He's looking at bacteria in very, very salty ponge, and he notices something when he's sequencing the genes.

Because this is getting in the late nineteen ninety when we finally can gene sequence.

But it's hard.

In science.

Sometimes a world changing breakthrough arrives at the end of a long chain of discovery, a chain that starts with an obscure or even trivial seeming observation.

So it was that in nineteen ninety a young microbiologist named Francisco Mohica began working on his PhD in his native city of Alecante, on the Mediterranean coast of Spain, a medieval port with narrow streets, colorfully painted houses, and sweeping views across the sea to Algiers.

Alcante was also the home to a collection of salty ponds ten times saltier than the ocean.

Mohika's research focused on the genomes of tiny bacteria like organisms thriving in the ponds, called archie.

He keeps seeing these repeated sequences in the genes of bacteria, and they're clustered repeated sequences, and he can't He thinks he's made a mistake.

It's like if you type a story and an old version of Microsoft word, and the paragraph keeps repeating.

You think, well, I didn't do that, that's a mistake.

But as he keeps testing it out, he sees these repeat.

These repeats also read the same forwards and backwards, like palindromes.

Walter Isaacson writes, they look like tiny knots and a string of otherwise regular genetic rope, and Mohika had no idea what they were.

Isaacson says that only got it more curious.

He goes to the library.

There's before you could google things, before there's a database.

So he goes to the library and looks up indexes and a Japanese scientists had seen this in a bacteria, and so soon you have a few scientists say why are there these things?

The Japanese scientists who had also noticed these clustered sequences was Yoshizumi is she No.

A few years before Mohika.

Ishino had found the same clusters in a very different type of bacteria.

In his paper on the discovery, he wrote that the biological significance of these sequences is not known.

Still, the fact that both researchers had found the same pattern in extremely different organisms convinced Mohika that these clusters might have an important purpose.

For years, he kept experimenting with them, leading a growing international network of scientists interested in figuring out their significance.

And the first thing they do is they try to figure out a name for it, and it's front Jay Skill Mohico, driving back from his wife, was on the beach and he was bored with the beach, goes back to his lab and he says, well, their cluster repeated sequences.

Mohika's thesis adviser had suggested the name tandem repeats, not exactly the catchist a colleague in the Netherlands suggested direct repeats.

That wasn't quite it either, So Mohika kept thinking and.

He comes up with the name Crisper.

And he said, because it's a memorable, fun name, it's not intimidating, And he then back engineers it.

I think it's clustered, repeated innerspace, palindropic, repeated sequence, whatever it may be.

But it was called Crisper just because he liked the name crisper.

And it doesn't have an e it's Chrisper with an out an ease, so it makes it look futuristic.

So he's the guy who first understands that bacteria have these repeated sequences and he names them, but nobody knows why they exist, and that's when the hunt begins.

Mohika had no way of knowing none, but this tiny palindrome gene he'd found inside assault loving bacteria would become the tiny engine.

I think a new revolution in gene editing.

I'm Evan Ratliffe and this is on Crisper, the story of Jennifer Downa, episode two Crisper.

It goes back to that sort of passion and obsession over these what seemed like tiny questions to us.

A guy in salt ponds who's just obsessed with the bacteria that live there, which kind of goes back to the sleeping grass and really wanting to know.

But this guy has no idea where this discovery is going to lead.

This is the big deal, which is it's pure curiosity about some quirk of nature, and you have no idea that it's going to lead to a tool to fight viruses, it's going to lead to a tool to edit jeens or anything else.

You're just curious why did nature do this?

And apparently the major journals also didn't know where it would lead since his findings were initially rejected.

He's a sort of unknown junior scientist, I think in Ali Spain.

And so one of the problems is you can't really make a discovery of science unless you can publish it.

I mean, that's the way we put the stamp on it.

And he's having trouble getting this published in a journal, and so are other people who are looking at Crisper because it's like, okay, fine, and even his advisors at the university it's like fine, fine, fine, you see bacteria repeat themselves a few times, but now go on to something that's important.

But Mohika suspected that there had to be a reason for these clustered sequences to keep showing up, and Isaacson says it was an instinct driven by a fundamental piece of knowledge.

Nature loves simplicity.

It's not going to have some complexity of repeated sequences unless there's a reason.

I mean, bacteria don't have that much genetic material, so you don't want to waste it repeating yourself.

So there must be a reason that these things exist.

As these basic scientists like Francisco Molica are doing this out of pure curiosity.

You have two food scientists who work for Denisko, one of these huge French food companies.

It's Rudolph Bolngu and Phelippe Porvath.

They're both French, but one of them is moved to North Carolina to study food.

And I'm thinking, this is the only guy I ever met who moved from Paris to North Carolina to study food.

And they make starters cultures for yogurt and cheese, and the starter cultures or bacteria.

And one problem they have is that viruses attack bacteria.

You think we got a problem with viruses man.

For two billion years or so, bacteria have been fighting off viruses.

It's the biggest battle on this planet.

It's ongoing.

And so these yogurt cultures are getting messed up by viruses.

And you have these two scientists who are sequencing the genetic code.

And the cool thing about DNISCO is it's got a whole database of every culture they've had going back to nineteen eighty or so, and so you can look at how the DNA changes and they discover that the crisper sequences or what's in between the crisper sequences are mug shots of the genetic code of some viruses that attack them.

And every time a new virus attacks, and every year or two or three, the bacteria that survive have some of that genetic code in these repeated sequences and clusters, and they realize this is a way that bacteria have a mug shot to know if there's a dangerous virus coming in and how will they kill it.

It meant that in the future the bacteria would know how to ward off those virus So it was in adaptive immune system against viruses, which may seem pretty technical, but it was quite useful in saving the yogurt industry.

And by the way, we didn't know it at the time, but understanding and adaptive immune system, they could fight off viruses that came in pretty handy for humans later on.

And that in and of itself, if you just told that story, that's a fascinating bit of science.

It's a huge, huge thing for Denisko and for anybody who eats yogurt and eats cheese.

We'd be in trouble every year, just like maybe we have trouble with bird flu every now and then we can't get eggs.

We'd have trouble with yogurt and cheese if the entire billion dollar industry of starter culture, you know, was wiped out.

So at this point in the story, we we sort of know what crisper is and we know what it does, but not how.

And so that's when Jennifer Downer re enters the picture for us, in that she has a conversation with one of her colleagues that leads her down the road to crisper because she wasn't studying crisper when this started.

Right, Jennifer data had a colleague at Berkeley named Jillian Banfield.

They hadn't really met each other because Berkeley is so big, but Jillian Banfield was just looking at bacteria from weird places like Yellowstone and others and noticing this crispher and they're trying to say, how does it work?

So she looks through the database at Berkeley for anybody who is studying RNA and RNA interference, and who pops up, of course, as Jennifer Dowder, because she's the RNA expert at Berkeley, and Jennifer was a biochemist, in other words, looking at the chemistry of how biology works.

And there's a subtle difference because Jillian Banfield was a microbiologist, meaning she looked at small organism.

She didn't look at test tubes.

She looked at real organisms and tried to figure out they work.

So you needed a combination of biochemistry and microbiology or biology of small things to make this work.

They met one afternoon at the Free Speech Cafe.

I love the name of it because those of us who are old enough to remember, Berkeley had a great free speech movement.

And so there's a cafe right as you come on to the campus near the library.

And Jillian Banfield has been studying Crisper and trying to figure out we know it tries to stop viruses that attack bacteria, but how does he do it?

What's the mechanism?

And she brings all these print outs and they talk about it, and Jennifer gets it and says, I'm not sure it's RNA interference, but there's a mechanism that these Crisper sequences in the bacteria.

Somehow or another, they have a mechanism that attacks viruses.

And she starts her lab looking into that question.

So she's intrigued enough to get her lab looking into it.

Right, she kind of is not absolutely sure.

But she likes Gillian Banfield when they meet at the cafe and it's like, you're really you're passionate about your little bacteria and you found in copper mine waste lands and something that have these repeated sequences and yeah, I've now read the papers and maybe, but she said, I don't think I have anybody in my lab who can do it.

And that's when a guy, Blake Whedon Have walks into Jennifer's lab and wants a job, and Jennifer's interviewing and he's one of those guys who grew up near a yellowstone and he loves collecting bacteria and he's sort of a microbiologist too, and he says I'm interested in Crisper, and Jennifer says being go, Okay, I got this project.

We're gonna work on it.

So there's a lot of serendipity there.

Isaacson had the chance to visit down his lab and he told me that what he saw helped him understand her process when it came to translating her initial curiosity into research.

I never actually knew what a scientist did every day, what scientists were, but what do they do like at two in the afternoon, three in the air and especially lab scientists, And so I got to go to the lab at Berkeley where Jennifer Dowd works.

One of the things is there's long benches.

It's called being a bench scientist, where you're seating there next to each other, and you have a sort of workspace that sometimes has a hood that ventilates things, and you've got test tubes and pipe pats, and you have a lab director like a Jennifer Dowd who comes up with the ideas of what are we going to test next, Let's try putting a little bit of RNA into this mixture in this test tube and see what happens.

She's gotten office.

She's looking at all their results, but also she's putting on the white down and she's putting on the latex gloves and going from station to station, bench to bench, say what are you doing with that experiment?

And she had certain secrets she sometimes used.

She said, one of them is RNA and says, when somebody's doing a big experiment and they can't figure out what's happening, she'll just say, what's the RNA doing?

And she said that's always a clue that opens things up.

The other she said was enzymes.

They spark an action.

They spark a neuron being or a muscle twitching, and it is something that instigates things.

It's like a match or a spark that allows something to happen.

And she says, the two things you remember when you're doing science inside of a cell or microbiology is enzymes RNA.

Those are the two keys.

Win in doubt in zionce and arna.

You know, they start on this journey.

They're trying to figure out how does crisper work, how does it do what we sort of know that it does.

And one of the first things they do along the way is organize a conference and bring in all these other people that study it.

And you could imagine it going the other way where they say, we don't want to talk to anyone because we are they're competitive.

They might discover it before on.

One of the things that I wanted to convey in the book is that science and discovery is a team sport and conferences really matter.

You bring people together, just the hash things around, just to you know, go to Alice Waters restaurant near Berkeley and sit upstairs and compare notes, and it's dangerous because scientists are sometimes competitive.

They want to get their paper published first, they want to win the prize, they want to get the patent.

But if you get them together at a conference, they can't help but sharing information.

And so people studying crisper decide, all right, it's a brand field.

What do you do.

Let's start a conference, and the first ones at Berkeley, and it's done by one of the yogurt scientists.

The Denisko researchers who discovered that crisper was a kind of immune system against viruses in their yogurt cultures.

The first speaker is Francisco Mohike.

The Spanish researcher who'd found crisper and salt loving bacteria and named it.

It comes all the way over from Spain.

And the rule is you get to talk about work that you haven't published, and you trust everybody not to try to steal it and to beat you into the publication.

And back then things were competitive, but it was a small enough community that they were good at sharing ideas.

The conferences on crisper in some ways reflected Jennifer's early experience, which is getting invited to Cold Spring Harbor where James Watson was convening conferences and doing them on genetics, but doing it on RNA world.

And she realized that gathering in a place like Cold Spring Harbor with its Blackfoot bar, where people would watch the Yankees at night but discuss uh, you know, biochemistry.

That's why she was interested in starting this Crisper conference with some of the yogurt scientists, with Francisco Mohico and others.

And these little personal interactions are how some of the kind of light bulbs go off for people.

We talk about enzymes being a protein that sparks things, that are a catalyst, and in some ways these conferences, these are catalysts that spark ideas and coming out of it people say, all right, I now see things in a new way.

We'll be right back.

The Chrisper Conference at Berkeley in two thousand and eight, the first international gathering on the subject, was success.

Interest in RNA was growing and researchers were finding new connections.

But Isaacson tells me that it was also around that time that doubtnas started to call into question what she was doing and why.

All scientists, including Jennifer Dowdner, are human.

They go through a bit of a midlife crisis.

She's depressed.

She's working on basic research at a lab at Berkeley, and even though Crisper has come along and it seems pretty exciting, she's like, what does it all mean?

Am I really doing anything useful?

And she decides, well, maybe I should just become a doctor and go to medical school or other things.

And she gets recruited to a company named Genentech, a very famous company.

Herbert Boyer and some of the pioneers of recombinant DNA and genetic engineering in the seventies had taken the intellectual property that they had created at universities like Stanford and Berkeley and made companies that created pharmaceuticals and other things based on recombinant DNA and genetic engineering.

And so she decides, I'm going to go to Genentech and actually apply science.

So it moves from the bench to the bedside of the patient and that lasts about two months.

She realizes she's made a big mistake.

That she loves having graduates soon.

She loves the research, the hunt, the discovery.

And she sits outside one night and it's raining and she just keeps crying and crying, thinking she's abandoned her post at Berkeley.

She's now in Corporate America and it's a great job, but it's not her.

And the head of the chemistry department at Berkeley, I think Jennifer's husband, Jamie Cade, calls up and says, hey, Jennifer's not doing well.

And the head of the chemistry department comes over and says, you want to come back to Berkeley.

She says yes, and that seems to be that almost move that then brings her back into basic science, basic research that itself seems to be some kind of catalysts like things really take off from there, starting with the Puerto Rico meeting and she meets sort of her intellectual and creative partner for the coming years.

We talk about how meetings and conferences and cold Spring holder labs serve as a catalyst like an enzyme to spark collaboration, and that happens at a Puerto Rico conference where there's a French scientist named Emmanuel Champantier who's also studying RNA and actually is understanding the mechanisms of RNA, how it works within enzyme to cut DNA, and she realizes that Jennifer Dowd is also doing it, and they walk along the cobblesome streets of Puerto Rico and they say, let's collaborate.

And that's how this beautiful partnership.

And Jennifer says to me and says to Emmanuel when we're talking, I almost became a French teacher.

And I imagine myself, as you know, being an elegant French person, and you're that person, but you're a scientist.

This will be a perfect combination.

But Sarpentier also seemed to have a little bit of this outsider perspective that you talked about earlier, feeling a little bit excluded, always moving from lab to lab.

She was very parapatetic still is, never stayed at a lab more than a year or two.

She was at the Max Plunk Institute in Berlin, but before that she had been in Sweden.

Before that she had been in Vienna, and then she moves every two years.

And in her life she never made commitments, never got married, never had kids, and that was just something about her.

In fact, there was always a slight distance, a shell around it.

But when they started out, clearly they found this commonality around trying to understand Crisper.

Can you walk us through what it was that they jointly discovered.

For Crisper to work, it's got to use RNA, which is the thing that goes into your cell and tells the cell how to build a protein, and it can be coded to do certain things.

And in Crisper, the RNA the coating had mundshots of various viruses.

But the question is then, how does it do something with it?

And the answer, as Jennifer always said, if something does something, your first answers, it must be an enzyme, a Crisper associated enzyme.

In other words, Down and Sharp were focused on really breaking down and understanding the Crisper mechanism, specifically how the RNA and it's a companying enzyme were able to work together.

And Isaacson tells me they were far from being the only ones.

Everybody is racing to figure out what it called Crisper cast systems.

And one of the discoveries that Jennifer and Emmanuel made is that there were actually two types of RNA.

One that you could consider a guide RNA that had the little code and it was a guide that we told it where to go.

But there was another snippet of RNA called tracer RNA, which was almost like a scaffolding it.

Now, this seems very technical, but you got to know exactly how it works if you're going to want to engineer it and make it a tool.

So there's a race around the world of people studying Chrisper cast this and Chrisper cast that.

But the breakthrough that seemed I'm small, but is a big one is to know all the ingredients and have it work in a test, to not just say I can make it work against this bacteria and yogurt culture, but say I'm putting these three ingredients in and these three things make it work.

By this point, DUBTNA had another researcher on the case, an RNA obsessed graduate student from the Czech Republic named Martin Yenick.

Yunich was an expert in crystallography, the same technique Rosalind Franklin had used that allowed Watson and Krik to understand the role of DNA.

And it's Martin Yenick, one of the graduate students, the lead graduate student in Jennifer's lab who's working on this, who sketches out on a whiteboard, here's what the trace RNA does.

Here's what the guide RNA does.

And here if you look at it and you see their chemical structure, they could actually fit together.

And let's figure out what's the essential part of each and make it so that you had a fused a single guide RNA that was as simple as possible.

The reason this is important is it's not just a discovery about nature.

Now you've done an invention.

You've done something that can be patented.

It is something that you've created, and that allows it to move past just being a basic science discovery into being a real breakthrough.

That's a technology breakthrough.

And something so small and so tactical, there's actually so much drama in it.

There's so much drama in the tracer RNA has two functions.

Yeah, and it's who's going to figure out that it has two functions?

And then who's going to publish the fact that it has two functions.

This is where we get back to the conferences.

They're all collaborating and figuring out you do this crasper cast system.

I'll work on this one.

Maybe I'll look at this room and they're sharing things.

But suddenly as they get closer, everybody wants to win the prize.

Of how does crisper work?

And so you have this conference in twenty twelve and a lot of people are racing to do the ingredients.

Jennifer and Emmanuel and their two graduate students have figured out every single element of how it works, and that weekend they're finishing off their paper.

They're rushing it off to a journal because it doesn't count unless you get it published, and so they're rushing into the journal Science.

They're showing all of the elements the crisper, the enzymes of cast, the trace RNA, the guide RNA, and they're even showing a tool they've been able to make to combine the two forms of their RNA to be a single guide RNA.

So, in other words, it's an engineered tool that makes this simpler.

And they're ready with all those elements, and everybody's at this conference.

They're all trying to present, and Jennifer and Emmanuel want priority.

They want to be the first to publish, they want to be the first to get patents, and so the competition comes in man.

And how does the competition drive the discovery without poisoning it is one of the questions that I feel like comes to the book that without creating rancor without creating bad feelings or even bad behavior.

Well, it sometimes does create bad feelings and bad behavior.

And this is how science advances, which is a mix of cooperation and competition.

You gotta have competition, because why are Emmanuel Sharpentay, Jennifer down and their two graduates can stay up twenty four hours a day around the clock, working in Europe and in Sweden and in Berkeley and the United States so that they can win the race.

That competition, and sometimes you're wondering what are they competing for?

Where they're competing for the prizes that matters.

They're competing for being published.

First, I think mainly they're competing for the recognition, but also they're competing for a lot of money.

Because you get a patent, you know you've hit the jackpot.

If you want to win the Nobel Prize, you're no longer going to be as cooperative of other people in the same field.

It was at that Chrisper conference in twenty twenty one that Jennifer Downa and Emmanuel Sharpga finally submitted their paper on Crisper Cast nine.

The first part of the name referring to the repeated clusters and cast nine, referring to the specific enzymes that essentially created these genetic scissors.

Isaacson says this was a pivotal moment.

At the end of Watson and Crick's paper on the structure of DNA, they do a breathtaking sentence it goes down in history, which is sort of, as I paraphrase it, it's not escaped our notice that what we have discovered by the structure can be a system for passing along genetic information.

In other words, a sentence that says, hey, this isn't just about RNA being fused.

This could have a big deal.

So at the end of the paper that Bonte and Dowd know Wright in twenty twelve, they basically mimic that sentence and it says, basically, it's not escaped our notice that this could become a tool to edit our DNA.

It's not escaped our notice it.

So it's simultaneously a little bit understated but also a little bit grandiose.

Yes, because the paper itself was just how does crisper form the right ingredients to cut the genetic material of a virus?

Well, that's really important to know, especially when we're finding viruses, But one order of magnitude more important is say, can we that into a tool where we can program it to edit our own DNA.

Doubton and Sharpenter had accomplished what just a decade ago seemed impossible.

The clustered sequences that Francisco Mohica had found in the salty ponds of his hometown were now fully understood as a mechanism for gene editing.

But they still needed to make the leap to turn the Crisper cast nine system into an active gene editing tool.

And Isaacson tells me Doubtna and Sharpenter faced one particularly fierce competitor.

The person at MI T Harper who is racing against them is Fung Jean.

Fung Jong originally sends an email to Jennifer Downa say I've read your piece.

I want to figure out how it's gonna work.

But they soon realized the stakes are too high, and they all become more secretive and more competitive.

That next time on douta on DOWDNA.

The Story of Jennifer DOWDNA is a production of Kaleidoscope and iHeart.

This show is based on the writing and reporting of Walter Isaacson.

It's hosted by me Evan Ratliffe and produced by Adrianna Tapeia with assistance from Alex Jan Unveld.

It was mixed by Kyle Murdoch and our studio engineer was Thomas Walsh.

Our executive producers are Kate Osbourne and Mangashatigudor from Kaleidoscope and Katrina Norvel from iHeart Podcasts.

If you enjoy hearing stories about visionaries and science and technology, check out our other series based on biographies by Walter Isaacson.

On Musk for an intimate dive into all the facets of Elon Musk and on Benjamin Franklin to understand how his scientific curiosity shape society as we know it.

Thanks for listening.