Establishing a Rational Design Algorithm for Higher-order Biosensors

Yale University, New Haven CT

Investigators

Abstract

Intellectual Merit: The control of gene expression is an important tool for metabolic engineering, the design of synthetic gene networks, gene-function analysis, and protein manufacturing. The most successful approaches to date are based on modulating gene production via an inducible coupling to known transcriptional effectors. However, the current set of useful regulatory elements lacks sufficient diversity to advance the abovementioned biotechnologies. Accordingly, the invention of novel higher-order biosensing proteins that modulate gene expression will catalyze a revolution in how we conduct basic and applied research over the next decade. The challenge now is how to translate knowledge regarding allosteric communication?a hallmark of biosensing?into a rational design protocol for cooperative function. Accordingly, the objective of this study is to establish an innovative rational design algorithm for creating higher-order biosensing elements that are highly sensitive and orthogonal to native functions. The novel molecular switches generated in the study will become the foundation of exciting technologies in natural and non-natural systems alike. To accomplish this objective, bio-inspired engineering principles that involve both experimental and computational strategies with feedback between the two will be employed. The technology developed in this proposal will exist at the intersection of engineering, life science and information technology. Thus, this research will advance both engineering and life sciences via the creation of not only novel but useful biosensing elements in addition to addressing complementary scientific questions. Broader Impacts: Establishing an integrated multidisciplinary program that is complementary to the aforesaid research initiative, while promoting diversity and increasing the involvement of underrepresented groups in biological engineering and science, will require the development of three underpinning and reciprocal criteria, namely: i) articulating the overarching goals of this research program and expressed interest in including underrepresented groups in these efforts to the broader community; ii) establishing a rigorous training initiative at both the undergraduate and graduate level; and iii) developing the necessary infrastructure to support these efforts. Likewise, this program will exist within the context of the mission goals and resources of the University. In turn, this effort will pave the way toward catalyzing a cultural change in undergraduate and graduate education, for students, faculty, and the University, by establishing an innovative model for promoting diversity and training in a fertile environment in the context of research that transcends traditional disciplinary boundaries. This initiative will contribute to the development of a diverse engaged science and engineering workforce, building a firm foundation for a lifetime of contributions to research, education and their integration.