This INSPIRE award is partially funded by the Software and Hardware Foundations Program in the Division of Computing and Communication Foundations in the Directorate for Computer and Information Science and Engineering, the Developmental Systems Program in the Division of Integrative Organismal Systems in the Directorate for Biological Sciences, and the Biological and Computing Shared Principles working group.
Every cell contains an extremely complex control system for functions essential for survival and reproduction of the organism. Identification of the design principles embodied in this poorly understood core regulatory circuitry of the cell is the focus of this project. In many ways, this cellular control system resembles the electronic systems that humans design, although it uses biochemical and genetic reactions instead of transistors as its underlying technology. Over many decades, electrical engineers have learned design principles that enable the design of robust, reliable systems. This project investigates whether cellular control circuitry makes use of these same principles, and whether there are new principles that can be learned from cells. This is addressed by analysis of the essential logic controlling the bacterium Caulobacter crescentus. Caulobacter control circuitry resembles asynchronous digital circuits, a type of digital design that does not use a global clock signal to coordinate the system. The design of reliable asynchronous circuits is a difficult engineering challenge, and many interesting methods for designing and analyzing these circuits have been developed.
This project maps out the essential control circuitry, which regulates the processes that are vital to cell viability, using a combination of laboratory and computational methods. The research integrates results from several types of high-throughput data, including ribosome profiling, RNA-seq data at various points in the cell cycle, and ChIP-seq, and combines that with computational DNA binding motif search. A hybrid continuous and discrete mathematical model will be developed for the essential cell regulatory system, and a homologous asynchronous digital circuit will be constructed and analyzed using model checking software. The circuit structure and model checking results are used to map existing asynchronous circuit design concepts to the biological domain, and to identify new circuit design methods that may have been selected by evolution that lead to the extreme robustness displayed by living cells.
