RNAi

RNAi

PBS Airdate: July 26, 2005

ROBERT KRULWICH: Correspondent Chad Cohen.

What if I told you that recently, scientists made a discovery that's so surprising and so powerful, not only are we about to know much, much more about how all these diseases work—Alzheimer's and asthma and arthritis and cancer and HIV and all the others—there's a chance, it's a real chance, that we can treat many of these diseases much more effectively? All because of this one discovery called RNAi, with a little "i" at the end, which I'll explain later. You don't hear much about it, but RNAi is a really big deal.

And the curious thing about it is the discovery of RNAi was an accident. It was a puzzle that appeared in a petunia. It was a purple petunia. But to fully appreciate this tale, let's back up a bit.

Every creature, and you know this from high school, is made from a recipe that comes from its DNA, spelled out in chemicals: "A"s and Cs and Ts and Gs, inside the famous double helix. Every creature has its own DNA, different for mice than for whales and for flowers. But to go from a chemical recipe, "A"s, Gs, and Ts, to a real creature that squeaks or soars through the air or turns gloriously pink, that requires RNA. RNA is the thing that turns you from a chemical code to a real, pulsing, living creature. RNA builds life.

That's big; so big, that to RNA researchers like Greg Hannon, RNA is more important than DNA.

GREGORY HANNON: DNA really works for RNA and proteins really work for RNA.

ROBERT KRULWICH: Would you get an argument, by the way, from somebody else?

GREG HANNON: Oh, undoubtedly. Sure.

ROBERT KRULWICH: So how do you get from DNA to become a real creature?

Well, let's take one of those fantastic voyages and we'll show you. We're going to find DNA in, well, we'll make it a typical cell. So we're going have to fly in and then go off to the nucleus of the cell, which we'll make a beautiful castle, the headquarters.

And there's the DNA, the master code, inside the nucleus. "DNA," says Greg, "never leaves the nucleus."

GREG HANNON: You ever meet one of those mean librarians? You know, the...

ROBERT KRULWICH: Yes.

GREG HANNON: ...Special Reserve section?

ROBERT KRULWICH: The ones that go, "Pow"

GREG HANNON: Right, you can take the thing, you can copy it, but you can't take the book, 'cause somebody else might need it.

ROBERT KRULWICH: So if DNA is locked in the nucleus, how do we get the information out to build our creature?

Well, that's what RNA does. That scribe copying recipes out of the cookbook and throwing them out the window, out to the cytoplasm sea that makes up most of the cell, all those recipes floating through the air? They are RNA.

And to finish up, in that sea, you see hundred of thousands of, well, we've made them into little guys with chef hats.

GREG HANNON: Those would be ribosomes. And in your world, they're chefs who are using the recipes that are written in the RNA.

ROBERT KRULWICH: And whenever a recipe lands on a chef, whatever it is, he cooks it?

GREG HANNON: Whatever it is, he cooks it.

ROBERT KRULWICH: And each recipe is for a protein. Proteins build cells: bone cells, brain cells, all cells. So, all these chefs are basically building you. You are made of proteins.

And because of RNA, we can copy, we can distribute, and we can cook up you and me. And RNA has been doing this for more than three billion years.

But there was something spectacular about RNA that nobody knew till just a few years ago, and they learned about it, as we told you, by accident.

RICHARD JORGENSEN: Here's a good one. Maybe this...

ROBERT KRULWICH: In 1986, geneticist Rich Jorgensen was working at a biotech startup company in California. He was asked to create a spectacularly dazzling flower...

RICHARD JORGENSEN: That looks good.

ROBERT KRULWICH: ...to attract investors.

RICHARD JORGENSEN: So that we could convince venture capitalists, investors, to give us more of the green stuff, more money.

ROBERT KRULWICH: Still, back in 1986, geneticists didn't know how to work that easily with, say, roses. And so...

RICHARD JORGENSEN: We began with a simple plant, regular, garden-variety petunias—petunias being a plant that were easy to introduce genes to in 1986.

ROBERT KRULWICH: And so they decided to create a very, very, very purple petunia.

Rich knew which gene produced purple. He knew how to sneak an extra copy of that gene into the plant's DNA—the master text to be copied by that monk-like scribe.

RICHARD JORGENSEN: It will be transcribed by the monk the same as any other gene. He'll throw the transcript out the window, into the cytoplasm, where the chef will be able to pick it up and use it.

ROBERT KRULWICH: Rich thought that if he added more purple recipes, he'd get a purpler petunia. So he did it, and he waited.

And what happened?

RICHARD JORGENSEN: We produced, instead, white flowers.

ROBERT KRULWICH: White flowers?

RICHARD JORGENSEN: The complete opposite of what we had expected, completely white flowers. We lost pigmentation completely. Our initial reaction was that something must have been wrong with the gene that we had engineered, introduced to the plant.

ROBERT KRULWICH: A mistake?

RICHARD JORGENSEN: A mistake. So we checked everything out, and there were no mistakes that we could find.

ROBERT KRULWICH: So why didn't the petunias turn purple? What happened?

ERIC LANDER: The petunia was a big puzzle. Nobody understood why, when you add an extra gene for purple, you should not get more purple, but less purple. It took a decade of brilliant scientists working on petunias and fruit flies and worms and other organisms to finally work out what was going on.

ROBERT KRULWICH: And what was going on is, quite by accident, Rich had discovered a secret inside living cells.

Cells, from time immemorial, have had a mortal enemy called the virus. So let's imagine that the virus is a pirate ship. It lands; it then sends the invaders inside the cell to shower recipes down to those cooks. But some of those recipes, you'll notice, look a little different. And what's in these recipes is not good for the cell.

GREGORY HANNON: No, it's decidedly not good for the cell, because the sole purpose of that virus is to make additional copies of itself, and to the point that the entire cell is filled up with this. And the cell explodes, releasing these viruses to go and then infect whatever other cells they can find.

ROBERT KRULWICH: So the theory is that long ago, cells developed a secret defense system, which we will call the Cop.

What the Cop does is, when viruses invade and create a shower of murderous recipes, the Cop looks and thinks, "Hmm, some of these have a very fishy shape."

It's a chemical difference, which comes down to some of the viral recipes are two pages instead of one, and one side is a mirror image of the other. But the point is, to the Cop there's something not right about this shape.

So when they see it in that shape?

ERIC LANDER: They say, "Virus!" They say...

ROBERT KRULWICH: Uh oh.

ERIC LANDER: ..."Uh oh."

ROBERT KRULWICH: And the Cop destroys the recipe.

Now when you say it "destroys," is this, should we think like a kung fu kind of thing? Is it like a "Hyeh!" sort of deal?

ERIC LANDER: Yeah, a little enzymatically, a little thermodynamics. Things like that.

ROBERT KRULWICH: Enzymatically?

ERIC LANDER: Enzymatic kung fu maybe, yeah.

ROBERT KRULWICH: The Cop destroys not only the oddly shaped version. Whenever he sees that recipe, oddly shaped, regular shaped, that recipe in any form must be destroyed to defeat the virus.

And the interesting thing is, until 1998, nobody knew that cells had this defense mechanism.

ERIC LANDER: We had no idea it was there. That's what's so amazing, is...this whole mechanism had been sitting there, where cells were able to tell that something was very funny when they saw mirror image messages and start not just destroying the messages, but destroying anything that looked like that message. They'd worked out this whole defense system against viral RNA, and we then accidentally stumbled into using it.

ROBERT KRULWICH: The accident was Rich Jorgensen's purple petunia. The question, remember, was, when Rich tried to make his petunia more purple, why did it turn white?

Well, the answer, it turns out, was that Rich, by accident, discovered the Cop. When Rich invaded the petunia cell and inserted his make-more-purple instructions, he didn't know it, but his purple instructions happened to have that suspicious viral shape.

So when the Cop saw the recipe, the Cop thought "Virus!" and destroyed every recipe for purple in the cell.

RICHARD JORGENSEN: So there's no possibility anymore of producing the purple pigment, because the purple transcripts are gone.

ROBERT KRULWICH: If there are no recipes for purple, the chefs don't cook purple.

RICHARD JORGENSEN: And because there's no purple pigment produced, the flowers will be white.

ROBERT KRULWICH: And that's how Rich and his petunias helped discover what we now call RNAi.

ERIC LANDER: RNAi means RNA interference, because the Cop is interfering with RNA messages, with the recipes in the cell.

ROBERT KRULWICH: And when scientists realized that every plant and animal cell has RNAi—a way to turn off the recipes, turn off genes—they thought, "Hmm, maybe we can use these Cops to work for us."

MARTY RUSSELL: Okay, Trevor?

ROBERT KRULWICH: Which brings us to Marty. Seventy-eight years old, she and her husband used to spend lots of time here, at their daughter's nursery.

MARTY RUSSELL: Thank you, Rosie.

ROBERT KRULWICH: Years ago, she enjoyed doing lots of things.

TREVOR RUSSSELL: Her passion was reading.

MARTY RUSSELL: Was, uh...

TREVOR RUSSELL: She would read everything...

MARTY RUSSELL: Golf.

TREVOR RUSSELL: Yeah.

MARTY RUSSELL: I loved to play golf, bridge.

ROBERT KRULWICH: But then Marty began losing her sight.

MARTY RUSSELL: Couldn't see. And I'd probably get the peppers in with the zucchinis, and there'll be big problems then.

ROBERT KRULWICH: So she went to her doctor, who told her...

MARTY RUSSELL: "You have macular degeneration."

ROBERT KRULWICH: A degenerative disease caused by too many blood vessels growing in the eye underneath the retina.

PETER KAISER, M.D. (Cleveland Clinic Cole Eye Institute): As these blood vessels grow, they leak out fluid and blood in the center of her vision, and it's as if you're looking through a very dirty windshield, essentially.

MARTY RUSSELL: I went home; I was just devastated.

ROBERT KRULWICH: So Marty volunteered to be a candidate for RNAi therapy, something so new, she's kind of a pioneer.

PETER KAISER: She was probably one of the first to get it for any disease whatsoever, specifically for macular degeneration.

Hey. How are you?

MARTY RUSSELL: Hello, Dr. Kaiser. How are you?

PETER KAISER: Good to see you. This is the V.I.P. room.

MARTY RUSSELL: I feel very honored.

ROBERT KRULWICH: The reason Marty has so many blood vessels growing in her eye, clouding her vision, is there's probably a mistake in her DNA, in a gene that produces too many recipes that say, "Make more blood vessels." So the chefs cook up proteins for more, and she ends up with too many blood vessels.

Her doctor wants her to have fewer blood vessels, but how do you get the chefs to make fewer blood vessels?

ERIC LANDER: It was pretty easy. You want to shut down a gene? Put in a copy of the gene with its mirror image...signals the cell, "Better shut this thing down."

PETER KAISER: We inserted a needle after numbing her up.

ROBERT KRULWICH: So the doctors put—literally injected—RNA recipes into Marty's eyes that said, "Make more blood vessels." But they made those recipes look dangerous, like viral recipes, hoping the Cop in Marty's cells would leap to it and destroy lots of recipes for more blood vessels, leaving Marty with fewer blood vessels.

They wanted the Cop to turn off Marty's disease.

Did it work?

PETER KAISER: Marty's vision has improved. It's a very promising result.

MARTY RUSSELL: I can play bridge now.

PETER KAISER: Which is very important.

MARTY RUSSELL: I'm not great, but it's part of my life.

ROBERT KRULWICH: She can see flowers again.

MARTY RUSSELL: Oh, some of them are just gorgeous.

ROBERT KRULWICH: So, apparently, they did trick the Cop in Marty's cells to reduce vein production, although not completely.

MARTY RUSSELL: I see the yellow. The inside is just a little cloudy, but I can see it.

PETER KAISER: There's a lot of questions still that need to be answered. This is not a treatment that is proven.

ROBERT KRULWICH: Can we deliver recipes to the right cells?

MARTY RUSSELL: Lovely.

ROBERT KRULWICH: Does the treatment last?

MARTY RUSSELL: That's beautiful.

ROBERT KRULWICH: All these are big questions. Still, in mice, RNAi has been effective with Huntington's Disease, Lou Gehrig's disease, hepatitis, breast cancer.

"So," says Greg, "if we ever work this out in humans..."

GREGORY HANNON: Any sort of disease that you can imagine becomes fair game.

ROBERT KRULWICH: All the diseases which would be helped if you shut off a gene?

GREGORY HANNON: Cancer, HIV, for example...

ROBERT KRULWICH: Wait a minute. Are you ...is this because you're just an RNA buff that you're saying...you've just listed cancer and HIV. These are famous, big, fat diseases.

GREGORY HANNON: ...arthritis...

ROBERT KRULWICH: Well, stop listing them and tell me, is this a prejudice that you're telling me or is this true? I mean, these are all candidates for this kind of therapy?

GREGORY HANNON: Certainly they are.

ROBERT KRULWICH: And finally, we have saved the best for last. The true power of RNAi goes even deeper than finding cures to terrible diseases. Because what RNAi does...remember, the Cop's job is to turn off information, turn off genes.

ERIC LANDER: The big problem of understanding, say, the human genome is you have 20,000 genes. How in the world are you supposed to know what each one does? Well, one very good way to start would be to turn off gene number one and see what went wrong.

ROBERT KRULWICH: So you could go through all the genes that make up a human or, for that matter, make up a petunia, and turn off each gene one at a time. If you trick the Cop to turn off gene number one, no color.

So gene number one is involved in color production. Try gene number two, no petals—gene number two, involved with petals. And so on.

GREGORY HANNON: You could make too many leaves; they could curl up; they could be upside down. Almost anything could happen.

ROBERT KRULWICH: But getting rid of the gene tells you what the gene does when it's working?

GREGORY HANNON: That's right.

ERIC LANDER: The RNAi discovery is just amazing. Ten years ago, when we were sitting around talking about what we would really need to understand the human genome, we all said we would need some magic way that you could turn off any gene at will, just based on knowing it's sequence. And what's happened is this discovery by scientists about RNAi has given us exactly that. It turns out that nature already had a way to turn off any gene at will.

RNAi

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Image credit: (purple petunia) © WGBH/NOVA

Gregory Hannon

Cold Spring Harbor Laboratory

Richard Jorgensen

University of Arizona

Peter Kaiser

Cleveland Clinic Cole Eye Institute

Robert Krulwich

Host, Radiolab

Eric Lander

The Broad Institute www.broad.mit.edu/about/bios/bio-lander.html