Microbial therapeutics is a growing field which uses engineered bacteria to fight various diseases and health conditions. Researchers from California Institute of Technology have now developed a temperature sensitive engineered microbial system. These microbes could, in theory, be administered to patients with specific diseases. Once the bacteria reach the site of interest, precise ultrasound pulses can be given to gently heat specific areas in the tissue that will activate release of therapeutics.
The researchers’ paper, published in Nature Chemical Biology, describes the engineering of these microbes using a process called ‘directed evolution’. The team first looked for naturally occurring genes that were temperature sensitive, and identified genes that could be activated at temperatures between 42 and 44 degrees. The investigators then evolved those genes and engineered them to be able to activate at lower temperatures of 36-39 degrees. By using these genetic switches, the researchers were able to turn the genes off and on based on temperature changes.
To address safety concerns, the team encoded the bacteria to self-destruct if it induces a fever in the patient, an indicator that the therapy is not working. They also designed them to destroy themselves at lower temperatures, for instance when they leave the body. This is to ensure that the genetically modified microorganisms do not spread into the wider environment.
Although these therapies are in their infancy, advances in engineering such as these will help towards development of therapeutics for treatment of a wide variety of diseases.
From the study abstract in Nature Chemical Biology:
“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 vivomicrobial 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.”
Study in Nature Chemical Biology: Tunable thermal bioswitches for in vivo control of microbial therapeutics…