Projects

To accurately assess the quality and positive/negative effects of advanced medical technologies, it is required to systemically analyze the distribution of administrated pharmaceutics as well as the biological response to such treatment. To this end, we have developed one of the world’s best tissue clearing, three-dimensional imaging, and image informatics pipeline named CUBIC, which enables multiple single-cell resolution imaging of whole organ and whole body and their quantitative analysis (Susaki, Cell 2014 and other publications). We have completed a quantitative comparative analysis of whole-brain neural activities in mice under several experimental conditions (Tatsuki, Neuron 2016; Murakami Nat Neurosci. 2018; Matsumoto Nat Protocols 2019). Furthermore, we have successfully established a basic pipeline for visualizing biopharmaceuticals and the biological responses to them at the whole-organ and whole-body scale (Kubota, Cell Rep. 2017; Tainaka, Cell Rep. 2018 et al.). We have licensed the technology to several companies and have entered into collaborative research agreements with them.
Based on these backgrounds, here we aim to accelerate and advance the whole-organ and whole-body imaging and informatics technology, notably solving the remaining technical obstacles. We will 1) establish an efficient three-dimensional histological staining technique, 2) further update the tissue clearing protocol, 3) construct single-cell resolution atlases as a reference for image informatics, and 4) create a package of these elemental technologies for licensing and distribution to companies. The project will provide a world-leading platform for cell labeling, tissue clearing, three-dimensional imaging, and analysis that contributes to the development and application of advanced medical technologies.

Figure 1: Chart of team organization
Under the principal investigator (Prof. Hiroki Ueda, Graduate School of Medicine, The University of Tokyo), we promote the research regarding “Development of whole-organ/body-scale evaluation technology for advanced medical technology.” The collaboration team at RIKEN (Dr. Rikuhiro Yamada, RIKEN Center for Biosystems Dynamics Research) is in charge of developing single-cell resolution organ atlases and conducting application studies. We have already introduced state-of-the-art light-sheet microscopes and tissue clearing/3D staining technologies.

Figure 2: Application of CUBIC technology 1: Whole-brain imaging and analysis of neuronal activities
Using a transgenic mouse strain (Arc-dVenus Tg) capable of labeling neural activities, we collected whole-brain images of mice with or without administration of MK-801, an NMDA receptor inhibitor. By our subsequent image analysis, we successfully identified neuronal cell groups exhibiting a specific response. Modified from Tatsuki et al. Neuron (2016) 90:70-85.

Figure 3: Application of CUBIC technology 2: a systemic analysis of cancer metastasis
We analyzed the mCherry-labeled cancer cell distribution in a mouse model by whole-body imaging using a light sheet microscope. We successfully detected micrometastases and performed their quantitative analysis by high-resolution imaging using a confocal microscope. Modified from Kubota et al. Cell Reports (2017) 20: 236-250.