Structural and molecular interrogation of intact biological systems
Open accessAbstract
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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CLARITY is a clearing technique that transforms intact brain tissue into nanoporous, lipid-free, hydrogel-tissue hybrids that are optically transparent but macromolecule permeable.
“Clear Lipid-exchanged, Anatomically Rigid, Imaging/immunostaining compatible, Tissue hYdrogel (CLARITY; Chung et al., 2013) is a clearing technique that transforms intact brain tissue into nanoporous, lipid-free, hydrogel-tissue hydrids that are optically transparent but macromolecule permeable.”
From The role of myelination in measures of white matter integrity: Combination of diffusion tensor imaging and two-photon microscopy of CLARITY intact brains (2017) · cites this paper as Chung et al., 2013
The Abstract describes CLARITY as transforming intact tissue into a nanoporous, optically transparent, macromolecule-permeable hydrogel hybrid; the ‘Hydrogel-electrophoretic tissue transmutation’ section describes lipid extraction. However, the citing sentence expands the acronym differently from the paper’s Methods > CLARITY section, which specifies ‘Acrylamide-hybridized Rigid’ rather than ‘Anatomically Rigid.’ (LLM, conf=0.84)
Experimental — accuracy not yet measuredCLARITY could be successfully performed despite the presence of a contrast agent in the hydrogel and minor deviations from the original published protocol.
“This demonstrated that CLARITY could be successfully performed despite the presence of a contrast agent in the hydrogel and minor deviations from the original published protocol (Chung et al., 2013).”
From The role of myelination in measures of white matter integrity: Combination of diffusion tensor imaging and two-photon microscopy of CLARITY intact brains (2017) · cites this paper as Chung et al., 2013
CLARITY achieves tissue transparency to enable deep laser penetration in normally highly light-scattering mouse brains, while preserving proteins in situ and the native 3D structure of brain tissue.
“CLARITY achieves tissue transparency to enable deep laser penetration in normally highly light-scattering mouse brains, while preserving proteins in situ and the native 3D structure of brain tissue.”
From The role of myelination in measures of white matter integrity: Combination of diffusion tensor imaging and two-photon microscopy of CLARITY intact brains (2017) · cites this paper as Chung et al., 2013
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- Authors
- 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.
- Affiliations
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Deisseroth, Karl
- ORCID
- Venue
- Nature
- Published
- 2013-04-10
- Volume
- 497
- Issue
- 7449
- Pages
- 332-337
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4092167
- OpenAlex
- W2076507262
- Cited by
- 2,008
- References
- 4
- Citations by year
- 2026: 83 · 2025: 112 · 2024: 115 · 2023: 104 · 2022: 144 · 2021: 183 · 2020: 187 · 2019: 164 · 2018: 185 · 2017: 165 · 2016: 187 · 2015: 170 · 2014: 129 · 2013: 78
- FWCI
- 114.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation
- Howard Hughes Medical Institute
- National Institutes of Health (DP1OD000616)
- Defense Advanced Research Projects Agency
- Samsung
- National Institute of Mental Health (R01MH099647)
- National Institute on Drug Abuse (R01DA020794, R37DA035377)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Cell Image Analysis Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- clarity, tissue transparency, hydrogel crosslinking, macromolecule permeability, mouse brain, human brain tissue, in situ hybridization, antibody labeling, lipid removal, formalin-fixed tissue, neuropsychiatric disorders
- MeSH terms
- Animals, Brain, Cross-Linking Reagents, Formaldehyde, Humans, Lipids, Permeability, Phenotype, Scattering, Radiation, In Situ Hybridization, Hydrogel, Polyethylene Glycol Dimethacrylate, Imaging, Three-Dimensional, Mice, Molecular Imaging
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