Zi Wang Thought He'd Cracked the Toxo Parasite. Then He Made His Breakthrough Disappear

Working a crowd, card-trick wizard Zi Wang is always in control. Around parasites, it's a different story.
Working a crowd, card-trick wizard Zi Wang is always in control. Around parasites, it's a different story. DANNY WICENTOWSKI

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Since 1991, Washington University scientist David Sibley has focused his lab on one subject: the Toxo parasite. - DANNY WICENTOWSKI
Since 1991, Washington University scientist David Sibley has focused his lab on one subject: the Toxo parasite.

David Sibley had already spent twenty years studying Toxo when Wang joined his lab in 2012. Sibley remembers giving the grad student a warning.

"When I agreed to let Zi do this project, I told him, 'Whether you prove it's probably right or whether you disprove it, you have to be willing to accept either outcome, and think that they're equally interesting.'"

It's early afternoon inside the Sibley Lab, and its namesake, a professor of molecular microbiology, sits behind his office desk. His bike leans on a wall just outside, and the door is covered with blown-up photos of Toxo, a subject that's captivated his entire scientific career. In the dyed colors of the photographs, the parasite's rosette form looks like a strangely delicate flower, one stained in garish greens, yellows and blues.

The lab opened in 1991, and on any given day, Sibley supervises more than a dozen projects while guiding the lab's ongoing work to deconstruct the mechanisms that make Toxo what it is. Around 2000, Sibley read the first studies that described curious behavioral changes in infected rodents, but until Wang, no one in the Sibley Lab followed up on that research.

In the brain, neurotransmitters work as chemical messages delivered to different parts of the body, triggering impulses that range from movement to emotion. The dominant theory for Toxo's behavioral modification was staked on a 1985 lab study, conducted a decade before scientists starting suspecting Toxo of precision brain-manipulation. It found that infected rodents' brains were being hit with a fourteen percent bump in the neurotransmitter dopamine.

Some neurotransmitters perform multiple functions, taking multiple pathways in the brain. Dopamine is one of the most versatile, affecting, among other things, motor control — people with Parkinson's suffer from low levels of dopamine — but also influencing such things as attraction, anticipation, reward and sexual gratification.

"If you alter levels of dopamine, you can change things fundamentally," Sibley says. "The idea was, the parasite lives in the brain, and they're making a precursor and sort of feeding this into the neurotransmitter system. That's what's causing the behavioral change."

Critically, the dopamine hypothesis seemed to account for the statistical connection between Toxo and schizophrenia, whose sufferers frequently have elevated levels of dopamine. Dopamine was also believed to be a likely cause of Toxo's mind-control powers in rats, as it is critical to the brain's processing of fear and risk responses.

If Wang could prove that Toxo relied on dopamine to make rats attracted to cats, that wouldn't just be news for the animal kingdom. Our species shares much of its biology with rodents, and scientists would be confronted with a strong suggestion that, for humans as well as mice, Toxo was not a benign guest.

But Sibley was skeptical of the dopamine theory. It was too simple. Toxoplasmosis threw the body's immune system into chaos, inflaming tissue and implanting thick-walled cysts in seemingly no order across the brain and skeletal muscle. Other unknown side effects could be at work simultaneously. And elevated dopamine levels in rat brains didn't explain why this multi-talented neurotransmitter was generating such specific cat-related behavior.

click to enlarge The parasite Toxoplasma gondii. - COURTESY OF DAVID SIBLEY
The parasite Toxoplasma gondii.

Wang, on the other hand, says he expected to confirm Toxo's secret assault on the brain. He believed he would prove the dopamine theory correct.

"I came into this with high hopes of solving this whole problem, and answering a huge puzzle about mental illness," Wang says. "I remember my first thesis committee meeting, the professors asking, 'What if you're wrong, what if you don't see these changes?' And I thought to myself, 'What a dumb question.'"

Despite Sibley's earlier admonition — that a researcher should accept either outcome — Wang readily admits that he undertook his research "desperately wanting this to be true." Decades of previous research backed up that optimism, and the theory made intuitive sense. Sure, Sibley's objectivity is noble, but nobility isn't always glorious. Wang wanted to be right. He wanted to build upon the work of the other scientists, to add his link to the chain of hypothesis and experiment.

Sibley's lab isn't equipped for behavioral tests — there are no mice in cages here — but its specialty in genetic engineering gave Wang exactly what he needed to evaluate the theory. He sought to build on the work of the 1985 study, as well as later experiments that appeared to confirm it.

In 2009, a British lab published a groundbreaking paper on Toxo, directly implicating two of the parasite's genes, AHH1 and AHH2, for the dopamine spike detailed in the 1985 study. Wang planned to target those genes.

Using genetic engineering, Wang would snip out the two dopamine-producing genes from Toxo, and then use that mutated parasite to infect mice. If the infected rodent brains showed dopamine levels similar to those in non-infected mice, it would suggest that Toxo had lost its dopamine-producing power.

Ultimately, if the theory was right, a mutated parasite that can't tweak dopamine should lose its mind-control powers, and the infected rodents would behave normally around cat urine.

On the other hand, if the infected animals' dopamine levels stayed high, the deleted genes couldn't be tied to the increased dopamine in the brain. Something else would have to be causing the elevated levels.

Wang's first step was to trick the parasite into erasing its own genes. He started by growing the parasite strain, nourishing them on a diet of foreskin stem cells. Then he electrocuted them repeatedly, until the current opened gaps in the cell wall large enough to introduce artificial "knock-out" genes designed to fool the cell's automatic repair function. Blind to the swap, the parasite replaced H1 and H2 for the lab-created filler DNA.

As precise as the lab tools were, the genes seemed to resist Wang's editing. After knocking out H2 in 2012, it took him four years to reach the moment where he skipped down the lab hallway believing he'd finally knocked out H1. He soon learned that his 2 a.m. victory dance was actually celebrating a false positive that set him back months.

Months later, he skipped down the hallway on yet another false positive. It wasn't until late 2016 that Wang finally managed to create a mutated version of Toxo missing its H1 DNA. Wang could finally celebrate in earnest.

But even at the height of his scientific optimism, Wang was bracing against a mounting pile of evidence that something was wrong with this model. In fact, the dopamine hypothesis was starting to fall apart.

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