Tucked into a suburban Long Island neighborhood, a 12-acre plot may be growing the future.

Under a blistering July sun, Zachary Lippman bends over a row of foot-high plum tomato plants to reveal budding yellow flowers that will each produce a tomato and ripen over the summer. Out here, on the grounds of a former dairy farm, it has all the appearance of age-old tradition.

But inside a nearby lab, Lippman advanced the selective breeding process with a little nip and tuck of the plant’s own DNA, and now the “edited” plant is about to bear fruit in the field.

“There’s a long way to go, but what we have able to do in the last four or five years is unbelievable,” says Lippman, a professor of genetics at Cold Spring Harbor Laboratory. “It’s science fiction.”

He created the plants using gene editing, a technology—based on a natural process—that allows researchers to cut out certain bits of DNA in order to control traits. The cell’s genetic structure then repairs itself automatically, minus the targeted gene. His tomatoes are now programmed to produce double the number of branches and, as a result, twice the tomatoes.

The Promise of Gene Editing

In medicine, gene editing could potentially cure inherited diseases, such as some forms of heart disease and cancer and a rare disorder that causes vision loss. In agriculture, the technique can create plants that not only produce higher yields, like Lippman’s tomatoes, but also ones that are more nutritious and more impervious to drought and pests, traits that may help crops endure more extreme weather patterns predicted in the coming years.



Today hundreds of research and development labs are at work testing the potential of Crispr—the technique’s acronym—to solve a range of food-related concerns for both consumers and growers: reduced-gluten wheat that could be tolerated by those with sensitivities, a mushroom that doesn’t brown when bruised or cut, soybeans lower in unhealthy fats, and even protecting the global chocolate supply—candymaker Mars is behind an effort to bolster cacao’s ability to fight off a virus that’s devastating the crop in West Africa.

What is Crispr? An alternative to transgenic engineering, Crispr is a gene-editing technique that’s applied to selective breeding. Scientists “edit” a plant’s genome to get desired traits. Here's how it works. Scientists first identify a gene responsible for a trait. Then they create a piece of RNA and an enzyme to target and “edit” the gene. The RNA, which mimics a strand of the targeted gene's DNA sequence, and a restriction enzyme (Cas9), which can sever DNA, are introduced into a cell. RNA guide “the tracking device” Cas9 “the genetic sicssors” DNA Targeted DNA sequence With its “guide” sequence, RNA locates and binds to its paired DNA sequence. The RNA also binds to the Cas9 enzyme, which cuts the DNA at the targeted location. Binding The Cas9 enzyme cuts across both strands of the DNA at the desired spot within the genome. Then a change, or mutation, is introduced. Cutting A trait can be added by removing the gene or introducing a variation. After the change, scientists rely on a cell’s own ability to repair its DNA sequence. Cell’s repairing enzyme Mutation Guide RNA and Cas9 are removed. The resulting plant can be crossed with the original one, and the DNA change passed on, the same as traditional breeding. Mutated plant Crispr is found in nature as a search-and- destroy METHOD used by bacteria to defend against invading viruses. GraphicS: ÁLVARO VALIÑO AND KELSEY Nowakowski. SOURCES: Shing F. Kwok, National Institute of Food and Agriculture, U.S. Department of Agriculture; Heike Sederoff, North Carolina State University What is Crispr? An alternative to transgenic engineering, Crispr is a gene-editing technique that’s applied to selective breeding. Scientists “edit” a plant’s genome to get desired traits. Here's how it works. Scientists first identify a gene responsible for a trait. Then they create a piece of RNA and an enzyme to target and “edit” the gene. The RNA, which mimics a strand of the targeted gene's DNA sequence, and a restriction enzyme (Cas9), which can sever DNA, are introduced into a cell. Cas9 “the genetic sicssors” RNA guide “the tracking device” Plant Cell DNA Targeted DNA sequence With its “guide” sequence, RNA locates and binds to its paired DNA sequence. The RNA also binds to the Cas9 enzyme, which cuts the DNA at the targeted location. The Cas9 enzyme cuts across both strands of the DNA at the desired spot within the genome. Then a change, or mutation, is introduced. Cutting Binding A trait can be added by removing the gene or introducing a variation. After the change, scientists rely on a cell’s own ability to repair its DNA sequence. Guide RNA and Cas9 are removed. The resulting plant can be crossed with the original one, and the DNA change passed on, the same as traditional breeding. Crispr is found in nature as a search-and- destroy METHOD used by bacteria to defend against invading viruses. Cell’s repairing enzyme Mutated plant Cell Mutation GraphicS: ÁLVARO VALIÑO AND KELSEY Nowakowski. SOURCES: Shing F. Kwok, National Institute of Food and Agriculture, U.S. Department of Agriculture; Heike Sederoff, North Carolina State University What is Crispr? An alternative to transgenic engineering, Crispr is a gene-editing technique that’s applied to selective breeding. Scientists “edit” a plant’s genome to get desired traits. Here's how it works. With its “guide” sequence, RNA locates and binds to its paired DNA sequence. The RNA also binds to the Cas9 enzyme, which cuts the DNA at the targeted location. Scientists first identify a gene responsible for a trait. Then they create a piece of RNA and an enzyme to target and “edit” the gene. The RNA, which mimics a strand of the targeted gene's DNA sequence, and a restriction enzyme (Cas9), which can sever DNA, are introduced into a cell. Binding Cas9 “the genetic sicssors” RNA guide “the tracking device” Plant Cell DNA Targeted DNA sequence A trait can be added by removing the gene or introducing a variation. After the change, scientists rely on a cell’s own ability to repair its DNA sequence. Guide RNA and Cas9 are removed. The resulting plant can be crossed with the original one, and the DNA change passed on, the same as traditional breeding. The Cas9 enzyme cuts across both strands of the DNA at the desired spot within the genome. Then a change, or mutation, is introduced. Crispr is found in nature as a search-and- destroy METHOD used by bacteria to defend against invading viruses. Cutting Cell’s repairing enzyme Mutated plant Cell Mutation GraphicS: ÁLVARO VALIÑO AND KELSEY Nowakowski. SOURCES: Shing F. Kwok, National Institute of Food and Agriculture, U.S. Department of Agriculture; Heike Sederoff, North Carolina State University

The first of these new gene-edited crops—canola—went on the market this year, with more coming in 2019. U.S. federal regulators say that because these plants do not contain foreign DNA—that is, DNA from viruses or bacteria, both used to create the first genetically-modified organisms, or GMOs—they don’t need the strict regulation and years of testing required for GMOs. On July 25, however, the European Union’s high court ruled for regulating gene-edited plants the same as GMOs.

Agricultural scientists have been improving plants through biotechnology for 25 years by transferring genes from one plant (or bacteria) species into another. These GMOs have allowed farmers to spray more herbicides without damaging their crops, or to create disease-resistant papayas in Hawaii, for example.

Even though science has not shown any human health effects of eating GMOs, they have been the target of consumer boycotts and tough government regulations throughout Europe and some U.S. states, spurred by distrust of the big corporations that create GMOs and the ramifications of mixing genes from two species.

But newer gene-editing tools such as Crispr (and there are others) achieve the same effects without transferring new genes from one organism to another. Gene editing is also simpler, cheaper, and faster than creating GMOs.

Because gene editing is relatively easy for those with proper training and basic lab facilities and not tightly controlled by a few companies, some experts say that it might allow developing nations to grow drought-free corn or nutrient-fortified vegetables without buying expensive seeds from large multinational firms. It’s also faster than growers methodically crossing generations of plant species to eventually get the desired trait—Crispr shaves years from that process.

‘An Ace Up Your Sleeve’

“This is about finding more efficient ways to improve crop productivity,” says Lippman, 45, who has been at the forefront of gene-editing research for the past decade.

For generations, commercial tomato breeders preferred fewer rather than too many branches, because the plant would fall under the weight of fruit or be unable to convert those extra flowers into fruits, compromising yields. “We had to find the sweet spot,” he says.

Crispr at Work: Boosting Everyday Foods In agricultural crops, such as these examples below, Crispr has the potential to impact yield, disease resistance, taste, and other traits. CHOCOLATE Scientists are working to boost the cacao plant’s immune system in order to resist to a virus ravaging West Africa’s crops. BANANAS Gene editing is being tested to produce a more resilient variety that can fight a deadly fungus attacking the global commercial supply. WINE Crispr may be a hedge against a powdery mildew that interferes with the sugar levels needed for wine-quality grapes. ZZZZZZ COFFEE To avoid the costly process of removing caffeine, which can also affect flavor, a bean variety has been edited to be naturally decaffeinated. RICE Researchers developed a variety that produces 25 to 30 percent more grain without compromising its tolerance to tough climate conditions. TOMATOES Geneticists identified 13 critical flavor notes in heirlooms. They may be added to modern varieties to increase flavor. CORN Scientists identified a gene in a native variety that produces more grain under drought conditions; it'll be added to modern varieties. MUSHROOMS Pennsylvania State University traced undesirable brown spots to a melanin gene; with a tweak, appearance and shelf life improved. WHEAT Scientists in Spain and the U.S. are modifying wheat to produce strains significantly lower in the gluten proteins that cause celiac disease. Crispr at Work: Boosting Everyday Foods In agricultural crops, such as these examples below, Crispr has the potential to impact yield, disease resistance, taste, and other traits. BANANAS Gene editing is being tested to produce a more resilient variety that can fight a deadly fungus attacking the global commercial supply. CHOCOLATE Scientists are working to boost the cacao plant’s immune system in order to resist to a virus ravaging West Africa’s crops. WINE Crispr may be a hedge against a powdery mildew that interferes with the sugar levels needed for wine-quality grapes. ZZZZZZ RICE Researchers developed a variety that produces 25 to 30 percent more grain without compromising its tolerance to tough climate conditions. COFFEE To avoid the costly process of removing caffeine, which can also affect flavor, a bean variety has been edited to be naturally decaffeinated. TOMATOES Geneticists identified 13 critical flavor notes in heirlooms. They may be added to modern varieties to increase flavor. CORN Scientists identified a gene in a native variety that produces more grain under drought conditions; it'll be added to modern varieties. WHEAT Scientists in Spain and the U.S. are modifying wheat to produce strains significantly lower in the gluten proteins that cause celiac disease. MUSHROOMS Pennsylvania State University traced undesirable brown spots to a melanin gene; with a tweak, appearance and shelf life improved. Crispr at Work: Boosting Everyday Foods In agricultural crops, such as these examples below, Crispr has the potential to impact yield, disease resistance, taste, and other traits. BANANAS Gene editing is being tested to produce a more resilient variety that can fight a deadly fungus attacking the global commercial supply. CHOCOLATE Scientists are working to boost the cacao plant’s immune system in order to resist to a virus ravaging West Africa’s crops. WINE Crispr may be a hedge against a powdery mildew that interferes with the sugar levels needed for wine-quality grapes. ZZZZZZ RICE Researchers developed a variety that produces 25 to 30 percent more grain without compromising its tolerance to tough climate conditions. COFFEE To avoid the costly process of removing caffeine, which can also affect flavor, a bean variety has been edited to be naturally decaffeinated. TOMATOES Geneticists identified 13 critical flavor notes in heirlooms. They may be added to modern varieties to increase flavor. CORN Scientists identified a gene in a native variety that produces more grain under drought conditions; it'll be added to modern varieties. WHEAT Scientists in Spain and the U.S. are modifying wheat to produce strains significantly lower in the gluten proteins that cause celiac disease. MUSHROOMS Pennsylvania State University traced undesirable brown spots to a melanin gene; with a tweak, appearance and shelf life improved.

After years of studying different genes, researchers were able to fine-tune branching by lowering the activity of certain genes, as well as making tomatoes easier to pick by ensuring that the green cap stays attached to the plant rather than the fruit.

“We are still working with everything that nature has provided. With traditional breeding, whatever traits nature has kicked out of the DNA, that’s the hand you have been played,” Lippman says. “With gene editing, now you are playing poker with aces up your sleeve.”

‘It’s Like Speeding on the Highway’

Still, not everyone is convinced that gene editing is an improvement over traditional breeding methods. Gene editing makes permanent changes in a plant’s genome that are passed on through seeds. Others say Crispr practitioners benefit from biotechnology regulations that haven’t kept pace with developments.

“This is the new kind of genetic engineering, whether you call it transgenic [GMO] or not,” says Jaydee Hanson, an analyst at the Center for Food Safety, a Washington, D.C.-based advocacy group. “It should be adequately regulated. We’re not saying it should be stopped—we should know what has been done.”

Yet proposed federal labeling rules exclude foods that use Crispr and other gene-editing techniques from those requirements since the mutations haven’t introduced bits of the so-called foreign DNA.

Experts in the field suggest that the ultimate success of gene editing will not be decided by scientists, entrepreneurs, or activists, but by shoppers and farmers.

One researcher says he could produce a tastier tomato through gene editing by increasing flavor-enhancing lycopene, but he’s holding back.

“I don’t want to be the first, but I’d like to be the second,” says Harry Klee of the University of Florida. “It’s like speeding on the highway.”

Klee has a good market for his seeds of traditionally cross-bred tomato varieties; he’s hesitant to introduce Crispr-edited ones because of the wild card of public reception.

Evolving With the Times

A few miles outside Clark, South Dakota, Jason McHenry and his father run a 1,500-acre farm, growing wheat, corn, soybeans, and livestock. About 20 years ago, the McHenrys planted genetically-modified corn and soybeans that resist pests like nematode worms and weeds, allowing them to use fewer chemicals.

“It simplified life and helped us get ahead of the weeds,” says McHenry, 33, a third-generation farmer. It also saved the operation money and boosted production.

Gene Editing Versus Genetically Modified Organisms Likened to accelerated breeding, Crispr’s relatively fast results and an open regulatory environment are driving scientific and commercial interest. • DNA origin and technique Transgenic Engineering (GMOs) A change is inserted at a random location in the genome, using genes from another species or synthetic genes. Crispr Gene Editing A change is made at a precise spot within a genome. Scientists remove or alter DNA native to the plant. • DETECTABLE Transgenic Engineering (GMOs) The transferred gene cannot be generated by breeding and makes the plant distinguishable from native plants. Crispr Gene Editing Plants created with this technique are practically indistinguishable from traditional selective breeds. • REGULATION Transgenic Engineering (GMOs) Regulation is rigorous; based on potential impact, the EPA, FDA, and USDA may all be involved to review dozens of studies and approve usage. $ $ Crispr Gene Editing Debate is ongoing. Current techniques that mimic natural processes are not subject to U.S. regulation; Europe's high court ruled for regulating them as GMOs. $ TIMING Research, development, and regulatory review Transgenesis (GMOs) 5 YEARS 10 Gene Editing (Crispr and other forms) 3 5 Traditional selective breeding, which crosses crops of the same or similar species to promote desirable traits, can take many years longer than designing GMO and gene-edited varieties. While both require years of research, development, and testing, agri-food created by Crispr requires less regulation than GMOs. Gene Editing Vs Genetically Modified Organisms Likened to accelerated breeding, Crispr’s relatively fast results and an open regulatory environment are driving scientific and commercial interest. Transgenic Engineering (GMOs) Crispr Gene Editing A change is made at a precise spot within a genome. Scientists remove or alter DNA native to the plant. A change is inserted at a random location in the genome, using genes from another species or synthetic genes. DNA origin and technique The transferred gene cannot be generated by breeding and makes the plant distinguishable from native plants. Plants created with this technique are practically indistinguishable from traditional selective breeds. Detectable $ $ $ Regulation is rigorous; based on potential impact, the EPA, FDA, and USDA may all be involved to review dozens of studies and approve usage. Debate is ongoing. Current techniques that mimic natural processes are not subject to U.S. regulation; Europe's high court ruled for regulating them as GMOs. Regulation TIMING Research, development, and regulatory review 5 YEARS 10 Transgenesis (GMOs) 3 5 Gene Editing (Crispr and other forms) Traditional selective breeding, which crosses crops of the same or similar species to promote desirable traits, can take many years longer than designing GMO and gene-edited varieties. While both require years of research, development, and testing, agri-food created by Crispr requires less regulation than GMOs. Gene Editing Versus Genetically Modified Organisms Likened to accelerated breeding, Crispr’s relatively fast results and an open regulatory environment are driving scientific and commercial interest. Transgenic Engineering (GMOs) Crispr Gene Editing A change is inserted at a random location in the genome, using genes from another species or synthetic genes. A change is made at a precise spot within a genome. Scientists remove or alter DNA native to the plant. DNA origin and technique The transferred gene cannot be generated by breeding and makes the plant distinguishable from native plants. Plants created with this technique are practically indistinguishable from traditional selective breeds. Detectable Regulation is rigorous; based on potential impact, the EPA, FDA, and USDA may all be involved to review dozens of studies and approve usage. Debate is ongoing. Current techniques that mimic natural processes are not subject to U.S. regulation; Europe's high court ruled for regulating them as GMOs. Regulation $ $ $ TIMING Research, development, and regulatory review Traditional selective breeding, which crosses crops of the same or similar species to promote desirable traits, can take many years longer than designing GMO and gene-edited varieties. While both require years of research, development, and testing, agri-food created by Crispr requires less regulation than GMOs. 5 YEARS 10 Transgenesis (GMOs) 3 5 Gene Editing (Crispr and other forms)

At the same time, he realizes that some consumers avoid GMOs, including his two sisters, who are raising families in the area. Soybeans have also been under pressure because soybean-based cooking oil is high in the trans fats that raise cholesterol levels and can contribute to heart disease. The FDA required food companies to remove them completely by June 2018.

But last year, at a meeting of South Dakota soybean producers, McHenry heard about a new kind of soybean plant that produces a healthier oil, high in oleic acid, found in olive oil and avocados.

The plant was created using Talen, another form of gene editing developed at the University of Minnesota and licensed by start-up biotech firm Calyxt. The soybean had changes in two genes involved in fatty-acid synthesis; the resulting oil has no trans fats and is suitable for cooking, frying, and baking.

McHenry and his father decided to plant 80 acres. “If we are going to make a healthier U.S., it has to start with us,” McHenry says. “My sisters lit up and said ‘this is what we need to do.’”

McHenry is now on his second crop. Calyxt provides the seeds and then buys back the soybeans after harvest. The company crushes them to extract the oil, while leftover “mush” gets fed to cows and pigs.

Market demand is also important to farmers like McHenry. “We started with one field and are just going to see how it works,” he says. “There’s no sense producing something if people don’t want it.”

Calyxt CEO Federico Tripodi says commercial food companies are evaluating the oil for cooking and as an ingredient in baked goods, nut butters, and vegetarian meat replacements. He hopes to have a buyer soon.

“In the U.S. there is widespread public distrust of GMOs,” Tripodi says. “In part this is due to a perception that these products are unnatural and developed for the benefit of large corporations, not consumers. At the same time, there are growing numbers of consumers with health-related fears, such as diabetes, obesity, and food allergies that directly impact their food choices.” In addition to its reduced-fat product, Calyxt is also developing a high-fiber, reduced-gluten wheat.

Exporting Knowledge

Plant geneticists are also hoping to bring gene editing to farmers in the developing world who lack resources and high-tech tools.

Samuel Acheampong grew up in a village outside Cape Coast, Ghana, where sweet potatoes are a staple. A graduate student at North Carolina State University, Acheampong is developing a bigger sweet potato using the Crispr technique.

Inside his laboratory at the sprawling campus in Raleigh, North Carolina, Acheampong explained how he mapped the genome of the American-bred variety of sweet potato he’s using in order to identify the location of a set of genes, called CWII, that regulate the flow of sugar from photosynthesis in the leaves to the roots and tubers.

By removing these inhibitors using Crispr, the plant can send more sugar to the roots. This extra sugar, he projects, will produce bigger sweet potatoes, his first goal.

While the molecular scissor-like Crispr process is fairly straightforward, identifying and sequencing the genes and analyzing their function can take several years, Acheampong says.

He’s started growing a few tiny sweet potato cells. The next step is performing the gene edit on the cells, turning the cells into plants, and then getting them big enough for the greenhouse and eventually field trials.

Acheampong is spending the summer collecting DNA samples from Ghana’s 50 sweet potato varieties. Once back to the lab, he’ll sequence their genomes to locate the CWII gene. In future experiments, he’ll use Crispr to shore up the plant’s resistance to several destructive viruses in Africa, along with boosting beta-carotene. Beta-carotene is a precursor for Vitamin A, which is needed to maintain the body’s immune system, particularly in pregnant women, children, and those who are HIV-positive.

“Vitamin A deficiency is a problem in Ghana. So you want to help to address this by improving the beta-carotene,” says Acheampong. “We can do this in two or three years. Whatever I learn here I’m taking back to Ghana.”

The Promise of Gene Editing The first successful application of Crispr came in 2013, and it's been driving buzz and investment ever since. It is currently the simplest, most accessible, and precise method of genetic manipulation. 462 Agri-food Case Studies Since CRISPR was first described in 2005, studies in scientific journals have risen sharply. 2 2005 2013 2017 Agri-food Patents 139 Crispr-linked development leaps with each year. 1 2013 2017 SOURCE: Nicholas Kalaitzandonakes, University of Missouri The Promise of Gene Editing The first successful application of Crispr came in 2013, and it's been driving buzz and investment ever since. It is currently the simplest, most accessible, and precise method of genetic manipulation. 462 Agri-food Patents 139 Agri-food Case Studies Crispr-linked development leaps with each year. Since CRISPR was first described in 2005, studies in scientific journals have risen sharply. 2 1 2005 2013 2017 2013 2017 SOURCE: Nicholas Kalaitzandonakes, University of Missouri The Promise of Gene Editing 139 Agri-food Case Studies 462 Agri-food Patents Crispr-linked development leaps with each year. Since CRISPR was first described in 2005, studies in scientific journals have risen sharply. The first successful application of Crispr came in 2013, and it's been driving buzz and investment ever since. It is currently the simplest, most accessible, and precise method of genetic manipulation. 2 1 2005 2013 2017 2013 2017 SOURCE: Nicholas Kalaitzandonakes, University of Missouri

‘Crispr has been democratized’

Fed by researchers like Acheampong, gene-editing technology is spreading rapidly from the U.S. and Europe to the developing world. One way to measure the rise of Crispr and other forms of gene-editing is by scientific publication.

From two dozen journal articles in all of 2008, Crispr-related scientific-paper submissions (for all applications, not just agri-food) now number 10 per day, and will shortly reach 10,000 total, according to Rodolphe Barrangou, a pioneer in the field and one of the discoverers of how bacteria use Crispr to fend off invading viruses. That finding led to applications in gene editing.

“Crispr has been democratized,” says Barrangou, who is editor in chief of the newly-established Crispr Journal and also oversees a multidisciplinary Crispr lab at NC State. “With 100,000 labs and 10 people per lab, we now may have over a million geneticists working with this technology.”

Barrangou started his career as a food scientist at DuPont. After he helped establish how Crispr works in nature in 2007, he used it to problem-solve in commercial yogurt and cheese starter cultures, where fermenting strains frequently get attacked by viruses. Today he and his lab are working to develop new probiotics that promote intestinal health.

Barrangou is naturally bullish on Crispr and its potential to both cure disease and help feed the world. Finding new ways to boost food production is essential, especially as climate change makes weather, water, and soil conditions more unpredictable. He’s also realistic that there are still a few bottlenecks to overcome.

“Academics are not going to feed the world,” says Barrangou in his campus office. “They are going to enable, with their scientific knowledge, people who can enable the world to feed itself. It’s the farmers who grow most of our foods, not the academics, and the farmers will get their seeds from seed companies.”

Slowly but surely, seed companies are tapping Crispr gene-editing for commercial crops destined to be ingredients derived from corn, wheat, flax, and canola. The next step will be foods like strawberries or tomatoes that consumers can actually touch and taste.

Bringing Work Home

For Zachary Lippman, the ultimate consumer litmus test was inside his own home: His wife, Shira, has reservations about eating food produced through biotechnology.

He’d scramble two tomatoes, one GMO and one non-GMO, behind his back and ask her to choose. Without knowing which was a GMO, she wouldn’t eat either one.

But over time, Lippman and his wife—and their six children—have chewed over the work he does. He says these family discussions have led to a better understanding of why people may have a hard time accepting gene-edited foods but also their benefits.

Now, when he plays the same guessing game using one of his gene-edited tomatoes, his wife has a different response.

“She’ll eat a tomato,” he said. The kids? None of them actually like tomatoes.