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limited by state law. Listen

2:12

to supported WNYC

2:14

studios. Why

2:21

do scientists want to remind you that RNA is

2:23

more than just part of the COVID vaccine? It's

2:26

in all of the food that we eat.

2:28

It's in every living being that

2:30

we encounter on our planet. It's

2:32

Monday, June 10th, and you're listening

2:35

to Science Friday. I'm

2:42

sci-fi producer Dee Peter Schmidt. We've

2:44

all heard of DNA, the genetic blueprint of

2:46

life, but off to the site

2:48

is RNA, DNA's lesser-known counterpart, which helps

2:50

actually implement those blueprints in our bodies.

2:54

DNA's gotten most of the spotlight over the

2:56

past half century, but that's changed in the

2:58

last few years thanks to the success of

3:00

the mRNA-based COVID vaccines, and

3:02

it's led to a renewed interest in

3:04

the potential medical applications for this tiny

3:07

molecular powerhouse. Here's our

3:09

flato with a scientist who sees

3:11

a bright future for RNA research.

3:13

Here to tell us how we

3:15

got here and why this misunderstood

3:17

molecule might be the key to

3:19

a next generation of big scientific

3:21

discoveries is Dr. Thomas Chek, distinguished

3:24

professor in biochemistry at the University

3:26

of Colorado in Boulder and author

3:28

of the book, The Catalyst, RNA

3:30

and the Quest to Unlock Life's

3:32

Deepest Secrets. He won the

3:34

Nobel Prize in chemistry for his RNA research

3:36

in 1989, and

3:39

I'm happy to welcome you to Science Friday. I'm

3:41

so happy to be here, Ira. Nice

3:43

to have you. You know, for

3:45

a lot of us, our first meaningful

3:47

interaction with RNA was with the mRNA

3:50

COVID vaccines. As someone who's

3:52

been studying this for decades, did

3:54

that also feel like a big moment for you

3:56

too? Well, it

3:58

was Ira, and I'll... talk a bit about

4:00

that, but I just need to

4:03

correct you a little bit and I hesitate to

4:05

do that. You said this was people's

4:07

first encounter with RNA,

4:10

but actually it's in

4:12

all of the food that we

4:14

eat, whether we're meat lovers or

4:17

vegetarians, it's in every living being

4:19

that we encounter on our planet.

4:21

And in fact, here in Boulder,

4:24

we might even say it's organic.

4:27

Let's talk about then what mRNA exactly

4:29

is. Tell us. It's

4:32

a copy of the instructions that

4:34

are stored in the DNA double

4:36

helix, but it's just a copy

4:39

of one of the two strands.

4:42

The bits of information in

4:44

the DNA, as most

4:46

people know, go by the letters

4:49

A, G, C, and T. And

4:52

RNA just copies those. It's

4:54

A, G, C, and U.

4:56

U in RNA is the

4:58

informational equivalent

5:00

of the T that is found

5:03

in DNA. So once

5:05

you've got this copy of

5:07

the DNA alphabet, this message

5:09

moves out from the cell

5:11

nucleus into the cell cytoplasm

5:13

where it instructs the formation

5:17

of particular proteins.

5:19

And if that's all that RNA

5:22

could do, it would

5:24

be important, but there are

5:26

many cooler things that we'll talk about,

5:28

I hope, in the next

5:30

minutes. Well, staying a little

5:32

bit about the rudimentary

5:34

knowledge that most of us,

5:37

we the public, don't have.

5:39

When we say RNA helps

5:41

make proteins, what do these

5:44

proteins turn into? What do

5:46

they do for us? Proteins are really

5:48

the movers and shakers in every

5:50

cell in our body. So they

5:52

are responsible as enzymes

5:55

for digesting the lunch

5:57

that I just consumed.

6:00

They allow our muscles to

6:02

move and they

6:04

are responsible for our hearts

6:06

to beat. They also

6:08

form the structures of the biggest

6:10

part of the structures of

6:13

all of our cells, all

6:15

living things. So proteins,

6:17

there are about 20,000 different ones

6:19

that make up a human

6:22

and proteins are really fundamental to

6:25

allowing life to exist as it

6:27

does. Well, let's begin. Tell us

6:29

about these other things that RNA

6:31

can do. Right. So

6:34

there are a lot of

6:36

RNAs that are called non-coding

6:38

RNAs because they don't

6:40

care at all about instructing

6:43

the formation of particular

6:45

proteins. Instead, they

6:47

do things like power

6:50

the immortality enzyme

6:52

called telomerase, which

6:54

keeps our stem cells and

6:56

our sex cells, our germline cells active

7:00

and growing. Unfortunately,

7:02

it also powers cancer

7:04

cells. Then there

7:06

are RNAs called siRNAs,

7:09

small interfering RNAs,

7:12

first found in a

7:15

minuscule roundworm, but

7:17

then found to also be in

7:20

all the cells in humans as well

7:22

and have been converted into

7:24

pharmaceutical agents, which are saving

7:27

people's lives. And

7:29

then another area that we could

7:31

touch on would be the CRISPR

7:33

genome editing machinery, which

7:36

derives its incredible specificity, its

7:38

ability to seek out a

7:40

particular part of a chromosome

7:42

to act on due to

7:44

the fact that it carries

7:46

around a guide RNA. So

7:49

those are just a few of

7:51

a dozen examples of major categories

7:53

of non-coding

7:56

RNAs. And

7:58

let's go back to... Us

8:00

meaning mRNA in terms of

8:03

the COVID vaccine. If

8:06

mRNA can be used to

8:08

fight viruses, can RNA

8:11

be used to fight other illnesses

8:13

we have? Well, that's the

8:15

big question right now. It

8:17

sure seems promising. And

8:20

the COVID-19 vaccines

8:22

really solved a lot of

8:24

technical problems that now can

8:26

be redirected for

8:30

vaccines and other therapeutics

8:32

towards other diseases. We're

8:35

hoping that a quick one

8:37

might be a flu vaccine

8:40

that would be much more

8:42

effective than the rather modest

8:44

efficacy, typically between 30 and 60% from

8:46

year to year of

8:50

the current flu vaccines. And

8:52

that's because the vaccine manufacturers,

8:55

it takes so long to

8:57

make the flu vaccine. Believe it or not,

9:00

a million chicken eggs per

9:03

year in the US alone

9:06

are hand injected with

9:08

an incapacitated flu virus to give

9:10

rise to the flu vaccine. So

9:12

this takes so long that we

9:14

don't, we have to start the

9:16

process before we really know which

9:19

subtype or which strain

9:22

of flu virus will be around in

9:25

flu season. Now with the mRNA vaccines,

9:27

it's so fast to make these

9:30

that one can wait until you

9:32

see what kind of flu virus

9:34

is starting to emerge and then

9:36

customize the vaccine. That's the

9:38

idea. And I'm hopeful that that will happen

9:40

within a few years.

9:43

What about the big C, cancer,

9:45

any hope there? That's really,

9:48

again, a little bit higher

9:50

hanging fruit, but I'm very

9:52

hopeful. At first when

9:54

I heard about cancer vaccines, I was

9:57

confused because we

9:59

think about. vaccines is protecting

10:01

us against pathogens, viruses,

10:03

bacterial infections. Cancer

10:05

is intrinsic to our own

10:08

human biology, gone haywire.

10:11

And so how can we possibly

10:13

vaccinate against that? Well, it turns

10:15

out that cancer cells are spewing

10:17

out a lot of mutated proteins,

10:20

and these proteins are enough different

10:22

from the proteins in

10:24

a healthy human cell that

10:26

we should be able to

10:28

train our immune system to

10:31

be on the lookout for them and

10:33

to kill any cells that

10:35

are producing these unnatural

10:39

proteins, that is cancer

10:41

cells. That's under development right

10:44

now. It's being tested? To

10:46

be, it's in clinical trials, the

10:48

first readout. It's a collaboration between

10:50

Moderna and Merck, and I have

10:52

to disclose that I was on

10:54

the board of directors of Merck for a dozen years.

10:57

So I've heard about this, but

10:59

it is public knowledge too. You

11:01

can find it on the internet,

11:03

and it seems hopeful. Speaking

11:06

of hopeful, let's talk about CRISPR. You brought

11:08

that up a short while

11:10

ago, CRISPR using RNA as a guide

11:12

to precisely target and modify

11:15

DNA sequences. What

11:17

kinds of benefits might we get from that?

11:20

The first CRISPR therapeutic was

11:22

actually approved both in the

11:25

UK and then in the

11:27

United States late

11:29

last year, so just a few months ago.

11:33

This was against the incredibly

11:35

debilitating disease, sickle cell

11:37

disease, particularly prominent in

11:40

the African American population.

11:44

The ability to allow these people

11:46

to not have a sickle cell

11:48

crisis where their red blood

11:51

cells distort into this

11:53

sickle shape and clog up

11:56

their capillaries, incredibly painful, prevents

11:58

moms from being able to take care

12:00

of their kids and hold down a job. This

12:03

could be a wonderful thing. But the

12:05

boundaries of this are

12:07

huge compared to just

12:10

sickle cell disease. So

12:12

many other diseases like

12:15

muscular dystrophy, cystic fibrosis,

12:18

enormous number of diseases

12:20

where we know the genetic

12:22

cause, we know which letter

12:25

in the DNA alphabet is

12:27

misspelled. But now with

12:29

CRISPR we can actually do

12:31

something. This week on

12:34

the New Yorker Radio Hour, Senator Raphael

12:36

Warnock, a Georgia Democrat on the election

12:38

and the soul of a nation. The

12:40

country has long been in a spiritual

12:43

crisis amplified by

12:46

the reality of Trumpism. This November

12:48

for me is much more than

12:50

an election. It's a spiritual battle.

12:53

Raphael Warnock on the New Yorker

12:56

Radio Hour from WNYC Studios. Listen

12:58

wherever you get your podcasts. In

13:03

your book you say that around three-quarters

13:06

of the human genome consists of

13:08

dark matter RNA with

13:11

unknown functions. Now I love this

13:13

comparison because I used

13:15

to bring this up with physicists who

13:17

talk about dark matter in the universe.

13:20

We don't know what 96% of the

13:22

universe is made out of. What

13:25

about this dark matter? What do you

13:27

mean by that exactly? And what kind

13:29

of breakthroughs do you anticipate happening here

13:31

in the dark matter in the RNA

13:34

version? Thank you for that

13:36

because it is fascinating

13:38

that three-quarters of

13:41

the human genome is not

13:43

copied into messenger RNA but

13:46

is copied into these

13:48

non-coding RNAs. The jargon

13:50

term for these is

13:52

link RNAs or long

13:54

non-coding RNAs. Different

13:57

ones are produced in the

14:00

skin cells in the liver cells

14:03

in neurons in the brain In

14:06

the heart muscle, so they tend

14:08

to be very tissue specific in

14:10

any one tissue you would not see all 75%

14:15

of the of this dark matter being

14:17

converted into RNA But if you add

14:19

up what all of the tissues in

14:22

the human body are able to produce

14:24

Then you see that most of it

14:27

is made into RNA in some tissue

14:29

or another But the dark RNA must

14:31

have some usage right? I mean or

14:33

else it wouldn't be conserved. I'm guessing

14:35

well Some

14:37

of us would agree with you. However,

14:39

I have friends

14:42

who are scientists who think it's

14:44

all Junk who

14:46

think it's noise that we

14:49

should say that about junk DNA didn't

14:51

we well that this is the junk

14:53

This is the junk RNA made from

14:55

the junk Right So

14:58

so if you believe in the junk model

15:00

you say okay junk DNA makes junk RNA

15:04

Let's throw it away and and of course,

15:06

that's what the cell does RNA Is

15:09

not nearly as stable as as

15:12

DNA. That's why we isolate

15:15

DNA from the from the woolly

15:17

mammoths that are encapsulated

15:19

in Glaciers

15:22

in Siberia, we can't get RNA out of

15:24

those Ancient cells, you

15:27

know, so maybe it's just being made

15:29

and thrown away It's just it's just

15:31

like life isn't perfect stuff

15:33

happens you get rid of it Are

15:36

we just haven't discovered yet what it does?

15:38

That's what I think Ira because

15:41

many of the non-coding RNAs like

15:43

the telomerase RNA For example is

15:46

CRISPR guide RNAs these small

15:48

Interfering RNAs before we knew their function They

15:51

would have been part of this dark matter

15:53

and they would have been branded as junk,

15:56

right? I get it I I know that

15:58

you and and others theorize that RNA

16:00

might have come before DNA

16:02

in terms of getting life

16:05

started on Earth. Fill us

16:07

in on that. Well, this is

16:09

a fascinating outcome

16:12

of our initial finding

16:14

that RNA could be

16:16

a biocatalyst, RNA with

16:18

enzyme-like properties. And

16:20

if you think about how life could have

16:22

started almost 4 billion years ago

16:25

on the primitive Earth, you

16:27

come up with the sort of mother of

16:30

all chicken and egg problems immediately. And that

16:32

is in order to have life, you need

16:34

to have some kind of an informational molecule

16:36

to be passed down to the next generation.

16:40

That could be DNA, but

16:42

DNA doesn't do anything. It

16:44

just sits there. It requires

16:46

protein enzymes to copy the

16:48

DNA and make daughter molecules

16:50

out of the mother molecule.

16:52

So to be passed down to the next

16:55

generation. So how could this have

16:57

happened 4 billion years ago?

16:59

Do we really believe that in the

17:01

same droplet of water

17:03

at the same time by

17:05

random chemical processes that DNA

17:08

and a machine that could

17:11

copy that DNA protein

17:13

enzyme could have occurred at

17:15

the same time seemed really

17:18

high hurdle for the start of life.

17:21

Now that we know that RNA,

17:23

that ribonucleic acid can

17:26

be both an informational molecule,

17:28

again, hearkening back to the

17:30

SARS-CoV-2 virus, just uses RNA.

17:33

So RNA can be an informational

17:35

molecule, but it can also be

17:37

a biocatalyst. And it can assemble

17:39

the A, C, G,

17:42

and U building blocks into larger

17:44

molecules. Maybe at the beginning there

17:46

was just RNA copying itself. And

17:49

the proteins in the DNA came along later.

17:52

Wow. I love to hear

17:54

this kind of thinking. Last question. You

17:56

wrote in your book that originally you

17:59

were, quote, DNA guy, but

18:01

then you switch to RNA. Do

18:03

you think you made the right choice there? It's

18:08

been good for me. Well,

18:12

why did you make that choice? Why did

18:14

you switch? Did you really recognize early on

18:16

that this is really good stuff? It

18:19

was serendipity, which

18:21

was, I think, best defined

18:23

by Winston Churchill, who is

18:25

said to have said many

18:28

a man stumbles over the truth,

18:30

but most get up, wipe themselves

18:32

off and hurry on as if nothing had happened.

18:36

We stumbled over a case where

18:38

the DNA was being made into

18:40

an RNA that was

18:42

rearranging its own internal

18:45

structure. It was cutting and

18:48

splicing itself. That

18:50

was worth investigating because this fact

18:53

that RNAs underwent

18:55

splicing, and in humans

18:57

especially, this is just rampant, that

19:00

RNAs are cut and rejoined after

19:02

they're made. But everyone

19:04

knew this was happening, but no one

19:06

knew the mechanism. As

19:08

a biochemist, I wanted to understand

19:11

how it happened. That's

19:14

what encouraged us to switch from

19:16

being DNA researchers to RNA

19:18

researchers and ultimately to find

19:22

this first example of RNA catalysis.

19:25

Well, I think you made the right

19:27

choice, Dr. Chek. I want to thank you for

19:29

taking time to be with us today. It's a

19:31

great book. Thanks so much. Dr.

19:34

Thomas Chek, distinguished professor in

19:36

biochemistry, University of Colorado in

19:38

Boulder. You can read

19:41

an excerpt from his new book, The

19:43

Catalyst, RNA, and the quest to unlock

19:45

life's deepest secrets. That's

19:48

at sciencefriday.com/RNA. And

19:50

that's it for today. Lots of folks help make the

19:52

show happen, including Phyllis Samerz Kathleen

19:55

Davis Jordan Smudgik Charles

19:57

Bergquist Next time, I have

19:59

the author of classic science. fiction stories

20:01

also wrote the military's textbook on Sciops.

20:03

Join us. I'm sci-fi producer

20:05

Dee Peterschmidt. When

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