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THE MARRIAGE OF OPTICS AND GENETICS:
A promising young union // that controls the firing of particular neurons // which have been reengineered to be activated by light // uncovering the brain’s mysteries with a flash

Age of Enlightenment

By Cathryn Delude // Photographs by Sam Kaplan // Spring 2013
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Photograph by Sam Kaplan

Much of what science knows about the human brain has come through deduction. If a stroke or trauma has destroyed a particular area, researchers can look at what that person can no longer do—talk, move the left pinky, do math—and infer that the affected region is linked to that behavior. In animal models, researchers often produce lesions artificially, or they inject a drug to inhibit or excite neural activity in a specific area. Yet as important as this approach has been, there are many things it can’t accomplish. Chief among those is pinpointing which of the many kinds of cells in a given brain region are the ones that matter.

As a result, when it comes to autism, Alzheimer’s disease and a long list of mental illnesses, what we do understand is dwarfed by all that we can only imagine. Treatments, too, are often a matter of trial and error. To try to prevent intractable epileptic seizures, for example, surgeons may destroy a part of the brain they believe is implicated. Often it works; sometimes it doesn’t. Understanding aberrant behavior, obsessive thoughts, learning disabilities, depression, anxiety, aggression—for all of those, the learning curve remains very steep.

Much of the problem stems from the brain’s sheer complexity. “It’s made of 100 billion interconnected cells, which fall into many distinct classes—differing by shape, molecular composition and function—and which change in different ways in different brain disorders,” says Edward Boyden, a neuroscientist and biological engineer in the MIT Media Lab, whose goal is to develop technologies for “fixing the broken brain.” But it’s not just the number of neurons that makes the brain so challenging; it’s also that they fire in essentially arbitrary numbers of patterns depending on what we are doing, perceiving and thinking, how we feel emotionally and whether we are well or sick. Moreover, some neurons excite other neurons, some inhibit others, and some fine-tune how sensitive other neurons are to being excited or inhibited. Neurons within the same brain region may connect to others locally or use long arms called axons to reach remote parts of the brain. Further complicating attempts to make sense of all this, diverse types of neurons are likely to be tightly intermingled in tiny volumes of brain tissue.

In 1979, Francis Crick, who helped discover the structure of DNA in the 1950s and later turned to neuroscience, cautioned that scientists could never understand the brain unless they could precisely control discrete sets of neurons to see what they do. “Without that level of understanding, I realized we cannot fully help patients with depression, schizophrenia and autism,” says Karl Deisseroth, a psychiatrist and neuroscience researcher at Stanford University.

But a new technology, optogenetics, which Deisseroth and Boyden helped develop at Stanford, along with Feng Zhang, a graduate student in Deisseroth’s lab, and two other researchers from Germany, Georg Nagel and Ernst Bamberg, could finally begin to map the brain’s vast frontiers. Combining optics and genetics, optogenetics allows scientists to control individual classes of neurons distributed among many other cell types—and with a flash of light.

Introduced in 2005, optogenetics remains a young technology. Yet like a child prodigy, it has garnered rave reviews. It has been called transformative, exquisite and a great leap forward. Researchers around the world are using it to illuminate—literally and figuratively—the mysterious brain and to investigate links between brain circuits and specific behaviors with a precision that could only have been imagined less than a decade ago.

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Raising the Voltage

Scientist Walter Rudolf Hess conducted one of the first experiments to test whether neural activity in a defined part of a cat's brain causes specific actions.

What’s Next for Optogenetics?

Using flashes of light to control brain cells may be only the beginning for a remarkable research tool.

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hed-dossier

1. “A History of Optogenetics: The Development of Tools for Controlling Brain Circuits with Light,” by Edward S. Boyden, F1000 Biology Reports, May 3, 2011. This account of the development of optogenetics, by one of its inventors, includes middle-of-the-night “aha!” moments, with credit given to other researchers and to serendipity.

2. “Dopamine Neurons Modulate Neural Encoding and Expression of Depression-Related Behaviour,” by Kay M. Tye et al., Nature, January 2013. This study provided new insights into the role of dopamine in symptoms of depression by probing for the underlying neural circuits. The researchers integrated optogenetics with electrophysiology and pharmacology and used specially designed devices to precisely track behavior.

3. “Optogenetics, Sex, and Violence in the Brain: Implications for Psychiatry” by David J. Anderson, Biological Psychiatry, June 15, 2012. This study found a surprising neural link between aggression and sex, raising provocative questions about whether faulty wiring could account for some sexual pathologies.

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