Synthetic Virology: Redesigning Viruses as Potent Precision Medicines

Viruses are Nature’s nanomachines, with outer coats that enable them to home to specific cells and tissues in the body, and a built-in cargo hold to carry genetic and molecular freight. The multiple tropisms and diverse biological properties of viruses are encoded in their ruthlessly minimalist nucleic acid genomes that target, reprogram and hijack specific cell types for their pathological propagation. Viruses have evolved, not through rational design, but through their accelerated mutation and proliferation rates relative to their hosts, channeling selection and optimization/adaptation. No natural virus has ever evolved to deliver a gene, kill a tumor cell, diagnose deadly cancers or promote wound healing.

Design is the ultimate test of understanding. Together with a deep mechanistic understanding of virus-host network interactions, the ability to systematically assemble modular DNA code into a functional self-replicating genome is the key to designing viruses as powerful precision medicines. To achieve this, we analyzed all human and animal adenoviruses and split their genomes into five discrete functional and transcriptional genomic modules that can be assembled in vitro using Adsembly in 4 hours. We have created libraries of each genomic module with rational mutations, structural variations and synthetic circuits that could be combined together to create over a billion novel viral candidates. In addition, we have developed RapAd capsid tropism functionalization technologies that enable multiple targeted and inducible tropisms to be achieved in vivo. This enables the design, assembly and screening of novel virus vectors, oncolytic and vaccines in an automated, high-throughput manner. We will discuss novel diagnostic “drones” that identify deadly cancers at the earliest stages; synthetic viruses that seek and destroy metastatic tumor cells and novel vectors that home to sites of inflammation to promote wound healing.