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Understanding and repairing complex biological systems, such as the
brain, requires new technologies that enable such systems to be
observed and controlled with great precision, across extended spatial
and temporal scales. We are discovering new molecular principles that
are leading to such technologies. For example, we recently discovered
that it was possible to physically magnify biological specimens
manyfold, in an even way, by embedding them in dense swellable
polymers, mechanically homogenizing the specimens, and then adding
water to isotropically swell the specimens. In this method, which we
call expansion microscopy (ExM), we enable scalable, inexpensive
diffraction-limited microscopes to do large-volume nanoscopy, in a
multiplexed fashion – important, for example, for brain mapping. As
another example, we discovered that microbial opsins, genetically
expressed in neurons, could enable their electrical activities to be
precisely driven or silenced in response to millisecond timescale
pulses of light. These tools, called optogenetic tools, are enabling
causal assessment of the contribution of defined neurons to behaviors
and pathologies in a wide variety of basic science settings. Finally,
we have developed new methods of directed evolution, and discovered
mutant forms of optogenetic tools that enable precision fluorescent
imaging of the high-speed voltage of neurons in the living brain. We
share all these tools freely, and aim to integrate the use of these
tools so as to lead to comprehensive understandings of neural
circuits.
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