The dawn of oxygen-producing life 2.5 billion years ago may have set the first biological clocks in motion. That is the suggestion of a provocative paper published online today in Nature1, which finds that enzymes that absorb the toxic by-products of oxygen respiration, such as hydrogen peroxide, wax and wane in a periodic fashion and exist across all domains of life.

Nearly all life keeps internal time through biochemical mechanisms known as circadian clocks. These cycle in a roughly 24-hour period in the absence of outside cues such as sunlight, and yet they also respond to outside signals to reset, says Akhilesh Reddy, a biochemist at the University of Cambridge, UK, who is lead author of the latest study. For a traveller to recover from jet lag, for instance, they must reset, or entrain, their circadian clock.

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Circadian clocks are deeply entwined in an organism’s daily life. They help plants to time the production of light-harvesting machinery in leaves, and allow monarch butterflies to navigate across North America. Single-celled algae lacking an internal clock can’t survive.

Despite their importance and universality, the genes that control circadian clocks in different organisms don’t have a lot in common, says Reddy. Clock genes from thale cress (Arabidopsis thaliana), for example, are very different to those of fruitflies and mammals, suggesting that the clocks did not evolve from a common ancestor. “We seem to have re-invented the wheel five times,” Reddy says.

A search through time

In search of a universal clock, Reddy and his colleagues turned their attention to enzymes called peroxiredoxins, which are present in nearly all life forms. The enzyme cycles between two chemical states, depending on whether it has reacted with hydrogen peroxide, a by-product of oxygen respiration that is harmful to cells. In 2011, Reddy’s team reported that the levels of peroxiredoxin in human red blood cells2 and marine algae3 cycle between these two states in a roughly 24-hour period.

Now, Reddy’s team have extended that observation to mice, fruitflies and plants, as well as bacteria and archaea — the first forms of cellular life to evolve more than three billion years ago or so. Peroxiredoxin also kept time in all these organisms in the absence of light, a hallmark of circadian clocks.

The peroxiredoxin, or metabolic, clock also does not depend on other circadian clocks, which rely on feedback loops — these are created when activation of a gene produces a protein that then blocks that same gene’s activation. Mutations that disabled these other clocks in fruitflies, plants, fungi and algae did not stop peroxiredoxin from cycling between its two states across the day.

Many of the internal workings of the metabolic clock remain a mystery, Reddy concedes. Peroxiredoxin may cycle between its chemical forms in the absence of other circadian rhythms, but Reddy’s team has not shown that traditional circadian clocks rely on the metabolic clock. They hope to manipulate the metabolic clock and test whether it influences other circadian clocks and an organism’s physiology. A metabolic clock cannot comprise just a single enzyme, so must also involve other, as-yet-unidentified components. “I don’t think any one molecule will be a timer in itself,” Reddy says.

Grandfather clock gene

But Reddy thinks that peroxiredoxin is a good candidate to be the grandfather of all biological clocks. He and his team hypothesize that the system emerged around 2.5 billion years ago in response to the emergence of photosynthesis in bacteria. This led to the gradual accumulation of oxygen in Earth’s atmosphere, known as the Great Oxidation Event.

The fact that photosynthesis relies on the Sun would have meant that oxygen levels during the Great Oxidation Event would have fluctuated across the day. Organisms that anticipated a periodic burst in oxygen by producing enzymes such as peroxiredoxin to cope with the toxic by-products of respiration may have been at an evolutionary advantage over others, Reddy’s team proposes.

Joseph Bass, an endocrinologist at the Northwestern University Feinberg School of Medicine in Chicago, calls this an “intellectually intriguing argument”. It presumes that circadian clocks evolved because they offered life a metabolic advantage to anticipating the presence of oxygen. But an alternative explanation is that circadian clocks may have evolved to cope with ultraviolet radiation from the Sun, he says, noting that the products of some circadian clock genes resemble enzymes that repair UV-damaged DNA.

“I think we still don’t fully know the answer to what the dominant pressure to evolve a circadian clock might have been,” Bass says.