How tiny artificial cells can keep perfect time for days

A speck of engineered biology no wider than a human hair has just pulled off something exquisite: it kept time as faithfully as a wristwatch for four straight days.

In the process, it offered scientists an unprecedented look at why the biological clocks inside every living thing – from cyanobacteria to humans – rarely skip a beat, even though the molecular world they inhabit is full of randomness.

The achievement comes from a collaboration at the University of California, Merced, led by bioengineer Anand Bala Subramaniam and chemist Andy LiWang.

The team reports that they have re‑created the simplest known circadian clock – a trio of proteins found in photosynthetic cyanobacteria – inside hundreds of fat‑bubble “cells” called vesicles.

Each miniature clock glowed in a 24‑hour rhythm for a minimum of four days according to first author Alexander Zhang Tu Li. This proves that everything the system needs to tick resides in those three proteins alone.

Making clocks from scratch

Biological clocks, or circadian rhythms, choreograph sleep-wake cycles, hormone surges, body temperature, and metabolism across the tree of life. But in their natural context – the crowded volumes of living cells – they also face fierce molecular noise.

Proteins constantly move and collide, while their concentrations shift with every round of cell growth or division.

Scientists have long wondered how these clocks stay so precise amid that chaos. Reconstituting them in stripped‑down, controllable environments lets researchers test which parts of the machinery really matter.

“This study shows that we can dissect and understand the core principles of biological timekeeping using simplified, synthetic systems,” Subramaniam explained.

Rebuilding time, protein by protein

To begin, the Merced group brewed purified versions of the cyanobacterial clock proteins KaiA, KaiB, and KaiC in test tubes.

KaiC is the hub of the system, adding and removing phosphate groups from itself in a slow, rhythmic cycle. KaiA and KaiB nudge that process forward and backward like molecular gears.

The twist was encapsulation. Using a microfluidic technique, the researchers sealed the three‑protein mix and a fluorescent tag inside lipid vesicles. These vesicles – essentially artificial cells – ranged from two to ten micrometers in diameter.

A temperature‑controlled confocal microscope then watched as each artificial cell vesicle brightened and dimmed in time with KaiC’s phosphorylation cycle.

When timing falls apart

The movies revealed a binary outcome. If a vesicle contained enough protein, its clock pulsed with textbook regularity.

If protein numbers dipped below a threshold (either because the total mixture was diluted or because the vesicle happened to be small), the rhythm collapsed. When the amount of clock proteins decreased or the vesicles were downsized, the rhythmic glow disappeared.

LiWang and Subramaniam next built a mathematical model that treated each vesicle like a tiny roulette wheel. Protein counts were allowed to vary randomly, just as they would in a real bacterium after cell division.

Once those numbers were fed into the equations that govern KaiC’s chemistry, the simulations reproduced the all‑or‑nothing behavior seen under the microscope. Higher protein counts made clocks more robust, showing that abundance is the first defense against disruptive molecular noise.

Gene loop keeps time

In cyanobacteria, the KaiABC clock also controls gene activity through a slower, secondary feedback loop. Many researchers assumed that this transcription-translation feedback loop is crucial for precision. The UC Merced model challenged that assumption.

According to the simulation, adding or removing the gene‑expression loop hardly changed individual vesicle rhythms at all. What it did change was synchrony.

Without the loop, clocks drifted apart; with it, vesicles stayed in sync for days. In other words, gene regulation acts like a conductor, keeping an orchestra of otherwise accurate drummers on the same beat.

The cyanobacterial clock, said Ohio State University microbiologist Mingxu Fang, “relies on slow biochemical reactions that are inherently noisy.” The new vesicle system “enables direct testing of how and why organisms with different cell sizes may adopt distinct timing strategies.”

Rethinking time in engineered cells

Intracellular clocks influence everything from metabolic health to the efficacy of chemotherapy. Yet therapies that try to tweak them often produce mixed results, partly because researchers lack ways to probe their mechanical guts.

A vesicle “test rig” solves that problem. By swapping in mutated proteins, or by crowding the vesicles with other molecules, scientists can now watch the gears grind – or stall – in real time.

The findings also matter to bioengineers who dream of programming synthetic cells.

Any molecular circuit that must run for hours or days (say, one designed to release drugs on a schedule) will face the same noise problem as a natural circadian clock. The UC Merced work shows a straightforward workaround: make plenty of parts.

Toward full synthetic cells

Several puzzles remain. Because some KaiB molecules stuck to the vesicle walls, the authors suspect that membranes themselves may regulate the clock in cyanobacteria. They plan to test this idea by inserting other membrane proteins.

They also hope to connect the vesicle clocks to simple gene networks, pushing the system closer to what a bacterium actually experiences.

For now, the take‑home message is elegant: time can keep itself, provided the machinery is dense enough and, when necessary, a coordinating signal brings the ensemble into phase.

The steady pulses inside these man‑made vesicles whisper of biological perfection. They’re proof that even the tiniest artificial cells can, quite literally, know what time it is.

The study is published in the journal Nature Communications.

Image Credit: UC Merced

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