“Phileas Fogg, the main character in Jules Verne’s acclaimed novel Around the World in Eighty Days, would not have suffered from jetlag during his trip, despite crossing multiple time zones. His body had plenty of time —more than three days per time zone—to adjust to the time differences encountered along his journey. Today, in the era of jet travel, we can cross several time zones in only a few hours; but our bodies suffer, as they struggle to adapt to the new time at our destination. Why can’t our physiology adapt more rapidly? What keeps it behind?” asked Carlos Ibáñez of the Department of Neuroscience at the Karolinska Institute and the IDG/McGovern Institute for Brain Research at Peking University.
“Our physiology is regulated by an internal clock that generates daily rhythms known as ‘circadian’, from the Latin circadiem, meaning ‘around one day’. Circadian rhythms are ancient and exist in all forms of life. Life on Earth is adapted to the rotation of our planet, and the internal clock anticipates day/night cycles, helping organisms optimise their physiology and behaviour,” explained Ibáñez. “Although the existence of a biological clock has been known for nearly a century, only recently have we begun to understand what it is made of and how it keeps ticking.”
Well known for his work on nervous-system development, metabolic regulation and the neurobiology of Alzheimer’s Disease and dementia, Ibáñez is a member of the Nobel Assembly which awards the Nobel Prize in Physiology or Medicine and it was his background research for the awarding of the 2017 Prize that sparked his interest in the circadian body clock. The 2017 Nobel Prize in Physiology or Medicine was awarded jointly to Jeffrey C. Hall, Michael Rosbash and Michael W. Young “for their discoveries of molecular mechanisms controlling the circadian rhythm”.
“It was a remarkable series of discoveries made during the 1990s by Hall, Rosbash and Young that finally elucidated how our biological clock ticks. The discomfort of jetlag is evidence of the strength of the clock, as it takes time for the machinery to readjust to a sudden change in environmental conditions. This mechanism has important implications for human health; not just jetlag, but also the incidence of chronic syndromes, such as cancer, metabolic and sleep disorders, and several neurological conditions.”
Ibáñez explained that a key feature of life on earth is the ability of organisms ranging from unicellular to multicellular to adapt their physiology and behaviour to the environmental, light and temperature changes that occur on the planet in 24-hour cycles. “24-hour cycles are an ancient and conserved rhythm,” he said.
From rhythms to clocks
And it’s a topic that has fascinated humans for centuries. Ibáñez indicated that the first known experiments were conducted during the 18th century, when astronomer Jean Jacques d’Ortous de Mairan studied mimosa plants, finding that the leaves opened towards the sun during daytime and closed at dusk. But when kept in darkness he found they still opened and closed which seemed to indicate the existence of some kind of biological clock.
How this clock worked and whether it was purely a reaction to external stimuli or governed by an endogenous clock was debated right up to the 20th Century. Ibáñez highlighted the seminal publications of German Biologist Erwin Bünning in the 1930s who proposed a model for endogenous circadian rhythms that suggested that these properties were genetically encoded.
Finding the clock genes
The next major breakthrough occurred in the 1970s with the work of Seymour Benzer and Ronald Konopka using Drosophilia fruit flies. They identified mutant fruit flies with altered circadian behaviour. Three distinct mutant types—arrhythmic, shortened and lengthened period—were identified. These mutations all involved the same functional gene on the X chromosome suggesting three mutations on one gene. They named the gene Period.
In 1984 Hall, Rosbash and Young succeeded in isolating the period gene. But finding the gene still didn’t explain exactly how the clock worked. Ibáñez explained that there were three components to the clock – a self-sustaining oscillator independent of outside outputs; as well as an output and entraining or input component.
He explained that when the period gene is active, period messenger RNA (mRNA) is made. The mRNA is transported to the cell’s cytoplasm and serves as template to produce PER protein. The PER protein accumulates in the cell’s nucleus, where the period gene activity is blocked. This gives rise to the inhibitory feedback mechanism underlying the circadian rhythm. Hall and Rosbash showed that PER, the protein encoded by period, accumulated during the night and degraded during the day.
In the 1990s Young discovered a further clock gene, timeless, encoding the TIM protein that was required for a normal circadian rhythm. He showed that when TIM bound to PER, the two proteins were able to enter the cell nucleus where they blocked period gene activity to close the inhibitory feedback loop. He later isolated another gene, doubletime, which encoded the DBT protein that delayed the accumulation of the PER protein. This provided insight into how an oscillation is adjusted to more closely match a 24-hour cycle.
“This concept of feedback and activation provided major insights into the highly complex world of circadian clockwork,” said Ibáñez.
But, if every cell has a clock how do you synchronise all of them?
Ibáñez explained that a small region of the brain called the Suprachiasmatic Nucleus (SCN) is the master pacemaker of circadian behaviour.
“The SCN has direct contact with cells in the retina so it’s directly influenced by light inputs. It has many functions including controlling the synchronisation of melatonin production from the pineal gland.”
“An intact SNC offers perfectly synchronised controls,” he added.
The circadian clock anticipates and adapts our physiology to the different phases of the day helping to regulate sleep patterns, feeding behaviour, hormone release, blood pressure and body temperature. And all of this has a profound impact on our health. Ibáñez pointed out that circadian dysfunction is linked to an increased risk of cancer, inflammation and neurological diseases.
“For example, some studies have shown links between night-shift work and breast cancer as well as between circadian disruption and prostate cancer. Circadian misalignment has also been associated with COVID infection.”
“Melatonin production is inversely correlated with cognitive function. We know that poor or fragmented sleep can cause various health problems including leading to a higher degree of neuropathologies such as Alzheimer’s.”
“None of these links are causative, but it’s clear that circadian disruptions make these conditions worse.”
“In some Alzheimer’s patients you also get direct damage to the SCN – it can degenerate – this has major health effects. It means the clocks would still be circadian but not synchronised. Overall, it’s important to try to correct sleep problems in people with dementia.”
Work is also ongoing in chronopharmacology – the study of time-dependent physiological responses to drugs and vaccines. “It looks at where outcome depends on time of administration. So, for example, people produce more antibodies when administered the flu vaccine in the morning. We know that anti-inflammatories, cancer therapies, and even aspirin, target genes whose activities are circadian.”
Ibáñez also explained though that some animals have adaptive behaviours despite the existence of the circadian clock. He pointed to the Svalbard Reindeer (Svalbard, also known as Spitsbergen or Spitzbergen, is a Norwegian archipelago in the Arctic Ocean). “The reindeer show no circadian behaviour during the winter and summer solstice. Their melatonin rhythm is not driven by circadian oscillation, but they remain acutely sensitive to the environment. We know they were found in this region from about 6 or 7000 years ago and this is likely to be an adapted behaviour.”
Michelle Galloway: Part-time media officer at STIAS
Photograph: Noloyiso Mtembu