What are the requirements to engineer dynamic therapies that evolve to suppress Pathogens and eliminate resistance?


Pathogens evolve resistance to virtually all therapeutics so a continual flow of new therapeutics is needed.  If the processes of co-evolution could be understood and harnessed, the evolution of resistance could potentially be circumvented.

As rapidly evolving systems, viruses present ideal system to study co-evolutionary dynamics.  To define the molecular determinants enabling co-evolution, we examine molecular parasites of viruses called Defective Interfering Particles (DIPs).  DIPs are viral deletion mutants that must compete with the wild-type virus for replication/packaging resources within the infected cell.  Consequently, DIPs acts as ‘cheaters’ and deprive wild-type viruses of critical replication machinery, reducing wild-type virus production.  DIPs arise spontaneously and even transmit through human populations (Aaskov et al. 2005).  Historically, DIPs have been discounted as experimental contaminants, but—being subject to the same selection pressures as wild-type viruses—they have the potential to continually co-evolve with wild-type viruses.  Thus, DIPs offer an attractive system to explore and define the determinants of co-evolution.

We have theoretically predicted determinants required for DIP co-adaptation (Rouzine and Weinberger, 2013) and we continue to be interested in understanding molecular determinants for co-adaptation both theoretically and experimentally.

Apart from understanding the basics of how parasites may arise, these studies also have potential therapeutic significance: DIP-based therapies are attractive candidates for population-wide infectious-disease control, especially in resource-limited settings (Notton et al., 2014).