Scientists at the Howard Hughes Medical Institute's Janelia Research Campus have developed a groundbreaking technique called WHOLISTIC, which enables researchers to simultaneously record real-time communication signals from nearly every cell in a living vertebrate. This method, detailed in the journal Nature, captures the cellular activity of all biological systems in a young zebrafish, from the cardiovascular system to the digestive system and the nervous system. This provides a complete, concurrent picture of how these systems interact as the fish swims, eats, and sleeps. This approach marks a significant first step in understanding the complex machinery of more complex organisms, such as humans. Nearly every cell in the body uses calcium ions to communicate with neighboring cells. By tracking these signals, scientists can understand how cells collaborate to perform essential functions, such as moving a muscle or fighting an infection. Over a decade ago, the Ahrens Lab and collaborators pioneered methods to image calcium signals across the entire brain of a larval zebrafish. For WHOLISTIC, Janelia researchers, working with collaborators at University College London, Virginia Tech, and Tsinghua University, built on this foundation by developing a way to introduce a calcium sensor into every cell in the fish's body. They also determined the optimal microscope to use, given the varying activity signals in different tissues and cell types, and developed computational methods to track and align these signals, identifying different cell types based on their activity patterns. Additionally, they used whole-body expansion microscopy to enlarge the fish tissue, revealing fine structural details that helped confirm the identity of cells captured by WHOLISTIC. The WHOLISTIC method allows researchers to study the fish at both the level of individual cells and the whole organism, simultaneously. Researchers are now adapting this method to Danionella, a fish that remains transparent throughout its life, allowing for the study of more complex behaviors than possible with the days-old larval zebrafish. This work could inform Janelia's recently launched effort to understand how a vertebrate brain generates behavior. The team hopes the technique will be used by scientists worldwide to answer their own questions about how the body works. In addition to sharing their fish with the scientific community and making their computational methods open source, the microscope used in the method is commonly found in biology labs, making it accessible to many researchers. The new method has already uncovered new insights into vertebrate physiology. It revealed the simultaneous activity of the brain and most organ systems at the level of individual cells, uncovering body-wide correlations in cellular activity that show widespread coupling between the brain, muscles, and organs. It also showed that many cell types across organs display characteristic temporal dynamics, which can help identify them even without specific labeling. The method uncovered body-wide physiological mechanisms that enable survival in low-oxygen conditions, finding that the brainstem controls the redirection of blood flow from the gut to the brain and muscles. Researchers observed traveling activity oscillations along the spinal cord and the brain that originate in ependymal cells during prolonged periods of motor quiescence, suggesting these cells may be involved in sleep. They also identified cell types that respond to cold, including chondrocytes, the main types of cells in cartilage, and found that ketamine stimulates the meninges along with neurons.