With accolades like “method of the year” and “breakthrough of the decade,” it’s easy to assume that optogenetics—a scientific technique for turning neurons on and off using light—is, indeed, a game-changing technology. The technique has already shown promise for treating blindness,1 quieting seizures,2 and homing in on the genetic causes of brain disorders like Parkinson’s disease.3 It has also played a large role in enabling the NIH’s BRAIN Initiative, which aims to map the activity of every cell in the human brain. But, has it lived up to its hype? And what does the future hold for using optogenetics beyond simply studying how the brain works—can it also be useful in treating diseases as diverse as autism, PTSD, and depression?
Optogenetics uses light to control neurons that have been made artificially sensitive to illumination. In the lab, scientists employ viruses to introduce genes for light-sensitive proteins into neurons. First discovered in microbes, these naturally occurring proteins, called opsins, react to light. Some proteins react to light by turning neurons on, or prompting them to fire, while others turn off neuronal activity. In this way, optogenetics targets specific, modified neurons in order to discover their function and how they’re connected within larger neuronal networks.
In 2005, Dr. Karl Deisseroth, a bioengineering professor at Stanford University and a member of the Howard Hughes Medical Institute, and then-graduate students Dr. Edward Boyden (now at MIT) and Dr. Feng Zhang (now also at MIT), published the first paper demonstrating the use of microbial opsin genes to control neuronal activity.4 In 2010, Nature Methods named optogenetics “Method of the Year,”5 and Science called it one of several “Breakthroughs of the Decade.”6
Optogenetics has indeed, come a long way since 2005. Its most valuable feature as a cutting-edge neuroscience tool is that it offers an unmatched level of precision in its ability to affect a specific neuron at a specific time.
Opsin proteins come from bacterial or algal genomes, where they fulfill their roles as light-activated membrane ion channels. Opsin genes are introduced into specific neurons via transfection where a virus transfers both the gene and its promoter into the host cell’s genome. “Thousands of labs around the world are now using these optogenetic techniques, and thousands of papers have been published with these methods,” Deisseroth says.
There are many tools in use, including engineered opsins that can be targeted to single neurons, groups of neurons, and connections between regions of the brain. Modified opsins include those engineered to recognize different colors of light (red, blue, or yellow); those that are activated quickly or slowly; and those that simply turn neurons on or off, resulting in a binary circuit that has many futuristic applications such as altering memories. Opsin-targeting strategies, Deisseroth says, are also using specialized viruses that only insert the opsin gene into cells of interest. “A key moment was when we were able to solve the structure of the microbial channel opsin, which allowed us to engineer it at will.”7,8,9
Recently, Ed Boyden’s group at MIT developed a “fast” opsin called Chronos,10 as well as two more opsins that are sensitive to red light, Chrimson and Jaws,11 which activate and silence neurons respectively. It’s nice, Boyden notes, “because it goes deep in tissue,” reaching regions that were previously untouchable by standard fiberoptic tools consisting of lasers that send light to very small implanted optical fibers.12 “One of the obstacles to applying optogenetics is how to deliver light deep in the tissue or body,” Dr. Hiromu Yawo, a neuroscientist doing cutting-edge opsin engineering at Tohoku University, says. Fiber optic light sources are mainly used today; however, Deisseroth indicates that two-photon “spots” of light have been successfully used in living animals.
When dreaming about the future of optogenetics, it’s important to consider that it is still early days. “We don’t have good maps of the brain, so using optogenetics is difficult for many scientific questions,” Boyden says. “We don’t often know where to stimulate.”
Activating deep brain tissue is also problematic. “As the visible light is absorbed by the tissue, the light sources have to be embedded in it for the optogenetic manipulation of deep tissue,” Yawo says. Infrared can go deep, but to date there is no opsin sensitive to this type of light. Additionally, viral vectors are difficult to apply to humans; neuronal selectivity depends on targeted promoters reaching their place in the genome. According to Yawo, these promoters are “mostly unidentified” in humans. “Even if identified, [the gene] is often too large to deliver efficiently or it is too weak to produce enough number of molecules to generate [a] response.”
There’s also cost. Says Deisseroth, “the main disadvantages include the light power requirements associated with targeting large numbers of individually specified cells. That requires fairly advanced and costly lasers.” However, standard optogenetics control is “actually relatively easy and cheap to do now, and we run training classes at Stanford to help people out in getting started,” he says.
While it has been mainly used as a way to study how individual neurons fire alone or in concert with other neurons or circuits of neurons, a slew of recent papers have helped elucidate pathways of many different diseases. For instance, research has demonstrated the use of optogenetics on D1 and D2 cells (types of dopamine receptors) in the striatum13 and subthalamic nucleus14 in mice, as a way to explore their role in Parkinson’s disease. Other work has involved finding what cells can be manipulated to alter fear memories, applicable to treating PTSD and other illnesses that revolve around conditioned fear responses;15 elucidating neural networks involved in autism;16 and testing the causal link between dopamine expression and positive reinforcement in mental health disorders like addiction17 and depression.18 Clinically, optogenetics could theoretically be used to treat diseases as diverse as Parkinson’s disease, PTSD, autism, schizophrenia, addiction, and depression, to name a few.
The future of optogenetics seems wide open. GenSight Biologics19, a company founded by leaders in the fields of ophthalmology and optogenetics, is aiming to use the technique to treat blindness caused by diseases resulting from cell loss in the retina, including glaucoma and retinal pigmentosa. Using optogenetics on other cell types has already gained some traction in research labs, with cardiac cells and stem cells being some of the prime non-neuronal targets. It’s also been adapted to study biochemical, instead of electrical, events, “opening the door to control of specific events in any cell in biology,” Deisseroth says. According to Yawo, events as diverse as “ionic microenvironment, signal transduction, enzymatic activity, and gene regulation are now under the targets of optogenetics.”
Optogenetics is being used in conjunction with other technologies too, to speed up the translation from lab to clinic. In a recent Science paper,20 scientists at the University of Geneva used a combination of deep brain stimulation—a proven tool to treat Parkinson’s disease—and a drug to block specific dopamine receptors to produce an “optogenetic-like” effect in lab mice. Ultimately, the mice’s cocaine use was reduced, underscoring the possibility of achieving the same effect in humans without having to solve the technological hurdles that applying optogenetics poses.
“The future is continued widespread use as a research tool,” Deisseroth says, to advance our still-small understanding of how individual neurons function in larger circuits. Indeed, when it comes to the brain, the whole is much greater than the sum of its parts, and optogenetics might be the best bet for probing not only deep, but far and wide.
Editor’s Note: Listen to Ed Boyden discuss his research in The Scientist’s on-demand webinar: New Models and Tools for Studying Synaptic Development and Function.
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