Phage therapy, which exploits the ability of certain viruses called bacteriophages to infect and replicate within bacteria, shows promise for treating antibiotic-resistant bacterial infections.

However, the design of such therapies depends on a solid understanding of how phages do their work.

"Phages can kill the cell immediately, or they can become dormant and kill it later," University of Delaware assistant professor of electrical engineering Abhyudai Singh explained. "The data reveal a high level of precision in the kill time. It takes about one hour for the virus to complete the process, but questions remain about how the cells control this precision in timing."

Singh and John Dennehy from Queens College and the Graduate Center of City University of New York have collaborated on research to shed light on the molecular basis for this process.

Their findings appear in a paper, "A First-Passage Time Approach to Controlling Noise in the Timing of Intracellular Events," that was published online Jan. 9 in Proceedings of the National Academy of Sciences.

Singh and doctoral student Khem Raj Ghusinga provided the theoretical contribution, and Dennehy supplied the biological foundation for the work, which has important implications for medicine.

"The problem is that while there is an overall precision to this process, there is also inherent randomness from cell to cell," Singh said. "So, our mathematical model is basically a framework, or model system, that brings order to this randomness and provides general biological insights that can be applied in the laboratory."

He explained that proteins called holins are essential for lysing, or destroying, the cell. They accumulate on the cell membrane, reach a critical threshold and then form holes that rupture the cell and release phage "babies." However, the same gene that expresses holin also expresses another protein called antiholin.

"It's curious that nature would make two versions of a protein that cancel each other out," Singh said. "It turns out that it's actually antiholin that makes the timing precise. If we remove antiholin, the variation in the process increases."

Singh said the formulas developed in the work provided counterintuitive insights into the regulatory mechanisms needed for scheduling an event at a precise time with minimal fluctuations.

"While we expected feedback to be an important part of the triggering mechanism, it turns out that negative feedback regulation can actually amplify noise, or confusion, in event timing," he said. "So, in some cases, such as with our work on lysis in bacteriophages, precision in timing is obtained with no feedback at all."

"We believe that the analytical results and insights we obtained in this work have broader implications for timing phenomenon in chemical kinetics, ecological modeling and statistical physics," Singh said.