Making ‘Smart Cells’ Smarter

For years, scientists have explored ways to alter the cells of microorganisms to improve how a wide range of products are made—including medicines, fuels, even beer.

But because cells are already programmed to carry out their normal, everyday business with maximum efficiency, altering their genetic and regulatory processes can be dicey. Any alterations to increase a cell’s production of a useful substance can upset these processes.

University of Maryland researchers led by bioengineering professor William E. Bentley are looking into the possibility that instead of relying on a single type of cell to do all the work, they can leverage “microbial consortia”—subpopulations of specialized cells that divvy up tasks—to successfully carry out the desired function.

The tradeoff is that directing a cell consortium to carry out specific tasks requires engineers to somehow regulate how many of each cell subpopulation are present. Until now, there’s been little research focused on developing devices or systems to automatically regulate the compositions of cellular subpopulations within a consortium. Generally, studies of cell consortia have required engineers to use painstaking manual techniques to strike that balance.

Bentley, director of the Robert E. Fischell Institute for Biomedical Devices, and his team are focused on reengineering cells so they’re able to coordinate their subpopulation densities autonomously. Their technique was highlighted in a Nature Communications paper published Wednesday.

“The key concept is that groups of cells can be engineered to self-regulate their composition, and no outside input is needed,” Bentley said. “For example, there’s no way to ensure that the bacteria engineered for use in the gastrointestinal tract will actually be retained or behave as we expect. And you can’t use convenient means such as magnetic or electrical fields to regulate bacteria in the gut, so why not incorporate the self-regulation property into the bacteria themselves?”

Like others in the field, Bentley and members of his Biomolecular and Metabolic Engineering Lab previously investigated “quorum sensing,”  or QS—a bacterial form of cell-to-cell communication—to engineer communication circuits between bacterial strains to coordinate their behaviors.

To create an autonomous system, Bentley and his team rewired the bacterial QS systems in two strains of E. coli so that the growth rate of communicating cell subpopulations within the consortia would be dictated by signaling between the cells. It’s a sort of feedback loop in which cells are able to sense and react to intercellular signaling molecules called autoinducers, which enable bacteria to work together of their own accord.

The breakthrough could be key to a host of new functions for “smart bacteria” developed through genetic engineering, ranging from drug delivery to water decontamination to new fermentation processes for the latest craft beverage.

“Increasingly, consortia of microbes will be tasked with converting raw materials into valuable products,” Bentley said. “The raw materials may be wastes or byproducts of industrial processes. The synthetic capabilities of consortia may far surpass those of pure monocultures, so methodologies that help to align consortia will be needed.”

Kristina Stephens of the Fischell Department of Bioengineering (BIOE) and Institute for Bioscience and Biotechnology Research served as first author on the Nature Communications paper. Maria Pozo, Chen-Yu Tsao and Pricila Hauk also contributed.