Structural and molecular interrogation of intact biological systems

Kwanghun Chung, Jenelle Wallace, Sung Yon Kim, Sandhiya Kalyanasundaram, Aaron S. Andalman, Thomas J. Davidson, Julie J. Mirzabekov, Kelly A. Zalocusky, Joanna Mattis, Aleksandra K. Denisin, Sally Pak, Hannah Bernstein, Charu Ramakrishnan, Logan Grosenick, Viviana Gradinaru, Karl Deisseroth

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Abstract

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.

Original languageEnglish
Pages (from-to)332-337
Number of pages6
JournalNature
Volume497
Issue number7449
DOIs
Publication statusPublished - 2013 May 16

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All Science Journal Classification (ASJC) codes

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Cite this

Chung, K., Wallace, J., Kim, S. Y., Kalyanasundaram, S., Andalman, A. S., Davidson, T. J., Mirzabekov, J. J., Zalocusky, K. A., Mattis, J., Denisin, A. K., Pak, S., Bernstein, H., Ramakrishnan, C., Grosenick, L., Gradinaru, V., & Deisseroth, K. (2013). Structural and molecular interrogation of intact biological systems. Nature, 497(7449), 332-337. https://doi.org/10.1038/nature12107