Salk researchers developed a technique of using sound waves to control brain cells, dubbed sonogenetics, to selectively and noninvasively switch on groups of neurons. It was first utilized on worms and now has actually been utilized on mammalian cells. This technique might be a benefit to science and medicine. Credit: Courtesy of the Salk Institute for Biological Studies
Salk scientists identify a sound-sensitive mammalian protein that lets them activate brain, heart or other cells with ultrasound.
Salk scientists have crafted mammalian cells to be triggered using ultrasound. The method, which the team utilized to trigger human cells in a meal and brain cells inside living mice, paves the method towards non-invasive variations of deep brain stimulation, pacemakers and insulin pumps. The findings will be released in Nature Communications today (February 9, 2022).
” Going wireless is the future for almost everything,” says senior author Sreekanth Chalasani, an associate professor in Salks Molecular Neurobiology Laboratory. “We currently understand that ultrasound is safe, which it can go through bone, muscle, and other tissues, making it the supreme tool for controling cells deep in the body.”
About a decade ago, Chalasani originated the idea of using ultrasonic waves to stimulate specific groups of genetically marked cells, and coined the term “sonogenetics” to explain it. In 2015, his group showed that, in the roundworm Caenorhabditis elegans, a protein called TRP-4 makes cells conscious low-frequency ultrasound. When the researchers included TRP-4 to C. elegans neurons that didnt normally have it, they might activate these cells with a burst of ultrasound– the same sound waves used in medical sonograms.
Nerve cells (magenta) in the mouse brain. The Chalasani lab made specific neurons reveal TRPA1 (white), so they can be triggered by ultrasound. Credit: Salk Institute
When the researchers attempted adding TRP-4 to mammalian cells, nevertheless, the protein was unable to make the cells react to ultrasound. A couple of mammalian proteins were reported to be ultrasound-sensitive, however none seemed perfect for scientific use. Chalasani and his associates set out to search for a brand-new mammalian protein that made cells extremely ultrasound sensitive at 7 MHz, thought about a safe and ideal frequency.
” Our technique was different than previous screens due to the fact that we set out to look for ultrasound-sensitive channels in a thorough method,” states Yusuf Tufail, a former project scientist at Salk and a co-first author of the new paper.
The scientists included numerous various proteins, one at a time, to a typical human research cell line (HEK), which does not normally react to ultrasound. They put each cell culture under a setup that let them monitor changes to the cells upon ultrasound stimulation.
Top from left: Sreekanth Chalasani and Corinne Lee-Kubli. Bottom from left: Marc Duque and Yusuf Tufail Credit: Top: Salk Institute. Bottom from left: Marc Duque and Yusuf Tufail.
After screening proteins for more than a year, and working their way through nearly 300 candidates, the scientists lastly discovered one that made the HEK cells conscious the 7 MHz ultrasound frequency. TRPA1, a channel protein, was known to let cells react to the presence of poisonous compounds and to trigger a variety of cells in the human body, including brain and heart cells.
However Chalasanis group discovered that the channel also opened in action to ultrasound in HEK cells.
” We were really shocked,” states co-first author of the paper Marc Duque, a Salk exchange student. “TRPA1 has actually been well-studied in the literature but hasnt been referred to as a classical mechanosensitive protein that you d anticipate to react to ultrasound.”
To evaluate whether the channel might trigger other cell key ins action to ultrasound, the team used a gene treatment technique to include the genes for human TRPA1 to a particular 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 triggered.
Clinicians treating conditions consisting of Parkinsons illness and epilepsy presently use deep brain stimulation, which involves surgically implanting electrodes in the brain, to trigger particular subsets of nerve cells. Chalasani states that sonogenetics could one day replace this technique– the next step would be developing a gene treatment delivery method that can cross the blood-brain barrier, something that is already being studied.
Perhaps sooner, he states, sonogenetics could be used to trigger cells in the heart, as a sort of pacemaker that requires no implantation. “Gene shipment techniques already exist for getting a brand-new gene– such as TRPA1– into the human heart,” Chalasani states. “If we can then utilize an external ultrasound device to activate those cells, that could really revolutionize pacemakers.”
For now, his group is performing more basic deal with exactly how TRPA1 senses ultrasound. “In order to make this finding better for future research study and medical applications, we hope to determine precisely what parts of TRPA1 add to its ultrasound level of sensitivity and fine-tune them to boost this sensitivity,” says Corinne Lee-Kubli, a co-first author of the paper and former postdoctoral fellow at Salk.
They also plan to perform another screen for ultrasound delicate proteins– this time trying to find proteins that can inhibit, or shut down, a cells activity in action to ultrasound.
Reference: “Sonogenetic control of mammalian cells using exogenous Transient Receptor Potential A1 channels” 9 February 2022, Nature Communications.DOI: 10.1038/ s41467-022-28205-y.
The other authors of the paper were Uri Magaram, Janki Patel, Ahana Chakraborty, Jose Mendoza Lopez, Eric Edsinger, Rani Shiao and Connor Weiss of Salk; and Aditya Vasan and James Friend of UC San Diego.
The work was supported by the National Institutes of Health (R01MH111534, R01NS115591), Brain Research Foundation, Kavli Institute of Brain and Mind, Life Sciences Research Foundation, W.M. Keck Foundation (SERF), and the Waitt Advanced Biophotonics and GT3 Cores (which get funding through NCI CCSG P30014195 and NINDSR24).
Salk researchers have actually engineered mammalian cells to be activated using ultrasound. The method, which the team used to trigger human cells in a meal and brain cells inside living mice, paves the way toward non-invasive variations of deep brain stimulation, pacemakers and insulin pumps. When the researchers added TRP-4 to C. elegans nerve cells that didnt typically have it, they might trigger these cells with a burst of ultrasound– the same noise waves utilized in medical sonograms.
When the researchers attempted adding TRP-4 to mammalian cells, however, the protein was not able to make the cells react to ultrasound. “If we can then use an external ultrasound gadget to activate those cells, that could really revolutionize pacemakers.”