Synthetic Virology: Reprogramming Viruses into Controllable Nanodevices

Viruses are nature’s nanomachines that already conduct amazing feats of biomolecular computation – they have evolved to recognize specific biomolecular inputs and produce functional outputs critical to the infection of their host organisms. Viruses have been harnessed over the last several decades as gene delivery vectors for a variety of biomedical applications. To make viral gene delivery a more predictable process, we must obtain control over the naturally encoded biomolecular programs already embedded in the viral capsids. Over the last several years, we have purposefully investigated ways to rewrite the details of what cues can be accepted as input and what functional outputs can be produced by the capsids. For example, we are in the initial stages of programming defined logic operators into the virus nanostructure and have successfully created virus prototypes that are activated by extracellular proteases. These protease-activatable viruses can be used for the treatment of diseases that exhibit signs of inflammation, such as cancer and a number of cardiovascular diseases. We are also investigating ways to render the viral transduction process controllable by externally applied light, which may enable enhanced, tunable, and spatially resolved transgene expression in target tissues. This effort represents a merger of virus capsid engineering and optogenetics (light-switchable proteins that can control biological processes) to create ‘bionic’ viruses with newfound abilities. Collectively, our work demonstrates how virus capsids can be designed to compute different aspects of their environment and to use this information to decide whether or not they perform a user-programmed output. Such synthetic viruses may find broad utility in the future as sophisticated biosensing and biomanipulating materials.