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Biomedicine

A Synchronous Clock Made of Bacteria

Such microorganisms might make environmental sensors or drug delivery systems.

It’s not your typical clock. Rather than a quartz movement and sweeping second hand, the heart of this device is a colony of genetically engineered bacteria. A deceptively simple circuit of genes allows the microorganisms to keep time with synchronized pulses of fluorescent light, beating with a slow, rhythmic flicker of 50 to 100 minutes.

Bacterial clock: Scientists have engineered bacteria to glow in synchronous waves, as shown in this still image from a video. The genetic circuit might one day be used to detect toxins or deliver drugs.

The bacteria represent the first synchronized genetic oscillator. Scientists say the tool will be foundational for synthetic biology, an offshoot of genetic engineering that attempts to create microorganisms designed to perform useful functions. The oscillator might one day provide the basis for new biosensors tuned to detect toxins, or for cellular drug delivery systems designed to release chemicals into the body at preprogrammed intervals.

Oscillators are an integral part of the biological world, defining cycles from heartbeats to brain waves to circadian rhythms. They also provide a vital control mechanism in electronic circuits. Biologists first set out to engineer a biological version more than a decade ago, creating a circuit dubbed the “repressilator.” (The creation of the repressilator, along with a genetic on-off switch, in 2000 is generally considered the birth of synthetic biology.) However, early oscillators lacked precision–the rhythm quickly decayed, and its frequency and amplitude couldn’t be controlled.

In 2008, Jeff Hasty and his team at the University of California, San Diego, created a more robust oscillator that could be tuned by the temperature at which the bacteria were grown, the nutrients they were fed, and specific chemical triggers. But the oscillations were still limited to individual cells–the bacteria did not flash together in time. In the new research, published today in the journal Nature, Hasty and colleagues build on this work by incorporating quorum-sensing, a molecular form of communication that many bacteria use to coordinate their activity.

The new oscillator consists of a simple circuit of two genes that creates both a positive and negative feedback loop. The circuit is activated by a signaling molecule, which triggers the production of both more of itself and of a glowing molecule called green fluorescent protein. The signaling molecule diffuses out of the cell and activates the circuit in neighboring bacteria.

The activated circuit also produces a protein that breaks down the signaling molecule, providing a time-delayed brake to the cycle. The dynamic interactions of different parts of the circuit in individual and neighboring cells create regular pulses of the signaling molecule and the fluorescent protein, appearing as a wave of synchronous activity. It’s “a feat analogous to engineering all the world’s traffic lights to blink in unison,” wrote Martin Fussenegger, a bioengineer at the Swiss Federal Institute of Technology, in Zurich, in a commentary accompanying the paper in Nature.

The colonies of bacteria are grown in a custom-designed microfluidics chip, a device that allows scientists to precisely control the conditions the microorganisms are exposed to. Changing the rate at which nutrients flow into the chip alters the period of the oscillations, says Hasty.

“The ability to synchronize activity among cells in a population could be an important building block for many applications, from biomedicine to bioenergy,” says Ron Weiss, a former TR35 winner and a bioengineer at MIT who was not involved in the research. For example, the bacteria could be engineered to detect a specific toxin, with the frequency of the fluorescence indicating its concentration in the environment. While a microscope is currently needed to read the output, Hasty’s team is now working on a version that can be seen with the naked eye.

The oscillator could also be used to deliver drugs, such as insulin, that function best when dosed at certain intervals. “In the future you could think of implants that produce a therapeutic effect,” says Fussenegger. The dosing of the drug would relate to the strength or amplitude of the oscillation, while the timing of the dosing would be determined by its frequency. “There would be nothing to worry about for the patient,” he says.

Researchers are now trying to make the system more robust, as well as to extend the timescale over which it can synchronize activity. They also want to combine it with previous genetic oscillators, and transfer it into different cell types that might be suited to different biotech applications.

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