PAGE 1 OF 2
by Dennis Meredith
Peering into the microscope, undergraduate HHMI research fellow Sarah Steele deftly pokes the platinum wire into the culture plate to snag her prize, a near-microscopic worm called Caenorhabditis elegans.
She repeats the delicate procedure, planting dozens of worms into another silver-dollar-sized culture plate, this one teeming with the lethal bacterium Pseudomonas aeruginosa—the cause of tenacious lung infections in people with cystic fibrosis.
At first, the transplanted worms continue their sinuous slithering through the gel. But soon they cease their wanderings, killed by the thick bacterial “lawn.”
The worms were doomed by a genetically flawed immune system, which Steele, her mentor, Duke University biologist Alejandro Aballay, and colleagues, found relies on a surprisingly direct link with the nervous system for coordination.
Researchers have long harbored the notion that the nervous system could influence the hair-trigger reaction of innate immunity—essential to instant defense against microbial invaders. They had established guilt by association: the same immune-triggering proteins exist in both the nervous system and the immune system. But they had no practical way to map the biological link between brain and immune system in higher animals, whose genetics and physiology are just too complex.
Enter C. elegans, which, with its modest 302 neurons all mapped and analyzed in detail, offers an ideal compromise between complexity and tractability to study the brain–immune linkage. Aballay's graduate student, Katie Styer, began testing mutants that had defects in various genes for receptors that might play a role in neural circuits most likely involved in the regulation of defense against pathogens.
“We found one particular mutant that died much faster than control wild-type animals when exposed to pathogenic bacteria,” says Aballay.
The scientists were surprised to find that the mutant worm harbored crippled versions of a gene called npr-1, which is expressed in at least 20 neurons in C. elegans. HHMI investigator Cornelia I. Bargmann at the Rockefeller University had identified npr-1 years earlier, not as an immune system regulator but as a controller of feeding behavior.
Bargmann found that the npr-1 gene codes for a receptor that regulates whether the worms prefer to feed family-style or alone. Maybe npr-1 wasn't really an immune link, Aballay reasoned at first. Perhaps the gene mutation changed the worms' behavior, altering their normal tendency to avoid pathogenic bacteria or to seek comfortably low oxygen concentrations.
Illustration: Deth Sun