Scientists seek cause for what makes good cell go bad

Genetic mutations – sudden, random and usually harmful changes to the structure of a gene – are only one factor that determines the ultimate fate of a cell. Chicago scientists have discovered that a non-genetic molecular process also can play a role, and that experimenters can influence this process in bacteria, they report in the April 1 issue of the journal Nature.

The research team, led by Philippe Cluzel, Assistant Professor in Physics at the University of Chicago, arrived at its finding by analyzing E. coli’s chemotaxis system, the system that transmits the biochemical signals responsible for cell locomotion.

“We studied this simple system in bacteria as a model system for the general study of signal transduction networks,” Cluzel said. “Signal transduction networks are everywhere in nature. The division of our cells is controlled by a signal transduction network, and its malfunction causes cancers.”

The network that controls the movement of E. coli, a single-celled organism, is much simpler than the system that divides human cells. But signal transduction networks exhibit the same design principles across species, Cluzel said. Consequently, researchers will now attempt to apply their research methods to higher organisms.

A combination of traditional genetic experiments and computer simulations contributed to the study. “The methods they’re using I think in many ways are the future of biology,” said Michael North, deputy director of the Center for Complex Adaptive Systems Simulation at Argonne National Laboratory. North, who did not participate in the study but who is familiar with its findings, lauded Cluzel and his co-authors for their mathematical rigor and for pushing signal transduction research to new levels of volume and efficiency. “They were able to collect more data than anyone had in the past by a wide margin,” North said.

Cluzel’s team focused its study on monitoring and analyzing the intracellular signals that control the bacterium’s flagella–its whip-like arms. The researchers found that they could affect how often the bacteria switched their direction of motion by altering the concentration of a key protein in its signal transduction network. Previous studies performed at the population level had concluded that the bacteria switched their direction at a steady rate. “We showed that at the single-cell level it was totally the other way around,” Cluzel said. “Variability is a part of nature and this can be regulated.”

Previous researchers had come to a different conclusion because they applied different statistical methods to their studies. Biologists usually average their data on the behavior of organisms because population statistics usually meet their experimental needs. But averaging eliminates much of the information scientists need to understand individual variability.

Like biologists, physicists also encounter widely fluctuating data in some of their experiments. This “noise” actually helps physicists determine the basic characteristics of conducting materials as electric signals travel through them. Similarly, Cluzel said, biological noise “can carry important information about the intracellular molecular mechanisms taking place within a cell.”

In addition to carrying out experiments on E. coli’s transduction network, the researchers also reproduced its components in a computer simulation and obtained the same results. In future studies, the team will apply similar approaches to characterize the molecular origin of cell fate variability in higher organisms.

Cluzel and his research team display a wide range of scientific training. Cluzel received his Ph.D. in physics at the Institut Marie Curie in Paris, where both a physicist and a biologist served as dual advisers for his research. Cluzel later spent four years conducting research in a molecular biology laboratory at Princeton University. He now is a member of the Institute for Biophysical Dynamics, which fosters scientific collaborations between physical and biological scientists at the University.

Cluzel’s co-leading authors include Ekaterina Korobkova, a graduate student in chemistry, and Thierry Emonet, a Research Associate in the Institute for Biophysical Dynamics, both at the University of Chicago. Completing the team are Jose Vilar, a theoretical physicist at the Sloan Kettering Cancer Center in New York, and Thomas Shimizu, who does computer simulations of cells, of Keio University in Japan.