"Programming Genomes to Expand Life's Functional Repertoire"
Molecular, Cellular, and Developmental Biology
A defining cellular engineering challenge is the development of high-throughput and automated methodologies for precise design and manipulation of genomes. To address these challenges, we develop technologies – MAGE (multiplex automated genome engineering) and CAGE (conjugative assembly genome engineering) – for versatile genome modification and evolution of cells. Our methods treat the chromosome as both an editable and evolvable template and are capable of simultaneously targeting many locations on the chromosome to fundamentally re-engineer genomes from the nucleotide to the megabase scale. I will present one application of MAGE to generate combinatorial genomic variants from a complex pool of synthetic DNA to diversify multiple genes for biosynthetic pathway optimization. I will also describe the integration of MAGE and CAGE to construct Genomically Recoded Organisms (GROs), replacing all 321 UAG stop codons with the synonymous UAA stop codon in E. coli. This GRO exhibited improved properties for incorporation of nonstandard amino acids that expand the chemical diversity of proteins in vivo and demonstrated multi-virus resistance. Finally, I will describe the engineering of the GRO to depend on synthetic amino acids aimed at construction of safe GMOs unable to grow in the wild. This work increases the toolbox for genomic and cellular engineering with the goal of expanding the functional repertoire of organisms.
Farren Isaacs is Assistant Professor of Molecular, Cellular and Developmental Biology and Systems Biology at Yale University. He received a B.S.E in Bioengineering from the University of Pennsylvania and Ph.D. in Biomedical Engineering-Bioinformatics at Boston University, where he pioneered the development of synthetic RNA molecules capable of probing and programming cellular function. As a research fellow in genetics at Harvard, he invented enabling technologies for genome engineering. His research is focused on finding ways to construct new genetic codes and reprogrammable cells that serve as factories for chemical, drug and biofuel production. He has been named a “rising young star of science” by Genome Technology Magazine, a Beckman Young Investigator by the Arnold and Mabel Beckman Foundation and recipient of a Young Professor award from DuPont.