Listening to the Brain: How Sound Can Command Neurons
I am a neuroscientist interested in understanding how the brain detects environmental changes and responds. For two decades, optogenetics has reigned as the go-to tool — engineered brain cells controlled with light. But that approach depends on surgically implanting optic fibers deep within the brain, a strategy that cannot be easily translated into people. I have wanted to figure out how to manipulate the brain without using light.
From Light to Sound
Sound control emerged from a simple idea: if brain cells could be made mechanically sensitive, then ultrasound could modify them. Ultrasound — sound waves beyond human hearing — is noninvasive and safe. Sound is a form of mechanical energy, and I figured that if cells could detect mechanical pressure, ultrasound could activate them. This research led us to the discovery of the first naturally occurring protein mechanical detector that made brain cells sensitive to ultrasound.
The Two-Stage Sonogenetics Process
Our technology works in two stages. First, we introduce new genetic material into malfunctioning brain cells using a virus as a delivery device. This provides the instructions for these cells to make ultrasound-responsive proteins. The next step is emitting ultrasound pulses from a device outside the body, targeting the cells with the sound-sensitive proteins. The ultrasound pulse remotely activates the cells.
Proof in Worms
We were the first to show how sonogenetics can activate neurons in a microscopic worm called Caenorhabditis elegans. Using genetic techniques, we identified a naturally occurring protein called TRP-4 — present in some of the worm's neurons — that was sensitive to ultrasound pressure changes. We demonstrated that neurons with the TRP-4 protein are sensitive to ultrasonic frequencies; sound waves at these frequencies changed the worm's behavior. We genetically altered two of the worm's 302 neurons and added the TRP-4 gene, and showed how ultrasound pulses could make the worms change direction, as if we were using a worm remote control. These observations proved that we could use ultrasound as a tool to study brain function in living animals without inserting anything into the brain.
Moving Toward Humans
Humans, unlike worms, do not naturally have the TRP-4 gene. So my plan is to introduce the sound-sensitive protein into the specific human cells we want to control. The advantage is that ultrasound won't interfere with other cells in the human body that lack the sound-sensitive protein. It is currently not known if proteins other than TRP-4 are sensitive to ultrasound. Identifying such proteins, if there are any, is an area of intense study in my lab and the field.
Advantages Over Existing Methods
The best part about sonogenetics is that it doesn't require a brain implant. We use artificially engineered viruses — unable to replicate — to deliver genetic material to brain cells. This allows the cells to manufacture sound-sensitive proteins. This method has been used to deliver genetic material to human blood and heart muscle cells in pigs. Sonogenetics, though still in the very early stages of development, offers a novel therapeutic strategy for various movement-related disorders including Parkinson's, epilepsy and dyskinesia. In all of these diseases, certain brain cells stop working and prevent normal movements. Sonogenetics could enable doctors to turn on or turn off brain cells at a specific location or time and treat these movement disorders without brain surgery.
Beyond Neurology
Our team is also working on expanding the sonogenetic technology. We have observed that certain plants, such as the "touch me not" (Mimosa pudica), are sensitive to ultrasound. Applying pulses of ultrasound to an isolated branch produces the same response as touching or shaking the leaves. We are also developing a different method to test if ultrasound can influence metabolic processes such as insulin secretion from pancreatic cells. The great potential for sonogenetics is that this technology could be applied to control nearly any type of cell: from an insulin-producing cell in the pancreas to pacing a heart.
Current Limitations and Future Directions
Sonogenetics is still in the very early stages of development. For this to work, the target region of the brain would need to be infected with the virus carrying the genes for the sound-sensitive protein. This has been done in mice but not yet in humans. Gene therapy is getting better and more precise, and I am hoping that other researchers will have figured out how to do this by the time we are ready with our sonogenetic technology. Our team has received substantial support to advance this technology, fuel the initial study and establish an interdisciplinary team. With additional funding from DARPA's ElectRx program, we can focus on finding proteins that can help us "turn off" neurons. We recently discovered proteins that can be manipulated to activate neurons (unpublished work). This is crucial for developing a therapeutic strategy that can be used to treat central nervous system diseases like Parkinson's.
Funding: Sreekanth Chalasani receives funding from the National Institutes of Health, Kavli Institute of Brain and Mind, and the Defense Advanced Research Agency's ElectRx program.
Sound Mind
The great potential for sonogenetics is that this technology could be applied to control nearly any type of cell: from an insulin-producing cell in the pancreas to pacing a heart. Our hope is that sonogenetics revolutionizes the fields of neuroscience and medicine.
