If the human nervous system were a vast 3D map spread throughout the body, most of that map has long remained unseen. Scientists could see individual cells or blurry regions of the brain, but they could not follow a single nerve fiber from a fingertip, through muscles and bones, all the way back to the spinal cord while preserving the entire structure intact.

"We just wanted to see what a single sensory neuron actually looks like. No one had ever done that before," Zhao Hu, an associate researcher at Chinese Institute for Brain Research (CIBR), told CGTN. 

Driven by that curiosity, the team led by Zhao embarked on an ambitious research journey. To achieve this goal, they pushed beyond the limits of existing technologies and created a series of new tools along the way. And these early "by-products" evolved beyond their supporting role, gradually revealing scientific and practical value in their own right.

Solving 'invisible' problem in life science

Before researchers can look deep inside biological tissue, the tissue must first be made transparent.

"Biological tissue is actually semi-transparent by nature," said Zhao. "There are two reasons tissue looks opaque. One is that things like pigments, blood and bone block light. The other and more important one is scattering. Our bodies contain many materials with different refractive indices, such as water and lipids. When light encounters all these different materials, it scatters instead of passing straight through," he explained.

Although tissue-clearing technologies have advanced significantly in recent years, they still face two major bottlenecks when applied to large samples such as an entire brain or even a whole body. First, tissues can't be made perfectly transparent, causing image quality to deteriorate with depth. Second, high-resolution microscope objectives have limited working distances, preventing them from imaging thick specimens.

To overcome these limitations, Zhao's team developed a new approach known as Transparent Embedding Solvent System (TESOS).

"Proteins – the main building blocks of our bodies – are actually transparent," said Zhao. "It's everything around them that makes tissue opaque. By removing water and lipids that contribute to light scattering and introducing a clearing solution that equalizes refractive indices, the tissue suddenly becomes remarkably transparent."

The cleared tissue is then embedded in a transparent and hardened resin, creating a stable structure resembling amber.

This design solves two long-standing problems simultaneously. It enables high-quality imaging deep within tissue while dramatically increasing mechanical strength – by more than 150-fold in brain tissue – allowing precise trimming and continuous imaging without deformation.

"Once tissue becomes transparent, we can use three-dimensional imaging systems such as confocal microscopes to scan layer by layer and reconstruct its internal structure in 3D," said Zhao.

What one lab could never do alone

"When we're building the microscopes we envision, we constantly come up with new ideas," said Zhao. "I might want to modify a component or create something entirely new. But I don't know mechanical engineering, machining or even technical drawing. I only have the idea."

He could simply reach out to CIBR's instrumentation center and describe what he had in mind. Engineers would then help design, fabricate and refine the components needed to make them a reality. According to Zhao, many of the technologies developed during the project would not have been possible without this level of institutional support.

Recently, the team completed what it says is the world's first whole-mouse-brain imaging project at 30-nanometer resolution.

"The final dataset was about 2 petabytes," said Zhao. "The amount of data is almost unimaginable. Just storing it becomes a challenge."

To handle these datasets, they developed new data-compression algorithms and processing software from scratch.

"Many new technologies emerged from this project," Zhao said. "New microscopes, new sample-processing methods, new labeling techniques and new software systems. Some of them are beginning to move toward applications beyond the original project."

Such achievements, he emphasized, would have been impossible for a single laboratory to accomplish alone.

"The conditions provided by CIBR are extremely unique. There are only a handful of places in the world that can provide this kind of environment," Zhao noted.

A technology beyond seeing

The value of TESOS extends far beyond producing striking images. The technology could become foundational infrastructure for neuroscience and biomedical research.

TESOS method is expected to help scientists build detailed wiring diagrams of the brain and body, while providing new insights into neurological diseases.

"Our biggest vision is to apply three-dimensional transparent imaging to medical pathology," he said.

Traditional pathology examines only thin slices of tissue, leaving most of a specimen unseen. Zhao's team is exploring a new approach – making entire samples transparent and imaging them in three dimensions, a strategy that may improve diagnostic accuracy and efficiency.

What began as an effort to simply see the nervous system more clearly may ultimately reshape how scientists and doctors see biology itself.