A team of UC Merced researchers has shown that tiny artificial cells can accurately keep time, mimicking the each day rhythms present in living organisms. Their findings make clear how biological clocks stay on schedule despite the inherent molecular noise inside cells.
The study, recently published in Nature Communications, was led by bioengineering Professor Anand Bala Subramaniam and chemistry and biochemistry Professor Andy LiWang. The primary writer, Alexander Zhang Tu Li, earned his Ph.D. in Subramaniam’s lab.
Biological clocks — also generally known as circadian rhythms — govern 24-hour cycles that regulate sleep, metabolism and other vital processes. To explore the mechanisms behind the circadian rhythms of cyanobacteria, the researchers reconstructed the clockwork in simplified, cell-like structures called vesicles. These vesicles were loaded with core clock proteins, one in all which was tagged with a fluorescent marker.
The bogus cells glowed in a daily 24-hour rhythm for a minimum of 4 days. Nonetheless, when the variety of clock proteins was reduced or the vesicles were made smaller, the rhythmic glow stopped. The lack of rhythm followed a reproducible pattern.
To clarify these findings, the team built a computational model. The model revealed that clocks grow to be more robust with higher concentrations of clock proteins, allowing hundreds of vesicles to maintain time reliably — even when protein amounts vary barely between vesicles.
The model also suggested one other component of the natural circadian system — accountable for turning genes on and off — doesn’t play a significant role in maintaining individual clocks but is important for synchronizing clock timing across a population.
The researchers also noted that some clock proteins are likely to persist with the partitions of the vesicles, meaning a high total protein count is mandatory to keep up proper function.
“This study shows that we are able to dissect and understand the core principles of biological timekeeping using simplified, synthetic systems,” Subramaniam said.
The work led by Subramaniam and LiWang advances the methodology for studying biological clocks, said Mingxu Fang, a microbiology professor at Ohio State University and an authority in circadian clocks.
“The cyanobacterial circadian clock relies on slow biochemical reactions which might be inherently noisy, and it has been proposed that prime clock protein numbers are needed to buffer this noise,” Fang said. “This latest study introduces a technique to look at reconstituted clock reactions inside size-adjustable vesicles that mimic cellular dimensions. This powerful tool enables direct testing of how and why organisms with different cell sizes may adopt distinct timing strategies, thereby deepening our understanding of biological timekeeping mechanisms across life forms.”
Subramaniam is a school member within the Department of Bioengineering and an affiliate of the Health Sciences Research Institute (HSRI). LiWang is a school member within the Department of Chemistry and Biochemistry, also affiliated with HSRI. He’s a fellow of the American Academy of Microbiology and the 2025 recipient of the Dorothy Crowfoot Hodgkin Award from The Protein Society.
The work was supported by Subramaniam’s National Science Foundation CAREER award from the Division of Materials Research and by grants from the National Institutes of Health and Army Research Office awarded to LiWang. LiWang was supported by a fellowship from the NSF CREST Center for Cellular and Biomolecular Machines at UC Merced.