Structural and molecular interrogation of intact biological systems.
Chung, Kwanghun 1,2; Wallace, Jenelle 1; Kim, Sung-Yon 1; Kalyanasundaram, Sandhiya 2; Andalman, Aaron S. 1,2; Davidson, Thomas J. 1,2; Mirzabekov, Julie J. 1; Zalocusky, Kelly A. 1,2; Mattis, Joanna 1; Denisin, Aleksandra K. 1; Pak, Sally 1; Bernstein, Hannah 1; Ramakrishnan, Charu 1; Grosenick, Logan 1; Gradinaru, Viviana 2; Deisseroth, Karl 1,2,3,4,*
[Article] Nature. 497(7449):332-337, May 16, 2013.

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: Obtaining high-resolution information from a complex system, while maintaining the global perspective needed to understand system function, represents a key challenge in biology. Here we address this challenge with a method (termed CLARITY) for the transformation of intact tissue into a nanoporous hydrogel-hybridized form (crosslinked to a three-dimensional network of hydrophilic polymers) that is fully assembled but optically transparent and macromolecule-permeable. Using mouse brains, we show intact-tissue imaging of long-range projections, local circuit wiring, cellular relationships, subcellular structures, protein complexes, nucleic acids and neurotransmitters. CLARITY also enables intact-tissue in situ hybridization, immunohistochemistry with multiple rounds of staining and de-staining in non-sectioned tissue, and antibody labelling throughout the intact adult mouse brain. Finally, we show that CLARITY enables fine structural analysis of clinical samples, including non-sectioned human tissue from a neuropsychiatric-disease setting, establishing a path for the transmutation of human tissue into a stable, intact and accessible form suitable for probing structural and molecular underpinnings of physiological function and disease.

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