Using light-sensitive proteins from a single-celled alga and a tiny LED “cuff” placed on a nerve, researchers have triggered the leg muscles of mice to contract in response to millisecond pulses of light.
The study, published in the journal Nature Medicine, marks the first use of the nascent technology known as optogenetics to control muscle movements. Developed by study coauthor Karl Deisseroth, an associate professor of bioengineering and of psychiatry and behavioral science at Stanford University, optogenetics makes it possible to stimulate neurons with light by inserting the gene for a protein called channelrhodopsin-2, from a green alga. When a modified neuron is exposed to blue light, the protein initiates electrical activity inside the cell that then spreads from neuron to neuron. By controlling which neurons make the protein, as well as which cells are exposed to light, scientists can control neural activity in living animals with unprecedented precision. The paper’s other senior author, Scott Delp, a professor of bioengineering, mechanical engineering, and orthopedic surgery at Stanford, says that the optical control method provides “fantastic advantages over electrical stimulation” for his study of muscles and the biomechanics of human movement.
Members of Deisseroth’s lab had engineered mice to produce channelrhodopsin-2 in both the central and the peripheral nervous systems. Michael Llewellyn, a former graduate student in Delp’s lab, developed a tiny, implantable LED cuff to apply light to the nerve evenly. He placed the cuff on the sciatic nerves of anesthetized mice and triggered millisecond pulses of light. This caused the leg muscles of the mice to contract. When Llewellyn compared the muscle contractions stimulated by light to those generated using a similar electrical cuff, he found that the light-triggered contractions were much more similar to normal muscle activity.
Muscles are made up of two different fibers: small, slow, fatigue-resistant fibers that are typically used for tasks that require fine motor control over longer periods, and larger, faster fibers that can produce higher forces but are more fatigue-prone. In the body, the small, slow fibers are activated first, with the large, fast fibers reserved for quick bursts of power or speed. When muscles are stimulated with electrical pulses, the fast fibers activate first. With the optogenetic switch, however, the fibers were recruited in the normal, physiological order: slow fibers first, fast fibers second. By altering the intensity of the light, Llewellyn found that he could even trigger only the slow fibers–a feat not possible with electrical stimulation.
In the near term, Delp says, the technology will improve the studies that his lab and others do on muscle activity in animal models of stroke, palsies, ALS, and other neuromuscular disorders. He also hopes that in time–a long time, he concedes–such optical switches could be used to help patients with physical disabilities caused by nerve damage such as stroke, spinal cord injury, or cerebral palsy. One possibility, he says, would be to use optical stimulation in place of functional electrical stimulation (FES), in which electrical current is applied to specific nerves or muscles to trigger muscle contractions. The U.S. Food and Drug Administration has already approved FES devices that can restore hand function and bladder control to some paralyzed people. However, FES can quickly lead to muscle fatigue. Delp hopes that, particularly with grasping functions, using optical stimulation might result in better fatigue resistance and perhaps finer muscle control.
“This is a brilliant study, really beautiful science,” says Robert Kirsch, a bioengineer at Case Western Reserve University and associate director of the Cleveland Functional Electrical Stimulation Center; he was not involved in the research. “I think there are many [clinical implications],” he says, although, like Delp and Llewellyn, he notes that many high hurdles must be cleared–not least of which is developing a safe, effective way to deliver the channelrhodopsin-2 gene to nerve cells in humans. Otherwise, Kirsch says, “my one objection would be their implication that they’ve solved the fatigue problem with FES. I’m pretty sure that hasn’t happened.” Instead, Kirsch believes that most of the fatigue seen in FES patients is due to muscle atrophy and weakness that develop in the chronically paralyzed.
C.J. Heckman, a professor of physiology at Northwestern University’s Feinberg School of Medicine, agrees: “It is true that a lot of the fatigue seen in FES patients is due to chronic muscle atrophy.” But, he says, “if you could stimulate the muscles in the correct recruitment order repeatedly over time, you could potentially recover a lot of muscle function.” This could help paralysis patients preserve their slow muscle fibers, “which would be a huge deal,” Heckman says. This is because those fibers do a huge percentage of the work muscles do–everything from maintaining posture to typing on a keyboard.
Delp also thinks that stimulation-based exercise could be an important application for optical muscle control, as could helping wheelchair-bound people stand to reach for books or plates in a cabinet. “I’m not super-high on controlling locomotion”–that is, walking–“with either electrical or optical stimulation, though,” Delp says. “It’s an incredibly complicated command-and-control scheme that’s really hard to coordinate.”
In the meantime, Delp and Llewellyn have begun an effort to use a different light-sensitive protein, halorhodopsin, to inhibit motor nerves in mice, with the idea of treating or even curing muscle spasticity, often a serious side effect to brain or spinal injury. Current treatments are far from ideal; doctors may inject botulinum toxin into the affected muscles every few months to paralyze them, use oral medications such as Valium that affect the whole body instead of just the affected muscle, or, in the most severe cases, cut the nerves or tendons of the spastic muscle–a permanent treatment that leaves the patient with no control over that muscle. Delp hopes that genetically engineering the nerves with halorhodopsin might enable people to use light to reversibly relax muscles affected with spasticity.
“I think that’s a great idea for treating spasticity,” says Jerry Silver, a neuroscientist at Case Western. There may be some difficulties along the way, though, he says. Working with Case colleagues, Silver has started a company called LucCell to develop clinical applications of optogenetics. In one company project, scientists are trying to use halorhodopsin and other inhibitory opsins in animal models to turn off the muscle that controls the bladder sphincter; their ultimate goal is to restore bladder function to paralyzed people. Though they have seen some physiological changes in how the sphincter muscle behaves, they haven’t been able to get it to relax enough. “We’re learning it’s easier to turn things on than turn things off,” he says. Still, the team is persisting, looking for better ways to deliver the gene to nerve cells and for ways to increase production of the protein on the cell’s surfaces.
“It all depends on the ability to get the transgene in the right place in the person’s genome without causing problems,” agrees Llewellyn. “It’s the main obstacle.”
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