Taking advantage of the genetic code's redundancy, a collaborative project led by researchers at Harvard University created a genetic code for the bacteria Escherichia coli that uses only 57 of the 64 natural codons (three-letter words that constitute the genetic code). They changed the meaning of the remaining seven codons to produce proteins with potential industrial uses. So far, tests introducing such changes into living cells show only very few cases of significant growth defects.
Reassigning several of the natural codons in a bacterial genome (complete genetic information) enables the development of microbial strains that produce new proteins that can perform novel functions, such as chemical reactions to efficiently deconstruct plant raw material to produce biofuels or biosensors that allow microbes to detect specific chemicals, while preventing the engineered strain from surviving if it escapes laboratory conditions. This research produced new design tools and knowledge of rules that scientists must observe to synthesize functional genetic elements and networks. This study shows that genetic recoding is possible and has uncovered fundamental design principles.
To construct a completely recoded Escherichia coli genome, the researchers first used computational tools to design a genomic sequence lacking all instances of seven redundant codons and synthesized the genome in 87 fragments spanning 50 kb each. Testing of 55 of these fragments, which contain 63 percent of the genome and 52 percent of essential genes, showed that most of them caused limited or no change in growth and transcription levels. The recoded version of one gene resulted in severe fitness impairment, but the researchers redesigned the gene, allowing the strain to survive. At the same time, the researchers optimized the design tools to further reduce potential growth defects in recoded microbes. This research demonstrates the feasibility of high-level recoding of microbial organisms to confer new functionality such as the development of new bioproducts. It also shows that genome-wide engineering approaches provide new knowledge on the fundamental principles that drive biological systems.
George M. Church
Department of Genetics, Harvard Medical School
Wyss Institute for Biologically Inspired Engineering
This work was supported by the Biological and Environmental Research program within the U.S. Department of Energy's Office of Science (award DEFG02-02ER63445). Authors also acknowledge support from the U.S. Department of Defense, the Origins of Life Initiative at Harvard University, and National Science Foundation.
N. Ostrov, M. Landon, M. Guell, G. Kuznetsov, J. Teramoto, N. Cervantes, M. Zhou, K. Singh, M. Napolitano, M. Moosburner, E. Shrock, B. Pruitt, N. Conway, D. Goodman, C. Gardner, G. Tyree, A. Gonzales, B. Wanner, J. Norville, M. Lajoie, and G. Church, "Design, synthesis, and testing toward a 57-codon genome." Science 353(6301), 819–822 (2016). [DOI: 10.1126/science.aaf3639].
The Scientist: Streamlining the E. coli Genetic Code
Additional: Non-DOE Interagency Collaboration