Biomolecular Ultrasound and Sonogenetics

Abstract

Visualizing and modulating molecular and cellular processes occurring deep within living organisms is fundamental to our study of basic biology and disease. Currently, the most sophisticated tools available to dynamically monitor and control cellular events rely on light-responsive proteins, which are difficult to use outside of optically transparent model systems, cultured cells, or surgically accessed regions owing to strong scattering of light by biological tissue. In contrast, ultrasound is a widely used medical imaging and therapeutic modality that enables the observation and perturbation of internal anatomy and physiology but has historically had limited ability to monitor and control specific cellular processes. Recent advances are beginning to address this limitation through the development of biomolecular tools that allow ultrasound to connect directly to cellular functions such as gene expression. Driven by the discovery and engineering of new contrast agents, reporter genes, and bioswitches, the nascent field of biomolecular ultrasound carries a wave of exciting opportunities.

Modular Thermal Control of Protein Dimerization

“…cellular functions 26 , as well as previous work on temperaturecontrolled transcription 12 . We anticipate that as external control of protein signaling becomes needed in more complex settings, such as cellular therapy 27 and engineered living materials 28 , this will provide a role for temperature-based control modalities that offer spatiotemporal specificity and penetration depth beyond those afforded by systemic drug delivery and optical methods 1,8 . We anticipate that the coiled-coil structure of TlpA will facilitate future use of TlpA-based thermomers to control a variety of protein functions.…”

“…Temperature offers an alternative mechanism for controlling biological signaling with several advantages over chemicals and light. Temperature can be applied to biological samples globally using simple heat sources or electromagnetic radiation, and can be targeted locally deep within scattering media using technologies such as focused ultrasound, providing spatial and temporal resolution on the order of millimeters and seconds, respectively 1,8 . Previous work on thermal control of cellular signaling has focused on temperature-actuated transcription and translation, taking advantage of endogenous heat shock promoters 9,10 , temperature-dependent RNA elements 11 , or heterologously expressed protein-based transcriptional bioswitches 12 .…”

Acoustic biomolecules enhance hemodynamic functional ultrasound imaging of neural activity

“…Here, we introduce a new class of hemodynamic enhancers for fUS based on acoustic biomolecules known as gas vesicles (GVs) (17,18). GVs comprise air-filled compartments with dimensions on the order of 200 nm, enclosed by a 2 nm-thick protein shell.…”

Genetically encoded nanostructures enable acoustic manipulation of engineered cells

“…These capabilities could be extended from in vitro devices to inside living animals or patients using emerging approaches for in vivo ARF 31 . Finally, GVs could be used as a nanoscale actuator to locally apply specific forces to biological systems, which may be useful for studies of endogenous mechanosensation or for engineered mechanisms of noninvasive cellular control 5 .…”

“…The ability to remotely manipulate and pattern cells and molecules would have many applications in biomedicine and synthetic biology, ranging from biofabrication 1 and drug delivery 2 to noninvasive control of cellular function [3][4][5] . Ultrasound offers unique advantages in such contexts over optical, magnetic and printing-based approaches due to its non-invasiveness, functionality in opaque media, and its relatively high spatial precision on the µm scale.…”