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 UCP1IV 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.