Published online 20 January 2010 | Nature | doi:10.1038/news.2010.21

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Bacterial clocks chime in unison

Genetic circuit allows entire colonies to keep time.

Flahs of light in bacterial colonyA burst of light from a colony of bacteria with coupled genetic clocks.Tal Danino/Octavio Mondragon-Palamino/Lev Tsimring

Scientists have made a microbial 'clock' consisting of many bacteria that count time together.

The feat is a step forward for synthetic biology, and could one day lead to the development of implantable drug dispensers that deliver regular doses of medicine inside the body. Previously, scientists had engineered only single cells to become oscillators — devices that could count time by performing a particular activity on a cyclical schedule.

"For the first time, it is possible to synchronize individual oscillators in different organisms of the same population," says Martin Fussenegger of the Swiss Federal Institute of Technology Zurich (ETH Zurich) in Basel, who was not involved with the latest research. "If it is implemented in mammalian cells, this could have a tremendous impact in the future."

The work, published in Nature1, involved transferring genes that are part of a natural bacterial communication system, called quorum sensing, from two species of bacteria into the Escherichia coli genome. Scientists wired the genes into a circuit so that one of the genes produces a molecule called acyl-homoserine lactone (AHL) that diffuses to other cells, where it ramps up production of more AHL. But the circuit was set up so that AHL also simultaneously activates another gene that results in the breakdown of AHL.

These counteracting positive and negative feedback loops act like the pendulum on a grandfather clock to tune AHL production in the bacterial colony so that it rises and falls on a regular cycle, report the researchers. The team was led by Jeff Hasty, a molecular biologist and bioengineer at the University of California, San Diego. A fluorescent reporter protein encoded by a gene attached to the circuit glows brighter when more AHL is made, allowing the scientists to watch as the E. coli population ramps its production of the molecule up and down in synchronicity (see Nature 's video).

Rhythm of life

In Hasty's system, the bacteria are lodged on a microfluidic device that contains tiny channels to allow nutrients to flow to the cells and waste products to flow away. The team reports that the timing and strength of the synchronized clock's oscillations depend on how quickly nutrients and waste are pumped through the channels of the device.

The researchers developed the device after many failed attempts at getting the experiment to work. Only after letting the experiment run overnight did they realize that it took the cells a certain time to grow to the exact density necessary to activate the quorum-sensing circuit they had built.

"We realized that we needed to build devices that accepted an overall number of cells within the range that would support oscillations and that would use flow to carry away this AHL molecule, because it doesn't degrade on its own," Hasty says.

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He suggests that the development of synchronized bacterial clocks could enable bacteria to be used as biological sensors. It could also allow scientists to improve their understanding of the dynamics of biological rhythms, says Fussenegger, who points out that many activities in the human body, such as the coordinated firing of neurons to produce signals that lead to thought and action, are examples of natural synchronization among cells.

"Maybe we could in the future design brain pacemakers, or understand a little more how cells synchronize themselves with their neighbours, or maybe how being out of sync has some pathological consequences," Fussenegger says. "Synchronized oscillation is really very important in biology."

Indeed, Hasty says that his work already reveals one provocative lesson about such natural circuits: that they don't need to be complicated to produce complicated patterns of activity.

"We get all of this complexity from two genes, so it's a nice example of how you don't need a lot of genes to get complex behaviours," Hasty says. 

  • References

    1. Danino, T., Mondragón-Palomino, O., Tsimring, L. & Hasty, J. Nature 463, 326-330 (2010). | Article
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