Immature Cells

Moderna started with essentially zero employees before becoming one of the biggest names in COVID-19 vaccines. We'll speak with the company's founders. And we'll find out what role Jennifer Aniston played in that origin story.  

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Episode Transcript

Speaker 1 (00:08):
School of humans. Growing up in Japan, Shinya Yamanaka broke
bones all over his body. He cracked them practicing judo
and snapped them playing rugby. So when he became a
doctor in nineteen eighty seven, he chose orthopedic surgery to
fix the broken bones of other athletes like himself, who

(00:29):
treated their bodies like crash test dummies. He was obviously
no dummy, but Yamanaka wasn't a very good surgeon either,
and he saw a lot of patients that he couldn't
help with the scalpel, Like his own father, who had
died of liver cirrhosis. Only research and new discoveries could
lead to their cures. Yamanaka changed paths, moving from the

(00:51):
operating table to the laboratory. Twenty years later, after many failures,
Yamanaka made one of the biggest discoveries in the history
of science. When we first start to form, you're just
a bunch of identical immature cells. As we grow, those
cells divide and multiply into different specialized cells like skin cells,

(01:15):
nerve cells, muscle cells, and brain cells. In two thousand
and six, Yamanaka discovered that these mature cells could be
reprogrammed to an immature state, and once the cells were
in an immature state, they could then be grown into
whatever types of cells were needed. He called these cells
induced pluripotent stem cells or IPS cells. Pluripotent basically means

(01:40):
that their cells that can become any other type of cell.
By adding just four genes into the skin cells of mice,
Yamanaka could reprogram them into immature cells that were just
like embryonic stem cells, cells that resemble those from an embryo.
As one article put it, it was like biological time travel.

(02:01):
Want to turn a skin cell into a muscle cell,
to help regrow a lost limb, Want to replace a
failing kidney. Now scientists had a place to start, and
that was only one of a million things that could
be done for human health with Yamanaka's reprogrammed cells. On
this episode of a Long Shot, we'll talk to one
scientist so inspired by Yamanaka's discovery that it changed the

(02:24):
entire course of his life. He'd go on to start
a little company called Maderna. We'll also talk about lipid nanoparticles,
the protective shell of the mRNA vaccines, and last we'll
hear about the role that Jennifer Andison's hair played in
this whole story from My Heart Radio and School of Humans.

(02:45):
I'm sean revive and this is long shot. The world
found out about Shinya Yamanaka's discovery on June thirtieth, two

(03:08):
thousand and six, when he gave a talk in Toronto
at an annual meeting of the International Society for Stem
Cell Research. The researchers in the room knew this was
a huge announcement. If Yamanaka could create embryonic like cells
in a mouse, then he can also do it in
a person. That could lead to nearly unlimited enhancements in
human health. I remember being in the audience and just

(03:31):
being blown away by his presentation. That's Canadian scientist Derek ROSSI.
The study is one that I returned to. I've read
it many times. I mean, it's really fantastic. We're talking
over zoom. He's wearing red rounded Andy warholesque glasses and
a black David Bowie T shirt. It's not the picture,

(03:53):
but it's a picture from the cover of Ziggy Stardust.
Derek is fifty five years old, but looks a bit younger,
with slick back fashionably graying dark hair. He's the CEO
of Convelo Therapy X, a company based in Cleveland. They
do work on multiple sclerosis. His parents were first generation Canadians.
They immigrated from Malta right after World War Two. His

(04:16):
dad worked at autobody shops and his mom ran a
daycare center. It was not a science family, but he
had a brother with an absolutely crazy love for wild animals,
and the house was filled with them. We literally had,
you know, an endless parade of really exotic animals marched
through our house, you know, from a great horned owl
we had, you know, as a pet in the home,

(04:38):
a raccoon, squirrel, you name the snake species, we had it.
We had a cayman brought he brought home an and eater. So,
of course Derek wanted to be a veterinarian until I
took a molecular biology course. Well it's a greade eleven
biology in high school. My teacher started to teach us

(05:00):
about molecular biology. He had just come out of college
and it was the early days of molecular biology, and
he started telling us about DNA replication and mRNA and
protein synthesis. Derek was hooked. He trained as a molecular
biologist at the University of Toronto, then moved to Helsinki,
Finland to get a PhD. He did a fellowship at

(05:21):
Stanford on stem cell biology, and then soon after he
heard that lecture about Shinya Yamanaka, he moved to Harvard
to teach. So if you took a skin cell, which
normally would live its whole hyphasis skin cell and wouldn't
turn into anything else, now Yamanaka could turn it into
something that cell type. Now that could become a hard cell,
or a brain cell, or a liver cell. So Yamanaka

(05:44):
publishes his paper and then the whole world is all
of a sudden using this technology to make pluripotent stem
cells to study disease and drug mechanisms and tissue engineering.
It's an enormous leap in medicine. It was that pervasive
and that applicable to so many different aspects of the
work that many different biologists were doing, from you know,

(06:06):
studying cell identity, to modeling disease in a dish, to
screening for therapeutics to move the needle on a particular disease.
When Derek started his own lab in two thousand and seven,
at Harvard, he and his colleagues took up a project
inspired almost entirely by Yamanaka's work, But there was one

(06:29):
major drawback to Yamanaka's method. To get cells to regress
to their embryonic like state, you had to use a
retrovirus that's a virus that inserts its RNA into your cells,
like coronavirus. To make the regress happen, Yamanaka added four
genes into a cell. They came to be known as
the four Yamanaka factors. But adding those genes means you

(06:52):
risked creating cancerous cells that would obviously not fly for
human patients. As we mentioned last episode, the saying amongst
scientists is that DNA makes RNA, makes protein, makes life.
I call it the trifect of life. DNA makes mRNA,
makes protein, makes life. What Yamanaka was doing was inserting

(07:15):
strands of DNA into cells in order to change them.
But in between inserting the DNA and the cell's changing,
there's a fundamental intermediary step. The cell has to interpret
what the DNA is saying, and it does this by
turning DNA into messenger RNA or mRNA, so that messenger

(07:36):
rna is basically a readable copy of the DNA. It's
the mRNA that instructs the cell to revert to its
immature state. But remember, inserting DNA was too dangerous, so
Derek's big change to Yamanaka's process was to just skip
that step. Post hocrofello. In my lab, doctor Luigi Warren

(07:56):
had the idea, very simple idea, just saying, hey, you
know we need to make these transcription factors. Let's just
skip the whole DNA part. Let's just use mRNA bypass
the DNA and get the mRNA into the cell. I'm
going to get a bit technical here, but I think
it'll be worth it. Most DNA, which stores our genetic information,

(08:17):
lives in the nucleus of cells. When DNA converts into
messenger RNA, that also happens in the nucleus, but then
it migrates to the cytoplasm. That's a thick fluid that
fills the cell. It's where proteins are made. When Derek
and his team wanted to send instructions to cells, they
needed to get mRNA straight into the cytoplasm of the

(08:38):
cells they were using in the lab. The problem, though,
arose when we introduced the RNA into cells in the dish.
What we were doing now was bringing it from outside
the cell to the inside of the cell. And the
challenge that we face though, was that the cells didn't
like that at all. When Derek tried to put mRNA

(09:00):
messenger ribonucleic acid right into some cells, the cells thought
they are being attacked. To the cell, it looks like
an invading virus, quite frankly, which caused the cell to
respond by saying, Oh, looks like a virus is coming in.
Let's kill our celves, you know, an altruistic suicide and
cell death, which is a good thing for the cell

(09:22):
to do, you know, rather than let it be hijacked
by a virus and have it made hundreds of thousands
of viral protocols. Again, Derek and his team weren't putting
viruses into cells, just some snippets of RNA, but the
cells thought it was a virus, so they needed to
work around a better way to get RNA into cells.

(09:43):
It turned out that a workaround already existed and have
been sitting around waiting for someone to use it. Catalan Corrico,
Hungarian immigrant and daughter of a butcher, was a floundering
scientist obsessed with RNA. She'd been working with RNA since
the nineteen eighties, floating from lab to lab, unable to

(10:06):
get one of her own. Instead, she had to work
under other seemingly more successful scientists. Many times now they
describe my life story, it sounds like, you know, struggle
and very difficult. Doctor Kurka was on break with her
new grandchild when we reached out. But here she is
in an online Q and A. But let me say

(10:27):
in advance, even if you know things didn't work out
how I expected, I was always happy, happy in the lab.
RNA was not exactly a hot topic during much of
her early career. It was unstable and very difficult to
work with, as Derek Rossi discovered, but Karko was obsessed

(10:48):
with it and believed RNA could be used to instruct
the body to make its own medicines. One day after
losing it another lab position, she met Drew Wiseman, a
researcher looking to make a vaccine for HIV at the
University of Pennsylvania. Kariko told Wiseman that she could make
anything with m RNA. They teamed up, but they ran
into the same issues that Derek Rossi would later when

(11:12):
Corico and Weissmann injected mRNA into mice, their cells saw
invaders and their immune systems attacked it. But they knew
that cells didn't treat all RNA as invaders. They had
to figure out why. It turns out that a component
of some types of RNA, a molecule called pseudouridine, can

(11:33):
help evade an immune system reaction. In other words, if
they added pseudouridine to the mr anda they were trying
to get into mouse cells, the cells would stop thinking
of it as an invader. Pseudouridine acted as a cloak.
And so we published the paper into CELS and five
and the drew said that, no, no, we can prepare.

(11:55):
People are inviting us everywhere. Oh waited. I mean we
did a lot of experts not sitting and waiting. But
you know, a couple of years best nobody cared, but
Derek Rossi cared. He read about Carrico and Weisman's cloaking
method and integrated it into his own work. And so
when we read that study, we thought, well, maybe we
could use these modified nucleosides to get mr ANDA into cells,

(12:19):
to get past these ancient sort of sensing mechanism rather
than killing the cells, because quite frankly, prior to doing that,
we killed a lot of cells in the dish as
a way of seeing if their MR and A modifications
worked in mice cells. Derek and Luigi Warren, his post doc,
would test it to create green fluorescent protein, literally coming

(12:43):
from jellyfish. Green fluorescent protein is sort of a standard
way of seeing if a protein creating method works in
a lab. If you shine some uvy light on them,
they'll glow green under the microscope and you can see
if your experiment works. Before they found Carrico and Weisman's
work on pseudourdine, they only got a little green, But

(13:04):
once they modified the RNA to include pseudouridine, things changed.
We could now get a lot of green cells in
the dish and very happily surviving and not dying anymore.
That was the technological breakthrough that led to the development
of modified RNA in the lab. They called it mod RNA.

(13:26):
So now Derek had a working method for putting the
four Yama naka factors into human skin cells and turning
them into immature embryonic like cells. Those cells could then
theoretically be turned into whatever types of cells they wanted.
For his work modifying RNA, Derek was named one of
the hundred most influential people in the World by Time

(13:47):
magazine in twenty eleven. The potential to do great things
was there, but first he wanted to turn his modified
RNA methods into a business, so he got a meeting
with one of the biggest serial entrepreneurs of our time.
An article in Harvard Business Review calls Bob Langer the

(14:08):
Edison of medicine. He's taught at MIT for decades and
as head of the eponymous Langer Lab, which churns out
new biotechnologies like a revd up vending machine. You know,
it's very interdisciplinary, and the kinds of problems we try
to do is it's still i would say, very basic
science and engineering, but basically to try to make discoveries

(14:32):
or create technologies that we feel can have a big
impact on the world. That's a little bit about the lab.
Bob has more than fourteen hundred pending or granted patents
and is the most cited engineer in history. His lab
has had a thousand or so students come through it
over the years, and together with Bob, the lab has
produced more than forty companies worth many billions of dollars.

(14:55):
That's been wonderful. I mean, I think those companies can
take some of the discoveries we make in academia and
get them out to the world. And there's nothing I
think more satisfying to the students who've worked these projects
and to see that happen and me too. In other words,
Bob is a super producer or a super supporter of
both technologies and businesses, mostly to do with medicines and

(15:16):
tissue engineering, but he's also worked in the hosts of
other fields, like a couple of years ago he helped
develop a technique for giving people invisible tattoos that contain
their medical history. And then there's that time he started
a company with Jennifer Aniston. We actually even got into
cosmetics once. We started a company with Jennifer Aniston, and
that's so called Living Proof, and so it's, you know,

(15:38):
to help people have less fisty hair and better hair
and stuff like that. It started when one of Bob's
former students came to see him one day and was like,
let's do some stuff with hair. So we took a
more fundamental look about why what causes FRIZ and basically
came up with some materials that are much more hydrophobic,

(15:59):
you know what, are repellent than what anybody ever did
before their solution scanning for approved compounds that were hydrophobic
and approved for human use, and found ones that were,
you know, super super hydrophobic, almost like as hydrophobic as
a teflon frying pan. And we tried it and it

(16:19):
worked really well. We got patents for it, and it
became very popular. It's actually used all over the world.
They also came up with a product to give hair
more body, and then they just needed a famous backer.
Some of the business people and the company, I guess
talked to some of Jennifer Anderson's agents, and he got
very excited about it. She actually came to my office
several times and actually asked really good questions. In twenty ten,

(16:43):
Bob Langer started yet another company. Derek Rossi, who was
a young professor at Harvard and came to see me
because he'd made a discovery that he could put certain
types of modified Messenger RNA in cells and make them
more like a stem cell. Here's Derek I was showing

(17:08):
the science to a colleague Kim Springer, who had experience
in biotech. He put me in touch with Bob Langer Earthly.
He said, oh, let's go get Bob's opinion on this.
So he emailed Bob, and then Tim and I traveled
over to Bob's office. Bob and Derek met, and Derek
explained the science, and Bob's reaction was, this is terrific.

(17:30):
What can I do to help? I just thought, what
can Bob do to help? And then I thought, well,
why don't I ask him to co found this company
with me? Because you know he's a delivery expert. When
Derek calls Bob Langer a delivery expert, he doesn't mean
he works for ups. Since the mid nineteen seventies, Bob
has been a pioneer in several methods of drug delivery.

(17:52):
Drug delivery means getting a medicine to its intended target
in the body, whether it's a certain part of the
brain or the liver, or to attack cancrous cells in
the skin. Drug delivery can also mean delivering the drug
consistently for time. That's called controlled release drug delivery. Bob
is sort of the founder of controlled delivery, a technology

(18:14):
that allows the large molecules of a drug to disperse
slowly into the body. Drug delivery can also mean protecting
the actual substance of a drug so that it can
get to its target in the body without degrading or
falling completely apart. Bob has used most of these delivery
methods in his work, and here's some of the super
cool technologies. He's helped develop. An implanted wafer that can

(18:38):
deliver chemotherapy directly to a brain tumor, contact lenses that
can deliver drugs through the eyes, controlled release systems that
use magnetism to increase the release of drugs in your body.
A huge part of Bob's work in drug delivery has
been with LNPs lipid nanoparticles. They're fatty spheres that carry

(19:00):
drugs into the body and that work really well carrying
DNA or RNA. Researchers, not just Bob, have been looking
at LMP's for drug delivery for decades. They play an
indispensable role in the mr anda COVID nineteen vaccines, allowing
the RNA to deliver its spike building instructions into our cells.

(19:23):
And to learn a bit more about them, I spoke
with another expert on LMPs. The much larger challenge was
to identify carriers systems that could deliver biological molecules inside cells,
and being able to do that efficiently has taken decades

(19:44):
to accomplish. That's doctor Thomas Madden. Thomas is a biochemist
and he's worked in the biotechnology field for like thirty years.
He's president and CEO of Acutous Therapeutics in Vancouver. Acutus
provides the lipid nanoparticle technology used in the mRNA based
Fiser vaccine. The vaccine itself was actually developed by a

(20:07):
German company called Bioentech. Thomas was introduced to Biointech by
Catlin Corrico. I asked Thomas to break down what a
lipid nanoparticle is. The nano refers to the fact that
the size range of these particles is in the nanomesa range,
So typically these particles are less than one hundred nanometers

(20:30):
and so that's why we were referred to it as nanoparticles.
A nanometer is a billionth of a meter. Lipids are
organic compounds that are insoluble in water but soluble in
other solutions. A lot of natural oils like olive oil
and canola oil and waxes like carnabo wax or bees wax.

(20:54):
Those are all lipids. They're tiny lipid spheres, you know,
they're less than a thousandth of the width of a hair,
and they have four different composed us that are all
required in order for them to work effectively. So they
have two lipids that are actually naturally occurring lipids. One

(21:15):
is cholesterol and another is caught diasterol phosphatyl choline. It's
a lipid that's found in our membranes, are biological membranes naturally.
LMPs also of two proprietary lipids, basically the secret formula
lipids that each maker of lipid natal particles uses lipids
that allow it to have the functionality that it needs.

(21:38):
Thomas couldn't talk specifics about this, but he did describe
these ingredients of LMPs in broader terms. The most important
one of these is caught an ionizable lipid, and it's
the lipid that really determines how effectively it looks like
a protein, how effectively it's taken up into cells, and
also how effectively it can allow the payload the drug

(22:02):
to be released into the interior of the cell. The
fourth component is called a peg lipid, and it's really
it coats the outside of the particle and it's intended
primarily to stabilize the particle when it's formed, and when
the drug is loaded inside, and during storage of the
vaccine or the therapeutic. So what he's saying is you

(22:28):
need to protect the mr anda from falling apart before
it reaches the cell. That's one job of lnp's The
second job is getting the mRNA into our cells. The
LNPs needs to be recognized by human cells, or else
the cells will just ignore them and not get any
instructions from the mr anda encapsulated within them. The way
they do this is to make the LMP spheares resemble

(22:50):
something called lipoproteins, which cells recognize and use to get
nutrients they need. So Acutus makes the surface of an
LMP look like the surface of a natural lipoprotein. And
when it has that surface characteristic, then there's just a
particular protein in the blood called apoe which will bind

(23:11):
to it, and that apoe is then recognized by cells.
There are receptors for it on the external surface of
the cells, so it'll bind to the cells and basically
tell the cells, you know, take me up. I've got
a a parcel containing lipids for you that you need
for metabolism. So we take advantage of that natural uptake

(23:34):
mechanism in order to you know, get these particles into
a cell. In case all of that was a little
too in the weeds, Thomas Madden sums it up with
a nice metaphor, you know, a really a good analogy
for for what our technology does. That's like a real
world example is if if you wanted to order a

(23:58):
really fragile glass ornament online and you wanted it delivered
to your to your home. If you use the equivalent
of our delivery technology, then the ornament would be would
be wrapped and packaged to protect it, and about how
rough the journey was to your to your house. The
package would would find your house, it would open the

(24:23):
front door by itself and let itself in, and then
it would unwrap itself. So the ornament is waiting for
you to come along and pick up in your hallway.
Lipid nanoparticles the FedEx of vaccines. When Derek Rossi went

(24:49):
to Bob Langer's office to present his idea for a
company that uses modified RNA to create new drugs. He
knew that Bob was a pioneer in delivering drugs into
the body. The Languor Lab had developed the first nanoparticles
that could deliver nucleic acids like RNA and many of
the principles and components behind the LMPs that are now
used in the mr anda COVID vaccines. And so in

(25:12):
the summer of twenty ten, Bob and Derek and another
scientist they brought in named Kenneth Chen got some funding
from a venture capital firm then called Flagship Ventures, and
together they started a company. But it wasn't much of
a company at first. There were no full time employees,
There was no office. And how many people worked at

(25:34):
the company when it was first founded. Was it literally
just the four of you or was there a whole
staff at the first No, it was nobody other I mean,
and we weren't none of us were full time. I
mean basically we would meet in Flagship's offices or my
office and you know, and just brainstorm, and you know,
that was probably the first six months. And back to Derek,

(25:54):
I kept my day job in academia, so I was
always you know, had my professorship at the med school.
Eventually the company did have a name. Maderna comes from
the term that we used in the lab describing the technology.
We called it mod RNA, So mod RNA, if you
put any in there, you get Maderna. That's where the
name came from. So in twenty ten they founded a

(26:18):
company called Maderna. Bob Langer has been on the Scientific
Advisory Board and on the board of directors ever since.
Derek Rossi was on the Scientific Advisory Board and on
the board of directors until twenty fourteen. By then, Maderna
had a new CEO and a president and was moving
towards bringing therapeutics to clinical trials with entire staff of hundreds.

(26:39):
Of course, Derek never predicted that Maderna, the company he
founded and then left, would go on to be one
of the first to create a vaccine against a global pandemic.
Derek has started a few more companies since then. Even
though he didn't play direct role in Maderna's blockbuster product,
he now spends a lot of his time talking about
the power of the COVID vaccines. I always believed in

(27:01):
the technology. I always believed that there would be modified mRNA.
I drank the kool aid a long time ago. I
always believe that it was going to be a new
class of medicines, and they're upon us, so that's pretty satisfying.
I spend most of my time these days, or since
the pandemics started talking about what mRNA is introducing mRNA

(27:26):
to the planet lately, talking a lot about what vaccines
are and trying to tackle this issue of vaccine hesitancy
because people are hesitant abou vaccines because they don't know
what the heck they are. So the whole idea with
vaccination is to prime your immune system so that it's
ready to spring into action should you get exposed to

(27:47):
a pathogen. It's something your immune system does on a
daily basis. It's doing it right now. It's also one
of the most tried and trude medicines that we've ever
had in the history of humanity. And the reason it's
so darned good is because you're really just asking the
immune system to do what it does on a regular basis.
That is, bottom line, what a vaccination is. Derek got

(28:11):
vaccinated before we spoke back in April this year. Moderna's
COVID nineteen vaccine has been approved for use in more
than fifty countries and has sold more than half a
billion doses of its vaccine. I figured it must have
been satisfying for Derrek to have finally gotten his jabs.
I waited my turn like everybody else, and when a

(28:31):
vaccine was offered to me, I took the one that
was offered to be which was Fiser. For his discovery
of induced pluripotent stem cells, Shinya Yamanaka was awarded the
Nobel Prize in Physiology or Medicine in twenty twelve. During
his Nobel lecture, he talked about the many roadblocks he
had throughout his career and the many mentors and colleagues

(28:54):
who helped him get through them. He also spoke about
the many scientists whose accomplishments were necessary before he could
have his own. That included discoveries in nineteen sixty two
at the University of Ford, in nineteen eighty one at
the University of Cambridge and the University of California, San Francisco,
in nineteen eighty eight at the University of Wisconsin, and
in two thousand and one at Kyoto University. Yamanaka knew

(29:17):
that his earth shattering discovery was built upon the backs
of many others, like how Derek Rossi's was built upon
Catlin Corrico's and Drew Weisman's and their work upon many others,
And like how the COVID nineteen vaccines are built upon
centuries of work in and outside of laboratories across many borders,
which is the whole point of this podcast. Next Monday,

(29:41):
December tenth, I'm going to see done Bell Prize one
behalful many scientists who have contributed to the generation of
IPS cells and who have contribute duty to the very
rapid progress of this technology. So I really hope that

(30:08):
end bury near future these technologies well help passions. On
the next episode of long Shot, we're going to talk
to some coronavirus patients who have never recovered. They suffer

(30:31):
vivid dreams, insomnia, and a host of other weird symptoms
that are nothing like the respiratory illness we think of
as COVID nineteen. They have long COVID and they've had
it since the beginning of the pandemic. Long Shot is
a production of School of Humans and iHeartRadio. Today's episode

(30:52):
of long Shot was produced, written, and narrated by me
Sean Revive. A co producer is Gabby Watts. Special thanks
to Noel Brown and iHeartRadio. Today's episode was fact checked
by Savannah Hugally. Executive producers are Virginia Prescott, Brandon Barr,
and ELC. Crowley. Long Shot was scored by Jason Shannon.
The score was mixed by Vic Stafford. Sound Design and

(31:14):
audio mixed was by Harper Harris with Tunewelders School of
Humans