Closing the Loop on Phage-bacteria Coevolution

Bacteria and their viruses, bacteriophage (phage), have co-evolved for millennia. In contrast, laboratory-based coevolution experiments usually last less than a month, often terminating when one species fails to adapt to the other, becoming dormant or extinct. Consequently, there is a poor understanding of the long-term efficacy of bacteriophage therapies (an emerging approach to tackling the Antimicrobial Resistance crisis), and how phage evolve more broadly. We propose a novel approach to coevolution experiments that would address this challenge: instead of open-loop resource-constrained cultures, we develop a closed-loop control approach to stabilise the typically unstable or oscillatory phage-bacteria population dynamics. Achieving this requires the control system to compensate for delays in phage incubation and respond to an evolving system, while only measuring bacterial density. To address it, we develop a model of phage-bacteria dynamics, prototype delay-compensating predictive control strategies, and demonstrate a measurement-aware state observer. Overall, this approach shows the ability to stabilise co-evolution, avoiding the common outcome of unstable or winner-takes-all outcomes. This promises to enable long-term lab coevolution of phage and bacteria, which would would give valuable insights into the mechanisms and timescales of bacteria overcoming phage therapies, and open the possibility of using evolutionary engineering to develop phage for novel biotechnological applications such as the fight against Antimicrobial Resistance.