The mechanism that controls the internal 24-hour clock of all forms of life from human cells to algae has been identified by scientists at the Universities of Cambridge and Edinburgh. The circadian clock arose early in the evolution of life. Its purpose is traditionally thought to enable organisms in adapting to the cycle of day and night. Recently, the vast extent and importance of circadian regulation has come to be more fully realized. In fact, research suggests that nearly all behaviors and physiology are somewhat controlled by the process.
Two new studies out today in the journal Nature from the Universities of Cambridge and Edinburgh give insight into the circadian clock which controls patterns of daily and seasonal activity, from sleep cycles to butterfly migrations to flower opening.
One study, from the University of Cambridge's Institute of Metabolic Science, has identified 24-hour rhythms in red blood cells. This is significant because circadian rhythms have always been assumed to be linked to DNA and gene activity, but – unlike most of the other cells in the body – red blood cells do not have DNA.
"We know that clocks exist in all our cells; they're hard-wired into the cell. Imagine what we'd be like without a clock to guide us through our days. The cell would be in the same position if it didn't have a clock to coordinate its daily activities," said Akhilesh Reddy, from the University of Cambridge and lead author of the study.
"The implications of this for health," he added, "are manifold. We already know that disrupted clocks – for example, caused by shift-work and jet-lag – are associated with metabolic disorders such as diabetes, mental health problems and even cancer. By furthering our knowledge of how the 24-hour clock in cells works, we hope that the links to these disorders – and others – will be made clearer. This will, in the longer term, lead to new therapies that we couldn't even have thought about a couple of years ago."
The Cambridge team incubated purified red blood cells from healthy volunteers in the dark and at body temperature, and sampled them at regular intervals for several days. They then examined the levels of biochemical markers – proteins called peroxiredoxins – that are produced in high levels in blood and found that they underwent a 24-hour cycle. Peroxiredoxins are found in virtually all known organisms.
A further study, by scientists working together at the Universities of Edinburgh and Cambridge, and the Observatoire Oceanologique in Banyuls, France, found a similar 24-hour cycle in marine algae, indicating that internal body clocks have always been important, even for ancient forms of life.
The researchers found the rhythms by sampling the peroxiredoxins in algae at regular intervals over several days. When the algae were kept in darkness, their DNA was no longer active, but the algae kept their circadian clocks ticking without active genes. Scientists had thought that the circadian clock was driven by gene activity, but both the algae and the red blood cells kept time without it.
Andrew Millar of the University of Edinburgh's School of Biological Sciences, who led the study, said: "This groundbreaking research shows that body clocks are ancient mechanisms that have stayed with us through a billion years of evolution. They must be far more important and sophisticated than we previously realised. More work is needed to determine how and why these clocks developed in people – and most likely all other living things on earth – and what role they play in controlling our bodies."
Elsewhere, another earlier study supports the suggestion that the function of ALL genes in mammals is based on circadian rhythms. This new research disproves the current theory that only about 10 percent of genes are affected by “nature's clock."
While scientists have long understood that circadian rhythms regulate many behaviors, this research indicates that daily rhythm dominates all life functions, particularly metabolism. The study presents oscillation as a very basic property of all genes in human and other mammals, as opposed to being a special function of a few particular genes, as previously believed.
"When we standardize genes onto a common scale that measures levels of expression, we could not find a single gene that did not oscillate," Colorado State University researcher Andrey Ptitsyn said.
Using advanced computer algorithms, Ptitsyn, was able to establish a baseline oscillation in over 98% of all genes. The vast majority of genes were previously not known to change their expression level in a daily cycle. Older studies may have inadvertently collected skewered information as well, as some of these oscillating genes have been used as a stable reference platform in past gene expression studies.
A better understanding of oscillation properties in the genes involved with metabolism is essential to scientific progress in terms of understanding how genes interact with and regulate health and disease. However, a better understanding of how our genes function should increasingly help individuals on practical level, as well.
"Anyone who diets, for example, knows you shouldn't eat late, and now we are getting closer to understanding why exactly," said Ptitsyn. "We discovered that all genes have a significant change in pattern of activity—or expression—throughout the day. Every pathway of gene expression is affected by circadian rhythms, and the timing of the rhythms from each group of genes that are synchronized is important."
Ptitsyn also discovered alternative short and long copies of some genes oscillating in the opposite phase. These genes are essential components of leptin signaling system, which is responsible for the sensation of satiety (feeling full) after eating. The oscillating pattern varies in different organs and determines the effect of leptin on regulation of the energy balance. Better understanding gene oscillation may provide researchers with clues for developing ways to treat people who chronically overeat, for example.
Ptitsyn discovered that because gene activity oscillates in a "finely orchestrated" system, gene expression is impacted by daylight and darkness, or the lack of either. The research revealed that when exposed to a constant state of dim light or darkness, the groups of genes that typically oscillate together—such as genes responsible for the function of an organ or a specific tissue—are chaotic under this state and no longer function as a group, although they continue to oscillate in this chaotic state.
Ptitsyn says, "It's like a conductor walking away from an orchestra during a performance; each musician continues to play, gradually going out of key with the others."
Similar future research may lend further insights into the importance of light and darkness exposure and how to maximize body functioning.
The Daily Galaxy via University of Cambridge