September 17, 2025 • 30 mins
Back in the 1990s, a young microbiologist in Alicante, Spain became obsessed with a strange pattern he observed in the genes of tiny organisms — a series of inexplicable clusters. And he wasn’t alone. All around the world, a network of scientists were growing curious as to what these genetic knots could be and all of their potential functions. Their curiosity would prove to be the foundation for a history altering discovery: the ability to edit our genetic code.
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Speaker 1 (00:13):
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.
Speaker 2 (00:29):
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
(00:51):
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.
Speaker 1 (01:11):
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,
(01:33):
he sees these repeat.
Speaker 2 (01:36):
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.
Speaker 1 (01:53):
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?
Speaker 2 (02:12):
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
(02:33):
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.
Speaker 1 (02:46):
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.
Speaker 2 (03:02):
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.
Speaker 1 (03:14):
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,
(03:36):
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.
Speaker 2 (03:52):
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
(04:12):
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.
Speaker 1 (04:30):
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?
Speaker 2 (04:47):
And apparently the major journals also didn't know where it
would lead since his findings were initially rejected.
Speaker 1 (04:54):
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
(05:16):
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.
Speaker 2 (05:29):
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.
Speaker 1 (05:39):
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
(06:01):
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
(06:22):
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
(06:43):
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
(07:07):
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,
(07:29):
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.
(07:52):
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,
(08:13):
but understanding and adaptive immune system, they could fight off
viruses that came in pretty handy for humans later on.
Speaker 2 (08:21):
And that in and of itself, if you just told
that story, that's a fascinating bit of science.
Speaker 1 (08:26):
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.
Speaker 2 (08:45):
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
(09:05):
this started.
Speaker 1 (09:06):
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
(09:27):
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
(09:50):
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
(10:12):
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
(10:36):
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.
Speaker 2 (11:02):
And she starts her lab looking into that question. So
she's intrigued enough to get her lab looking into it.
Speaker 1 (11:10):
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
(11:30):
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,
(11:51):
and Jennifer says being go, Okay, I got this project.
We're gonna work on it. So there's a lot of
serendipity there.
Speaker 2 (11:57):
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.
Speaker 1 (12:07):
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,
(12:30):
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
(12:50):
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
(13:11):
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
(13:35):
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
(13:57):
the two keys.
Speaker 2 (13:59):
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.
Speaker 1 (14:22):
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
(14:45):
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.
Speaker 2 (15:07):
The Denisko researchers who discovered that crisper was a kind
of immune system against viruses in their yogurt cultures.
Speaker 1 (15:13):
The first speaker is Francisco Mohike.
Speaker 2 (15:16):
The Spanish researcher who'd found crisper and salt loving bacteria
and named it.
Speaker 1 (15:21):
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
(15:42):
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,
(16:07):
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.
Speaker 2 (16:22):
And these little personal interactions are how some of the
kind of light bulbs go off for people.
Speaker 1 (16:28):
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.
Speaker 2 (16:49):
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.
Speaker 1 (17:11):
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
(17:33):
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
(17:53):
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
(18:18):
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
(18:38):
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
(18:59):
comes over and says, you want to come back to Berkeley.
Speaker 2 (19:02):
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
(19:22):
and creative partner for the coming years.
Speaker 1 (19:26):
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,
(19:50):
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,
(20:15):
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.
Speaker 2 (20:28):
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.
Speaker 1 (20:37):
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,
(20:58):
and that was just something about her. In fact, there
was always a slight distance, a shell around it.
Speaker 2 (21:05):
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.
Speaker 1 (21:16):
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?
(21:40):
And the answer, as Jennifer always said, if something does something,
your first answers, it must be an enzyme, a Crisper
associated enzyme.
Speaker 2 (21:51):
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.
Speaker 1 (22:09):
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
(22:29):
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
(22:51):
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
(23:12):
three ingredients in and these three things make it work.
Speaker 2 (23:19):
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.
Speaker 1 (23:35):
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
(23:56):
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
(24:20):
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.
Speaker 2 (24:37):
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.
Speaker 1 (24:55):
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
(25:17):
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
(25:37):
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
(26:01):
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.
Speaker 2 (26:19):
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.
Speaker 1 (26:33):
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,
(26:55):
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.
(27:18):
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.
Speaker 2 (27:29):
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.
Speaker 1 (27:49):
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,
(28:11):
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.
Speaker 2 (28:31):
It's not escaped our notice it. So it's simultaneously a
little bit understated but also a little bit grandiose.
Speaker 1 (28:39):
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
(29:02):
can program it to edit our own DNA.
Speaker 2 (29:06):
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
(29:26):
tells me Doubtna and Sharpenter faced one particularly fierce competitor.
Speaker 1 (29:33):
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.
Speaker 2 (29:57):
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.
(30:19):
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
(30:40):
curiosity shape society as we know it. Thanks for listening.
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.
Speaker 2 (00:29):
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
(00:51):
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.
Speaker 1 (01:11):
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,
(01:33):
he sees these repeat.
Speaker 2 (01:36):
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.
Speaker 1 (01:53):
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?
Speaker 2 (02:12):
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
(02:33):
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.
Speaker 1 (02:46):
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.
Speaker 2 (03:02):
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.
Speaker 1 (03:14):
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,
(03:36):
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.
Speaker 2 (03:52):
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
(04:12):
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.
Speaker 1 (04:30):
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?
Speaker 2 (04:47):
And apparently the major journals also didn't know where it
would lead since his findings were initially rejected.
Speaker 1 (04:54):
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
(05:16):
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.
Speaker 2 (05:29):
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.
Speaker 1 (05:39):
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
(06:01):
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
(06:22):
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
(06:43):
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
(07:07):
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,
(07:29):
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.
(07:52):
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,
(08:13):
but understanding and adaptive immune system, they could fight off
viruses that came in pretty handy for humans later on.
Speaker 2 (08:21):
And that in and of itself, if you just told
that story, that's a fascinating bit of science.
Speaker 1 (08:26):
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.
Speaker 2 (08:45):
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
(09:05):
this started.
Speaker 1 (09:06):
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
(09:27):
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
(09:50):
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
(10:12):
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
(10:36):
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.
Speaker 2 (11:02):
And she starts her lab looking into that question. So
she's intrigued enough to get her lab looking into it.
Speaker 1 (11:10):
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
(11:30):
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,
(11:51):
and Jennifer says being go, Okay, I got this project.
We're gonna work on it. So there's a lot of
serendipity there.
Speaker 2 (11:57):
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.
Speaker 1 (12:07):
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,
(12:30):
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
(12:50):
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
(13:11):
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
(13:35):
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
(13:57):
the two keys.
Speaker 2 (13:59):
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.
Speaker 1 (14:22):
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
(14:45):
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.
Speaker 2 (15:07):
The Denisko researchers who discovered that crisper was a kind
of immune system against viruses in their yogurt cultures.
Speaker 1 (15:13):
The first speaker is Francisco Mohike.
Speaker 2 (15:16):
The Spanish researcher who'd found crisper and salt loving bacteria
and named it.
Speaker 1 (15:21):
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
(15:42):
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,
(16:07):
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.
Speaker 2 (16:22):
And these little personal interactions are how some of the
kind of light bulbs go off for people.
Speaker 1 (16:28):
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.
Speaker 2 (16:49):
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.
Speaker 1 (17:11):
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
(17:33):
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
(17:53):
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
(18:18):
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
(18:38):
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
(18:59):
comes over and says, you want to come back to Berkeley.
Speaker 2 (19:02):
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
(19:22):
and creative partner for the coming years.
Speaker 1 (19:26):
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,
(19:50):
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,
(20:15):
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.
Speaker 2 (20:28):
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.
Speaker 1 (20:37):
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,
(20:58):
and that was just something about her. In fact, there
was always a slight distance, a shell around it.
Speaker 2 (21:05):
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.
Speaker 1 (21:16):
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?
(21:40):
And the answer, as Jennifer always said, if something does something,
your first answers, it must be an enzyme, a Crisper
associated enzyme.
Speaker 2 (21:51):
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.
Speaker 1 (22:09):
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
(22:29):
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
(22:51):
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
(23:12):
three ingredients in and these three things make it work.
Speaker 2 (23:19):
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.
Speaker 1 (23:35):
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
(23:56):
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
(24:20):
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.
Speaker 2 (24:37):
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.
Speaker 1 (24:55):
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
(25:17):
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
(25:37):
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
(26:01):
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.
Speaker 2 (26:19):
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.
Speaker 1 (26:33):
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,
(26:55):
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.
(27:18):
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.
Speaker 2 (27:29):
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.
Speaker 1 (27:49):
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,
(28:11):
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.
Speaker 2 (28:31):
It's not escaped our notice it. So it's simultaneously a
little bit understated but also a little bit grandiose.
Speaker 1 (28:39):
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
(29:02):
can program it to edit our own DNA.
Speaker 2 (29:06):
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
(29:26):
tells me Doubtna and Sharpenter faced one particularly fierce competitor.
Speaker 1 (29:33):
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.
Speaker 2 (29:57):
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.
(30:19):
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
(30:40):
curiosity shape society as we know it. Thanks for listening.
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