Scientists transplant ‘body clock’ in E. coli: Genetically engineered circadian E. coli could be used to formulate therapeutic strategies for improvement of drug interactions and specific release.

Scientists at the Harvard University have successfully transplanted the circadian rhythm from the photosynthetic cyanobacteria into the bacterial species E. coli. Transplanting the protein circuit that regulates these rhythms and linking them to a fluorescent protein allowed the scientists to observe the E. coli glowing at regular intervals throughout the cycle.  

‘Body clocks’, scientifically known as circadian rhythms, control the timings of various biological, physiological and metabolic mechanisms, such as hunger, sleep and fatigue. They exist in humans and various other species, including plants, animals, cyanobacteria and fungi. These rhythms are adapted in accordance to the Earth’s rotation and alternate over a cycle of approximately 24 hours.

The study was led by revolutionary Harvard synthetic biologist Pamela Silver, PhD, a core faculty 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.

Scientists have been able to harness this mechanism from cyanobacteria and transplant it into E. coli, a non-circadian species. This novel experiment was reported in a study published 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,” Silver explained.

The team of scientists used E. coli because biologists often refer to it as the ‘workhouse’ of cell species – its internal mechanism is well-understood and it is fairly easy and safe to conduct genetic alterations. The resulting genetically engineered circadian E. coli has the potential to be incorporated in probiotic pills, allowing doctors to monitor all the diverse bacterial species that reside in the human gastrointestinal tract.

To generate a circadian rhythm in E. coli, the protein circuit that regulates circadian alterations in cyanobacteria was modularly removed. The circuit was then transplanted into E. coli and was linked to certain additional gene expression components, which significantly influenced behavioral and metabolic functions in accordance with day and night. In the genetically programmed E. coli, the circadian circuit was connected with fluorescent proteins – these lit up every time a circadian oscillation occurred, creating a rhythmically glowing E .coli that confirmed the experiment’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,” remarked first author, Anna Chen, a systems biology graduate student at the Wyss Institute and Harvard Medical School.

The biological clock in humans, if disrupted, leads to a variety of metabolic disorders, such as glucose intolerance and obesity. Certain cancer-treating drugs have been seen to fluctuate in their effectiveness based on when they were taken according to the patient’s circadian cycle. The genetically engineered circadian E. coli created in this study could very well be used to formulate therapeutic strategies for the improvement of drug interactions and specific release. This could energize cancer treatments and clinical applications, and even lead to the treatment of jet-lag as well.

“Circadian rhythm has an enormous impact on our health and how we respond to our environment – so the opportunity to tap into those controls, using genome engineering to rewire genetic circuits, opens an exciting new path for treating disease and regulating a wide range of physiological behaviors,” stated the Wyss Institute Founding Director Donald Ingber, MD, PhD.