Applying 'rock-paper-scissors' gene circuits to cancer therapy

gloved hand holding up bacteria culture
Several research teams are exploring the use of gene circuits for delivering therapies directly to tumors. (Gett/jarun011)

Bacteria can be useful tools for expressing and deliver anti-cancer drugs, because they can be modified to carry non-native DNA and can colonize at tumor sites. However, such systems often stop working soon due to mutations that are driven by evolutionary selection.

Bioengineers at the University of California San Diego have developed a “rock-paper-scissors” (RPS) method to extend the life of gene “circuits” so that bacteria carrying them can produce cancer-killing payloads for extended periods.

Instead of using one bacterial strain, the RPS system employs three engineered E. coli subpopulations, each of which can replace the others. The system lowers the rate of genetic mutations in bacteria and therefore is able to keep the drug-producing circuits running. That allows for efficient delivery of cancer combination therapies, the researchers reported in the journal Science.

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Jeff Hasty, Ph.D., and colleagues at UC San Diego, working with collaborators at the Massachusetts Institute of Health, previously developed a synthetic biology construct that carries a “kill” circuit. It allows a bacterial colony to self-destruct when it grows to a certain size and then releases a therapeutic payload within the tumor environment. The cycle continues as a few of the surviving bacteria regrow. By limiting the bacterial population, the scientists were able to reduce the drug’s effects on healthy tissues. But the circuit eventually lost function due to mutations.

For their current project, the scientists introduced three E. coli strains in a “rock-paper-scissors” dynamic, in which the “rock” strain can kill the “scissors,” strain but will be destroyed by the “paper” bugs. Because each strain can be killed by a subsequent strain, a circuit that has mutated can be replaced by the next strain, giving scientists external control over the process without interrupting circuit function.

Previously, “once you lose functionality in your genetic circuit, there is nothing to do but start over,” Michael Liao, the study’s first author and a Ph.D. candidate at UCSD, said in a statement. “Our work shows there is another path forward, not just in theory, but in practice. We’ve shown that it’s possible to keep circuit-busting mutations at bay. We found a way to keep hitting reset on the mutation clock.”

Hasty and two of his collaborators have co-founded a company called GenCirq, which looks to take their research into the clinic.

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The use of gene circuits in oncology as been explored by other research groups. A year ago, an MIT team built a single strand of RNA that carried genetic information for a therapeutic and RNA-binding proteins. The latter acted as switches for gene transcription that could be controlled by small-molecule drugs. Senti Bio co-founder Timothy Lu and colleagues at MIT borrowed an electronics concept known as “AND gates” for gene circuits that allow for a therapy to act only when two cancer biomarkers are present.

Hasty’s team figures the cycling approach may work for more than just a three-strain system. Additional microbes could be programmed to produce different drugs, potentially offering precise combination therapies to treat cancer, the researchers argue.

The scientists are now looking to optimize the RPS system for further testing. If successful, it could be applied in many fields, including cancer therapy, bioremediation and bioproduction, they believe. 

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