Biology has long relied on tools that zoom in on one piece of an organism at a time. Microscopes reveal fine cellular detail, dissection maps out organs, and X-rays expose internal structures. Yet these approaches tend to study systems in isolation, making it difficult to see how living cells communicate across the entire body. Now, researchers have developed a way to watch cells in distant parts of an organism signal to one another in real time. The work has been presented in the journal Nature.
A New Window Into Whole-Body Cellular Activity
“This work bridges two fundamental scales of biology – the cell and the organism – such that we can now fill that observability gap,” says computational neuroscientist Virginie Ruetten, who developed the technique with a team based at the Howard Hughes Medical Institute in the US. “There are some really basic properties that were just missing because it’s been very difficult to look at cellular responses at scale.”
The method is called WHOLISTIC, short for WHole-Organism Live-Imaging System for recording Tissue and IntraCellular activity. It captures cellular activity across an entire body, second by second.
Transparent Fish as Model Organisms
So far, Ruetten and colleagues have used WHOLISTIC to real-time signaling in naturally transparent animals. They began with larval zebrafish and then moved to another freshwater fish, Danionella cerebrum, which remains transparent into adulthood. Both fish are important model organisms in scientific research. Observing how their cells communicate across different organ systems could help scientists understand how similar systems in our own bodies might work.
Calcium as a Universal Signal
Calcium is a near-universal signal that cells use to communicate. It is involved in a wide range of biological processes: it helps muscles contract and synapses fire, and it is crucial at the start of life when sex cells are fertilized, as well as at the end when cells are programmed for death.
WHOLISTIC uses genetic engineering to make nearly every cell in the body express fluorescent calcium sensors. These sensors light up when calcium levels inside cells shift. A single fluorescence channel allows organs and tissues to be identified by their distinct visual textures. Areas with a yellow glow show stronger fluorescence from the calcium sensor.
Connecting Fields of Study
“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,” says neuroscientist Misha Ahrens, whose lab hosted the research. “This now allows all these fields – physiology, neuroscience, behavior, cell biology – to connect and study all of them in the same animal.”
Unexpected Findings
The whole-body imaging approach has already produced surprises. The scientists saw calcium sensors in a fish’s chondrocytes – the main cells that form cartilage – flaring up in response to cold. They were also surprised to see the brain’s protective tissue layers, the meninges, responding to ketamine, not just its neurons.
At a broader scale, the body’s rhythms became visible in new ways. “At the multi-organ scale, it revealed unknown muscle synergies and muscle–organ interactions,” the authors report in their paper. “At the whole-organism scale, the method captured brainstem-controlled redistribution of body-wide blood flow.”
Looking Ahead
The team hopes scientists around the world will adopt this method for their own research, offering unprecedented insight into the body as a whole. The research is published in Nature.
