Researchers have successfully engineered the neurons of live mice to respond to ultrasound, allowing them to activate cells in the animals’ motor cortices and control the movement of their legs. Presenting their findings in the journal Nature Communications, the study authors explain that their technique also works on human cells in a dish, and could one day lead to the development of non-invasive pacemakers and deep brain stimulation delivery systems.
Dubbed sonogenetics, the use of ultrasound to activate cells was first developed by study author Sreekanth Chalasani and his colleagues at the Salk Institute several years ago. In a 2015 paper, the team revealed that a protein called TRP-4 – which controls the activation of cells by regulating the movement of charged ions across their membranes – responds to ultrasonic waves.
They, therefore, engineered the cells of roundworms to contain TRP-4, and found that they were able to manually activate these cells using ultrasound. However, when the researchers repeated the experiment using mammalian cells, they were unable to generate the same results.
In their new study, the authors set out to identify similar proteins that can be used to ultrasonically activate mammalian cells. To do so, they genetically engineered human embryonic kidney (HEK) cells to express a series of different proteins, before exposing them to pulses of ultrasound.
After testing a total of 191 different candidate proteins, the study authors noted that a compound called TRPA1 consistently caused cells to respond to ultrasound. Sometimes referred to as the Wasabi receptor, TRPA1 is similar to TRP-4 in that it is a channel protein, meaning it plays a role in the activation of cells by allowing calcium ions to cross the cellular membrane.
In humans, TRPA1 generally responds to pain, heat, and irritants, triggering reactions like coughing or teary eyes. When HEK cells expressing this protein were exposed to ultrasound, the researchers detected an influx of calcium ions across the channel, indicating cellular activation.
Taking their work a step further, the study authors genetically modified mice to express TRPA1 in the neurons of their motor cortices. Pulsing these rodents with ultrasonic waves consistently caused them to move their right fore and hindlimbs, although movement of the left limbs occurred less frequently.
At the same time, the researchers detected an increase in a protein called c-fos – which is a marker of neuronal activity – in the rodents’ sonogenetically altered brain cells, confirming that these limb movements were indeed produced by the ultrasound-induced activation of these neurons.
According to the authors, sonogenetics could one day eliminate the need for surgical implants such as pacemakers in heart patients or neural electrodes in those suffering from epilepsy. Obviously, this will depend on the development of novel gene therapies that can safely introduce TRPA1 or other similar proteins into human brain cells, yet Chalasani is optimistic about the prospects for his technique.
“Going wireless is the future for just about everything,” he said in a statement. “We already know that ultrasound is safe, and that it can go through bone, muscle and other tissues, making it the ultimate tool for manipulating cells deep in the body.”
“Gene delivery techniques already exist for getting a new gene – such as TRPA1 – into the human heart,” he added. “If we can then use an external ultrasound device to activate those cells, that could really revolutionize pacemakers.”