Bacteria flip on/off switch when stressed

CALTECH (US) — Instead of shifting from one steady state to another in response to stress, cells use a pulsating mechanism—a simple series of actions that may also drive other cellular processes.

Researchers studied how a bacterial species called B. subtilis responds to a stressful environment—one without food, for example. In such conditions, the single-celled organism activates a large set of genes that help it deal with hardship, by aiding cell repair.

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Previously, biologists had thought the bacteria would handle the stress by turning on the relevant genes and simply leaving them on until the stress goes away.

Instead, the researchers found that B. subtilis continuously flips these genes on and off. When faced with more stress, it increases the frequency of the pulses. The pulsating action is like switching the heater on full blast for a brief period every few minutes, and turning it on and off more frequently if you want the house to be warmer.

“It’s a very different view of how a cell can respond to a particular stress,” says James Locke, a postdoctoral scholar at California Institute of Technology (Caltech). Locke and graduate student Jonathan Young are the lead authors on a paper describing the work, published online in Science.

The researchers introduced a chemical to B. subtilis that inhibits the production of ATP, the energy-carrying molecules of cells. The team found that the stress induced by this chemical triggers interactions within a set of genes—collectively called a genetic circuit that contains a set of positive and negative feedback loops and generates sustained pulses of activity in a key regulatory protein called sigma B.

The researchers attached fluorescent proteins to the circuit, causing the cells to glow green when sigma B was activated. By making movies of the flashing cells, the team could then study the dynamics of the circuit.

The key to this pulsating mechanism is the variability inherent in how proteins are made, the researchers say. The number of copies of any specific protein in a given cell fluctuates over time. The bacterial gene circuit amplifies these molecular fluctuations, also called noise, to generate discrete pulses of sigma B activation. The stress also activates another key protein that modulates the pulse frequencies.

By turning a steady input (the stress) into an oscillating output (the activation of sigma B) the genetic circuit is analogous to an electrical inverter, a device that converts direct current (DC) into alternating current (AC), explains Michael Elowitz, professor of biology and bioengineering at Caltech and coauthor of the paper.

“You might think you need some kind of elaborate circuitry to implement that, but the cell can do it with just a few proteins, and by taking advantage of noise.”

This work provides a blueprint for how relatively simple genetic circuits can generate complex and dynamic behaviors in individual cells, the researchers say.

“We’re excited to think that similar mechanisms may occur in other cellular processes,” Locke says. “It’d be interesting in the future to see which aspects of this circuit architecture also appear in more complex systems, such as mammalian cells.”

“With this work and recent work in other systems, we’re starting to get a glimpse of just how dynamic cellular control systems really are,” Elowitz adds. “That’s something that was very difficult to see in the past.”

The research was funded by the National Institutes of Health, the National Science Foundation, the Packard Foundation, the International Human Frontier Science Organization, and the European Molecular Biology Organization.

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