Two important tools for elucidating the brain's anatomy and function and one of the creative minds behind them

Karl Deisseroth, a psychiatrist and neuroscientist in the Bioengineering Department at Stanford University, was reBrain imagecently portrayed in "Lighting the Brain" in the New Yorker magazine (18 May 2015). Several things about his personality and approach struck me. First, his interest in creative writing. His early dream in high school was to be a writer. As an undergraduate and also as a graduate student at Stanford in medicine and neuroscience he took writing classes. He remains an avid reader of fiction and poetry and is finishing a book of essays and short stories. Deisseroth says he perceives a connection between scientific inquiry and creative writing: "In writing, it's seeing the truth--trying to get to the heart of things with words and images and ideas. And sometimes you have to find unusual ways of getting to it."

What's he getting at? How has this approach manifest?

Deisseroth is atypical in working directly with psychiatric patients as well as conducting neuroscience research in the lab. He says that listening to his psychiatric patients provides a source of ideas and possible hypotheses and also concentrates his mind. He is motivated greatly by the frustration he feels firsthand when working with psych patients who are being prescribed medications without a clear understanding of how the brain works and of the mechanisms of psychiatric disease.

One depressed patient reported to Deisseroth that just looking at an object such as a piece of paper could fill him with hopelessness and dread. To Deisseroth, this way of phrasing the experience of depression was interesting. He could take that statement and design animal studies of object aversion to try to learn more about the disease and to characterize treatments.

Deisseroth manages to successfully compartmentalize the competing demands of his life (research, clinical practice, and family) so that he can focus and think through complex problems. For maximum creativity and problem-solving, he says he stops all physical activity, is completely still, and allows ideas to float up "like bubbles in liquid". After identifying a problem he wants to work on, he writes and sketches his ideas, drawing them to life, and identifying ways to chip away at the problem.

Deisseroth's two main contributions have been to successfully apply and extend optogenetic techniques in psychiatry and neurology research and to develop a technology ("CLARITY") to make biological tissues such as mammalian brains translucent and accessible to molecular probes.

In the 1970s, light-sensitive proteins called opsins typically found in eye photoreceptors were found in bacteria in saline lakes. Francis Crick, the co-discoverer of DNA structure, noted in 1979 that engineering a tool to turn specific neurons on and off using light would be highly valuable in neuroscience research. In 2002, Miesenbock at Sloan Kettering used an opsin from the fruit fly retina to render a brain cell light sensitive. This opsin required three proteins to act together; to adapt to a living animal meant having to import genes to code for all three proteins. In 2003, a German team discovered a microbial opsin (channelrhodopsin-2 ChR2) isolated from green algae that when introduced into human embryonic kidney cells converted light into electricity in a single step at virtually the speed of electrical impulses in the brain. Deisseroth together with PhD student Feng Zhang then isolated a rat neuron and introduced the ChR2 using a benign lentivirus. When the neuron was flashed with blue light, the cell produced strong action potentials. Further development by Deisseroth's lab in 2004-2009 extended this work in vivo and addressed the problems of targeting specific brain cells, ensuring that the ChR2 would only be produced in the desired neurons, and delivering light to the neurons via fiber-optic wires attached to a laser diode. Opsins can be used to "play in" behaviors (ie, cause a behavior) but also to "read out" behaviors (ie, determine circuit activity when a lab animal performs a behavior). Today thousands of labs worldwide are using optogenetic techniques in many areas of brain research.

Deisseroth's second major project, initiated in 2010, is a method of making brain tissue transparent using acrylamide-based hydrogels. This technique involves injecting a clear acrylamide hydrogel into the tissues, soaking the brain in warm water, and running a gentle electric current through the tissues to drive the fats out. What remains is the neural circuitry suspended in the transparent hydrogel. The CLARITY method, first reported in 2013, has been endorsed by the BRAIN Initiative and adopted as a critical piece in a connectomics project to map the mouse brain, comprising nearly a hundred billion neurons and hundred trillion connections. Papers using CLARITY have been published in areas of Alzheimer's disease and multiple sclerosis (MS) animal models.

Colapinto J. Lighting the brain. The New Yorker, May 18 2015, 74-83.

Chung K, Wallace J, Kim SY, Kalyanasundaram S, Andalman AS, Davidson TJ, et al. Structural and molecular interrogation of intact biological systems. Nature 2013; 497(7449):332-7.