Often referred to as the "body clock", circadian rhythm controls what time of day people are most alert, hungry, tired or physically¹ primed due to a complex biological process that is not unique to humans. Circadian rhythms, which oscillate over a roughly 24-hour cycle in adaptation to the Earth's rotation², have been observed in most of the planet's plants, animals, fungi³ and cyanobacteria, and are responsible for regulating many aspects of organisms' physiological⁴, behavioral and metabolic⁵ functions. Now, scientists led by the pioneering Harvard synthetic⁶ biologist Pamela Silver, Ph.D., have harnessed the circadian mechanism⁷ found in cyanobacteria to transplant the circadian wiring into a common species of bacteria that is naturally non-circadian. The novel work, which for the first time demonstrates the transplant of a circadian rhythm, is reported in a new study in Science Advances.

 

"By looking at systems in nature as modular, we think like engineers to manipulate and use biological circuits in a predictable, programmable way," said Silver, who is a Core Faculty⁸ member at the Wyss Institute for Biologically Inspired Engineering at Harvard University and a Professor in the Department of Systems Biology at Harvard Medical School. 

 

Silver's team used this methodology to successfully transplant a circadian rhythm into the bacterial⁹ species E. coli, which is widely used as a "workhorse" cell species by biologists due to how well it is understood and the ease in which E. coli can be genetically¹¹ altered. The genetically engineered circadian E. coli designed by Silver could one day be used in probiotic pills as a way to monitor the gut¹² microbiota, which is the collective and diverse set of bacterial species that flourish in the human gastrointestinal tract¹³ and contribute to many different health factors.

 

To create a circadian rhythm in E. coli, the protein circuit responsible for regulating circadian oscillations was modularly removed from cyanobacteria, a photosynthetic¹⁴ bacteria species that is the only bacteria known to naturally contain a circadian rhythm. The protein circuit was then transplanted into E. coli, where it can be connected to additional gene¹⁰ expression components¹⁵ to potentially influence metabolic and behavioral functions in programmable relation to the day-night cycle. In the experimental E. coli, the circuit was linked to fluorescent¹⁶ proteins that lit up each time the circadian oscillations were triggered, causing the E. coli to glow rhythmically¹⁷ in a stunning¹⁸ visual confirmation¹⁹ of the transplant's success.

 

"The ultimate dream application would be to deliver these circadian E. coli to an individual in pill form, which could allow the circadian rhythm to be linked to additional biological circuits in order to perform a precisely-timed release of drugs, or to be able to sense and influence the host's circadian rhythm," said the study's first author, Anna Chen, a systems biology graduate student at the Wyss Institute and Harvard Medical School.

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