To study and manipulate heterogeneous epigenetic states that operate during ageing

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

A central debate in ageing research is whether ageing is simply due to wear and tear, or to a hard coded ageing programme in our genes. While a decline in cellular and organismal functions with age might suggest the former, the large variability observed in the lifespans of closely related species may support the hypothesis that ageing is a regulated process. A number of biomarkers of ageing have been identified, such as telomere erosion and p16 expression. In mammals, ageing is accompanied by global changes in DNA methylation, characterised by global hypomethylation and focal hypermethylation (mainly of CpG islands). Recently, a “clock” was described that can predict human chronological age based on specific changes at a discrete set of CpG sites throughout the genome65. This (DNAm) clock has since been shown not only to predict chronological age ±3.6 years but also biological age, providing a potential measure of an organism’s health in the context of its chronological age. For example, the clock of the liver “ticks” faster in individuals with fatty liver disease. Some organs however such as the cerebellum and potentially the placenta show a different methylation age trajectory.
 
Description We have discovered the first non-human epigenetic ageing clock in the mouse, based on sequencing the methylome in many tissues and at many age-stages. From this we derived a tissue-independent age-predictor. This can predict chronological age +/- 3.3 weeks and also records biological interventions that shorten lifespan, such as for example ovariectomy or high fat diet (PMID 28399939).
We have identified ageing related DNA methylation signatures in mouse liver that are characteristic of lifespan-extending interventions, particularly dietary restriction and reduced TOR signalling (rapamycin treatment) (PMID 30462643).
Exploitation Route We have filed a patent application on the mouse epigenetic clock. This clock could be useful for others who are using mouse models to look for nutritional influences on life expectancy or who are looking to develop life-extending or rejuvenating drugs, especially as the results of certain treatments may already be recorded in the ageing clock at a relatively young age, thus saving time and cost. This patent application has led to a collaboration with a small company, Shift Bioscience, who were partially embedded in our lab in 2018.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

URL https://www.babraham.ac.uk/our-research/epigenetics
 
Description We contributed to a parliamentary POSTNOTE on the ageing process and health. We have successfully applied for a Royal Society science exhibit Race Against the Ageing Clock 2018, and organised this very successful Royal Society exhibit which involved 42 staff members from our Epigenetics ISPG and an audience of 8400 general educated members of the public. We applied for a patent on the mouse epigenetic ageing clock, and embedded a small company who work on the epigenetics of ageing, Shift Bioscience, in our ISPG. Finally, our former PhD student Tom Stubbs established in 2018 the company Chronomics who work on using DNA methylation profiling for health assessment and lifestyle choices.
First Year Of Impact 2018
Sector Healthcare
Impact Types Societal,Policy & public services

 
Description Member SAB Max Planck Institute for Ageing Cologne
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a advisory committee
 
Description Postnote to Parliament on ageing
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description Steering board Human Cell Atlas
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description Flagship
Amount € 1,000,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 02/2019 
End 03/2020
 
Title C elegans Metabolic Reconstruction Model 
Description Merged and re-annotated C elegans Metabolic Reconstruction Model 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? Yes  
Impact This is a great improvement to the C elegans research community 
 
Title PCR Bayes 
Description Novel algorithm to quantify expression and biological variability of steady state transcripts 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact This is a novel tool which extends the capabilities of C elegans researchers to quantitate biological noise in single worms 
 
Title Single cell triple-omics 
Description Single cell triple-omics combining transcriptome, methylome, and chromatin accessibility from the same single cell. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact This method was just published. 
 
Title Transcriptome datasets of reproductive tissues in ageing females (GSE98901) 
Description RNA-seq datasets of trophoblast, endometrium and deciduae of mouse conceptuses developed in young versus aged females 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Significant changes imposed by maternal age on expression profiles of endoemtrial tissue and decidual development. Work shows the impact of the older female on reproductive success, unrelated to oocyte fitness. 
 
Description Collaboration with Linda Partridge and Andreas Beyer 
Organisation Max Planck Society
Department Max Planck Institute for the Biology of Ageing
Country Germany 
Sector Academic/University 
PI Contribution We helped to conceive the study, profiled methylomes and transcriptomes and interpreted data
Collaborator Contribution They helped to conceive the study and provided ageing mouse cohorts with switched dietary restriction
Impact One publication so far (Hahn et al 2017). Multidisciplinary with epigeneticists, ageing researchers, and lipidomics researchers involved.
Start Year 2014
 
Description Collaboration with Oliver Stegle 
Organisation EMBL European Bioinformatics Institute (EMBL - EBI)
Country United Kingdom 
Sector Academic/University 
PI Contribution We conceived the study and provided sequencing datasets and interpretation.
Collaborator Contribution They helped with conceiving the study and provided computational analysis and modelling.
Impact Initial work has been published in Stubbs et al 2017. The work is multidisciplinary involving epigeneticists and computational biologists and modellers.
Start Year 2016
 
Description Collaboration with Sharahgim Tajkbash 
Organisation Pasteur Institute, Paris
Country France 
Sector Academic/University 
PI Contribution Help with single cell sequencing and analysis of muscle stem cells
Collaborator Contribution Collected muscle stem cell samples for sequencing
Impact First paper is in revision. Involves cell biology, organismal biology, computation, epigenetics, sequencing.
Start Year 2017
 
Description Cornelia De Moor 
Organisation University of Nottingham
Department School of Mechanical, Materials and Manufacturing Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution DeMoor lab has brought to us her expertise on RNA technology
Collaborator Contribution DEMoor lab has optimised an LRPAT technology to measure polyA length to C elegans.
Impact DEMoor lab has optimised an LRPAT technology to measure polyA length to C elegans.
Start Year 2016
 
Description Deciduoma 
Organisation National Institute of Environmental Health Sciences
Department Reproductive and Developmental Biology Laboratory
Country United States 
Sector Public 
PI Contribution Characterisation of reproductive defects in older females
Collaborator Contribution Decidualisation model to assess the effect in the absence of an implanting embryo
Impact Collaborative publication (PMID: 28874785)
Start Year 2016
 
Description Development of computational methods for the quantification of biological variability 
Organisation EMBL European Bioinformatics Institute (EMBL - EBI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of an algorithm based on Bayesian statistics that quantifies variability in steady state levels of mRNA from nanofluidics-based PCR.
Collaborator Contribution Development of an algorithm based on Bayesian statistics that quantifies variability in steady state levels of mRNA from nanofluidics-based PCR.
Impact It is a multi-disciplinary collaboration involving high end PCR technology and statistical modelling.
Start Year 2015
 
Description Human Cell Atlas 
Organisation Broad Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Contributed to formulating the white paper of the Human Cell Atlas.
Collaborator Contribution Conceived the project and brought the international consortium together.
Impact The white paper was published Regev et al 2017. It involves single cell biologists and computational and modelling scientists.
Start Year 2016
 
Description Jesus Gil senescence 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Contributed single cell sequencing and analysis.
Collaborator Contribution Conceived and conducted the study.
Impact Publication Aarts et al 2017. Involves senescence biologists, single cell biologists, computational biologists.
Start Year 2016
 
Description Jurkowski 
Organisation University of Stuttgart
Country Germany 
Sector Academic/University 
PI Contribution Helped with reagents and interpretation.
Collaborator Contribution Conceived and conducted study.
Impact Publication Stepper et al 2017. Involves biochemists, epigeneticists.
Start Year 2016
 
Description Kosuke Yusa 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We have together conceived and conducted experiments to identify new regulators of human pluripotency and reprogramming using genome-wide genetic screens.
Collaborator Contribution Our partner provided expertise about the screen design, provided the cell line and lentiviral library, and sequenced the DNA samples.
Impact Manuscript in preparation.
Start Year 2017
 
Description Ludovic Vallier 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution We are working jointly on investigating the role of TGFb signalling in the control of human pluripotent states.
Collaborator Contribution Our partner provided expertise in TGFb signalling, contributions to experimental design, conducted experiments, and were jointly involved in interpreting results.
Impact The major output so far is the collection of data.
Start Year 2018
 
Description Sean Bendall 
Organisation Stanford University
Country United States 
Sector Academic/University 
PI Contribution We are working together to devise new ways to measure and understand heterogeneity in human pluripotent cells, including being able to associate protein, epigenetic and signalling variability in the same individual cells.
Collaborator Contribution Our partner is a leader in the field of mass cytometry and is contributing to the experiment design and execution, including data analysis.
Impact This collaboration led to additional funding through the BBSRC UK - USA Partnership Award.
Start Year 2017
 
Description Tony Green 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Helped with single cell RNA sequencing and interpretation.
Collaborator Contribution Conceived and conducted the study.
Impact Published Kirschner et al 2017. Haematologists, single cell biologists, ageing biologists.
Start Year 2016
 
Description Uterine pathologies and maternal age 
Organisation University of Edinburgh
Department MRC Centre for Reproductive Health
Country United Kingdom 
Sector Public 
PI Contribution Molecular assessment of changes occurring in older females
Collaborator Contribution Pathological characterisation and assessment of uterine pathologies that become more frequent with age
Impact Collaboration established. Application for future funding in progress.
Start Year 2017
 
Title Novel Age Calculation Method 
Description Method to calculate methylation age 
IP Reference WO2018146482 
Protection Patent application published
Year Protection Granted 2017
Licensed Yes
Impact Too early as this started in 2018
 
Description Babraham Schools day 2018 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Experiments on epigenetics for local 6th form schools
Year(s) Of Engagement Activity 2018
 
Description Cambridge Epigenetics Club 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact 150 people attended an evening of scientific presentations and networking as part of the Cambridge Epigenetics Club. This happens ~6 times per year. I organise these events with colleagues at the University of Cambridge, and the Club is sponsored by Abcam. The main outcomes are to bring together people from academia, industry, schools, and the general public to interact and discuss cutting edge epigenetics research.
Year(s) Of Engagement Activity 2018,2019
URL https://www.abcam.com/events/cambridge-epigenetics-club
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Babraham Institute exhibit on the Epigenetic Ageing Clock presented at the Cambridge Science Festival, involving activities and question/answer interactions with members of the public
Year(s) Of Engagement Activity 2018
 
Description Computational Modeling in Biology Network 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I created COMBINE to coordinate the development of standards in computational systems biology. The initiative includes several workshops a year (discussion of future standards, implementation of current standards, and end-user training), diffusion lists, social media dissemination.
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015
URL http://co.mbine.org
 
Description GENIE network of C elegans researchers 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Joining this pan european network has allowed us to attend conferences, network with other C elegans labs across Europe and obtaining funding to organise a workshop on C elegans metabolic reconstruction.
Year(s) Of Engagement Activity 2015,2016,2017,2018
 
Description GENiE workshop "Extending the consensus representation of C. elegans metabolism" 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact https://www.helmholtz-muenchen.de/genie-workshop-2017/program/index.html
Year(s) Of Engagement Activity 2018
URL https://www.helmholtz-muenchen.de/genie-workshop-2017/program/index.html
 
Description Invited speaker to a conference: "Systems biology of model organisms" 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited speaker at workshop "Systems biology of model organisms" held in Bordeaux, France.
Year(s) Of Engagement Activity 2019
 
Description Nine invited presentations at international meetings, including EMBO, FASEB, Keystone, American Association for Cancer Research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Conference presentations about our research
Year(s) Of Engagement Activity 2018
 
Description Organisation of C.elegans Cambridge local area meetings 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact An audience of about 10-15 science labs from around the Cambridge area attend these events, including many PhD students and postdocs. The aim of these meetings is dissemination of techniques and science as well as networking.
Year(s) Of Engagement Activity 2015,2017,2018
 
Description Partcipation in The Future of Ageing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A representative of the Casanueva lab attended a debate on the future of gein at London School of Economics geared towards general public.
Year(s) Of Engagement Activity 2018
 
Description Presenter and organising committee for RSSE exhibit "Race Against the Ageing Clock" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Major exhibit at the Royal Society Summer Exhibition, also at Cambridge Science Fare and other events. Based on research from Reik lab and Babraham scientists on the discovery of mouse ageing clock. Involved scientists at all levels from Babraham discussing ageing research with scientifically engaged public. RSSE was attended by ~8000 people, and the Babraham Exhibit was popular and busy, resulting in numerous discussions of the ageing process and the potential for therapeutic approaches to ageing at all levels with members of the public.
Year(s) Of Engagement Activity 2018
URL https://royalsociety.org/science-events-and-lectures/2018/summer-science-exhibition/exhibits/ageing-...
 
Description Royal Society Summer Exhibition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Babraham Institute exhibit on the Epigenetic Ageing Clock as invited entry presented at the Royal Society Summer Exhibition, involving activities and question/answer interactions with members of the public, fellows of the Royal Society, policymakers
Year(s) Of Engagement Activity 2018
 
Description Savile Club epigenetics talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presentation about epigenetics at the London Savile Club
Year(s) Of Engagement Activity 2018
 
Description Sophianum School collaboration - Technasium 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact The Babraham Institute is continuing to coordinate activities supporting its commitment as a signatory of the Concordat on Openness on Animal Research. Institute staff, including animal unit managers, have been working closely with a school in the Netherlands to prepare and launch the Institute's contribution to the national 'Technasium' education programme, which aims to draw together students and industry.

Two projects, developed in collaboration with the Institute's Public Engagement team and teachers from the Sophianum School in Gulpen, will challenge students to research and design systems to improve the efficiency and safety of animal care systems. A third project will require the students to research how legislation regulating the use of animals in science, as well as public opinion, can vary throughout Europe and the world.

A two-day visit on 19th & 20th May will kick-start a 10-week programme for the 15-year old students, who will work in teams and compete to design the best solutions to the challenges. The Institute's animal technicians will monitor student progress by commenting on YouTube videos posted fortnightly by the teams. Regular video calls into the animal unit and the Institute's laboratories will allow live discussion between the students, the animal technicians and the scientists who use animals as part of their research.

The challenge projects will finish in July, with the winning Sophianum team coming to the Babraham Institute as part of their prize. The students will visit Institute animal facilities and will get a chance to see the award-winning camera system which displays live feeds from the facility - allowing groups to appreciate first-hand both the animal care environment and the nature of working within an animal research unit.

This pilot project will also involve sixth-form students at the school who will learn about the Institute's research and take part in workshops to discuss the ethics of the use of animals in science. The Institute has been running ethics workshops for secondary and sixth form students since 2005, with contributions from Understanding Animal Research, the European Animal Research Association and the Institute of Animal Technology.

The success of the Technasium project will be evaluated by both the Institute and Sophianum School, with a view to developing future challenges.
Year(s) Of Engagement Activity 2017,2018
 
Description SysMod 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I organised the 2nd meeting of the ISCB Community of Special Interest SysMod. Up to 270 people attended depending on the talk.
Year(s) Of Engagement Activity 2017
 
Description Talk at Cambourne Library 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 15 general audience attended an Epigenetics presentation and discussion
Year(s) Of Engagement Activity 2018
 
Description UKRI launch 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact UKRI launch event 2018
Year(s) Of Engagement Activity 2018
 
Description WT/EBI course in silico systems biology 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact I organised this one-week course, and gave presentations entitled: "What is Systems Biology? Where does it come from?", "The many faces of modelling in biology", "Modelling in systems biology, a few challenges", "From art to engineering: two decades of standards and tools towards digital organisms", "Modelling chemical kinetics" plus a tutorial on stochastic simulations of biological systems.
Year(s) Of Engagement Activity 2017
 
Description Wellcome Genome Campus Cell Fate Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact This was an invitation only workshop organised by us on the Hinxton campus which brought together some of the international leaders working on cell fate biology and pathology.
A meeting report was produced subsequently.
Year(s) Of Engagement Activity 2018
 
Description eLife Community Webinar - Refreshing approaches to researcher evaluation 
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 I animated a webinar discussing various ways to bypass the traditional publication-based evaluation of researchers.
Year(s) Of Engagement Activity 2017