New technique records nearly every cell’s activity in a living animal

Scientists at HHMI's Janelia Research Campus have developed a technique that can simultaneously record real-time communication signals from nearly every cell in a living vertebrate — a first in biology that offers an unprecedented window into how the body's organs and systems coordinate in real time.

A New Way to Listen to the Body

The method, called WHOLISTIC (WHole Organism Live Imaging System for recording Tissue and IntraCellular activity), was developed by Virginie Ruetten, a postdoctoral researcher in the lab of Janelia Senior Group Leader Misha Ahrens, and published Wednesday in Nature. By tracking calcium signals — the molecular currency cells use to communicate with their neighbors — the system captures cellular activity across the cardiovascular, digestive, and nervous systems of a larval zebrafish all at once.eurekalert+2

The technique builds on more than a decade of work by the Ahrens Lab, which pioneered methods to image calcium signals across the entire brain of a larval zebrafish. WHOLISTIC extends that approach to the whole body, using high-speed volumetric fluorescence imaging and computational tools to track and align signals across tissues and cell types.phys

"This work bridges two fundamental scales of biology — the cell and the organism — such that we can now fill that observability gap," Ruetten said.eurekalert+1

Early Discoveries

The method has already yielded findings, including the discovery that the brainstem controls the redirection of blood flow from the gut to the brain and muscles during low-oxygen conditions. Researchers also observed traveling activity oscillations along the spinal cord originating in ependymal cells during periods of motor quiescence, suggesting these cells may play a role in sleep. The system further revealed that ketamine stimulates the meninges along with neurons, and identified chondrocytes — the main cells in cartilage — as responsive to cold.phys

"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 brainstem and the bladder," Ahrens said.hhmi+1

Looking Ahead

The team, which included collaborators at University College London, Virginia Tech, and Tsinghua University, is now adapting the method for use in Danionella, a fish that remains transparent throughout its life, enabling study of more complex behaviors. The microscope the method uses is commonly found in biology labs, and the computational tools are open source, making the approach accessible to researchers worldwide.hhmi+2

"There are no hidden parts anymore, in the end, and at that point, I think we have a chance for a real, full understanding," Ahrens said.phys