Creative Minds: Modeling Neurobiological Disorders in Stem Cells

Feng Zhang

Feng Zhang

Most neurological and psychiatric disorders are profoundly complex, involving a variety of environmental and genetic factors. Researchers around the world have worked with patients and their families to identify hundreds of possible genetic leads to learn what goes wrong in autism spectrum disorder, schizophrenia, and other conditions. The great challenge now is to begin examining this growing cache of information more systematically to understand the mechanism by which these gene variants contribute to disease risk—potentially providing important information that will someday lead to methods for diagnosis and treatment.

Meeting this profoundly difficult challenge will require a special set of laboratory tools. That’s where Feng Zhang comes into the picture. Zhang, a bioengineer at the Broad Institute of MIT and Harvard, Cambridge, MA, has made significant contributions to a number of groundbreaking research technologies over the past decade, including optogenetics (using light to control brain cells), and CRISPR/Cas9, which researchers now routinely use to edit genomes in the lab [1,2].

Zhang has received a 2015 NIH Director’s Transformative Research Award to develop new tools to study multiple gene variants that might be involved in a neurological or psychiatric disorder. Zhang draws his inspiration from nature, and the microscopic molecules that various organisms have developed through the millennia to survive. CRISPR/Cas9, for instance, is a naturally occurring bacterial defense system that Zhang and others have adapted into a gene-editing tool.

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Cool Videos: Reconstructing the Cerebral Cortex

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This colorful cylinder could pass for some sort of modern art sculpture, but it actually represents a sneak peak at some of the remarkable science that we can look forward to seeing from the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. In a recent study in the journal Cell [1], NIH grantee Jeff Lichtman of Harvard University, Cambridge, MA and his colleagues unveiled the first digitized reconstruction of tissue from the mammalian cerebral cortex—the outermost part of the brain, responsible for complex behaviors.

Specifically, Lichtman’s group mapped in exquisite detail a very small cube of a mouse’s cerebral cortex. In fact, the cube is so tiny (smaller than a grain of sand!) that it contained no whole cells, just a profoundly complex tangle of finger-like nerve cell extensions called axons and dendrites. And what you see in this video is just one cylindrical portion of that tissue sample, in which Licthtman and colleagues went full force to identify and label every single cellular and intracellular element. The message-sending axons are delineated in an array of pastel colors, while more vivid hues of red, green, and purple mark the message-receiving dendrites and bright yellow indicates the nerve-insulating glia. In total, the cylinder contains parts of about 600 axons, 40 different dendrites, and 500 synapses, where nerve impulses are transmitted between cells.

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Creative Minds: Meet a Theoretical Neuroscientist

Sean Escola

Sean Escola

Most neuroscientists make their discoveries in a traditional laboratory or clinical setting. Sean Escola, a theoretical neuroscientist at Columbia University in New York, just needs a powerful computer and, judging from his photo, a good whiteboard.

Using data that he and his colleagues have recorded from living brain cells, called neurons, Escola crunches numbers to develop rigorous statistical models that simulate the activity of neuronal circuits within the brain. He hopes his models will help to build a new neuroscience that brings into sharper focus how the brain’s biocircuitry lights up to generate sensations and thoughts—and how it misfires in various neurological disorders, particularly in mental illnesses.

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