2017 Babraham Institute Annual Research Report The world’s ageing population is a Global Grand Challenge facing us all and affecting governments, Life sciences healthcare and research worldwide. In the UK, nearly 1 in 5 people are now over 65 and this is expected to rise to 1 in 4 by 2050. We’re living much longer than ever before, but we’re not living healthier. Our bodies still decline into old age at around the same point that they always have, a concept called healthspan. If our research for society is to keep functioning, we must find ways to extend our healthspan soon.
The Babraham Institute unites wide-ranging expertise in fundamental biology to address these challenges. lifelong health We aim to gain a detailed understanding of ageing and lifelong health by studying epigenetic changes to gene regulation, investigating how cells respond to diet and their environment and examining the role of the immune system in health throughout our lives.
2 3 Contents
1 2 3 4 5 Immunology Signalling Epigenetics Nuclear Dynamics Facilities
Director’s welcome 6-7 The persistence and activation PI3K enzyme signalling within cells 22 Epigenetic reprogramming in Structure and function of Bioinformatics 54 of lymphocytes 12 development and ageing 34 the genome 44 Performance in 2017 8-9 Signals controlling cell Biological Chemistry 55 Maintaining a healthy fate decisions 23 Stress, metabolism and effects on Making enough different antibodies Impact: immune system 13 healthy ageing 35 to fight infection 45 Biological Support Unit 56 Engaging with our research 64-67 Autophagy pathways: How white blood cells respond cell eating from inside and out 24 The effect of age on womb Keeping genes silent 46 Flow Cytometry 57 to vaccination 14 function and pregnancy 36 Dynamics of autophagy in Mechanisms of genome Gene Targeting & PI3K proteins in immunity, animal cells 25 How cells interact with architecture 47 Genome Editing 58 infection and cancer 15 their environment 37 Modelling biological systems 26 The logic of gene regulation Imaging 59 Moderating the reactions Epigenetic legacies from eggs 38 from a distance 48 of the immune system 16 Understanding how fats Lipidomics 60 keep us healthy 27 Epigenetic regulation of How the environment Research feature: human development 39 changes genome function 49 Mass Spectrometry 61 Vaccinations: a Global Challenge 18-19 Cell signalling through Rho-GTPase and GEF proteins 28 Research feature: Research feature: Next Generation Sequencing 62 Informing Policy on Ageing 40-41 The Sounds of the Genome 50-51 Research feature: Making the Most of Signalling Research 30-31
4 www.babraham.ac.uk 5 Director’s welcome
Each year, the Babraham Institute’s cutting-edge research pushes the boundaries of what we know about fundamental human biology. In line Our Science with the BBSRC Strategic Priority: Science for Health, our mission is to tackle the challenges of an ageing population by making discoveries that 2017 has been a time of change for the Institute, but this has not diminished our position as a world-leading 119 enhance lifelong health and wellbeing. centre of excellence and this year has produced some outstanding highlights. We have developed a means to study the epigenetic clock in mice providing a new way to understand and measure ageing (1), devised a system This Annual Research Report is a collection of the ground-breaking progress the Institute has made in 2017 and our plans for the future. VISITING RESEARCHERS for tracking stem cell development (2), made discoveries about the dynamics of DNA (3) and uncovered a new Through the Feature articles included, we explore how the Institute maximises its impact by working with industry, academia, politicians and mode of cell cannibalism (4). As we move into 2018, I look forward to welcoming new research groups who we the public to share our findings and use our research to drive meaningful changes and greater scientific awareness. will be recruiting to join the Institute and lead our research in exciting new directions. Our Facilities We are privileged to have nine outstanding scientific facilities which have provided peerless support to 118-19 2 30-31 3 40-41 4 50-51 researchers at the Institute and beyond throughout 2017. Together with our research groups they have Vaccinations, Making the Most of Informing Policy The Sounds of developed techniques and tools to address specific research challenges and many of these are being used by Research features: a Global Challenge Signalling Research on Ageing the Genome researchers worldwide. The specialised training sessions offered by the facilities attract delegates from from far afield and continue to be in high demand from both academia and industry. 96 Our Impacts PUBLICATIONS The Institute’s impact activities through knowledge exchange, commercialisation, public engagement and communications have had many successes through the year. In particular, 2017 saw the Institute host the Ageing Cell conference attracting renowned specialists in ageing research from across the world. Events like this emphasise the Institute’s focus on collaboration and on working at a global scale to drive scientific progress and wider impacts. Towards the end of the year we were also thrilled to win an award for Openness in Animal Research from Understanding Animal Research in recognition of our school outreach work. 130 COMMERCIAL PROJECTS
Key Awards I hope you enjoy discovering more about n Institute Director, Professor Michael Wakelam was awarded the prestigious Morton the Institute and our Lectureship by the Biochemical Society research as you read n Dr Rahul Roychoudhuri was awarded a Lister Prize by the Lister Institute for this report. Preventive Medicine
Professor Michael Wakelam n Dr Peter Rugg-Gunn successfully secured his tenured position in the Institute’s Institute Director Epigenetics Programme Professor Michael Wakelam Institute Director
Publications More Institute press releases at www.babraham.ac.uk/news
1. Tick Tock, stay ahead of the ageing clock! https://www.babraham.ac.uk/news/2017/04/tick-tock-stay-ahead-of-the-ageing-clock 2. A Tale of Two States https://www.babraham.ac.uk/news/2017/03/a-tale-of-two-states 3. Genetic DJ: Growing cells remix their genes https://www.babraham.ac.uk/news/2017/07/genetic-dj-growing-cells-remix-their-genes 4. Cannibal cells may limit cancer growth https://www.babraham.ac.uk/news/2017/07/cannibal-cells-may-limit-cancer-growth
6 7 Performance in 2017 2017 income 2017 successes
Working with others in 2017 £3.2M £31M OUR COLLABORATIVE £6.5M £10.7M Core ISP grants & BBSRC ACADEMIC PROJECTS non-grant income 44 31 111 Competitively awarded 50 ACTIVE PROJECTS COUNTRIES ORGANISATIONS grant income in 2017 UK AND WORLDWIDE £10.7M Income from services PUBLIC ENGAGEMENT EVENTS provided by the Institute Other INVOLVING 130 Working with commercial partners Value of all grants awarded in 2017 RESEARCHERS
IP AGREEMENTS 9,000 £0.9M PEOPLE ENGAGED CONSULTANCIES £4.4M UK funders £3.5M International grants* COLLABORATIONS 96 0 10 20 30 40 50 60 70 PUBLICATIONS NEW IN 2017 79 RESEARCH PUBLICATIONS 17 Value of UK grants awarded in 2017 REVIEWS People we’ve trained in our scientific facilities this year
Openness on Animal Research £0.5M £1.3M £3.6M INFORMAT CYTOME IMAGING IO ICS LOW TR BBSRC Awards 2017 Winner B F Y £1.7M MRC £0.6M Cancer Research UK Wellcome Trust £0.8M Lister Institute of Preventive Medicine Innovative UK Rosetrees Trust
*International grant sources: 11 1167 927 140 100 European Commission (EC), European Molecular Biology Organisation (EMBO), SENS Research Foundation PhDs COMPLETED 8 9 110-19 Immunology Group leaders The immune system includes cells called lymphocytes, a type of white blood cell, that defend the body from infections including bacteria, viruses and fungi as well as cancer. As we age, the immune system tends to weaken and this contributes to the increased risk of illness during old age. A weakened immune system also means that older people don’t always respond fully to vaccinations. By studying a combination of human samples and mouse models we aim to enhance our understanding of the role of lymphocytes in the immune system. We do this by examining: n The mechanisms linking ageing to reduced response to vaccinations n How lymphocytes interact with cells in the lungs to prevent infections n How different molecular signals influence gene activity and ultimately the growth and Martin Geoff Michelle Klaus Rahul behaviour of lymphocytes Turner Butcher Linterman Okkenhaug Roychoudhuri
10 11 Immunology
The persistence and activation of lymphocytes Maintaining a healthy immune system
We study molecular mechanisms that Progress in 2017 Defending the body from disease regulate changes in gene expression We showed that, in B cells, the RBP requires an effective immune system needed to produce, maintain and encoded by the Zfp36l1 gene was with stable populations of mature T activate cells, called lymphocytes, in essential for the survival of a subset of B and B lymphocytes – types of white the immune system. Our work focuses lymphocytes called Marginal Zone B cells. blood cells. A group of proteins Martin Turner Geoff Butcher on the role of proteins that bind to It suppressed genes normally expressed by called GIMAPs, play an important but messenger RNA – molecules that other types of B cells and so contributed ill-understood role in ensuring there Group members provide the essential intermediate to the maintenance of cellular identity. We Group members are always enough of these cells. By Senior research associates: step in information transfer from DNA identified that another RBP, TIA1, binds Postdoctoral researcher: studying GIMAPs we can improve our Sarah Bell to proteins. These proteins regulate to and suppresses mRNA encoding the John Pascall understanding of lymphocyte survival Manuel Diaz-Munoz how lymphocytes behave by exerting tumour suppressor p53. DNA damage and discover new opportunities to treat Research assistant: (Left in 2017) quantitative and qualitative control on released p53 mRNA from control by TIA1. Silvia Innocentin certain diseases. messenger RNA. This led to an increase in p53 proteins Postdoctoral researchers: Scientific History Elisa Monzon-Casanova as part of the DNA damage response. Current Aims Dr Butcher is in the process of concluding Cesare Sala We also showed that the polypyrimidine We study RNA binding proteins (RBPs) his work on GIMAPs in preparation for (Left in 2017) tract binding protein was critical for the Structured Illumination Microscopy (SIM) images because they control gene expression retirement in 2019. Having joined the Alexander Saveliev selection of B cells in the germinal centre. for the RNA binding proteins ELAVl1 (red) and DCP1 firstly by regulating the abundance of the Institute in the late 1970s, he has led a Michael Screen It regulated alternative splicing of genes (green) with DNA stained in blue in activated B Ram Venigalla mRNA produced by a gene and secondly lymphocyte cells group here since 1987 and served as Head needed for rapid B cell proliferation. by controlling the types of mRNA produced of Immunology during the late 1990s. PhD students: through processes such as alternative Fengyuan Hu His group has made significant and long- splicing and polyadenylation. The activities Twm Mitchell Selected Impact Activities lasting contributions to understanding (Started in 2017) of RBPs are regulated by systems that n Part of the EU H2020 COSMIC the immune system and its role in David Turner sense changes in the cellular environment. Consortium aiming to develop human health. Amongst these, work with Moreover, these systems integrate Visiting students: ways to combat diseases of the Jonathan Howard and Nobel Prize-winner signal transduction with epigenetic and Irene Salvia immune system César Milstein led to what became known transcriptional control (the rate at which Eugenie Werbenko as the first ‘useful’ monoclonal antibodies. mRNAs are produced) to enable dynamic n Hosted projects for the Institute Research assistants: For the first time homogeneous antibody changes in gene expression and the Schools’ Day Kirsty Bates reagents could be produced to specifically maintenance of stable cellular states. Vanessa D’Angeli n Developing a partnership with target any chosen molecule and were These are fundamental processes for (Started in 2017) CRT and Celgene a key step towards revolutionary all cells and our focus is on how RBPs antibody therapies. An artistic representation of an antibody regulate immunity. A second major contribution, again with lymphocytes are dependent on GIMAP1 Meanwhile, work on GIMAP6 demonstrated Jonathan Howard, was the discovery for their survival. The investigation showed that it has a role in autophagy – a process of the TAP peptide transporter, which that losing GIMAP1 from lymphocytes of destruction often used to recycle is involved in how cells alert CD8+ T leads to fatal damage, which appeared to old or damaged parts of a cell – inside lymphocytes to potential illnesses. be initiated inside mitochondria – the lymphocytes. Its absence leads to an power plants of the cell. How GIMAP1 intermediate T lymphocyte deficiency. Progress in 2017 normally supports mitochondrial health Like GIMAP1, it may also influence Recent work has concentrated on two is currently unknown. mitochondrial health by preventing of the GIMAPs. Work on GIMAP1 has autophagy from removing damaged or shown that essentially all mature T and B unnecessary mitochondria.
Publications www.babraham.ac.uk/our-research/lymphocyte/martin-turner Publications www.babraham.ac.uk/our-research/lymphocyte/geoffrey-butcher
n Datta et al. (2017) Survival of mature T cells in the periphery is intrinsically dependent on GIMAP1 in mice. Eur J Immunol. 47:84-93 n Newman, R. et al. (2017) Maintenance of the marginal zone B cell compartment specifically requires the RNA binding protein ZFP36l1, Nat. Immunol. 18(6):683-693 n Díaz-Muñoz, M.D. et al. (2017) Regulation of mRNA translation and subcellular location controls protein synthesis of key modulators of the DNA damage response during B cell activation, n Pascall et al. (2018) GIMAP6 is required for T cell maintenance and efficient autophagy in mice. PLoS ONE (accepted for publication). Nat. Commun. 8(1):530. PMID: 28904350 n Monzón-Casanova, E. et al. (2018) The RNA binding protein PTBP1 is necessary for B cell selection in germinal centers, Nat. Immunol. 19, 267–278
12 13 Immunology
Klaus Okkenhaug has now left the Institute to take up the Chair of Immunology at the Department of Pathology, University of How white blood cells respond to vaccination Cambridge. He is pleased to have spent 15 wonderful years at the Babraham Institute.
Our ageing population creates a new Current Aims is the collaboration of multiple cell types: challenge for medical science; to At the heart of the immune response proliferating B cells, T follicular helper cells PI3K proteins in immunity, infection and cancer facilitate healthy ageing. With age, to vaccination is the germinal centre (Tfh), T follicular regulatory cells (Tfr) and the function of the immune system (GC) – a dynamic structure that forms follicular dendritic cells. Our research aims The PI3K family of enzyme proteins declines, rendering older people in secondary lymphoid tissues (lymph to understand the function of these cell Michelle Linterman Klaus Okkenhaug control many aspects of immune more susceptible to infections and nodes) after immunisation, and produces types in a normal response to vaccination, function. PI3Ks are required for the less able to benefit from vaccination. long-lived plasma cells and memory B cells. and to determine how this changes with normal development and survival of Group members Group members Our research aims to understand how Plasma cells secrete antibodies that block advancing age. lymphocyte immune cells. They also Research fellow: the immune system changes with pathogens from establishing an infection Research fellows: Progress in 2017 allow the immune system to respond Alice Denton age, to determine if we can improve and memory B cells ensure long-term Anita Chandra In the past year our team has extensively to and protect against infections and vaccination efficacy in older people. immunity. A defining property of the GC Andrew Conway Morris Postdoctoral researchers: characterised the cellular changes that cancer. We aim to better understand Alexandre Bignon occur in the GC response with advancing Postdoctoral researchers: how drugs that target specific PI3Ks can (Left in 2017) age in mice. We have been able to confirm Krishnendu Chakraborty best be exploited for clinical benefit. Edward Carr Fabien Garcon our findings from animal models by Danika Hill (Left in 2017) Current Aims Wim Pierson running human influenza vaccination Birthe Jessen We aim to understand how the PI3Ks (Left in 2017) studies, and assessing the behaviour of (Left in 2017) control the development and function of Louise Webb human cells in culture. We have found Amy MacQueen the immune system. Much of our work that not all cell types are weakened in (Left in 2017) PhD students: has focused on the role of the PI3Kδ older individuals and we have shown that Priya Schoenfelder isoform which is found in many cells of Marisa Stebegg Anne-Katrien Stark Alyssa Silva-Cayetano dendritic cells and CD4+ helper T cells the immune system. PI3Kδ is the target Ine Vanderleyden have impaired activation with age. In PhD students: for the drug Idelalisib which is now the next year, we aim to understand the Rafeah Alam approved for the treatment of certain Visiting students: molecular basis that underpins reduced Christina Courreges Nathan Benac immune cell cancers affecting B cells. cellular function. Fiorella Cugliandolo However, many questions remain about (Left in 2017) Saad Idris the impact of PI3Kδ inhibition on different Clotilde Hennequin (Left in 2017) Mouse bone marrow stained for hematoxylin and eosin. The image contains mutated B lymphocytes that cause (Left in 2017) Ai Hui Doreen Lau types of cell in the immune system, lymphomas. Selected Impact Activities both in health and diseases. Moreover, Research assistants: Daisy Luff n Television interview with BBC Look the recent discovery of patients with a Sigrid Fra-Bido This has allowed us to identify cellular and East (West) Research assistant: primary immunodeficiency syndrome (Started in 2017) Bahram Firouzi biochemical mechanisms that contribute Selected Impact Activities Silvia Innocentin (called APDS) caused by over activation of n Presentation of our human (Left in 2017) to immunodeficiencies in APDS. In parallel, n Wellcome Trust Clinical Fellowships PI3Kδ raises further questions about the vaccination work to the public at our colleagues at GSK have initiated a for Anita Chandra and Andrew physiological role of this enzyme. the Cambridge BioResource Open clinical trial using their PI3Kδ inhibitor Conway Morris evening Progress in 2017 nemiralisib. This demonstrates the n Klaus Okkenhaug appointed as relevance of our work using genetic models This image shows the localisation of different immune cells in a mouse Peyer’s patch. Peyer’s patches are lymphoid n Multiple presentations of our We have developed a mouse model Professor of Immunology at the organs in the lining of the intestine. Here, B and T cells participate in the so-called germinal centre response to inform the development and use of work at the 19th Germinal Centre of APDS and shown that it reproduces University of Cambridge to produce antibodies in response to the gut microbiota. Naïve B cells are shown in orange (anti-IgD), while novel therapeutics. Conference, Venice, Italy many aspects of the human disorder. proliferating cells – including germinal centre B cells – are blue (anti-Ki67). All T cells are stained green (anti-CD3) n Organised Keystone Meeting: PI3K and regulatory Foxp3+ T cells can be recognised by their purple centre (anti-Foxp3). Pathways in Immunology, Growth Disorders and Cancer
Publications www.babraham.ac.uk/our-research/lymphocyte/michelle-linterman Publications https://www.path.cam.ac.uk/directory/klaus-okkenhaug/
n Coulter, T.I. et al. (2017). Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: A large patient cohort study. J Allergy Clin. Immunol. 139, 597-606 e594 n Fonseca, V.R. et al. (2017) Human blood Tfr cells are indicators of ongoing humoral activity not fully licensed with suppressive function, Sci. Immunol. 2(14) n Kishore, M. et al. (2017). Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis. Immunity 47, 875-889 e810 n Bignon, A. et al. (2017) Escherichia coli Heat-Labile Enterotoxin B Limits T Cells Activation by Promoting Immature Dendritic Cells and Enhancing Regulatory T Cell Function. Front. Immunol., 8:560 n Mauro, C. et al. (2017). Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4(+) T Cell Differentiation via PI3K p110delta-Akt-Mediated Signals. Cell Metab. 25, 593-609 n Vanderleyden, I. and Linterman, M.A. (2017) Identifying Follicular Regulatory T Cells by Confocal Microscopy. Methods Mol. Biol. 1623:87-93
14 15 Immunology
Moderating the reactions of the immune system
Progress in 2017 An international collaboration with scientists in the US and UK has led us to discover a human disease called BACH2-related immunodeficiency and Rahul Roychoudhuri autoimmunity (BRIDA). This disease results from changes to the BACH2 gene, which we Group members found is required for the differentiation of Postdoctoral researchers: Treg cells and long-lived memory cells. Teresa Lozano (Started in 2017) We have developed tools to monitor key Rabab Nasrallah factors involved in early and late Treg cell specification at a single-cell level PhD students: (see figure) and examined epigenetic Francis Grant factors involved in this process. We have Charlotte Imianowski (Started in 2017) gained insights into how dysfunction of Firas Sadiyah T cells and myeloid cells contributes to immunosuppression. We are developing Visiting researchers: powerful CRISPR-Cas9 based approaches Shaun Png Flow cytometry results showing different amounts of proteins inside individual cells. Bach2 and Foxp3 are to systematically examine the control of T (Left in 2017) both proteins that control gene expression in cells called CD4+ thymocytes when they begin specialising to Michaela Pucci become Treg cells. Both proteins play essential roles in the development of Treg cells. Appropriate development cell functions. (Left in 2017) and maintenance of Treg cells populations is required throughout the lifecourse to prevent otherwise lethal Panagiota Vardaka inflammation. (Started in 2017) Selected Impact Activities Volunteer: n We were awarded a Lister Institute Melanie Stammers Effector T cells (Teff) of the immune Current Aims (Left in 2017) system can prevent infections and 1. To determine the control processes that Research Prize recognising the cancer but they can also cause influence gene expression and guide medical significance of our work autoimmune and allergic inflammation. the production of the cells involved in on tolerance These harmful responses are restrained tolerance and immunosuppression, n We received funding from by tolerance mechanisms, which called regulatory T (Treg) cells Cancer Research UK (CRUK) to prevent harmful and potentially 2. To establish the role of enhancers in support collaboration between lethal inflammatory responses. cell type-specific gene expression the Institute and CRUK-Therapeutic While tolerance mechanisms are and regulation of the production and Discovery Laboratories to develop beneficial, a similar process – called function of Treg and effector T (Teff) new therapies immunosuppression – restricts the immune system’s ability to tackle 3. To understand how Teff cells are n We hosted students as part of chronic infections and cancer. We study regulated and constrained by Schools’ Day, using flow cytometry molecular mechanisms of tolerance and their surroundings, particularly in to spot the differences between immunosuppression, their effects as we immunosuppressed tissues such as groups of cells age and their roles in disease. within tumours
Publications www.babraham.ac.uk/our-research/lymphocyte/rahul-roychoudhuri n Afzali, B. et al. (2017) BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat Immunol 18:813-823 n Igarashi, K. et al. (2017) BACH transcription factors in innate and adaptive immunity. Nat Rev Immunol 17:437-450
16 17 Immunology
‘Our immune system is Vaccinations: amazingly complex and a Global Challenge continues to pose significant scientific challenges’
The Institute’s research is having a major impact on global public health. Although the first take part in research and who terms – why people respond so vaccines were developed more than two centuries ago, infectious diseases such as malaria have already donated DNA. differently to existing malaria “The Cambridge Bioresource is a vaccines, and discover whether and influenza still affect millions of people each year. By improving our understanding of phenomenal research resource; it new adjuvants could make malaria the immune system and its response to modern vaccines, the Institute is paving the way for allows us to design much smarter vaccines more effective. After better vaccines that will protect more people from life-threatening diseases. studies because we can select people analysing samples from children with particular genotypes and recruit vaccinated with RTS,S (which is the people to studies much more quickly best malaria vaccine on the market than before.” but one with plenty of room for improvement), the team uncovered These studies are revealing why older When it comes to human health, in the Institute’s Immunology Most malaria vaccine trials are run in important differences in the immune people produce fewer antibodies our immune system is our most research programme, is making European populations, and success cells of children who respond well after ‘flu vaccination, opening up important defence against illness important advances in both. here often fails to translate to those to the vaccine compared with those new ways of making vaccines more and disease. Producing antibodies in most need – the people who live who do not. They also made new “One of our major goals is to effective. “We’ve run two studies is one of the ways that the immune in malaria-endemic areas. discoveries in the adjuvant trials. improve vaccine efficacy as we age. showing that the T cell response is system counteracts pathogens – the The seasonal ‘flu vaccine provides Most vaccines provide protection impaired,” she says. “And now we “We’ve just finished a study in young causes of illness. Yet, this system is 80% protection against infection against infection via production of know where the cellular defect lies, Africans that clearly shows that a new not perfect. Sometimes the body if you’re aged between 18 and 60. antibodies, the proteins our immune it should be possible to change adjuvant does a good job of boosting produces antibodies against the Over the age of 60 vaccine efficacy cells secrete. In ‘flu, for example, the adjuvants – the ingredients in T cells,” she concludes. “Being wrong things – resulting in allergies, decreases – and for people over 70 these antibodies bind to the virus vaccines that stimulate the immune involved in trials of new adjuvants autoimmune diseases and organ it’s only 25% effective,” she explains. and prevent it from infecting our system – to boost these T cells.” is very exciting. Our research shows rejection – while at other times it “This does not mean that older cells. At the same time, antibodies that these adjuvants could help boost fails to produce enough antibodies Thanks to support from the Global people shouldn’t get vaccinated, signal to other immune cells to the T cell response after vaccination to fight infections including malaria Challenges Research Fund, Michelle is because complications associated destroy the virus. Our immune in older people, and it illustrates that and influenza. And as we age, our working on large-scale collaborative with ‘flu can be very serious. But it systems are very diverse, which our fundamental science is crucial immune system becomes less vaccine trials in malaria-endemic does mean there’s an opportunity helps to protect us from pandemics, to delivering better vaccines across adept at combatting infection and Tanzania and Mozambique. Her aim to improve the way these vaccines but complicates vaccination the world.” responding to vaccination. is to understand – in immunological work for older persons.” programmes as individual responses As well as being extraordinarily to vaccines are very variable. Part of the problem arises from powerful, our immune system is how clinical trials have traditionally What’s needed is more cleverly- amazingly complex and continues been run. Almost all immunology designed trials, which is exactly to pose significant scientific research – including vaccine trials what Michelle and her team are challenges. Key among these is how ‘Our fundamental science is crucial to – is done in young animals and doing in both Cambridge and to design ‘flu vaccines that are more people; what’s lacking is research East Africa. To design better ‘flu delivering better vaccines across the world’ effective in an ageing population, in the populations that vaccines studies, she’s using the Cambridge and how to boost the efficacy of most need to protect. This is true Bioresource, a unique panel vaccines to prevent malaria. Dr not only of ‘flu but in malaria too. of 17,000 volunteers willing to Michelle Linterman, a Group Leader
18 19 220-31 Signalling Group leaders The process of cell signalling consists of several interconnected mechanisms that allow cells to communicate, co-ordinate and respond rapidly to change. By examining these signalling mechanisms and their interactions we seek to understand the effects of signalling on cell growth, survival and behaviour. Our current focus is to discover the role that signalling has in helping cells to respond and adapt to damage, illness, dietary changes and ageing by investigating: n How cells called neutrophils detect and respond to infections n How changes in diet affect metabolism and growth n The effect of signalling mechanisms on the rate of ageing n The role of autophagy in recycling cell components following damage or starvation Len Simon Oliver Phill Nicholas Nicolas Michael Heidi Stephens Cook Florey Hawkins Ktistakis Le Novère Wakelam Welch
20 21 Signalling
PI3K enzyme signalling within cells Signals controlling cell fate decisions
Signalling pathways are biological Current Aims 3. Investigating the chemical details of Information from a cell’s surroundings systems that allow cells to communicate Our work covers three aspects of why PI(3,4,5)P3 and PI(3,4)P2 have contribute to how it behaves and how it and respond to changes in their PI3K signalling. such significant effects inside cells. will change in the future – called cell fate surroundings. This can include changes In addition, we are developing mass decisions. Proteins called protein kinases in the levels of hormones, growth 1. Understanding how phosphatase spectrometry approaches to better influence cell fate decisions – whether Len Stephens Simon Cook factors or nutrients. One such signalling enzymes regulate signal strength and measure PI(3,4,5)P3 and PI(3,4)P2 for to divide, change cell type or die – by Programme leader pathway involves the production of duration by reducing levels of PI(3,4,5)P3 research and clinical purposes. transmitting information from the chemical signals called PI(3,4,5)P3 and PI(3,4)P2. Group members outside into the cell. We are interested in Progress in 2017 and PI(3,4)P2 by proteins called Senior research associates: how protein kinase pathways function, 2. Examining the differences between We have identified a role for the tumour phosphoinositide 3-kinases (PI3Ks). Kathy Balmanno how they are controlled and how they PI3K isoforms to inform pharmaceutical suppressor PTEN as a major regulator of This pathway plays a major role in the Rebecca Gilley determine cell fates. organisations (GSK, AstraZeneca & Karus PI(3,4)P2 levels (See figure). By investigating regulation of growth, metabolism, and Therapeutics) hoping to develop anti- different PI3K isoforms, we have uncovered Postdoctoral researchers: Current Aims immunity, and changes to this pathway inflammatory/anti-cancer drugs that some key properties that allow growth Anne Ashford Our current work is focused on studying are seen during ageing and in various Emma Duncan target PI3Ks. factors to selectively activate PI3Kα and two particular protein kinase families: human cancers. (Started in 2017) β in fibroblast cells, and revealed how Andrew Kidger the extracellular signal-regulated kinases Phill Hawkins inflammatory stimuli activate PI3Kγ in Pamela Lochhead (ERKs, such as ERK1/2) and the related neutrophil immune cells. We are also dual-specificity tyrosine phosphorylation- Growth factors Matthew Sale Group members beginning to understand the roles of regulated kinases (DYRKs, such as DYRK1B PhD students: several proteins in the creation of new, and and DYRK2). These protein kinases affect Senior research associates: Rachael Huntly the recycling of existing, PI lipid molecules the cell by regulating other specific proteins Karen Anderson Cell surface receptors Emma Minihane Sabine Suire involved in PI3K signalling. Finally, we Richard Odle (substrates), changing their properties have worked with other researchers and Jack Prescott (activity, location, binding partners). We Postdoctoral researchers: Representative high-content microscopy (HCM) images showing the rapid nuclear accumulation of p-ERK1/2 (red) PI4P PI(4,5)P companies to measure PI(3,4,5)P3 levels Kate Stuart want to understand how the ERKs and the David Barneda 2 following 2h treatment of HCT116 cells with the catalytic ERK1/2 inhibitor (ERKi) BvD-523. In contrast, the dual- in different contexts both for research and DYRKs control cell fate decisions by defining Tamara Chessa Class I PI3K Visiting researchers: mechanism ERKi SCH772984 effectively inhibits ERK1/2 phosphorylation. The nucleus is stained with DAPI (blue) Simon Cleary PTEN PTEN clinical trials. Victoria Johnson how their activity is controlled, where in and a total ERK1/2 (green) control is shown. Image: Dr Andrew Kidger, Cook lab. David Gyori (Left in 2017) the cell they function and by identifying INPP4B 5 P’tases Eleftherios Karanasios Diane Proudfoot the substrates (proteomics) and the gene PI3P PI(3,4)P2 PI(3,4,5)P3 Natalie Rynkiewicz expression programmes (genomics) that Selected Impact Activities Research assistant: cells to undergo programmed cell death Selected Impact Activities n Presented our work at four they control. PhD students: Megan Cassidy by apoptosis. We have found that ERK1/2 n RAS pathway drug discovery Piotr Jung international conferences and (Started in 2017) Progress in 2017 signalling protects cells against apoptosis collaboration with PhoreMost Anna Kielkowska several UK and EU universities Effectors Effectors Effectors It is increasingly important to understand by supporting the production of funded by Innovate UK. Barzan Sadiq (eg Tks5, Lpd) (eg Akt1/2, Dapp1) (eg Btk, Grp1) n We collaborated with where in the cell protein kinases function. pro-survival proteins. In new work, we have Accompanying KEC blog by Visiting scientists: pharmaceutical organisations (GSK, To do this we have used a novel chemical identified a range of DYRK substrates and Rebecca Gilley Maifa Belghoul AstraZeneca, Karus) and academic biology approach in which a very selective are investigating their role in the clearance Jeanne Bertrand n Industrial collaborations on ERK groups in four different countries ERK1/2 inhibitor that becomes fluorescent of damaged and misfolded proteins. Vishnu Janardan inhibitors (Astex Pharmaceuticals), Cell growth and movement inside cells allows us to directly visualise Damaged proteins accumulate in our Piotr Kobialka n Took part in the Institute Schools’ MEK inhibitors (AstraZeneca) ERK1/2 in cells. ERK1/2 signalling seems to cells as we grow old and in some diseases Monica Sanchez Day giving student groups the and ubiquitylation (MISSION be key in determining whether, and how, so we are working with pharmaceutical Kasia Zator An outline of the PI3K signalling pathway. Stimulation of PI3K by receptor proteins leads to the conversion of PI(4,5) chance to get hands-on with Therapeutics) P2 to PI(3,4,5)P3. Phosphatase enzymes convert PI(3,4,5)P3 back to PI(3,4)P2 or to PI(4,5)P2. The balance of these cells die. For example, the accumulation of companies to help guide their drug Senior technician: research in the lab molecules affects how a cell behaves. The PTEN protein primarily acts as a 3-phosphatase, limiting PI(3,4,5)P3 damaged or misfolded proteins can drive discovery efforts. n Hosted two teachers (Helen Keith Davidson levels. Loss of PTEN increases PI(3,4,5)P3 leading to excessive growth signalling and cancer. We have now shown Penketh and Sarah Hyland) on a that PTEN also acts as a PI(3,4)P2 phosphatase and we plan to look at the role of PI(3,4)P2 in tumours. STEM Insight placement
Publications www.babraham.ac.uk/our-research/signalling/len-stephens /phillip-hawkins Publications www.babraham.ac.uk/our-research/signalling/simon-cook n Malek, M. et al. (2017) PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K. Mol. Cell. 68: 566-580 n Sipthorp, J. et al. (2017) Visualisation of Endogenous ERK1/2 in Cells with a Bioorthogonal Covalent Probe. Bioconjug. Chem. 28:1677-1683 n Durrant, T.N., Hutchinson, J.L. et al. (2017) In-depth PtdIns(3,4,5)P3 signalosome analysis identifies DAPP1 as a negative regulator of GPVI-driven platelet function. Blood Adv. 1:918-932 n Cook S. et al. (2017) Control of cell death and mitochondrial fission by ERK1/2 MAP Kinase signalling. State-of-the-art review. FEBS Journal 284:4177-4195 n Cerny, O. et al. (2017) cAMP Signaling of Adenylate Cyclase Toxin Blocks the Oxidative Burst of Neutrophils through Epac-Mediated Inhibition of Phospholipase C Activity. J Immunol. 198:1285-1296 n Darling, N.J. et al. (2017) ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death. PLoS One 12(9): e0184907
22 23 Signalling
Autophagy pathways: cell eating from inside and out Dynamics of autophagy in animal cells
developed in our lab, we are now Through a process called autophagy, Progress in 2017 exploring the role of this pathway in cells are able to digest parts of We have made use of a combination of Selected Impact Activities the immune system and extending our themselves as a way to repair damage genetic experiments, live imaging and n Gave invited talks in Germany, knowledge of its regulation. The future or to provide a source of nutrients to super resolution microscopy to study Canada, Finland, Japan, Croatia, hope is that we can manipulate the help survive starvation. My group aims mitophagy. Our work has established Argentina and the UK on Oliver Florey Nicholas Ktistakis pathway for therapeutic benefit. to understand how this pathway is a clear order for the activation of key autophagy regulation triggered and what the molecular details cell components involved in the early Progress in 2017 n Hosted the Economics Minister Group members Group members of the autophagic response are. stages of autophagy and mitophagy. In The lab has had a great year, publishing of Greece at the Babraham Postdoctoral researchers: Postdoctoral researcher: collaboration with the group of Eeva Liisa papers that extend our understanding of Current Aims Institute to discuss the success of Joanne Durgan Ziyue Li Eskelinen in Finland, we have reconstructed how cancer cells cannibalise each other By screening many different chemicals, the Babraham Research Campus Nathaniel Hoyle (Left in 2017) electron microscopy data to reveal the (Started in 2017) and the unconventional autophagy we have identified one with a role in in fostering academic and PhD students: rearrangements of cell membranes that Elise Jacquin pathway that regulates many important autophagy. We are in the process of commercial innovation Sara Valladoid happen during mitophagy. Drawing on (Left in 2017) processes in the cell, including how the establishing how this chemical alters the (Left in 2017) images from living cells we’re also working n Dr Ktistakis is the President of immune system responds to pathogens – dynamics of mitochondrial autophagy PhD students: Qijia Yu in collaboration with the group of Nicolas the Cambridge Hellenic Learned the causes of illness. (mitophagy) in mammalian cells. We Katherine Fletcher (Left in 2017) Le Novère here at the Institute. We are Society (consisting of academics are also examining how autophagy is Katie Sloan generating computer models of and professionals of Geek/Cypriot Visiting researchers: modulated during the differentiation Visiting researchers: Maria Luisa Giudici autophagy and using these to compare origin) that organises seminars Selected Impact Activities of stem cell-like iPS cells into neuronal Alice Buckingham (Left in 2017) between non-selective and selective and other activities throughout n lineages – nerve and brain cells. As part of (Left in 2017) Publication in eLife on cell Varvara Kandia autophagy processes. the year Munaye Lichtenstein cannibalism in cancer featured (Left in 2017) this work we have generated iPS cells with (Left in 2017) in a number of science blogs and changes to their genes which affect the Visiting students: Pablo Romero Clavijo magazines autophagy process. Qashif Ahmed (Left in 2017) n Dr Joanne Durgan attended a (Left in 2017) Climate Reality Leadership Corps George Borakis training seminar in Pittsburgh USA. Ren Liu (Left in 2017) She is now initiating a Green Labs Ronak Shah initiative at the Babraham Institute (Left in 2017) Image shows a MEF cell – a type of cell that is easy to grow and study in the lab – targeting an autophagy protein n Katherine Fletcher, a PhD student called LC3 (green) to a phagosome housing a dead cell (red). Phagosomes, approximately meaning ‘eaten body’, Research assistants: in the lab, took part in a range are structures in cells that contain things that have been brought in from outside the cell. Maria Manifava of public engagement activities Peri Tate including poster presentation (Started in 2017) Cells need to be able to break down Current Aims sessions for Cambridge Academy and recycle parts of themselves, a We are continuing our key goal of for Science & Technology process called autophagy, so they understanding the upstream regulation can stay healthy. Disruption of this and downstream consequences of a process is associated with many ‘non-canonical’ autophagy pathway, age-related effects, including cancer which utilises some of the molecular and neurodegeneration. Our research machinery used in autophagy to target explores the molecular mechanisms external material eaten by cells, such as Similarities and differences between non–selective and selective autophagy. In both cases, a new compartment forms in the cell surrounding other existing cell components. underlying autophagy and several pathogens and dead cells. This impacts This is akin to the soap bubble on the left or the tarpaulin cover on the right. Non-selective autophagy generates a randomly sized ‘bubble’, called an autophagosome that similar pathways to understand their many important processes within the cell. engulfs material indiscriminately. By contrast, selective autophagy has a specific target in the cell, and generates an autophagosome that precisely fits around that target so roles in health and disease. Using innovative reagents and strategies that it can be isolated from the rest of the cell and efficiently broken down for recycling. Credits: pixabay and yes2tech on Instructables.com
Publications www.babraham.ac.uk/our-research/signalling/oliver-florey Publications www.babraham.ac.uk/our-research/signalling/nicholas-ktistakis
n Karanasios, E. et al. (2016) Autophagy initiation by ULK complex assembly on ER tubulovesicular regions marked by ATG9 vesicles. Nat. Commun. 7:12420 n Durgan, J. et al. (2017) Mitosis can drive cell cannibalism through entosis. eLife, 6:e27134 n Manifava, M. et al. (2016) Dynamics of mTORC1 activation in response to amino acids. eLife. 5. pii: e19960 n Jacquin, E. et al. (2017) Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation. Autophagy, 13:854-867 n Walker, S.A. et al. (2017) Correlative Live Cell and Super Resolution Imaging of Autophagosome Formation. Methods Enzymol. 587:1-20 n Fletcher, K. et al. (2017) The WD40 domain of ATG16L1 is required for its non-canonical role in lipidation of LC3 at single membranes. EMBO J. n Florey, O. & Ktistakis, N.T. (2017) editors Autophagy Protocols (46 authors). Methods Mol. Biol. in press
24 25 Signalling
Modelling biological systems Understanding how fats keep us healthy
Complex behaviours of biological Fat molecules, also called lipids, play viral infection. We’re also studying how cells In collaboration with Professor systems arise from the ever-changing many roles inside and outside of cells. maintain the correct levels of lipid needed Jane McKeating in Oxford, we have interactions of their many parts. To For example, they act as barriers, for healthy ageing. also discovered that a lipid called understand this behaviour and the carry signals and are energy sources. lysophosphatidic acid, which is made Progress in 2017 effect of various changes including Amongst other things, lipids are signals outside cells, supports the replication Nicolas Le Novère Michael Wakelam Dietary restriction (DR) involves limiting the ageing and disease, we need to consider that help cells to respond to changing of hepatitis C virus in liver cells food intake of an animal. We have shown these systems as a whole. This is only diet, infections and ageing. By using a particularly when they are deprived that DR – an extensively documented Group members possible using computers to analyse Group members range of methods to examine different of atmospheric oxygen. condition that extends lifespan in a variety Postdoctoral researchers: large amounts of data, and simulate Postdoctoral researchers: lipids inside and outside of cells we aim of organisms – alters the lipid profile of the Piero Dalle Pezze mathematical models reproducing the Andrea Lopez to enhance our understanding of the mouse liver. DR causes a decrease in lipid Varun Kothamachu systems. Our particular interest lies in (Started in 2017) varied roles they perform. content in cells. In addition, the lipids that Selected Impact Activities (Left in 2017) examining links between cell signalling, Maria Ciaccia Current Aims are synthesised contain smaller fatty acid n Represented the Babraham Lu Li metabolism and epigenetics. (Left in 2017) An Nguyen Anna-Karin Johnsson We research how lipids inside and outside molecules – ones with shorter chains of Institute partnership with the Current Aims Aveline Neo of cells drive signalling and metabolic carbon atoms. This helps to explain why DR Cambridge Academy for Science PhD students: (Started in 2017) and Technology, through the Janna Hastings Our work focuses on two main topics. First, pathways that are necessary for cells to protects ageing animals from the ill effects the regulation of intracellular signalling, An Nguyen survive in response to changes such as the of fat accumulation. design and provision of an Vincent Knight Schrijver Simon Rudge Juliette Pearce in particular examining how cells decode loss of nutrients, the loss of oxygen, and employer-led three-month Qifeng Zhang learning Challenge Project Manusnan Suriyalaksh calcium, cAMP and phosphoinositides (Left in 2017) signals and how they decide on the correct n Hosted four summer students Visiting researchers: PhD student: ACSS2 ACSS2 + DAPI Sven Bergmann response to these signals. And second, (Nuffield, sixth-form and University the interplay between metabolism and Arsalan Azad Stuart Edelstein Mathematical model of a bi-stable switch regulated by cAMP chemical signals and regulating protein phosphatase (Left in 2017) undergraduates) (Left in 2017) epigenetic regulation of genes i.e. how 2A function. Upper-left, a schematic view of the biological components of the switch showing how cAMP molecules n Industrial collaboration on Pınar Pir changes to the availability of metabolites work with ARPP-16, MAST and PKA proteins to regulate Protein Phosphatase A. Background, equations describing Visiting students: autotaxin inhibitors with Cancer and energy in the cell regulate the the relationships between MAST, PKA and two states of ARPP-16. Lower-right, experimental measurements used to Beth Cragoe Visiting students: (Started in 2017) Research Technology Stephen Cole expression of genes, during development, estimate some of the values needed for the equations, calculated using our software Sbpipe. tissue repair and ageing. We study these Daniel Gentle (Left in 2017) (Started in 2017) processes in a range of biological models, Agathe Delaune figure). We also launched a community (Left in 2017) including embryonic stem cells, heart Research assistant: effort to reconstruct the entire metabolism n Participated in an eLife Hamza Umut Karakurt cells and neurons. In addition, we develop Dorottya Horkai of the nematode worm C. elegans. Together Community Webinar aimed at (Left in 2017) software tools to improve the building (Left in 2017) with gene expression, protein and early career researchers Furkan Kurtoglu and sharing of mathematical models and (Left in 2017) metabolite measurements, the resulting numerical simulations. n Released of over 6,000 patient Deriya Sebukhan model is expected to be a key resource to specific computational models of (Left in 2017) Progress in 2017 investigate the impact of metabolism on tumour metabolism, free through Letizia Vestito In collaboration with Yale University, epigenetics and ageing. (Left in 2017) the BioModels database we uncovered a signalling switch that Research assistant: responds to cAMP signals in neurons from Microscopy imaging of the ACSS2 protein (red) in HEK-293 cells, a type of human cells often studied in the lab. Nicolas Rodriguez the part of a brain involved in reward Selected Impact Activities ACSS2 is a key enzyme that acts at an early step in the synthesis of lipids and is found throughout cells. Images and locomotion. Combining biochemical n Coordinated the Systems Modeling were taken using the Nikon A1R confocal microscope at 60x magnification. DAPI was used to show DNA in the cell approaches and mathematical modelling, Community of Special Interest nucleus (blue). Scale bar 0.05 mm. Image credit: Dr Arsalan Azad. we identified a switch-like mechanism for of the International Society for inhibiting or activating a key regulatory Computational Biology protein, called Protein Phosphatase A (see
Publications http://lenoverelab.org Publications www.babraham.ac.uk/our-research/signalling/michael-wakelam n Malek, M. et al. (2017) PTEN regulates PI(3,4)P2 signalling downstream of class I PI3K. Mol. Cell. 68(3): 566-580 n Hartler, J. et al. (2017) Deciphering lipid structures based on platform-independent decision rules. Nat. Methods. 12:1171-1174 n Diaz-Muñoz, M.D. et al. (2017) Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells. Nat. Commun. 8:530 n Hahn, O. et al. (2017) Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol. 18, 56 n Musante, V. et al. (2017) Reciprocal regulation of ARPP-16 by protein kinase A and MAST-3 kinase provides a cAMP-regulated switch in protein phosphatase 2A inhibition. eLife 6: e24998 n Farquhar, M.J. et al. (2017) Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication. J Hepatol. 66, 919-929
26 27 Signalling
Cell signalling through Rho-GTPase and GEF proteins
Proteins known as Rho-GTPases are Progress in 2017 molecular switches that enable cells We recently generated a mouse model Selected Impact Activities to move through their surroundings. that allows us to monitor the activity of n Awarded a BBSRC iCASE PhD We study how these Rho-GTPases are Rac – a type of Rho-GTPase protein – in studentship in collaboration with controlled, particularly by other proteins real time within living cells and tissues. Vernalis Research Ltd, Cambridge Heidi Welch called GEFs that switch them on. Our One of our projects involved helping our n Presented to the PhD Training recent research has identified new roles collaborators to establish a similar mouse Programme, Biomedical Center, Group members of GEFs in the immune system and model for monitoring the activity of the Ludwig Maximilian University in cancer. In addition, we have made related Rho-GTPase called RhoA. This Senior postdoctoral Munich, Germany, Nov 2017 researcher: progress in understanding how GEFs work showed that RhoA is mostly active Kirsti Hornigold are controlled and we developed tools at the rear of migrating white blood cells, n Ran a ‘prep you own DNA and test your ancestry by PCR’ lab on PhD students: for monitoring Rho-GTPase activity its activity increases as the cells approach Elizabeth Hampson inside cells. sites of infection, and the activity oscillates Schools’ Day 2017 (Started in 2017) throughout the cell during migration in a Current Aims Chiara Pantarelli similar way to Rac activity. Elpida Tsonou We previously discovered a family of GEF proteins that we called P-Rex. We have Visiting students: described how one of these proteins, Alejandro Kauil P-Rex1, controls how white blood cells are Anna Mandel drawn to the site of an infection and help (Started in 2017) to fight the disease once they arrive. Research assistant: Laraine Crossland P-Rex1 and other GEFs inside blood platelet cells play surprisingly large roles in these processes (see figure). Our current aim is to evaluate the importance of a protein called Norbin – a regulator of P-Rex1 which we recently identified – in controlling defence against infections. We are also investigating the functions of other GEFs in the immune Platelet GEFs control the tissue recruitment of white blood cells. GEF proteins P-Rex1 and Vav activate platelets and system, studying the roles of P-Rex GEFs in make them become sticky during inflammation and infections. The sticky platelets glue themselves to white blood metabolism, and developing new methods cells and to the blood vessel wall. These sticky platelet bridges enable the white blood cells to move into infected for monitoring GEF activity. tissues to fight germs. Platelets without P-Rex1 and Vav cannot do this, so white blood cells cannot reach infected tissues, which can cause immunodeficiency. However, the lack of platelet glue also reduces overall inflammation which can help by improving inflammatory conditions such as allergic reactions.
Publications www.babraham.ac.uk/our-research/signalling/heidi-welch n Hornigold, K. et al. P-Rex1. Encyclopedia of Signaling Molecules, 2nd Edition, Ed. S Choi. in press n Pitchford, S. et al. (2017) Platelets in neutrophil recruitment to sites of inflammation. Curr. Opin. Hematol. 24:23-3 n Nobis, M. et al. (2017) A RhoA-FRET biosensor mouse for intravital imaging in normal tissue homeostasis and disease contexts. Cell Rep. 21:274-288
28 29 Signalling
‘The fact we work alongside scientists from Making the Most of so many varied companies enables us to Signalling Research turn new ideas into new collaborations’ So after coffee and conversation, “Our dream is that if we find things Simon took advantage of the binding to KRAS, we can work with Babraham Research Campus crystallographers to discover where Collaboration Fund (BRCCF) it’s binding. And once we know the Bringing together the Institute’s researchers with scientists in the 60 companies on the – a scheme that encourages structure, we can design a drug-like Babraham Research Campus is helping turn innovative ideas into new benefits for human collaboration between Institute molecule that does the same thing.” researchers and their neighbouring health – fast. Over the past two years, members of the Signalling research programme have If the collaboration ultimately leads biotech companies – to set up a transformed a conversation over coffee into a collaboration that could deliver new ways of to new drugs for diseases like collaboration. And after successfully pancreatic cancer, it will mark an treating some of the most intractable human cancers. showing that they could build extraordinary advance. But it’s the Simon’s knowledge of KRAS into huge potential that this way of PhoreMost’s screening technology, working represents that’s the real they were awarded £600,000 funding game changer, Simon believes. from Innovate UK in 2017 to get a As Dr Simon Cook has discovered, – but also because the gene that All that could be set to change new procedure up and running. “I’m a great believer in publicly- caffeine can be a powerful catalyst. controls this pathway, KRAS, is one thanks to the unique environment funded research – the Institute does Nine months on and Simon’s team In the past 18 months, what began of the most common oncogenes in of the Babraham Research Campus. world-class research on a budget and are close to perfecting a system with as a conversation over coffee with human cancer.” Just metres away from Simon’s lab – because our funding comes from scientists from PhoreMost – one which has over 25 years experience PhoreMost. The new cell line will In fact, KRAS mutations are taxation we have a duty to squeeze of the 60 biotech companies that in KRAS biology – is the innovative be able to indicate whether or not responsible for almost 30% of all every possible impact out of it. The share the Babraham Research drug discovery company PhoreMost. a molecule has inhibited the KRAS human cancers, including 25% of fact we work alongside scientists Campus – has developed into a Spun out of the University of pathway by living or dying. When non-small cell lung cancer, 40% of from so many varied companies collaboration that could yield new Cambridge in 2014, PhoreMost has KRAS is switched on, the cells die; colorectal cancer and up to 90% of enables us to turn new ideas into new ways of treating some of the most developed a completely new way conversely, anything that inhibits pancreatic cancer, which remains collaborations.” intractable human cancers. of screening diseased cells to find KRAS means the cells survive. These one of the hardest of all cancers to hidden targets that can then be cells can then be studied to find out Working this smartly radically Simon, a group leader in the treat. But although scientists have turned into drugs for previously exactly what protected them. speeds up the time it takes to turn Institute’s Signalling research known for more than 30 years that new knowledge into impact. “On untreatable diseases. “The first step is using PhoreMost’s programme, works on protein mutations in KRAS cause cancer, average it takes 17 years to translate technology to find these cryptic kinases. By attaching phosphate they have struggled to develop It’s hard to imagine a more basic innovation into a new drug or spaces on KRAS that have defied groups to cellular proteins, these drugs that inhibit KRAS. promising pairing. “PhoreMost are company. That’s too long and too enzymes help to form our cells’ literally next door to my lab – we conventional drug discovery,” The biggest barrier is KRAS’s random,” Simon concludes. “The communication system, switching often bump into them over coffee he explains. biochemistry. “It’s properties are Babraham Research Campus shows on and off their most basic functions – so I knew about their technology. unique. It binds to a co-factor called that we can work much more cleverly. – from surviving or dying to dividing They can interrogate novel GTP, which in an ideal world would Here, we can facilitate and accelerate and differentiating. druggable spaces in proteins that make a good drug target,” Simon – funding basic bioscience and conventional drug discovery hasn’t “We’ve been interested in one explains. “But the affinity with which ‘It takes 17 years to translate basic bringing people together who might been able to find – and we had the of these pathways, called ERK, it binds is so tight – and it’s such a otherwise never have talked.” targets they needed,” Simon recalls. for many years,” he says, “partly small protein – that it’s always been innovation into a new drug or company… “Using their SITESEEKER platform because we want to understand its viewed as un-druggable.” to find a new druggable space for basic biology – how it controls cell we can work much more cleverly’ the KRAS pathway we’re studying division, survival and differentiation seemed like a perfect partnership.” 30 31 332-41 Epigenetics Group leaders Inside cells, genetic information stored in DNA is packaged by proteins into a structure called chromatin. Epigenetics is the study of chemical modifications to DNA and to chromatin and the effects that these modifications have on genome function. Epigenetic marks are involved in the creation of different types of cells from stem cells and epigenetic changes over time are associated with ageing. Epigenetic marks also provide a form of cellular memory, recording certain information about past events and potentially carrying it between parent and child. Our work in this area aims to enhance our understanding of how epigenetics shapes human development and affects healthy ageing by examining: n How stem cells develop into different types of cells n How subtle epigenetic differences influence cell diversity Wolf Olivia Myriam Jon Gavin Peter n The impacts of diet on epigenetics, health and ageing Reik Casanueva Hemberger Houseley Kelsey Rugg-Gunn n The inheritance of epigenetic memory between generations n How life events affect biological ageing through the epigenetic clock n New approaches and technologies to drive further progress
32 33 Epigenetics
Epigenetic reprogramming in development and ageing Stress, metabolism and effects on healthy ageing
We are interested in epigenetic Progress in 2017 We are now able to view ageing as Progress in 2017 mechanisms in mammalian We have established the first systematic Selected Impact Activities a genetically controlled system that We have developed and optimised Selected Impact Activities development and ageing. Epigenetic molecular map, based on single cell n POSTnote parliamentary briefing we can potentially learn to regulate. techniques and statistical methods to n We have successfully launched mechanisms are able to regulate gene transcriptome sequencing, of cell fate on ‘The ageing process and health’ Of the thousands of genes that have assess variability in gene expression. Using WormJam, a community driven expression and can behave as a form decisions in early mouse development. been linked to ageing, many affect these techniques, we have examined the effort geared towards improving Wolf Reik n Speaker at ‘The many faces of Olivia Casanueva of memory that records the history of a Interestingly, we found that slight how living things deal with external expression of stress and nutrient responsive the C. elegans metabolic Programme leader epigenetics’ interdisciplinary cell. These mechanisms include chemical variations in gene expression, called ‘noise’, challenges linked to stress and nutrition. reconstruction network. workshop Oxford with natural and genes and found that variation between changes to DNA or DNA-associated increases before cells become committed Group members Such findings underscore the balance worms can have an effect on fitness and Including organising two Group members social scientists proteins. We are particularly interested to becoming different cell types. We Lab manager: between genes and environment that overall survival. In particular, non-genetic GENIE/COST workshops Senior research scientists: in how epigenetic memory is established have established the first non-human n Contributed to a social science Sharlene Murdoch govern our lifespans. Our lab aims to variation in tissues from the brain and gut n Our collaboration with the Wendy Dean when cells become different from each ageing clock based on epigenetic DNA (ethnography) research project understand the non-genetic influences Postdoctoral researchers: can have long-term consequences Sophianum School and the Fatima Santos at the University of York about other in early embryonic development, methylation. The clock is accurate enough Salah Azzi on lifespan and responses to stress by for healthspan. Postdoctoral researchers: Technasium Scheme won and how such epigenetic memory to record the chronological age of mice our researchers titled ‘Modelling (Started in 2017) using the nematode worm C.elegans as a Irina Abnizova By examining the first molecular events an Openness in Animal decays during ageing. with an error of 3.3 weeks. Interestingly, Ageing @ BI’ Laetitia Chauve model organism. (Started in 2017) that occur during early ageing in both Research award biological interventions that shorten Cheryl Li Rebecca Berrens Current Aims Current Aims normal and long-lived animals we have Stephen Clark lifespan (ovariectomy, high fat diet) Juan Rodriguez-Molina n Presentation at Pint of science We are examining the link between Our overarching aim is to understand the identified key gene expression switches. Melanie Eckersley-Maslin accelerate the clock. (Left in 2017) festival “epigenetics: Nature vs Poppy Gould epigenetic marks in a cell, the epigenome, Bhupinder Virk molecular details of ageing and to discover These switches regulate genes involved nurture” and sharing C.elegans Irene Hernando Herraez and the activity of different genes. We (Started in 2017) new ways to slow or even reverse the in metabolism and contribute to early research with primary and Mario Iurlaro have developed technologies to record the ageing process. With that goal in mind, we PhD students: global metabolic remodelling events. secondary school students (Left in 2017) epigenome in parallel with transcription use C. elegans to understand: We have also improved the C. elegans Christel Krueger Janna Hastings – the first step in the process of gene Metabolic Reconstruction network and are Hisham Mohammed Abraham Mains 1. The significance of non-genetically expression – inside single cells. We are Manusnan Suriyalaksh developing several modelling approaches Carine Stapel encoded variation in the expression of Young adult worms after heat shock (a sudden (Started in 2017) using this to understand why stem cells to characterise gene expression switches Visiting researchers: genes that respond to external cues increase in temperature; 34°C for 30 mins). DNA inside Thomas Stubbs develop into different cell types – for and metabolic fluxes during early ageing. cells is stained in blue. Messenger RNA (mRNA) from Rebeca Aldunate such as temperature and nutrients. Ferdinand Von Meyenn example specialising to become blood or the hsp-90 gene are in red and mRNA from the hsp-70 (Left in 2017) We are interested in finding how early PhD students: muscle rather than gut cells. We are also gene are in green. Rob Jelier molecular differences in the way worms Celia Alda trying to find out how the epigenome (Left in 2017) Diljeet Gill respond to stress can influence and be changes with age, including at the single Bwarenaba Kautu Tim Lohoff (Left in 2017) predictive of lifespan. (Started in 2017) cell level, and how this may affect cell and Renoja Kalaichelvan Daniel Martin organ function as we age. 2. The early global metabolic remodelling Kunanayagam Julia Spindel events that occur at the beginning of (Started in 2017) Visiting researchers: Philip Leaning ageing, in both normal and long-lived Marloes Blotenburg (Left in 2017) worms. Our aim is to identify potential (Left in 2017) Pia Todtenhaupt nutritional interventions that can delay Federico Di Tullio (Started in 2017) the process of ageing. (Started in 2017)
Image of fluorescently labelled embryonic stem cells. These cells have been modified to mimic the effects of epigenetic reprogramming changes that happen in developing embryos. DNA in the cells is marked in blue. Red indicates cells that contain active transposons – mobile pieces of DNA that can become active during reprogramming.
Publications www.babraham.ac.uk/our-research/epigenetics/wolf-reik Publications www.babraham.ac.uk/our-research/epigenetics/olivia-casanueva n Berrens, R.V. et al. (2017) An endosiRNA-Based Repression Mechanism Counteracts Transposon Activation during Global DNA Demethylation in Embryonic Stem Cells. Cell Stem Cell 21(5):694-703 n Kelsey, G., Stegle, O., Reik, W. (2017) Single-cell epigenomics: Recording the past and predicting the future. Science 358(6359):69-75 n Mohammed, H et al. (2017) Single-Cell Landscape of Transcriptional Heterogeneity and Cell Fate Decisions during Mouse Early Gastrulation. Cell Rep. 20(5):1215-1228 n Stubbs, T.M., et al. (2017) Multi-tissue DNA methylation age predictor in mouse. Genome Biol. 18(1):68
34 35 Epigenetics
The effect of age on womb function and pregnancy How cells interact with their environment
E3.5 uterus Young female E3.5 uterus Aged female Progress in 2017 We study how cells adapt to their Current Aims Progress in 2017 During 2017, we established that age environment at the genetic and n Determine how new genetic changes We have published the first clear impedes the capacity of uterine cells to epigenetic level, particularly how occur and whether these can be demonstration that certain complex cells respond to the pregnancy hormones they adjust to challenging and toxic stimulated by the environment can stimulate genetic changes at particular oestrogen and progesterone. This hormonal environments. This contributes to our sites in their genome. We’ve also shown that Myriam Hemberger Jon Houseley n Establish when and how drug signal normally triggers a reaction called understanding of how our cells change they do this to accelerate the acquisition of resistance occurs in cancer cells decidualisation, in which cells lining the in response to environmental pressures new traits. This suggests that changes such Group members uterus transform to support embryo Group members and as a consequence of ageing. Our n Understand the mechanistic link as drug resistance are not always random Postdoctoral researchers: implantation and early placenta formation. Postdoctoral researchers: work aims to discover ways of improving between nutrients in the environment and may be preventable. Using yeast as a Sarah Burge In aged mice, the decidualisation response Prasanna Channathodiyil health throughout life and to find better and the ageing process model of cell biology, we have also shown Vicente Perez-Garcia is slower. Moreover, some cells in aged Cristina Cruz approaches to chemotherapy. that the effects of ageing depend on the Claire Senner uteri lack the progesterone receptor Alex Whale environment. The decline of ageing cells is Ruslan Strogantsev protein. These aged cells also show slower PhD students: not absolute and aged cells are fitter than PhD students: proliferation rates and reduced levels of Dorottya Horkai young cells in some circumstances. This Stephanie Chrysanthou the signalling molecule pSTAT3. Together, (Started in 2017) is helping us to understand the impact of (Left in 2017) these molecular changes underpin the Ryan Hull nutrition on the ageing process. Dominika Dudzinska decidualisation and placentation defects Andre Zylstra Georgia Lee Uteri from young and aged female mice 3.5 days into pregnancy. The progesterone receptor protein (PGR) is we observe in older female mice that Visiting student: (Started in 2017) shown in green and DNA labelled in blue using a stain called DAPI. White arrows point to the luminal epithelium lead to a dramatic increase in Matthew Jackson Natasha Morgan (LE) – cells that line the uterus – with strong PGR expression. In young females the PGR signal is evenly distributed developmental abnormalities. (Left in 2017) Laura Woods throughout the entire LE. Red arrows in aged uteri point to regions of the LE with reduced PGR levels. Selected Impact Activities Research assistants: n Article featuring our research on Visiting students: Monica Della Rosa stimulated mutation in Quanta Cheryl Lee A functional placenta is critical for Current Aims (Left in 2017) and WIRED magazines (Left in 2017) normal embryonic development It is well known that maternal age has Selected Impact Activities Michelle King Anne Rummenie n Talk at Cambridge Therapeutics (Started in 2017) n Article on our ageing research in (Left in 2017) and lifelong health. The placenta a profound impact on fertility and Grazia Pizza Cambridge Independent Jerome Seitz develops from cells derived both reproductive success, an association Forum from the embryo and from the commonly attributed to the decrease (Left in 2017) (Left in 2017) n Radio interviews for n Research Presentation at the mother. Trophoblast stem cells in egg cell fitness. The potential impact “2nd DNA Replication as a Source Research assistant: DeutschlandFunk and the Naked originate from the fertilised embryo of ageing on the uterus has not been Mrs Elena Fineberg Genetics podcast with Kat Arney of DNA Damage Conference” in and come together with cells from investigated to the same extent. During Rome, July 2017 Research associate: the mother’s uterus to form a highly 2017, we focused on finalising our ongoing n Institute Public Engagement Prize Hai-Yan Lin unique integrated unit. We focus studies in which we were specifically & presentation at Royal Society (Left in 2017) on how genes are regulated during investigating the effect of maternal age on Partnership Conference for Claire placenta formation and the effects of uterine cells. This work was based on our Senner and 6th form pupils from maternal age on this process. observation that, in mice, the physiological Hitchin Girls’ School environment of older mothers has a greater impact on placental and fetal development In yeast, older cells (blue) are at a disadvantage during growth in their normal environment yet they are actually than the age of the egg cells themselves. fitter in non-optimal environments compared to younger cells (orange).
Publications www.babraham.ac.uk/our-research/epigenetics/myriam-hemberger Publications www.babraham.ac.uk/our-research/epigenetics/jon-houseley n Brighton, P.J et al. (2017) Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium. eLife 6 n Hull, R.M. et al. (2017) Environmental change drives accelerated adaptation through stimulated copy number variation. PLoS Biol. 15: e2001333 n Turco, M.Y. et al. (2017) Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat. Cell Biol. 19, 568-577 n Frenk, S. et al. (2017) Aging yeast gain a competitive advantage on non-optimal carbon sources. Aging Cell 16: 602-604 n Woods, L. et al. (2017) Decidualisation and placentation defects are a major cause of age-related reproductive decline. Nat. Commun. 8, 352 n Sayou, C. et al. (2017) RNA Binding by Histone Methyltransferases Set1 and Set2. Mol. Cell Biol. 37: e00165-17
36 37 Epigenetics
Epigenetic legacies from eggs Epigenetic regulation of human development
As well as genetic information, the egg How DNA is packaged in cells and in gene regulation and chromatin We defined genes that are activated at and sperm also contribute epigenetic the use of biochemical switches in organisation as cells become pluripotent either the early or late stages of naïve annotations that may influence the genome are key aspects of the and how this happens against a backdrop cell formation, and we have used genetic gene activity both during and after epigenetic control of gene activity. of widespread epigenetic reprogramming. approaches to ask which of these genes fertilisation. We examine epigenetics We are interested in understanding We will also investigate how human are required for reprogramming. Mapping Gavin Kelsey Peter Rugg-Gunn during egg development and the effects how epigenetic processes are pluripotent cells undergo specialisation DNA interactions has also revealed of epigenetic marks on gene activity in established during human development towards mature tissues such as pancreatic how rewiring of gene regulation occurs Group members the embryo. Our goal is to understand Group members and during the differentiation of stem beta cells, and whether we can make this between different cell states. Postdoctoral researchers: whether, through epigenetics, factors Postdoctoral researcher: cells to form various cell types. This is more efficient by toggling epigenetic Hannah Demond such as a mother’s age or diet have Clara Novo important for understanding health switches at key stages in the process. Courtney Hanna consequences on the health of a child. and for finding ways to use stem cells in Selected Impact Activities PhD students: Progress in 2017 Elena Ivanova regenerative medicine. n Clara Novo co-organised the first Current Aims Amanda Collier One highlight this year was charting EU-LIFE International Postdoc PhD students: We investigate how epigenetic states are Charlene Fabian Current Aims the first molecular roadmap of the Jessica Elmer Retreat, held in Lisbon in October set up in oocytes – which develop into Visiting researcher: Our aim is to understand how epigenetic transition between naïve and primed (Left in 2017) Eleanor Sheekey Ginatare Sendzikaite egg cells – and influence gene expression processes help to control human human pluripotent states. By identifying n Clara Novo spoke about her in the embryo. For example, repressive (Left in 2017) development and stem cell differentiation, new ways to isolate early-stage naïve research at the Cambridge ‘Pint of Visiting researchers: chromatin marks in oocytes lead to long- in particular as cells enter and exit an cells, we have revealed exciting insights Science’ Festival Zahra Anvar term silencing of genes inherited from unspecialised state called pluripotency. into the dynamics and the interplay of (Started in 2017) n Peter Rugg-Gunn helped to draft the mother, particularly in cells that will Over the next year, we would like to find epigenetic and transcriptional events Antonio Galvao new guidelines for assessing the form the placenta. We are also interested out what mechanisms drive the changes that occur during cell reprogramming. safety of human pluripotent stem Visiting students: in how variations in DNA methylation, cells in clinical applications Erika Herrera another type of epigenetic mark, come (Left in 2017) about in oocytes and whether we can use Giulia Guarnieri this variation as a marker for oocyte quality (Left in 2017) Kristina Wendelboe Olsen and embryo potential. To investigate these (Left in 2017) questions, we develop methods to profile epigenetic information in small numbers of A mouse egg cell inside an ovary. DNA in each cell is shown in blue, epigenetic methylation marks are shown in single cells. green. Image: Dr Courtney Hanna Progress in 2017 A major advance has been our ability epigenetic information. For example, we to map chromatin states – how the find that methylation on DNA can prevent n Lecture “Animal Models to Study chromosomes themselves are modified H3K4me3 modification on chromosomes. Human Disease” for the Institute of – in very small numbers of cells. This has This indicates a link between genetic Continuing Education, University revealed some unexpected properties of information in DNA and the positioning of of Cambridge by Courtney Hanna the epigenetic landscape in oocytes, such H3K4me3 in the genome. n Visit to the University of Jordan, as widespread accumulation of H3K4me3, Amman as part of Global a modification normally tightly associated Selected Impact Activities Challenge Research Fund (GCRF) with active gene promoters. Using genetic n Teacher training session on how Impact Accelerator Award (IAA) mutants we investigated interactions to measure epigenetic marks to promote infrastructure between H3K4me3 and other layers of in the genome using current for bioinformatics analysis We recently identified a set of cell-surface proteins that can distinguish between naïve and primed human pluripotent stem cells (left). By using specific antibodies to visualise these proteins, we can now track and isolate specific cell types during the transition between naïve and primed states (centre). Gene expression analysis reveals the similarities sequencing technologies and training and differences between each of the isolated cell populations (right) and tells us about the pathways that contribute to cell state changes.
Publications www.babraham.ac.uk/our-research/epigenetics/gavin-kelsey Publications www.babraham.ac.uk/our-research/epigenetics/peter-rugg-gunn n Gahurova, L. et al. (2017) Transcription and chromatin determinants of de novo DNA methylation timing in oocytes. Epigenetics & Chromatin 10:25 n Collier, A et al. (2017) Comprehensive Cell Surface Protein Profiling Identifies Specific Markers of Human Naive and Primed Pluripotent States. Cell Stem Cell 20: 874-890 n Kelsey, G., Stegle, O. and Reik, W. (2017) Single-cell epigenomics: recording the past and predicting the future. Science 358:69-75 n Rugg-Gunn, P (2017) Naive pluripotent stem cells as a model for studying human developmental epigenomics: opportunities and limitations. Epigenomics 9: 1485-1488 n Hanna, C.W. et al. (2018) MLL2 conveys transcription-independent H3K4me3 in the oocyte. Nat. Struct. Mol. Biol n Freire-Pritchett, P et al. (2017) Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells. eLife 6. pii: e21926
38 39 Epigenetics Informing Policy on Ageing ‘Our research on healthy ageing has a direct impact on the nation’s heath’ Ensuring that the Institute’s world-leading research has a direct impact on people’s health means translating – and contextualising – our science for many audiences. st are beginning to understand the As well as public health and the For parliamentarians and policy makers, healthy ageing is among the 21 century’s most processes that occur in our bodies development of new drugs, his pressing problems. So as well as pioneering research on healthy ageing, we’re ensuring that cause ageing – the damage that research has other less obvious yet science is accessible to decision makers through our knowledge exchange programme. accumulates over time which causes far-reaching implications, he adds: ageing and age-related disease. The “Insurers might be very interested interest now is to look for ways to in people’s biological age, which reduce this damage, either via new raises many policy questions. And if drugs or changes in lifestyle,” she says. it’s possible to influence the ageing Across a handful of generations, For the past 30 years, the Institute interviews with academic, industry, process with drugs in the future, I The POSTnote, published in average life expectancy in the has pioneered research into government and third sector think this has broader implications for February 2018, will be used by UK has doubled. A baby girl born epigenetics – the mechanisms that stakeholders. In 2017, Sarah Worsley, population structure.” parliamentarians and policy makers in 1841 could expect to live just control the way our genes function a third-year PhD student at the who will be increasingly called on Being involved in research that’s beyond her 42nd birthday; one born – revolutionising our concept of University of East Anglia spent three to regulate new drugs and set new likely to have profound impacts on in 2016 can expect to live until the healthy ageing biology. In 2017, months as a NERC-funded intern directions in public health, ensuring society as well as health makes him age of 83. This extraordinary change for example, Institute researchers at POST, producing a POSTnote that the Institute’s research has a think about his science from new is a triumph of public health; but identified a mouse epigenetic on the biological basis of ageing direct impact on the nation’s heath. perspectives. “It makes us frame it also presents major health and ageing clock and showed that and how the ageing process can “Nutrition and other environmental questions in a different way,” he says. social challenges. Today, longer lifestyle changes known to shorten be manipulated to promote better factors influence the epigenome and “It’s important to inform parliament life expectancy is associated with lifespan, including a high fat diet, health later in life. can have long lasting consequences, and our policy makers about scientific increasing incidence of chronic sped up the clock. “Collating 30 interviews into a not only for our health but that of thinking, because new science diseases, from dementia and Doing ground-breaking science, four-page briefing and explaining future generations,” says Wolf. raises so many new ethical and diabetes to arthritis and cancer, however, is not enough. To maximise complex science for an audience legal questions.” putting pressure on unpaid carers as the impact of our research, we that has no knowledge of biology well as health and social services. have to make it accessible to is challenging,” Sarah explains. The POSTnote ‘The Ageing Process and Health’ is available online to download* Helping people remain healthier parliamentarians and policy makers, “Visiting scientists at the Babraham for longer is key to addressing and last year Professor Wolf Reik and Institute, Newcastle University and these issues, and the Institute Dr Jon Houseley of the Epigenetics the University of Southampton was plays a pivotal role in advancing research programme contributed to vital to get the background to the fundamental scientific knowledge a new POSTnote. biology of ageing. They told me ‘It’s important to inform parliament and and making it available to decision about their work, and where they POST – the Parliamentary Office of makers. Healthy ageing research thought it fitted into policy and our policy makers about scientific thinking, Science and Technology – provides spans and unites the Institute’s treatments for age-related diseases.” balanced, accessible overviews scientific themes. Our aim is to because new science raises so many new of scientific research. One of the The POSTnote introduces the idea of understand how our bodies change tools it uses to put research into biological versus chronological age, as we age and how this impacts ethical and legal questions’ a policy context that can be used the epigenetic clock, and considers our lives so that science can inform in Parliament is the POSTnote. potential therapies and public lifestyle changes, policies and These concise peer-reviewed health policy interventions opening treatments to help people stay briefings distil literature reviews and up through this research. “Scientists *https://researchbriefings.parliament.uk/ResearchBriefing/Summary/POST-PN-0571 healthier as they get older.
40 41 442-51 Nuclear Dynamics Group leaders Each cell contains a massive amount of genetic information stored on strands of DNA inside the cell nucleus. These strands are not randomly packed into cells but are highly organised. Different pieces of DNA are found in different places and often active genes are found together in specific locations. All of this means that physical changes in DNA organisation can affect how our genes, and our cells, behave. Our research investigates how the physical organisation of DNA affects gene activity and how this changes in different types of cells and as we age. We do this by exploring: n How DNA is organised inside different types of cells n The location of active and inactive genes inside cells n How different proteins reorganise the genome to alter gene activity Peter Anne Sarah Karen Mikhail Patrick n 3D computer modelling methods to understand genome organisation Fraser Corcoran Elderkin Lipkow Spivakov Varga-Weisz
42 43 Nuclear Dynamics
Professor Fraser is now primarily based at the Department of Biological Science, Florida State University From April 2018, the Corcoran group will be part of our Immunology research programme Structure and function of the genome Making enough different antibodies to fight infection
Our two-metre long genome is Current Aims Hi-C to gain insights into the variability and large DNA regions in the nucleus affects packed into a nucleus just a fraction The spatial organisation of the genome dynamics of chromosome organisation in antibody production. This will increase of a millimetre across. Yet, what’s truly is tissue-specific and has been linked to a cells, and Promoter Capture Hi-C (PCHi-C) 10000 our understanding of normal antibody Peter Fraser astonishing is that our genomes are range of processes in the cell nucleus. These to link regulatory elements across the Anne Corcoran production and help us to understand the Programme leader highly folded and organised inside include gene activation, gene silencing, genome with their target genes. 7500 events that cause leukaemias. the nucleus. Changes in DNA folding genomic imprinting, DNA repair, DNA Group members Progress in 2017 Progress in 2017 Group members can control gene expression, affecting replication, and genome maintenance. Using an improved single cell Hi-C method, Senior research associate: 5000 We have invented VDJ-seq, a method which Postdoctoral researchers: how cells develop and respond to We study the interplay between genome we have captured thousands of genome Daniel Bolland detects multiple antibody gene sequences. Tauanne Amarante the environment. The links between conformations from individual cells. This 2500 (Left in 2017) organisation and genetics could change structure and function both at the level of Postdoctoral researcher: VDJ-seq can show which genes are typically Jonathan Cairns our understanding of health, ageing single cells and cell populations. We have has allowed us to connect complex features Lyubomira Chakalova Vκ−Jκ1 recombination frequency used the most to make antibodies and how of chromosome architecture to changes as (Started in 2017) 0 this changes during disease. We have used Biola Javierre and disease. developed a technique called single-cell 2−137 14−126pg 11−114pg 15−103 6−25 3−4 Hashem Koohy cells grow and divide. We have also been 1−135 11−125 2−112 20−101−2 8−18pg 3−3 this technique to study the genes used PhD students: 1−133 1−122 14−111 14−100 6−17 3−2 Wing Leung able to complete 3D virtual models of 1−132 17−121 1−110 1−99 3−12 3−1 Peter Chovanec 14−130 9−120 2−109 12−98 3−10 to make the immunoglobulin kappa light Jorg Morf entire genomes. 9−129 9−119pg 1−108pg 10−95 3−9 Olga Mielczarek 9−128pg 1−117 11−106pg 13−84 3−7 chain (Igk) protein. We have discovered that Takashi Nagano (Left in 2017) Forward strand 17−127 2−116pg 16−104 13−82pg 3−5 some Igk genes are used much more often Stefan Schoenfelder We have generated detailed maps of 67500000 68000000 68500000 69000000 69500000 70000000 70500000 Sam Rees than others. By examining transcription contacts between genes and proposed 9−124 1−88 4−77pg 4−68 4−55 12−44 8−34 8−21 Sven Sewitz Carolyn Rogers 9−123 4−86 4−75pg 4−61 4−54 5−43 6−32 8−19 Csilla Varnai 10−96 13−85 4−74 4−59 4−53 12−41 8−30 8−16 factors and histone modifications near the gene regulatory regions using Promoter (Started in 2017) 10−94 4−83pg 4−73 4−60pg 4−51 12−40pg 8−28 6−15 19−93 4−81 4−72 4−58 4−50 5−39 8−27 6−14 IgK genes, we found that frequently used Steven Wingett Capture Hi-C in a range of human and 4−92 4−80 4−71 4−57−15−48 12−38 8−24
Visiting researcher: Reverse strand 4−90 4−79 4−70 4−57 12−46 5−37 8−23−1 Igk genes have very specific signatures. mouse cell types. Our goal is to enhance 12−89 4−78 4−69 4−56pg 5−45 18−36 6−23 PhD students: Jannek Hauser We are now investigating whether ageing Stephen Bevan our understanding of gene expression (Left in 2017) affects the use of IgK genes and the Marco Michalski control, and to understand how genetic (Left in 2017) corresponding signatures. changes outside of genes relate to This image shows the many different genes in the immunoglobulin kappa DNA region, colour coded by gene Visiting scientists: human diseases. family. The length/height of each line indicates how often each gene is used to make antibodies. Elad Chomsky Selected Impact Activities (Left in 2017) The immune system creates antibody Current Aims Selected Impact Activities n New Epigenetics exhibit for Giuseppina Pisignano proteins to help fight diseases. We aim to understand how the genes (Left in 2018) n CHROMOS public displays at Hills Road Biology Day and Antibodies are made by white blood that make up antibody proteins come Gordana Wutz the Cambridge Science Festival Cambridge Science Festival cells called B lymphocytes. By mixing together in many different combinations (February 2017), London Science Research assistant: and matching genetic information, these to generate the enormous numbers of n Patent granted in US and Europe on Museum (September 2017) and Clare Murnane cells can produce billions of different different antibodies we need to fight assay to detect antibody sequences ZKM Karlsruhe (ongoing) antibodies to combat different diseases. infections. This process involves epigenetic n Invited speaker at Successful n We have provided training in We are interested in the mechanisms mechanisms at many different levels. We Women in Science Capture Hi-C methodology for involved in the development of B aim to understand how mechanisms like Symposium, Basel visiting scientists from Florida lymphocytes and their ability to make transcription factor binding and histone and Vienna antibodies. Reduced ability to produce modifications affect which genes are n Talk at FASEB meeting, USA, effective antibodies is one of the reasons more frequently used. We’re also looking on Gene Expression in the the immune system weakens as we age. at how the large-scale 3D folding of these Immune System
A visual representation of DNA molecules (chromosomes) within a cell. The packing of chromosomes into cells can affect the accessibility of different genes and chromosomes are packed differently inside different cells.
Publications https://www.bio.fsu.edu/faculty.php?faculty-id=pfraser Publications www.babraham.ac.uk/our-research/lymphocyte/anne-corcoran n Nagano, T et al. (2017) Cell-cycle dynamics of chromosomal organization at single-cell resolution. Nature 547: 61-67 n Matheson, L.S. et al. (2017) Local chromatin Features including PU.1 and IKAROS Binding and H3K4 Methylation shape the repertoire of immunoglobulin Kappa genes chosen for V(D)J n Rubin, AJ et al. (2017) Lineage-specific dynamic and pre-established enhancer-promoter contacts co-operate in terminal differentiation. Nat. Gen. 49: 1522 recombination. Front. Immunol. 8:1550 n Siersbaek, R et al. (2017) Dynamic rewiring of promoter-anchored chromatin loops during adipocyte differentiation. Mol. Cell 66: 420-435 n Levin-Klein, R. et al. (2017) Clonally stable Vκ allelic choice instructs Igκ repertoire. Nat. Commun. 8:15575 n Collier, A.J. et al. (2017) Comprehensive Cell Surface Protein Profiling Identifies Specific Markers of Human Naive and Primed Pluripotent States. Cell Stem Cell 20: 874-890
44 45 Nuclear Dynamics
In 2018, Sarah Elderkin becomes a Visiting Researcher at the Institute In 2018, Karen Lipkow becomes a Visiting Researcher at the Institute Keeping genes silent Mechanisms of genome architecture
X M Each cell contains a huge amount of DNA packed into a small space inside 19 3 the nucleus. Despite the crowding, the 18 4 Sarah Elderkin Karen Lipkow DNA is highly organised with active 17 5 genes often found together in the same Group members 16 Group members parts of the nucleus. By combining Postdoctoral researchers: Postdoctoral researcher: computing and biology, we’re examining Louise Matheson Sven Sewitz the physical and biological mechanisms
Salah Azzi 6 responsible for organising DNA
PhD students: (Left in 2017) 15 inside cells. Latifa Aljebali Zahra Fahmi Current Aims
Visiting student: Inside cells, DNA is packaged with histone
7 Ema Etchegaray proteins to form chromatin. In our latest
14
8 (Left in 2017) work we have been investigating how the
13
9 mobility of different chromatin regions 12 PRC1 protein complexes spatially restrain the genome in mouse stem cells. PRC1 staining as pink dots in the nucleus of an embryonic stem cell (left). A representation affects genome organisation. Using the of contacts between different chromosomes (centre), line thickness indicates strength of interaction. Interactions of all 22,000 genes throughout the genome. Image: yeast S. cerevisiae, and computer models Dr Veronique Juvin. of chromatin, we showed that the number of extra proteins attached to a section of chromatin affects its mobility. We went on We examine gene expression and Current Aims to show that changing mobility helped the how genes can be rapidly activated We are particularly interested in groups chromatin to organise into structures that or silenced when cells change type. of proteins called Polycomb Repressive aid proper gene regulation. We are particularly interested in how Complexes (PRC), which reduce or silence stem cells are able to develop into a gene expression. Although most genes range of different types of cell through affected by PRC are silent, some remain the process of differentiation. Precise active. With colleagues at EMBL-EBI we control of gene activity is key to recently showed that these genes are controlling these changes while helping more noisy than normal, meaning that different types of cell to remain healthy their activity varies between cells. Noise and perform specialised tasks. can be important in helping cells to make decisions and our findings indicate that Methods for analysing the dynamic genome. The four aspects of studying genome organisation and the key PRC helps to generate this genetic noise. techniques used in these areas (outer rings) are united through bioinformatics and computational approaches. This helps us to gain a more complete view of how DNA organisation changes within cells. The centre shows simulated movements of a yeast chromosome demonstrating the dynamics of chromosome conformations over a short period of time.
Publications www.babraham.ac.uk/our-research/affiliated-scientists/sarah-elderkin Publications www.babraham.ac.uk/our-research/affiliated-scientists/karen-lipkow n Kar et al. (2017) Flipping between Polycomb repressed and active transcriptional states introduces noise in gene expression. Nat. Commun. 8:36 n Sewitz et al. (2017) Heterogeneous chromatin mobility derived from chromatin states is a determinant of genome organisation in S. cerevisiae. bioRxiv (preprint)
46 47 Nuclear Dynamics
Mikhail Spivakov will take up a new position at the Medical Research Council’s London Institute of Medical Sciences in 2018 Patrick Varga-Weisz will take up a new position at the University of Essex in 2018 The logic of gene regulation from a distance How the environment changes genome function
Many genes are controlled by pieces Current Aims Progress in 2017 The cells that line the gut form a layer Corcoran, Peter Fraser, Mikhail Spivakov of a certain type of epigenetic mark – a of regulatory DNA found elsewhere in Our group studies the basic principles of In collaboration with Peter Rugg-Gunn’s called the intestinal epithelium that and Sarah Elderkin to do this for B cell chemical modification that alters gene the genome. Some of these regulators gene regulation and their implications and Peter Fraser’s groups, we mapped absorbs nutrients, supports good precursor cells in the immune systems of activity. This type of epigenetic mark is Mikhail Spivakov are close to the genes they affect for ageing, development and disease. We the loops between genes and their Patrick Varga-Weisz bacteria and protects against infections. mice and we are extending these kind of known as crotonylation and it is particularly but some are not. We are interested combine experimental approaches with regulatory elements in unspecialised How factors such as diet and bacteria studies now to intestinal stem cells. abundant in the gut epithelium. Our work Group members in understanding the relationships computational analyses using advanced human embryonic stem (ES) cells and in Group members impact on health, ageing and the has shown how SCFAs affect crotonylation between different genes and their tools, some of which we develop ourselves. developing neurons derived from these immune system through changes in Progress in 2017 levels. Therefore, our study illuminated a Senior postdoctoral Postdoctoral researchers: Fibre, such as pectin from apples, is an researcher: regulators and understanding how Much of our work is focused on the logic cells. We found that these loops were Juri Kazakevych gene organisation and regulation is an new link between gut microbiota and the Hashem Koohy they impact on development, ageing of gene regulation by genomic elements extensively rewired when the ES cells went Anke Liebert important question. important part of our diet, yet the human genome of intestinal epithelial cells. and disease. that are found some distance away from through the process of differentiation to (Left in 2017) genome doesn’t include the genes needed Postdoctoral researcher: Current Aims the genes they regulate, such as gene become neurons. This is also consistent Claudia Stellato to digest fibre. We can only digest fibre Jonathan Cairns Our lab studies how bacteria in the gut enhancers. To link these elements to their with the enhancer regions switching on (Left in 2017) thanks to the bacteria in the gut which do interact with the cells of the intestinal Selected Impact Activities PhD students: target genes, we use the Promoter Capture and off. Additionally, we contributed to have the biological machinery needed to PhD students: epithelium and control gene regulation in n Rachel Fellows, was interviewed by Lina Dobnikar Hi-C (PCHi-C) technique developed in studies that identified possible target genes Rachel Fellows break down fibre. By doing so the bacteria these cells, by affecting how the genome is BBC Radio Cambridgeshire about Joanna Mitchelmore the Fraser group. This method affected by non-coding mutations that Elena Stoyanova generate molecules called short chain Michiel Thiecke packaged. her research in the wake of the makes it possible to map the are associated with human disease. This fatty acids (SCFAs). These are taken up by Visiting students: publication of her work Visiting students: connections of gene involved examining what gene promoters Raquel Manzano We also explore how ageing affects the cells lining the gut, called intestinal Pawel Bednarz n Co-organiser, “The Ageing Cell” RNA-Seq promoters across the loop close to mutation sites. (Left in 2017) gene expression through chromatin epithelial cells, and provide an important (Left in 2017) H3K4me3 conference, Babraham Institute H3K4me1 whole genome and Calvin Rodrigues dynamics – how the genome is arranged energy source. We have shown that SCFAs Will Orchard H3K27ac
ESCs at high resolution. (Left in 2017) and moves within cells. We have worked lead to changes in gene expression. They (Started in 2017) H3K27me3 States SOX2 Promoter CHi-C in collaboration with the labs of Anne do this by increasing the abundance
SOX2 SOX2-OT 50kb FXR1 SOX2-OT LOC100996490 FLJ46066 Selected Impact Activities DNAJC19 SOX2-OT n The CHROMOS project (see feature).
SOX2 Promoter CHi-C Presented at Cambridge Science States H3K27me3 Festival, London Science Museum H3K27ac H3K4me1 Lates and at venues abroad NECs H3K4me3 RNA-Seq n Valeriya Malysheva has taken part in the Roche Continents programme exploring the intersection of science and art
How the promoter of the SOX2 gene in human ES cells (upper; ESCs) and neural progenitor cells (lower; NSCs) interacts (purple arcs) with other parts of the genome. Also shown is information on gene expression (mRNA-seq) and the patterns of various epigenetic modifications (H3K27me3, H3K27ac, H3K4me1, H3K4me3). The accessibility of DNA in different parts of the genome is shown as chromatin states defined jointly based on these epigenetic patterns (active chromatin, green; poised chromatin, orange; Polycomb-associated chromatin, red; intermediate, yellow; background, grey). Heatmaps (top and bottom) show information on all interactions in the region (the promoter has most contacts with regions in yellow), Lining of the mouse large intestine. DNA in shown in red. Histone-crotonylation, an epigenetic mark involved in gene activation, shown in green. Yellow indicates both features together.”
Publications lms.mrc.ac.uk/research-group/functional-gene-control Publications www.essex.ac.uk/people/varga22401/patrick-varga-weisz n Freire-Pritchett, P. et al. (2017). Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells. eLife 6: e21926 n Fellows, R. et al. (2018) Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat. Commun. n Petersen, R. et al. (2017). Platelet function is modified by common sequence variation in megakaryocyte super enhancers. Nat. Commun. 8: 16058 n Rodrigues, C. et al. (pre-pub) A Suv39H1-low chromatin state drives migratory cell populations in cervical cancer. bioRxiv 241398 n Burren, O.S. et al. (2017). Chromosome contacts in activated T cells identify autoimmune disease candidate genes. Genome Biol. 18: 165
48 49 Nuclear Dynamics
‘We wanted to express the data The Sounds of the Genome in this unadulterated form, so you can experience the real The Institute does world-leading research, and using public engagement to enthuse, excite science in action’ and inspire is a key part of our mission. This year, we teamed up with two innovative artists to transform our data into a virtual reality experience. The result, CHROMOS, is allowing new audiences to discover the DNA drama that goes on inside the nucleus of a single cell. The result is CHROMOS: shimmering “Its success shows that by finding strands of DNA dancing to complex, new ways to help our scientists tell layered melodies played on a sansula, their stories, the Institute can do a magical thumb piano made from ground-breaking public engagement small metal tines. The video has as well as world-leading research.” From Twitter to CGI, new technology computer modelling has revealed understand how the activity of the been viewed thousands of times is re-shaping how we work, play and the 3D organisation of DNA in single genes encoded in DNA affect health, And for Institute researchers like on YouTube and the VR experience communicate. But when Dr Mikhail nuclei for the first time. disease and ageing. Mikhail, it’s been hugely rewarding. enjoyed by audiences at London’s Spivakov from the Institute’s Nuclear “As a biologist I’m passionate about Our DNA is often represented While for scientists the findings Science Museum, the Cambridge Dynamics research programme finding ways to make our science as pairs of discrete X-shaped have important implications for Science Festival and the Open Codes sent a tweet to music producer more accessible, to help people chromosomes, but the reality human health, for Max they provide exhibition at ZKM Karlsruhe as well as Max Cooper, neither thought that understand what we do and why we is altogether messier and more artistic inspiration. “This process of in Berlin and Lisbon. a 140-character message would do it,” he concludes. “It was amazing dynamic. With more than two simulated folding to create our best evolve into a ground-breaking People’s responses, says Tacita, have to see how the project took real data metres of DNA packed into each guess of real chromosome structure public engagement project. been amazing: “Our aim was to spark from the lab and turned it into a cell’s nucleus, our chromosomes is a beautiful process, so this beauty conversation, make people think multidimensional experience which Max – whose work spans dance- usually resemble a tangled ball of became the focus of the project,” differently and engage audiences allows people to get more closely floor techno to fine art sound wool rather than neatly twisted he explains. And to bring out its who would perhaps not usually acquainted with our DNA, what it design – has more in common with skeins of yarn. full beauty, he decided to get CGI engage in science research. And does and how it looks, making it Mikhail than meets the eye. With A-lister Andy Lomas – whose film This tangle of DNA is constantly we’ve achieved that. It’s been almost palpable.” a PhD in computational biology credits include Hollywood hits from moving, folding and refolding into a major success.” but no formal music training, Max Avatar to the Matrix movies – To find out more about CHROMOS go different arrangements. When is fascinated by the rhythms of the on board. The project has also attracted to www.babraham.ac.uk/CHROMOS sections of DNA move from the natural world and the capacity of art attention from the public centre to the periphery of the cell, Andy developed a way of and music for scientific storytelling. engagement community. “CHROMOS meeting and parting company from transforming gigabytes of the was a significant investment for the “Mikhail tweeted Max inviting others, they are effectively switched Institute’s raw data into video Institute and very different from him to visit the Institute,” recalls on and off in a way that enables the sequences and a virtual reality anything we’ve done before,” she says. public engagement manager Tacita complex machinery of the cell to experience while Max produced Croucher. “He’d seen some work that function correctly. a musical score. “We wanted Max was doing, thought it was really to express the data in this Because they can now study cool, and wondered whether they unadulterated form, so you can the relationship between DNA could collaborate.” experience the real science in structure and function in single action,” Max explains. “It’s a glimpse After meeting Mikhail and his team, cells, researchers will be able to ‘By finding new ways to help our scientists tell into the complexity and form of one Max decided that they should work ask questions that would have of the most important molecular their stories, we can do ground-breaking public together on a project inspired been impossible to answer before structures in all of life.” Dr Csilla Varnai’s research, whose – questions that should help them engagement as well as world-leading research’
50 51 52-63 111213141516171819202122MTXY678910 5 X=Chr3:102.3 Mbp-Chr6:10.1 Mbp Y=Chr3:104.3 Mbp-Chr6:8.2 Mbp Facilities 5
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Bioinformatics Biological Chemistry Biological Support Unit Flow Cytometry Gene Targeting
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Imaging Lipidomics Mass Spectrometry Sequencing
52 53 Facilities
Bioinformatics Biological Chemistry
Research increasingly includes the The Biological Chemistry group provides our suggestions using chemical and Capabilities creation of large amounts of data support for scientists working at the analytical tools. n Chemical synthesis of standards and and the use of computers to manage interface between chemistry and reagents which are not commercially In addition to our collaborations with and process that information. The biology at BI. We bring an understanding available the research groups we are investigating Bioinformatics facility provides of chemistry and it’s application to Simon Andrews Jonathan Clark the chemical changes which occur in n Analysis of biological molecules by mass infrastructure to support the analysis solving biological problems along Facility head Facility head connective tissues as we age. spectroscopy of biological data. We provide guidance with the capability to implement and training in data analysis, statistics n Development of new reagents and Facility members Facility members and data management to both internal analytical methods Biological statistician: and external groups. We also develop Postdoctoral research n Help and advice on any aspect of the Anne Segonds-Pichon novel tools, and administer the scientists: Izabella Niewczas application of chemistry/biochemistry to Bioinformaticians: Institute’s computing cluster. Mel Stammers the exploration of biological problems Laura Biggins Capabilities (Started in 2017) Christel Krueger Progress in 2017 n A group of six bioinformaticians Felix Krueger During 2017 we have supported groups and statistisiticians with biological Steven Wingett throughout the Institute on a wide range backgrounds who can advise or of varied projects. These have ranged Training developers: practically help you with your analyses. Jo Montgomery from synthetic chemical projects to make (Started in 2017) n A 700 node compute cluster to perform compounds which are not commercially Bhupinder Virk small- or large-scale data processing. available, through to developing new (Left in 2017) analytical methods to analyse lipids in cell n A suite of tools developed in-house for extracts. In addition to these activities we the analysis of sequence data, designed have continued to run routine lipid analysis to be used by both biologists and for a number of groups, both within the bioinformaticians. Institute and externally. n A comprehensive set of training courses to allow biologists to develop their informatics and statistical skills. Selected Impact Activities n Through 2017 we have run many Progress in 2017 commercial PIP3 analysis samples Over the last year the group has greatly for a number of pharmaceutical expanded its training programme, running Selected Impact Activities n Presented at the Festival of companies studying the action of 34 courses on site in addition to those at n Helped organise the UK Genomics on how biases Pi3Kinase inhibitors in a clinical Cambridge University, the EMBL-EBI and on bioinformatics core facility in sequencing can produce setting other academic and commercial sites. We meeting bringing together misleading results now have a modular set of statistics courses bioinformatics services from n We have provided lipid analysis which cover all of the basic areas biologists academia and industry for a number of external academic are likely to need in their research. We have groups through 2017 also expanded our sequencing training to n Organised the first Cambridge cover more techniques, such that we now Bioinformatics Hackathon have an integrated set of courses to cover to encourage new basic skills, application specific analysis collaborative projects and statistics.
Publications www.bioinformatics.babraham.ac.uk Publications www.babraham.ac.uk/science-services/biological-chemistry n Hahn, O. et al. (2017) Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol. 18, 56 n Mouhannad Malek, Anna Kielkowska et al. PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K, Molecular Cell, 2017, Volume 68, Issue 3, Pages 566-580 n Gahurova, L. et al. (2017) Transcription and chromatin determinants of de novo DNA methylation timing in oocytes. Epigenetics & Chromatin 10:25 n Wingett, S. et al. (2017) Cambridge Bioinformatics Hackathon 2017. F1000 Res. 6-1942
54 55 Facilities
Tim Pearce Facility head Biological Support Unit Flow Cytometry
Facility staffing: Flow cytometry allows cells to Capabilities Progress in 2017 2 Deputy facility be identified, counted, analysed n Cell Sorting Service carried out by In the past year, the Flow Cytometry Core heads and sorted on the basis of specific cytometry experts using state of the art has continued to provide an excellent 2 Unit managers physical or chemical features. For cell sorters service to Institute scientists, external companies and academics with utilisation 2 Deputy unit Rachael Walker example, it can detect and separate n Training for scientists to use 5 High-End of the high-end analysers and cell sorters. managers Facility head different cells found in the immune Analysers using up to 30 parameters The three 5 laser, 20 parameter BD 8 Supervisors system. The Flow Cytometry facility provides a world-class service to n Merck Millipore Amnis Imagestream LSRFortessa analysers with in core facility, 3 Deputy Facility members enable the research goals of the MkII for analysing of cells using have continued to be heavily used and have Supervisors Attila Bebes Institute. We help scientists from both image cytometry played an important role in generating data 22 Experienced Animal (Started in 2017) for publications by Institute scientists. Technicians Arthur Davis the Institute and external companies n Modular Theoretical Training Course Rebecca Roberts with experimental design, training, Awarded a BBSRC ALERT-16 grant in April 7 Junior Animal which has already been attended Barbara Sobotic Technicians troubleshooting and data analysis. by over 400 delegates including 2017 for an additional BD FACSAria Fusion (Started in 2017) international delegates cell sorter which will strengthen the cell 4 Service Technicians The use of animals in research continues n The bio-science units surround the Lynzi Waugh sorting capabilities of Babraham Institute’s (Left in 2017) 2 Veterinarians to be key in helping to understand central services unit which utilises Selected Impact Activities Flow Cytometry Facility. 1 Technical Services biology and disease. The Biological robotic cage-washing technology and n As part of our recruitment manager Support Unit provides state of the art automated sterilisation processes to initiative and commitment to 1 Facility housing and care for pathogen-free provide equipment and consumables to the Concordat of Openness the administrator/ rodents used in both academic and each of the animal holding areas. BSU attended a careers fair at the Selected Impact Activities Import and Exports private company research programmes. Guildhall Cambridge promoting n Lectured on the EMBO Practical manager Progress in 2017 Our team of professionally qualified careers in animal technology Course: The Fundamentals of animal technicians provide expert n Over the last year, the BSU has 3 Apprentices n In Nov 2017, the BSU conducted High-Speed Cell Sorting at technical support to researchers by successfully implemented a centralised a virtual tour to a local community EMBL, Heidelberg undertaking regulated procedures, genotyping service using Transnetyx as group offering members of the maintaining the animal health barrier the external provider. Transnetyx offers n Organised the flowcytometryUK public a chance to understand and undertaking animal husbandry. genotype results within 72hrs of the meeting in London, exploring samples being sent with an accuracy how a modern animal advances and interesting Capabilities of 99.97%, which allows for greater facility operates applications of cytometry n The BSU is made up of four bio-science efficiencies with colony management n A team of BSU managers gave a n Delivered a webinar on Data units, each performing a unique role in and scientific research. presentation entitled ‘A holistic Management in a Shared the provision of flexible services to meet approach to building design’ n As part of a continued career Resource Laboratory (SRL) for the dynamic requirements of biological outlining the BSU concept development programme the first class the International Society for the research. We have a mix of animal including, design, construction, of apprentices have graduated with Advancement of Cytometry (ISAC) technicians and service technicians who operation and future proofing perform daily husbandry duties and all three successfully being employed provide essential services to the facility. as qualified Junior Animal Technicians within the facility. n Our animal technicians hold Home Office Personal Licences enabling n The BSU provides rentable space and us to provide technical support for technical support to a number of researchers. We have a commitment to commercial companies. Income from up-hold the highest standards of animal this venture doubled in 2017. welfare in all aspects of our work.
www.babraham.ac.uk/science-services/biological-support-unit Publications www.babraham.ac.uk/science-services/flow-cytometry
n Cossarizza, A. et al. (2017) Guidelines for the use of flow cytometry and cell sorting in immunological studies, Euro. J. Immunol. 47(10), 1584-1797 n Collier, A.J. et al. (2017) Comprehensive Cell Surface Protein Profiling Identifies Specific Markers of Human Naive and Primed Pluripotent States. Cell Stem Cell 20: 874-890 n Frenk, S. et al. (2017) Aging yeast gain a competitive advantage on non-optimal carbon sources. Aging Cell 16: 602-604 n Kalkan, T. et al. (2017) Tracking the embryonic stem cell transition from ground state pluripotency. Development 141 (7) 1477-9129
56 57 Facilities
Gene Targeting & Genome Editing Imaging
Our modern understanding of our genes makes it possible for researchers to alter individual genes to study their functions. The Gene Targeting facility can design and create specific genomic Dominik Spensberger Simon Walker modifications by using techniques such Facility head Facility head as CRISPR/Cas9. We are able to produce genetically altered mouse models, Dominik left the Institute Facility members in 2017, our future services embryonic stem cells and other cell are currently under review lines. The facility can aid in the design, Deputy manager: generation, targeting, screening and Hanneke Okkenhaug evaluation of genetic modifications.
Green laser light illuminates a microscope slide using one of our confocal microscopy systems.
The Imaging facility provides a range Progress in 2017 of services to support the Institute’s Imaging remains a key investigative tool Selected Impact Activities research. These include access to state for Institute research and has contributed n Launched our Introduction to of the art light microscopy technology, to a number of high profile publications ImageJ courses. We anticipate training and support for a variety of this year (see below). We are also an adding an intermediate level different imaging approaches. We important resource for commercial users ImageJ course and an Imaris provide advice on experiment design and have an increasing portfolio of both course soon campus-based and external companies and offer an advanced image processing n We welcomed two primary accessing our facility. and analysis service. school visits this year, introducing children to the wonderful world Capabilities We are continually looking to improve of microscopy and discussing n Super resolution fluorescence imaging and expand our range of equipment how imaging supports the (SIM & STORM) and services, and have been fortunate to secure BBSRC funding for a new Institute’s research n High content imaging and high electron microscopy capability. This new n We hosted two undergraduate content screening instrument (due to arrive early 2018) student visitors looking to increase will enable us to correlate 3D cellular n Image analysis software and training their knowledge and experience of ultrastructure with specific events of fluorescence microscopy n Focused Ion Beam/Scanning Electron interest seen in living cells. Microscope (coming 2018)
www.babraham.ac.uk/science-services/gene-targeting Publications www.babraham.ac.uk/science-services/imaging
n Malek, M. et al. (2017) PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K. Mol. Cell. 68: 566-580 n Durgan, J. et al. (2017) Mitosis can drive cell cannibalism through entosis. eLife, 6:e27134 n Diaz-Muñoz, M.D. et al. (2017) Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells. Nat. Commun. 8:530
58 59 Facilities
Lipidomics Mass Spectrometry
Lipidomics involves analysing the full Mass spectrometry techniques can Capabilities n Quantitation of DNA modifications, compliment of lipid (fat) molecules be used to analyse the structures of n Three high resolution tandem mass particularly cytosine modifications 5mC, found in cells, tissues and biological molecules. They have many applications spectrometers within the Facility, and 5hmC, 5fC, 5caC fluids. The aim is to provide a detailed in studying different biological shared access to a state of the art n Development of novel mass yet complex view of molecules in a molecules. The Mass Spectrometry Michael Wakelam David Oxley Orbitrap Fusion Lumos instrument spectrometric analytical methods biological system. These methods can facility uses the latest mass Facility head Facility head located in the Biochemistry be used to understand cell structures, spectrometry approaches and develops Department at Cambridge University Progress in 2017 signalling and regulation and the data new methods to support the Institute’s We have successfully modified the tandem Group members Facility members can be used in a system-wide approach research. We collaborate with colleagues n Full range of high sensitivity mass mass tagging (TMT) methodology to Qifeng Zhang to understand metabolic changes in Senior research assistant: across all of the Institute’s research spectrometric analyses for protein enable the multiplexed quantitative (Left in 2017) health and disease. The Lipidomics Judith Webster programmes. identification, quantitation analysis of very low levels of affinity purified Andrea Lopez facility can identify and semi-quantify and characterisation signalling complexes. In collaboration (Started in 2017) Postdoctoral researcher: a range of neutral, phospho- Katarzyna Wojdyla with Institute research groups, we have and sphingolipids. applied this to the analysis of PI3-kinase signalling in prostate, MEFs and T-cells. We Capabilities have also developed an isotope-dilution n Extraction, separation and mass spectrometric method for the measurement of neutral lipids, accurate absolute quantitation of Erk1 and sphingolipids and phospholipids 2 phosphorylation, which we are using in n Bioinformatic analysis of lipidomics collaboration with Simon Cook’s group data to allow determination of biological to monitor the response of cancer cells to pathways in which lipid molecules various conditions. are modified n Identification of novel lipids Selected Impact Activities Progress in 2017 n Collaboration with groups at The facility has undergone changes Cambridge University on DNA in personnel over the past year, which modifications in cancer and in temporarily reduced our capability. New intestinal epithelial cells appointments Andrea Lopez and Greg West n Commercial work for several are now in place and have relaunched the campus companies facility. n Hosted two teachers from In addition to our LC-MS capability we are Manchester and Bury St Edmunds now co-grant holders of LIPID MAPS with as part of the STEM Cardiff University and UCSD in the USA, this Insight Programme has significantly expanded our lipidomics bioinformatics capability. Selected Impact Activities n Together with colleagues in Austria, n Presented lipidomics data at the Germany, Singapore and the Keystone lipidomics meeting, the USA, developed bioinformatics international Metobolomics and methodology for platform- the Austrian proteomics meeting independent identification of lipid structures from MS data
Publications www.babraham.ac.uk/science-services/lipidomics Publications www.babraham.ac.uk/science-services/mass-spectrometry n Nguyen, A. et al. (2017) Using lipidomic analysis to determine signaling and metabolic changes in cells. Curr. Op. Biotech. 43, 96-103 n Langie, S.A. et al. (2017) The Ageing Brain: Effects on DNA Repair and DNA Methylation in Mice, Genes (Basel) 8(2). pii: E75 n Hahn, O. et al. (2017) Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol. 18, 56 n Yang, J. et al. (2017) Establishment of mouse expanded potential stem cells, Nature 550, 393-397 n Hartler, J. et al. (2017) Deciphering lipid structures based on platform-independent decision rules. Nat. Methods. 12:1171-1174
60 61 Facilities
Next Generation Sequencing
high-precision fluidics of a Hamilton NGS Star. The facility team contributed to the successful grant application for this instrument. The Hamilton NGS Star has been fully installed, and protocols for Kristina Tabbada running library preparation on the unit are Facility head being developed. The Hamilton NGS Star is expected to decrease the time required Facility members for library preparation, whilst improving Clare Murnane consistency and eliminating the variation between users that occurs as a result of manual handling.
Selected Impact Activities n Participated in the Facility Open Day 2017, in which the Babraham Institute Core Facilities welcomed visitors from around the Campus who were interested in their services and technology n Hosted student tour groups n Organised a Users Group Meeting involving NGS service users Sequencing large amounts of DNA Capabilities and Illumina representatives to from many samples – a process called We offer a range of services that allow users discuss ‘Index Hopping Effects and high – throughput sequencing, has the to select platforms, read length and depth Mitigation Strategies’ potential to further our understanding of coverage. Our instruments include: of mechanisms for gene regulation. It n can also help to enhance our knowledge HiSeq 2500 for high-throughput of DNA organisation and structure. The projects Next Generation Sequencing (NGS) n MiSeq for validation or long facility provides researchers with access sequence runs to cutting edge sequencing technology to advance their research. n NextSeq for sequencing depth with a fast turnaround The NGS Facility now offers a start-to-finish library preparation service for specific Progress in 2017 library types, including standard RNA-seq Whilst continuing to offer a state of and low-input RNA-seq. This includes RNA the art sequencing service, the NGS quality control (QC), sequencing library Facility is developing an automated preparation and library quality control. library preparation service using the
Publications www.babraham.ac.uk/science-services/sequencing-facility n Matheson, L.S. et al. (2017) Local chromatin Features including PU.1 and IKAROS Binding and H3K4 Methylation shape the repertoire of immunoglobulin Kappa genes chosen for V(D)J recombination. Front. Immunol. 8:1550 n Wutz, G. et al. (2017) Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins. EMBO J 36:3573-3599 n Stubbs, T.M., et al. (2017) Multi-tissue DNA methylation age predictor in mouse. Genome Biol. 18(1):68
62 63 64-67 Impact By working with organisations and communities in the local area and beyond, we help to ensure that the results of our research have greater impacts for society and the economy. Our goal is to help more people to live healthier lives by raising public awareness and rapidly transforming the latest science into new healthcare, policies and technologies.
64 65 Impact Engaging with our research
Public Engagement and Science Through our European Commission- Schools’ Day reached its 23rd year, Communication (PESC) are an funded ORION project we will community groups visited for virtual established part of our research explore the concepts of Open tours of our animal facility, and we culture. Institute researchers and Science with public dialogues and hosted a number of events during scientific staff have a thirst for the ‘co-creative’ research projects. In Cambridge Science Festival. Our curious and unknown, a passion 2018 we’ll be showcasing our latest Royal Society Partnership Grant for their work and an enthusiasm ageing research, with a new exhibit Projects with schools in Hitchin and to share, discuss and consider ‘Race Against the Ageing Clock’ at Colchester, also came to an end with public opinion. The Institute’s PESC the Royal Society Summer Science students showcasing their work at programme provides opportunities Exhibition in July. We’ll also be the Royal Society. for all to be involved through providing new opportunities for Finally, we were delighted to discussions, exhibits, festivals and students and teachers to learn about be awarded an Understanding hands-on activities, student and cutting-edge research through Animal Research Openness Award, teacher lab days, and community Schools’ Day, BioscienceLITES, ethics recognising our commitment to group talks and tours. workshops and more! openness around the use of animals Our Goals 2017 Review in research, particularly our work Our PESC programme is going from This year saw the launch of a new with the students at Sophianum strength to strength, thanks to the science-art project developed in School, in the Netherlands. commitment of both students and collaboration with our researchers, In total, over 130 staff and students staff. We are developing a new PESC CHROMOS – a virtual reality participated in 50 events, engaging strategy with a vision to maintain experience, video and music tracks with 9000 people of all ages, from an open and accountable approach, offering a unique perspective on the Cambridge, the UK and beyond. which ensures our research genome (see Page 50). excellence contributes to culture, society, economic development and growth. www.babraham.ac.uk/about-us/impact/public
Look out for our new ‘Race Against the Ageing Clock’ exhibit launching in 2018.
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