognize proteins, maybe they don't recognize DNA
or recognize protein, but they do something else.
2:46So we just want to know everything. And then
2:48if we find something that does what we are
looking for, we try to turn it into a tool.
2:53But before you can do any of that, well,
you have to understand how things work at
2:57the most fundamental level. And Zhang has
been doing that since he was a kid. His
3:01parents were both computer scientists who
took an active interest in his education.
3:04Rather than rote learning, Zhang
was encouraged to take things apart,
3:08break them down and figure it out. Maybe it's
not surprising then that his first foray into
3:12science was through computers and coding. As
a pre-teen, he took apart his PC and used the
3:16parts to build other computers. But like many
childhood obsessions, that quickly changed.
3:20The turning point really came when I was, I think,
in seventh grade. I went to a Saturday enrichment
3:28class and the topic was molecular biology. What
biology meant completely changed for me. Because
3:35the thought is that there are these underlying
principles of how there's DNA, and the DNA has
3:41a code, and the code can be then turned into
protein. And so you have all these different
3:46components of a biological system of a cell that
work together. And if you change the code you
3:53change how the cell behaves. You can put a gene
like a unit of instruction into a cell. And you
3:59can get a cell to do something different than they
did before. So that made it seem like a computer.
4:05And just like there were logical principles
to writing code, there were logical,
4:09fundamental principles to how the natural
world was built. Once Zhang realized this,
4:13he began looking for ways to tinker
with the building blocks of life,
4:16starting in high school when he
volunteered at a local gene therapy lab.
4:19There he studied green fluorescent protein,
a protein from jellyfish that glows under
4:23certain circumstances. You can attach it to other
proteins and follow the glow around. So Zhang used
4:28it to track proteins in viruses and figure out how
they infect cells and make copies of themselves.
4:33Later, as an undergraduate at Harvard,
4:35he would use GFP to reveal how the influenza
virus enters cells. But other scientists would
4:40take their basic research on green
fluorescent protein even further.
4:43So one way that you might imagine using this
is if you want to study how cancer cells spread
4:49in the body, how it metastasizes. You can
take a cancer cell, you can put this green
4:55fluorescent protein gene into that cancer
cell. The cell will start to make it and it
5:00will be able to glow green. Then you put this
GFP labeled cell into a mouse. And this cancer
5:07cell will start to divide, replicate and will
start to spread. So now you take the mouse,
5:12you just image it, and you just look
for where there are green cells. And
5:16you can get a sense of how widely this
cancer cell is able to grow and spread.
5:22Zhang continued to seek out other biological
systems that answered the questions he had
5:26about how life functions. He went on to
Stanford to get his PhD, but in 2009,
5:30he made his way back to Harvard and started
toying with different ways of editing genes.
5:34There, he began work on something that would
change his life and biotechnology forever.
5:39We humans have immune systems to protect us
from harmful organisms. Well, microbes like
5:43bacteria and archaea are no different. They
have sequences of DNA that help defend them
5:48against viruses. Those sequences are called, you
guessed it, CRISPR. The term describes their OG
5:53biological definition. It's short for clustered
regularly interspaced short palindromic repeats,
5:59and they work a little like a
molecular cut and paste tool.
6:02First, a snippet of RNA, DNA's one-stranded twin,
6:05acts like a little tour guide by matching
the sequence it targets, enabling it to
6:09enter the nucleus of a cell and latch on to
a section of matching DNA. It brings along
6:14an enzyme called a CRISPR associated protein,
or CAS, that then cuts the section of DNA out.
6:19Several other researchers around the
world were figuring out how CRISPR works,
6:23including Emmanuelle Charpentier and Jennifer
Doudna, who won the Nobel Prize for its discovery.
6:29But a lot of the early research was focused on
how it works in bacteria. Zhang was in awe of
6:34this biological system and wanted to see if
he could co-opt it to edit bigger genomes.
6:39So one of the things that is really exciting
that has happened in biology is the mapping
6:45of the human genome. Scientists have been
able to map the genome of healthy people
6:50and people who are affected by specific
diseases. And by comparing their DNA,
6:55you can start to identify genetic
differences or mutations that cause disease.
7:00If you know the genetic cause for disease,
the tantalizing idea is if you can go into
7:06those cells and be able to reverse that
mutation back to the normal DNA sequence.
7:13And so this is a holy grail for medicine.
This can, you know, undo the underlying
7:20cause so that you make the cell healthy again.
The way to do that is through gene editing.
7:25So these are DNA sequencing machines.
7:29Each one of these machines, we can put in many,
7:32many molecules of DNA. We can study
what the sequence of DNA is. And these
7:37are larger capacity machines. For example,
this can do a whole human genome in a day.
7:43Woah. The human genome has,
like, how many base pairs?
7:473 billion base pairs. And that
can sequence that in a day.
7:52This sequence that in a day. Yeah. That's right.
7:55Science is amazing. Wow. Okay.
7:57with a system called CRISPR Cas9, named
for the protein it uses to cut out DNA.
8:02And he was the first to get it to work in
eukaryotes, specifically mice and humans.
8:06Over the next eight years, Zhang and his team
hunted down new Cas systems from different
8:11bacteria, then engineered them to seek out
different sections of DNA. Cas12a, for example,
8:16is smaller than Cas9 since it only needs a single
RNA to guide it instead of the two that Cas9 has.
8:23Its smaller size means it's easier to get into
cells. There are only so many ways to break
8:27through the cell membrane, and the smaller the
better. Cas12a also makes kind of a jagged cut,
8:32which in the gene editing world is a good thing,
since cutting DNA straight leaves a blunt end
8:37that can mutate more easily. Understanding
those CRISPR systems soon led to treatments.
8:42Once you sort of understood how CRISPR works,
8:45how did you translate that into treatments
for different disorders? Basically,
8:49how did you go from sort of this gene splicing
stage to implementing that into living cells?
8:54The first thing to do is try to figure out
what are all of the pieces that constitute a
8:59CRISPR system, and then we have to engineer
them to get them to work in a human cell.
9:05What is the genetic mutation that
you're trying to repair? Once you
9:10identify that then you can go to the
computer. You can design the guide RNA
9:16to reprogram the CRISPR system to be
able to recognize that mutation in the
9:21human cell. Once you have the RNA sequence,
you can use chemical synthesis to make it.
9:26So you just go online, open up a website, you
can type in the sequence, submit the order,
9:32usually maybe $20 or something like that.
And then in a couple of days you get a Fedex
9:38envelope with a little tube. In the tube is the
guide RNA. And so that's all you have to do.
9:44I don't even have words. That
is so - that's fascinating.
9:48So you're quite literally just ordering the parts
that you need to fix certain pieces of the DNA?
9:57Right. Now, once you get that working, that's on
the inside of a human cell, right? So then you had
10:02to figure out, how do you deliver this into enough
cells? Like, for example, if you want a target
10:08muscle to be able to treat muscular disorder,
you have to get it into all of the muscle cells,
10:15right? So there are different delivery systems
that researchers have been developing.
10:19The results have been amazing. So far, CRISPR
has been investigated as a treatment for at
10:24least 18 different disorders, from sickle cell to
leukemia. Usually, scientists edit the cellular
10:30DNA in the lab and then return those cells to
the people affected where the cells replicate.
10:34But in a stunning story in 2025, it was used for
the first time to rewrite DNA in a living person:
10:40that infant Hank mentioned earlier. It
was a life-saving miracle that probably
10:45won't be the last of its kind. For all its
triumphs, though, CRISPR isn't perfect.
10:48CRISPR is a gene editing method. And so
for diseases where we know the underlying
10:55genetic cause, CRISPR is a good way to treat it.
10:59But there are diseases where it's more
complicated. It's not caused by a single genetic
11:05mutation. And those are much harder to treat
with CRISPR. Because you don't really know where
11:11in the genome to change to be able to restore
the function of that cell or that tissue. So
11:17we need new delivery capabilities that can allow
CRISPR to access these other parts of the body.
11:24Those limitations meant something better had to be
out there. So he went back to the drawing board,
11:28back to pulling life apart to see how it
works. He began studying a curious set of
11:33genes he and his colleagues discovered
just a few years ago. Like CRISPR,
11:37they were made up of short repeating
sequences of genetic information,
11:40plus a protein that can cut DNA, although this
time they were mostly found in viruses rather
11:45than bacteria. Zhang and his team
called the genetic sequences TIGR.
11:49Can you tell me what TIGR the acronym stands
for, and what exactly does all of that mean?
11:56Yeah. TIGR. T-I-G-R stands for tandem interspaced
guide RNA. And so it's a long stretch of DNA that
12:07is kind of repetitive. So it repeats itself
over and over and over again, but it's not
12:12an exact repeat because there are snippets of
it or stretches of it that are not repeated.
12:19And those happen to be the guide sequences that
direct the TIGR-Tas system to different targets.
12:27Just like CRISPR was serving as an immune system
for bacteria under our noses for a long time,
12:32TIGR-Tas has just been hanging out, waiting to be
discovered, but the team doesn't totally know what
12:37it does yet. Viruses are pretty simple things,
and it's not really clear why they need such a
12:42sophisticated DNA targeting system when their job
is usually just to get into a cell and reproduce.
12:47We see the system in both bacteria and
also viruses that infect bacteria. And
12:54it may be a system that's involved in
bacterial and also viral warfare. You know,
13:00they are fighting against each other in nature.
So it may be a system where viruses use a TIGR
13:08system to direct itself to be able to insert
into a bacteria's genome, as a way to find a
13:15home and land there. And then bacteria may use
it as a way to fight off the viruses, to degrade
13:25it before it's able to insert itself. So it's
probably involved in some processes like this.
13:31That's really interesting.
13:32Yeah. And that's what's really cool about nature
is that you have these competitive situations.
13:36Because it's life or death they try really hard to
come up with a lot of really powerful solutions.
13:43Looking at these things and understanding how they
work, I think we can discover a lot of interesting
13:49biology, and probably many of them we can
harness and engineer into useful biotechnology.
13:55Regardless of what TIGR-Tas does in viruses,
the team thinks this system has the potential
13:59to do a lot of the things CRISPR does
for us, only better. Unlike CRISPR,
14:04TIGR-Tas reads both sides of the DNA
double helix when deciding where to target,
14:09potentially making it more accurate in where it
decides to make a cut. TIGR-Tas is also smaller,
14:14which could help it sneak into more places in
the body. And those aren't the only advantages.
14:18There are cases where CRISPR is trying to
achieve single letter precision modification,
14:24but because it opens up a 5 to 8 letter long
window, you cannot have a single letter precision.
14:33Whereas with TIGR-Tas, because it can
make smaller windows of DNA accessible,
14:40it can overcome that limitation.
14:43Continuously we have to look for new things
either from nature or try to engineer
14:50CRISPR and combine CRISPR with other things,
to enable these new sort of capabilities.
14:58Zhang and his team still need
to learn more about how TIGR
15:01operates in viruses and other microbes
to know exactly what it can do for us.
15:05Can you explain some of the
experiments that you do with TIGR-Tas,
15:09and what exactly you hope to learn from them?
15:12When we find TIGR-Tas, one of
the first things we'll do is
15:16we'll synthesize the DNA sequence
for the entire TIGR-Tas system,
15:21and then we'll transplant that into a bacteria.
And so we'll take the synthesized TIGR-Tas genes,
15:27and we'll transfer into E. coli, and
we'll grow up the bacteria in the lab.
15:31We might try to purify the protein from the
bacteria so that we can study the TIGR-Tas protein
15:37in a very well controlled test tube environment.
Or, we'll try to put it into a human cell. So
15:44these are sort of cells growing in petri dishes,
and we grow them in the incubator, and then we can
15:52transfer the TIGR-Tas system into those cells,
and then we can measure to see what happens.
15:57And the lab is doing all sorts
of experiments to that end.
16:00So these are centrifuges, we use them
to spin down things that we're trying to
16:06study. So, for example, to get
a gene delivered into a mouse,
16:11we might use a viral vector. So this is a
hollowed out virus always sticking to the top.
16:18And then, to concentrate it, we have to spin
it really fast because there are very small
16:24particles. And you have to spin a very, very high,
sort of, multiple of gravity in order for it to
16:31come down. So this is what we do. So we take one
of these rotors and we put it into the machine,
16:37like this. And then we'll just close the lid and
it'll start to spin. And it'll spin very fast.
16:46This can be as fast as 100,000
times gravity. Yeah. So if it's
16:52a human that would be smushed down.
16:54Oh my gosh, I'm - because as a
marine scientist, my reference is,
16:58like, pressure at the bottom of
the ocean. And I'm assuming that
17:03this spinning this fast, that this
is significantly higher pressure.
17:08How many times gravity.?
17:09100,000 times gravity.
17:12All of this is still in the "pull it apart to see
how it works" phase. Once they understand that,
17:17they'll have a better idea of how it might be used
therapeutically. But potentially this TIGR system
17:22could make CRISPR look like an opening act.
That groundbreaking CRISPR treatment in 2025
17:27rewrote the DNA of cells in the infant's liver,
and it seemed to have worked incredibly well.
17:33But it's easy to get treatments to go to
the liver. The liver detoxifies things,
17:36so whenever the body sees something
weird, it's off to the liver with you.
17:40And cells in the liver divide a lot, which
is required for CRISPR to do its thing. So
17:45imagine a disease where the problematic
cells are harder to reach or dividing
17:48less. Think of something like Alzheimer's or
Parkinson's or other diseases of the brain.
17:53What potential does TIGR-tas have for treating
different diseases of the nervous system?
17:58The TIGR-Tas system is a compact system
which makes delivery of the TIGR-Tas system
18:05more convenient than a bigger system
like Cas9. So, things like ALS,
18:11or Huntington's disease, or other
things where there is a known,
18:17genetic basis that we might be able to use
it to treat. We're working on trying to
18:23further improve the TIGR-Tas system so that
it's more effective. And also doing studies
18:30to understand, how do we best deliver them into
the brain, to be able to treat different things?
18:36Nature is very wise, you know, it has all
these really cool innovations and solutions to
18:42all of these different problems that plants and
animals and organisms have faced over the, you
18:49know, millions and billions of years of evolution.
And so, so, yeah, we just want to go and learn.
18:54What is the enjoyment that you get from
doing all of this really cool work?
18:58I think the whole process is enjoyable.
19:00Yeah. Okay. Awesome.
19:01Like getting answers to questions is
very satisfying. Because it makes you
19:05understand something. And oftentimes
because we're working on research,
19:10so we're working on questions that
no one knows the answer about before,
19:13when we find the answer we're the first
person in the world to know the answer to
19:17something. And that is satisfying because
you are kind of pushing the frontier.
19:22What are your ultimate goals
for the work that you're doing?
19:24Thinking that there are these biological
problems and we can take an engineer's
19:28approach to understand what is wrong with the
system, how do we fix it? And then use these
19:35sort of fundamental, basic principles of DNA,
and genetics to develop new solutions. There's
19:42still much more to do. But I think it's just
rewarding that we can make progress and make,
19:50you know, treatments for diseases
that people couldn't treat before.
19:53If the results are anything like the last
time Zhang got interested in something,
19:56it could be world changing.
20:00SciShow Field Trips are made with our friends at
HHMI's Tangled Bank Studios. We've come together
20:05to bring you face to face with researchers
at the cutting edge of scientific discovery.
20:09You can watch more of Tangled Bank's
science content at tangledbankstudios.org.
