A circadian clock transplant gives E. coli rhythm

The time tinker could be used to treat jet lag, produce drugs

Circadian rhythm graphs

DAILY RHYTHM  By transplanting a molecular clock into E. coli bacteria, researchers can control the timing of the production of a protein that glows green, as seen in this diagram.

Anna H. Chen

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A ticking clock in the belly warned Captain Hook of a crocodile’s approach. A different kind of internal clock in gut bacteria may one day prove just as helpful.

Researchers have transplanted a simple circadian clock from cyanobacteria — also known as blue-green algae — into E. coli. The feat, researchers report June 12 in Science Advances, is a first step toward creating organisms that may stave off jet lag or even make drugs on a schedule.

The cyanobacterium Synechococcus elongatus has one of the simplest mechanisms for generating daily, or circadian, rhythms. Its core clock consists of just three proteins: KaiA, KaiB and KaiC. During the day, KaiA prods KaiC to pin a phosphate molecule to itself, so that KaiC is studded with phosphate at dusk. Then at night, KaiB inhibits KaiA, allowing KaiC to strip off its phosphate and start the morning unencumbered. The three proteins will endlessly repeat the cycle once a day, even in a test tube. The alga uses its clock to time important processes, such as photosynthesis.

Anna Chen, a synthetic biologist at Harvard Medical School, and colleagues wondered whether they could put the algae clock into a bacterium that doesn’t have its own circadian clock. “When I started this project people said, ‘Oh, that’s been tried before. Don’t even bother. It doesn’t work,’” says Chen. “I ignored their advice.”

Getting the three clock gears into E. coli wasn’t the hard part. The trick was devising a switch to let the clock turn on production of green fluorescent protein, or GFP, at the same time each day. Once the team engineered this switch and put it along with the clock cogs and GFP into E. coli, the bacteria pulsed with fluorescent green light about once every 24 hours, the researchers report.

GREEN GLOW E. coli bacteria blink on and off after a circadian clock and fluorescent protein transplant. The successful transplant into an organism that doesn’t have its own internal clock means that researchers may one day be able to build clocks that can be used in drug production or easing the effects of jet lag.Seth Kroll/Wyss Institute at Harvard University, Anna H. Chen

Chen and her colleagues are experimenting with ways to set the clock using light or other cues.

The system could be used in E. coli or other microbes to time production of other proteins, drugs or industrial products produced by bacteria, she says. Chen and her colleagues also speculate that gut microbes engineered with their own circadian clocks could be used to counteract the effects of jet lag. Last year, researchers reported that jet lag throws gut microbes out of sync with their host’s normal rhythms, setting up the hosts, such as mice or people, for obesity and diabetes (SN: 11/29/14, p. 12). 

The theoretical potential of transplanted clocks is exciting, says microbiome researcher Eran Elinav of the Weizmann Institute of Science in Rehovot, Israel. But researchers don’t yet know if gut bacteria with their own clocks will coordinate well with the host’s clocks. And efforts to get bacteria, introduced through supplements or yogurt, to stick around and become part of the natural collection of gut microbes haven’t worked so far. Still, “it is a fresh idea that would need to be explored,” Elinav says.

Circadian biologist John O’Neill at the MRC Laboratory of Molecular Biology in Cambridge, England, is more skeptical. Such technology is decades away at least, he says. Besides, he adds, “I would think there are easier ways of combatting jet lag than drinking a cocktail of genetically modified E. coli.” 

Tina Hesman Saey

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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