Key Takeaways
We can’t hear it, but the different parts of our body are in constant conversation, communicating to keep the entire system running efficiently.
For biologists, being able to listen in on this discussion is a long-sought-after goal. Over the years, researchers have caught snippets of these exchanges, but the complete dialogue has remained out of reach.
Now, scientists at HHMI’s Janelia Research Campus have figured out a way to hear the entire conversation. WHOLISTIC or WHole Organism Live Imaging System for recording Tissue and IntraCellular activity lets researchers simultaneously record real-time communication signals coming from nearly every cell in a living vertebrate.
The technique, developed by Virginie Ruetten , a postdoc in the lab of Janelia Senior Group Leader Misha Ahrens, and collaborators, captures the cellular activity of all the biological systems in a young zebrafish at once — from the cardiovascular system to the digestive system to the nervous system — providing a complete, concurrent picture of how they interact as the fish swims, eats, and sleeps.
It’s a first step toward understanding the machinery of more complex organisms, like humans. Uncovering what each cell in our body is saying, when, and to whom would deepen our understanding of how bodies work and what happens when they don’t, opening potential new paths to treat many diseases.
“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 Ahrens. While different biological disciplines have been focused on certain systems and scales, “this now allows all these fields — physiology, neuroscience, behavior, cell biology — to connect and study all of them in the same animal.”
A New Method to Study Cellular Communication
Nearly every cell in the body uses calcium to communicate with its neighbors. By tracking these signals, scientists can understand how cells work together to carry out many different processes, from moving a muscle to fighting an infection.
More than a decade ago, the Ahrens Lab and collaborators pioneered methods to image calcium signals across the entire brain of a larval zebrafish. They developed ways to outfit neurons with sensors that light up when there’s a change in calcium and to see these signals inside the tiny, transparent fish as it behaves under a microscope.
For WHOLISTIC, Janelia researchers, working with collaborators at University College London, Virginia Tech, and Tsinghua University, built on this work:
The method allows researchers to study the fish at both the level of individual cells and the whole organism, all at once, says Ruetten, who performed the research as a joint graduate student with Ahrens and Maneesh Sahani, Director of the Gatsby Computational Neuroscience Unit at UCL.
“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.”
Looking Beyond the Larval Zebrafish
The researchers are now adapting the new method to Danionella , a fish that remains transparent throughout its life, allowing researchers to understand more complex behaviors than is possible with the days-old larval zebrafish. The work could help inform Janelia’s recently launched effort to understand how a vertebrate brain generates behavior .
The team hopes the technique can 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 the method uses is commonly found in biology labs, making it accessible to many researchers.
Ahrens says WHOLISTIC allows scientists to more fully understand the biological networks controlling the body, which may not be in one place but distributed among different organs and systems. For example, neuroscientists typically look at the brain and the cells that make it up to understand what gives rise to behavior, which Ahrens likens to trying to understand a large corporation by only looking at one department.
“Instead, you have to look at the flow of information and the participation of people in the entire building, and then you need to take into account all the other companies it’s connected to,” he says. “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.”
Being able to see and put together more pieces of the entire system will allow researchers to simplify more difficult problems, like understanding and predicting how animals carry out complex behaviors, Ahrens says.
“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.”
SIDEBAR: What WHOLISTIC is Revealing
The new method has already uncovered new insights about vertebrate physiology, including:
Nature
Imaging cellular activity across all organs reveals body-wide circuits'
9-Sep-2026