Researchers at the University of California, Merced have demonstrated that artificial cells can maintain regular timekeeping, similar to the circadian rhythms found in living organisms. The study, published in Nature Communications, was led by bioengineering professor Anand Bala Subramaniam and chemistry and biochemistry professor Andy LiWang. Alexander Zhang Tu Li, a Ph.D. graduate from Subramaniam’s lab, served as the first author.
The team investigated biological clocks—also known as circadian rhythms—which regulate essential 24-hour cycles such as sleep and metabolism. By reconstructing these clock mechanisms inside vesicles, which are simplified cell-like structures containing core clock proteins (one marked with a fluorescent tag), researchers observed that these artificial cells emitted light in a consistent 24-hour cycle for up to four days.
When researchers decreased the number of clock proteins or reduced vesicle size, the rhythmic glow disappeared in a predictable way. Using computational modeling, they determined that higher concentrations of clock proteins enhance the reliability of timekeeping across many vesicles—even if protein levels vary slightly between them.
The model also indicated that another element involved in natural circadian systems—responsible for gene activation—is less important for individual cellular clocks but is needed to synchronize timing among groups of cells.
Researchers found some clock proteins adhere to vesicle walls, making it necessary to have high total protein levels for proper function.
“This study shows that we can dissect and understand the core principles of biological timekeeping using simplified, synthetic systems,” said Subramaniam.
Mingxu Fang, a microbiology professor at Ohio State University who specializes in circadian clocks, commented on the significance: “The cyanobacterial circadian clock relies on slow biochemical reactions that are inherently noisy, and it has been proposed that high clock protein numbers are needed to buffer this noise. This new study introduces a method to observe reconstituted clock reactions within 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 part of UC Merced’s Department of Bioengineering and affiliated with its Health Sciences Research Institute (HSRI). LiWang belongs to the Department of Chemistry and Biochemistry at UC Merced and is also an HSRI affiliate. He is recognized as a fellow by the American Academy of Microbiology and will receive the Dorothy Crowfoot Hodgkin Award from The Protein Society in 2025.
Funding for this research came from several sources including Subramaniam’s National Science Foundation CAREER award from the Division of Materials Research; grants from both the National Institutes of Health and Army Research Office awarded to LiWang; as well as support through an NSF CREST Center fellowship at UC Merced.
