Now Laura Knoll of the University of Wisconsin at Madison has thrown her fellow researchers a lifeline. Her team finally worked out why Toxo only has sex in cats. It then used that knowledge to break the species barrier, allowing the parasite to complete its life cycle in mice for the first time. The study is available online and is set to be published in a scientific journal after three reviewers described it as “truly remarkable,” “transformative,” and “a key breakthrough.”
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“It’s a major finding,” Rima McLeod of the University of Chicago Medical Center told me. “It’s the first time that the cat cycle has been recapitulated outside of cats.” That breakthrough could spare a lot of felines, and compensate for the closure of the Maryland facility. “Now we won’t have to use companion animals, which will make a lot of people happy, including us,” Knoll says. “No one wants to use cats in their research.”
At first, Knoll’s colleagues Bruno Di Genova and Sarah Wilson tried rearing Toxo on cat organoids—lab-grown balls of feline intestinal tissue. It didn’t work: The parasites grew, but never reached the sexual stage. The team wondered whether it had missed an important nutrient; perhaps a fatty acid, which Toxo is known to scavenge from its hosts. And sure enough, when the team added linoleic acid, “we had sex all over the place,” Knoll says.
Our guts convert linoleic acid into other substances that regulate our immune systems, control blood pressure, and more. This transformation depends on an enzyme called delta-6-desaturase, or D6D for short. And cats, it turns out, are the only mammals that don’t make D6D in their guts. They can still produce the enzyme in other organs, but they shut it off in their intestines. Knoll suspects that they did so because they evolved in desert environments, and adapted by preserving their fatty acids. Indeed, linoleic acid makes up 25 to 46 percent of fatty acids in a cat’s blood, but just 3 to 10 percent of those in a mouse’s.
Cat-food manufacturers and other researchers figured these details out in the 1970s, Knoll says, but the Toxo community was largely unaware of them. And yet, they perfectly explain the parasite’s life cycle. Toxo only has sex in cats because it depends on linoleic acid, and cats are the only mammals that build up enough of the stuff. “Whenever I give talks, I often get the question: Why the cats? What’s special about the cats?” Knoll says. “Now we have an answer.”
Once the team figured out that linoleic acid was the key, it set about trying to figure out how to shut down D6D in mice. Fortunately, a drug that blocks the enzyme was commercially available. The team fed it to mice, along with a linoleic-rich diet and some Toxo. After a week, it saw signs that the parasites had reached the sexual stage, and were making oocysts, the sporelike structures that spread Toxo infections to new hosts. “The first experiment we did, we could see oocysts being pooped out in the mouse feces,” Knoll says. “That was super cool.”