Breakthrough: Unlikely Heroes

The messenger RNA vaccines against Covid-19 seem to have emerged out of nowhere. But they’re based on decades of painstaking work, done in relative obscurity, by researchers who believed in the promise of the technology even if few others did.

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Episode Transcript

Speaker 1 (00:00):
On a warm September day in Berlin, Hungarian biochemist Catalan
Cattico walks into the nearly century old auditorium at Berlin's
chetty Tay Hospital. She takes her seat in the front
row of a World Health Organization event. She surrounded by
politicians and public health leaders. Just a year earlier, there

(00:24):
would have been little reason for Catalan to be there
at all. A few of the other guests would have
even known her name, But now she's a guest of honor.
Catalan spent her life researching messenger RNA, the tiny postal
workers that carry genetic instructions inside cells. For decades, few

(00:45):
paid attention to what she found that has now changed. Yes.
Even at the event in September, German Chancellor Angelo Meeric
called praises Catalan for not giving up. The German Chancellor
tells the audience that Catalan's thirty years of effort laid

(01:09):
the groundwork for our current fight against COVID nineteen. In
her own remarks, Catalan says her collaborators deserve credit too.
First of all, I would like to correct you because
there are many, many people contributed to it, and I
was just one of them. And I am glad that
I go also goold have I am just representing all

(01:31):
of those fellow scientists. Then she makes a plea, but
the dignitaries in the audience to give people with ideas
that seem crazy a chance. Those who who might have
an idea which is too weird to support, maybe they
get more support and sort of problems we were facing
the future. Catalan doesn't stick around long for drinks. Afterward,

(01:58):
She's at the co check In less than an hour,
She's going to Budapest. They're painting her picture onto the
side of a building there. She's only awards circuit, but
she says she'd rather be back in her lab as
soon as possible. Catalan helped lay the groundwork for a
most important weapon against the deadly virus that has so

(02:18):
far killed more than five million people around the globe.
She never expected that, but she also showed the world
the potential for a new technology, messenger RNA, And this
is what Catalan had hoped for all along. This is
a story about what most people would agree is the

(02:40):
biggest success of the pandemic. Messenger RNA vaccines could never
have proven themselves so quickly outside the crucible of that
first pandemic year. The technology may well win some researchers
and Nobel Prize. It will almost certainly have big implications
for the future of medicine. Odds are you've taken one

(03:02):
of these mr Anda vaccines yourself, and you might think
you know the story of how they swooped onto the
world stage so quickly, But odds are you don't know
the half of it. This is also the story of
as unlikely a bunch of world saving heroes as you'll
ever encounter. My name is Naomi Kraski, and I'm a

(03:24):
health journalist for Bloomberg News. In the first half of
the season, you've heard about the lingering consequences of COVID
for many patients and hospitals. Now we'll tell you about
the consequences for science. They're a lot more hopeful. From
the Prognosis podcast, this is Breakthrough. I first heard of

(03:59):
messenger are A vaccines more than a year before the
mysterious new virus emerged in Wuhan. The biggest buzz in
the drug industry at that time was the idea of
using the immune system to attack tumors and help cancer
patients live longer. Scientists were trying a bunch of different

(04:19):
ways to do this, and a source told me I
should talk to the people at a German startup called BioNTech.
Inside European biotech, everybody knew them, but outside that insular
world a few people had ever heard of them. They
were trying to make something that had failed many times before,

(04:40):
a cancer vaccine, but they were trying to do it
using messenger RNA. Here's BioNTech CEO Uger Shahin speaking at
a tech conference called codex in. I think you have
to dare to start without having all solutions in the hand,
hoping that something would come up. It was fascinating stuff,

(05:04):
full of hope and cutting edge science, but as is
often the case in the risky business of biotech, it
wasn't at all clear that the MR and A vaccines
would actually work. I wrote a feature story for the
news wire, then moved on to other topics and went
on maternity leave. Then in January my boss called. He

(05:25):
said a new story was keeping him busy, strange new
coronavirus that had emerged in China and was spreading around
the world. It's too bad you're not here now, he said.
It'll probably be all over by the time you're back.
Of course, when I came back to the office the
next month, it wasn't over. It was spreading. I live

(05:46):
in Germany. A few weeks later we went into our
first lockdown, and it's still not over. The world has changed.
We're still finding out just how much our story starts.
In nine the modern study of human genetics was just

(06:11):
getting going. Only eight years prior, scientists had discovered the
double helix structure of DNA. Now they were trying to
figure out how cells act on the instructions encoded in
the genes. A team from the Pastor Institute in Paris
identified an elusive molecule that copies pieces of genetic code

(06:32):
and delivers its instructions into the machinery of the cell.
They named it messenger RNA. RNA stands for ribonucleic acid,
where DNA is a double strand RNA is a single strand.
There are a few types of RNA that play important

(06:53):
roles in sending DNA's instructions to cells, and messenger RNA
is essentially leave the errand boy. One of the best
explanations I've heard of how the biology works comes from
Derek Rossy Harvard University stem cell biologists. M RNA is

(07:13):
actually a necessary and obligate intermediate between genes, which are
encoded in DNA and live in the nucleus, and proteins,
which do all the busy work of the cell. But
they're made in another part of the cell called the cytoplasm,
so the two don't meet the nason the nucleus, protein

(07:35):
synthesis is and the cytoplasm. So there had to be
an intermediate molecule, which was discovered to be messenger RNA
an appropriate an appropriate name. It carries the message encoded
by the gene out to allow that sort of code
to be turned into something that has utility, something that
has function proteins, So DNA makes mRNA makes protein, makes

(08:00):
all of life. Three French scientists shared a Nobel Prize
in nineteen sixty five for the discovery of m r
and A, but for decades after that, m RNA wasn't
a very high profile area for research. Part of the
reason was that the molecules fragile and hard to work with.

(08:20):
Scientists didn't figure out how to synthesize it in the
lab until in the nineteen nineties. The field Superstars focused
on DNA instead. DNA was easier than RNA to work
with and more stable. It was also in the limelight
thanks to the mapping of the genome and the Human
Genome Project that lasted from two thousand three. Scientists focused

(08:46):
on the idea of curing illnesses by fixing errors in
the genome, but there were a few exceptions researchers who
stuck with m RNA despite the challenges both scientific and personal.
One of them came from Hungary. By the time the
pandemic was a year old, her name would be known
around the world as the woman who pioneered mr and

(09:08):
A vaccines. She would be covered endlessly in newspaper articles
and TV shows. But each time I think I've learned
everything about her story, something new turns up to surprise me.

(09:29):
Catalan Cadko was born in Hungary. In she's in grade
school when the first MR and A discoveries are being lauded.
The Poster Institute and Nobel Prizes would have seemed very
far away to her. She grows up under communism in
gishuis Sarash, a small town in the countryside of eastern Hungary.

(09:53):
Her father is a butcher, but she knows even as
a teenager that she wants to be assigned best. Catalan
declined to be interviewed for this podcast. I and others
that Bloomberg had already spoken to her many times, and
she said she wants to focus again on her work
after being on the interview circuit. I get where she's

(10:14):
coming from, so we decided to draw from what I
think is her most unusual interview. She's spoken May with
Clube Radio, an independent broadcaster based in Budapest. We've dubbed
her voice from her native Hungarian Madam, I'm not a
special person at all. I saw that my parents were called,

(10:35):
and I also tried to help them. Along with my siblings.
We studied odd that was our job as Catalan earned
her PhD in Hungary at the University of second just
a two hour drive from where she grew up. She
started her postdoctoral research in the same city at the

(10:57):
Biological Research Center of the Hungarian Academy of Sciences. In
eight As a PhD student in Hungary, she worked with
RNA for the first time. It was the start of
a lifelong obsession. In she got the opportunity to move
to the US for a job at Temple University in Philadelphia.

(11:22):
She took it, moving with her husband and toddler daughter.
The Hungarian government only allowed them to bring a hundred
dollars with them. Legally, they sold another nine hundred pounds
about one thousand, two hundred dollars into her daughter's teddy
bear alment. We flew off. We didn't have any foreign renatives.

(11:46):
We couldn't count on anyone to send us money. What
she found wasn't what she had expected either. She says
the lab wasn't as well equipped as the one back home,
and one of the co workers doors and yelled. After
a week she wanted to leave. She stayed out of

(12:06):
necessity and out of hope. Were in survival mode, and
I thought I would learn something interesting and we would survive.
And this is what changes people, that they become so
defenseless and they must rely on their talent and make
do with the best they can. By nine, things were

(12:28):
looking slightly better. Catalan got a research assistant professor position
at the University of Pennsylvania. This was a chance to
make a name for herself maybe eventually get tenure. Because
of the way these jobs work, she was expected to
win her own grant funding to support her research, but
she ran into a big roadblock. She was still obsessed

(12:49):
with m R and A. Well she had seen so
far in her experiments convinced her that it would make
a better medicine than d n A. But no, but
the else agreed. She wrote a lot of grand proposals,
at one point one every month, she told us, but

(13:10):
nobody wanted to fund the experiments she wanted to do.
Nobody wanted to fund work on m R and A.
She didn't exactly make it easier on herself. One thing
I learned from her Hungarian interview was that she wasn't
a networker. Instead, she wanted to spend her time at

(13:30):
the lab bench doing science. Should I always keep those
meetings filled with small talk, which could have held my career?
Those really drove me crazy. Even in stores if they
were long lines, I thought, you're stealing my time, would you?

(13:53):
Elliott barn Nathan was her boss at the time. He's
a cardiologist who was then an associate professor of medicine
at Penn. Elliott was later to leave academia for a
drug industry career. He's an executive at Johnson and Johnson now,
but he remembers Catalan. Well, so the first thing is

(14:14):
she's incredibly hard working and and brilliant, I mean, really
truly brilliant. And the thing that's interesting is that she's
a voracious reader, and and so she would always read
science and Nature and come into the lab this morning
with the latest, you know, issue of science that you

(14:34):
hadn't even come across my desk yet, and she had
already read it and figured out somebody researching something completely
different in a different content and a different disease entity.
But there was a kernel here that was going to
help us do the next step of what we needed
to do. And she was always connecting the dots. Messenger

(14:58):
r n a degree quickly in the body. There are
enzymes that break loose mrn a down outside of cells,
but it also goes away quite quickly once it's delivered
its message inside the cell. Catalan thought that would actually
be a good thing. She reasoned that you could use
m RNA to flip a switch in the self for

(15:20):
a limited period of time. Elliott told me the idea
would be for it to have the desired effect then
go away. But convincing the scientific establishment to give her
experiments a chance proved very, very difficult. They could only
see the challenge, not the potential benefit for them. mRNA

(15:42):
was too fragile, too fleeting a dead end, so it
was very It was very heretical back in those days.
People said, oh, you're crazy, you know, m RNA will
never work, it's too unstable. But she really firmly belowd
She had a vision that it was doable. It was
just we needed to figure out how to do it.

(16:05):
Elliott used his own research funding to subsidize Catalan's experiments.
They had some successes, but time and time again she
failed to get grant funding. In she was stripped of
her assistant professor title and demoted to essentially a glorified
lab researcher. It seemed unlikely that she would ever get

(16:27):
her own lab. People just couldn't see the see the
truth of it. Unfortunately, it was a bitter blow. After
making it all the way from Ural Hungary depend one
of the top research institutions in the world, Catalan faced
the very real possibility that she might have to stop

(16:48):
doing the work that she loved. At the same time,
she was dealing with a cancer scare and her husband
was stuck back in Hungary for more than four months
due to a processing to life for his green card.
In the Hungarian radio show, she's interviewed alongside a singer
named Zoran Stephan of It. The show has a unique format.

(17:11):
It tries to put two people from totally different walks
of life on the air together. In this case, Oron
wrote Catalan's favorite song, a ballot called Diamond and Gold.
She chokes up when she talks about listening to him
sing when things got tough, that did That's offen. Oran

(17:34):
released the song in the same year. Catalan moved to
the US and was the frontman for two Hungarian rock
bands in the nineteen sixties and nineteen seventies. Under a
communist regime that opposed rock music, he knew a singer
or two about persevering during tough times. Zorn's song is

(17:54):
about how you need to work hard and stay the
course to achieve your goals. Diamond and Gold of a
nice shine, he says, but you need to dig deep
to get it. This resonates with Catalan. She digs a
long time before she hits pe dirt, and even when
she does, she's one of only a few who recognizes
what she's found. The first time I interviewed Catalan was

(18:26):
in summer. Each time she speaks, I'm struck by how
little bitterness she expresses about getting shut out by the
academic establishment for so long. She sounds disappointed, yes, and
sometimes frustrated. She also talks about how she really got
a raise. She was hired at forty dollars, and two

(18:48):
decades later she was making sixty dollars, which she says
is less than what a laptech would make. But I
got the impression that because she managed to keep on
doing science, the lack of our cognition and low pay,
these were secondary concerns. Here. She is earlier this year,
speaking for a Bloomberg project about the one year anniversary

(19:09):
of the pandemic. This is previously unaired audio. As long
as I was in the lab and focus what I
can do, I was very happy. I mean, at the weekends,
long days. And my husband once said that, you know,
probably my earning is first than in a McDonald's, because
he collplated probably won all right, So as a biochemist

(19:33):
in the nineteen nineties, she was probably making less per
hour than I did at the time. Babysitting the kids
on my street in Elliott barn Nathan, who was subsidizing
Catalan's work at Penn, left the university to take a
job at a biotech. She managed to find a spot

(19:53):
in another lab, but she needed a close collaborator, someone
enthusiastic about the science with the cloud, to ensure she
could fund her projects. How she found this person is
one of those great water cooler moments that will probably
go down in science textbooks. In early Catalan started seeing

(20:15):
a new face at the Xerox machine where she'd copy
the academic journal articles that she read so eagerly. He
was an immunologist named Drew Wiseman, fresh off a fellowship
at Tony Fauci's lab at the National Institute's of Health.
Drew was also a voracious suiteader of journal articles. Back

(20:36):
in those days, you'd have to hunt them up in
the library or somebody else's lab, then copy them and
take them home. They weren't online. Drew says. They copied
hundreds of articles before I ran into Katie Carrico over
a Xerox machine and we would both sort of fight

(20:56):
over it, but really just wait for each other to finish,
and we started talking. Drew was interested in dendridic cells,
which helped the immune system adapt to fight new intruders.
They migrate throughout the body and collect foreign things, so
that includes viruses, bacteria, parasites, tumor cells, and they bring

(21:23):
those two lymph nodes where they start immune reaction. And
why that's important for a vaccine is that they're the
critical cell that picks up a vaccine and turns on
the immune reactions. Drew wanted to work on an HIV vaccine.

(21:43):
Catalan thought m RNA could help. We started talking and
I told her about my interest in dendrodic cells and HIV,
and she told me about her interest in m RNA.
So we started working together and we started doing experiments
together other and and that's where our collaboration started. It's

(22:04):
important to note that up until then, Catalan wasn't really
thinking about RNA as something you'd used to make a vaccine.
She wanted to make treatments to use mRNA to spur
the cells machinery to make a protein that the body
needs to heal itself. In that sense, Wiseman's involvement broadened

(22:25):
her perspective. I should also note that some experiments at
that point had already shown the promise of using genetic
material to spur the body's cells to produce vaccine. Researchers
at Merk and Co. Were able to spurn immune response
in mice by injecting them with DNA that contained instructions

(22:46):
for influenza proteins. But seeing something working animals and having
it work in humans, those are two very different things.
The old line in this mice lie and and macacs exaggerate,
So if it happens in a mouse, that's never a

(23:07):
guarantee it'll happen in the human. The body has multiple
lines of defense against any m RNA that looks like
it might not belong. These guards are enzymes that will
break down loose m RNA found outside a cell. If
m RNA conduct those attacks and try to get inside

(23:27):
a cell, its troubles aren't over. Derrick Rossi, Harvard stem
cell scientists we heard from earlier, says the cell's first
response is to do the exact opposite of what you'd
want if you're going to use m RNA for a therapy.
It's to stop making any proteins at all that doesn't
want viral proteins being made in the cell. And then

(23:49):
if the response is robust enough, it triggers these ultruastic
self kill pathways uh and they die because it's better
for the cell to die than it is to serve
as a manufacturing facility for a hundred thousand viral particles. Essentially,
the sell flips a self destruct swich. This makes a

(24:11):
lot of sense from a biological standpoint. It ensures cells
stay on track, make the right amount of the right protein,
and don't get duped into producing a pathogen. But to
use mr and A as a drug, Catalan and Drew
had to figure out how to get it into the
cell without flipping that self destruct switch. That was a

(24:33):
lot of years of research. It's about seven years of
work together. And what we did is we first had
to figure out why it was inflammatory, So what receptors
was it activating, How was it being recognized. So we
found some receptors, other people found receptors. In total, there

(24:56):
are seventeen of them, and we started to look at
how RNA interacted with those receptors. They did years of
painstaking experiments trying to disable the self destruct switch. Finally
the breakthrough came in an unexpected place. You could say

(25:16):
Look played a role. Look made possible by years of
hard work. Catalan's old boss, Elliott Barnathan, explained it to me.
She's a brilliant scientist, and you know, sometimes it's the
controls that you use that really help you to make
the advance. Is not necessarily what the experiment is, but

(25:38):
how well controlled it was. The control group is the
part of the experiment where you usually don't change anything,
the part that's supposed to serve as a comparison to
show whether the hypothesis you're testing is true. Catalan was
using a special type of RNA called transfer rna as
a control in one of her experiments. This t RNA

(26:02):
has an important difference compared to mRNA. There's a different
arrangement of a structural piece called uridine. So Catalan uses
this t RNA in the control group and she notices
something unusual. The immune response inflammation didn't happen in those cells.

(26:23):
That was sort of the light bulb that went off
in her head. She decides to make a slight modification
to the RNA molecule to mimic what naturally occurs in
transfer rna bingo. The cells don't try to fight off
the foreign RNA, and even better, they make ten times
as much protein, and so it was a double whammy.

(26:45):
And that was really the fundamental patent that both Maderna
and the fisor bio in tech vaccines use in terms
of m RNA therapy. In two thousand five, Catalan Currico
and Drew Wiseman published a paper laying out their method

(27:08):
for modifying r n A. I asked Drew what he
thought would happen next. So that was one of my
more embarrassing moments, because what I said to Katie after
the paper was published was that our phones are going
to start ringing off the hook, and people are going
to call us up and want to work with RNA,
and drug companies are gonna want to use RNA, and

(27:32):
our phones never ran. We would sit there looking at
the phone, and nothing happened. In days and weeks and
months and years went by and nothing happened. Nobody was interested.
Even though we published how to make it work well
and how to use it as a drug, nobody was interested.

(27:52):
I find that astonishing. I asked him what he thought
that was. You know, I think that even though we
published that paper, they still said RNA is too difficult
to work with and they just didn't want to work
with RNA. Catalan said she felt like Cassandra, the mythological
trojan priestess who finds that her gift of prophecy is

(28:15):
really a curse. I mean, I knew that it can
be used for everything, and you know, kind of a
Cassandra feeling that I can see the future and nobody
believes me. Catalan and Drew filed for a patent to
keep on doing experiments, but it would take someone with
more salesman skills to bring the technology to the limelight.

(28:41):
Derek Rossi, who we heard from earlier, had been a
postdoctorate fellow at Stanford University when Drew and Catalan published
their study. He didn't read it at the time, but
a few years later at Harvard he ran into it
while trying to solve a problem in stem cell biology.
He wanted to convert cells back into a state similar

(29:02):
to that of an embryonic stem cell, a state from
which a cell can turn into any type of cell
in the body. A Japanese researcher named Shinya Yamanaka had
shown this was possible, but he had used a virus
to deliver the genetic cargo to reprogram the cells, which
scarred the cell. Derek wanted to use m RNA instead.

(29:25):
He decided to try a test protein first, something that
would be easy to recognize if it worked. We encoded
for the gene for the green fluorescent protein, which is
a jellyfish gene that fluoresces green under a certain wavelength
of light uh, and we synthesized that m RNA and

(29:47):
then we put it onto cells human cells in a
dish and we got a few green cells, but we
got a lot of dead cells and bed cells. Of course,
was not a our goal. We were not trying to
make a plateful of dead cells. Nope, they wanted green cells,
or rather, they wanted to get the cells to express

(30:09):
this green fluorescent protein. So we realized we had another challenge.
Why what was killing all these cells? When we introduced
the mRNA they almost gave up. But then Derek turned
to academic journals to see if anybody else had run
into this issue, and that is where we came across

(30:31):
the work of Captaalin Trico and Drew Weissman, whom in
two thousand and five published a seminal paper which, by
the way, got largely ignored by the academic press. Derek's
team followed the instructions in the paper swapping the modified

(30:51):
building blocks for the RNA. And now when we put
that jellyfish mRNA onto cells, essentially all the cells in
the dish where happy and blasting expression of this GFP protein.
So we were no longer killing cells on mass in
the dish. And that that discovery that they made, I

(31:12):
believe is well, it's fundamental to this entire field. Uh
And I believe it's going to earn them a Nobel
prize because it really is what allows these mr and
A vaccines and any mRNA therapeutic down the road. It's
the enabling sort of peace to the puzzle. Derek's team

(31:33):
published a paper in showing that they could use mr
and A to reprogram human skin cells. Now this was
sexy enough to get people's attention. It made a huge splash.
You may have seen the headlines. Scientists can now take
an ordinary cell from the body and transform it into
a cell that's very similar to an embryonic stem cell.

(31:55):
Most of the media reports were about the stem cells,
not the mr and a technolo oology, and that was exciting. Indeed,
from a basic science perspective, but Derek was already thinking
about the broader potential, and I was thinking to myself, Okay,
there's a lot of attention being given to the cell
based aspect of this, but nobody's really sort of recognizing

(32:18):
the modified m R and A based aspect. So I
should go out and try to start a company around this,
and that's that's the origin of Maderna. And I went
out and convinced some early investors and people that has
had potential, and it sort of launched launches the industry.
I guess Harvard colleague introduced Derek to venture capital company

(32:41):
Flagship Pioneering, which founded Moderna in operations began the next year.
Industry veterans signed on, including Stefan pan Cell and experienced
French executive who took the CEOs job at Moderna. The
company stayed private for eight years, raising two point five

(33:02):
billion dollars in venture capital and drug company investment. Along
the way, then had one of the biggest I p
O s in biotech history in December. Along the Way,
Moderna earned a reputation for secrecy until it published a
few scientific papers, preferring to keep its discoveries under wraps.

(33:24):
Derek left the company he founded in to focus on
his research. Catalan still reflects with wonder on how Bancel
and Moderna were able to collect so much money when
she wasn't even able to get a research grant. I concluded,
probably I did not explain well because look, come, come

(33:44):
a salesman the like Stefanson, poor, and when he goes
to have a breakfast reader Sioan, then in ten minutes
already two million dollar. He could convince him that that
mRNA is good for everything. And I said the same
to people, and they didn't even give me for the research.

(34:14):
But in Germany, a very different competitor was also working
on the m R and A technology. Husband wife team
Uger Shahina notes them to Achi founded BioNTech in two
thousand eight. Before Derrick Cross's work brought the idea of
modified m R and A into the limelight, the pair

(34:34):
had spent years pursuing immune based treatments for cancer. Starting
in the nineteen nineties at the University Medical Center of
the Johanna Schuttenberg University in minz Uger had started exploring
m R and as delivery method in two thousand something.
His wife once told me was considered a crazy idea
at the time, where moderna was polished and corporate from

(34:57):
the start. BioNTech an academic vibe who uses his university
email address. They've published hundreds of scientific papers. Who were
hired Catalan Cardicho away from PENN. They put out a
press release saying that her work had opened a new

(35:20):
field of therapy. She finally got her own lab just
down the hall from the CEO S office. Catalan says
she joined because she wanted to see her work in action.
I wanted to see the first patient to be treated,
some one person at least. I wanted to see that, okay,

(35:41):
this modified Emma and he helped one one person at least.
How the story would go from there, well, she never
expected that. That's next time on Breakthrough. Next week on Breakthrough,

(36:03):
we'll tell you about the frantic ten months of COVID
nineteen vaccine development that silenced the doubters in the scientific community.
At least it was highly likely that this is going
to be a pandemic, and we started to discuss what
we can do. This episode of Prognosis Breakthrough was written

(36:24):
and reported by me Naomi Kresky. So for Foreheads is
our senior producer. Carl Kevin Robinson Jr. Is our associate producer.
Our theme music was composed and performed by Hannis Brown.
Veronica Guyash did voice over, and Emma Cord, Bob Langrath,
and Sultan Shimon contributed reporting. Rick Shine is our editor.

(36:47):
Francesca Levy is the head of Bloomberg Podcasts. Be sure
to subscribe if you haven't already. If you liked this episode,
please leave us a review. It helps others find out
about the show. Thanks for listening.