Reengineering Life is a series from OneZero about the astonishing ways genetic technology is changing humanity and the world around us.
On a sunny Tuesday in April, amid a global pandemic, a newborn calf took his first shaky steps in a barn outside Sacramento. Animal geneticist Alison Van Eenennaam and postdoctoral researcher Joey Owen, looked on in awe. This wasn’t just any bull calf. This animal had been gene edited so that he could eventually produce more male offspring than normal.
The bull calf, affectionately named Cosmo, was the result of five years of research. Nine months earlier, Van Eenennaam, Owen, and a team of seven other scientists used the gene-editing tool CRISPR to insert a gene into cow embryos, including the embryo that eventually became Cosmo. The gene, SRY, is responsible for male sex development in cattle, and adding it to a female essentially swaps its sex. The researchers’ goal was to make a bull that would father mostly boys.
“The idea was actually suggested to me by a cattle operation,” Van Eenennaam, PhD, a researcher at the University of California, Davis, tells OneZero.
Male cattle are better for beef production than their female counterparts because they have bigger muscles, gain weight faster, and require less food to put on extra pounds. Overall, bulls are about 15% more efficient than females at converting food into weight, she says. More males could mean fewer cattle to produce the same amount of beef — a win for ranchers and potentially the environment.
To make Cosmo, the researchers injected about 200 cow embryos with CRISPR and the SRY gene. They also added a green fluorescent protein, commonly used in biomedical research, that would glow if an embryo was successfully edited. About two dozen embryos ended up surviving in the lab, and just nine of those embryos glowed green.
CRISPR works by making a targeted break in DNA using a guide molecule that finds the right location in the genome and a cutting protein that slices the targeted genetic sequence. It’s relatively easy to use CRISPR to delete a gene, but inserting a new gene is more difficult.
The researchers took the nine edited embryos and transferred them into female cows. Five later, only one cow got pregnant. Then it was a waiting game for the rest of the heifer’s nine-month pregnancy. Due March 30, Cosmo arrived a week late, on April 7, while the state of California was on lockdown due to the coronavirus.
“That was an anxious week,” Van Eenennaam recalls. She and her team revealed Cosmo’s existence on July 23 at the virtual meeting of the American Society of Animal Science. The results have not yet been published in a peer-reviewed scientific journal.
Like humans, cows have a 50-50 chance of having male or female offspring, which have XY and XX sex chromosomes respectively. But Cosmo is expected to produce more than the normal proportion of male calves. In addition to having 50% XY males, 25% of his offspring are predicted to be XX females and carry the SRY gene, making them have male genitals and, the team hopes, the bigger muscles associated with males. So, in total, 75% of his offspring are expected to have male traits.
Researchers don’t yet know for sure whether Cosmo will actually produce more males than non-gene-edited cows since he won’t reach sexual maturity for about a year. At that point, researchers can use Cosmo to breed, and then they could have their answer.
Jon Oatley, PhD, director of Washington State University’s Center for Reproductive Biology and a member of a national task force on gene editing in food animals, cautions that the report is preliminary.
Even if Cosmo has XX offspring that inherit the SRY gene, he says there’s no guarantee that they will look like typical bulls. He says animals with this genetic makeup would be similar to humans with Klinefelter syndrome, a condition that results when males inherit an extra X chromosome. People with the condition often have developmental abnormalities, including smaller muscles.
“Considering that the hope for XX cattle with the added SRY gene is for them to develop muscle similar to XY counterparts, the potential for reduced muscle mass seems a defeating purpose in my opinion,” Oatley says.
The researchers’ use of the green fluorescent protein, which comes from jellyfish, also presents an issue, he says. The protein is routinely used in lab animals being studied for biomedical research, but it’s not used in animals produced for food. Van Eenennaam says if she were to seek regulatory approval for the bulls, the fluorescent protein would be removed.
The team also discovered a surprise in Cosmo’s DNA after his birth. They took a sample of his blood, extracted a bit of DNA and sequenced it to determine whether they had successfully inserted the SRY gene in the right spot. It turned out they had, but instead of one copy of the gene, which was expected, the scientists found seven. Cosmo seems perfectly healthy, so these extra copies are probably not harmful. But the finding shows that CRISPR can have unintended effects in the genome.
There was another accidental addition: some bacterial DNA used to deliver the CRISPR system into Cosmo’s cells also got integrated into his genetic code. A similar mistake had happened before with hornless dairy cows that Van Eenennaam produced with Minnesota-based biotech company Recombinetics and other scientists at UC Davis.
To make those cows, scientists used an older gene-editing approach called TALENS. Last year, they reported that genome-edited bulls passed the hornless trait onto their offspring. Many cattle breeds naturally grow horns, but they’re typically removed to prevent injuries to other animals and humans. This practice is controversial because it’s painful to cattle. Using gene editing to delete the gene responsible for horns has been proposed as a pain-free alternative for cows.
In China, researchers have also used CRISPR to produce cows resistant to bovine tuberculosis, a contagious animal disease similar to the human version. The disease can be costly to farmers since infected cows are killed in order to stop the spread of the disease.
For now, the gene-edited cows that Van Eenennaam and her team are producing will be used for research purposes only and will not enter the food supply. Currently, the U.S. Food and Drug Administration regulates gene-edited animals as if they are drugs, making the approval process long and daunting. No gene-edited food animals are on the market yet in the United States.
Elsewhere, some major beef-producing countries like Argentina and Brazil seem more open to gene-edited livestock. But a plan to introduce gene-edited cows in Brazil was put on hold last year due to the bacterial DNA found in in the Recombinetics’ cattle. In China, researchers are also gene-editing pigs to be resistant to African swine fever, which is decimating the pork country’s pork supply. But the United States, says Van Eenennaam, is likely years away from having gene-edited cows or pigs on the market. “I don’t think that you will see them in America anytime soon.”