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Age of Enlightenment

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Yet for all that optogenetics has revealed in experiments with rodents, it’s not clear how or even whether similar techniques might work in the human brain. To answer that question, researchers need to demonstrate that opsins can control neurons in primates and affect their behavior.

An important step came in 2009, when Ed Boyden, working with MIT neuroscientist Robert Desimone and then postdoctoral scholar Xue Han, showed that he could optogenetically control the firing of ChR2 neurons in the rhesus monkey brain, safely and over the long term. Then Boyden worked with MGH’s Vanduffel to manipulate a subtle behavior in primates. In a study published in the Sept. 25, 2012 issue of Current Biology, the scientists targeted a well-defined neural circuit involved in a task often used to study visual perception in monkeys and humans.

For this task, two monkeys gaze at a focal point on a computer screen and move their gaze only when there’s a certain visual cue in the periphery of their view. If successful, they receive a sip of apple juice. The researchers inserted ChR2 (the light-activated protein that excites neurons) into a brain region in which signals from the retina mingle with those from the front of the brain containing information about what to pay attention to and what rewards to expect. By illuminating those neurons, both monkeys performed the task measurably faster, though nothing else about their behavior was altered. That meant the intervention had discretely targeted a key neural pathway involved in this task, and it augmented the neural circuit and enhanced performance.

Simultaneous fMRI scans of the monkeys’ brains showed that the focused stimulation activated a distributed network of brain regions previously seen in brain imaging studies of the task. “That confirmed that the stimulated region was functionally connected and was doing what it was supposed to do,” says Rosen, who helped with this part of the study.

For this technology to become useful in people, it will have to overcome two significant obstacles—optogenetics’ physical invasiveness and the need to use gene therapy to infect human neurons with light-activated opsins.

On the first count, though optogenetics would require implants into the brain, optic fibers are smaller, narrower and more pliable than Deep Brain Stimulation (DBS) electrodes, and scientists are developing materials that will be more compatible with brain tissue. Boyden is working on less invasive techniques, including a wireless method to control light probes. He’s also developing opsins that respond to red light, because red light waves travel farther through the body’s tissue than other kinds of light, and so could illuminate a larger area and require fewer implants. On the horizon, artificial cellular receptors that are activated by drugs rather than by light could eliminate the need to have an optic device in the brain or body.

Moreover, while past gene therapy trials have had problems, Rosen believes the research is progressing, noting examples of genetic manipulation using viruses to target immune systems in end-stage cancer patients. Most likely, the first optogenetic applications will be for severely ill patients who would be candidates for DBS—people with Parkinson’s, epilepsy or severe depression—and also for certain kinds of blindness and spinal cord injury, which would not require tampering with the brain itself. In the case of blindness, opsins introduced into the retinal cells could fire upon exposure to natural light, perhaps filtered and preprocessed by specialized eyeglasses.

Farther down the road, Boyden envisions being able to use optogenetics to overcome cognitive and other deficits in patients with disabilities or neurodegenerative disorders.

Yet if and when optogenetics has direct therapeutic applications, the value of those are likely to be dwarfed by continuing discoveries in basic science, suggests Stanford’s Deisseroth. Already, he says, “just having a better understanding that these behavioral symptoms result from an explicit problem in the brain’s circuit can help my patients seeking to understand their troubling symptoms.”

And while optogenetics may never answer all of the questions about the brain’s daunting complexity, it could continue to help us understand what’s going on in the brains of millions of people with mental illnesses, depression or uncontrolled aggression, or those suffering from trauma, developmental brain disorders and degenerative brain diseases. And that knowledge, says Boyden, an engineer at heart, could lead to new approaches to therapy. Once you know how a complex system goes wrong, he says, you can figure out how to fix it.

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

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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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