CRISPR is one of the biggest biotech game  changers of all time, right up there with   figuring out the structure of DNA in the  first place.

In a little over a decade,   scientists went from wondering if this  gene editing tool could even work in   humans to rewriting a living infant's DNA  to administer a life saving treatment.  But CRISPR didn't start with a grand plan  to solve genetic disorders. It started with   a curiosity about how bacterial immune  systems worked.

A scientist named Feng   Zhang was one of the people studying  an element of those immune systems,   and he would use what he learned to help  pioneer CRISPR gene editing in human cells.  But apparently he was just getting started  because Zhang is back in the lab studying   another seemingly niche area of molecular biology  that may have even bigger implications. It's a   set of genes called TIGR that are found in  some viruses and single-celled organisms,   and they may be an even more powerful tool  than CRISPR for certain kinds of gene editing.  And that sounds like a story big enough to  tell in person. And that's why we created   a new series called SciShow Field  Trips.

Each episode we get out of   the studio and we visit a lab where  cutting edge science is happening. Our good friend Jaida Elcock  talked to Zhang in Boston,   and she has the scoop on a scientist  who reverse engineers life itself. Thanks, Hank.

On any given day, you might  find Feng Zhang meeting with colleagues to   discuss data in a lecture hall, teaching at MIT  or right here at the Broad Institute in Cambridge,   Massachusetts. Although he's won countless  awards, including the National Medal of   Technology and Innovation, he still  loves the thrill of everyday lab work.  You can actually see with your eyes how something  is changing, or how a cell or an animal is   behaving. Sometimes maybe you make an observation  that's not exactly related to the original   question, but it can sort of inspire you to think  about something new.

And oftentimes in science is   the least expected result that really inspires  you to come up with something novel and new.  Zhang's work often falls under what's  called basic science or basic research.   This tends to mean figuring out  how stuff works at a fundamental   level without an immediate application,  like a blockbuster drug or a new kind   of rocket engine. But Zhang usually has a  vision of where such things could lead.  When we are trying to do research, we have  some hypotheses. So, for example, we want   to know if there is a system in a bacteria that  might be able to recognize DNA, or maybe it can   recognize proteins, maybe they don't recognize DNA  or recognize protein, but they do something else.

So we just want to know everything. And then   if we find something that does what we are  looking for, we try to turn it into a tool.  But before you can do any of that, well,  you have to understand how things work at   the most fundamental level. And Zhang has  been doing that since he was a kid.

His   parents were both computer scientists who  took an active interest in his education. Rather than rote learning, Zhang  was encouraged to take things apart,   break them down and figure it out. Maybe it's  not surprising then that his first foray into   science was through computers and coding.

As  a pre-teen, he took apart his PC and used the   parts to build other computers. But like many  childhood obsessions, that quickly changed.  The turning point really came when I was, I think,  in seventh grade. I went to a Saturday enrichment   class and the topic was molecular biology.

What  biology meant completely changed for me. Because   the thought is that there are these underlying  principles of how there's DNA, and the DNA has   a code, and the code can be then turned into  protein. And so you have all these different   components of a biological system of a cell that  work together.

And if you change the code you   change how the cell behaves. You can put a gene  like a unit of instruction into a cell. And you   can get a cell to do something different than they  did before.

So that made it seem like a computer.  And just like there were logical principles  to writing code, there were logical,   fundamental principles to how the natural  world was built. Once Zhang realized this,   he began looking for ways to tinker  with the building blocks of life,   starting in high school when he  volunteered at a local gene therapy lab.  There he studied green fluorescent protein,  a protein from jellyfish that glows under   certain circumstances. You can attach it to other  proteins and follow the glow around.

So Zhang used   it to track proteins in viruses and figure out how  they infect cells and make copies of themselves. Later, as an undergraduate at Harvard,   he would use GFP to reveal how the influenza  virus enters cells. But other scientists would   take their basic research on green  fluorescent protein even further.  So one way that you might imagine using this  is if you want to study how cancer cells spread   in the body, how it metastasizes.

You can  take a cancer cell, you can put this green   fluorescent protein gene into that cancer  cell. The cell will start to make it and it   will be able to glow green. Then you put this  GFP labeled cell into a mouse.

And this cancer   cell will start to divide, replicate and will  start to spread. So now you take the mouse,   you just image it, and you just look  for where there are green cells. And   you can get a sense of how widely this  cancer cell is able to grow and spread.  Zhang continued to seek out other biological  systems that answered the questions he had   about how life functions.

He went on to  Stanford to get his PhD, but in 2009,   he made his way back to Harvard and started  toying with different ways of editing genes.   There, he began work on something that would  change his life and biotechnology forever.  We humans have immune systems to protect us  from harmful organisms. Well, microbes like   bacteria and archaea are no different. They  have sequences of DNA that help defend them   against viruses.

Those sequences are called, you  guessed it, CRISPR. The term describes their OG   biological definition. It's short for clustered  regularly interspaced short palindromic repeats,   and they work a little like a  molecular cut and paste tool.  First, a snippet of RNA, DNA's one-stranded twin,   acts like a little tour guide by matching  the sequence it targets, enabling it to   enter the nucleus of a cell and latch on to  a section of matching DNA.

It brings along   an enzyme called a CRISPR associated protein,  or CAS, that then cuts the section of DNA out. Several other researchers around the  world were figuring out how CRISPR works,   including Emmanuelle Charpentier and Jennifer  Doudna, who won the Nobel Prize for its discovery.   But a lot of the early research was focused on  how it works in bacteria. Zhang was in awe of   this biological system and wanted to see if  he could co-opt it to edit bigger genomes.

So one of the things that is really exciting  that has happened in biology is the mapping   of the human genome. Scientists have been  able to map the genome of healthy people   and people who are affected by specific  diseases. And by comparing their DNA,   you can start to identify genetic  differences or mutations that cause disease.

If you know the genetic cause for disease,  the tantalizing idea is if you can go into   those cells and be able to reverse that  mutation back to the normal DNA sequence.   And so this is a holy grail for medicine.  This can, you know, undo the underlying   cause so that you make the cell healthy again.  The way to do that is through gene editing.  So these are DNA sequencing machines.  Oh. Whoa.  Each one of these machines, we can put in many,   many molecules of DNA. We can study  what the sequence of DNA is.

And these   are larger capacity machines. For example,  this can do a whole human genome in a day. Woah.

The human genome has,  like, how many base pairs? 3 billion. 3 billion base pairs. And that  can sequence that in a day.  This sequence that in a day. Yeah.

That's right.  Science is amazing. Wow. Okay.    Zhang tinkered   with a system called CRISPR Cas9, named  for the protein it uses to cut out DNA.   And he was the first to get it to work in  eukaryotes, specifically mice and humans.

Over the next eight years, Zhang and his team  hunted down new Cas systems from different   bacteria, then engineered them to seek out  different sections of DNA. Cas12a, for example,   is smaller than Cas9 since it only needs a single  RNA to guide it instead of the two that Cas9 has.   Its smaller size means it's easier to get into  cells. There are only so many ways to break   through the cell membrane, and the smaller the  better.

Cas12a also makes kind of a jagged cut,   which in the gene editing world is a good thing,  since cutting DNA straight leaves a blunt end   that can mutate more easily. Understanding  those CRISPR systems soon led to treatments.  Once you sort of understood how CRISPR works,   how did you translate that into treatments  for different disorders? Basically,   how did you go from sort of this gene splicing  stage to implementing that into living cells?  The first thing to do is try to figure out  what are all of the pieces that constitute a   CRISPR system, and then we have to engineer  them to get them to work in a human cell.

What is the genetic mutation that  you're trying to repair? Once you   identify that then you can go to the  computer. You can design the guide RNA   to reprogram the CRISPR system to be  able to recognize that mutation in the   human cell.

Once you have the RNA sequence,  you can use chemical synthesis to make it. So you just go online, open up a website, you  can type in the sequence, submit the order,   usually maybe $20 or something like that.  And then in a couple of days you get a Fedex   envelope with a little tube. In the tube is the  guide RNA.

And so that's all you have to do. I don't even have words. That  is so - that's fascinating.   So you're quite literally just ordering the parts  that you need to fix certain pieces of the DNA?

Right. Now, once you get that working, that's on  the inside of a human cell, right? So then you had   to figure out, how do you deliver this into enough  cells?

Like, for example, if you want a target   muscle to be able to treat muscular disorder,  you have to get it into all of the muscle cells,   right? So there are different delivery systems  that researchers have been developing.  The results have been amazing. So far, CRISPR  has been investigated as a treatment for at   least 18 different disorders, from sickle cell to  leukemia.

Usually, scientists edit the cellular   DNA in the lab and then return those cells to  the people affected where the cells replicate. But in a stunning story in 2025, it was used for  the first time to rewrite DNA in a living person:   that infant Hank mentioned earlier. It  was a life-saving miracle that probably   won't be the last of its kind.

For all its  triumphs, though, CRISPR isn't perfect.  CRISPR is a gene editing method. And so  for diseases where we know the underlying   genetic cause, CRISPR is a good way to treat it. But there are diseases where it's more  complicated.

It's not caused by a single genetic   mutation. And those are much harder to treat  with CRISPR. Because you don't really know where   in the genome to change to be able to restore  the function of that cell or that tissue.

So   we need new delivery capabilities that can allow  CRISPR to access these other parts of the body. Those limitations meant something better had to be  out there. So he went back to the drawing board,   back to pulling life apart to see how it  works.

He began studying a curious set of   genes he and his colleagues discovered  just a few years ago. Like CRISPR,   they were made up of short repeating  sequences of genetic information,   plus a protein that can cut DNA, although this  time they were mostly found in viruses rather   than bacteria. Zhang and his team  called the genetic sequences TIGR.

Can you tell me what TIGR the acronym stands  for, and what exactly does all of that mean?  Yeah. TIGR. T-I-G-R stands for tandem interspaced  guide RNA.

And so it's a long stretch of DNA that   is kind of repetitive. So it repeats itself  over and over and over again, but it's not   an exact repeat because there are snippets of  it or stretches of it that are not repeated.   And those happen to be the guide sequences that  direct the TIGR-Tas system to different targets. Just like CRISPR was serving as an immune system  for bacteria under our noses for a long time,   TIGR-Tas has just been hanging out, waiting to be  discovered, but the team doesn't totally know what   it does yet.

Viruses are pretty simple things,  and it's not really clear why they need such a   sophisticated DNA targeting system when their job  is usually just to get into a cell and reproduce.  We see the system in both bacteria and  also viruses that infect bacteria. And   it may be a system that's involved in  bacterial and also viral warfare. You know,   they are fighting against each other in nature.  So it may be a system where viruses use a TIGR   system to direct itself to be able to insert  into a bacteria's genome, as a way to find a   home and land there.

And then bacteria may use  it as a way to fight off the viruses, to degrade   it before it's able to insert itself. So it's  probably involved in some processes like this. That's really interesting.  Yeah.

And that's what's really cool about nature  is that you have these competitive situations.   Because it's life or death they try really hard to  come up with a lot of really powerful solutions.   Looking at these things and understanding how they  work, I think we can discover a lot of interesting   biology, and probably many of them we can  harness and engineer into useful biotechnology. Regardless of what TIGR-Tas does in viruses,  the team thinks this system has the potential   to do a lot of the things CRISPR does  for us, only better. Unlike CRISPR,   TIGR-Tas reads both sides of the DNA  double helix when deciding where to target,   potentially making it more accurate in where it  decides to make a cut.

TIGR-Tas is also smaller,   which could help it sneak into more places in  the body. And those aren't the only advantages.  There are cases where CRISPR is trying to  achieve single letter precision modification,   but because it opens up a 5 to 8 letter long  window, you cannot have a single letter precision. Oh, okay.  Whereas with TIGR-Tas, because it can  make smaller windows of DNA accessible,   it can overcome that limitation.  Yeah.  Continuously we have to look for new things  either from nature or try to engineer   CRISPR and combine CRISPR with other things,  to enable these new sort of capabilities.

Zhang and his team still need  to learn more about how TIGR   operates in viruses and other microbes  to know exactly what it can do for us. Can you explain some of the  experiments that you do with TIGR-Tas,   and what exactly you hope to learn from them?  When we find TIGR-Tas, one of  the first things we'll do is   we'll synthesize the DNA sequence  for the entire TIGR-Tas system,   and then we'll transplant that into a bacteria.  And so we'll take the synthesized TIGR-Tas genes,   and we'll transfer into E. coli, and  we'll grow up the bacteria in the lab. We might try to purify the protein from the  bacteria so that we can study the TIGR-Tas protein   in a very well controlled test tube environment.  Or, we'll try to put it into a human cell.

So   these are sort of cells growing in petri dishes,  and we grow them in the incubator, and then we can   transfer the TIGR-Tas system into those cells,  and then we can measure to see what happens. And the lab is doing all sorts  of experiments to that end. So these are centrifuges, we use them  to spin down things that we're trying to   study.

So, for example, to get  a gene delivered into a mouse,   we might use a viral vector. So this is a  hollowed out virus always sticking to the top.  Oh, okay. And then, to concentrate it, we have to spin  it really fast because there are very small   particles.

And you have to spin a very, very high,  sort of, multiple of gravity in order for it to   come down. So this is what we do. So we take one  of these rotors and we put it into the machine,   like this.

And then we'll just close the lid and  it'll start to spin. And it'll spin very fast.  How fast? This can be as fast as 100,000  times gravity.

Yeah. So if it's   a human that would be smushed down.  Oh my gosh, I'm - because as a  marine scientist, my reference is,   like, pressure at the bottom of  the ocean. And I'm assuming that   this spinning this fast, that this  is significantly higher pressure.  That's right.  How many times gravity.? 100,000 times gravity.  That's not real.  All of this is still in the "pull it apart to see  how it works" phase.

Once they understand that,   they'll have a better idea of how it might be used  therapeutically. But potentially this TIGR system   could make CRISPR look like an opening act.  That groundbreaking CRISPR treatment in 2025   rewrote the DNA of cells in the infant's liver,  and it seemed to have worked incredibly well.  But it's easy to get treatments to go to  the liver. The liver detoxifies things,   so whenever the body sees something  weird, it's off to the liver with you.   And cells in the liver divide a lot, which  is required for CRISPR to do its thing.

So   imagine a disease where the problematic  cells are harder to reach or dividing   less. Think of something like Alzheimer's or  Parkinson's or other diseases of the brain.  What potential does TIGR-tas have for treating  different diseases of the nervous system? The TIGR-Tas system is a compact system  which makes delivery of the TIGR-Tas system   more convenient than a bigger system  like Cas9.

So, things like ALS,   or Huntington's disease, or other  things where there is a known,   genetic basis that we might be able to use  it to treat. We're working on trying to   further improve the TIGR-Tas system so that  it's more effective. And also doing studies   to understand, how do we best deliver them into  the brain, to be able to treat different things?

Nature is very wise, you know, it has all  these really cool innovations and solutions to   all of these different problems that plants and  animals and organisms have faced over the, you   know, millions and billions of years of evolution.  And so, so, yeah, we just want to go and learn. What is the enjoyment that you get from  doing all of this really cool work? I think the whole process is enjoyable.  Yeah.

Okay. Awesome.  Like getting answers to questions is  very satisfying. Because it makes you   understand something.

And oftentimes  because we're working on research,   so we're working on questions that  no one knows the answer about before,   when we find the answer we're the first  person in the world to know the answer to   something. And that is satisfying because  you are kind of pushing the frontier.  What are your ultimate goals  for the work that you're doing?  Thinking that there are these biological  problems and we can take an engineer's   approach to understand what is wrong with the  system, how do we fix it? And then use these   sort of fundamental, basic principles of DNA,  and genetics to develop new solutions.

There's   still much more to do. But I think it's just  rewarding that we can make progress and make,   you know, treatments for diseases  that people couldn't treat before.  If the results are anything like the last  time Zhang got interested in something,   it could be world changing.  SciShow Field Trips are made with our friends at  HHMI's Tangled Bank Studios. We've come together   to bring you face to face with researchers  at the cutting edge of scientific discovery.   You can watch more of Tangled Bank's  science content at tangledbankstudios.org.