Janelia Method Captures Body-Wide Cell Communication in Zebrafish

Scientists at HHMI’s Janelia Research Campus have developed a way to simultaneously record real-time communication signals coming from nearly every cell in a living vertebrate. The method, called WHOLISTIC, or WHole Organism Live Imaging System for recording Tissue and IntraCellular activity, was developed by Virginie Ruetten, a postdoc in the lab of Janelia Senior Group Leader Misha Ahrens, and described in a recent Nature paper.

By capturing the cellular activity of all of a larval zebrafish’s biological systems at once—cardiovascular, digestive, and nervous—the technique gives a complete, concurrent picture of how these systems interact as the fish swims, eats, and sleeps, a step toward Janelia’s goal of understanding how the brain generates complex behavior. “We know that evolution has produced functioning organisms, but evolution didn’t care whether a decision was implemented in the brain’s prefrontal cortex or in a connection between the brain stem and the bladder,” Ahrens says. The method, he adds, “allows all these fields—physiology, neuroscience, behavior, cell biology—to connect and study all of them in the same animal.”

Nearly every cell in the body uses calcium to communicate with its neighbors, and tracking those signals shows how cells coordinate processes from moving a muscle to fighting an infection. Building on earlier lab work imaging calcium signals across a zebrafish’s brain, the team got a calcium sensor into every cell in the fish’s body and built computational methods to track and identify cell types, confirming identities with whole-body expansion microscopy. “This work bridges two fundamental scales of biology—the cell and the organism—such that we can now fill that observability gap,” Ruetten says. “There’s some really basic properties that were just missing because it’s been very difficult to look at cellular responses at scale.”

Researchers are now adapting WHOLISTIC to Danionella, a fish that stays transparent into adulthood, to study more complex behaviors than are possible in days-old larval zebrafish. They’re sharing their fish and computational methods with other scientists, and the microscope the method relies on is already common in biology labs.

Ahrens compares the approach to understanding a corporation by looking at every department at once: “Being able to observe them all at the same time will allow you to make these causal inferences about what’s connected to what and at what time—and many of them may not be the usual suspects like neurons.” “There are no hidden parts anymore, in the end, and at that point, I think we have a chance for a real, full understanding,” he says. “It’s a long way away, but I think this sort of approach provides some hope that we’ll get there eventually.”