What Is Gene Editing and Why It Goes Beyond GMOs

On an otherwise chilly April morning, Zachary Lippman, Ph.D., and I stood basking in the artificial heat and humidity of a greenhouse at Cold Spring Harbor Laboratory—the famous Long Island research facility that pioneered the discovery of DNA—and stared at the future of agriculture. It was a tomato plant, but it was unlike any that has ever existed. Where most are long and leggy, this one was short and bushy. Where most string out their fruit on individual stems, this boasted dense clusters of bright-red cherry tomatoes, like grapes on a vine. Lippman, a plant geneticist with a buzzcut, beard and an infectious enthusiasm for anything with leaves, created the plant using CRISPR, a new gene-editing technique that's revolutionizing plant breeding. And he believes this technology is at the forefront of a wave that—if consumers accept it—could make crops hardier, higher-yielding and more sustainable, plus make food that's more nutritious and delicious.

"Look at this cluster!" Lippman said, kneeling down to grab a handful of fruit. "This is an extreme example where we started with a cherry tomato that was very tall and made three gene edits." Tweaking the first two pieces of DNA made the plant short and prolific, and the third dramatically shrank the length of stem between each fruit, transforming the plant into a stubby, tomato-producing dynamo perfect for urban vertical farms, where crops are grown in a confined, indoor space. Vertical farming has several environmental benefits: it can reduce the food miles our produce travels (and the carbon footprint) and protect crops from weird weather like extreme storms or droughts (looking at you, climate change). It also requires a lot less land and resources than a traditional farm.

Breakthroughs like this tomato are the promise of CRISPR, which has been transforming the biological sciences—from medicine to agriculture—since arriving on the scene in 2012. CRISPR is a microscopic molecular tool that can be programmed to make precise changes to the DNA of any living thing. It is remarkably accurate and easy to use. (See "CRISPR: Explained," below.) The majority of earlier genetically modified crops (GMOs) involved shuttling entire genes between species and was so inexact that typical projects took years, but CRISPR and other gene-editing technologies can change individual letters of DNA in an existing organism, mimicking the kind of random mutations that breeders have historically depended on.

What really blew Lippman away is how fast it works. Where traditional breeders can require decades to make a new variety, patiently crossing and backcrossing different strains and hoping the right traits come together, he was able to take a cell from an old cherry tomato, change the traits he wanted using CRISPR, and grow new plants in a few months. (See "4 Ways New Crop Varieties Are Made," below.)

And even though one dwarf cherry tomato is not going to change the world, many experts believe that the kind of meticulous gene editing now possible will trigger a new green revolution in agriculture—and none too soon. Already, the world's farmers lose up to 25% of their harvest due to drought and heat stress. As climate change continues to sizzle, the number of crop failures will rise. But researchers like Lippman are beginning to design crops that can tolerate higher temps and produce more food using less water and fewer chemicals. And that could make the difference between a food-secure world and a much scarier one. In fact, a recent study published in the journal Transgenic Research found that the majority of the 114 experts surveyed (a mix of scientists, scholars, biotechnology pros and government officials) believe gene editing has the potential to improve crop yields, quality, climate resilience and global food security, and 68% agree it could help reduce agriculture's environmental footprint.

As I squatted to check out the shiny clusters of crimson fruit, I could feel the first churnings of a paradigm shift in my head. I'd always been skeptical of GMOs. But the more I spoke with Lippman and other plant people, and learned about techniques like CRISPR, the more I began to wonder if the old GMOs were just an awkward adolescent stage of the technology, and if this latest generation of plants might indeed make our food supply more sustainable, secure and delicious.

The Roots of Genetic Modification

Most people don't realize that ag giant Monsanto's embrace of genetic engineering in the 1970s and 1980s was supposed to help free farmers from their dependence on chemicals. The alarming hazards of DDT and other pesticides had become clear, and scientists at Monsanto began to experiment with ways to use genetics to incorporate natural forms of pest control into crops. Their first success was Bt corn and cotton, which contained a gene from a naturally occurring soil bacterium (Bacillus thuringiensis) that made the crops toxic to certain worms that infest them—but had no effect on other bugs or mammals. Bt crops reduced the amount of pesticides farmers had to use on these crops by up to 99%.

If Monsanto had continued down this path, the history of GMOs might have been very different. But instead, the company pivoted its focus to making crops resistant to Roundup, its blockbuster herbicide, by inserting a gene from another bacterium. Roundup Ready field corn (grown for livestock feed, ethanol and processed foods, as opposed to sweet corn) and soybeans were released in the 1990s. Farmers loved them. Instead of laborious and imprecise weed control, they could just spray their crops with glyphosate (the active chemical in Roundup) and kill them all. Today, most field corn and soy planted in North America is Roundup Ready, and global use of glyphosate has exploded.

Many consumers worry about the impact of all this herbicide residue on both their health and the environment, but there's another more fundamental concern. Taking a gene from an organism like a bacterium and transferring it to a wildly different one like a corn plant just seems creepy. Might there be unintended consequences to mixing genes in ways nature never would have allowed? Despite scientists' assurances that GMOs are safe to eat, many consumers want no part of them. That hasn't prevented GMO corn, soy and canola from taking over the food supply, where they are fairly invisible and eaten every day. Fruits and veggies, however, have remained largely untouched. It can cost hundreds of millions of dollars to develop a GMO and shepherd it through the steep regulatory hurdles the USDA imposes on transgenic crops. And considering the likely public backlash, few companies are willing to risk it.

But when Lippman read the first papers on CRISPR, he knew that crop breeding had changed forever. "I grabbed a sticky note and wrote 'promoter CRISPR' and stuck it to my desk. There were things that I'd always wanted to try, but I'd pushed them to the back of my mind because there were no tools to do them. As soon as the studies hit, those ideas—like promoter CRISPR—went right to the front. It's a wicked exciting time," he said as we examined dozens of gene-edited tomatoes in the Cold Spring Harbor greenhouse.

Every gene in plants and animals, he explained, comes with a piece of DNA called a promoter, which controls the energy of that gene. If the gene is the car, the promoter is the gas pedal. By using CRISPR to fiddle with promoters, Lippman could make any gene run fast, slow or not at all. It would be much easier to do, and importantly, there would be no foreign genes in the plant—because he'd be tweaking the tomato's own DNA. All these changes were things that might occur naturally if a breeder got very, very lucky. Lippman hoped this would make gene-edited crops less disquieting to consumers and federal regulators.

Last year, the USDA confirmed that it won't treat these crops any differently than traditional ones, stating that "USDA does not regulate or have any plans to regulate plants that could otherwise have been developed through traditional breeding techniques," because the agency considers these newly created plants "indistinguishable from those developed through traditional breeding methods." That hugely reduces the time and money required to bring a gene-edited food to market, making it viable for smaller specialty crops and independent companies—meaning we're going to see lots of them. Already in the works: disease-resistant cacao and bananas, caffeine-free coffee beans, flavor-boosted strawberries and tomatoes, nonbrowning mushrooms and apples, and many more. (See "Grocery Shopping Is About to Change," below.)

Some of the most promising gene-edited crops are coming from Calyxt, a Minnesota company that uses a technique similar to CRISPR, called TALEN. In February, the company began selling the first gene-edited food, a soybean oil called Calyno that's made from soy but has a fat profile similar to olive oil. Other crops in development at Calyxt include a higher-fiber wheat, alfalfa that livestock can more easily digest (resulting in lower methane emissions), a canola oil with an even-healthier fat composition and a potato that can better withstand cold storage.

But will people eat them? Many consumers and advocacy groups remain deeply suspicious of gene editing. In a 2018 Pew Research Center survey, 59% of respondents said they believe GM foods will lead to health problems and 56% deemed them bad for the environment. (Although 76% said they could increase the global food supply.) Leading the anti-CRISPR fight on the nonprofit side is Friends of the Earth, which published a report in 2018 titled Gene-Edited Organisms in Agriculture: Risks and Unexpected Consequences. As co-author of the report Dana Perls explained, "New genetic engineering techniques like gene editing are risky ... [and these] new GMOs must be properly assessed for health and environmental impacts before they enter the market and our food system." Among the concerns the report details is that CRISPR may create unintended genetic changes or errors, or alter important genes in a way that has safety implications for human health and the environment.

Are they really fundamentally dicier than traditionally bred crops, though? Not necessarily. As Lippman pointed out to me, the type of changes CRISPR makes are exactly what's been happening in our crops for thousands of years, resulting in bigger fruits or seeds, better yields and more predictable growth. Mutations happen every time an organism reproduces: of the billions of letters of DNA in its genome, thousands get miscopied and occasionally something amazing results. That's what drives evolution. So worrying about a single edited gene, Lippman said, makes no sense. "It's one mutation in a sea of ones that already exist. Every plant you eat contains thousands of new mutations," he shrugged. "How do you feel?"

Megan J. Palmer, Ph.D., a senior research scholar at Stanford's Center for International Security and Cooperation, who is an expert on assessing the dangers of new technologies, agreed. "Risk is relative," she told me. "We tend to underestimate the risks of familiar technologies and over estimate the risks of new ones. Traditional breeding can introduce more random mutations than gene editing does." Palmer said we also need to consider the changing context in which we assess new techniques: "We know that we're going to be confronted with all sorts of risks in the future, such as those accompanying climate change. If these technologies might help to manage them, that's an important consideration."

Beyond Tomatoes and Mushrooms

No matter how many experts affirm the safety of gene-edited foods, for consumers the creep-factor looms. That's why the most promising engineered organism in agriculture might be one that people don't have to eat at all. It's a microbe called Proven, and it's what North Dakota farmer Chad Rubbelke treated his wheat seeds with before planting them this spring.

Rubbelke farms 3,000 acres of durum wheat, soybeans, sunflowers, canola and flax on land that goes back in his family for generations. But he's part of a new wave of young, environmentally conscious, tech-savvy farmers who are shaking things up in the Midwest, and he thinks Proven can greatly reduce the use of nitrogen fertilizer, which is one of agriculture's biggest environmental problems.

Nitrogen is essential for plant growth, and our fast-growing crops require an intense supply of it. But only about half of the 120 million metric tons of fertilizer applied each year actually make it into crops. "Getting nitrogen into the ground is probably the biggest headache a farmer has," said Rubbelke. "It's expensive. And to get it on at the right stage is next to impossible." If conditions are too wet, it runs off into rivers, where it causes dead zones that choke the life out of the seas they empty into. If conditions are too dry, it vaporizes into the air and becomes a major greenhouse gas. By EPA estimates, fertilizer application produces 74% of all U.S. emissions of nitrous oxide—a particularly noxious form of greenhouse gas (it's 300 times more potent than carbon dioxide). Forgoing that fertilizer, however, is not currently an option; without it, we'd only produce half as much food, and 3 billion people worldwide could go hungry.

Proven may change that. In the fluorescent-lit grow room of a Berkeley, California, startup called Pivot Bio, I examined dozens of corn and soybean plants in sand-filled boxes. Living symbiotically on their roots were Proven microbes (which had been applied to the seeds). They have been designed to continuously pull nitrogen from the air—something most plants are incapable of doing on their own—and spoon-feed it directly to the plants' roots. In the natural world, some microbes do this in modest amounts, but gene editing has kicked the process up several notches. As the plants grow, the microbes colonize and provide a steady diet of nitrogen without losing any to the water or air. And while Proven can't make enough nitrogen to completely replace the use of fertilizer, its impact could still be huge.

That got Chad Rubbelke's attention. "I was sold! Something that's non-chemical and can help the environment could be a big player on our farm," he said. "If we can use a microbial to get the nitrogen bump when we need it without having to apply it ourselves, it could relieve 50% of our fertilizer needs." That, in turn, would significantly reduce nitrogen runoff and greenhouse gas emissions. By midsummer, he'd already seen results in his wheat crops too. "When we took samples, every single one showed a noticeable difference from the untreated wheat," said Rubbelke. "The Proven wheat was noticeably taller and had a larger root mass. It was exciting and I hope these results lead to greater yield in the end."

Research Pivot Bio has conducted suggests that if a third of America's corn farmers adopted Proven, it would be the greenhouse-gas equivalent of taking nearly 1.5 million cars off the road and could prevent 500,000 metric tons of nitrates from leaching into waterways. When I sat down with Pivot Bio CEO Karsten Temme, Ph.D., at a conference table near the grow rooms, he told me so far, so good: "In 2018, we tested Proven with a few dozen farmers. We said, 'Try our product and see what you think.' Every single one of them has already signed up to be a commercial customer this year. We were blown away." The company could only produce enough Proven to supply a few hundred growers in 2019, but with investors such as Bill Gates' Breakthrough Energy Ventures backing it, Temme expects to expand to thousands in 2020.

Pivot Bio has numerous competitors in the field of engineered "biologicals"— microbes and enzymes that bolster plants in various ways. While several are trying to crack the fertilizer problem, others aim to help plants tolerate stress from heat or drought. "Microbes are like an extension of the plant's immune system," Temme explained. "They can help it withstand climate change and make the whole ag system more resilient and sustainable." Other biologicals are being designed to fight weeds. And when that happens, Rubbelke said, he'll be first in line: "We don't like using herbicides as much as you guys don't like hearing about them!"

Toward a More Diverse Food System

As excited as Lippman gets about the new tomatoes he's making, the thing that excites him most about CRISPR isn't tomatoes at all. "Come look at this," he said, leading me to another part of the greenhouse where a scraggly hedge dominated one wall. "You're looking at the wild ancestor of tomatoes. In its native environment of Central and South America, the tomato is not an annual. It's a tall, bushy, woody perennial." He lifted a leaf to reveal a tiny green nubbin. "See this little fruit right here? It's not going to get bigger than a tiny marble."

Over thousands of years, growers were able to increase the size of the tomato by continuously selecting plants with mutations that made larger fruits—but right up until the 1920s, most tomatoes were sprawling. Then a Florida farmer discovered a plant with a freak mutation that made it compact and densely fruited, and it engendered the modern tomato industry. Suddenly they could be grown as row crops and easily harvested. Most commercial varieties are descended from that original plant.

And that's how it is for most of our food crops, Lippman told me. Each depended on rare mutations to turn them into something that could be farmed. "Of the hundreds of thousands of plant species, tens of thousands are edible," he said. "We probably eat a few hundred." In other words, for every tomato or artichoke that became domesticated, another 500 edible wild fruits and vegetables didn't. And for every useful gene we've drafted into agriculture, another 500 are sitting on the sidelines. Who knows what fresh ways to address drought, heat, disease, pests, nutrition, flavor and other future challenges might be found in all that accumulated natural wisdom?

"We're opening up these reservoirs of genetic diversity in nature!" Lippman exclaimed, hustling me across the greenhouse to look at two sprawling shrubs. "I think there's real potential to make this a major berry crop." Dangling beneath the leaves of one plant were papery lanterns, each holding a single, small fruit. They were groundcherries, tasty wild plants that naturally produce just one fruit per branch. "I love the flavor of these things," Lippman said. "But they're the worst producers imaginable and they take forever to fruit. It's a nightmare. But we can make them more compact, flower faster and have more concentrated fruit."

Sure, it's just a groundcherry (OK, maybe a delicious groundcherry), but if CRISPR can put them in the supermarket at a decent price, who knows what else it might add to our repertoire?

Lippman picked a groundcherry, peeled back the lantern, and handed it to me. "Smell it. They're so good. All those pineapple and vanilla scents." Standing there in that glassed-in garden, I held the fruit up to my nose and debated whether to take a bite. It smelled strange but alluring, new and yet deeply familiar, like something from our primeval past. I was all in.

CRISPR: Explained

CRISPR is the catchy acronym for a decidedly uncatchy term: Clustered Regularly Interspaced Short Palindromic Repeats. In 2012, a team of scientists at the University of California, Berkeley, led by Jennifer Doudna, Ph.D., a professor of chemistry and molecular and cell biology, discovered how to use CRISPR to make targeted gene edits in virtually any organism. The gene editing works on animals too. Researchers have big plans for hornless cows (which wouldn't have to undergo painful and labor-intensive dehorning), chickens that are immune to bird flu, and pigs that don't get porcine reproductive and respiratory syndrome (which costs American farmers billions of dollars per year). Unlike plants, the FDA does regulate gene editing in animals—it currently applies the same rules as it does for GMOs—making it too expensive and time-consuming to bring most of them to market. Here's a more detailed look at how the technology works to edit genes.

1. Scientists identify the gene for a trait they want to edit.

2. They then design a strand of guide RNA (a molecule that can locate and read the genetic information contained in DNA) to match the exact sequence of DNA in that gene. An enzyme—typically one called Cas9—that acts as a kind of molecular scissors, is attached to the RNA.

3. The CRISPR construct is added to a test tube or petri dish along with the cell to be edited.

4. The guide RNA searches the cell's genome until it finds the matching sequence of DNA—sort of like picking a suspect out from a (very large) police lineup—then locks on.

5. The Cas9 "scissors" then snip the DNA at that exact point. If scientists simply want to disable the gene, that's enough. But they can also make an edit by adding a new piece of DNA with the sequence of a new trait they want.

6. Cells have natural repair enzymes that stitch broken DNA strands back together. If a new piece of DNA has been added, it will be stitched into the gap, changing the gene.

7. As the cells reproduce, they will all have the new DNA and express the desired trait.

4 Ways New Crop Varieties Are Made

How gene editing is different from GMO and other plant-breeding methods

TRADITIONAL BREEDING

First employed: Since humans began cultivating plants (around 23,000 years ago).

How it works: Breeders cross-pollinate two varieties of the same species. The resulting seeds have a mix of genes from the two parents, along with normal random mutations. Breeders grow them and select the plants with the most desirable traits. This method also includes hybrids, which began in the 1920s: two completely different plants are crossbred to produce offspring that have traits from both parents, such as crossing a lemon with a mandarin orange to make a Meyer lemon. (Heirlooms, on the other hand, are propagated through open pollination—letting plants go to seed and then saving and replanting those seeds. Occasionally, natural mutations occur and farmers select for the traits they like and grow those new varieties.)

Number of genes affected: A few genes to entire genomes.

Federal regulation: None.

Used on: Almost everything we eat.

MUTAGENESIS

First employed: 1950s

How it works: Seeds are exposed to radiation and/or chemicals to produce mutations in their genes, then germinated. Breeders select the most interesting results (which are unpredictable) and crossbreed them with existing varieties.

Number of genes affected: Hundreds to thousands.

Federal regulation: None.

Used on: Many common foods, such as red grapefruit, rice, cacao, barley, wheat, pears, peas, peanuts and peppermint.

GENETIC MODIFICATION (aka GMO, or transgenics)

First employed: 1980s

How it works: Genetic engineers isolate an entire gene from one species and insert it into an entirely different species.

Number of genes affected: One to eight.

Federal regulation: High

Used on: Crops such as field corn, soybeans, canola, eggplant and papaya.

GENE EDITING

First employed: 2010s

How it works: Genetic engineers use CRISPR or other molecular tools to make specific changes in the DNA of individual plant cells.

Number of genes affected: One or more.

Federal regulation: None

Used on: About 25 foods so far, including rice, corn, wheat, citrus, potatoes and coffee.

Grocery Shopping Is About to Change

These are Some gene-edited foods you could see over the next few years:

Disease-Resistant Bananas

Why: To protect Cavendish, the main commercial banana variety, from devastation by diseases, including one caused by a fungus called Fusarium.

Drought-Tolerant Soybeans

Why: To maintain global food production during hotter, drier summers.

Compact, High-Yield Tomatoes

Why: To advance vertical farming and reduce land requirements on traditional farms, increase yield, reduce food miles, improve drought tolerance.

Bigger, Hardier Sweet Potatoes

Why: To improve food security in Africa. The sweet potatoes will also have boosted levels of beta carotene to treat vitamin A deficiency.

High-Yield Rice

Why: To improve food security in Asia.

Disease-Resistant Cacao

Why: To knock out a gene, making the plant immune to a pathogen that currently destroys 20-30% of cacao pods annually.

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ROWAN JACOBSEN is the author of several books, including American Terroir. He received a James Beard Award for his EatingWell feature "Or Not to Bee."