The translation apparatus is the cell's factory for protein biosynthesis, stitching together amino acid substrates into sequence-defined polymers (proteins) from a defined genetic template. The extraordinary synthetic capability of the protein biosynthesis system has driven extensive efforts to harness it for societal needs in areas as diverse as energy, materials, and medicine. For example, recombinant protein production has transformed the lives of millions of people through the synthesis of biopharmaceuticals and industrial enzymes. In nature, however, only limited sets of protein monomers are utilized, thereby resulting in limited sets of biopolymers (i.e., proteins). Expanding nature's repertoire of ribosomal monomers could yield new classes of enzymes, therapeutics, materials, and chemicals with diverse chemistry. In the short term, this will expand the genetic code in a unique and transformative way. In the long-term, knowledge gained will allow researchers to diversify, evolve and repurpose the ribosome and the entire protein synthesis system to generate non-natural polymers as new classes of sequence-defined, evolvable matter. This proposal will also promote interdisciplinary education, including the specific expansion of STEM education and career opportunities for underrepresented minorities and women. Students will be trained to integrate principles from genome engineering, systems biology, and synthetic biology. As a form of outreach, the investigators will create experiential learning modules that bring synthetic biology research to K-12 and undergraduate classrooms and connect students to the science being done at our institutions. This new outreach program will ensure that advances made in this project benefit a broader community and will contribute to motivating and training young scientists and engineers.

In this project, the investigators seek to repurpose the translation apparatus for making new proteins containing multiple mirror-image D-alpha-amino acids. By seamlessly melding the integration of bottom-up engineering design, genome engineering, and full-scale systems optimization, the project will create a new framework for studying and engineering translation and the genetic code. This framework will be instrumental in sustaining the much-anticipated transformation in expanding the range of genetically encoded chemistry in living systems, with the potential for significant breakthroughs. For example, understanding the structural and substrate flexibility of the protein synthesis machinery may provide insights into life's origin and also lead to general rules for engineering protein synthesis to meet societal needs. From an engineering perspective, the research could enable scalable mirror image polypeptide synthesis, opening the door to cheaper and more effective peptidomimetic enzymes, materials, and drugs, and expanding the scope of synthetic and chemical biology. In sum, it is expected that this project will provide new directions for academic and industrial enterprises related to engineering translation, while simultaneously training the next generation of scientists and engineers to be full participants in the work force.

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Northwestern University at Chicago
United States
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