Karl Deisseroth is using light as a type of remote control to manipulate cells and tease out the daunting complexity of muscle, heart tissue, and particularly brain tissue.

Deisseroth, an HHMI early career scientist at Stanford University, is part of a growing community of researchers, including several HHMI investigators, who draw upon genomics, genetic engineering, biochemistry, molecular biology, microbiology, biophysics, bioengineering, and optics to tease out the complexities of brain circuitry and to manipulate researcher-specified cells (such as the motor cortex cells of the marching mouse) among thickets of diverse cell types.

Patients with optical fibers inserted into their brains are not on the agenda, says Deisseroth, a psychiatrist who sees patients one day a week. But the laboratory approaches he and others have been developing could reveal telling details about healthy and dysfunctional brains that point the way to improved treatments for people. Today's therapies—drugs, electroshock, surgery—sometimes work. But “they are crude and have side effects,” he says, because they are not very selective about the cells and tissues they affect. “My patients have motivated me to find elegant tools that speak the language of the brain.”

Edward Boyden, a former postdoctoral fellow of Deisseroth who now runs the Synthetic Neurobiology Group at the Massachusetts Institute of Technology, has taken early steps in the direction of human applications. In April 2009, he and colleagues published a paper in Neuron reporting that the same kind of protocol underlying the marching mouse can work, apparently safely, in macaque monkeys. And in 2008, he and two colleagues launched the start-up Eos Neuroscience in San Francisco, whose mission, according to its website, is to “develop treatments for chronic neurological disorders.”

Fixing brains is quite an ambition for a field that commandeered its core technology from single-celled organisms.

Bacteria, fungi, plants, and other organisms use a repertoire of molecular switches that respond to light. Spanning the membranes of many of these microbial species are light-activated gates and pumps that control the passage of positively charged sodium, potassium, calcium, and hydrogen ions or negatively charged chloride ions.

Those ancient, light-activated membrane gates and pumps can be transferred into other cells of the living kingdom, including mammalian brain and muscle cells, with genetic engineering techniques. Once transferred, those mobile modules become controllable with light. “If you can do that,” says synthetic biologist and HHMI investigator Wendell Lim at the University of California, San Francisco (UCSF), “you have an extraordinarily powerful tool. You can use light to perturb systems and modify them. We can get a kind of systematic control that we have not had before.”

Photo: Darcy Padilla

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