This is a transcript of the Gastropod episode, What’s CRISPR Doing in Our Food?, first released on October 7. It is provided as a courtesy and may contain errors.
NEWSCASTER 1: Cue the worldwide CRISPR frenzy! At the University of California, scientists used a form of CRISPR to edit mosquitoes so they can’t transmit malaria. Their colleagues are modifying rice to better withstand floods and drought.
NEWSCASTER 2: Scientists say it could someday eliminate inherited diseases like some cancers, hemophilia, and sickle cell anemia.
NEWSCASTER 3: Researchers in Massachusetts have created piglets that might one day provide livers, hearts, and other organs for humans. They used a gene editing technology called CRISPR to remove viruses from pigs that could cause diseases in humans.
NEWSCASTER: This is CRISPR?
SCIENTIST: This has CRISPR in it.
NEWSCASTER: So this is what’s revolutionizing science and biomedicine?
CYNTHIA GRABER: Wow, listening to that, it seems like scientists have discovered something that is going to change basically everything.
NICOLA TWILLEY: If you’ve been following the news at all, this whole CRISPR thing gets waved around like it’s literally a magic wand. But we at Gastropod are always a little suspicious of magic, especially when it comes to science—so we decided to get to the bottom of it.
GRABER: And find out what CRISPR means for the future of food. That’s right, this is Gastropod, the podcast that looks at food through the lens of science and history, I’m Cynthia Graber—
TWILLEY: And I’m Nicola Twilley. And this episode we are talking about CRISPR. Which I will say has a nice name, I like crispy things in general. But isn’t CRISPR just genetic engineering, like GMOs, with a shiny new rebrand for today?
GRABER: Right. How is it different from or the same as what scientists have already done to genetically modify foods? What is CRISPR?
TWILLEY: And will it really change what we eat? Or are we eating CRISPRed foods already and we just don’t know it.
GRABER: Should we be worried or excited? We promise you, when it comes to CRISPR and food, we’ve got it. Plus, the secret CRISPR in your yogurt.
TWILLEY: The yogurt story is the CRISPR story you won’t have heard anywhere else. And it involves microbes, so, you know, DRINK!
GRABER: So you’ve probably figured out that CRISPR is a gene-editing tool, but we wanted to learn what it is, and how it was discovered. This might sound a little strange, but trust us—to learn about CRISPR, we drove out to DuPont’s dairy culture plant and we met with a yogurt scientist named Dennis Romero.
DENNIS ROMERO: Okay, we’re in Madison, Wisconsin. It’s a kind of a dreary-but-sunny, if that makes sense, day. Winter’s coming. Anyway, we’re on the southeast side of the city, kind of on the corner. This used to be all farmland in the day but the plant which is just across the street was put up in the late 1960s, to make starter cultures.
TWILLEY: “Winter is coming,” I understand, but I don’t remember dairy starter cultures from Game of Thrones.
GRABER: You listeners know that cheese and yogurt is basically milk that’s gone bad, but in a good way. Bacteria have had their way with it. But when I leave milk in the fridge and the bacteria get going, it smells and tastes pretty gross.
ROMERO: Dairy cultures than would be bacteria that were originally found in the milk and over the years were selected and chosen. because they didn’t turn the milk that kind of a kind of funny sour nasty-tasting mess that you’d find, but they actually turned it into something quite pleasant like cheese and yogurt.
GRABER: In the past, someone might have made this discovery and then saved a little bit of the good yogurt to make the next batch. You can still do this today—take some yogurt you like and use it to make more yogurt.
TWILLEY: I have done this, in my one-and-only moderately successful attempt to make yogurt at home.
GRABER: But this is not what industrial yogurt makers do. They buy a package of just the right freeze-dried microbes from a dairy culture company—and DuPont is one of the biggest dairy culture companies in the world.
ROMERO: This red pouch one is called Yomix. It’s used to make any of a number of yogurts. And you just sprinkle this into the cheese milk or the yogurt milk in this case, and stir, and off it goes. It looks like a like a package of instant oatmeal, that’s about the size. And think about several billion bacteria in there that could turn, you know, many, many gallons of milk into yogurt.
TWILLEY: Dennis and his colleagues at DuPont have isolated and catalogued all the strains of all the bacteria that you might want to use to make yogurt. They know which strains of bacteria are the ones that will give you that nice, sour tang, and which make your yogurt more creamy, and which can help make it thicker or thinner.
ROMERO: In this catalogue, we’ve characterized these strains for these properties. And we give these recommendations to our sales people who talk with our customers, the cheese makers and yogurt makers, knowing what the bacteria or the culture can do, then they can recommend a specific culture to them to make what they’re looking for.
GRABER: All these bacteria that Dennis studies and that DuPont sells—they’ve been carefully selected to also be super fast and super reliable. The customers can make the same texture and taste of yogurt each time. This means the dairy culture business is big business.
ROMERO: Oh, how big? I don’t have the exact numbers. That’s something that I have no idea. I mean it’s hundreds of millions of dollars worth—even more I guess.
TWILLEY: But sometimes something bad happens at the yogurt factory. The company is using the cultures it bought from DuPont, but their yogurt is just not coming out right.
ROMERO: On occasion it can be kind of chunky and grainy looking. That’s probably a bacteriophage that attacked the fermentation at some point in time.
GRABER: This is the nemesis of yogurt culture bacteria. Bacteriophage are usually just known as phage, and a phage is a tiny, tiny virus that attacks bacteria.
TWILLEY: You think microbes are small and everywhere, but phage are even smaller, and even more ubiquitous. There are more phage on earth than every other organism, including bacteria, put together. And phage cause a trillion, trillion infections in bacteria every second.
ROMERO: That’s the one thing that will disrupt the cheese maker or yogurt manufacturers’ process more than anything else. You know, if you ever catch the flu, you don’t feel too good. You’re kind of slow, you’re kind of sluggish. Well, the bacteria if they catch the flu, they can feel that way. Worse yet, they tend to explode. So, not a good thing.
TWILLEY: Sometimes my head feels like it’s going to explode when I catch the flu. But actually exploding is a whole other level of bad.
GRABER: Dennis took us into his lab and introduced us to Annie Millen, a scientist with his group, and she showed us a clear circle of agar gel on a petri plate. They’d grown yogurt bacteria on the gel, and then infected the bacteria with phage.
ANNIE MILLEN: This phage is pretty deadly. So on this one, there’s still the hazy bacterial lawn in the background. But there are really large circular zones of death where it’s just clear.That’s all where the bacteria has died, and it just looks like nothing. because there’s nothing there anymore.
ROMERO: Can you hear the bacteria? “Ahh, I’m popping, I’m bursting.”
GRABER: Obviously, it’s not a great thing when your yogurt-making bacteria explode, because they’re no longer making your yogurt.
TWILLEY: In the past, when a yogurt company would call Dennis and say “Oh no, our starter cultures aren’t working and the microbes are all exploding”—the first thing Dennis would suggest was that they clean the entire factory from top to bottom.
GRABER: Because Dennis wants the yogurt maker to try to get rid of the phage. Though of course that’s pretty tough given how tiny and plentiful they are.
TWILLEY: And then Dennis would give them a new set of cultures. But they weren’t the same strain—he’d deliberately give them different strains of bacteria that could make the same yogurt, but that might be tougher than the microbes that exploded.
ROMERO: One of the unique things about them is that they have different sensitivities to these bacteriophages. And just like human beings, you know, Nicky could catch the flu. But, Cynthia, you could be sitting right next to her but you’d be perfectly fine because you are immune to whatever she’s got. And the bacteria kind of behave the same way. The key point here is you have to find two strains that will do the same thing except for their sensitivity to a given bacteriophage.
GRABER: Okay. So this is what’s been going on for a really long time in the yogurt business. Phage kill your batch of yogurt, you buy a new strain of yogurt culture, and so on. But then, a few years ago, something really exciting happened.
ROMERO: For me, this is actually kind of an interesting story of how science actually happens. I mean it’s not something that you plan for, you know, and say today I’m going to discover CRISPR. I wish I could have said that but, no, that’s not really the way it happened
TWILLEY: The context here is that it was the early 2000s, and genetic sequencing had got faster and cheaper and so DuPont decided to sequence some of their key yogurt bacteria.
ROMERO: We were looking for a way to identify our different strains in a very quick and rapid way. Because, you know, they don’t sit there and go “Hi, I’m Bob,” ‘Hi, I’m Steve,” whatever. And so there’s a lot of work that has to go on to determine, yes, this is strain one, strain two, strain three.
GRABER: And in doing these genetic sequences to try to identify their dairy culture bacteria, Dennis and his colleagues noticed these kind of weird stretches of DNA, a whole bunch of them. Nobody really knew what they were, but they’d been observed before, and so people called them this complicated name: Clustered Regularly Interspaced Short Palindromic Repeats. CRISPR.
ROMERO: It was a very short repeated sequence, of the same sequence repeated over and over and over again, with something that was seemingly nonsensical stuck in the middle of each of these little repeats.
TWILLEY: Like everyone, Dennis and his colleagues had no idea what these nonsensical CRISPR sequences did. But they realized they might make for a good fingerprint.
ROMERO: So we started to sequence more of them and, oh, look, you know, there’s something interesting. There’s subtle differences between them. That little piece of nonsensical DNA—you can line these up, because some of the strains have the same ones. And then at some point they start having different ones.
GRABER: At the time Dennis and his colleagues had another research project going on. They were taking cultures of yogurt that had gotten sick from phage, and they’d see if any of the bacteria lived through the infection. And some always did.
TWILLEY: So they took a look at these survivors—the phage-resistant bacteria—and they noticed a difference in the CRISPR section of their genome.
ROMERO: On one end, the phage-resistant variant had a couple extra pieces inserted in there. And I think it was that moment where, like, for any scientist there was like the, “Aha!”
GRABER: The aha was the idea that this tiny bit of code, the part that they had no clue what it did—this might be the part that made the bacteria able to survive an attack from that particular phage.
ROMERO: And my first thought was, can it be that simple? Think about this bacteria having 2 million base pairs that tell it what to do how to live and how to work. That two little pieces of DNA, about 30 nucleotides or 30 letters stuck in the correct place, can actually confer the ability of this bacterium to resist a bacteriophage, so it lives.
TWILLEY: This is Dennis and his colleagues’ breakthrough. They are the ones who figured out that maybe these CRISPR sequences in bacteria that no one understands what they do—maybe they’re to do with immunity to phage.
GRABER: So then the first order of business to test this idea is to figure out where the sequences come from.
ROMERO: So when we took a look, the only difference that we could tell, at least from what we were looking at, was: the sequences in the CRISPR array came from the bacteriophage. Oh, that’s interesting.
TWILLEY: Those nonsensical repeats in the bacteria’s genome? They were little chunks of phage DNA.
GRABER: To test whether the phage DNA is what helps with immunity, they did an experiment to try to figure out if the bacteria that survive a phage attack have bits of code that match to that exact phage.
ROMERO: So it’s really, really simple. You take the bacteriophage, you mix it with the bacteria, and then you throw it on this agar nutrient plate and see what lives. And you take what lives. And we look at the CRISPR loci—and oh look, it’s got a couple, one or two extra spacers in it again. And you look at the spacers and they come from the bacteriophage. So now you have this—hey, the two are connected in some way shape or form.
GRABER: So basically, somehow, it seems like that tiny bit of phage DNA gets into the bacteria, and the bacteria then become immune to that phage.
TWILLEY: Which is extremely exciting. Dennis’s next experiment was designed to confirm that that is really what’s going with CRISPR. If he inserted a little piece of phage DNA—one of those little CRISPR sequences—into a yogurt-making bacteria that was not immune to that particular phage, would that bacteria become immune?
ROMERO: And surprise, surprise—well, maybe not a big surprise. Yes, it was. Oh, okay. So now it’s absolutely clear: without ever having seen the bacteriophage, we can provide this immunity, this resistance to it.
GRABER: The way that this happens out in the real world is: some of the yogurt-making bacteria survive a phage attack. And the ones that survive keep a little mug shot of the evil phage that tried to kill them. In this case, the mugshot is a snippet of phage DNA.
TWILLEY: The survivor bacteria hold onto this mugshot in case they ever meet that evil phage again. And they stick in their DNA, for safekeeping, right next to where they keep their phage-killing weaponry.
GRABER: And one of those weapons? It’s a tiny protein called Cas9—CRISPR-associated protein number 9. And what this tiny little protein does is it snips. It’s basically a pair of scissors that just slices straight through phage DNA.
TWILLEY: And when your DNA gets sliced, you don’t really work as well. In fact, you are often toast, especially if you are a phage.
GRABER: The whole system together is super cool: mugshot plus scissors equals immune system.
ROMERO: People have described the CRISPR array as being something like memory for the bacteria. And it really is because it’s a memory of what viruses, in this particular case, what phages that they’ve been exposed to. So that in the future should the daughter cells of that CRISPR-ized—that’s what we call it—bacterium meets that phage again, it knows what to do to protect itself.
TWILLEY: This system is actually found in a lot of bacteria, although not all. It’s not unique to dairy cultures though, but, because we love yogurt and cheese and the microbes that make them so much, that’s where we first noticed it
GRABER: Dennis had been looking for a way to fingerprint his bacteria strains, but this—this was something else altogether.
TWILLEY: This was transformational. Dennis could use this natural bacterial immune system, CRISPR, to cure his customer’s sick dairy cultures.
ROMERO: So, cool. This makes life easy for us. So we go through the process of vaccinating or immunizing the bacteria, and then putting them back out there in situations where we know there’s a bacteriophage present, and they perform perfectly fine. It makes life much more simple for us and we can go off and study other things. It sounds ridiculously simple when I put it that way, but that’s what it does.
TWILLEY: Within a year, Dennis and DuPont were immunizing all their starter cultures and selling these CRISPRized microbes to their customers.
ROMERO: Essentially, it’s pretty much just like the flu vaccine. You try to find the most prevalent ones that are impacting the industry at that time.
GRABER: And any time there’s a new phage that appears, they can add that mug shot to the bacteria’s collection, too.
ROMERO: So, in essence—we joke about this—but from the perspective of sensitivity to a bacteriophage, we can immortalize that particular strain.
TWILLEY: Dennis and his team just keep adding new mugshots.
ROMERO: There’s no limit that we found just yet to how many spacers it can acquire. So it just goes on and on and on.
TWILLEY: For the past fifteen years, almost all commercial, industrial-type yogurt—which is basically all the yogurt in the supermarket—has contained CRISPRized bacteria.
ROMERO: We tell this to people. You’ve been eating CRISPRized cultures forever—you just didn’t realize it.
TWILLEY: This is something you never hear in all the hype about CRISPR. We’re already eating it all the time, thanks to the microbes in our dairy.
GRABER: These CRISPRized cultures are totally standard in the dairy industry these days. The yogurt companies are thrilled, DuPont is thrilled, Dennis and his colleagues are thrilled. The yogurt is a better, more consistent texture, they don’t have to add any extra thickeners in case the microbes are falling down on the job, they don’t have to rotate strains of microbes, it’s great.
ROMERO: Yeah, you know, it’s a living system. And one’s ability to control it to some degree so that you get the same thing out every day is a big deal.
TWILLEY: A couple of key words here are ‘living system’ and ‘to some degree.’ We’re talking about biology, so, of course, it’s not 100 percent under human control and the same every time. For one, not all yogurt bacteria even have this kind of immune system, so they can’t be vaccinated against phage. Also, some phage can evolve to beat CRISPR or work around it. But, still.
GRABER: Yeah, still. It’s changed the yogurt business.
TWILLEY: And honestly, that’s kind of the least of it.
GRABER: Right, as you heard at the beginning of the show, CRISPR is actually changing the world. We asked Dennis if he and his colleagues had any idea when they discovered this system what other researchers might end up doing with it.
ROMERO: We joke amongst ourselves that one of the first exercises was we wrote down all these experiments and possible applications and things. And we really went to town with that. What could you imagine that this could be useful for?
TWILLEY: The way Dennis and his colleagues saw CRISPR was as a way to create immunity. So in their brainstorming session, they came up with lots of cool ideas—outside of the yogurt business—where immunity would be useful.
ROMERO: So one of the things I thought was really, really interesting and gratifying for me personally was we had written down: would this be something that could somehow be adapted to confer immunity to things like influenza or HIV?
TWILLEY: Scientists are currently doing exactly that—there’s brand new research using CRISPR as a tool to cure HIV and the early results seem promising.
GRABER: But the part Dennis and his team didn’t predict is that CRISPR would become a tool for editing nearly everything. And that’s exactly what’s happened.
ROMERO: I’m still kind of awestruck by it all because, at least for me, I just—I find this fun. And to be able to come across something like CRISPR-Cas and see the impact that it’s having on life and people in general? I sit there and I think about it and go, wow, I had something to do with that. I mean, how lucky can one be?
GRABER: That’s kind of every scientist’s dream, to see research they’ve been a part of having such a major impact.
TWILLEY: But all this came out of something super non-world-changing—yogurt. No offense to yogurt, which I love, but you know what I mean. So how did CRISPR make it out of the yogurt factory and into nearly every genetics lab in the world?
GRABER: That’s just what what we’re going to reveal next.
GRABER: To answer the question of how CRISPR became the hottest new thing in genetic engineering, we need to take a step back.
JENNIFER KUZMA: Right. Well, since about the mid-1980s, we’ve been genetically engineering plants.
TWILLEY: Jennifer Kuzma is a trained biochemist who co-directs the Genetic Engineering and Society Center at North Carolina State University. And she told us that back in the 80s, before CRISPR, scientists had a couple of ways to insert new genes into plants—but they had no control over where that new gene ended up in the plant genome.
KUZMA: Like, you take a gene from, for example, a fish—and it would land anywhere into the crop that you wanted to place it in, let’s say tomatoes.
GRABER: This very example that Jennifer is using, this is one of the most famous early examples of genetic engineering. The idea was that this cold-water fish called the winter flounder had an antifreeze gene that helped it survive icy temperatures, and this gene could help tomatoes survive frost.
TWILLEY: So scientists put the antifreeze gene in the tomato. And then a bunch of people freaked out about the resulting fish-tomato.
PROTEST CHANT ON NEWSREEL: Hey hey, ho ho, GMOs have got to go!
NEWSCASTER: These protesters want this grocery chain and others to stop carrying foods with genetically-modified ingredients.
PROTEST CHANT ON NEWSREEL: Careful what you put on your grocery shelf!
NEWSCASTER: This man’s costume is meant to illustrate genetically-altered fruit that’s been given fish genes to make it hardier in cold weather. They call it Frankenfood, and they say it’s bad for people, bad for the environment.
TWILLEY: As it turns out, the fish-tomato didn’t do so well in field trials either, so it never made it to market. But that didn’t stop companies from creating all sorts of other GMOs. You’ll maybe have heard of Golden Rice, the rice with extra vitamin A—that comes from scientists inserting a daffodil gene and a gene from a soil bacterium in ordinary rice. There’s also pink pineapples and faster-growing salmon and non-browning apples, all with genes borrowed from different species. You can’t buy all of these yet, but they’re all approved for sale, at least under U.S. regulations.
GRABER: But, really, until now, most of the research on genetically modified foods has been focused on making plants resistant to certain weed killers. That meant that farmers could use those herbicides in the field, the chemicals would kill all the unwelcome plants, but the crops would still be going strong because they were resistant to that weed killer. So you have GM herbicide resistant corn, wheat, soy—and these are all being sold and used today, and if you eat processed foods in America, you are eating these GM crops.
TWILLEY: That might come as a shock to you. Especially because there’s still a lot of public discussion about whether genetically modified crops are really safe—safe for the environment, safe for human health. In the European Union, they’re mostly banned.
KUZMA: Genetic engineering has a pretty rough history when it comes to foods and there’s been quite a bit of controversy over genetically modified foods and whether or not they should be labeled and people seeking to avoid them through buying organic or non-GM products.
GRABER: Proving something is safe in terms of our health is really hard, but so far none of the studies have shown that these GM crops are bad for us. Whether their main use—making crops resistant to weed killers—is an overall win for growers and for the environment or not, is definitely questionable.
TWILLEY: That’s been the story of genetically modified crops up till now. But today, GMOs are sort of old school. The cool kids are all using CRISPR to create new crops. It evolved in microbes, and Dennis and his colleagues still use it in yogurt cultures. But it turns out that, with a little bit of tweaking, the CRISPR-Cas9 system can be used in all sorts of living things.
GRABER: As Dennis explained, there are two parts to CRISPR. There’s a piece that slices, that’s Cas9, and then there’s a piece that recognizes phage DNA, that’s CRISPR. But imagine this—you could put a different piece of plant or animal genetic code instead of phage DNA next to those scissors. Now you can direct the scissors to cut a very precise piece of DNA in, say, a tomato.
YIPING QI: And then you allow the sort of error-prone DNA repair pathway to repair the broken DNA. The result in most cases is a gene knockout
GRABER: Yiping Qi is a genetics researcher at the University of Maryland.
TWILLEY: And this process Yiping’s describing, works like this: instead of hunting down phage and slicing them to death, this tweaked CRISPR-Cas9 system will hunt down the DNA sequence of your choice, and slice it. The sliced DNA tries to repair itself, but usually there’s a kind of scar, where it was sliced, and the gene at that point, where the scar is, doesn’t work anymore. And there you go. You’ve knocked out a gene from the tomato’s DNA—the exact gene you wanted to get rid of. And, unlike the old-school fish tomato style GMOs, you’re not adding any new genes.
GRABER: Dennis and his colleagues figured out how bacteria use this slicing system to kill phage in the mid-2000s, and they published papers on it in 2007. About five years later, two different groups of scientists both claimed to have been the ones to figure out how to use this CRISPR system to edit something other than yogurt-making bacteria—and they’re fighting about it in court. Because it seems so flexible and so useful in genetics and human health, and all of this promises to bring in so much money—it’s a huge patent battle.
TWILLEY: But what do we care about here at Gastropod? Obviously, our friends, family, world peace, but, you know, mostly food! And CRISPR is set to transform our crops, too.
QI: I mean that CRISPR has been really put in to many, many crops. Almost nearly all the crop plants which you can transform, such as the wheat, maize, and sugar cane, and tomato. Many, many—like even carrots, which I have worked with a collaborator.
GRABER: This is a different technique, and it’s being used in a different way.
KUZMA: With transgenic technology, it was very costly to bring a crop to market. Very costly to engineer it. With CRISPR technology, we’re seeing a wider variety of products. So not only, you know, your commodity crops like corn and soybeans and cotton but more minor vegetable and fruit crops.
TWILLEY: Including ones that are so minor that you may not have even heard of them. We’re talking about crops that don’t necessarily even make it to the store right now.
JOYCE VAN ECK: So they’re referred to as either underutilized or orphan crops.
TWILLEY: This is where we’re going next. To the crop orphanage, where some of the most minor fruits and vegetables of all are about to be rescued thanks to the magic of CRISPR!
VAN ECK: Yeah, these orphan crops out there, without anyone to care for them. LAUGHS
TWILLEY: And we’re going to visit the orphans with Joyce Van Eck. She’s a bio-engineer at Cornell.
GRABER: Though she’s laughing, Joyce does care about them. These crops are orphans because they’re not the type of plants we grow in a big monoculture. They’re tough to grow on a large scale, so they’re not traded internationally, and they don’t get a lot of research love.
TWILLEY: Joyce has picked out a particular orphan to adopt. It’s called the ground cherry, and it comes from the same family as peppers and tomatoes. It’s like the underachieving, less loved sibling.
VAN ECK: It’s this cute little yellow fruit that is surrounded by a husk. It’s kind of like, if you think of a little fruit in a balloon. And it’s related to tomatillos. If you’re familiar with tomatillo, it looks like a tomatillo. But it’s much smaller and it’s yellow. And it’s got—tomatillo is a tart flavor, but ground cherry has a sweeter flavor.
GRABER: When I had a ground cherry for the first time, about a decade ago, I totally freaked out in surprise and delight. They’re sweet and addictive, and I get so excited when I see them for a few weeks a year at the farmers market. But they’re expensive, and they’re not around for long. Because, like other orphan plants, they’re kind of a pain to grow.
VAN ECK: The plants are very… have this wild growth habit. They grow very large and they’re unmanageable. And also they’re called ground cherry because the fruit drops to the ground. Which you can imagine makes it very difficult for harvesting if you were, say, in a larger agricultural production setting.
TWILLEY: Funnily enough, ground cherry’s rockstar cousin, the tomato, also had many of these annoying characteristics back in the day. But over the course of time, humans bred those out.
GRABER: And then geneticists like Joyce figured out what genes in the tomato had changed over domestication to make the tomato more user-friendly. You know, the fruit grew more orderly on the vine, it didn’t drop on the ground, it was the right size.
VAN ECK: We decided to look for a plant species that was more distantly related from tomato but also was underutilized and had very little domestication or crop improvement effort. And that happened to be the ground cherry.
TWILLEY: Could Joyce and her colleagues use CRISPR to deliberately make a change in the ground cherry that had been just a lucky mutation that humans noticed and then kept breeding into the tomato?
GRABER: Take the out-of-control growth of the ground cherry. Joyce knew just what gene should in theory turn that off. When this gene is working, like in the ground cherry, plants just grow wild. But if that gene gets harmed when the CRISPR system slashes at it, then the plants should be much more compact.
TWILLEY: So Joyce built a little CRISPR set-up to target the ground cherry version of the gene that she knew turned off the wild growth in tomatoes. And she put that CRISPR system in some ground cherries. And, hey presto, her new look, CRISPRerized ground cherry was the opposite of its old, spidery, long-trailing self. The DNA that coded for that kind of unmanageable growth was gone, and so the plant now… self-prunes.
VAN ECK: Oh, it was—it was dramatic. It was a huge difference in what we were seeing. We went from plants that were, I’d say, five feet tall for the non-CRISPR, non-edited lines at maturity, to plants that were maybe two feet tall.
GRABER: Now, if plant breeders wanted to breed this type of self-pruning trait into a ground cherry the traditional way, they’d find a ground cherry plant that happened to be small and compact but maybe it didn’t taste as sweet, and they’d breed it with a sweeter one, and then grow the new plants out, then find out which offspring was both sweet and self-pruning, and they might have to do that a bunch of times.
TWILLEY: And if they were very, very, very lucky, they’d end up with a ground cherry that was everything they wanted. But they might retire first.
VAN ECK: Yeah. So it would take definitely more than 10 years to be able to do that type of work.
GRABER: But CRISPR is dramatically faster, and more targeted. It took Joyce and her colleagues only two years to get self-pruning ground cherries.
VAN ECK: So our work with the CRISPR is taking this angle where we’re using CRISPR to fast-track domestication, fast-track improvement.
GRABER: This was an amazing improvement, but it’s not enough yet. Joyce has spoken to local farmers around Cornell, and they say there’s a bunch of other changes that would help ground cherries go mainstream.
VAN ECK: We have a long wish list.
GRABER: It’s possible that for some of the items on Joyce’s wish list—things like fruit size, or whether the fruit drops on the ground before it ripens—if Joyce wants to change these, it might not be as easy as just targeting one gene. Genes often aren’t direct codes, one gene does one thing. It often takes multiple genes that work together to create something like drought-resistance or flavor.
TWILLEY: In its native bacteria, CRISPR usually goes after one thing at a time. But scientists have taken the CRISPR system and tweaked it so it can go find and slice multiple different things simultaneously. That means that Joyce could potentially design one CRISPR system that would target all the however many genes she needs to target in ground cherry to deal with its fruit drop problem.
GRABER: Or you could use CRISPR to target lots of different genes that change different traits all at the same time. This is a pretty new and super useful development— Yiping Qi has just successfully tried it in rice.
QI: We simultaneously targeted three genes and focusing on the trait which is about seeds. So we were able to enhance the number of seeds produced per plant and also how big the seed is, you know, per grain. So putting them together, sort of targeting them together, we were able to drastically enhance the yield.
TWILLEY: The main thing that makes CRISPR so useful for these kinds of edits is how precise it is. In a lot of crops, a piece of DNA that affects yield might be pretty tightly connected to, say, the DNA for a certain kind of disease resistance. In normal breeding, you can’t break that link—which means you can’t disconnect one trait from the other. But Jennifer says that CRISPR is kind of like a scalpel—it can get in there and separate even tightly connected genes.
KUZMA: With CRISPR, we can go in and we can make very precise, targeted changes at particular locations in the DNA. So it’s kind of like taking paper to pen like you would edit a book. You can go in and you can edit the letters in a word or you can change different phrases or you can edit whole paragraphs with CRISPR technology at very specific locations.
GRABER: We should say, none of these CRISPRed crops are available in stores yet, but some are pretty close. CRISPR is fast, it’s inexpensive, it’s precise, scientists love it, breeders love it. I mean, what’s not to love?
TWILLEY: I’m so glad you asked Cynthia, because I am falling head over heels for this CRISPR magic. But then, my cynical bitter side is saying—hey, there must be a downside. And my cynical bitter side will be right back to talk about that after we tell you about one more sponsor this episode.
GRABER: So—downsides. A couple of years ago, scientists were super excited about a gene-edited cow.
NEWSREEL: This is Brie. He might look like any other cow, but there’s one little thing about him that sets him apart from his breed. Brie has never grown a pair of horns. And that wasn’t a fluke of nature.
GRABER: Brie the cow wasn’t edited using CRISPR, but using a similar set of genetic scissors from bacteria. Scientists used these scissors to create a cow that wouldn’t grow any horns, so the animals couldn’t gore farmers or other animals.
TWILLEY: Normally, a cow’s horns have to be removed by hand, which some people say is painful for the animal. So this genetic edit was pretty cool. Except that it turned out that the edit was not quite as precise as the scientists had hoped.
GRABER: Two things happened. First, a bit of that foreign bacterial DNA was left in the animal—it was supposed to have been removed entirely.
TWILLEY: That’s a problem because now the hornless cow has got a little bit of alien DNA inserted in it. So rather than being one of these new school gene-edited organisms, it’s more like an old school GMO, like the fish tomato.
GRABER: And second, there was an accidental bit of DNA that also got inserted, and this one seems to have to do with antibiotic resistance. So like maybe if the animal got sick, antibiotics wouldn’t work as well. That’s pretty bad.
TWILLEY: So long story short, yes, these new gene editing techniques, including CRISPR, they are super precise, but they’re still not 100% precise. That antibiotic resistance—scientists call that kind of unwanted extra edit an “off-target effect.” Doing your edits with CRISPR should lead to way fewer off-target effects than the old-school, blast-your-gene-into-the-DNA method. But there could still be some.
GRABER: In plants, breeders and researchers like Joyce so far haven’t seen any major bad side effects from CRISPR. They are keeping an eye out, of course. And, of course, regulators are going to be asking questions about things like this before they approve any new crop for the market, right?
TWILLEY: You say “of course,” but, actually, Jennifer told us that that’s one of the things about CRISPR-edited crops. They’re not regulated like conventional GMOs.
GRABER: And this is where things get even weirder and more complicated. The Department of Agriculture, the USDA, has to approve crops grown in the field. And the way the regulations are written now, a crop is only considered genetically modified if it has foreign DNA in it. But it’s easy to use CRISPR to make a change and then get rid of it, so there’s no bacteria left.
KUZMA: And so therefore we have a couple dozen and probably more, approaching 30 to 40 now, crops that have not been regulated from a pre-market standpoint and didn’t have to undergo field trials by the United States Department of Agriculture.
TWILLEY: This is actually one of the things that scientists and start-ups love about CRISPR. Yes, they love how precise it is. But they also love the price tag. Because putting a GMO crop through field trials—that’s really, really expensive.
KUZMA: Some have estimated hundreds of millions of dollars to get a crop, a genetically engineered crop through the regulatory system. Now I don’t think it’s that high. But it is costly. At least a million, probably.
GRABER: Yes, CRISPR scientists love that regulatory loophole. But as it turns out, CRISPR can be used to insert a foreign gene, too, and it can do so a lot more precisely than genetic engineering systems did in the past. That’s something Yiping has been working on, but it’s not easy.
TWILLEY: In other words, Yiping thinks you could one day use CRISPR to put a fish gene in a tomato, and you could do it with great precision.
GRABER: But then it would be regulated the way the original fish tomato was, and, like we said, that cost a lot of money.
TWILLEY: But, for now, like Jennifer says, the USDA is not bothering itself with CRISPRed crops. Because they don’t have new DNA. But there’s a different agency in charge of approving whether that crop makes it to market as a human food. The Food and Drug Administration.
KUZMA: Now FDA does have a policy and it’s a voluntary policy—the Food and Drug Administration—to review these cops for food safety concerns.
GRABER: That voluntary policy just compares the CRISPRed food and makes sure that it’s substantially the same as the non-edited food. But again, voluntary.
TWILLEY: Jennifer says most companies seem to be going along with this voluntary check. And, in fact, to give credit where credit is due, it was the FDA that caught the problems with extra bacterial DNA in those hornless cows. The company wanted to send them out to the slaughter house to turn into hamburgers, and so the FDA took a look. They literally examined the genetic code of these new hornless cows, and they spotted the extra bits of DNA that weren’t supposed to be there, and they said, “Excuse me, we seem to have a problem here.”
GRABER: This is exactly what the FDA is looking for—these off-target effects, unexpected side-effects that might have come along with the intentional gene editing.
KUZMA: And so they do check for things like, is what you’re modifying going to cause more allergens in the food, or is it going to decrease the nutritional value of the food, or increase the toxicants in plants. Plants have a lot of toxic chemicals to ward off pests. And so whenever you make a genetic modification it can increase or decrease those toxins and the nutrients as well.
TWILLEY: So having the FDA check all that sounds like a good idea. But, Jennifer told us that what’s not happening is any ecological field testing for environmental effects—so like effects on pollinators or other plants. That kind of testing would be done by the USDA, and, like we said, they don’t screen these new crops unless they contain foreign DNA.
GRABER: This loophole seems like it could potentially be an issue—but, in a way, Jennifer says the loophole has been good for the field, because there’s been a lot more creativity. More scientists have been able to use CRISPR to see how it could help improve all sorts of crops, and not just the big money-making ones. They’re using it on orphans like ground cherries.
TWILLEY: And regionally important crops like cassava and millet that millions of people depend on in developing countries but that have never had the kind of investment that gets lavished on commodity crops like corn and wheat.
KUZMA: And you can do things that are better for the environment or better for health without having to really recoup your investment in the technology. So some people say it has a democratizing force on the technology, so that a wider variety of actors not only big industry are able to play in this space of CRISPR technology
GRABER: And because CRISPR is so fast, so inexpensive, and can target multiple regions of the genome, scientists are using it to try to make changes in response to the challenges that farmers are facing now, as the climate’s changing. They’re trying to do things like make plants more drought resistant, or capable of tolerating hotter temperatures.
QI: So I think CRISPR can sort of help us catch up climate change.
TWILLEY: This is not a super inspiring reason to love CRISPR—basically, everything is going to hell so fast the plants can’t keep up so we have to use CRISPR to help them evolve faster—but hey, that’s the boat we’re in these days.
GRABER: Another sucky thing that CRISPR might help with—nearly all the bananas that are grown commercially in the world are all the exact same variety, and they’re threatened by a banana fungus. Scientists are using CRISPR to try to help make our bananas resistant to that fungus. Again, crappy reason—can’t we just start eating different types of bananas? But CRISPR does seem to offer one potential solution, if it works.
TWILLEY: Maybe more excitingly, CRISPR can also help us move away from those kind of monocultures and that reliance on just a dozen major crops. That’s part of why Joyce is CRISPRing the ground cherry.
VAN ECK: So there’s a big emphasis right now especially on diversifying our diets. Eating more fruits and vegetables, you know. And is ground cherry going to be a huge production like tomato or corn? No, but again it does give us another option for not only fresh fruit but it can be used as dried and put in granola and cereals and jams and juices as well.
GRABER: But. But, but, but. It won’t surprise regular Gastropod listeners to know that CRISPR is not the solution to all our problems.
TWILLEY: We are not going to wake up tomorrow to a supermarket full of new and improved CRISPRized crops. For one, CRISPR works slightly differently in every different plant, and not all plants are super amenable to being CRISPRed. We’ll still need traditional breeding—CRISPR is not going to replace that.
GRABER: Plus, biology is super complicated. We haven’t sequenced the genomes of all the plants. And doing it at the level of detail you’d need for CRISPR takes a long time and is really expensive. And even if we have that, we don’t know what all the genes do. And even when we do think we know that, well, we’re often wrong. Biological systems are not like a computer code, where basically you write something and the computer responds the way you tell it to.
TWILLEY: Meanwhile, while we figure out the biology, we also need to figure out the policy side. There are a lot of things we could get right with CRISPR-edited crops that we got wrong with GMOs. Like clear and transparent labeling.
KUZMA: I think by putting these genetically engineered products on the market back in the mid-90s without people really being aware and without labeling them, I think people felt duped or tricked in a way in that, oh really? I’ve been eating these for 20 years and I don’t know?
GRABER: And so in order to change the conversation around these next-gen gene-edited foods, Jennifer thinks they should be labeled, too.
KUZMA: I mean, the way I view it is if you think this technology—which I used to be a plant bio-engineer—if you think it’s wonderful and it can do great things and you’re sure about its safety, then label it and be proud of it and show people what it can do for them. Show them how you can make tastier products or more nutritious products or healthier products or ones that are better for the environment, that use less pesticides or less fertilizer. Show them that and be proud of it and label it.
TWILLEY: Some of the scientists who work with CRISPR in crops share Jennifer’s opinion. And some are like, well, we don’t need to be labeled or regulated because this is so precise and nothing is a problem, and just leave us alone to work our magic. And to a large extent, they have a point—most CRISPRed crops seem just fine.
GRABER: But Jennifer thinks a little bit of caution and little bit more public discussion is a good thing. The plants seem fine, but they’re new—plus, Jennifer says that caution and discussion and transparency will help us all be more comfortable with using these technologies.
KUZMA: I know I tend to feel better knowing that somebody is looking out for me with consumer products, whether they be food or otherwise.
GRABER: Personally, I’m with Jennifer.
TWILLEY: It’s hard to predict how CRISPR might transform our food. Our yogurt has been CRISPERized for more than a decade and, in some ways, it seems like nothing has changed. But Dennis told us that in fact, CRISPRed bacteria are so reliable and high performing that yogurt companies don’t have to use additives to make sure they get the texture and creaminess they want. The microbes don’t need that back-up anymore, so those kinds of stabilizers and thickeners are being used less often.
GRABER: And so maybe if CRISPR can help Asian farmers produce more rice in their rice paddies, they’ll earn more money, which is great, and also maybe something else could happen—maybe they won’t have to convert more land to farmland, which could potentially be better for the environment. Dennis had no idea what was going to happen when they discovered how CRISPR worked in bacteria, and we don’t know where CRISPR is going to take us next.
TWILLEY: Cynthia, you asked at the beginning of the show whether we should be worried or excited about CRISPR in our food. And the answer is yes. Worried and excited.
GRABER: How about cautious and excited? That’s how I’m feeling.
TWILLEY: OK cautious, excited, and kind of amazed that I finally understand what all the hype is about.
GRABER: Thanks this episode to Dennis Romero and Annie Millen at DuPont.
TWILLEY: And to their former colleague Rodolphe Barrangou for originally telling me the CRISPR yogurt story back in 2014.
GRABER: Thanks also to Joyce Van Eck at the Boyce Thompson Institute, to Jennifer Kuzma at NC State, and to Yiping Qi at the University of Maryland—we have links to them and their work at gastropod.com. And I highly recommend you try a ground cherry if you’ve never had the pleasure.
TWILLEY: Finally, thanks to our fabulous former intern, Emily Pontecorvo, for finding some of the news footage we played during this episode. We miss you, Emily!
GRABER: We’ll be back in two weeks with something we’ve definitely earned this episode—a drink! But not just any drink. All I’ll say is three dots and a dash. Can you break the code?