It was another Saturday in the lab, the time past 2 a.m. Zi Wang was again spending it alone, with the parasite.
Located behind access-restricted doors on the ninth floor of a research building on the campus of the Washington University School of Medicine, the lab is active at all hours, bustling with staff scientists, post-doc researchers and graduate students. They work under the watch of Dr. David Sibley, each investigating some aspect of the parasite Toxoplasma gondii, commonly shortened to Toxo.
Toxo is a single-celled parasite that infects billions of people. It causes a disease called toxoplasmosis, and while many people who are infected never even realize it, for some with weakened immune systems, it's a monster capable of killing its host. It can damage the eyes or other organs. For infants who are affected in the womb, it can lead to brain damage.
No vaccine currently exists for Toxo. Scientists have spent the last century piecing together how Toxo spreads, infects and attacks the immune system. One day, scientists hope, these discoveries will become building blocks for effective treatment.
In 2016, Wang was a 28-year-old Ph.D. candidate. He had joined the Sibley Lab because he was drawn to a different question involving the parasite, one that's even less understood than its effects on the body. He wanted to explore its effects on the mind — specifically the minds of rodents.
Researchers running behavioral tests in the mid-1990s first began noticing that rats and mice infected with Toxo lost some of their natural fear of cats. In fact, the rodents seemed attracted, sexually, to the scent of their predator's urine.
Originally a fringe line of inquiry, it gained credence as a half-dozen labs corroborated the strange effect. Scientists began to ponder what it meant. Clearly, the theory went, the parasite was messing with its victims' brains.
There was an elegant logic at play, and it posed an irresistible puzzle for the young scientist: Toxo, for all its widespread success, can only reproduce in cat intestines. (That's one reason pregnant women are warned against handling cat feces.) Turning a mouse into a zombie that's horny for its natural predator has all the marks of a good deal for the parasite, shuttling it to its preferred feline host.
Another angle spurred Wang's interest: a different, more human-centric question.
"These parasites are obviously altering the behavior of mice when they get into the brain," Wang says. "And three billion people have this in their head."
Now employed as a scientist at Sigma-Aldrich, Wang's current work focuses on testing and performing product demonstrations for gene-editing equipment. Still, he's no less fascinated by the question behind Toxo's mind-control powers. For him, it's the one that got away.
Several studies had detected statistical connections between Toxo infection and mental illness, particularly schizophrenia. But without a mechanism, and without explaining how Toxo might cause mental problems, these studies are essentially correlation, an interesting connection and little more.
The question for Wang, in his own words: "Is this causing subtle behavioral change for huge chunks of people?"
During his time in the Sibley Lab, Wang's research was unique among his colleagues. He wasn't studying one small battlefield after another in the parasite's war on the immune system. Instead, he sought to conclusively evaluate researchers' best theory of Toxo's brain manipulation.
It was, Wang says, "a beautiful theory."
The delicate genetic engineering consumed more than five years of his life, and his conclusion couldn't have been more different from his expectations. Not only did Wang rip enormous holes in the hypothesis, but his results called into question longstanding assumptions about the parasite's activity in the brain. He had set out expecting to make a breakthrough, and instead added doubt. He made a mess of the beautiful theory.
Yet, Wang still looks back at that Saturday in 2016 with wistfulness, particularly that moment, early in the morning, when he bolted up from his samples and let out a whoop, bounding into the hallway on a dual rush of relief and triumph.
"I was skipping down the halls of the lab at two in the morning, just screaming, jumping for joy," he recalls. "I was convinced that what I had was what I was looking for."