Most population-based studies that focus on the behavior of idealized average cells are used to contextualize our understanding of the bacterial cell cycle. While these methods are indisputably useful, their mechanistic significance is limited by the fact that they must rely on the behavior of idealized average cells, because the growth and physiology of a single cell are stochastic.

To close this gap, a team of biologists and physicists from Washington University in St. Louis and Purdue University used actual single-cell data to create an updated framework for understanding the relationship between cell growth, DNA replication and division. in a bacterial system.

They sought to understand how these stochastic cells, or these “erratic” individual bacterial cells, manage to skillfully coordinate DNA replication with growth and division so that the overall events happen in the correct order despite the “noise” of each process.

To answer this question, scientists carefully looked at single-cell growth data from the model organism Escherichia coli collected by the Jun Laboratory at the University of California, San Diego. They then created a simple mathematical model that correctly matched each cell’s data and reflected the complex, unpredictable behavior of the individual cells.

Others had seen that the basic cell cycle phases of DNA replication and cell division were interdependent based on average cell behavior. Scientists, however, did not see it that way.

Petra Levin, the George William and Irene Koechig Freiberg Professor of Biology in Arts & Sciences at Washington University, said: “Decades of genetic and molecular studies indicate that while DNA replication and division are coordinated, they are not interdependent. As long as there are mechanisms to prevent division across uncopied chromosomes or to resolve the situation in the unlikely event that it does happen, all is well. E. coli does not have cell cycle checkpoints like eukaryotic cells.”

Scientists, meanwhile, discovered that it was easy to understand the data of each cell. Each cell contains three (stochastic) timers, which operate similarly to the happy tune from above, and whose orchestration controls the sequence of cell cycle events.

Based on this idea, scientists found that they could predict the sequence of DNA replication initiation, the end of DNA replication, and division based on when the three timers go off and reset independently. His predictions were in excellent agreement with existing data on DNA replication and cell division of individual cells in many different growth conditions.

By describing a stochastic, non-deterministic relationship between DNA replication and cell division, the authors have changed the way scientists understand a basic process in cell biology.

Iyer-Biswas, a physicist at Purdue University with expertise in both first-principle physics theory, said: “Our ultimate goal is to build a community around high-precision approaches in biology that seamlessly integrate theory and experiment. A more immediate goal is to transcend system-specific details and provide a unifying framework applicable to other bacterial species.”

Magazine reference:

  1. Sara Sanders, Kunaal Joshi et al. Beyond the Mean: An updated framework for understanding the relationship between cell growth, DNA replication and division in a bacterial system. PLOS Genetics. DOI: 10.1371/journal.pgen.1010505