Illuminating Biology Through Phage-Assisted Continuous Evolution
Speaker: Dr. Ahmed H. Badran (Principal Investigator, Chemical Biology Fellow, The Broad Institute of MIT and Harvard)
Darwinian evolution has given rise to a spectacular diversity of biomolecules, each of which is uniquely tailored to provide an evolutionary advantage in the requisite niche. Relying on this natural abundance of biological activities has facilitated a variety of areas of research including drug discovery, protein therapeutics, designer organisms, and much more. Yet this approach often falls short when the activity of interest cannot be found in nature. Directed evolution is seeks to complement this deficiency by invoking Darwinian principles in the laboratory to accelerate the discovery of biomolecules with researcher-dictated properties, but requires extensive researcher intervention to arrive at desired activities. To alleviate this significant shortcoming and facilitate the discovery of complex biological functions in short time scales, we developed Phage-Assisted Continuous Evolution (PACE), a general methodology for the rapid directed evolution of arbitrary biomolecular activities. PACE takes advantage of the M13 bacteriophage life cycle, where the activity of the evolving biomolecule results in the production of a missing viral protein, enabling robust positive selection and accelerating the rate of laboratory directed evolution by 100-fold. Using this platform, we have rapidly evolved enzymes to have radically altered specificities without sacrificing activity, generated efficient mechanisms for comprehensively surveying sequence space of arbitrary proteins, predicted resistance mechanisms to clinically used antiviral therapeutics, generated genome-editing agents with improved specificity in human cells, and overcome bioinsecticide resistance through novel protein-protein interactions. Lastly, we are motivated to study the ribosome through the lens of evolution, aiming to understand the origins of cellular translation.