Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing

CHAPTER 21 FARM AID

In the late 1990s, Mark Lynas was a proud environmental activist, a member of a group called Earth First! that would frequently lay waste to fields of genetically modified (GM) crops with machetes in the middle of the night. In 1998, Lynas devised a plan that, if successful, would have made him a household name. Hatched in secret for fear of being bugged, Lynas and his fellow hoodlums decided to kidnap Dolly the sheep.

Created by a Scottish team at the Roslin Institute led by Keith Campbell and Sir Ian Wilmut, the lamb formerly known as 6LL3, cloned from an ovine mammary gland cell, was born in July 1996. Affectionately renamed by a technician, Dolly lived at the Institute just outside Edinburgh. Her birth was kept secret until the results were published to worldwide acclaim and angst six months later. Posing as a researcher, Lynas was granted access to the Institute’s library, before hunting for the shed holding the world’s most famous sheep. Meanwhile, a female accomplice posed as a lost American tourist outside the institute’s perimeter. The audacious plan might have worked, except that Dolly’s whereabouts weren’t signposted. Nor was it immediately obvious how to tell Dolly apart from the hundreds of other sheep in the facility. “The Roslin scientists had outfoxed us by hiding Dolly in plain sight,” Lynas later confessed.¹

Several years after his Scottish caper, Lynas had an epiphany. The more he researched the science underlying genetically modified organisms (GMOs) and climate change for books such as Six Degrees, the more he realized his blinded ignorance. Indeed, the evidence overwhelmingly supports the safety of GMOs. In 2016, the National Academies of Science, Engineering and Medicine published a major report concluding that GMOs did not harm animals nor cause any health problems in humans in the food supply.² A group of more than one hundred Nobel laureates called on Greenpeace to end its opposition to GMOs.³

Lynas admitted his own mistakes during a keynote speech in 2013 at a major farming conference before a shocked audience.⁴ He apologized for ripping up GM crops and helping to demonize a technology with profound environmental benefits. He was immediately accused of being a Monsanto shill and worse. A journalist meeting the reformed Lynas at his home near Oxford remarked that the former ecowarrior was handsome and vaguely fashionable, in the manner of a member of Coldplay whose name you can’t quite remember.⁵

Many scientists believe the biggest impact of CRISPR will come not in pharma but in farming. “The most profound thing we’ll see in terms of CRISPR’s effects on people’s everyday lives will be in the agricultural sector,” predicts Doudna.⁶ “The CRISPR craze has pretty much swept through plant biology,” agrees Dan Voytas, a professor at the University of Minnesota and cofounder of Calyxt.⁷ In 2017, state-owned ChemChina bought Syngenta, one of the top three agbiotech companies along with Germany’s Bayer and Corteva, for $43 billion. China is undertaking a massive effort to improve the quality of many key crops using CRISPR.⁸

Indeed, some commentators have been stressing this point since the birth of the CRISPR revolution in 2012-13. While most of the fanfare centered on CRISPR’s potential for treating human disease, some commentators, including British author and politician Matt Ridley, were struck by the implications for crops. Ten thousand years ago, farmers in what is now Turkey used cross-breeding to select a random mutation in wheat plants in the Q gene on chromosome 5A, which rendered the seed head less brittle and the seed husks easier to harvest efficiently.⁹

In 1798, English political economist Thomas Malthus published a famous treatise in which he showed that human population growth was outstripping the increase in agricultural productivity. The growing competition for resources leads inevitably to a Malthusian collapse caused by war, famine, or pestilence. In her book The Age of Living Machines, MIT president emerita Susan Hockfield argues that Malthus was wrong because of the repeated invention of new technologies that have increased agricultural productivity. One example was the introduction of four-field crop rotation, which succeeded (you guessed it) three-field crop rotation in the 18th century. Another is the extraordinary story of William Vogt and guano.

Vogt was an ecologist, ornithologist, and environmentalist, profiled in Charles Mann’s book The Wizard and the Prophet.¹⁰ Vogt (the prophet) discovered a natural resource—mountains of guano, or bird excrement, as birds roosted on the Chincha Islands off the coast of Peru. The nitrogen-rich guano was used for fertilizer, providing a large portion of Peru’s national income. In 1948, Vogt wrote about the earth’s “carrying capacity” caused by fundamental ecological processes that set limits on what we can do—or as Mann calls it, the first “we’re going to hell” book. After studying the cormorants and the weather patterns, Vogt concluded it was not possible to obtain more guano, “to augment the increment of excrement.” But as Hockfield points out, the export of guano to Great Britain caused another surge in agricultural productivity.

The wizard adversary to Vogt’s prophet was plant geneticist Norman Borlaug, the father of the Green Revolution. In the mid-1950s, Borlaug, an expert at interspecies hybridization, developed semi-dwarf wheat, which probably saved millions of lives after it was introduced to India in 1962, earning him a Nobel Prize. It now makes up 99 percent of all wheat planted around the world.

To speed up the generation of mutations, Lewis Stadler reported the first use of radiation mutagenesis to create novel mutations in plants in 1928. Half a century ago, scientists used a nuclear reactor to shoot gamma rays at barley seeds, inducing a plethora of random mutations in the DNA. One result was “Golden Promise,” a high-yielding, low-sodium barley variety popular with (ironically) organic farmers and brewers.

In the late 1970s, Mary-Dell Chilton, a researcher at Washington University in St. Louis, discovered that crown gall disease, a plant tumor, was caused by a bacterium called Agrobacterium inserting a sliver of its own DNA into the plant. That prompted the idea that the same bacterium could be used like a gene therapy vector to shuttle desired genes into plants. In January 1983, along with two other researchers, Chilton gave a talk at the annual Miami Winter Symposium, that she called “the symbolic coming of age of genetic engineering.”¹¹ Indeed, Chilton is recognized as a pioneer of agricultural biotechnology and crop improvement. The method wasn’t called gene editing, but some did label it gene jockeying. Genes can also be introduced more directly, literally shooting them into plants as DNA-coated tungsten or gold particles with a gene gun.

Two decades ago, scientists at Syngenta inserted gene sequences from maize, encoding four enzymes into rice plants so that they could synthesize vitamin A, thereby creating transgenic “golden” rice. In Bangladesh, about one in five children are vitamin A–deficient. After interminable delays, the Bangladesh authorities are close to approving Golden Rice.

Anti-GMO activists may be aghast to learn that many of their favorite all-natural foods were in fact genetically modified by nature centuries or millennia ago. In 2015, scientists stumbled upon the fact that every domesticated breed of sweet potato contains DNA from the Agrobacterium. “All the sweet potatoes we eat are GMOs,” says Johns Hopkins’ professor Steven Salzberg.¹² To that list, we can add bananas, cranberries, peanuts, walnuts, and two of my favorite beverages—tea and beer (hops).

To develop the new technologies that will feed almost 10 billion by 2050, not just accounting for our ballooning population but helping crops survive a changing climate, Hockfield says we’re going to have to invent our way out.¹³ CRISPR gave agricultural scientists a new razor-sharp tool in their gene-editing toolbox to complement if not supersede ZFNs and TALENs. The technology can prevent mushrooms browning, produce strawberries with a longer shelf life, and tomatoes that stay longer on the vine. Bing Yang’s group at Iowa State University has engineered promoter mutations to generate resistance to bacterial blight in rice.¹⁴ But for all the progress being made in Iowa cornfields, New York greenhouses, and Beijing rice paddies, scientists must also hope for some natural variation in the minds of regulators and politicians, especially in Europe.

For a serendipitous heirloom of our ability to engineer desirable traits in plants, exhibit A comes the Italian Renaissance artist Giovanni Stanchi. A Stanchi masterpiece from the mid-1600s depicts a selection of fruits—peaches, pears, and a watermelon cut open revealing contents that are almost unrecognizable. The flesh is mostly white, with pale red swirls and dark black seeds. It bears almost no resemblance to the succulent red flesh (the placenta) of the modern domesticated watermelon, as breeders selected for the lycopene-rich flesh.¹⁵

Go back even further to a few thousand years ago, the small fruit from southern Africa would have to be cracked open with a stone. A mere six varieties begat some 1,200 today. But humankind has been doing this since the dawn of agriculture almost 10,000 years ago. The domestication of maize from teosinte in Central America began when farmers in what is now Mexico practiced selective breeding. Corn today looks nothing like the “natural” crop. Nor do peaches or tomatoes or many other common fruits and vegetables.

But selective breeding only goes so far. “Nature hasn’t given us enough mutations,” says Zach Lippman, a leading plant geneticist at Cold Spring Harbor Laboratory (and an HHMI investigator). Lippman has had a peculiar fascination with tomatoes since he worked on a Connecticut farm as a teenager. Few consumers relish the anemic tomatoes typically available in the local supermarket. Lippman believes gene editing can lead to big improvements.

In 1923, researchers reported a natural mutation in a farmer’s field in Florida. Randomly, a rare mutant tomato plant had developed the property of self-pruning. Crossing these plants was predicted to give rise to “a valuable new race of early tomatoes.” These compact “determinate” varieties grow three to four months until they mature and ripen. A busy determinate tomato plant can give rise to twenty pounds of fruit and is the preferred plant for ketchup and paste production.

Tomato plants are grown in long rows, collected when they turn a greenish-orange hue, and then hauled into storage until they are gassed with ethylene to start the ripening process. But as Lippman says, nature hasn’t given farmers enough mutations to play with, at least not on a practical timescale. Additional mutations could relieve compact growth to make plants a bit larger, thereby increasing fruit yield. Before CRISPR, Lippman had to treat seeds with chemicals that randomly mutagenize the DNA and then manually search for desirable mutations by scouring row after row of tomatoes. He spent four years compiling a toolkit of new mutations, where several mutations worked collectively to build a higher-yield tomato plant. There had to be an easier way.

CRISPR technology is not about introducing foreign DNA, but working with the plant’s own DNA and enhancing natural repair processes. For example, a desirable trait in tomatoes is called jointless, in which the stem leading to the fruit lacks a knuckle or joint. Fresh market tomatoes crossbred with the jointless trait enables high-throughput production and less damage during handling. Lippman’s group used CRISPR to engineer a jointless line of tomatoes without having to cross different strains, and can apply this to any variety.¹⁶ His lab has also introduced mutations in the promoter of the self-pruning (SP) gene to create a sort of genetic rheostat, tuning the degree of inactivation to help growers adapt tomatoes to more northern latitudes with longer days but shorter growing seasons.¹⁷

Another fruit of interest is the humble groundcherry (also known as a strawberry tomato). A native plant of Central America, the groundcherry is an orphan crop that never made it in the agricultural major leagues. It’s drought-resistant and has a “tropically intoxicating” flavor, Lippman says, but they have long branches and the fruit are fussy to grow. Using CRISPR, Lippman seeks to shortcut thousands of years of selective breeding by introducing several gene edits, influencing traits such as plant size and architecture, fruit size, and flower production.¹⁸ Green groundcherries are naturally the size of marbles, but disrupting the CLAVATA1 gene produces fruit that are 25 percent larger. Moreover, modifying the groundcherry counterpart to the SP gene produces more compact plants that are easier to harvest.¹⁹

CRISPR edits are not GMOs. Whereas CRISPR cuts the genome in a precise spot, it is the cell’s natural DNA repair process that stitches the ends back together. The resulting mutation is no different than what might arise using chemical mutagens or X-rays or occur naturally. That is the enlightened verdict of the U.S. Department of Agriculture (USDA), which decided to treat CRISPR edits no differently than other methods of mutagenesis.

But the Europeans disagreed. In 2018, the European Court of Justice (ECJ) ruled that gene-edited crops do fall under GMO guidelines. Criticism rained down from all quarters: “illogical,” “absurd,” and “catastrophic” were representative reviews. Lynas said the ruling was “like saying doctors can use [a] blunderbuss but not [a] scalpel.” Placing CRISPR and GMOs in the same bucket was like “the Catholic Church classifying ducks as fish,” lamented Ewan Birney, a prominent British geneticist. Clive Brown, the chief technology officer of Oxford Nanopore, fumed: “If only these twits”—the ECJ—“realized that all of their beloved vegetables and most farm animals are hideous mutants.” And British Conservative MP Owen Paterson said the European Union was condemning itself to become “the world museum of farming.”²⁰

In China, genome-edited crops are currently regulated as GMOs, but discussions with the Chinese government will likely turn things around. “We are hoping for a better solution than in Europe,” says Gao Caixia, a plant biologist at the Chinese Academy of Sciences in Beijing.²¹

We have a global food problem. Worldwide, says Mick Watson, a geneticist at the Roslin Institute, there are about a billion people in the world who are obese and a billion people who are hungry. “This should be a problem that’s pretty easy to solve, by taking the food away from the obese people.”²² Watson’s facetious sense of humor may not be to everyone’s taste but it does not diminish a serious message. The growing world population means that over the next fifty years, the world’s farmers will have to produce more food than in the past 10,000 years combined. This has ramifications for the CRISPR craze, too. Imagine if we were able to cure all diseases, using CRISPR and other medical innovations. Watson says we wouldn’t all live forever—we’d die of starvation.

The commercial potential of genome editing in the plant world has not been lost on the CRISPR community. With few exceptions, fruit and vegetable consumption in the United States has not improved in fifty years. There are some interesting exceptions, which have nothing to do with biotechnology. Introduced in 1986, the baby carrot has led to a dramatic increase in carrot consumption—3.8 billion pounds of the vegetable per year. In 2008, improvements in farming enabled blueberries to be delivered across the country year-round, resulting in a doubling of annual consumption to 600 million tons.

In 2017, Feng Zhang, David Liu, and Keith Joung, three cofounders of Editas, decided to get the band back together to apply their genome-editing prowess to plants. Pairwise Plants secured a five-year deal with Bayer, owner of Monsanto, to develop improved row crops and boost farm productivity, aiming to make foods that are more affordable, convenient, and sustainable.

Gene editing does not introduce a foreign gene, as happens in GMOs—but introduces a specific change to the DNA, usually to a sequence that already exists in nature. Besides speed and specificity, gene editing offers another benefit. Traditional selection leads to a loss of genetic diversity as lines are crossed and back-crossed. Gene editing can introduce traits without backcrossing, preserving or reintroducing lost variation. Early studies have used CRISPR-Cas12a to cut genes in corn and soybeans.

Gene-edited plant products made a high-temperature, low-key debut in the United States in March 2019, as the donut-frying oil at the Minnesota State Fair. Calyxt, a subsidiary of the French biotech company Cellectis, introduced Calyno, a gene-edited high oleic soybean oil. The oil has zero trans fats and 20 percent less saturated fat than its counterpart. Ironically, most of the soybean oil produced in the US is genetically modified, but Calyxt thinks Calyno—modified using TALENs rather than CRISPR—will prove a healthy, more neutrally flavored alternative to olive oil.

Calyxt says its gene-editing approach will give the American people “healthier food ingredients without compromising the taste of what they already love.” For cofounder Voytas, that means a household staple: “We’d like a piece of Wonder Bread to meet all your daily requirements of fiber.”²³ Thanks to the USDA regulations, Calyno proudly sports a “non-GMO” label, which doesn’t sit well with environmental groups that refuse to recognize the distinction between genome editing and transgenic modification. Calyxt’s edited soybean plants in South Dakota and Corteva’s “waxy” high-starch corn in Iowa—destined for emulsifiers and glue sticks—are just the first seedlings in a forest of gene-edited crops and foods destined for consumers and livestock, from wheat and potatoes to alfalfa plants.

In China, much of Gao Caixia’s efforts are on improving wheat, which imposes an extra two degrees of difficulty. The wheat genome is three times larger than the human genome and even larger than corn, soybean, or rice. Moreover, the wheat genome is hexaploid, meaning it has not one pair of chromosomes (a diploid genome) but three pairs. This extra redundancy means gene editors have to work three times as hard to target a particular gene. But Gao’s team has engineered wheat lines that are resistant to powdery mildew²⁴ and herbicide resistance by inactivating the acetolactate synthase gene.²⁵ She’s also engineering tomatoes like Lippman to change the plant’s architecture, flowering time, and vitamin C content.

Many genome-editing applications are designed to help farmers increase the yield of their crops. But in some alarming cases, genome editing is the key to the species’ very survival. Take orange growers in Florida, the world’s second biggest producer behind only Brazil. They have seasonal challenges to overcome: arctic air plunges courtesy of the polar vortex, Atlantic hurricanes tearing up orchards, not to mention political headwinds impacting migrant workers. But the biggest threat is from an invisible source that was only first noticed in the Sunshine State in 2005.

The fruits that supply your freshly squeezed morning orange juice were first cultivated in China some 4,000 years ago, and imported to Europe about five hundred years ago. But a bacterial disease called huanglongbing (HLB), also known as yellow dragon disease or citrus greening disease,^I has decimated the citrus industry in Florida and may do the same in California. It is caused by a bacterium called Candidatus Liberibacter asiaticus (CLas). The bacteria are spread by an insect, the Asian citrus psyllid, which feasts on phloem the way mosquitoes gorge on blood.

HLB causes the roots of infected trees to swell and then shrink, depriving the plant of water and nutrients. Meanwhile, the leaves producing sugars via photosynthesis can’t transfer them to the rest of the plant because the phloem is blocked. It’s like being starved and constipated at the same time.²⁶ The affected oranges are green, misshapen, and sour, unsuitable for consumption or even concentrate. “It’s like AIDS but in citrus,” is a common saying in Florida farming circles.²⁷

First detected in southern China about one hundred years ago, HLB probably arrived in the United States surreptitiously in the 1990s. Research is hampered by the difficulty in culturing CLas in the laboratory. The economic damage in China, South America, and now Florida is reaching pandemic proportions, with orange groves and fruit production dropping 20–30 percent in the past decade. Tens of millions of trees have been lost worldwide; tens of thousands of jobs and some $5 billion in Florida alone are at risk.

Traditional weapons are ineffective. The insect that carries HLB is hardy with a range that can evade pesticide sprays. Antibiotics are of limited value, as spraying is unable to reach the bacteria hovelling deep inside the orange trees. Many farmers resort to spraying a chemotherapy cocktail of herbicides, pesticides, and fertilizer to combat HLB and citrus canker.

Until recently, it didn’t appear that orange trees or any other cultivated citrus crops possessed any natural immunity. Hope grew a few years ago in the form of the Sugar Belle, a cross between a sweet clementine and the Minneola tangelo that is naturally resistant to CLas, growing more phloem to counteract the infection. Another idea is phage therapy, genetically arming a virus that, like CLas, naturally infects the phloem. And then there’s CRISPR:²⁸ one idea is to pump up the promoter that governs activity of a family of plant protease genes to combat the bacteria. But there are challenges in editing polyploid plant species like citrus.²⁹ The clock is ticking in Southern California as HLB threatens commercial groves.³⁰

Southern Gardens Citrus, a subsidiary of U.S. Sugar, is spending millions of dollars on transgenic oranges in a bid to save the entire orange business facing collapse. “We are science geeks,” the firm declares proudly on its website. Obviously claims of “100 percent natural” won’t fly with the insertion of a transgene. “People are either going to drink transgenic orange juice or they’re going to drink apple juice,” is how one scientist puts it.³¹

One strategy is to create a “transgenic tree”—a more hostile environment for the bacteria or the insect. Botanist Erik Mirkov has considered scorpion venom, beetle toxin, even a pig gene. But you don’t need a PhD to realize that consumers would prefer not to have their orange juice spiked with sarcophagus beetle toxin DNA.³² The most palatable prospect is an antibacterial gene derived from spinach that encodes a defensin, a hole-puncher protein that punctures the CLas outer membrane. If Southern Gardens can navigate the approval processes, commercial transgenic trees could be planted soon.^II

In 1923, Eddie Cantor had a No. 1 hit record with, “Yes! We Have No Bananas,” written by Frank Silver and Irving Cohn. Silver based the song on a lament he heard from a Greek vegetable stand proprietor on Long Island. Back then, the tasty variety of banana on sale was known as Gros Michel. But in the early 1900s, plantations in Central and South America were attacked by a fungus called Panama disease. By the 1950s, the Gros Michel had vanished from fruit stands. The fungus, which invades the plants via the roots, is almost impossible to eradicate from contaminated soil. In 2009, author Dan Koeppel, who literally wrote the book on bananas, was in the Democratic Republic of Congo, when he chanced upon someone ferrying bananas across a river. To his astonishment, he recognized them as the vanishingly rare Gros Michels. He peeled back the thick skin and savored his first bite as if sampling a vintage Château Margaux. His verdict was robust, creamy, with notes of… “It tastes more like a banana,” he said approvingly.³³

The banana industry was saved from collapse by the Cavendish variety, derived from plants grown in the 1830s at Chatsworth House, an English stately home. The Cavendish is an inferior fruit in most respects but became a commercial mainstay thanks to its resistance to the Panamanian fungus. Or at least it was before “bananageddon.” We can’t say we weren’t warned.

The Cavendish is a monoculture, incapable of evolving because every fruit is a genetic clone. The Panamanian fungus, however, is under no such constraint, and a new strain called Fusarium TR4 (or Tropical Race Four) identified the Cavendish’s Achilles’ heel. TR4 arose in Taiwan in the 1980s, spread to Australia, and in 2014 jumped to Africa and the Middle East. Five years later, in August 2019, the Colombian Ministry of Agriculture declared a national emergency as TR4 struck in South America, the source of three quarters of the world’s banana exports.³⁴

There are more than a thousand varieties of banana, but whether consumers, who eat one hundred billion bananas a year, will accept a substitute that doesn’t look like a traditional banana is a big question. Maybe they would prefer a fruit that has been genetically modified? A British company, Tropic Biosciences, is using CRISPR to reprogram some of the plant’s own RNA interference defenses to target the fungus.³⁵ The company is also engineering coffee plants that will be genetically depleted of caffeine.

The threats to oranges and bananas illustrate the dilemma that all farmers and agricultural biotech business are now confronting: how to reassure the public that genetically modified, potentially gene-edited, fruits and crops are safe in an age of misinformation, fake news, and a legacy of anti-GMO disinformation. Some manufacturers have brazenly capitalized on this fear and ignorance by slapping “non-GMO” labels on all sorts of foods and fruits—even those that by definition cannot be genetically modified. Take water—an oxygen atom sandwiched between two hydrogen atoms—or salt, the simple union of sodium and chloride ions. These are two of the most natural, ancient compounds on earth. They couldn’t be genetically modified if you tried.

Klaas Martens, an organic farming luminary in New York State, is a long-standing opponent of GMOs and the uses of genetic engineering technology such as Roundup for a manageable problem. “When the only tool you have is a hammer, everything turns into a nail,” Martens says. But he sees CRISPR as a promising tool that could in some instances be compatible with organic agriculture if it could enhance the natural system.³⁶

In Africa and Asia, climate change, disease, and political turmoil pose grave threats to agriculture. The picture in Africa is decidedly mixed. The country furthest along is South Africa, which has been growing GMO maize for a long time. Ruramiso Mashumba, a farmer from Zimbabwe, says there is no other option for his colleagues than genome editing. The effects of climate change, pests, and disease mean farming is not feasible. “The only option is to improve cultivars we have to sustain farming,” he says. “At the end of the day, food is key.”³⁷

A good example is work on cassava, or yuca, a staple tuber crop for some 800 million people across Africa, Asia, and Latin America because its roots are rich in carbohydrates. But this hardy plant also produces a toxin—a chemical related to cyanide—that if insufficiently processed can cause konzo, a motor neuron disease leading to paralysis. CRISPR offers a means to remove the cyanogens by inactivating the genes encoding a pair of enzymes in the cyanogen biosynthetic pathway. Regenerating whole plants harboring these two dormant genes could eliminate konzo. Researchers are also using CRISPR to engineer resistance to the RNA virus that causes cassava brown streak disease.³⁸ There have been some promising early results, but the virus’s capacity to evolve will not make things easy.

Many African nations don’t see anything special in CRISPR. In 2012, Kenya summarily banned the import of GMO foods,³⁹ triggered by the publication of a controversial study by French biologist Gilles-Éric Séralini. Feeding rats a GM maize produced by Monsanto, the French group sensationally reported large tumors in rats.⁴⁰ A companion documentary directed by Jean-Paul Jaud called Tous Cobayes? (All of Us Guinea Pigs Now?) railed at the health risks posed by GM crops and nuclear accidents, raising the unthinkable possibility that a Fukushima-style explosion would not only result in millions of evacuations but also, worse, vineyards in Bordeaux contaminated by radiation.

The Séralini study was retracted by the journal editors two months later,⁴¹ citing flimsy evidence including insufficient animals tested, only to be republished by another journal two years later.⁴² Despite widespread renunciation, Séralini remains an influential figure in Kenya. Only in 2019 did the Kenyan government finally give limited approval to farmers to plant GMO cotton.⁴³ In Uganda, despite extensive debate on a biosafety bill, negative opinions about GMOs on public health prevail. Some opponents argue (falsely) that GMOs result in obesity, as in America.

Nnimmo Bassey, the Nigerian environmentalist, is deeply concerned about climate change, warning that ocean acidification and coastal erosion will breed conflict in his home country. But Bassey doesn’t distinguish between the polluters helping to incinerate the planet and industrial corporations seeking to impose genetically edited crops across the continent. Bassey accuses them of cynically taking advantage of poor, hungry Africans purely to gain market access. “They want to bring in new forms of control, new colonial ideas,” he says. “In each situation we have alternatives. Food is not just something you swallow. It is life, it is celebration, a cultural activity.”⁴⁴

The three “big Ag” players—Bayer/Monsanto, ChemChina/Syngenta, and Corteva, born out of the 2017 Dow-DuPont merger—know they face an uphill battle. Neal Gutterson, Corteva’s chief technology officer, told me it’s important for African scientists to drive the research, not a bunch of American executives flying in to push their latest technology.⁴⁵ There are myriad applications for CRISPR that could result in earlier release onto the market of edited crops, or more important, create bespoke varieties with improved disease resistance or nutritional value.⁴⁶ The European market wants an alternative to palm oil, which is currently produced in Malaysia and Indonesia with devastating costs to the ecosystem. With some judicious gene editing, sunflowers can be turned into a palm oil substitute. “The beauty of the technology,” Gutterson says, “is when major societal needs can be addressed by emerging technologies.”

In The Happiness Hypothesis, psychologist Jonathan Haidt introduced the metaphor of the elephant and the rider. The rider is the rational side of our brain, the elephant is the emotional side. While it may appear that the rider is in control, should there be any sort of conflict or disagreement, the elephant is likely to win out. Convincing the public at large, suspicious if not downright hostile to GMOs, that CRISPR and other emerging techniques are safe remains a gargantuan challenge.

If CRISPR is going to help us feed the planet, its impact won’t just be felt in the plant kingdom. Livestock and other animals stand to benefit from genome editing to provide disease resistance and other benefits. Selective breeding over recent decades has resulted in some impressive improvements in yield and meat production, averaging around 20–30 percent annually. But with the world population on pace to exceed 9 billion people by 2050, these advances are insufficient at best, trivial at worst.

While genome editing appears the only viable solution to ensuring food security by improving the yield of crops and livestock, regulatory agencies take a different view. In the United States, the regulation of gene editing in plants by the USDA is much less constrained than that of livestock, which is governed by the FDA. When laws don’t evolve in keeping with technology, the regulatory agencies are obliged to fit a square peg into a round hole—make the science fit into the existing regulatory framework.

In 2017, the FDA declared that any edited animal DNA would be considered for regulatory purposes to be a drug.⁴⁷ This sets up the ludicrous situation where farmers could over time breed a line of dehorned cattle using traditional methods and the FDA would barely bat an eyelid. But expedite the process using CRISPR to engineer the identical genetic tweak and the agency flips out. In Europe, the situation is reversed. Advocates believe that gene editing of food products should be judged on the ends rather than the means. “This technology was developed largely with public funding, and the public should benefit from its intelligent and careful application,” argued a group of gene-editing supporters in 2016.⁴⁸

It is quite fitting that the arduous journey of the first GMO fish to market should be that of the salmon. In 1989, the transgenic AquAdvantage salmon was first created in the laboratory by a Massachusetts company, AquaBounty. The gene construct transferred into salmon eggs included a growth hormone gene promoter that allows the fish to grow faster than normal. The modified fish reaches a weight of 500 grams in about 250 days, compared to 400 days for its unmodified sibling. These fast-growing fish, reaching maturity in half the normal time, make land or indoor farming of salmon in 70,000-gallon fiberglass tanks economically feasible. (It’s not only healthier for the fish, it abolishes any risk of GMO fish escaping into the wild—especially in landlocked Indiana. Even if they did, the salmon are sterile.)

AquAdvantage salmon were approved for sale in Canada in 2016, a year after the FDA assessed that the transgenic salmon were safe. In May 2019, a shipment of 90,000 eggs left Prince Edward Island, Canada, cleared customs in Chicago, and arrived in Albany, Indiana—1,000 miles from the nearest ocean. After two decades and more than $100 million in regulatory costs, AquAdvantage could finally be sold in the United States. Whether any business will be convinced to sell a big GMO-labeled fish remains to be seen. While AquaBounty touts its supersized fish as sustainable, the situation is not. The enormous promise of CRISPR for food production will be crushed unless gene editing is decoupled from GMOs. Tellingly, AquaBounty has used CRISPR to produce fast-growing tilapia, but opted to produce them in Argentina where the regulatory hurdles were lower.

CRISPR is also coming to livestock, offering a faster, more controlled version of the sort of natural breeding that farmers have been performing for generations. But while the USDA sees it this way, the FDA doesn’t, preferring to classify genome editing as a fancier GMO. In livestock, gene editing cows so that females carry the SRY male sex-determining gene would ensure an excess of males, which farmers prefer. Another example involves the polled gene.

There are more than 270 million dairy cows worldwide producing more than 700 billion liters of milk annually. But within the past 1,000 years, a spontaneous mutation in their cousins, the Angus beef cow, resulted in cows that naturally lacked horns. This polled mutation has been selectively bred in Angus cows—hornless animals are easier to house and manage, safer for animals and humans alike.^III But most dairy cows do not carry this variant and must have their horns debudded painfully, using a hot iron or chemical cauterization. Many farmers have resisted cross-breeding polled animals, believing that other traits, including milk production, would suffer.

Recombinetics, a Minnesota company, used TALENs to engineer the polled mutation into the DNA of dairy cows.⁴⁹ The first calf born using this precision breeding method was named Spotigy (“spotty guy”) for the black spots where the horns would normally be. At University of California Davis, near Sacramento, Alison Van Eenennaam, a livestock gene-editing evangelist, looks after polled cattle at the so-called Beef Barn. Van Eenennaam was working with a pair of gene-edited polled bulls when she learned that the FDA’s guidance would classify gene-edited animals the same as GM animals producing veterinary drugs. “We went from having two bulls that were polled to having two 2,000-pound drugs,” Van Eenennaam shrugged.⁵⁰

It got worse. In 2019, FDA bioinformatician Alexis Norris was running computer searches to examine the possibility of gene editing causing off-target effects. She came up empty, but instead, she discovered something awry at the polled locus itself: traces of foreign DNA derived from the plasmid vector used to conduct the original editing, including antibiotic resistance genes.⁵¹ Antonio Regalado’s headline hit the nail on the head: “Gene edited cattle have a major screwup in their DNA.”⁵²

The episode was not only embarrassing but costly. Recombinetics was on the verge of breeding hornless dairy cows in Brazil, beginning with sperm from Spotigy’s half-brother, Buri. Only Buri’s calves would be carrying foreign antibiotic resistance genes, making them textbook GMOs. Gene-edited cows from Brazil may be off the table for now, but using CRISPR will allow Recombinetics and others to engineer more precise edits for polled dairy, heat-tolerant beef cattle, and more.

CRISPR will also be an essential tool in the development of disease-resistant livestock. At the University of Missouri, Randall Prather has produced thousands of genetically modified pigs harboring dozens of edited or modified genes. The swine genome is the same size as the human genome and as we saw with eGenesis, well suited to CRISPR gene editing. Prather says, “We alter a handful of [DNA] bases and someone’s going to say, ‘well, you can’t eat that’? I have a hard time with that.” He has a right to be exasperated. Every cell division is accompanied by about thirty random mutations, and we don’t know whether they’re bad or good.

Prather’s focus is porcine reproductive and respiratory syndrome (PRRS), caused by a virus that infects white blood cells in the lung leading to viremia. The disease was first detected in the United States in 1987, and in Europe three years later. The economic toll is massive—about $2.5 billion annually in the United States and Europe combined, or more than $6 million a day. Prather and other researchers have identified a cell-surface protein called CD163 as the gatekeeper for PRRS viral entry (analogous to CCR5 and HIV) and thus the prime target for engineering PRRS resistance. With CRISPR technology, the Prather lab was transformed, producing gene-edited piglets in just six months.

To test the CD163 theory, Prather shipped some edited pigs to Bob Rowland at Kansas State University in a blinded experiment. The pigs—edited and controls—were exposed to the virus that causes PRRS while being kept in the same pen. After a month, the lungs were tested for virus. Rowland emailed Prather while on a beach vacation in Florida. “Pigs 40, 43, and 55 remained negative,” he said, not knowing those were the gene-edited pigs. Rowland’s technicians thought there had been a mistake—they’d never seen pigs resist the virus. Similar results have been reported by groups in China and the Roslin Institute, but Roslin scientist Christine Tait-Burkhard says it will still be a while “before we’re eating bacon sandwiches from PRRS-resistant pigs.” The technology has been licensed to a British company, Genus, which is seeking regulatory approval.

This is just one lab, one disease. African swine fever (ASF), bovine respiratory disease, pig influenza, and chicken influenza are just a few of the other diseases that CRISPR can help.⁵³ Between 2018–2019, 150–200 million pigs in China and other parts of Asia became infected with the deadly ASF. Millions of animals have been slaughtered, the price of pork doubling as a result. The disease has reached Europe and is on the verge of entering the United States. At CAS, one of Prather’s former trainees, Zhao Jianguo, is leading the charge to develop ASF-resistant hogs, by targeting a gene called RELA. He already made his mark leading a team effort to render pigs more resistant to cold weather by using CRISPR to knock in a mouse gene called UCP1^IV that helps them burn more fat.⁵⁴

What we’ve seen above are some early glimpses of the potential—for that is all it really is right now—of CRISPR to transform agriculture and help feed the planet. The Green Revolution and other agricultural advances of the 20th century were part of an explosion in new technology, much of it arising from the convergence of physics with engineering. Just as scientists decoded the physics parts list in the 20th century, the new century will be driven by the parts list of biology—the seminal discoveries of molecular biology spinning off the double helix and the genomic revolution. In the first two decades of the 21st century, we advanced from a White House celebration of the first human genome sequence for about $2 billion to a genome center like the Broad Institute churning out a human genome every five minutes for less than $1,000.

Whether the CRISPR revolution will match the Green Revolution is impossible to say. I’m not suggesting genome editing is the answer to feeding the planet, but it shouldn’t be stymied by overregulation or anti-GM hysteria. “We’re not special,” says Charles Mann soberly. Like protozoa feasting on unlimited nutrients, we’re going to hit the edge of the petri dish. Soon. The wizards of Mann’s book believe in GM and ultimately genome-edited crops as part of humankind’s solution, while the prophets preach conservation and human connection. But the wizards have failed miserably to persuade the public to embrace GM technology, leaving an uphill road for CRISPR.

Mann believes the two camps have much more in common than they let on. There can be a future that embraces genome-edited crops while recognizing the damage caused by industrialization. One idea is that plant scientists should prioritize trees and tuber crops such as cassava or potatoes, rather than wheat and other cereals.

In a greenhouse on the campus of North Carolina State University, Rodolphe Barrangou walks me through a row of young poplar trees, some twelve feet high, all carrying CRISPR-edited genes. These are the first shoots of TreeCo, “the North Carolina Tree Company,” Barrangou’s latest commercial venture, launched with fellow faculty member Jack Wang, appropriately set in the wood basket of the world. Poplars are abundant trees used for plywood, furniture, and paper. Genome editing can improve the abundance of pulp and lower waste, with applications ranging from climate resilience to timber to bioenergy. Barrangou isn’t planning to feed the world just yet: first, he’d like to become the R&D engine for the lumber and forestry industry. But if not him, then surely someone else.

By the time we hit the edge of the petri dish, we’re going to need even better gene-editing tools. Fortunately, in this remarkably innovative arena, they’re already coming online.

I. The disease was originally called huanglengbing (“yellow shoot disease”), but differences in pronunciation resulted in a change to huanglongbing, which was made official in 1995.

II. Sadly Mirkov won’t see the fruits of his labors: he died after a short illness in 2018.

III. The Celtic polled variant is a duplication of 212 bases that replaces a ten-letter stretch in an intergenic region on cow chromosome 1. The resulting hornless trait is inherited in dominant fashion, although the precise mechanism is unknown.

IV. Pigs carry a UCP1 gene but it is nonfunctional. In the experiment, the Chinese team knocked in the mouse counterpart.