Scientists engineered synthetic cells that accurately keep time using biological clock proteins, offering new insights into how circadian rhythms resist molecular noise.
Researchers at UC Merced have successfully created tiny artificial cells capable of keeping time with remarkable precision, closely resembling the natural daily cycles observed in living organisms. This discovery offers new insight into how biological clocks maintain accurate timing, even amid the random molecular fluctuations that occur within cells.
Published in Nature Communications, the study was led by bioengineering Professor Anand Bala Subramaniam and Professor Andy LiWang of the chemistry and biochemistry department. The lead author, Alexander Zhang Tu Li, completed his Ph.D. under Subramaniam’s guidance.
Biological clocks, commonly referred to as circadian rhythms, are internal systems that manage essential 24-hour cycles such as sleep, metabolism, and other key bodily functions. To better understand how these rhythms operate in cyanobacteria, the research team recreated the timing mechanism inside simplified, synthetic cell structures known as vesicles. These vesicles were filled with the core proteins that drive the biological clock, with one protein labeled using a fluorescent marker to make the timing activity visible.
The engineered cells emitted a consistent glowing signal that followed a 24-hour cycle for at least four days. When either the concentration of clock proteins was decreased or the vesicle size was reduced, the rhythmic glow disappeared. This disruption occurred in a consistent and predictable pattern.
Modeling Clock Stability
To explain these findings, the team built a computational model. The model revealed that clocks become more robust with higher concentrations of clock proteins, allowing thousands of vesicles to keep time reliably — even when protein amounts vary slightly between vesicles.
The model also suggested another component of the natural circadian system — responsible for turning genes on and off — does not play a major role in maintaining individual clocks but is essential for synchronizing clock timing across a population.
The researchers also noted that some clock proteins tend to stick to the walls of the vesicles, meaning a high total protein count is necessary to maintain proper function.
“This study shows that we can dissect and understand the core principles of biological timekeeping using simplified, synthetic systems,” Subramaniam said.
A New Tool for Circadian Biology
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 expert in circadian clocks.
“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,” Fang said. “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.”
Reference: “Reconstitution of circadian clock in synthetic cells reveals principles of timekeeping” by Alexander Zhan Tu Li, Andy LiWang and Anand Bala Subramaniam, 21 July 2025, Nature Communications.
DOI: 10.1038/s41467-025-61844-5
Subramaniam is a faculty member in the Department of Bioengineering and an affiliate of the Health Sciences Research Institute (HSRI). LiWang is a faculty member in the Department of Chemistry and Biochemistry, also affiliated with HSRI. He is 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.
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