Seminars

Biological engineering has long relied on the canonical genetic code to permit efficient transgenic production of drugs, materials, and food. Unfortunately, the highly conserved genetic code has also permitted the escape of recombinant DNA and the emergence of antibiotic resistant pathogens. By redefining how DNA is deciphered, we hope to produce genetically recoded organisms (GROs) that are safe and useful. To this end, we have developed genome engineering technologies capable of reassigning the genetic code. We believe that genome design is the main barrier to creating synthetic organisms, so we have adopted an in vivo genome editing strategy that facilitates rapid genetic prototyping and viability testing in real time. As a first step to engineering orthogonal organisms that are genetically isolated, resistant to viruses, and capable of accessing unnatural amino acid chemistries, we are using this approach (1) to reassign the UAG codon genome wide and (2) to reassign several sense codons in the essential ribosomal genes. Our results indicate that codon usage is surprisingly flexible, although some designs are deleterious for unknown reasons. As we continue to learn the complex rules of genome organization and function, combinatorial testing and redesigns will be essential for changing the genetic code.