Researchers at the University of Tokyo have achieved a groundbreaking advancement in biological imaging with the publication of a landmark paper in Cell, introducing the CUBIC Organ/Body Atlas. This innovative resource provides three-dimensional, single-cell-resolution maps of eleven adult mouse organs and an entire neonatal mouse body, revolutionizing how scientists study complex biological systems. Led by Prof. Hiroki R. Ueda from UTokyo's Department of Systems Pharmacology, the work builds on over a decade of pioneering tissue clearing techniques, enabling unprecedented whole-organ and whole-body visualization without slicing samples.

This breakthrough addresses long-standing challenges in microscopy, where light scattering in opaque tissues limited imaging depth. By rendering tissues transparent while preserving cellular structures, the atlas captures the precise coordinates of every cell, facilitating cellome-wide phenotyping—comprehensive analysis of all cells in an organism. The technique's application to newborn mice marks a first, offering insights into early developmental processes critical for understanding congenital diseases and organ formation.

🧬 Evolution of Tissue Clearing: UTokyo's CUBIC Legacy

Tissue clearing emerged as a transformative method in the early 2010s, making biological samples optically transparent for deep imaging. UTokyo's Ueda lab introduced CUBIC (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis) in a seminal 2014 Cell paper, pioneering hydrophilic reagents that delipidate, decolorize, and match refractive indices without damaging proteins. This allowed whole-brain imaging at single-cell resolution using light-sheet fluorescence microscopy (LSFM).

Over the years, advanced CUBIC protocols expanded to whole organs and bodies, incorporating electrolyte-gel models of tissues for uniform clearing. Protocols like CUBIC-L/R series optimized delipidation, staining, and decolorization steps, preserving fluorescence for months. UTokyo's iterative refinements, published in Nature Protocols and others, set global standards, with reagents now commercialized via CUBICStars.

• Hydrophilic solvents remove lipids while maintaining tissue integrity.
• RI-matching eliminates light refraction for uniform transparency.
• Compatible with immunostaining and genetic reporters for multi-omics integration.

In Japan, this positions UTokyo as a leader in bioimaging, fostering collaborations with RIKEN and fostering interdisciplinary higher education in systems pharmacology and pathology.

The Cell Paper: Unveiling the CUBIC Organ/Body Atlas

Published on February 25, 2026, in Cell (DOI: 10.1016/j.cell.2025.12.057), the paper by Ueda and colleagues details the atlas construction. Spanning UTokyo's Graduate School of Medicine, RIKEN, Osaka University, and Kurume University, the multinational effort optimized protocols for eleven organs (brain, heart, lung, liver, kidney, spleen, pancreas, intestine, bladder, testis, bone marrow) and a P1 (postnatal day 1) whole mouse body.

The atlas contains digitized cell coordinates, akin to a 'whole-cellome' map paralleling genomics atlases like the Allen Brain Atlas. JST-funded and announced in a UTokyo press release, it highlights Japan's investment in cutting-edge life sciences.

Key quote from the abstract: "The CUBIC Organ/Body Atlas contributes to establishing a common cellomics workflow for systems-level understanding of organisms."

Optimized Tissue Clearing Protocols

The core method refines CUBIC for diverse tissues. Tissues undergo perfusion fixation, delipidation with detergents like Triton X-100, decolorization via bleaching agents, and RI-matching with fructose or urea-based solutions. For newborn mice, gentler conditions prevent shrinkage, achieving >90% transparency in 3-7 days.

Step-by-step:

• Fixation: Paraformaldehyde perfusion preserves structure.
• Delipidation: Aminoalcohols and detergents remove lipids (48-72h).
• Decalcification/Staining: EDTA for bones; antibodies for proteins.
• Clearing: ScaleCUBIC-2 for final transparency.

exMOVIE: Engineering a New Era in Imaging

A novel LSFM system, exMOVIE (extended Multi-Objective Volumetric Imaging Engine), overcomes limitations of commercial setups. Featuring a long working distance (>10cm) and sub-micron axial resolution, it images whole organs in hours, stitching terabyte-scale volumes via BigStitcher.

For the neonatal body (∼1.5cm), it captured billions of cells, detecting nuclei via DAPI staining. Computational pipelines segment cells, generating probabilistic maps for registration across samples.

This hardware-software integration exemplifies UTokyo's translational research, bridging engineering and biology in graduate programs.

Mapping Millions: Atlases and Cell Insights

The atlas reveals organ-specific cell densities: e.g., brain ∼10^7 cells/cm³, liver higher due to hepatocytes. Newborn body maps highlight developmental gradients, with neural progenitors prominent.

Supplemental tables detail cell counts (Table S1), densities (S2). 3D immunostaining profiles immune cells body-wide, uncovering heterogeneity missed in 2D slices.

Transforming Developmental and Disease Research

In development, atlases track organogenesis, comparing P1 body to adult for growth trajectories. Disease applications include tumor mapping, as prior CUBIC visualized metastases.

Neuroscience benefits: circadian atlases (related Ueda work) overlay rhythms on structural maps.Cell paper For Japan, aids aging research amid demographic shifts.

Neuroscience Revolution: Brain-Wide Cellomics

Whole-brain atlases enable circuit mapping, complementing connectomics. Ueda's prior work imaged 72 million cells in adult brains; this extends to multi-organ context, revealing brain-immune interactions.

Potential: Alzheimer's plaque distribution, stroke recovery in 3D.

UTokyo's Role in Japan's Higher Ed Innovation

UTokyo's Systems Pharmacology integrates computation and experiment, training PhDs via RIKEN ties. Funded by JST/AMED, it exemplifies Japan's Moonshot program for cellomics.UTokyo press release (Japanese) Boosts Japan’s global rank in life sciences.

Explore research jobs in bioimaging at Japanese universities.

Photo by mos design on Unsplash

Future Horizons and Collaborative Potential

Atlas paves for human-scale clearing, AI-driven analysis. Ueda envisions 'cellomics' as genomics successor. Global data sharing via CUBIC-Cloud accelerates discoveries.

For academics, opportunities in Japanese higher ed abound. Check Rate My Professor for Ueda's courses, higher ed jobs, and career advice. Japan leads; join the revolution.