Using a set of three complementary engineered bacteria enables protection of desired “circuitry” for drug production.

Engineered bacteria can be very effective at producing complex molecules, including active drug substances. Typically, fermentation is conducted at large scale in manufacturing plants, after which the drug substance is purified and then formulated into a final drug product. The use of drug-producing bacteria as therapies themselves –– where the drug is produced at the target site in the body –– is also being explored.

In both cases, there is a limit to the viability of engineered bacteria, because they tend to suffer from high mutation rates, with the mutations typically leading to reduced function. Cloning strategies have been used to extend the time period for desirable activity. Now, researchers at the University of California San Diego have developed an alternative approach –– the use of a system of three bacteria that all contain the desirable circuitry but are designed to kill off the others when they lose their functionality.

Specifically, three strains of Escherichia coli were designed so that each strain could kill or be killed by one of the other two when genetic mutations reach a level sufficient to reduce productivity. In microfluidic devices, this approach was shown to result in rapid cycling of the strains for increased stability of the desired gene circuit functionality during cell culture.

The scientists refer to their approach as the rock–paper–scissors” dynamic, with the “rock” strain able to kill the “scissors” strain but susceptible to destruction by the “paper” strain. As one strain loses functionality, it is killed off and replaced by the next, providing continued operation of the biological circuit.

The scientists have founded the company GenCirq to develop the technology for use in human therapeutics. They are also considering the use of a combination of bacteria that produce different drugs, enabling the in situ production of precision combination therapies for cancer treatment. The approach also has the potential for use in other fields, such as bioremediation and biomanufacturing.