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"The future of almost everything is going to be wireless," said senior author Sreekanth Chalasani, associate professor in Salk's Molecular Neurobiology Laboratory
.
"We already know that Ultrasound is safe and can pass through bone, muscle and other tissues, making it the ultimate tool for manipulating cells in the deepest layers of the body
About a decade ago, Chalasani pioneered the idea of using ultrasound to stimulate specific populations of genetically tagged cells, and coined the term "sonic genetics" to describe it
.
In 2015, his team discovered that, in the worm, a protein called TRP-4 sensitizes cells to low-frequency ultrasound
However, when the researchers tried to add TRP-4 to mammalian cells, the protein failed to make the cells respond to ultrasound
.
Several mammalian proteins have been reported to be ultrasound-sensitive, but none seem ideal for clinical use
"Our approach is different from previous screenings because we set out to look for ultrasound-sensitive channels in a comprehensive manner," said Yusuf Tufai, a former project scientist at Salk University and one of the first authors of the new paper.
Tufail) said
.
The researchers added hundreds of different proteins at a time to a common human research cell line (HEK), which typically does not respond to ultrasound
.
They then placed each cell culture under a device that let them monitor how the cells changed when stimulated by ultrasound
After more than a year of screening and through nearly 300 candidate proteins, the scientists finally found a protein that makes HEK cells sensitive to the 7 MHz ultrasonic frequency
.
TRPA1 is a channel protein known to allow cells to respond to the presence of toxic compounds and activate a range of cells in the body, including brain and heart cells
But Chalasani's team found that in HEK cells, the channel was also opened by ultrasound
.
"We were really surprised," said Marc Duque, one of the paper's first authors, an exchange student at Salk University
.
"TRPA1 has been well-studied in the literature, but has not been described as a classical mechanosensitive protein that you can expect to respond to ultrasound
To test whether the channel could activate other types of cells in response to ultrasound, the team used a gene therapy approach that added the gene for human TRPA1 to a specific set of neurons in the brains of living mice
.
When they applied ultrasound to the mice, only neurons with the TRPA1 gene were activated
Clinicians treating conditions such as Parkinson's and epilepsy currently use deep brain stimulation, where electrodes are surgically implanted in the brain to activate certain subsets of neurons
.
Sologenetics could one day replace this approach, Chalasani said—the next step would be to develop a gene therapy delivery method that can cross the blood-brain barrier, which is already being studied
Perhaps in the near future, he said, ultrasound genetics could be used to activate heart cells as a pacemaker that doesn't require implantation
.
"Gene delivery technology already exists to implant a new gene -- such as TRPA1 -- into the human heart," Chalasani said
.
"If we could activate these cells using an external ultrasound device, that could revolutionize pacemakers
.
"
Currently, his team is conducting more fundamental research into how TRPA1 senses ultrasound
.
"To make this finding more useful for future research and clinical applications, we wanted to determine exactly which parts of TRPA1 contribute to its ultrasound sensitivity, and adjust them to improve this sensitivity," said one of the paper's first authors.
said Corinne Lee-Kubli, a former postdoctoral researcher at Salk University
.
They also plan to conduct another screen for ultrasound-sensitive proteins -- this time looking for proteins that inhibit or shut down the cell's activity in response to ultrasound
.
The other authors of the paper are Uri Magaram, Janki Patel, Ahana Chakraborty, Jose Mendoza Lopez, Eric Edsinger, Rani Shiao and Connor Weiss of Salk University; and Aditya Vasan and James Friend of UC San Diego
.
This work was supported by the National Institutes of Health (R01MH111534, R01NS115591), the Brain Research Foundation, the Kavli Institute for Brain and Mind, the Life Science Research Foundation, the WM Keck Foundation (SERF) and the Waitt Advanced Biophotonics and GT3 Core (with grants from NCI CCSG P30014195 and NINDSR24)
.
Video: https://youtu.
be/tNnRd0JfT4o
Journal Reference :
Marc Duque, Corinne A.
Lee-Kubli, Yusuf Tufail, Uri Magaram, Janki Patel, Ahana Chakraborty, Jose Mendoza Lopez, Eric Edsinger, Aditya Vasan, Rani Shiao, Connor Weiss, James Friend, Sreekanth H.
Chalasani.
Sonogenetic control of mammalian cells using exogenous Transient Receptor Potential A1 channels .
Nature Communications , 2022; 13 (1) DOI: 10.
1038/s41467-022-28205-y
