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In Hopes Of Fixing Faulty Genes, One Scientist Starts With The Basics

Jennifer Doudna and her colleagues found an enzyme in bacteria that makes editing DNA in animal cells much easier. (Cailey Cotner/UC Berkeley)

Whether they admit it or not, many (if not most) scientists secretly hope to get a call in October informing them they've won a Nobel Prize.

But I've talked to a lot of Nobel laureates, and they are unanimous on one point: None of them pursued a research topic with the intention of winning the prize.

That's certainly true for Jennifer Doudna. She hasn't won a Nobel Prize, but many are whispering that she's in line to win one for her work on something called CRISPR/Cas9 — a tool for editing genes.

The idea came when she and her colleagues at the University of California, Berkeley were in essence trying to figure out how bacteria fight the flu. The goal was really more of a basic science question, Doudna says.

It turns out bacteria don't like getting the flu any more than the rest of us do. Bacteria have special enzymes that can cut open the DNA of an invading virus and make a change in the DNA at the site of the cut — essentially killing the virus.

I thought, wow, if this could work in animal or plant cells, this could be a very, very useful and very powerful tool.
Jennifer Doudna

As Doudna was studying a group of these enzymes, she realized something. The enzymes had what amounted to a short template inside that could attach to a specific string of letters in the viral DNA. What if she could modify the template so that it could recognize any DNA sequence, not just the sequences in viruses?

"I thought, wow, if this could work in animal or plant cells, this could be a very, very useful and very powerful tool," she says.

What's more, with CRISPR/Cas9, you not only can recognize a viral sequence — you can modify it, too. "You can take it out, or you can change it, or you can add to it," says Doudna.

That's incredibly valuable, because it's been a frustrating time for biomedical researchers. The Human Genome Project gave them what amounts to the genetic book of life. The question is, what do you do with that information?

"You've got the book," says Doudna. "And you can see there's a word that's incorrect on page 147, but how do I get there and erase that word and fix it?"

Until now, the tools for fixing or replacing a gene in animals were cumbersome, if they worked at all. CRISPR/Cas9 changes that by allowing scientists to work inside cells, making changes in specific genes far faster — and for far less money — than ever before.

The implications for medicine could be enormous. Let's say two people who are each carriers of the cystic fibrosis gene want to have children but don't want to risk having a child with the disease. Doctors already can use IVF to create an embryo; one day they might also be able to use CRISPR/Cas9 to then fix the damaged gene.

It's also possible to imagine treating blood disorders, like sickle cell anemia, that are caused by a single gene.

"You can envision removing blood cells from a patient, doing the editing and putting those cells back into the patient," Doudna says.

In addition to the positive uses of CRISPR/Cas9, Doudna acknowledges there is a dark side. Genetically modifying human beings brings to mind images of Frankenstein monsters. And the technique could be used for trivial or even harmful uses.

"Once the discovery is made, it's out there," says Doudna. "Anybody with basic molecular biology training can use it for genome editing. That's a bit scary."

Her work with CRISPR/Cas9 comes at an interesting time for Doudna. Yes, she's had a successful career in research, but, as the years wore on, she'd started to have a nagging worry that her science wasn't solving any societal problem, wasn't making people's lives better.

Now, with this new tool, she thinks there's good likelihood that it will.

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Transcript

STEVE INSKEEP, HOST:

Researchers are asking if they can cure certain health problems simply by going to the genetic defects that caused them.

RACHEL MARTIN, HOST:

This is a goal of what's called personalized medicine. That means tailoring a treatment so precisely to you that if a single damaged gene causes you trouble, doctors could fix the gene. A scientist at the University of California in Berkeley developed a tool that may make that possible.

INSKEEP: We're going to hear about this from NPR science correspondent Joe Palca. He's been exploring the minds and motivations of scientists and inventors as part of his project Joe's Big Idea. And Joe, along with his producer, Rebecca Davis, went to visit this scientist Jennifer Doudna in Berkeley.

JOE PALCA, BYLINE: For the past couple years, I've been hearing about this new tool that scientists have gotten their hands on that's letting them do really interesting things with genes. And I wanted to meet the people who invented it, so I said, come on, Rebecca, let's go to Berkeley and visit Jennifer Doudna 'cause she's one of the inventors. And as we're walking across the campus to Doudna's office, Rebecca spotted something that seemed kind of oddly prophetic.

REBECCA DAVIS, BYLINE: Hey, Joe.

PALCA: What?

DAVIS: Parking spaces reserved for Nobel Laureates. It says Nobel Laureate Reserved Space. Parking permit required at all times.

PALCA: You see, Nobel Laureates get primo parking spots right next to their office. And the reason I thought this was prophetic is there's some people whispering that Doudna might be in line for a Nobel for this new tool she's invented.

DAVIS: Well, it's certainly made her a rock star in the science world. And if you remembered, Joe, when we got to her office, we realized we were lucky to get any time with her at all.

PALCA: Yeah, yeah. Just get a load of her schedule.

JENNIFER DOUDNA: I'm going to New York City for the Janssen Award ceremony. I'm going to Rockefeller University for a lecture. I'm going to the University of Edinburgh. I'm going to Heidelberg...

PALCA: What's Doudna done that makes her such a hot ticket? Well, actually she was working on a fairly esoteric subject - how bacteria fight off viral infections - when she stumbled across something that she wasn't expecting to find at all. And it's something that could really have a huge impact on biology. She realized that you could modify what bacteria do to viruses and instead use that to make specific change in the sequence of a specific gene.

DOUDNA: Yes, yes. You can take it out, or you can change it, or you can add to it.

DAVIS: She's talking about editing, right?

PALCA: Yeah, you can edit the genome. You can make changes. And the reason that's important is that this has been a kind of a frustrating time for geneticists because the Human Genome Project gave them lots of information about genes. It kind of gave them the book of life.

DOUDNA: The question is, what do you do with that information? You have the information. You've got the book, and you can see there's a word that's incorrect on page 147. But how do I get there and erase that word and fix it, replace it?

PALCA: And now you can.

DAVIS: And so what Jennifer and people like her are thinking is, aha, here's a tool that's going to allow us to really hammer at some really intractable problems with genetic diseases.

PALCA: Like, what about a family with a child with an inherited genetic disorder like cystic fibrosis?

DOUDNA: You could tell couples that you could repair that and repair it such that a child that, you know, otherwise would grow up having some very difficult-to-deal-with genetic disease could be cured.

PALCA: Or she said you could also do it for adult diseases, like let's say you have a blood disease like sickle cell anemia that's caused by a problem with a single gene.

DOUDNA: You can envision removing blood cells from a patient, doing the editing and then put those cells back into the patient.

PALCA: Now, really being able to fix people's genes using this tool, that's still a ways off. But Jennifer's really confident that it's going to happen.

PALCA: And even before coming up with this new gene-editing tool, Jennifer Doudna had a pretty stellar scientific career. But there's nothing about her early childhood that would even make you think she was going to be a scientist someday.

DAVIS: That's right. She was born in Washington, D.C. but moved to Hawaii when she was 7. And the move was a bit traumatic. Compared to the native Hawaiian girls, Jennifer really stuck out. And they didn't hesitate to let her know.

DOUDNA: They would say, oh, why is your nose so big, and why are your eyes blue, and why is your hair like it is? And, you know, I was also taller than most of the other students. So, you know, I just felt like, gee, I really must be some creature (laughter).

DAVIS: You're laughing about it now, but I can imagine as a child, that it would've had an effect of some sort?

DOUDNA: Well, it was incredibly - I mean, I just remember waking up every morning. I really couldn't eat. I had no appetite. I just had to face going to school, and I knew I was going to be in this sort of somewhat hostile environment all day. And so I just sort of felt pretty isolated.

DAVIS: So with all that time on her hands when she wasn't hanging out with friends, she actually started hanging out in libraries and reading books and books about science and nature and really kind of getting into it. But she never thought about being a scientist herself, until one day she met this woman.

DOUDNA: Beautiful, blonde hair, you know, very feminine woman who came to our high school. And she was a scientist working at the Cancer Center on Oahu, and she was talking about how cells go from being normal tissues to becoming cancerous. And I suddenly realized that's what I want to do. I want to be her.

PALCA: And in a way, she did become her. She didn't go into cancer research specifically, but she went into research about studying how cells work and how the stuff inside them works. But now she's added this new element - modifying how cells work by changing their genes. And there's a scary side to all this. I mean, after all, we're talking about tinkering with the very essence of life.

DAVIS: And that really resonated with me when we were out there in California actually because I was reading Mary Shelley's "Frankenstein," which is very much a tale of what happens when you tinker with the very essence of life. And in that case, it went horribly awry. But we talked to Jennifer about this darker side of the technology, and she admitted, yeah, she's thought about it, too.

DOUDNA: I have definitely had moments of thinking about, you know, you can't put the genie back in the bottle. Once the discovery is made, it's out there. And it's a technology that's easy enough to use that anybody with basic molecular biology training can use it for genome editing. It's a bit scary. You know, as time goes by, it's more and more clear how powerful a technology it really is. And so I've had moments of - I wouldn't say cold sweats, but (laughter), you know, waking up in the night thinking, wow, that's kind of profound.

PALCA: But it's profound in a way that anybody can grasp, and I was really struck by the way she described her son's reaction when she told him about it.

DAVIS: Andrew, that's right.

DOUDNA: Well, mom, does that mean that you could - could you actually change the genes in a cell? Could you change the DNA sequence in - could you change the DNA sequence in my cells? And then I realized, wow, he gets it.

DAVIS: Which really pleases Jennifer because she figures the more people get it and use it and work with it and think about it, the more really useful this new editing tool will become.

PALCA: And one other things I like about this story is how unexpected her discovery of this powerful new genome-editing tool was. I mean, there she was, studying how bacteria get the flu essentially. And while it was interesting and intellectually satisfying work, she started having this kind of uncomfortable nagging feeling like maybe her work was interesting, but maybe it wasn't really going to make a difference.

DOUDNA: And honestly more frequently and recently, as I've got a bit older, I guess, you know, and you start to - I don't know if it's middle-age crisis or what it is - but, you know, you start to think about, what's been the real impact of our work, right? Are we solving any problems in society? Are we doing work that's going to make people's lives better?

PALCA: And now with this new tool, she feels she is going to make people's lives better. And it all came about because she was studying how bacteria get the flu.

DOUDNA: For me, this just kind of really hammers home the serendipity of science.

PALCA: That's what I really like about this. This discovery of something that is really important, but it wasn't exactly what you were looking for.

INSKEEP: That's NPR science correspondent Joe Palca and producer Rebecca Davis. You can hear more stories in Joe's Big Idea series at npr.org. And if you know an interesting scientist you think Joe should speak with, send him a tweet @JoePalca that's P-A-L-C-A. Transcript provided by NPR, Copyright NPR.

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