Genetics of sleep regulation and function: the AKR genes in Drosophila
Lead Research Organisation:
Imperial College London
Department Name: Life Sciences
Abstract
Sleep needs no introduction. We humans spend about one third of our lifetime asleep but no one knows why. Astonishingly, sleep still remains one of the most puzzling problems of biology despite decades of research. While something is known about the mechanisms regulating occurrence of sleep, nothing is known about its functions: why sleep deprivation has detrimental effects on the body and the brain? Why is sleep restorative? What happens in our cells as we sleep? Why sleep architecture and sleep needs are so different amongst different individuals and why do they change so much as we age? The answer to those questions is likely to be in our genes: gene activity may explain what happens at the cellular level when we sleep and similarly when we deprive ourselves from resting. Our laboratory has chosen to explore genetics of sleep using the fruit fly Drosophila melanogaster as animal model. Drosophila is arguably the most powerful and most commonly used genetic animal model. Importantly, not only do flies sleep but in fact their sleep vastly reminds of human sleep: flies sleep at night like us; their sleep is restorative; sleep deprivation leads to detrimental performances and eventually to death; their sleep is homeostatically regulated (i.e. a sleep deprived fly will have stronger sleep pressure) and, importantly, their sleep is modulated pharmacologically by the same compounds that are known to affect human sleep, such as caffeine or modafinil, suggesting an evolutionary conservation for functions and genetics of sleep. Understanding the basic biology of sleep is not just a fascinating scientific puzzle: it is also key to understand and mitigate the effects of social sleep deprivation, insomnia or sleep disorders - a very pressing need for today's society.
Recently we have identified a new gene called allnighter. Flies that are mutant in the allnighter gene sleep considerably less than normal (50% less). We aim to elucidate the biology behind this observation. Some of the questions we are addressing are: how does allnighter work to regulate sleep duration? How do allnighter mutant flies cope with sleep deprivation? Is allnighter acting in the brain of the fly and , if yes, in what neurons exactly? What is the general mechanism of action of allnighter and is there a functional allnighter equivalent in other species? Finally, the allnighter gene shares similarities with other known genes affecting sleep in flies and rodents: we aim at exploring those connections too, arguing this will provide a new perspective on the mystery of sleep function.
Recently we have identified a new gene called allnighter. Flies that are mutant in the allnighter gene sleep considerably less than normal (50% less). We aim to elucidate the biology behind this observation. Some of the questions we are addressing are: how does allnighter work to regulate sleep duration? How do allnighter mutant flies cope with sleep deprivation? Is allnighter acting in the brain of the fly and , if yes, in what neurons exactly? What is the general mechanism of action of allnighter and is there a functional allnighter equivalent in other species? Finally, the allnighter gene shares similarities with other known genes affecting sleep in flies and rodents: we aim at exploring those connections too, arguing this will provide a new perspective on the mystery of sleep function.
Technical Summary
Sleep is an evolutionary conserved animal need. All organisms that have been tested so far have shown to possess and to require the basic characteristics of sleep: that is circadian and homeostatic regulation, restorative effects of sleep, detrimental effects of sleep deprivation. Our laboratory studies genetics of sleep in Drosophila melanogaster, with the aim of uncovering genes and mechanisms regulating sleep functions and regulation.
Recently, we have identified a new mutation, allnighter, that leads to an abnormally short sleeping phenotype in Drosophila. The allnighter gene is predicted to encode for at least two proteins belonging to the family of Drosophila Aldo Keto Reductase genes, an evolutionary conserved family of NAD(P)(H) oxidoreductases that reduce aldehydes and ketones to alcohols. Interestingly, Drosophila melanogaster is predicted to have 12 AKR genes, of which two appear to play a crucial role in regulating sleep: allnighter and Hyperkinetic. Hyperkinetic, together with Shaker and Sleepless, is believed to modulate sleep length through regulation of cellular K+ currents.
This work has two main objectives: 1) characterise how allnighter regulates sleep; 2) investigate what role the AKR domains of allnighter and Hyperkinetic play in their function and whether any other Drosophila AKR protein is involved in sleep regulation.
Recently, we have identified a new mutation, allnighter, that leads to an abnormally short sleeping phenotype in Drosophila. The allnighter gene is predicted to encode for at least two proteins belonging to the family of Drosophila Aldo Keto Reductase genes, an evolutionary conserved family of NAD(P)(H) oxidoreductases that reduce aldehydes and ketones to alcohols. Interestingly, Drosophila melanogaster is predicted to have 12 AKR genes, of which two appear to play a crucial role in regulating sleep: allnighter and Hyperkinetic. Hyperkinetic, together with Shaker and Sleepless, is believed to modulate sleep length through regulation of cellular K+ currents.
This work has two main objectives: 1) characterise how allnighter regulates sleep; 2) investigate what role the AKR domains of allnighter and Hyperkinetic play in their function and whether any other Drosophila AKR protein is involved in sleep regulation.
Planned Impact
Other than the impact on academia discussed above, we will work to ensure our research will also have proper economic and societal impacts. In this section we discuss who might benefit from this research and how. In the next section we will highlight what will be done to ensure that potential beneficiaries have the opportunity to engage with this research.
Societal impact.
Sleep is not merely a fascinating biological problem, but also a topic of medical and social relevance. Sleep deprivation has become an endemic condition in our modern 24/7 society, where artificial lights, television sets and alarm clocks dictate our activity and rest. According to the latest "Great British Sleep Survey" published in 2011 and directed by Prof. Cloin Espie, 51% of Britons will lament sleep problems of sort, mainly linked to insomnia. It is estimated that about one third of the population in western countries is chronically sleep deprived and that one quarter is regularly working night shifts, thus impairing not only their sleep quality but also their circadian rhythms. How can our study help solve this issue? Firstly, by raising awareness. Scientific studies on sleep and sleep deprivation are usually very well received by the public and highly covered on national and international press ("Google News" reports 132000 news entries containing the keyword sleep, only in 2013). Any scientific study that addresses the consequences of sleep deprivation will help the public understand the importance of a good night's sleep on our health. In our experience, the mere fact that we study sleep using fruitflies as animal model will increase even further the public interest for our research: the very concept that flies can sleep like humans, be sleep deprived and suffer of learning impairment is very fascinating for the public (and in fact for scientists, too!). The second potential effect of our research has to do with the science itself: discovering new genes regulating sleep duration or sleep function means providing the pharmaceutical industry of a new potential target for sleep-related drugs. This is particularly relevant in our case, because the AKR proteins that we are studying are well known drug targets for a number of conditions (e.g. steroid production, immunoresponse, cancer).
Economic impact.
As for the societal impact, also the economic impact has a short term and a long term component. The long term component is linked to the general consequences of improving sleep conditions in people's life: the estimated economic cost of sleep deprivation in the USA alone is $20-30 billions [Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. ISBN 030965727X]; 20% of all road accidents are associated with driver sleepiness and sleep deprivation can affect virtually any other risky human activity, from operating machineries to performing surgery. Therefore, the economic impact of ameliorating sleep conditions is astonishingly high.
The short term component relates to translating the work from academia to industry: as mentioned above, any novel sleep-regulating gene is a potential target for a sleeping pill of the future. Importantly, also the technological aspects of our work are of interest to industry: some of the machines and techniques we have built are now commercially available, produced and sold by a London based startup for which I have acted as mentor and advisor for the past year (more about this in "Pathways to Impact".)
Societal impact.
Sleep is not merely a fascinating biological problem, but also a topic of medical and social relevance. Sleep deprivation has become an endemic condition in our modern 24/7 society, where artificial lights, television sets and alarm clocks dictate our activity and rest. According to the latest "Great British Sleep Survey" published in 2011 and directed by Prof. Cloin Espie, 51% of Britons will lament sleep problems of sort, mainly linked to insomnia. It is estimated that about one third of the population in western countries is chronically sleep deprived and that one quarter is regularly working night shifts, thus impairing not only their sleep quality but also their circadian rhythms. How can our study help solve this issue? Firstly, by raising awareness. Scientific studies on sleep and sleep deprivation are usually very well received by the public and highly covered on national and international press ("Google News" reports 132000 news entries containing the keyword sleep, only in 2013). Any scientific study that addresses the consequences of sleep deprivation will help the public understand the importance of a good night's sleep on our health. In our experience, the mere fact that we study sleep using fruitflies as animal model will increase even further the public interest for our research: the very concept that flies can sleep like humans, be sleep deprived and suffer of learning impairment is very fascinating for the public (and in fact for scientists, too!). The second potential effect of our research has to do with the science itself: discovering new genes regulating sleep duration or sleep function means providing the pharmaceutical industry of a new potential target for sleep-related drugs. This is particularly relevant in our case, because the AKR proteins that we are studying are well known drug targets for a number of conditions (e.g. steroid production, immunoresponse, cancer).
Economic impact.
As for the societal impact, also the economic impact has a short term and a long term component. The long term component is linked to the general consequences of improving sleep conditions in people's life: the estimated economic cost of sleep deprivation in the USA alone is $20-30 billions [Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. ISBN 030965727X]; 20% of all road accidents are associated with driver sleepiness and sleep deprivation can affect virtually any other risky human activity, from operating machineries to performing surgery. Therefore, the economic impact of ameliorating sleep conditions is astonishingly high.
The short term component relates to translating the work from academia to industry: as mentioned above, any novel sleep-regulating gene is a potential target for a sleeping pill of the future. Importantly, also the technological aspects of our work are of interest to industry: some of the machines and techniques we have built are now commercially available, produced and sold by a London based startup for which I have acted as mentor and advisor for the past year (more about this in "Pathways to Impact".)
Organisations
People |
ORCID iD |
Giorgio Gilestro (Principal Investigator) |
Publications
Beckwith EJ
(2019)
Sleep in Drosophila and Its Context.
in Frontiers in physiology
Beckwith EJ
(2017)
Regulation of sleep homeostasis by sexual arousal.
in eLife
French AS
(2021)
Sensory processing during sleep in Drosophila melanogaster.
in Nature
Geissmann Q
(2017)
Ethoscopes: an open platform for high-throughput ethomics
Geissmann Q
(2019)
Most sleep does not serve a vital function: Evidence from Drosophila melanogaster
in Science Advances
Geissmann Q
(2017)
Ethoscopes: An open platform for high-throughput ethomics.
in PLoS biology
Geissmann Q
(2019)
Rethomics: An R framework to analyse high-throughput behavioural data.
in PloS one
Stahl BA
(2017)
To rebound or not to rebound.
in eLife
Description | In all animals, sleep pressure is under continuous tight regulation. It is universally accepted that this regulation is described by a two-process model, integrating both a circadian and a homeostatic controller. From a biological perspective, much is known about the molecular and cellular underpinnings of the circadian regulator, but very little about the homeostatic regulator - and even less on how these two interact to create a functional "somnostat". With this work, we identified a Drosophila model of a somnostat, that - for the first time - could be used to study how circadian rhythms and homeostatic sleep pressure coordinate an animal's drive to sleep. We have identified a gene, ninna nanna, whose expression labels the two complementary components of a functional sleep-regulating circuit. Peculiarly, the ninna nanna gene gives rise to two alternatively spliced isoforms: one (ninna) is expressed and functions in the presynaptic, circadian component of the circuit; the second (nanna) is expressed and functions in the postsynaptic, homeostatic component of the circuit. Our underlying working hypothesis is that ninna and nanna may act as molecular sensors for intracellular levels of NADP(H)and NAD(H), their respective co-factors. |
Exploitation Route | This work can impact mainly at two levels: 1. Scientific impact Providing a new framework for studying how circadian rhythms integrate with homeostatic drive would provide for the first time with a biological sandbox for the so-called "two-process model" of sleep regulation. Not just our Drosophila colleagues but the sleep field at large will benefit from having access to a genetically amenable model of neurons integrating circadian rhythms and homeostatic process. The Drosophila model for sleep is a recent one, having been officially introduced in 2000. Yet, with almost 600 publications, flies have already played a pivotal role in our understanding of sleep, uncovering new genes and highlighting new circuits. Because sleep is such a conserved phenomenon in the animal kingdom, every biological component that is found in flies is likely to reflect a general principle that will help to elucidate the problem in humans too. For biology, genetics, and behaviour, sleep has many parallels with the field of circadian rhythms. Drosophila has been instrumental to understand the former and there is no reason to think they will not be equally instrumental in understanding the latter. Finally, the fact that Drosophila could be used to study the regulation of sleep has a strong appeal in scientific terms but also in terms of animals replacement (3Rs). 2. Societal impact Impact on society of study like this one could be very big. We would show the public that reductionists approaches are still very powerful in science and highlight, once more, the power of employing Drosophila even when studying subjects that are complex as sleep. We have a strong track record of bringing our research to the public, with frequent schools seminars and workshop; large public engagements; visibility on the internet and on social networks; TED talks (see https://lab.gilest.ro/outreach/ ). In our experience, the use of Drosophila to study sleep is always fantastically well received, for it merges two fascinating aspects of research that happen to be understandable and understood by the many. |
Sectors | Healthcare |
Description | BBSRC Impact Accelerator Award |
Amount | £15,000 (GBP) |
Organisation | Imperial College London |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2016 |
End | 07/2016 |
Description | EMBO LTF |
Amount | € 60,000 (EUR) |
Funding ID | ALTF 57-2014 |
Organisation | European Molecular Biology Organisation |
Sector | Charity/Non Profit |
Country | Germany |
Start | 02/2015 |
End | 01/2017 |
Description | MSCA IF |
Amount | € 280,000 (EUR) |
Funding ID | 705930 |
Organisation | Marie Sklodowska-Curie Actions |
Sector | Charity/Non Profit |
Country | Global |
Start | 02/2017 |
End | 01/2019 |
Title | Ethoscopes: an open platform for high-throughput ethomics |
Description | We developed and presented ethoscopes, machines for high-throughput analysis of behaviour in Drosophila and other animals. Ethoscopes provide a software and hardware solution that is reproducible and easily scalable. They perform, in real-time, tracking and profiling of behaviour using a supervised machine learning algorithm; can deliver behaviourally-triggered stimuli to flies in a feedback-loop mode; are highly customisable and open source. Ethoscopes can be built easily using 3D printing technology and rely on Raspberry Pi microcomputers and Arduino boards to provide affordable and flexible hardware. All software and construction specifications are available at http://lab.gilest.ro/ethoscope. |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | The paper describing our method was published only recently. For now, the Impact has mainly been in terms of media attention. See for instance: https://www.the-scientist.com/?articles.view/articleNo/51189/title/3-D-Printed-Ethoscopes-Lower-Barriers-to-Large-Scale-Fly-Behavior-Studies/ https://3dprintingindustry.com/news/3d-printed-device-studies-life-flies-better-understanding-ai-123058/ http://lab.gilest.ro/wp-content/uploads/2017/03/ethoscope_magpi.pdf https://hackaday.com/2017/10/22/apparently-fruit-flies-like-a-raspberry-pi/ |
URL | https://lab.gilest.ro/ethoscope |
Title | ethoscope |
Description | The laboratory is currently developing a brand new system to detect sleep in flies. This system is based on a open source philosophy and uses a combination of open source software, consumer hardwares and 3d printing to create a ready to use, powerful platform. The software component of ethoscope was created in our laboratory, is based on Python and it is released as Open Source (via https://github.com/gilestrolab/ethoscope). The electronic/hardware of ethoscope is based on a microcomputer called Raspberry PI, created and distributed by the eponymous UK charity foundation ( https://www.raspberrypi.org/about ). Raspberry PIs are arguably one of the most successful accessible-hardware product ever created and possibly one of the greatest example of the powerful mix between academia (in this case University of Cambridge, UK) and Open Source philosophy. Finally, the assembly structure of the ethoscope is obtained using 3D printing technology, meaning that hardware blueprints can also be released as Open Source (via https://github.com/gilestrolab/ethoscope_hardware) and replicated by anyone with access to a 3D printer. |
Type Of Technology | New/Improved Technique/Technology |
Year Produced | 2016 |
Impact | This is not published yet but it has become the standard acquisition platform in our laboratories and created plenty of collaborations so far. |
URL | https://github.com/gilestrolab |