The brain has a brake against seizures. A parasite turns it off
Ira Blader was looking for an enzyme inside samples of infected brain tissue. It should have been everywhere.
It seemingly vanished.
The enzyme produces gamma-aminobutyric acid, or GABA, the chemical that helps keep neurons from firing out of control and helps prevent seizures. In healthy tissue, it appears throughout the brain. In the infected samples, there was nothing.
“We couldn’t see any of this enzyme, and that’s crazy,” Blader said. “So we wanted to know why we couldn’t.”
What researchers found reframed the question. The enzyme had not stopped being produced; it was being eliminated. The brain’s own scavenger cells, which normally clear away damaged material, were being drawn to the precise connections that hold seizures in check, wrapping around them and consuming them. Some of those cells still carried the missing protein inside.
The brain’s cleanup system was dismantling its own defense against seizures.
What draws those cells to the wrong place is the question Blader has spent years pursuing, and it begins with a parasite most people carry without knowing it. Toxoplasma gondii infects roughly one-third of the world’s population. It slips in quietly, usually through undercooked meat, then settles into the brain and goes dormant for life. That silence is the whole point.
“It wants to get in there, and it wants to stay quiet, and then just wait for the opportunity to get transmitted to another host,” said Blader, head of the Department of Biomedical Sciences and Pathobiology at the Virginia-Maryland College of Veterinary Medicine. A parasite that kills its host quickly is a parasite that fails. Toxoplasma plays a longer game.
The danger comes when the immune system can no longer hold the line. In people with advanced AIDS, in cancer patients on immune-suppressing therapy, and in some unborn children, the dormant parasite reactivates and multiplies in the brain. The patient begins having seizures. Doctors have known this for decades. Blader is the one who couldn’t stop asking why.
“I asked neurologists and infectious disease doctors why they have seizures, and no one can tell me why,” he said. The answer he kept getting was a single word: inflammation. Enough for a physician treating the symptom. Not enough for him. “I still didn’t really get it.”
This spring, the National Institute of Neurological Disorders and Stroke awarded him a five-year grant to answer the question. The federal award, from one of the most competitive sources of funding in biomedical research, marks the kind of science taking root at the veterinary college.
Two mysteries remain
The discovery leaves two questions open: What signal summons the scavenger cells to those particular connections, and what tells them to start consuming once they arrive?
Blader suspects an immune protein called complement C3 plays a role in consuming those specific connections, although which cells produce it and which carry its receptor remain unknown. And to answer what attracts the scavenger cells, his team will isolate the affected neurons and knock out suspect genes one at a time until the one responsible for the engulfment reveals itself.
The work has a homecoming quality. It began at Virginia Tech years before Blader arrived to lead the department, and the disease exists exactly where a veterinary college does its best thinking, at the seam between animal and human health. Toxoplasma moves between species, and related parasites cause neurological diseases in pets and livestock. Whether they all break the brain the same way is the door Blader wants to open next.
The discovery, not the cure
Basic research has two halves: the discovery of how something works, and the use of that discovery to build new treatments. Blader works on both, and his lab has a compound it has considered testing. But his focus right now sits firmly on the first half.
“You ask what drives me,” he said. “For me, it’s the discovery part.”
It traces back to a graduate student who could not stop wondering how one cell communicates with another, and who landed in parasite research almost by accident in the Stanford laboratory of John Boothroyd. “It was the best decision I made,” he said. “He taught me everything I know.”
What pulled Blader toward this work in the first place was a pair of questions he has never quite shaken. “Why, when we’re stressed out, are we more prone to getting infected?” he said. “And then why, if we’re infected with something, are we more stressed out?”
