Turning up the heat with therapeutic microbes

Caltech study examines engineered bacteria that could be triggered to release medicine when tissue is heated with ultrasound

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PASADENA, Calif.--While bacteria are generally known as the enemy, the recent developments with CRISPR/Cas9 gene editing have shown some benefits to traditional pathogens. Research has shown that there are some types of bacteria that migrate to tumor sites, attracted to the low-oxygen environments, and can be engineered to release therapeutics onto tumors. And recent work out of Caltech has highlighted another kind of potential: using temperature to engage genetic switches in bacteria and trigger the release of therapeutics for targeted treatment.
There are many applications for such an approach. The affect tissue could be carefully heated using ultrasound to trigger the bacteria, or the bacteria could be triggered to stop administering medicine or even self-destruct if an individual's body temperature increases due to a fever.
"Bacteria can be designed to act like special agents fighting disease in our bodies," says Caltech's Mikhail Shapiro, assistant professor of chemical engineering and Heritage Principal Investigator, whose overall research goal is to create new ways to both visualize and control cells—bacterial cells and human cells—for medicinal purposes. "We're building walkie-talkies for the cells so we can both listen and talk to them."
“In our lab we really focus on developing the fundamental molecular technologies that would give cells capabilities to communicate from inside the body,” he added in a video interview. “Cells can be programmed to hone to certain locations in the body and they can execute therapeutic programs; for example, they can synthesize and release proteins that will have some kind of therapeutic effect on the surrounding tissues.”
The work was published in Nature Chemical Biology in a study titled “Tunable Thermal Bioswitches for In Vivo Control of Microbial Therapeutics.” Mikhail Shapiro, assistant professor of chemical engineering and Heritage Principal Investigator, was principal investigator on the study, with Dan Piraner and Mohamad Abedi, graduate students in Shapiro's lab, were co-lead authors.
Shapiro's team worked to find a method that would enable the use of microbial therapeutics without worrying about them traveling to undesired parts of the body, and found heat manipulation to be an effective, precise method. Ultrasound tools can heat tissues gently and with accuracy to the millimeter.
"We can spatially and temporally control the activity of the bacteria," noted Abedi. "We can communicate with them and tell them when and where something needs to be done."
In their search for genetic switches whose activity is mediated by temperature, the team found two possibilities: a protein in Salmonella bacteria, and a protein that originates from a bacterial virus known as a bacteriophage. The two proteins bind to DNA in order to turn a genetic circuit on or off in response to temperature.
With the candidates identified, the researchers used “directed evolution,” a protein engineering technique pioneered by Frances Arnold of Caltech, to evolve the proteins in the lab and adjust their switching temperatures. The Salmonella protein was originally activated by temperatures of between 42 and 44 degrees Celsius (107.6 and 111.2 degrees Fahrenheit), but after being subjected to engineering, the team produced versions activated by temperatures between 36 and 39 degrees Celsius (96.8 and 102.2 degrees Fahrenheit).
This study was funded by the Defense Advanced Research Projects Agency, the Weston Havens Foundation, the Burroughs Wellcome Career Awards at the Scientific Interface and the Heritage Medical Research Institute, as well as through graduate fellowships from the National Science Foundation and the Paul and Daisy Soros Fellowship for New Americans. Other Caltech co-authors include Brittany Moser, now a Ph.D. student at UC Irvine, and research technician Audrey Lee Gosselin.
SOURCE: Caltech press release

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