How Shining Light Into the Brain Can Switch On an Erection or Switch Off Pain
Blue lights and gene therapy could potentially be used to treat blindness, PTSD, and obesity.
Image: Josh Jennings/Vimeo
Studying the brain can be like attempting marine biology from outer space—tools like dyes, electrodes, and MRIs provide some sense of active grey matter without harming the patient. These techniques don't let neurologists tinker with the individual mechanics of neurons, however. Now, at least in the lab, optogenetics—using light to control individual neurons in living creatures—has become one of the most important methods for gathering precise biological information about the brain.
Take anger. Like most other emotions, we still don't understand the precise neurological mechanism that produces it. In 2011, David Anderson and researchers at CalTech examined the ventrolateral region of the ventromedial hypothalamus (VMHvl), an area of the mouse brain shown to fire when mice get aggressive. They injected DNA encoded with a protein that was sensitive to blue light into about a thousand of the mouse brain's 40 million neurons. The researchers then aimed a blue light on the area through a tiny fiberoptic tube that snaked into the mouse's brain. When the blue light was on, the males turned aggressive with other mice—including females, which is uncommon—and even attacked an inflated rubber glove. When the light went off, so did the anger.
The ability to switch cells on and off instantaneously is the real key with optogenetics. Injections and pills can also switch off cells, but this can take time and is far less targeted. Optogenetics, which has been used to do everything from simulate the effects of ketamine to giving a mouse a boner, lets researchers isolate specific functions of cells.
A mammal's electrical wiring depends on gated channels in the cell membrane that shuttle ions in and out. This changes the charge and propagates an electrical signal, whether that's telling your finger to move or the cognitive process of interpreting these words. Dr. Christof Koch, chief science officer of the Allen Institute for Brain Science points out that brain activity is largely a game of patterns—how do thousands of neurons and millions of connections between those neurons fire in relation to one another to create a memory, summon an emotion, or twirl your fingers? Figuring out what each is doing has been one of researchers' biggest challenges.
"You need to know the detailed flow to these types of neurons," Koch says. "You want to be able to turn those neurons on and off."
But were optogenetics to become an actual clinical treatment technique, it could mean activating or deactivating parts of the brain or other tissues in the body. In April, researchers at Washington University were able to switch off portions of the mouse brain that caused pain. While most work with optogenetics has been on neurons, researchers are now testing other tissues like muscles and penises.
Anderson's lab has also explored the mouse's central amygdala and shown how to tinker with appetite, raising all kinds of hope about new diet controls.
A Google trends search for "optogenetics" shows the sharp increase in news about the technique in the last five years. Koch credits the fast expansion of the technique to open sharing about best practices. Stanford University, home of Dr. Karl Deisseroth, one of the technique's primary creators, posts reams of technical information for anyone to access.
Recently researchers in Germany showed that if they flashed a light at a mouse's larynx, they could actually control the little muscles that governed the windpipe
Here's (roughly) how optogenetics works. Scientists hunt down or develop proteins that activate when zapped with specific wavelengths of light—typically a dark blue. Members of channelrhodopsin, a protein family that helps algae detect light, are often used; when activated, they induce a change in a mammalian neuron's voltage potential. In neurons, this means ability to transmit a signal. Researchers then insert the gene that codes for that protein inside the cells—by no means an easy task, but one that's getting easier with better gene therapy techniques. As the organism starts generating the protein on its own, researchers can zap the relevant cells with light and induce the desired change with the cell.
Or as Koch puts it, "You hack nature."
Koch is effusive in noting how optogenetics has "profoundly" changed physiological research, but the concepts have been kicking around for a few decades. Francis Crick, who received the Nobel Prize for outlining the three dimensional structure of DNA, proposed stimulating cells with light in 1979. In the early 2000s, a group of scientists started making real advances with the technique, and in 2013 the Brain Research Foundation awarded its annual Brain Prize to Ernst Bamberg, Edward Boyden, Peter Hegemann, Gero Miesenböck, Georg Nagel, and Deisseroth for "their invention and refinement of optogenetics." Science magazine listed it as one of the breakthroughs of the decade.
Optogenetics has also done wild work in tinkering with memory. Nobel Prize winning MIT neuroscience professor Susumu Tonegawa's lab "switched" the emotional association mice had with certain memories. Using a fiber optic cable that pierced the mouse's skull and targeted the hippocampus—which records the particulars of memories—Tonegawa's team could make a mouse think that the part of the cage where it had recently been shocked was actually a relaxing place to hang out. The researchers believe that someday a similar technique could be used to treat post-traumatic stress disorder.
This kind of research could also help patients suffering from degenerative disorders such myotonic dystrophy or ALS, says Dr. Julio Vergara of UCLA's department of physiology studies. As neurons die, the muscles they control atrophy. But in many cases, the muscle cells are still healthy; they're just not receiving signals from the brain. "If the central nervous system can't access the muscles, we can use light," Vergara says.
Recently researchers in Germany showed that if they flashed a light at a mouse's larynx, they could actually control the little muscles that governed the windpipe. Click the light on; the larynx opens. Click it off; it closes.
As with most things science, it will probably be some time before we see these sorts of optogenetics applications outside the lab and inside living patients. Could the foreign proteins induce an allergic reaction? How fast does the protein degrade in the body? How do you keep the protein in the patient's cells? How do you keep light focused on the tissue if that tissue is deep inside a human? "All those questions have to be answered," Koch said.
He sees the first clinical application in treating blindness. Light naturally filters into the eyes so if the goal is to activate photoreceptors in the back of the eye to overcome blindness, no external lighting source is needed, as it is in the dark caverns of the brain. "You bypass the defect," he says.
But Koch concedes there is at least another decade of research before that kind of body hack could be reality. "That is the difference between demonstrating a proof of principle in a mouse," he says. "Anytime you're compromising the integrity of the skull, it takes a while."
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