Journal
NATURE CHEMICAL BIOLOGY
Volume 14, Issue 4, Pages 352-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-018-0004-9
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Categories
Funding
- Lefler Center for the Study of Neurodegenerative Disorders
- HHMI Simons Faculty Scholars Program
- IET Harvey Prize
- MIT Media Lab
- New York Stem Cell Foundation-Robertson Award
- Human Frontier Science Program [RGP0015/2016]
- NIH [1R43MH109332, 1R24MH106075, 2R01DA029639, 1R01EY023173, 1R01NS087950, 1R01MH103910, 1R01GM104948]
- NIH Director's Pioneer Award [1DP1NS087724]
- Simons Fellowship
- Samsung Fellowship
- NSF Fellowship
- Open Philanthropy Project
- NATIONAL EYE INSTITUTE [R01EY023173] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM104948] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R24MH106075, R01MH103910, R43MH109332] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS087950, R01NS104892, DP1NS087724, U01NS099691] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA029639] Funding Source: NIH RePORTER
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We developed a new way to engineer complex proteins toward multidimensional specifications using a simple, yet scalable, directed evolution strategy. By robotically picking mammalian cells that were identified, under a microscope, as expressing proteins that simultaneously exhibit several specific properties, we can screen hundreds of thousands of proteins in a library in just a few hours, evaluating each along multiple performance axes. To demonstrate the power of this approach, we created a genetically encoded fluorescent voltage indicator, simultaneously optimizing its brightness and membrane localization using our microscopy-guided cell-picking strategy. We produced the high-performance opsin-based fluorescent voltage reporter Archon1 and demonstrated its utility by imaging spiking and millivolt-scale subthreshold and synaptic activity in acute mouse brain slices and in larval zebrafish in vivo. We also measured postsynaptic responses downstream of optogenetically controlled neurons in C. elegans.
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