Imagine a future in which crippling epileptic seizures, faltering hearts and diabetes could all be treated not with scalpels, stitches and syringes, but with sound. Though it may seem the stuff of science fiction, a new study shows that this has solid real-world potential.
Sonogenetics – the use of ultrasound to non-invasively manipulate neurons and other cells – is a nascent field of study that remains obscure amongst non-specialists, but if it proves successful it could herald a new era in medicine.
In the new study published in Nature Communications, researchers from the Salk Institute for Biological Studies in California, US, describe a significant leap forward for the field, documenting their success in engineering mammalian cells to be activated using ultrasound.
The team say their method, which they used to activate human cells in a dish and brain cells inside living mice, paves the way toward non-invasive versions of deep brain stimulation, pacemakers and insulin pumps.
“Going wireless is the future for just about everything,” says senior author Dr Sreekanth Chalasani, an associate professor in Salk’s Molecular Neurobiology Laboratory. “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.”
Chalasani is the mastermind who first established the field of sonogenetics a decade ago.
He discovered that ultrasound — sound waves beyond the range of human hearing — can be harnessed to control cells. Since sound is a form of mechanical energy, he surmised that if brain cells could be made mechanically sensitive, then they could be modified with ultrasound.
In 2015 his research group provided the first successful demonstration of the theory, adding a protein to cells of a roundworm, Caenorhabditis elegans, that made them sensitive to low-frequency ultrasound and thus enabled them to be activated at the behest of researchers.
This was a milestone achievement for the credibility of the field, but Chalasani’s team soon hit a stumbling block. The same protein that was so successful in sensitising roundworm cells produced no discernible effect at all in mammalian cells. While sonically controlling roundworms is undoubtedly cool, without making the leap to mammalian cells, the potential medical revolution would be dead in its tracks.
Undeterred, Chalasani and his colleagues set out to search for a new protein that would work in mammals.
Although a few proteins were already known to be ultrasound sensitive, no existing candidates were sensitive at the clinically safe frequency of 7MHz – so this was where the team set their sights.
“Our approach was different than previous screens because we set out to look for ultrasound-sensitive channels in a comprehensive way,” says Yusuf Tufail, a former project scientist at Salk and a co-first author of the new paper.
The screening process took over a year and encompassed nearly 300 candidate proteins which they tested on dishes of a common human research cell line, but at last the team struck gold. TRPA1, a channel protein that lets cells respond to the presence of noxious compounds and activates a wide range of cells in the body, was the winner, responding to the 7MHz ultrasound frequency.
“We were really surprised,” says co-first author of the paper Marc Duque, a Salk exchange student. “TRPA1 has been well-studied in the literature but hasn’t been described as a classical mechanosensitive protein that you’d expect to respond to ultrasound.”
To test whether TRPA1 could activate cell types of clinical interest in response to ultrasound, the team used a gene therapy approach to add the genes for human TRPA1 to a specific group of neurons in the brains of living mice. When they then administered ultrasound to the mice, only the neurons with the TRPA1 genes were activated.
This leap from theory to physical demonstration is a huge step forward for the burgeoning field. Though it is early days, Chalasani believes the next steps are within reach.
Clinicians treating conditions including Parkinson’s disease and epilepsy currently use deep brain stimulation, which involves surgically implanting electrodes in the brain, to activate certain subsets of neurons. Chalasani says that sonogenetics could one day replace this approach—the next step would be developing a gene therapy delivery method that can cross the blood-brain barrier, something that is already being studied.
Perhaps sooner, he says, sonogenetics could be used to activate cells in the heart, as a kind of pacemaker that requires no implantation.
“Gene delivery techniques already exist for getting a new gene – such as TRPA1 – into the human heart. If we can then use an external ultrasound device to activate those cells, that could really revolutionise pacemakers.”
Though sonogenetics could one day circumvent medications and invasive surgeries, for now the team is sticking with nailing down the fundamentals. Their current focus is on determining exactly how TRPA1 senses ultrasound, which could allow this sensitivity to be tweaked and enhanced.