Graduate student, California institute of technology (Caltech)
Remote-controlled microbes that can be triggered with ultrasound to release therapeutics
Recent advances in Synthetic Biology enabled us to equip engineered cells with preprogramed genetic circuits granting them the ability to carry a wide range of sophisticated functions deep inside our body. While these advancements are paving the way to revolutionize medicine there still exists a major limitation that hinders the potential of cell-based therapies. When deployed deep inside our body, there is virtually no way to communicate with engineered cells and update their pre-programmed commands. Real time communication is crucial especially in a dynamic environment such as our bodies where the capability to intervene by terminating or tuning the function of engineered cells can make or break a therapy. Therefore, for the past couple of years I have been focused on developing a channel to communicate with engineered cells deployed deep inside our body. To this end, I chose ultrasound as a modality to enable this capability since it can penetrate deep inside tissues and reach cells anywhere in the body. One major hurdle to using ultrasound is that naturally cells do not have receivers that recognize ultrasound signals. Luckily, Salmonella evolved “TlpA” a temperature sensitive protein that can act as an ultrasound receiver. While the function of this protein is not clear in their host organism they function as a great ultrasound receiver to sense minimal temperature elevations caused by an ultrasound beam. Upon sensing an ultrasound signal TlpA can drive a cascade of events transforming that signal into a modular biological response. I have recently shown that we can program cells to incorporate TlpA and use it as a cellular walkie-talkie. I also demonstrated that we can communicate with engineered cells deep inside the body by simply transmitting an ultrasound signal. As a follow up to this work, I am developing thermally-controlled therapeutic agents with potential applications in cancer immunotherapy. Salmonella is a great candidate since they have advantages as chasses for therapy development due to their ability to colonize tumors after oral administration. In particular, Salmonella typhimurium has been engineered to release cell killing factors in tumors. However, a significant challenge in Salmonella-based therapeutics is their wide dissemination throughout the body. By engineering S. typhimurium to be activated by Ultrasound, I will enable site-specific activation of therapies resulting in safer and more precise therapeutic cells.
Abstract: Temperature is a unique input signal that could be used by engineered microbial therapeutics to sense and respond to host conditions or spatially targeted external triggers such as focused ultrasound. To enable these possibilities, we present two families of tunable, orthogonal, temperature-dependent transcriptional repressors providing switch-like control of bacterial gene expression at thresholds spanning the biomedically relevant range of 32-46 °C. We integrate these molecular bioswitches into thermal logic circuits and demonstrate their utility in three in vivo microbial therapy scenarios, including spatially precise activation using focused ultrasound, modulation of activity in response to a host fever, and self-destruction after fecal elimination to prevent environmental escape. This technology provides a critical capability for coupling endogenous or applied thermal signals to cellular function in basic research, biomedical and industrial applications.
Pub.: 15 Nov '16, Pinned: 30 Jun '17