ERA SynBio: Design and Synthesis of a Bio-orthogonal Genetic System

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Synthetic biology holds great promise as a scientific discipline that can answer fundamental biological questions as well as contribute to many practical applications. A key obstacle for this field is the concern about escape of an engineered organism into the environment. To address this and other concerns, this research consortium that engages researchers in the US, UK, France and Spain will engineer an independently replicating element (called an episome, which is not integrated into the DNA of the host cell) that consists of non-natural nucleic acids. These episomes will have genetic material based on TNA (threose-based nucleic acid) along with a system that replicates and expresses proteins from the episome. An autonomous TNA-based episome could not be propagated in nature (outside the laboratory) because TNA precursors do not occur naturally. The consortium of investigators each will develop specific components to be incorporated into the TNA episome, which will be transferred into a bacterial host. The research project, while high risk, is anticipated to generate high impacts in terms of providing enabling technologies to advance a synthetic biology-inspired bioeconomy. It will also generate insights into the evolution of genetic material. The training potential of this project is exceptional in that the students and junior researchers will gain valuable transdisciplinary and international training.The goal of this project is to re-structure the central dogma of molecular biology by developing an all-TNA episome based on bacteriophage Phi29 that can replicate in vitro and eventually inside living cells using an orthogonal cellular machinery engineered for this purpose. The engineered system will store protein-coding information in TNA polymers that will replicate independently of the cellular genome. The TNA coding information will be transcribed by an evolved RNA polymerase that can recognize the TNA template and produce natural messenger RNAs for translation into functional proteins.This project is funded through a transnational funding mechanism between the United States National Science Foundation and European Funding Agencies that are part of the European Commission endorsed Research Area Network in Synthetic Biology. The United States component of this project is co-funded by programs in Systems and Synthetic Biology (Directorate for Biological Sciences) and Biotechnology and Biochemical Bioengineering (Directorate for Engineering).