Rather than shrinking doctors down and sending them inside a patient Fantastic Voyage-style, recruiting microbots and engineered bacteria into the fight against cancer or disease might be more realistic options. A new study from Caltech suggests a way to control bacteria created for just such a mission, by manipulating the temperature around them to trigger when and where they release medicine, and when they might need to self-destruct.

Already, microbes are being tested for their ability to fight disease, but being sent into the body without a clear goal isn't enough, as they tend to wind up in other organs, not just at the site of a tumor. If bacteria release a medicine payload in the wrong part of the body, a treatment may not be as effective, and side effects may occur. To combat this, the Caltech researchers developed a technique to control where the bacteria travel, and make sure they only target the desired areas.

"Bacteria can be designed to act like special agents fighting disease in our bodies," says Mikhail Shapiro, principal investigator on the study. "We're building walkie-talkies for the cells so we can both listen and talk to them."

These "special agents" get their orders through changes in temperature, which doctors could potentially trigger with directed pulses of ultrasound. To develop bacteria that respond to thermal cues, the researchers sought out genetic switches that already depend on temperature, and eventually settled on two candidate proteins: one from Salmonella, and another from a bacteriophage.

Using an engineering technique called "directed evolution," the team evolved versions of the proteins that activated at temperatures between 36º and 39º C (96.8º and 102.2º F). When these genetic switches are connected to certain processes, deliberate changes in temperature can trigger the desired results. As an example, the team drew a picture with bacteria in a petri dish (below), with parts that glow different colors based on the temperature.

As an example of the thermal controls, the Caltech team drew a picture with bacteria in a petri dish: at 37º C, bacteria in the tree shape glow green, and at 42º C, those in the sun shape glow red Shapiro Lab/Caltech

"When we were thinking about how to get bacteria to sense temperature, we looked at nature and found a few systems where bacteria can do this," says Dan Piraner, co-lead author of the study. "We tested the performance, found the ones that had the best switching performance. From there, we went on to find that they could be tuned and amplified. It all started with what nature gave us, and engineering took us the rest of the way."

With these thermal switches, the bacteria can be instructed to release drugs only at certain temperatures. Then, using directed pulses of ultrasound to heat tissue at the required part of the body, scientists could direct bacteria to activate the treatment only at a tumor site, keeping those that wandered off the beaten track from causing complications in other parts of the body.

"We can spatially and temporally control the activity of the bacteria," says Mohamad Abedi, co-lead author of the study. "We can communicate with them and tell them when and where something needs to be done."

Temperature could also act as a kill-command if necessary, like MIT's "dead man's switch" system. These engineered bacteria could be instructed to terminate themselves if the temperature gets too cold – say, if they were passed out of the body through defecation – or too hot, in the case of a fever which might indicate that a patient isn't responding too well to the treatment.

The research was published in the journal Nature Chemical Biology. The team discusses the project in the video below.

Source: Caltech