CAD tools for RNA engineering: SynBERC researchers have developed CAD-type tools for engineering RNA components that hold enormous potential for microbial-based production of advanced biofuels and other goods now derived from petrochemicals. (Image by Zosia Rostomian, Berkeley Lab)The computer assisted design (CAD) tools that made it possible to fabricate integrated circuits with millions of transistors may soon be coming to the biological sciences. SynBERC researchers have developed CAD-type models and simulations for RNA molecules that make it possible to engineer RNA devices for controlling genetic expression in microbes. This holds enormous potential for microbial-based sustainable production of advanced biofuels, biodegradable plastics, therapeutic drugs and a host of other goods now derived from petrochemicals.

“Because biological systems exhibit functional complexity at multiple scales, a big question has been whether effective design tools can be created to increase the sizes and complexities of the microbial systems we engineer to meet specific needs,” says Jay Keasling, SynBERC Director and co-author of the paper. “Our work establishes a foundation for developing CAD platforms to engineer complex RNA-based control systems that can process cellular information and program the expression of very large numbers of genes. Perhaps even more importantly, we have provided a framework for studying RNA functions and demonstrated the potential of using biochemical and biophysical modeling to develop rigorous design-driven engineering strategies for biology.”

"We created a coarse-grained mechanistic model of device function emphasizing tunable design variables to identify parameters that produce device outputs meeting targeted performance criteria," said James Carothers, first author of the paper. "To physically implement functional devices, we devised a method for designing transcripts with kinetic RNA folding simulations. Twenty-eight expression devices were assembled from component parts generated and characterized in vitro, in vivo, and through simulation to program expression levels of a reporter gene and production fluxes of p-aminophenylalanine (p-AF), a chemical precursor of bioactive compounds and industrial polymers. The excellent quantitative agreement between the design specifications and the device functions (94% correlation) experimentally validates the underlying models and the overall approach, suggesting a route to develop CAD tools for RNA-based genetic control systems." 

The work establishes a conceptual and experimental framework for the development of CAD software to engineer versatile RNA devices with immediate usefulness as controllers for metabolic pathways and genetic circuits. Ultimately, this could lead to a full-fledged CAD platform for creating and debugging RNA-based control systems that can process cellular information and coordinate the timing and expression levels of very large numbers of genes. More broadly, the successful development of this approach shows how biochemical and biophysical modeling can be used to manage biological complexity and create CAD-based approaches for biology analogous to those found in other engineering fields.

"We've started to integrate part of the design platform we developed with existing tools such as Device Editor and J5," added Carothers. "In the first stage this will involve the 'transcript design' part of the overall strategy.  Eventually we hope to develop full-fledged CAD tools for engineering genetic control systems that can be used to implement designs that come from metabolic systems modeling."

More information:
Full press release at Berkeley Lab News website
Full paper on Science Magazine website