A More Humane Livestock Industry, Brought to You by Crispr

Hopes were running high for cow 401, and cow 401 serenely bore the weight of expectations. She entered the cattle chute obligingly, and as the vet searched her uterus, making full use of the plastic glove that covered his arm up to his shoulder, she uttered nary a moo. A week ago, Cow 401 and four other members of her experimental herd at UC Davis were in the early stages of pregnancy. But now, following a string of disappointing checkups, it was all down to her. Alison Van Eenennaam, the animal geneticist in charge of the proceedings, kept watch from off to one side, galoshes firmly planted in the damp manure, eyes fixed on a portable ultrasound monitor. After a few moments, the vet delivered his fifth and final diagnosis. “She’s not pregnant,” he said. Van Eenennaam looked up. “Ah, shit,” she muttered.

Cow 401 and her herdmates were the product of two and a half years of research, Van Eenennaam’s attempt to create a strain of gene-edited cattle specially suited to the needs of the beef industry. Had everything gone as planned, all the calves in this experiment would have been born male—physiologically, at least. Like humans, cattle carry two sex chromosomes; those born XX are female, and those born XY are male. But it isn’t the Y that makes the man. It’s a single gene, called SRY, that briefly flickers to life as an embryo grows and instructs it to develop male traits. Using Crispr, Van Eenennaam’s team added a copy of SRY to the X chromosome too. That way, even if a cow was born genetically female, she’d be expected to appear male all the same. Since beef ranchers generally prefer males to females (more meat for the money), Van Eenennaam believed there could someday be a market for these Crispr’d animals.

More than that, though, the project was a proof of concept. One of Van Eenennaam’s goals is to make the raising of livestock not only more efficient but also more humane. If a calf’s sex could be altered with a copy-paste of a single gene, that might pave the way for all kinds of experimentation—and not only in the beef business. Although ranchers may prefer male animals, their colleagues in the egg and dairy industries favor females. Since bulls can’t make milk and roosters can’t lay eggs, it’s cheaper to destroy them than raise them to adulthood. But if you could ensure that only heifers and hens are born, the carnage wouldn’t be necessary.

The Davis team wasn’t yet sure what had gone wrong with the pregnancies. They’d done their work with such care. First they located a target area on the bovine genome and created a custom set of Crispr scissors to cut the DNA and insert the new gene. Then they took a trip down the interstate to a slaughterhouse in Fresno, where they purchased a fresh batch of ovaries. Back in the lab, they aspirated the eggs, fertilized them, and set their Crispr scissors loose. They let the resulting embryos grow for a week, biopsied them to make sure the edits had gone as planned, then froze them until the cows were ready for implanting.

Perhaps, Van Eenennaam thought, the arduous process had simply knocked the life out of the embryos. “Science is a bitch,” she said with a shrug. But there was a more troubling possibility—an issue with the gene edit itself. On a map of the bovine X chromosome, the location where they’d inserted SRY seemed to be within a stretch of extraneous code, far from any life-critical genes. But then again, the map they currently had was about as accurate as a 16th-century atlas of the New World, full of unknown and mislabeled territories. Maybe, by tinkering in the wrong place, they had arrested development in the womb.

Twenty-five years ago, Van Eenennaam was a student at Davis in the early days of the GMO craze. Animal scientists, long limited by the pace of traditional trial and error breeding, could now mix and match genetic traits from different organisms, giving their livestock strange new powers. At Davis, for instance, they engineered a line of goats that carried a human protein called lysozyme in their milk. (Later on, researchers realized that, when fed to children in the developing world, that milk could prevent diarrhea.) As a young faculty member at Davis in the mid-2000s, Van Eenennaam explored a method for modifying cows to produce milk with extra omega­-3s. Then, just as she prepared to begin experiments in actual cattle, she says, the money dried up.

Around that time, the Food and Drug Administration had decided to classify genetic modifications to food animals as veterinary drugs. At specific issue were transgenes—DNA ported from one species into another—which, in the agency’s view, altered “the structure or function” of the animal. This meant that scientists would have to submit to an expensive approval process before anything reached the grocery store. There were calls for reform, but policymakers lacked the will to implement regulatory changes that would both promote research and assuage people’s growing fears about GMOs. With no path to commercialization in sight, and with the looming threat of a public backlash, the institutions that had funded the work ended their support. Only one animal from that period, the AquAdvantage­ Salmon, has since been approved for human consumption, though no one in the US is eating it yet, owing to regulatory hand-wringing over how it should be labeled. The lysozyme goats still amble, idly, around a pasture on the Davis campus.

Van Eenennaam argues that Crispr experiments like hers—those not involving transgenes—should be treated differently. As she sees it, the technology is just a faster, more precise version of what farmers have done for centuries, because it makes changes that could have occurred in the organism on their own. The US Department of Agriculture, which oversees gene editing in plants, appears to share this view; in March 2018, it decided, in most cases, to regulate this use of Crispr like it does traditional breeding methods. But the most recent guidance from the FDA, issued in January 2017, seems to lump gene editing in with the old GMO techniques. That’s because, as the agency sees it, both approaches present similar risks, not only to people but also to animal welfare—something the USDA doesn’t have to consider. Van Eenennaam worries that the same fears and heel-dragging as before could scuttle the field before it has a chance. “The engineering debate killed my career,” she says. “Now this editing debate has the potential to kill my students’ careers.”

For all the anxiety and ambiguity surrounding Crispr, there’s little doubt that it could revolutionize farming as Van Eenennaam hopes. In January, British researchers announced plans to raise chickens with an immunity to influenza. A small genomic incision, they hypothesized, could prevent the virus from infecting its hosts. That would not only save chickens from untimely demise but also cut out a likely conduit for a devastating human pandemic. You may not like the idea of Crispr meddling with grandma’s chicken pot pie recipe, but would you relent if it could stop the next Spanish flu?

“I’d hope so,” says Randall Prather, a geneticist at the University of Missouri. His lab has raised pigs that are resistant to porcine reproductive and respiratory syndrome, or PRRS, an untreatable disease that costs the US swine industry more than half a billion dollars each year. The solution, he says, comes down to modifying as few as two DNA base pairs out of 3 billion. Prather licensed the technology to a British company called Genus, which says it expects to spend tens of millions of dollars on the FDA approval process.

Yet not all Crispr experiments in livestock offer such unambiguous benefits. Many merely aim to improve efficiency, speeding up the process that gave us broiler chickens four times the size they were in Eisenhower’s day. That fuels perceptions that gene editing will only encourage the worst inclinations of factory farming. In Brazil, for example, scientists recently bred Angus cattle that carry a heat-tolerance gene called Slick. While this could eventually be a path to readying the global cattle industry for climate change, for now it likely means that the Brazilian Amazon will have to support even more cows than it already does.

Robbie Barbero, who led efforts to modernize biotech regulations in the Obama White House, says that it’s time for the FDA to offer some clarity. “In the absence of a regulatory path that’s rational and easy to understand, it will be almost impossible for any animals to make it to market,” he says. With transgenes, he argues, it was possible to wrap your head around the logic of regulating changes as drugs. “But when you’re talking about regulating changes to the genome that could’ve happened naturally, you’re asking to stretch the imagination,” he says. The draft guidance, Barbero notes, was intended as a starting point, not the final word.

If and when the FDA decides to weigh in, says Hank Greely, a bioethicist and professor of law at Stanford, it will have to reckon with the unique risks of gene editing—that an edit might produce new allergens, for example, or spread from livestock to their wild cousins. His underlying fear, however, is “the democratizing nature of Crispr.” An argument against GMOs was that the expense of creating them would consolidate power in the hands of wealthy multinationals; a company such as Monsanto would spend millions engineering a new transgenic crop, then sell it to struggling farmers at an exorbitant price. But the remarkable ease of gene editing, Greely says, could have the opposite effect. It could push certain rogue actors—say, “a guy with a dog kennel or a biologically sophisticated rancher”—toward cavalier, DIY experimentation. That’s why Greely thinks researchers should be required to register their edits.

For now, though, political momentum appears once again to have stalled. That’s left nascent projects, like Van Eenennaam’s, waiting for answers.

If there is a purgatory for gene-edited cattle, it can be found in the Davis Beef Barn, which is home to six young penitents. About five years ago, their father, a bull, was genetically dehorned by a Minnesota-based company called Recombinetics. Just as egg farmers prefer hens, dairy farmers prefer polled, or hornless, cows. Often they’ll prevent the horns from growing by burning them off with a hot iron or applying caustic chemicals. So, using a Crispr-like technology known as Talens, Recombinetics gave the bull two copies of the polled variation, in the hope that none of his descendants would have to undergo the procedure.

Five of those hornless descendants turned out to be male, which meant they wouldn’t be much use to the dairy industry anyway. Van Eenennaam has asked the FDA for permission to sell them as food. “They’re either all going to be incinerated or they’re all going to become steaks,” she explains. One of the bulls gently sniffs her fingers through the wooden slats of the pen. “Sorry to talk about this in front of you guys.”

Princess, the lone polled female, is hanging out a few pens away. Before she and her brothers can be introduced into the food supply, the FDA requires that they pass a range of tests, both genetic and physical. Their gene-edited uncle supplied the meat for quality testing; now Princess will be bred so that, when her milk comes in, it can be analyzed. But Van Eenennaam says the agency hasn’t told her clearly what results it is looking for, almost as though it’s searching for the risks it wants to regulate. For instance, the FDA asked her to confirm, via full genome sequencing, that there had been no unintended edits that jeopardized the animals’ safety. But sequencing the same genome 20 times over, as Van Eenennaam did, will turn up slightly different results with each pass. And besides, she says, even if you could pinpoint any errant edits, what would they tell you about the animal’s health? She advocates a wait-and-see approach: “There’s a natural evaluation process called ‘living’ that will weed out anything that’s weird.” (The FDA does not comment on pending applications.)

Even as Van Eenennaam and her calves are hung up in regulatory limbo, she is looking ahead to the next step in the process: scaling up genetic improvements on the ranch. Unlike pigs and chickens, whose reproduction is strictly controlled, beef cattle tend to procreate unsupervised, out on vast grazing ranges. This makes it hard to ensure that desirable traits, like swift growth or well-marbled meat, get passed down. Van Eenennaam thinks she’s found a solution. She plans to take a group of bulls, knock out the gene that allows them to create sperm, and swap in a replacement from a superior animal—perhaps even one that carries the edits for hornlessness or all-male offspring. The result would be ordinary bulls with, as Van Eenennaam puts it, “excellent balls.” Rather than spreading their own mediocre genes, they’d spread the elite genes of others—and they’d do it faster than ranchers could manage on their own.

Van Eenennaam and her colleagues are also focused on getting their earlier experiment working. After the disappointment of the pregnancy checks, they soon came up with two possible explanations for what went wrong: Either they inserted the SRY gene in the wrong place or they damaged the embryos in the lab—perhaps during the biopsy, when they were checking to see whether the edit took. In the next stage of the project, they’ll investigate both possibilities at once. First, they will insert SRY into a completely different chromosome, at a location where other researchers have successfully dabbled in mice. But this edit will be different from the last one: It will include a gene, borrowed from a jellyfish, for red fluorescence. If the insertion is successful, the cells will simply glow, no biopsy required.

It’s not an ideal solution. If all goes well, Van Eenennaam won’t have gene-edited cattle, as she originally intended; she’ll have a transgenic herd. So while she’d hoped to get the FDA’s blessing to sell the animals at the end of her research, she now plans to incinerate them instead. Even the mothers, which naturally share small amounts of genetic material with their offspring, could be considered tainted. “I’ve been resisting putting a transgene in,” she says. “But we’re just going to have to bite the bullet and kill them and their mothers and everything that touches them.”

Van Eenennaam does the math: $15,000 to buy 10 cows from a local rancher, plus $8 a day, each, to pasture them until a Christmas birth. Her grant will have ended by then, and she worries she won’t get another one.

Gregory Barber (@GregoryJBarber), a WIRED staff writer, wrote about selling his personal data on the blockchain in issue 27.01.

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