MICA Cryo-chronobiology: how do cold-inducible chaperones maintain neural clock function under brain temperature fluctuation?
Lead Research Organisation:
MRC Laboratory of Molecular Biology
Department Name: Cell Biology
Abstract
Biological clocks are fundamental to life, adapting us to predictable changes in our environment. Disruption of these clocks occurs in several brain disorders including dementia - a leading cause of death in the UK. Understanding how clocks work means that we can control them; a fresh strategy to tackle some of our most complex global health challenges.
At the molecular level, feedback loops support daily 'circadian' rhythms in cell function throughout the body. The 24-hour cycle of these rhythms is resistant to temperature variation, ensuring that cellular clocks do not speed up or slow down at different body temperatures. Remarkably however, cellular clocks synchronize to daily changes in body temperature, which means they must sense and respond to temperature shift. This 'temperature paradox' of the clockwork remains unexplained, especially for the brain where nerve cell activity produces rapid changes in brain temperature. What then keeps our brain cell clocks ticking robustly as brain temperature changes?
Circadian rhythms and responses to cold are critical cellular functions that have been retained throughout evolution. Cold-inducible chaperones (CICs) are highly active proteins at cold temperatures; they safeguard the manufacture of key cellular proteins under conditions that would normally halt protein production. CICs do this by binding to messages transcribed from the DNA in each of our cells so that these messages can be translated into proteins that are critical for cell survival, including components of the clockwork. CIC activity also cycles in a circadian manner, responding to daily changes in body temperature. I propose that CIC-clock protein interactions are critical to timekeeping in brain cells. I will test whether these interactions are required to maintain brain cell clock function as brain temperature changes.
Data from patients with brain injury show that, like body temperature, human brain temperature cycles with a 24-hour rhythm. However, brain and body temperature are not the same, and we need to know what happens in the healthy brain. In collaboration with Edinburgh Imaging, I will use a non-invasive MRI scan technique to map brain temperature in healthy volunteers at different times of the day. In parallel, I will monitor brain temperature cycles in mice remotely using radio transmitters. These experiments will establish normal human brain temperature ranges, and separate the effects of circadian and sleep-wake cycles on brain temperature rhythms.
Experiments in Cambridge will then determine the impact of CIC versus clock protein disruption on brain cell circadian rhythms under simulated brain temperature cycles. The brain cell clock will be characterized 'in a dish' by tagging CIC and clock proteins with luminescent reporters in brain cells grown from human stem cells. This will make it possible to monitor the cyclic abundance of CIC and clock proteins in real time over several days at different temperatures, and during transitions between them. CIC and clock proteins will then be manipulated so that they are trapped in different parts of the cell and can no longer interact with each other. This 'trapping' will be entirely reversible such that CIC-clock interactions can be switched on or off during temperature shifts, to see what effect this has on clock function. Finally, radio transmitter experiments will be repeated in mice carrying genetic mutations in CIC and clock proteins. This work will establish a basis for modulating CIC-clock interactions in human cellular models of dementia and other chronic brain disorders. I predict that boosting CIC activity will protect and restore clock function in vulnerable brain cells. The results could ultimately lead to new treatments for a range of disorders in which circadian rhythms are disrupted, and also new ways to manage our 'circadian health' in the modern world.
At the molecular level, feedback loops support daily 'circadian' rhythms in cell function throughout the body. The 24-hour cycle of these rhythms is resistant to temperature variation, ensuring that cellular clocks do not speed up or slow down at different body temperatures. Remarkably however, cellular clocks synchronize to daily changes in body temperature, which means they must sense and respond to temperature shift. This 'temperature paradox' of the clockwork remains unexplained, especially for the brain where nerve cell activity produces rapid changes in brain temperature. What then keeps our brain cell clocks ticking robustly as brain temperature changes?
Circadian rhythms and responses to cold are critical cellular functions that have been retained throughout evolution. Cold-inducible chaperones (CICs) are highly active proteins at cold temperatures; they safeguard the manufacture of key cellular proteins under conditions that would normally halt protein production. CICs do this by binding to messages transcribed from the DNA in each of our cells so that these messages can be translated into proteins that are critical for cell survival, including components of the clockwork. CIC activity also cycles in a circadian manner, responding to daily changes in body temperature. I propose that CIC-clock protein interactions are critical to timekeeping in brain cells. I will test whether these interactions are required to maintain brain cell clock function as brain temperature changes.
Data from patients with brain injury show that, like body temperature, human brain temperature cycles with a 24-hour rhythm. However, brain and body temperature are not the same, and we need to know what happens in the healthy brain. In collaboration with Edinburgh Imaging, I will use a non-invasive MRI scan technique to map brain temperature in healthy volunteers at different times of the day. In parallel, I will monitor brain temperature cycles in mice remotely using radio transmitters. These experiments will establish normal human brain temperature ranges, and separate the effects of circadian and sleep-wake cycles on brain temperature rhythms.
Experiments in Cambridge will then determine the impact of CIC versus clock protein disruption on brain cell circadian rhythms under simulated brain temperature cycles. The brain cell clock will be characterized 'in a dish' by tagging CIC and clock proteins with luminescent reporters in brain cells grown from human stem cells. This will make it possible to monitor the cyclic abundance of CIC and clock proteins in real time over several days at different temperatures, and during transitions between them. CIC and clock proteins will then be manipulated so that they are trapped in different parts of the cell and can no longer interact with each other. This 'trapping' will be entirely reversible such that CIC-clock interactions can be switched on or off during temperature shifts, to see what effect this has on clock function. Finally, radio transmitter experiments will be repeated in mice carrying genetic mutations in CIC and clock proteins. This work will establish a basis for modulating CIC-clock interactions in human cellular models of dementia and other chronic brain disorders. I predict that boosting CIC activity will protect and restore clock function in vulnerable brain cells. The results could ultimately lead to new treatments for a range of disorders in which circadian rhythms are disrupted, and also new ways to manage our 'circadian health' in the modern world.
Technical Summary
Molecular clocks drive cellular circadian rhythms to run with a consistent ~24h period, despite changes in body temperature. This temperature compensation remains unexplained, especially for the brain where temperature varies with neuronal activity. Cold-inducible chaperones (CICs) regulate clock transcripts in the nucleus and are themselves circadian-regulated. I predict that CIC-clock interactions are critical to temperature-compensated neural timekeeping, and that failure of this mechanism underlies circadian disruption in chronic brain disorders. This proposal tests whether CIC-clock interactions are required to maintain neural clock function as brain temperature changes. Data from brain-injured patients, magnetic resonance spectroscopy imaging of healthy volunteers and radiotelemetry in mice will determine how brain temperature varies with circadian time. The human neural clock and its circadian proteome will be characterized in stem cell-derived neurons and glia expressing bioluminescent CIC/clock reporters, complemented by quantitative protein mass spectrometry. By inducible and conditional exogenous regulation, CIC/clock proteins will be reversibly trapped in the cytoplasm to uncouple CIC-clock interactions during temperature shift. Mechanistically this will reveal which CIC is most important to neural timekeeping, and which neural cell type is most vulnerable to CIC-clock disruption. Finally, a transgenic mouse lacking this CIC in the key cell type will be generated for radiotelemetric monitoring, alongside existing CIC and clock mutants. Together, these experiments will establish a basis for modulating CIC-clock interactions in neurodegenerative disease models. This work will deliver new tools, resources and knowledge with far-reaching applications for chrono/neurobiologists and immediate translational relevance to critical care patients. The goal is to transform molecular understanding of CIC-clock interactions into treatments for chronic brain disorders.
Planned Impact
Our strategy is truly 'bedside to bench, and back again', addressing an important clinical knowledge gap, whilst answering a fundamental question about the molecular clockwork. Outcomes could impact directly on critical care patient monitoring guidelines, with potentially far-reaching, long-term impacts on brain health and society. Stakeholders who might benefit directly or indirectly from this research exist in all sectors:
(1) Commercial sector: recalibrating the neural clock with molecular cryobiology could offer timely inspiration to big pharma, promoting renewed investment in chronic brain disorders. 50% of the targets of the most widely used drugs are regulated by the clock, expanding the potential for drug repurposing and chrono-medicine. Several brain disorders are linked to circadian disruption including Alzheimer's disease and epilepsy. The Cambridge Biomedical Campus is a hub for companies that develop (AstraZeneca) or invest in (GSK) new treatments for these disorders, and biotechnology companies that generate platforms to model them (Elpis BioMed). Insights may be of interest to precision engineers (Innovia Technology) and manufacturers of 'blue screens' and wearable technology. Future spinout innovations would contribute to the economy through raising capital and creating jobs.
(2) Public goods and services: primary interest will come from NHS healthcare services (critical care, neurology and neuroimaging). Human circadian brain temperature data might reconcile conflicting outcomes of cooling trials and change the way in which patient temperature is used to guide diagnosis and targeted temperature management.
(3) Voluntary sector: there has never been a greater urgency to develop treatments for brain disorders. Health charities (Alzheimer's Research UK, Epilepsy Research UK, Wellcome Trust) and joint investment initiatives (UK Dementia Research Institute) might wish to invest in follow-on studies. Patient support networks could play a role in designing these studies.
(4) Policy-makers: by 2050, 135 million people are expected to be living with dementia; this major healthcare challenge is set to become a global economic crisis. Aside from effects on brain health, circadian disruption has a broader impact on workforce productivity. Interested parties would include governments and government-supported initiatives (The Dementia Discovery Fund), and public-private partnerships (Dementias Platform UK). Public Health England is keen to assess how light pollution impacts on human circadian health, and therefore might be interested in research that enhances understanding of the human neural clock.
(5) Wider public: patients, carers, shift workers, travellers, and computer/smartphone users. Concerns are growing about the impact of shift work on long-term health, and 'blue light' on neurodevelopment and the ageing brain.
(6) Project team: opportunities for training and acquisition of transferable skills will arise through this work. Benefits include increased employability, inspiring the next generation of researchers, facilitating procurement of follow-on funding, and ultimately strengthening the UK R&D base
SMART impact goals
(1) Securing new partnerships (collaborative agreements) for innovation, commercialization and discovery
(2) Revised guidelines for patient temperature monitoring and interpretation
(3) Engaging with health charities and patient support networks
(4) Presenting interim results to policy makers and government-supported funding bodies
(5) Effective public engagement
(6) Funding awards and research placements
References
Roenneberg T and Merrow M (2016) Curr Biol 26:R432-43
http://www.wish.org.qa/wp-content/uploads/2018/01/WISH_Dementia_Forum_Report_08.01.15_WEB.pdf
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/690846/CMO_Annual_Report_2017_Health_Impacts_of_All_Pollution_what_do_we_know.pdf
(1) Commercial sector: recalibrating the neural clock with molecular cryobiology could offer timely inspiration to big pharma, promoting renewed investment in chronic brain disorders. 50% of the targets of the most widely used drugs are regulated by the clock, expanding the potential for drug repurposing and chrono-medicine. Several brain disorders are linked to circadian disruption including Alzheimer's disease and epilepsy. The Cambridge Biomedical Campus is a hub for companies that develop (AstraZeneca) or invest in (GSK) new treatments for these disorders, and biotechnology companies that generate platforms to model them (Elpis BioMed). Insights may be of interest to precision engineers (Innovia Technology) and manufacturers of 'blue screens' and wearable technology. Future spinout innovations would contribute to the economy through raising capital and creating jobs.
(2) Public goods and services: primary interest will come from NHS healthcare services (critical care, neurology and neuroimaging). Human circadian brain temperature data might reconcile conflicting outcomes of cooling trials and change the way in which patient temperature is used to guide diagnosis and targeted temperature management.
(3) Voluntary sector: there has never been a greater urgency to develop treatments for brain disorders. Health charities (Alzheimer's Research UK, Epilepsy Research UK, Wellcome Trust) and joint investment initiatives (UK Dementia Research Institute) might wish to invest in follow-on studies. Patient support networks could play a role in designing these studies.
(4) Policy-makers: by 2050, 135 million people are expected to be living with dementia; this major healthcare challenge is set to become a global economic crisis. Aside from effects on brain health, circadian disruption has a broader impact on workforce productivity. Interested parties would include governments and government-supported initiatives (The Dementia Discovery Fund), and public-private partnerships (Dementias Platform UK). Public Health England is keen to assess how light pollution impacts on human circadian health, and therefore might be interested in research that enhances understanding of the human neural clock.
(5) Wider public: patients, carers, shift workers, travellers, and computer/smartphone users. Concerns are growing about the impact of shift work on long-term health, and 'blue light' on neurodevelopment and the ageing brain.
(6) Project team: opportunities for training and acquisition of transferable skills will arise through this work. Benefits include increased employability, inspiring the next generation of researchers, facilitating procurement of follow-on funding, and ultimately strengthening the UK R&D base
SMART impact goals
(1) Securing new partnerships (collaborative agreements) for innovation, commercialization and discovery
(2) Revised guidelines for patient temperature monitoring and interpretation
(3) Engaging with health charities and patient support networks
(4) Presenting interim results to policy makers and government-supported funding bodies
(5) Effective public engagement
(6) Funding awards and research placements
References
Roenneberg T and Merrow M (2016) Curr Biol 26:R432-43
http://www.wish.org.qa/wp-content/uploads/2018/01/WISH_Dementia_Forum_Report_08.01.15_WEB.pdf
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/690846/CMO_Annual_Report_2017_Health_Impacts_of_All_Pollution_what_do_we_know.pdf
Organisations
- MRC Laboratory of Molecular Biology (Fellow, Lead Research Organisation)
- University of Manchester (Collaboration)
- UNIVERSITY OF LEICESTER (Collaboration)
- University of Newcastle (Collaboration)
- NORTHUMBRIA UNIVERSITY (Collaboration)
- University of Warwick (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
- University of Sheffield (Collaboration)
- UNIVERSITY OF GLASGOW (Collaboration)
- Elpis BioMed Ltd (Collaboration, Project Partner)
- John Innes Centre (Collaboration)
- TSE Systems (Collaboration)
- Medical Research Council (MRC) (Collaboration)
- University of Bristol (Collaboration)
- EARLHAM INSTITUTE (Collaboration)
- NHS Lothian (Project Partner)
- Royal Veterinary College (Project Partner)
- University of Edinburgh (Project Partner)
Publications
Eaton SL
(2019)
CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease).
in Scientific reports
Putker M
(2021)
CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping.
in The EMBO journal
Rzechorzek N
(2024)
Circadian clocks in human cerebral organoids
Rzechorzek N
(2023)
Healthy human brains have a daily heatwave
in Temperature
Rzechorzek NM
(2019)
Network analysis of canine brain morphometry links tumour risk to oestrogen deficiency and accelerated brain ageing.
in Scientific reports
Rzechorzek NM
(2022)
A daily temperature rhythm in the human brain predicts survival after brain injury.
in Brain : a journal of neurology
| Title | A daily temperature rhythm in the human brain predicts survival after brain injury |
| Description | Video abstract linked to the published article in Brain |
| Type Of Art | Film/Video/Animation |
| Year Produced | 2022 |
| Impact | Invited talks, podcasts, and journalist interviews |
| URL | https://doi.org/10.1093/brain/awab466 |
| Title | HEATWAVE - a 4D map of human brain temperature |
| Description | Videos and interactive 3D maps than can be used to explore healthy adult human brain temperature in space and time. |
| Type Of Art | Film/Video/Animation |
| Year Produced | 2021 |
| Impact | TBC |
| URL | https://www2.mrc-lmb.cam.ac.uk/groups/oneill/research/heatwave/ |
| Title | SRBR 2022 Biennial Conference Logo |
| Description | Logo created and chosen for the SRBR 2002 Biennial Conference in Amelia Island, Florida |
| Type Of Art | Artwork |
| Year Produced | 2022 |
| Impact | Outreach to the international chronobiology community as an ambassador for the O'Neill Lab; raising the profile of our research. |
| URL | https://srbr.org/2022-conference/ |
| Description | Active member of inFOCUS Clinical Review Team |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Impact | inFOCUS is an innovative veterinary journal watch that keeps practitioners up-to-date with the latest research papers, critically appraised topics, articles, and more that have the potential to positively impact patient care. By subscribing to the free inFOCUS service - emailed six times per year - practitioners can save time and stay informed about the latest published developments in the veterinary profession. Through a series of summaries, inFOCUS will highlight key findings, explore limitations and provide the relevant take-home messages. Subscribers can choose to read full articles that are of most interest by following the links in each summary, and they can search the inFOCUS website if they want to go back and examine previous summaries. Plus, reading and reflecting on summaries and original material counts towards practitioners' CPD. inFOCUS is produced by RCVS Knowledge's Library & Information Services team, who watch the content of over 100 veterinary journals and other key sources to compile a shortlist of the most important articles for each bi-monthly email. Articles are assessed by the Clinical Review Team who score them against set criteria relating to relevance, quality and interest to the veterinary practitioner. The top-scoring articles are then reviewed and summarised with helpful commentary, and sent directly to subscribers to help improve the quality of care they deliver. |
| URL | http://www.infocusvj.org/ |
| Description | BSAVA PetSavers Grants Awarding Committee - Panel Member |
| Geographic Reach | National |
| Policy Influence Type | Participation in a guidance/advisory committee |
| Impact | Guiding distribution of funds to well-constructed projects that meet FINER criteria in the context of companion animal research Supporting the funding of promising early-career researchers and helping to develop new funding schemes to help bridge research funding gaps for veterinary professionals Providing advice to support research aims of early-career researchers, either as feedback for grant applications, or feedback on interim reports of funded projects Helping to ensure that funded projects have tangible positive impacts on clinical practice and patient care and adhere to Good Clinical Practice standards and ethics |
| URL | https://www.bsava.com/About-us/PetSavers |
| Description | BioClocks UK |
| Geographic Reach | National |
| Policy Influence Type | Influenced training of practitioners or researchers |
| URL | https://www.bioclocks.uk/ |
| Description | MRC Laboratory of Molecular Biology representative on the UKRI Researcher Development Concordat Employer Working Group |
| Geographic Reach | National |
| Policy Influence Type | Contribution to new or Improved professional practice |
| Description | Wilderness Medical Society Charles S Houston Grant |
| Amount | $5,000 (USD) |
| Organisation | Wilderness Medical Society |
| Sector | Learned Society |
| Country | United States |
| Start | 04/2020 |
| End | 05/2021 |
| Title | A novel radiotelemetry system to record EEG, EMG, brain and body temperature in mice |
| Description | A novel bespoke radiotelemetry implant has been developed for mice has been tested in a pilot study. This implant enables simultaneous longitudinal measurement of EEG, EMG, brain temperature and body temperature. This implant resides completely within the animal enabling full freedom to express normal behaviour, use a running wheel, and engage with other forms of enrichment. It is not currently commercially available but we have completed validation experiments (the results of which will be published with Open Access), after which the product can be commercialised and made available to other researchers. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2021 |
| Provided To Others? | No |
| Impact | This system enables longitudinal non-invasive (remote) assessment of brain temperature, body temperature, brain activity, and muscle activity in mice. The quality of this high temporal resolution data will enable the reduction of the number animals ultimately needed to answer research questions. The major 3Rs advantage of this system is refinement - no foreign material lies external to the mouse, the mouse is not tethered, and it is free to express all natural behaviours and make use of enrichment including a running wheel. The system is entirely compatible with a typical circadian setup such that running wheel activity and infrared activity can be recorded alongside the readouts from the transmitter. This provides the richest exploration of sleep/wake cycles and temperature cycles than has ever been possible before, under conditions that present negligible stress to the mouse. This is important not only for welfare, but in order to obtain physiologically-relevant data from mice under various paradigms such as those mimicking shift work. This is especially critical for circadian experiments, where the impact of stress can have a serious negative impact on data quality and lead to misinterpretation of the results. |
| Title | Assessment of daily brain temperature variation in healthy human volunteers using Magnetic Resonance Spectroscopy (MRS) |
| Description | Development of protocol to non-invasively measure daily brain temperature variation in healthy men and women using MRS. The method enables assessment of brain temperature in different brain regions and at different times of day, and normalizes this data to individual chronotype. |
| Type Of Material | Physiological assessment or outcome measure |
| Year Produced | 2022 |
| Provided To Others? | Yes |
| Impact | For the first time, we have been able to determine how normal human brain temperature varies by time of day, age, across deep and superficial brain regions, and between sexes. This has transformed our understanding of normal human brain temperature and helped to develop a new outcome predictor for traumatic brain injury (a daily rhythm in brain temperature). The Open Access output arising from this work has been cited 13 times since publication in June 2022, and currently has an Altmetric Score of 2389 - the highest Altmetric Score for any output from the journal Brain from Cambridge, and the third highest from the the journal Brain since Altmetric scoring began (3rd out of 7212 outputs). It is in the top 5% of all research outputs scored by Altmetric. The data from this work has been used to increase the physiological relevance of human neural platforms in the lab. |
| URL | https://academic.oup.com/brain/article/145/6/2031/6604351 |
| Title | Bespoke portable thermal device for cell cultures |
| Description | A bespoke next-generation portable hot plate with independent temperature control of base and lid and an uninterruptible power supply to enable researchers to transfer cell culture plates from one location to another without temperature changes. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2022 |
| Provided To Others? | Yes |
| Impact | The capacity to temperature-control our in-house experiments and the opportunity to transport cell cultures from collaborators. This next generation has enhanced temperatures stability and the UPS enables disconnection from the mains without any temperature changes for up to 30min. The heated lid prevents heat loss from the top of culture plates. |
| Title | BioClocks UK |
| Description | BioClocks UK is a new research network to support UK chronobiology. The main objectives are to increase the visibility of UK chronobiology research, and provide easier access to field-relevant resources, expertise, training, networking and public engagement events, collaborations and funding. We believe this will have a major positive impact for new researchers joining a diverse but quite complex research field. We also hope this will help improve standardisation of field-specific terminology and methods, and increase collaborations within and beyond the UK, thus strengthening the output and impact of our research. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. |
| Type Of Material | Improvements to research infrastructure |
| Year Produced | 2022 |
| Provided To Others? | Yes |
| Impact | N/A |
| URL | https://www.bioclocks.uk/ |
| Title | Generating PER2::LUC human Glutamatergic iNeurons |
| Description | Human H9 NGN2 OPTi-OX pluripotent stem cells (which can be directly differentiated into glutamatergic cortical neurons using doxycycline) were CRISPR/Cas9 gene-edited to stably express a translational clock gene reporter (i.e. luciferase under the control of PER2 translation). This reporter can be used to monitor PER2 oscillations in human neurons. |
| Type Of Material | Cell line |
| Year Produced | 2021 |
| Provided To Others? | Yes |
| Impact | The ability to monitor circadian rhythms in human iNeurons longitudinally via PER2::LUC bioluminescence. The same cell line has been used to generate human cerebral and renal organoids. Bioluminescent cerebral organoids have enabled us to explore circadian rhythms in this platform, in collaboration with other labs. Such platforms enable us to investigate human neural circadian rhythms in vitro, thus replacing and reducing the number of animals used in research. |
| Title | Generating PER2::LUC human iGABA Neurons |
| Description | Human iPS OPTi-OX pluripotent stem cells (which can be directly differentiated into GABAergic cortical neurons using doxycycline) were CRISPR/Cas9 gene-edited to stably express a translational clock gene reporter (i.e. luciferase under the control of PER2 translation). This reporter can be used to monitor PER2 oscillations in human neurons. |
| Type Of Material | Cell line |
| Year Produced | 2023 |
| Provided To Others? | Yes |
| Impact | The ability to monitor circadian rhythms in human iNeurons longitudinally via PER2::LUC bioluminescence. Such platforms enable us to investigate human neural circadian rhythms in vitro, thus replacing and reducing the number of animals used in research. |
| Title | Generation of human 'clock gene' reporter pluripotent stem cell line (Bmal1:luciferase) |
| Description | Human H9 NGN2 OPTi-OX pluripotent stem cells (which can be directly differentiated into glutamatergic cortical neurons using doxycycline) were transduced via lentivirus to stably express a transcriptional clock gene reporter (i.e. luciferase under the control of Bmal1 transcription). This reporter can be used to monitor Bmal1 oscillations in human neurons. |
| Type Of Material | Cell line |
| Year Produced | 2019 |
| Provided To Others? | Yes |
| Impact | The ability to monitor circadian rhythms in human glutamatergic iNeurons longitudinally via Bmal1:Luc bioluminescence. The same cell line has been used to generate human cerebral organoids. Bioluminescent cerebral organoids have enabled us to explore circadian rhythms in this platform, in collaboration with other labs. Such platforms enable us to investigate human neural circadian rhythms in vitro, thus replacing and reducing the number of animals used in research. |
| Title | Optogenetics platform with programmable high spatiotemporal resolution |
| Description | Re-engineering of an LED platform to enable high throughput optogenetic manipulation of a range of cell culture plate types within a standard humidified incubator. This bespoke device is remotely programmable and has a 'sandwich' design to enable top and bottom illumination with multiple wavelengths of light simultaneously (multiplexed activation of different optogenetic constructs) |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2022 |
| Provided To Others? | No |
| Impact | This tool has enabled us to conduct temperature-controlled and spatiotemporally-resolved manipulation of ion movements in mammalian cells. |
| Title | HEATWAVE: a 4-dimensional map of human brain temperature |
| Description | From the Circadian Brain Temperature (CiBraT) Study we have collected sufficient data to provide a resource that researchers and the public can use to explore how healthy adult human brain temperature varies by time of day, brain region, and sex called 'HEATWAVE'. This resource is free to access. Our related manuscript also shows how brain temperature varies with age. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2021 |
| Provided To Others? | Yes |
| Impact | A better understanding of normal temperature ranges of the human brain that can be used by clinicians and researchers for infectious disease screening and interpreting temperature trends in patients with brain injury. This dataset also serves as a reference against which brain temperature rhythms in patients with acute and chronic brain disease can be compared in future studies. We have used these data to successfully predict ICU survival in patients with brain injury based on the presence/absence of a diurnal rhythm in brain temperature. |
| URL | https://www2.mrc-lmb.cam.ac.uk/groups/oneill/research/heatwave/ |
| Description | A 3Rs approach to recording daily brain temperature rhythms in mice using a next-generation telemetric implant |
| Organisation | TSE Systems |
| Country | Germany |
| Sector | Private |
| PI Contribution | We bring expertise in chronobiology and monitoring of circadian rhythms of behaviour in mice. I bring experience in neurosurgery and I have also provided the basic design of an implant that will simultaneously meet our research needs and fully engage with 3R objectives to improve the welfare of animals used in telemetry experiments. |
| Collaborator Contribution | The partner brings expertise in microengineering - in particular the development of radiotelemetric implants for mice. |
| Impact | Output - a novel bespoke telemetry implant has been developed which meets our specific research needs and has been tested in a pilot study. This implant is not currently commercially available but we are currently conducting validation experiments (the results of which will be published with Open Access), after which the product will be fully commercialised and made available to other researchers. Multidisciplinary: microengineering and microsurgery; implantable technology; chronobiology |
| Start Year | 2019 |
| Description | BioClocks UK |
| Organisation | Earlham Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Part of a team of UK chronobiologists who have developed a research network. My main contributions have included branding (name, logo), development of a web platform to support the UK chronobiology community (https://www.bioclocks.uk/), and contributing to grant applications for research network funding. The main objectives are to increase the visibility of UK chronobiology research, and provide easier access to field-relevant resources, expertise, training, networking and public engagement events, collaborations and funding. We believe this will have a major positive impact for new researchers joining a diverse but quite complex research field. We also hope this will help improve standardisation of field-specific terminology and methods, and increase collaborations within and beyond the UK, thus strengthening the output and impact of our research. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. |
| Collaborator Contribution | BioClocks UK is a hub for biological rhythms research in the UK, providing information and resources for people working in our chronobiology community, whilst keeping the general public and our global collaborators updated about what we do. Over several decades, UK circadian research has delivered fascinating insights into fundamental biology driven by adaptation to life on a rotating planet. Understanding biological rhythms has direct applications for improving physical and mental health; providing insights into the treatment of circadian- and sleep-related disorders, the effect of disease, ageing, and stress on body clocks, and informing precision medicine. Our community can help build resilient and sustainable agricultural systems, improve food security, and enhance our preparedness for emerging diseases in a changing climate. Across the UK, there are over 100 groups delivering impactful research into biological rhythms across diverse model biological systems. The strength of chronobiological research in the UK owes much to the success of regular UK Clock Club meetings which have provided a basis for knowledge-exchange and collaboration within the biological clocks community. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. See here to see the role of each BioClocks UK Team Member: https://www.bioclocks.uk/team-3 |
| Impact | https://www.bioclocks.uk/ |
| Start Year | 2022 |
| Description | BioClocks UK |
| Organisation | John Innes Centre |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Part of a team of UK chronobiologists who have developed a research network. My main contributions have included branding (name, logo), development of a web platform to support the UK chronobiology community (https://www.bioclocks.uk/), and contributing to grant applications for research network funding. The main objectives are to increase the visibility of UK chronobiology research, and provide easier access to field-relevant resources, expertise, training, networking and public engagement events, collaborations and funding. We believe this will have a major positive impact for new researchers joining a diverse but quite complex research field. We also hope this will help improve standardisation of field-specific terminology and methods, and increase collaborations within and beyond the UK, thus strengthening the output and impact of our research. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. |
| Collaborator Contribution | BioClocks UK is a hub for biological rhythms research in the UK, providing information and resources for people working in our chronobiology community, whilst keeping the general public and our global collaborators updated about what we do. Over several decades, UK circadian research has delivered fascinating insights into fundamental biology driven by adaptation to life on a rotating planet. Understanding biological rhythms has direct applications for improving physical and mental health; providing insights into the treatment of circadian- and sleep-related disorders, the effect of disease, ageing, and stress on body clocks, and informing precision medicine. Our community can help build resilient and sustainable agricultural systems, improve food security, and enhance our preparedness for emerging diseases in a changing climate. Across the UK, there are over 100 groups delivering impactful research into biological rhythms across diverse model biological systems. The strength of chronobiological research in the UK owes much to the success of regular UK Clock Club meetings which have provided a basis for knowledge-exchange and collaboration within the biological clocks community. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. See here to see the role of each BioClocks UK Team Member: https://www.bioclocks.uk/team-3 |
| Impact | https://www.bioclocks.uk/ |
| Start Year | 2022 |
| Description | BioClocks UK |
| Organisation | Northumbria University |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Part of a team of UK chronobiologists who have developed a research network. My main contributions have included branding (name, logo), development of a web platform to support the UK chronobiology community (https://www.bioclocks.uk/), and contributing to grant applications for research network funding. The main objectives are to increase the visibility of UK chronobiology research, and provide easier access to field-relevant resources, expertise, training, networking and public engagement events, collaborations and funding. We believe this will have a major positive impact for new researchers joining a diverse but quite complex research field. We also hope this will help improve standardisation of field-specific terminology and methods, and increase collaborations within and beyond the UK, thus strengthening the output and impact of our research. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. |
| Collaborator Contribution | BioClocks UK is a hub for biological rhythms research in the UK, providing information and resources for people working in our chronobiology community, whilst keeping the general public and our global collaborators updated about what we do. Over several decades, UK circadian research has delivered fascinating insights into fundamental biology driven by adaptation to life on a rotating planet. Understanding biological rhythms has direct applications for improving physical and mental health; providing insights into the treatment of circadian- and sleep-related disorders, the effect of disease, ageing, and stress on body clocks, and informing precision medicine. Our community can help build resilient and sustainable agricultural systems, improve food security, and enhance our preparedness for emerging diseases in a changing climate. Across the UK, there are over 100 groups delivering impactful research into biological rhythms across diverse model biological systems. The strength of chronobiological research in the UK owes much to the success of regular UK Clock Club meetings which have provided a basis for knowledge-exchange and collaboration within the biological clocks community. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. See here to see the role of each BioClocks UK Team Member: https://www.bioclocks.uk/team-3 |
| Impact | https://www.bioclocks.uk/ |
| Start Year | 2022 |
| Description | BioClocks UK |
| Organisation | University of Bristol |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Part of a team of UK chronobiologists who have developed a research network. My main contributions have included branding (name, logo), development of a web platform to support the UK chronobiology community (https://www.bioclocks.uk/), and contributing to grant applications for research network funding. The main objectives are to increase the visibility of UK chronobiology research, and provide easier access to field-relevant resources, expertise, training, networking and public engagement events, collaborations and funding. We believe this will have a major positive impact for new researchers joining a diverse but quite complex research field. We also hope this will help improve standardisation of field-specific terminology and methods, and increase collaborations within and beyond the UK, thus strengthening the output and impact of our research. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. |
| Collaborator Contribution | BioClocks UK is a hub for biological rhythms research in the UK, providing information and resources for people working in our chronobiology community, whilst keeping the general public and our global collaborators updated about what we do. Over several decades, UK circadian research has delivered fascinating insights into fundamental biology driven by adaptation to life on a rotating planet. Understanding biological rhythms has direct applications for improving physical and mental health; providing insights into the treatment of circadian- and sleep-related disorders, the effect of disease, ageing, and stress on body clocks, and informing precision medicine. Our community can help build resilient and sustainable agricultural systems, improve food security, and enhance our preparedness for emerging diseases in a changing climate. Across the UK, there are over 100 groups delivering impactful research into biological rhythms across diverse model biological systems. The strength of chronobiological research in the UK owes much to the success of regular UK Clock Club meetings which have provided a basis for knowledge-exchange and collaboration within the biological clocks community. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. See here to see the role of each BioClocks UK Team Member: https://www.bioclocks.uk/team-3 |
| Impact | https://www.bioclocks.uk/ |
| Start Year | 2022 |
| Description | BioClocks UK |
| Organisation | University of Edinburgh |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Part of a team of UK chronobiologists who have developed a research network. My main contributions have included branding (name, logo), development of a web platform to support the UK chronobiology community (https://www.bioclocks.uk/), and contributing to grant applications for research network funding. The main objectives are to increase the visibility of UK chronobiology research, and provide easier access to field-relevant resources, expertise, training, networking and public engagement events, collaborations and funding. We believe this will have a major positive impact for new researchers joining a diverse but quite complex research field. We also hope this will help improve standardisation of field-specific terminology and methods, and increase collaborations within and beyond the UK, thus strengthening the output and impact of our research. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. |
| Collaborator Contribution | BioClocks UK is a hub for biological rhythms research in the UK, providing information and resources for people working in our chronobiology community, whilst keeping the general public and our global collaborators updated about what we do. Over several decades, UK circadian research has delivered fascinating insights into fundamental biology driven by adaptation to life on a rotating planet. Understanding biological rhythms has direct applications for improving physical and mental health; providing insights into the treatment of circadian- and sleep-related disorders, the effect of disease, ageing, and stress on body clocks, and informing precision medicine. Our community can help build resilient and sustainable agricultural systems, improve food security, and enhance our preparedness for emerging diseases in a changing climate. Across the UK, there are over 100 groups delivering impactful research into biological rhythms across diverse model biological systems. The strength of chronobiological research in the UK owes much to the success of regular UK Clock Club meetings which have provided a basis for knowledge-exchange and collaboration within the biological clocks community. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. See here to see the role of each BioClocks UK Team Member: https://www.bioclocks.uk/team-3 |
| Impact | https://www.bioclocks.uk/ |
| Start Year | 2022 |
| Description | BioClocks UK |
| Organisation | University of Glasgow |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Part of a team of UK chronobiologists who have developed a research network. My main contributions have included branding (name, logo), development of a web platform to support the UK chronobiology community (https://www.bioclocks.uk/), and contributing to grant applications for research network funding. The main objectives are to increase the visibility of UK chronobiology research, and provide easier access to field-relevant resources, expertise, training, networking and public engagement events, collaborations and funding. We believe this will have a major positive impact for new researchers joining a diverse but quite complex research field. We also hope this will help improve standardisation of field-specific terminology and methods, and increase collaborations within and beyond the UK, thus strengthening the output and impact of our research. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. |
| Collaborator Contribution | BioClocks UK is a hub for biological rhythms research in the UK, providing information and resources for people working in our chronobiology community, whilst keeping the general public and our global collaborators updated about what we do. Over several decades, UK circadian research has delivered fascinating insights into fundamental biology driven by adaptation to life on a rotating planet. Understanding biological rhythms has direct applications for improving physical and mental health; providing insights into the treatment of circadian- and sleep-related disorders, the effect of disease, ageing, and stress on body clocks, and informing precision medicine. Our community can help build resilient and sustainable agricultural systems, improve food security, and enhance our preparedness for emerging diseases in a changing climate. Across the UK, there are over 100 groups delivering impactful research into biological rhythms across diverse model biological systems. The strength of chronobiological research in the UK owes much to the success of regular UK Clock Club meetings which have provided a basis for knowledge-exchange and collaboration within the biological clocks community. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. See here to see the role of each BioClocks UK Team Member: https://www.bioclocks.uk/team-3 |
| Impact | https://www.bioclocks.uk/ |
| Start Year | 2022 |
| Description | BioClocks UK |
| Organisation | University of Leicester |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Part of a team of UK chronobiologists who have developed a research network. My main contributions have included branding (name, logo), development of a web platform to support the UK chronobiology community (https://www.bioclocks.uk/), and contributing to grant applications for research network funding. The main objectives are to increase the visibility of UK chronobiology research, and provide easier access to field-relevant resources, expertise, training, networking and public engagement events, collaborations and funding. We believe this will have a major positive impact for new researchers joining a diverse but quite complex research field. We also hope this will help improve standardisation of field-specific terminology and methods, and increase collaborations within and beyond the UK, thus strengthening the output and impact of our research. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. |
| Collaborator Contribution | BioClocks UK is a hub for biological rhythms research in the UK, providing information and resources for people working in our chronobiology community, whilst keeping the general public and our global collaborators updated about what we do. Over several decades, UK circadian research has delivered fascinating insights into fundamental biology driven by adaptation to life on a rotating planet. Understanding biological rhythms has direct applications for improving physical and mental health; providing insights into the treatment of circadian- and sleep-related disorders, the effect of disease, ageing, and stress on body clocks, and informing precision medicine. Our community can help build resilient and sustainable agricultural systems, improve food security, and enhance our preparedness for emerging diseases in a changing climate. Across the UK, there are over 100 groups delivering impactful research into biological rhythms across diverse model biological systems. The strength of chronobiological research in the UK owes much to the success of regular UK Clock Club meetings which have provided a basis for knowledge-exchange and collaboration within the biological clocks community. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. See here to see the role of each BioClocks UK Team Member: https://www.bioclocks.uk/team-3 |
| Impact | https://www.bioclocks.uk/ |
| Start Year | 2022 |
| Description | BioClocks UK |
| Organisation | University of Manchester |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Part of a team of UK chronobiologists who have developed a research network. My main contributions have included branding (name, logo), development of a web platform to support the UK chronobiology community (https://www.bioclocks.uk/), and contributing to grant applications for research network funding. The main objectives are to increase the visibility of UK chronobiology research, and provide easier access to field-relevant resources, expertise, training, networking and public engagement events, collaborations and funding. We believe this will have a major positive impact for new researchers joining a diverse but quite complex research field. We also hope this will help improve standardisation of field-specific terminology and methods, and increase collaborations within and beyond the UK, thus strengthening the output and impact of our research. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. |
| Collaborator Contribution | BioClocks UK is a hub for biological rhythms research in the UK, providing information and resources for people working in our chronobiology community, whilst keeping the general public and our global collaborators updated about what we do. Over several decades, UK circadian research has delivered fascinating insights into fundamental biology driven by adaptation to life on a rotating planet. Understanding biological rhythms has direct applications for improving physical and mental health; providing insights into the treatment of circadian- and sleep-related disorders, the effect of disease, ageing, and stress on body clocks, and informing precision medicine. Our community can help build resilient and sustainable agricultural systems, improve food security, and enhance our preparedness for emerging diseases in a changing climate. Across the UK, there are over 100 groups delivering impactful research into biological rhythms across diverse model biological systems. The strength of chronobiological research in the UK owes much to the success of regular UK Clock Club meetings which have provided a basis for knowledge-exchange and collaboration within the biological clocks community. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. See here to see the role of each BioClocks UK Team Member: https://www.bioclocks.uk/team-3 |
| Impact | https://www.bioclocks.uk/ |
| Start Year | 2022 |
| Description | BioClocks UK |
| Organisation | University of Warwick |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Part of a team of UK chronobiologists who have developed a research network. My main contributions have included branding (name, logo), development of a web platform to support the UK chronobiology community (https://www.bioclocks.uk/), and contributing to grant applications for research network funding. The main objectives are to increase the visibility of UK chronobiology research, and provide easier access to field-relevant resources, expertise, training, networking and public engagement events, collaborations and funding. We believe this will have a major positive impact for new researchers joining a diverse but quite complex research field. We also hope this will help improve standardisation of field-specific terminology and methods, and increase collaborations within and beyond the UK, thus strengthening the output and impact of our research. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. |
| Collaborator Contribution | BioClocks UK is a hub for biological rhythms research in the UK, providing information and resources for people working in our chronobiology community, whilst keeping the general public and our global collaborators updated about what we do. Over several decades, UK circadian research has delivered fascinating insights into fundamental biology driven by adaptation to life on a rotating planet. Understanding biological rhythms has direct applications for improving physical and mental health; providing insights into the treatment of circadian- and sleep-related disorders, the effect of disease, ageing, and stress on body clocks, and informing precision medicine. Our community can help build resilient and sustainable agricultural systems, improve food security, and enhance our preparedness for emerging diseases in a changing climate. Across the UK, there are over 100 groups delivering impactful research into biological rhythms across diverse model biological systems. The strength of chronobiological research in the UK owes much to the success of regular UK Clock Club meetings which have provided a basis for knowledge-exchange and collaboration within the biological clocks community. Our mission is to consolidate, engage, and expand our research network in order to establish and nurture robust cycles of discovery to impact. See here to see the role of each BioClocks UK Team Member: https://www.bioclocks.uk/team-3 |
| Impact | https://www.bioclocks.uk/ |
| Start Year | 2022 |
| Description | Circadian rhythms in Huntington's Disease |
| Organisation | University of Cambridge |
| Department | John van Geest Centre for Brain Repair |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We are providing expertise in chronobiology and in vitro characterization of circadian rhythms in human cell lines, including derivation of clock gene reporter lines and CRISPR/Cas9 gene editing |
| Collaborator Contribution | Our partners are providing Huntington's Disease patient cell lines |
| Impact | We have successfully characterized circadian rhythms in 5 patient lines and 6 healthy control lines |
| Start Year | 2020 |
| Description | Circadian rhythms in cerebral organoids |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Laboratory of Molecular Biology (LMB) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | CRISPR gene-edited and lentiviral-transduced stem cells with bioluminescent clock reporters Design of experiments and collection of data from bioluminescent organoids |
| Collaborator Contribution | Expertise and support in culturing human cerebral organoids Nucleofector equipment |
| Impact | Novel platforms for exploring human neural circadian rhythms |
| Start Year | 2022 |
| Description | Developing cellular platforms for manipulating intracellular ions via optogenetics |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Laboratory of Molecular Biology (LMB) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I have used optogenetic constructs provided by Andrew Trevelyan's lab to develop cellular platforms for manipulating intracellular ions via optogenetics. I have contributed to the design and refinement of a novel bespoke optogenetics LED platform to activate these constructs in cells with high spatiotemporal resolution in a standard temperature-controlled, humidified incubator. |
| Collaborator Contribution | Provision of optogenetic constructs Technical/engineering support (LMB electronics workshop) |
| Impact | Personal training in cloning and optogenetics; the resultant platforms can be used to progress my research as well as that of the host lab |
| Start Year | 2022 |
| Description | Developing cellular platforms for manipulating intracellular ions via optogenetics |
| Organisation | University of Newcastle |
| Country | Australia |
| Sector | Academic/University |
| PI Contribution | I have used optogenetic constructs provided by Andrew Trevelyan's lab to develop cellular platforms for manipulating intracellular ions via optogenetics. I have contributed to the design and refinement of a novel bespoke optogenetics LED platform to activate these constructs in cells with high spatiotemporal resolution in a standard temperature-controlled, humidified incubator. |
| Collaborator Contribution | Provision of optogenetic constructs Technical/engineering support (LMB electronics workshop) |
| Impact | Personal training in cloning and optogenetics; the resultant platforms can be used to progress my research as well as that of the host lab |
| Start Year | 2022 |
| Description | MICA Cryo-chronobiology |
| Organisation | Elpis Biomed Ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | I bring experience in differentiating, maintaining, validating and experimenting with human stem cell-derived neuronal and glial cell types (particularly in the context of temperature shift). My supervisor brings extensive knowledge of circadian experimental design and extraction of molecular readouts from multiple cellular platforms, including OPTi-OX-derived cultures. We have provided optimised protocols for our partners at the Hubrecht Institute to collect circadian readouts from human and mouse organoids. |
| Collaborator Contribution | Elpis BioMed Ltd. (now Bit Bio Ltd) is providing key reagents and resources (OPTi-OX cell lines) as well as technical guidance on assay development using these bespoke cultures. Hubrecht Institute has provided human and mouse stem cell-derived organoids and collected circadian data from them under our guidance. |
| Impact | No outputs or outcomes as yet Multi-disciplinary: synthetic and stem cell biology; chronobiology |
| Start Year | 2019 |
| Description | Rapid circadian re-Entrainment to modify Sleep parameters upon acute hypoxic Exposure after jeT lag (RESET): a randomised, crossover trial. |
| Organisation | University of Edinburgh |
| Department | Medical School Edinburgh |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have provided expertise in chronobiology, clinical study design, research ethics for healthy volunteer studies, and chronobiology. I am the primary supervisor for the undergraduate medical student leading on this project at the University of Edinburgh/Bolivia; I am also Chief Investigator of the RESET trial. We have also provided research equipment for the expedition (on loan) including actigraphy devices, data transfer docks, and expedition laptops. |
| Collaborator Contribution | APEX: trial participants, expedition logistics, data collection University of Edinburgh: co-sponsorship of trial and intellectual expertise/input University of Sheffield: intellectual expertise/input NHS Lothian: use of clinical research facilities and co-sponsorship of trial Condor Instruments Ltd: loan of actigraphy devices and discount on new devices |
| Impact | No outputs or outcomes as yet - the research studies for the APEX 6 expedition are currently under ethics review; the expedition was postponed from 2020 to 2022 due to the COVID pandemic Multidisciplinary: high altitude medicine, wilderness medicine, chronobiology, sleep medicine, clinical trials Trial registration: https://doi.org/10.1186/ISRCTN76074900 |
| Start Year | 2019 |
| Description | Rapid circadian re-Entrainment to modify Sleep parameters upon acute hypoxic Exposure after jeT lag (RESET): a randomised, crossover trial. |
| Organisation | University of Sheffield |
| Department | Department of Infection, Immunity and Cardiovascular Disease |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have provided expertise in chronobiology, clinical study design, research ethics for healthy volunteer studies, and chronobiology. I am the primary supervisor for the undergraduate medical student leading on this project at the University of Edinburgh/Bolivia; I am also Chief Investigator of the RESET trial. We have also provided research equipment for the expedition (on loan) including actigraphy devices, data transfer docks, and expedition laptops. |
| Collaborator Contribution | APEX: trial participants, expedition logistics, data collection University of Edinburgh: co-sponsorship of trial and intellectual expertise/input University of Sheffield: intellectual expertise/input NHS Lothian: use of clinical research facilities and co-sponsorship of trial Condor Instruments Ltd: loan of actigraphy devices and discount on new devices |
| Impact | No outputs or outcomes as yet - the research studies for the APEX 6 expedition are currently under ethics review; the expedition was postponed from 2020 to 2022 due to the COVID pandemic Multidisciplinary: high altitude medicine, wilderness medicine, chronobiology, sleep medicine, clinical trials Trial registration: https://doi.org/10.1186/ISRCTN76074900 |
| Start Year | 2019 |
| Description | The Circadian Brain Temperature (CiBraT) Study |
| Organisation | University of Cambridge |
| Department | Department of Clinical Neurosciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Contributions made by me: Conceptualization; Methodology; Validation; Investigation; Data Curation; Writing; Visualization; Project Administration; Funding Acquisition. Contributions made by my supervisor: Conceptualization; Methodology; Validation; Visualization; Supervision. |
| Collaborator Contribution | University of Edinburgh (Centre for Clinical Brain Sciences and Edinburgh Imaging): Methodology; Software; Validation; Formal Analysis; Investigation; Resources; Data Curation; Visualization; Supervision; Project Administration. CENTER-TBI (Participants and Investigators): Software; Investigation; Resources; Data Curation NHS Lothian (Department of Anaesthesia, Critical Care and Pain Medicine): Methodology; Software; Validation; Formal Analysis; Investigation; Resources; Data Curation; Supervision; Project Administration. University of Cambridge (Department of Clinical Neurosciences, Addenbrooke's Hospital): Software; Investigation; Resources; Data Curation |
| Impact | Open access 4D map of human brain temperature 'HEATWAVE' https://www2.mrc-lmb.cam.ac.uk/groups/oneill/what-we-do/heatwave/ Five abstracts submitted for research meetings: (1) Clinical Academics in Training Annual Conference (CATAC) 2020 (Bristol) 'Diurnal brain temperature mapping by Magnetic Resonance Spectroscopy (MRS): a prospective cohort study in healthy volunteers.' Conference postponed to 2022 due to pandemic (2) Society for Research on Biological Rhythms (SRBR) 2020 (Amelia Island, Florida) 'Human brain temperature around the clock - why keeping a cool head is beyond your control'. Conference transitioned to remote/online due to pandemic - poster presented. (3) UK ClockClub Spring Symposium 2022 (University of Oxford) 'A daily temperature rhythm in the human brain predicts survival after traumatic brain injury'. Outcome pending. (4) Clinical Academics in Training Annual Conference (CATAC) 2022 (Bristol) 'A daily brain temperature rhythm predicts survival after traumatic brain injury'. Outcome pending. (5) Society for Research on Biological Rhythms (SRBR) 2022 (Amelia Island, Florida) 'A daily temperature rhythm in the human brain predicts survival after traumatic brain injury'. Outcome pending. Full manuscript published as preprint on medRxiv and currently accepted in press in journal Brain; press release prepared for publication in June 2022 Invited clinical translational talk given at Brain Conference 2022 (online) Multidisciplinary: Medical Physics, Neuroimaging, Chronobiology, Intensive Care Medicine |
| Start Year | 2019 |
| Description | The Circadian Brain Temperature (CiBraT) Study |
| Organisation | University of Edinburgh |
| Department | Centre for Clinical Brain Sciences (CCBS) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Contributions made by me: Conceptualization; Methodology; Validation; Investigation; Data Curation; Writing; Visualization; Project Administration; Funding Acquisition. Contributions made by my supervisor: Conceptualization; Methodology; Validation; Visualization; Supervision. |
| Collaborator Contribution | University of Edinburgh (Centre for Clinical Brain Sciences and Edinburgh Imaging): Methodology; Software; Validation; Formal Analysis; Investigation; Resources; Data Curation; Visualization; Supervision; Project Administration. CENTER-TBI (Participants and Investigators): Software; Investigation; Resources; Data Curation NHS Lothian (Department of Anaesthesia, Critical Care and Pain Medicine): Methodology; Software; Validation; Formal Analysis; Investigation; Resources; Data Curation; Supervision; Project Administration. University of Cambridge (Department of Clinical Neurosciences, Addenbrooke's Hospital): Software; Investigation; Resources; Data Curation |
| Impact | Open access 4D map of human brain temperature 'HEATWAVE' https://www2.mrc-lmb.cam.ac.uk/groups/oneill/what-we-do/heatwave/ Five abstracts submitted for research meetings: (1) Clinical Academics in Training Annual Conference (CATAC) 2020 (Bristol) 'Diurnal brain temperature mapping by Magnetic Resonance Spectroscopy (MRS): a prospective cohort study in healthy volunteers.' Conference postponed to 2022 due to pandemic (2) Society for Research on Biological Rhythms (SRBR) 2020 (Amelia Island, Florida) 'Human brain temperature around the clock - why keeping a cool head is beyond your control'. Conference transitioned to remote/online due to pandemic - poster presented. (3) UK ClockClub Spring Symposium 2022 (University of Oxford) 'A daily temperature rhythm in the human brain predicts survival after traumatic brain injury'. Outcome pending. (4) Clinical Academics in Training Annual Conference (CATAC) 2022 (Bristol) 'A daily brain temperature rhythm predicts survival after traumatic brain injury'. Outcome pending. (5) Society for Research on Biological Rhythms (SRBR) 2022 (Amelia Island, Florida) 'A daily temperature rhythm in the human brain predicts survival after traumatic brain injury'. Outcome pending. Full manuscript published as preprint on medRxiv and currently accepted in press in journal Brain; press release prepared for publication in June 2022 Invited clinical translational talk given at Brain Conference 2022 (online) Multidisciplinary: Medical Physics, Neuroimaging, Chronobiology, Intensive Care Medicine |
| Start Year | 2019 |
| Title | HEATWAVE: a 4-dimensional map of brain temperature in healthy adults |
| Description | The Circadian Brain Temperature (CiBraT) Study was funded by this MRC Clinician Scientist Fellowship. The results of the study have been published with Open Access in the journal Brain (https://doi.org/10.1093/brain/awab466). HEATWAVE is an Open Access resource developed from the results of the study and can be explored here: https://www2.mrc-lmb.cam.ac.uk/groups/oneill/research/heatwave/ |
| Type | Management of Diseases and Conditions |
| Current Stage Of Development | Refinement. Clinical |
| Year Development Stage Completed | 2020 |
| Development Status | Actively seeking support |
| UKCRN/ISCTN Identifier | N/A |
| Impact | The publication received a lot of interest from basic and clinical researchers, the media, and the public, with a current Altmetric Score of 2389 and 13 citations since June 2022. I have been invited to give 4 talks and recorded a podcast as a result of this work which was reported by 254 news outlets with a global reach. |
| URL | https://doi.org/10.1093/brain/awab466 |
| Title | The RESET trial: can a novel intervention rapidly re-adjust the body clock to treat jet-lag in healthy volunteers and improve their sleep at high altitude? |
| Description | Biological clocks regulate how our body works, and they must synchronize to our 24-hour world. Environmental timing cues feed into a 'master clock' in the brain, which then synchronizes clocks throughout the body. Light-dark cycles, meal times, and steroid hormones form the strongest cues, tuning our internal clocks to the day-night rhythm. Genetic variation determines how our body clocks align with this rhythm, thus resulting in different 'chronotypes' (i.e. 'morning larks' and 'night owls'). Annually, millions of people stretch the limits of their body clock by rapidly crossing multiple time zones. Temporary misalignment between an individual's body clock and local time in their destination produces 'jet lag', the symptoms of which subside as the body clock adapts to the new time zone. Disruption of our body clocks-as occurs with jet lag and shift work-has far-reaching health effects, playing a role in cancer, diabetes, heart disease, and dementia. If we could rapidly reset the body clock to better accommodate our modern lifestyles, this could have enormous health benefits. An intense challenge is faced by visitors to high altitude, since exposure to a low-oxygen environment often coincides with jet lag. A prominent feature of both jet lag and ascent to high altitude is sleep disturbance. Most studies of sleep at altitude have failed to control for individual chronotype and body clock function-factors which could substantially modify the body's adaptation to a new time zone. Research on APEX 6 addresses an important knowledge gap; the impact of individual chronotype and jet lag on how the body copes with high altitude. The RESET trial builds on this by testing whether a multi-factorial intervention can accelerate resetting of body clocks and improve sleep function in healthy volunteers exposed to jet lag and high altitude. The trial launched in summer 2022 and data collection is now complete. |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Early clinical assessment |
| Year Development Stage Completed | 2022 |
| Development Status | On hold |
| Clinical Trial? | Yes |
| UKCRN/ISCTN Identifier | ISRCTN |
| Impact | Outcome of trial pending. The trial was conducted by a group of undergraduate medical students during the APEX 6 Expedition to Bolivia. This was an opportunity for these students to get hands-on clinical research training in the extreme high altitude environment. The research being conducted on the expedition is relevant to those who visit hypoxic environments but also to patients at sea level who are suffering from hypoxia. |
| URL | https://www.altitude.org/ |
| Title | A next-generation telemetric implant for remote, non-invasive monitoring of daily brain temperature rhythms in mice |
| Description | A novel bespoke telemetry implant has been developed which meets our specific research needs and is currently undergoing validation. The single implant remotely records brain temperature, body temperature, EEG, and EMG simultaneously and at high temporal resolution without the need for tethering or any other intervention that would interfere with normal physiological and behavioural activity in mice. Such features are essential assessing circadian rhythms and ensuring the longitudinal welfare (including enrichment) of experimental mice. This implant is not currently commercially available but pending validation results in the coming year, our collaborators at TSE Systems expect to fully commercialise the product. |
| Type Of Technology | New/Improved Technique/Technology |
| Year Produced | 2020 |
| Impact | TBC |
| Description | 'I'm A Scientist, Stay At Home 2020' - Medical Research Zone Winner (Week 2) |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Schools |
| Results and Impact | In March 2020, schools were closed due to the COVID-19 pandemic, creating uncertainty in education. Many STEM enrichment activities for students were cancelled. I'm a Scientist, Stay at home was launched to allow school students to stay connected with STEM from April to July. Students could log in and take part whether they were at school or at home, reconnecting with their teachers and each other. 2,500 STEM professionals signed up to take part and inspire students across the UK. Over 800 schools registered for their students to stay engaged with science, engineering and maths. The Medical Research Zone ran over 12 weeks as part of the Stay at home activities and was funded by the Medical Research Council with additional funding from UKRI. 135 scientists created profiles in the Zone. 121 engaged with students in live chats and answering questions. 104 of the scientists were new to the I'm a Scientist activities. Scientists from a broad range of areas and career stages took part. 91 live chats took place during the activity. On average, 7 researchers attended each live chat session. 229 posted questions were approved and sent to the researchers who responded with 636 answers. 1,248 students from 53 schools all over the UK logged into the Zone. 33 of these schools had taken part in a previous I'm a Scientist activity. 8% of active students were from widening participation schools, and 55% from underserved schools. Medical Research Zone was one of the busiest of the Stay at home zones, with numbers above average in almost all categories. For example, students from 53 schools took part in the zone, in comparison to the average of 32 schools. There were 91 live chats compared to the average in the zones of 55. Chats themselves were busy, producing an average of 279 lines per session, compared to the average 227 lines. 33 out of the 266 Ask questions were about coronavirus, and COVID-19 was the most used keyword. However, this didn't dominate the conversations. There were many questions about the scientists' research, with almost a third of all questions in Ask about careers and education. Common discussions in Chats were about disease and viruses, cells, DNA, and how drugs affect the body. |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://about.imascientist.org.uk/2020/medical-research-zone-report-stay-at-home-2020/ |
| Description | Invited clinical translation talk at The Brain Conference 2022 'Daily brain temperature rhythms and their clinical value' |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Brain has published landmark papers in clinical neurology and translational neuroscience since 1878. The Guarantors of Brain aim to promote teaching, education and research in neurology and related disciplines, and they started the Brain Conference in 2021 to further fulfil this mission. In 2022, the BRAIN Conference took place online, on 24-25 February. This two-day conference featured a wide range of speakers from around the globe, and a panel of leading scientists and clinicians, at the forefront of their fields, who curated and chaired topic sessions featuring a mix of teaching talks and research presentations. Brain has a broad readership, comprising both clinicians and scientists within the neurosciences. The conference was aimed at the general readership - clinicians, scientists, students, and senior faculty. There were more than 800 attendees at the conference. I was invited to give the clinical translation talk in the 'Sleep and Circadian Rhythms' session which led to interesting discussions with the audience and other speakers; many people were surprised by the data I was presenting about human brain temperature - and they reported that this changed their thinking about this topic. |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://thebrainconference.co.uk/ |
| Description | MRC Festival of Research: I'm A Scientist Get Me Out Of Here - Winner (Week 3) |
| Form Of Engagement Activity | Engagement focused website, blog or social media channel |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Schools |
| Results and Impact | The MRC Festival Zone was a four-week-long online event funded by the Medical Research Council (MRC) as part of the MRC Festival of Medical Research. 25 MRC researchers and technical staff put up profiles on the website, and 24 of these engaged with students throughout the month in live CHATs and the ASK section. 1,204 students from 33 schools all over the UK logged in to the zone over the four weeks. 79% of the schools were widening participation and/or underserved, an increase from 59% in 2018's event. In the ASK section, 342 questions were approved and sent to the researchers and technical staff, who between them wrote 2,072 answers. 63 online live CHATs took place during the event, including four evening CHATs where students could join in from home with their family. An average of six researchers came to each session, giving students a wide variety of roles and people to find out about.The 25 MRC researchers and technical staff were either funded by the MRC, or working within an MRC establishment. On the website, each participant filled in a profile page to share information about themselves, their jobs and their career paths for students to read and start thinking about what to ask them. The profiles also included details about any other MRC Festival activities they were part of. In total, 33 schools took part in live CHATs in the MRC Festival Zone. 26 of those schools (79%) were widening participation (WP) and/or under-served (U), the criteria for which is defined on this website: about.imascientist.org.uk/under-served-and-wp/ Each live CHAT lasts for 30 minutes and involves researchers and technical staff connecting with a class to answer their questions in real-time. Ask questions are sent to the researchers and technical staff outside of the CHATs and can be answered at any time. Across the four-week event there were 63 live CHATs, equalling 29,683 lines of conversation between students and the MRC researchers and technical staff. Students sent 342 approved questions through ASK during the MRC Festival Zone and received 2,027 answers. Compared with a typical two-week I'm a Scientist Zone from June this year, the 4-week MRC Festival Zone reached three times as many schools, offering more students the chance to connect with researchers and technical staff. Students were able to vote each week for their favourite to take home the prize money. At the end of the week, the votes were counted and a Weekly Winner was announced. This change from last year gave participants some measure of how they were doing during the event, and encouraged students to return to the site and keep voting for their favourites each week. The average number of votes per student increased from 0.53 to 0.76. I was the winner of Week 3, and across the fours weeks I provided more answers to students' questions than any other researcher. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://imascientist.org.uk/ |
| Description | MRC LMB Microscopes for Schools Science Image Award |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | The Science Image Award is a friendly image competition for primary schools, aimed at pupils in Year 5/6. The pupils use a hand-held digital microscope (DinoLite) provided free-of-charge for two weeks to take images of biological samples (e.g. insects, plants) that they have collected. The school then submits their best images to an annual competition. The aim of the Science Image Award is to stimulate the scientific curiosity of the children by connecting the microscopic world to everyday life. The winning school will be awarded a prize of a digital imaging system from our sponsor Brunel Microscopes, and the second and third prize winners will receive wooden scopes, at the end of the school year. The winning school will be awarded a digital imaging system. The Science Image Award is open to any primary school in the Cambridgeshire area. I was involved in filming the launch video for the competition. |
| Year(s) Of Engagement Activity | 2019,2020 |
| URL | https://www2.mrc-lmb.cam.ac.uk/microscopes4schools/award.php |
| Description | Media related to Brain publication - 'A daily temperature rhythm in the human brain predicts survival after brain injury' |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Multiple interviews/impacts in relation to Brain paper including UKRI/MRC Press Release, LMB Insight on Research, LMB In The News, Nature Research Highlights, New Scientist, La Recherche, Neue Zürcher Zeitung, The Science Breaker, Frank Luerweg, German radio, social media. Current Altmetric Score = 2389 Highest Altmetric Score for any output in the journal Brain from Cambridge, UK 3rd highest ever Altmetric Score for any output in the journal Brain (3rd out of 7212 articles since Altmetric Scores began) In the top 5% of all research outputs scored by Altmetric Attention breakdown Mentioned by 254 news outlets 10 blogs 700 tweeters 2 Facebook pages 3 Redditors 61 readers on Mendeley Other summary metrics located here: https://oxfordjournals.altmetric.com/details/125575752 Article cited 13 times since June 2022 |
| Year(s) Of Engagement Activity | 2022,2023 |
| URL | https://www.nature.com/articles/d41586-022-01654-7 |
| Description | Podcast about research on the APEX 2020 expedition to Bolivia |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Podcast by Expedition Leader Sophie Hattersley about the research studies on APEX 6, in particular circadian research supported by our lab |
| Year(s) Of Engagement Activity | 2020 |
| URL | https://www.7thairwave.com/single-post51.html |
| Description | See Your Cells at Cambridge Science Festival |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | I helped with the 'See Your Cells' exhibit at the Cambridge Academy for Science and Technology. This enabled members of the public to take a buccal swab of their own cheek cells, prepare and stain a slide of these, and look at them under a microscope. It was also an opportunity for them to ask about our research at the LMB, and for children to look at larger biological specimens using dissecting microscopes. There were people of all ages visiting the stand; they were really excited and surprised to see bacteria in their own cheek cells and this sparked plenty of discussion about the microbes than live on/within our bodies. Many people were also interested to hear about my clinical work with neurological patients which generated much discussion about neurodegenerative disorders, as well as the circadian rhythms research I undertake in the lab. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://www.sciencefestival.cam.ac.uk/ |
| Description | The Brain Podcast - Brain temperature and timekeeping |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | The Brain Podcast is the official podcast of the journals Brain and Brain Communications. In this seventh episode we chat with Dr Nina Rzechorzek, lead author of the article entitled: A daily temperature rhythm in the human brain predicts survival after brain injury We discuss how brain temperature was measured using invasive and non-invasive methods to identify a physiological daily rhythmicity. The loss of this brain temperature rhythm was strongly predictive of survival in patients with traumatic brain injury. Our longest episode to date but packed with fascinating science! This episode was hosted, edited and produced by Xin You Tai; co-hosted by Andreas Thermistecleous; co-produced by Joanne Bell; original music by Ammar Al-Chalabi. |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://sites.libsyn.com/424160/brain-rhythm?tdest_id=3590520 |
| Description | Winner of the SRBR 2022 Biennial Conference Logo Competition |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | SRBR Logo 2022 Time is not lost. With this logo I wanted to capture the chaos and hope of the last two years. The main theme-that biological oscillations are complex, were perturbed by a critical global stimulus, and returned with greater 'robustness' than before-comes with the subtle caveat that all of this is inevitably cyclic. There are several references to oscillatory phenomena, reflecting the rhythms we study and the waves on Amelia Island that I have dreamt about! This dream-like state is psychedelic; an expansion of consciousness that many of us have felt during the isolation and warped reality of a pandemic. Icons on the left represent role reversal-a 'caged human' running fast (but backwards) on a wheel of panic to remain productive, whilst other animals observe the futility of our behaviour, exploiting the freedom they find in this human-free world. Telemetric radiowaves symbolise our remote communication with each other whilst data is collected remotely from us via the global network. After hitting the singularity, the limit cycle of life is ultimately rescued by the boundless support and unshakable optimism of a dog. The colours reflect the light and dark of this period, but are bright and bold to achieve a childlike sense of joy and excitement about the future; a revitalized trajectory driven forward by the next generation of eager scientists. Overall, this is a celebratory thank you to all those who have kept the chronobiology field ticking along through very challenging times, and to my mentor John O'Neill-with a promise that something goodwill eventually emerge from the chaos! |
| Year(s) Of Engagement Activity | 2022 |
| URL | https://srbr.org/2022-logo-competition/ |