The ticking of the biological clock
CINCHRON Comparative INsect CHRONobiology Project Objectives
Biological rhythms have evolved so that organisms can anticipate both daily and seasonal changes in their environment and then adapt their behaviour accordingly. Researchers in the CINCHRON project are investigating the clock in a range of different insects, work that has relevance for understanding daily rhythms in humans, as Professor Charalambos Kyriacou explains. CINCHRON’s aim is to study the circadian and seasonal rhythms using a variety of insect models:
A lot of research into the circadian clock has historically focused on Drosophila, the fruit fly. Indeed, a Nobel Prize in Medicine/ Physiology was awarded in 2017 to the three US geneticists who identified the major clock genes in the fly. However, less is known about clocks in other insects, an issue that researchers in the CINCHRON project are addressing. “The aim of CINCHRON is to expand our knowledge of the biological clock into other species beyond Drosophila,” outlines Professor Charalambos Kyriacou, the project’s coordinator. The idea of the project is to study clocks in insects such as the pea aphid, which has a significant impact on crop productivity, as well as species like bees and silkmoths which have clear economic value. This research is being conducted against a backdrop of wider concern about the impact of climate change. “With climate change, the range of tropical insects is expanding – we’re already seeing that around the Mediterranean,” explains Professor Kyriacou. “We’re getting these insects – disease vectors – expanding their ranges. We want to understand their basic biology, including their circadian clock, which controls the timing of everything they do.”
Circadian and seasonal clock The circadian clock in these insects is typically localised in a very limited set of ‘clock’ neurons in the brain and these cells regulate rhythmic behaviour over the course of a day. Fruit flies tend to be crepuscular, meaning that they are very lively in the morning and just before dusk, but much less active in the middle of the day. “An insect wakes and has its morning burst of activity, then a siesta, then its evening behaviour. There is evidence that these neurons are divided into a ‘morning’ and an ‘evening’ oscillator, and they talk to each other. It’s important to be rhythmic, it’s a fitness character. An insect needs to anticipate when light’s coming on or off so they can get their physiology ready to meet the demands of the day or night. These rhythms are adaptive, and they can be adjusted,” explains Professor Kyriacou.
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suzukii that in recent years has become a major world-wide fruit pest. The simplest solution to pest control is to spray insecticide in whatever quantities are required, and while this approach may kill the insect, Professor Kyriacou says it also often causes wider issues. “Indiscriminate spraying leads to serious pollution problems,” he points out. Disrupting the seasonal clock of these insects would represent a highly attractive alternative. “If we can disrupt the seasonal clock so that these insects don’t go into hibernation, then the winter climate will kill them. That’s the idea, but we’ve first got to understand hibernation in order to be able to manipulate it,” acknowledges Professor Kyriacou. “We’ve made considerable progress in terms of understanding how the circadian and seasonal clocks talk to each other. If we can somehow disrupt the seasonal clock with a biological compound that’s specific to a pest species, then that would have implications for their hibernation and be less polluting than chemical control.”
Shift work This research also holds wider relevance in terms of understanding circadian rhythms in humans and the impact of sleep disruption on personal health. About a quarter of the Western population work shifts, disrupting sleeping patterns, and evidence shows that these people are at higher risk of experiencing health problems. “People who work shifts tend to die earlier, have more cardiovascular and metabolic problems, and are also more likely to develop cancer. It’s a major problem, and it costs Western economies billions every year,” explains Professor Kyriacou. A deeper understanding of the circadian clock could help researchers devise methods to prevent chronodisruption, a topic which Professor Kyriacou says is the focus of a lot of attention. “Some of my colleagues in Europe and the US are making small molecules that can interact with some of the key clock proteins. The aim is to shift the phase of the clock and prevent the social jetlag that shift workers experience,” he outlines.
If we can disrupt
Inner clock: the circadian rhythm changes according to the light-dark cycle. This is the clock that regulates behaviours and physiological processes that change with a period of 24 hrs. DNA (the hour hand of the clock) hosts the genes that control the circadian system and it is possible to study them using molecular biology techniques, symbolised by the pipette (the minute hand). Medial clock: the seasonal clock controls those behaviours and processes that cycle with a period of one year (migration, hibernation etc). The seasonal clock is controlled by the changes in temperature and length of daylight. Outer clock: the different insects that CINCHRON is exploiting as model organisms to study the clocks. There are 12 insects positioned along the circadian and seasonal clocks. If an insect is represented more than once, it means that more than one lab is working on it. The four fruit flies (at 1, 5, 7 and 11) are different from one another to show different mutations that are used in our studies. Figures created by Joanna Szramel, Terence Al Abaquita, and Giulia Manoli Early Stage Researchers of the CINCHRON project.
There are 15 different PhD projects within CINCHRON, focusing on both the circadian and seasonal clock in several insect species. The seasonal ‘clock’ is important for hibernation. “An insect’s hibernation is called diapause. In some insects it’s brought on by reduction in temperature, but in most it’s photoperiodic, so short days and long nights (there is evidence that the 24 hour timer can measure these day/night lengths in some insects) heralds the oncoming winter so that insects can hibernate till the longer days of spring arrive,” outlines Professor Kyriacou. The relationship between the circadian and seasonal clocks has long
been a subject of scientific debate; Professor Kyriacou says recent evidence suggests that they are closely related. “If you disrupt some of the clock genes that build the molecular oscillator, you get very strong changes in what we call the seasonal phenotype,” he says. “For example, our colleagues in Groningen are studying a parasitic wasp called Nasonia that can be used for the biological control of pests. With techniques like Crispr-cas9, you can now disrupt these 24 hour clock genes and examine the effects on seasonal hibernation.” This could open up new possibilities in the control of species like pea aphids or Drosophila
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the seasonal clock so that these insects don’t go into hibernation, then winter will kill them. That’s the idea, but we’ve got to understand hibernation in order to be able to manipulate it. A further aspect of the project’s agenda centres around research into the immune system in insects, which is known to have a circadian cycle. One project in CINCHRON involves examining the circadian clock and the immune system in the silkmoth, a species vulnerable to severe bacterial infections which can wipe out entire colonies. “Our colleagues in Italy are studying when silkmoths are more susceptible to getting infection. They’ve made significant progress in understanding the chrono-cycle of the immune system in silkworms, and how we can adjust the way they are raised to try and prevent them getting these bacterial infections,” says Professor Kyriacou. A similar approach could potentially be applied to boost resistance to infection in all organisms, not just insects, says Professor Kyriacou. “All organisms are resistant to infection in a circadian cycle,” he stresses.
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The CINCHRON project itself is nearing the end of its funding term, but there are plans to continue the research and broaden out into further areas, including the possibility of studying insects like the soldier fly. Several companies in Europe and the US are farming soldier flies as animal feed, and while many people today may find the prospect of eating them unpalatable, Professor Kyriacou says the idea is attracting interest as a potential source of nutrition. “With food security becoming an ever more pressing issue, we’ve got to look at alternative sources of food,” he stresses. Knowledge of circadian rhythms could help companies farming these insects to maximise productivity, a topic Professor Kyriacou plans to explore. “A new project would investigate how to optimise the rearing of these insects that are becoming important sources for animal feed, and could feed humans in the future,” he says.
The CINCHRON project is comprised of four workpackages, with the shared goal of developing a deeper understanding of biological clocks in insects. The four workpackages are centered around circadian chronobiology, seasonal chronobiology, metabolic chronobiology and commercial chronobiology. There are 15 different PhD projects within CINCHRON, in which researchers are investigating different topics around insect chronobiology. The researchers collaborate extensively across the different workpackages, sharing knowledge as they seek to both gain deeper insights into the clock, and also apply them in the practical context.
Project Funding
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 765937
Contact Details
Dr Valeria Zonato Research Centre Manager Genetics and Genome Biology Department University Road Leicester LE17RH T: + 0116 252 3249 E: vz12@le.ac.uk W: www.cinchron.org W: www.neurogeneticsleicester.com
Prof. Charalambos Kyriacou
Dr Valeria Zonato
Valeria Zonato is the manager of the CINCHRON network, which offers training and funding to several PhD students working in the field of insect chronobiology. She has a PhD in genetics and genome biology. Charalambos Kyriacou is a Professor in the Genetics department at the University of Leicester. He has published widely in biological rhythms and evolution and neurogenetics of fly behaviour.
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