Janet Thorton job pack June 2021 v1

Janet Thornton Fellowship Carla Jones Former Janet Thornton Fellow & International Women’s Day award winner 2021

Introduction to Sanger Institute from Mike Stratton It’s an exciting time to join us as we continue to build an international centre for scientific, business, cultural and educational activities emanating from Genomes and BioData. With a significant expansion of our Wellcome Genome Campus on the horizon, we are now able to shift our horizons to ask and answer even bolder questions. Our mission is “to maximise the societal benefit of knowledge obtained from genome sequences”. The ambition of Genome Reserach Limited, with our Campus partners, is to progressively strengthen its well-established foundations in scientific research and discovery, and to build on them, developing the Wellcome Genome Campus over the forthcoming 25 years. Genomic research is still in the foothills of extracting and using the knowledge buried in the 6 billion letters of code in the human genome. The ever increasing numbers of human genomes sequenced for research or clinical diagnosis will reveal patterns and motifs that will shape health and disease research for decades to come. When we also consider the rest of the genomes on Earth the potential is vast and the Wellcome Sanger Institute will be in the vanguard of this revolution in science and society. Professor Sir Mike Stratton, FMedSci FRS Director of the Wellcome Sanger Institute and Chief Executive Officer of the Wellcome Genome Campus

About Wellcome Sanger Institute Our Mission Our Benefits To maximise the societal benefit of knowledge obtained from genome sequences. Our employees have access to a comprehensive range Delivery of this mission will have three elements: of benefits and facilities including: • Research: advancing understanding of biology • 25 days annual leave (extra 1 day to a maximum of using genome sequences and other types of large- 30 days for every year you work) scale biological data. • Innovation: applying genome science for human • Auto-enrolment into a generous Group Defined health and other societal benefits. Contribution Pension Scheme, with enhanced • Learning and Engagement: fostering knowledge company contribution exchange and discussion of the scientific, medical and wider implications of genomes. • Up to 2 days annual paid volunteering leave • yUeparto 10 days paid Emergency Carers Leave per Our Structure • Family friendly environment including options The high-throughput, large-scale biological research undertaken at the Wellcome Sanger Institute is a for flexible and part-time working, an on-site central defining characteristic distinguishing our Workplace Nursery Salary Sacrifice Schemes for science from that of most research institutes and pre-school children and Summer holiday club universities. Our science is organised into • Life Assurance – six times your pensionable pay if Programmes, led by our Faculty who conceive and you are a member of our pension scheme deliver our science, and is supported by our Scientific • Group Income Protection Scheme Operations teams responsible for all data production (if on a contract exceeding 12 months) pipelines at the Institute. • Enhanced maternity, and parental leave The data production platforms are organised into a • Access to a substantial number of courses and single management structure. This ensures that we have training events onsite refined processes and ensures that we have appropriate • Private Healthcare Scheme levels of investment and manning, with robust forward- • Eyecare and Dental payment plans planning and realistic targets. • Concessions and discounts from our corporate perks site Our Campus Set over 130 acres, the stunning and dynamic • hFolemxieb-lewowrokrinkginga,vawiliathblae mixture of on-site and Wellcome Genome Campus is the biggest aggregate concentration of people in the world working on the Our open approach common theme of Genomes and BioData. It brings together a diverse and exceptional scientific The Wellcome Sanger Institute is an Equal Opportunity community, committed to delivering life-changing employer. We aim to attract, recruit, retain and develop science with the reach, scale and imagination to pursue talent from the widest possible talent pool, thereby some of humanity’s greatest challenges. Find out more gaining insight and access to different markets to about our Genome Wellcome Campus. generate a greater impact on the world. We positively encourage applications from suitably qualified and eligible candidates regardless of sex, race, disability, age, sexual orientation, gender reassignment, religion or belief, marital status, or pregnancy and maternity status. We are open to a range of UK-based flexible working options including part-time or full-time employment as well as flexible hours due to caring or other commitments.

Wellcome Sanger Institute Our mission is to maximise the societal benefit of knowledge obtained from genome sequences. The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large- scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; we share our data, results, tools and technologies across the world to advance science. Our findings are used to improve health and to understand life on Earth. Our science is large-scale and organised into Programmes, led by our Faculty who conceive and deliver our science, and supported by our Scientific Operations and IT teams responsible for all data production pipelines, compute and storage facilities at the Institute. With secured funding from Wellcome Trust, we are able to strategically focus our work in five key research fields: Cancer, Ageing and Somatic Mutation Provides leadership in data aggregation and informatics innovation, develops high-throughput cellular models of cancer for genome-wide functional screens and drug testing, and explores somatic mutation’s role in clonal evolution, ageing and development. Cellular Genetics The Programme is focused on cell-atlasing and cellular genetics. It uses these approaches to map cells in the human body combining cutting-edge methodologies and computational approaches. This enables us to understand what the identity of cells are, how they are regulated, relationships between them and importantly how this can change during development, health disease and ageing. Human Genetics Applies genomics to population-scale studies to identify the causal variants and pathways involved in human disease and their effects on cell biology. It also models developmental disorders to explore which physical aspects might be reversible. Parasites and Microbes Investigates the common underpinning mechanisms of evolution, infection and resistance to therapy in bacteria and parasites. It also explores the genetics of host response to infection and the role of the microbiota in health and disease. Tree of Life Tree of Life investigates the diversity of complex organisms - animals, plants, fungi and protists - through genomic sequencing and analysis to understand their evolution, and provide resources for species conservation, ecosystem monitoring and future biotechnologies.

About the Janet Thornton Fellowship We understand that even a short time out of research can have an impact on your career, which is why we have created a postdoctoral fellowship providing an additional opportunity specifically for those who have been out of scientific research for 12 months or more to return to high-quality postdoctoral training. One Fellowship is awarded each year. Each Fellowship lasts for three years and can be worked full time, part time or flexibly. Fellowships are awarded after a competitive selection process, with applicants applying to one of the broad project outlines listed below. Applicants are encouraged to make contact with the named supervisors. Projects CRISPR/Cas screens to dissect the cellular networks that drive inflammatory bowel disease Supervisor: Dr Rebecca McIntyre, [email protected] The experimental arm of the Anderson Lab at the Wellcome Sanger Institute (WSI), led by Dr Rebecca McIntyre, is performing high throughput genetic screens to better understand the role of non-coding DNA in inflammatory bowel disease. The Anderson Lab have led many of the genome-wide association studies of inflammatory bowel disease patients, which have revealed that many disease loci fall in non-coding regions of the genome. As such, the mechanistic association with disease for many loci remains unknown. We are currently generating single cell genomics data for thousands of patient samples in close collaboration with the IBD Bioresource, at Addenbrooke’s, and our pharmaceutical partners, to identify the most important genes, pathways and cell types for IBD. The next step is to use CRISPR-Cas screens of primary immune cells, iPSC-derived model cell lines and mucosal organoids to explore the networks that underpin these genes and pathways for therapeutic benefit. Screen hits will be validated using molecular, (e.g. transcriptomics) and phenotypic (e.g. cell proliferation, migration and degranulation) assays. This is a really exciting opportunity to better understand the role of gene regulatory regions associated with predisposition to disease, and ultimately, to identify potential therapeutic targets. The Anderson Lab has a strong track record in supporting those returning to research after career breaks. For example, Dr. Rebecca McIntyre returned to experimental research in 2017 after a two-year career break, and our former Janet Thornton Fellow, Dr Carla Jones Bell, successfully completed her Janet Thornton Fellowship and was promoted to Senior Staff Scientist in the Trynka Lab at Wellcome Sanger Institute last year. Candidates with a strong background in immunology or mucosal immunology are encouraged to apply.

Janet Thornton Fellowship Projects Genomic and computational dissection of tissue architectures Supervisor: Sarah Teichmann, [email protected] Single cell genomics and spatial gene expression technologies can now be combined to provide high resolution maps of tissues. These methods are now routine, robust and scalable, and can be applied to mapping tissues in human development as well as mature adult tissues across the lifespan and across genders, and in health versus disease states. There are fundamental questions about cell lineages (e.g.in haematopoiesis, immunity, etc.), systems (e.g. skin, vasculature, immunity) and organs (e.g. kidney, lung, reproductive tissues, endometrium/decidua etc.) that can be addressed with these approaches. We welcome postdoctoral projects that focus on specific biological tissues or systems, as well as on general overarching questions that span multiple tissues. We also value methods development projects (computational or experimental) that advance the study of tissue architectures using genomics technologies. Integrating comparative high-throughput whole genome transcriptomics and phenotyping: comparing endemic and epidemic Vibrio cholerae Supervisor: Nicholas Thomson, [email protected] Project type: Laboratory based, with bioinformatics Overall aims - To understand phenotypic variation across the Vibrio cholerae species that has facilitated the emergence of the current serogroup O1 seventh pandemic El Tor (7PET) lineage. We will use high- throughput transcriptomics to identify genetic systems which explain how the pandemic lineage has adapted to human carriage and has apparently ‘de-adapted’ to survive and persist in the environment, compared to other lineages in this species. We will think about how these functions relate to changes in the environmental niche through climate change and population density and movement by adapting our assays to reflect the conditions we find in cholera endemic regions and hotspots. Background - Diarrhoeal disease is ranked as the fourth most important cause of death worldwide and the second cause of years of productive life lost due to premature mortality or disability (160 million cases and 750,000 fatalities in the under-fives alone). A small number of bacterial pathogens, including Vibrio cholerae, Shigella spp, enterotoxigenic Escherichia coli, Salmonella spp. and Campylobacter spp., account for a significant percentage of all diarrhoeal diseases in these countries. Cholera alone accounts for 3-5 million cases of diarrhoea and 120,000 fatalities per annum. Previously, V. cholerae were classified as pandemic or non-pandemic based on their serogroup defined by their O-antigen that define their O serogroup. However, we now know that even this most basic definition is inaccurate. Our global phylogeographic surveys have shown that a single lineage of V. cholerae, dubbed 7PET, is responsible for the current and seventh pandemic of cholera (1961-present), By comparing genomic and epidemiological and phenotypic data for cholera and V. cholerae we know that although the O1 serogroup is characteristic of 7PET strains it is not an exclusive association. Similarly, our recent work has shown many of the virulence functions synonymous with pandemic cholera are present in non-7PET V. cholerae lineages. Hence, the presence of pathogenicity islands, and the toxin encoding CTX prophage, do not necessarily indicate ability to cause epidemic disease. We propose that dissection of disease, transmission dynamics, and mechanisms associated with ecological specialisation, will explain why 7PET has become the dominant cause of cholera epidemics worldwide. For this work, using our phylogenetic framework, we have selected live isolates from our sequenced biobank. These represent the full genetic diversity of 7PET and include examples of the wider V. cholerae species phylogeny. Our ultimate aim is to explain, at the molecular level, the stark differences in spread and disease seen for different V. cholerae ecotypes.

Janet Thornton Fellowship Projects Approach - We will link our existing genomic data, and readouts from in vivo challenge models with high throughput cross-species comparative transcriptomics. By integrating these data using selected species- wide natural isolates we aim to identify biological signatures that define different ecotypes (in its simplest form that would be epidemic vs non-epidemic), We will select phylogenetically diverse V. cholerae isolates for transcriptome analysis using our genome data and approaches we have existing expertise in. These will represent the major lineages defining epidemic and endemic lineages and, where possible, include multiple isolates per lineage to represent the full genetic diversity within those lineages. We will build on our preliminary data, demonstrating differences between 7PET and non-7PET V. cholerae strains, by monitoring RNA from cultures grown to mid-exponential growth phase at 30°C or 37°C. We will combine these data with high-throughput phenotypic analyses generated using the Biolog phenotypic microarray as we have done for other enteric pathogens previously. Using these data, we will determine if either ‘lineage’ or ‘lifestyle’ better explains differences in the observed transcriptional and phenotypic profiles and therefore the patterns of spread and disease globally. To provide support for the machine learning and statistical methods needed we will collaborate with Prof. Jukka Corander (Sanger Institute Associate Faculty; University of Helsinki) who has deep domain expertise in this area. Relevant References Kachroo, P. et al. Integrated analysis of population genomics, transcriptomics and virulence provides novel insights into Streptococcus pyogenes pathogenesis. Nat Genet 51, 548-559, doi:10.1038/s41588- 018-0343-1 (2019). Domman, D. et al. Integrated view of Vibrio cholerae in the Americas. Science 358, 789-793, doi:10.1126/ science.aao2136 (2017) Weill, F. X. et al. Genomic history of the seventh pandemic of cholera in Africa. Science 358, 785-789, doi:10.1126/science.aad5901 (2017). Dorman, M et al.,Genomics of the Argentinian cholera epidemic elucidate the contrasting dynamics of epidemic and endemic Vibrio cholerae. Nat Commun. 2020 Oct 1;11(1):4918. doi: 10.1038/s41467-020- 18647-7. PMID: 33004800.

Janet Thornton Fellowship Projects Integrative analysis of gene expression patterns and allelic diversity in circulating clinical populations of Treponema pallidum subsp. pallidum, the causative agent of syphilis Supervisor: Nicholas Thomson, [email protected] Project type: Laboratory based, with bioinformatics Overall aims - Very little is known about the basic biology and pathogenesis of causative agent of syphilis, T. pallidum subsp. pallidum (TPA), mainly as a result of the inability to propagate these bacteria in axenic culture. Despite being limited only to strains propagated in experimental animals, a recently described in vitro Sf1Ep co-culture system has opened new avenues in treponemal research. The overall aims of this project are to take advantage of this discovery to describe the global gene expression patterns of phylogenetically selected TPA strains using high-throughput transcriptomics, and, correlate the whole transcriptome data with genomic and allelic diversity we see in circulating clinical TPA populations. Background - Syphilis has been a major scourge on human populations for centuries. If untreated, syphilis can lead to severe damage of multiple organs, stillbirth in pregnant women and serious disease in congenitally infected children. Despite the availability of effective treatment, the last decade has witnessed a dramatic global re-emergence of this disease, with the annual worldwide incidence reaching more than 5.6 million, and the number of reported cases more than doubled in USA, Canada and Western Europe. Although several decades of extensive clinical experience have shown the efficacy of treating syphilis with penicillin, the need to administer this antibiotic parenterally has led to the use of second line oral antibiotics, including macrolides (e.g., azithromycin) as first-line drugs for treatment or prophylaxis in some countries. Linked to this there is currently an increasing trend in the number of macrolide - resistant TPA strains across the globe. TPA belongs to a group of pathogenic treponemes causing other human infections including yaws (T. pallidum subsp. pertenue; TPE) and bejel (T. pallidum subsp. endemicum; TEN). Despite these bacterial subspecies being extremely similar at the genomic level (differing in regions covering approximately 20 kbp across the whole genome), the resulting diseases are characterized by different manifestations, level of invasiveness, and transmission route. The high level of conservation means that any insights made in one subspecies will have relevance to the others. This is important because in addition to the increase in TPA infections globally, the WHO has launched a campaign for eradication of yaws by administration of mass azithromycin treatment (macrolide) in countries with a higher prevalence of this disease. This is despite a paucity in our understanding of the basic evolutionary biology of treponemes. The lack of biological insight affects our ability to interpret changes in the genome that differentiate ‘pathotypes’ and threatens our ability to even track their spread or declare their successful eradication. A better basic science understanding of their biology is critical to all these efforts. Until recently, it was not possible to culture pathogenic treponemes in vitro and the experimental approaches have been restricted to the rabbit infection challenge model. As with several bacteria that are recalcitrant to axenic culture, genomics has yielded valuable insights. Using SureSelect technology, we sequenced hundreds of strains isolated directly from clinical material from around the world and provided high-level description of treponemal genomic diversity. Importantly, many of the strains sequenced at the Sanger Institute have also undergone limited passage in the rabbit model, meaning we have access to live treponemes with corresponding genomes. We are currently introducing a new in vitro model for cultivability of TPA, meaning we will be the first laboratory in the UK able to cultivate TPA in vitro and, to our knowledge, the fourth laboratory in the word that successfully adopted this technology. The combination of the “state of art“ skills required for in vitro cultivation of pahogenic treponemes, the access to the treponemal living cells representing different phylogenetic lineages and sublineages, and finally the high throughput next generation sequencing capacity available at Sanger Institute put us to a perfect position to explore the basic biology of TPA beyong genomics, and, for the first time, explore the regulation of gene expression of these pathogens.

Janet Thornton Fellowship Projects Approach - We will link our existing genomic data with high throughput comparative transcriptomics aiming to describe the global gene expression patterns of different TPA strains. We will build on our preliminary data and use already established pipelines for RNA seq experiments. More specifically, we will describe different transcriptional alteration in strains belonging to TPA from two genetically distinct lineages of syphilis (SS14, Nichols) and define important strain differences between the two genetic lineages responsible for the current upturn in disease: biological advantages/disadvantages of particular strains during in vitro cultivation (‘slow’ growing vs. ‘fast’ growing). Consequently, we will be able to provide unique insights into the gene expression profiles of this pathogen in a complex environment. We will clarify which genes of treponemal genomes are highly expressed in culture and differentially expressed between strains. The identified genes and pathways will be compared against the broader diversity of Treponema, enabling an understanding of the essentiality of those functions and the differing frequencies of different alleles showing functional variations and if this is linked to success in their global spread. Relevant References Edmondson DG, Hu B, Norris SJ. Long-Term In Vitro Culture of the Syphilis Spirochete Treponema pallidum subsp. pallidum. mBio. 2018 Jun 26;9(3). Beale MA, Marks M, Sahi SK, Tantalo LC, Nori AV, French P, et al. Genomic epidemiology of syphilis reveals independent emergence of macrolide resistance across multiple circulating lineages. Nat Commun. 2019 Jul 22;10(1):3255. Beale MA, Marks M, Cole MJ, Lee M-K, Pitt R, Ruis C, et al. Contemporary syphilis is characterised by rapid global spread of pandemic Treponema pallidum lineages. medRxiv. 2021 Mar 28;2021.03.25.21250180. Marks M, Fookes M, Wagner J, Butcher R, Ghinai R, Sokana O, et al. Diagnostics for Yaws Eradication: Insights From Direct Next-Generation Sequencing of Cutaneous Strains of Treponema pallidum. Clin Infect Dis. 2018 Mar 5;66(6):818–24.

Role Profile Current job title: Postdoctoral Fellow Reports to: Member of Faculty or other senior scientist Working pattern Equal consideration will be given to individuals who wish to work full time (37 hours p/w), part time or flexibly. Management Training and supervision of graduate and undergraduate responsibility for: students as appropriate Role purpose and To carry out original research within a defined scientific area primary objective appropriate to the team and publish it, while receiving training in research skills from a variety of sources. Core Accountabilities [in approximate order of importance to role purpose]: 1. To plan a programme of research that is original but fits within the general research area of the team, taking into account the relevant literature, own experience, and advice from the team leader and other appropriate scientists. 2. To carry out the research, developing the practical skills required for successful completion. 3. To analyse data and write up results for publication, and to deal with all aspects of the publication process. 4. To communicate the results through other relevant means, such as talking or presenting posters at scientific meetings 5. To seek appropriate training, including taking an active part in any training programmes organised for postdoctoral training fellows. This will include transferable skills training. 6. To take a full part in the general duties of the team, and to pass on skills and knowledge to other team members and visitors. To take part in wider Sanger Institute activities as appropriate. 7. To complete training period in a timely manner, publish the research and document any unpublished data and materials before moving on to a new position. Interacts with Purpose of the interaction Own team and others at Transfer of knowledge, skills, in both directions the Institute Collaborators and other Seeking and passing on knowledge, reagents scientists worldwide as appropriate to project

Describe the most complex/challenging aspects of the role Planning and carrying out research, and striking an appropriate balance between fitting in with the goals of the team and developing their own independent research projects. Knowledge, skills and experience required: E = Essential D = Desirable • PhD in a relevant subject area (E) • Knowledge of a range of research techniques and methodologies in experimental/computational areas (E) • Research expertise in an area that will complement and enhance the Institute’s research strategy and goals (E) • Ability to develop research objectives, projects and proposals for own and joint research, with the assistance of a mentor if required (E) Competencies and Behaviours • Commitment to personal development and updating of knowledge and skills (E) • Working collaboratively with others and building working relationships with stakeholders at all levels (E) • Demonstrates inclusivity and respect for all (E) • Highly developed communication skills to engage effectively with a wide-ranging audience, both orally and in writing, using a range of media (E) • Ability to plan and prioritise own work in order to meet deadlines, including using initiative to plan research programmes (E) • Experience of carrying out both independent and collaborative research (E) Other information about the role not covered elsewhere This is primarily a training post, with associated responsibility of the faculty team leader and Sanger Institute to ensure training is delivered. Eligibility The Janet Thornton Fellowship is open to scientists who: • Have had a break from scientific research, of 12 continuous months or more, for any reason • Are not currently working in scientific research • Have at least one years’ postdoctoral experience • Will be able to start within six months of being offered the role

Application Process Application process One Fellowship per year will be awarded after a competitive selection process, with applicants applying to the broad project. Please contact Dr Saher Ahmed, Head of Equality, Diversity and Inclusion on [email protected], if you would like to discuss the role further or would like support with the application process. Applications should be accompanied by: • a covering letter • a current CV • the names of two referees • the project they are applying to • the reason(s) for their break from scientific research • a career development plan Your applications should be made online via https://jobs.sanger.ac.uk Deadline The deadline for initial applications to the project outline is Sunday 25 July 2021. The project Faculty lead will then work with one selected candidate to further develop the proposal, with a deadline of Thursday 30 September 2021 for final submission. Reasonable adjustments We are committed to creating an environment where everyone can fulfill their potential and thrive. We welcome and encourage applications from all parts of the community. If you require reasonable adjustments during the recruitment process, please contact the recruitment team via [email protected]. Behavioural Competency Framework We strive to create opportunities that spark conversations and inspire new thinking as we pursue our common goal of scientific research to maximise the benefits of knowledge obtained through genome sequences. To guide us, we have recently defined a set of core behaviours that we value and lay out our expectations for everyone. By demonstrating these attitudes and behaviours throughout GRL we will build and support an inclusive culture where every member of our community is respected, heard and supported. We have identified the following six core competencies: • Collaboration • Communication • Leadership • Results-Driven • Innovation • Integrity

Equality, Diversity and Inclusion In April 2020 we were awarded the Athena SWAN Silver award, having been one of the first research institutes to achieve the Bronze award in April 2014. The organisation values the diversity of its employees, students, visiting scientists and collaborators and is committed to providing equal opportunities. The diversity of our workforce is of critical importance in drawing together the talent, skills and experience on which we depend to conduct world-class science and support biomedical discovery. Our strategy is to foster an inclusive culture where everyone can thrive and diversity is celebrated. For more information about EDI at GRL see our Equality in Science Programme: https://www.sanger.ac.uk/about/equality-science Sanger is a workplace that is committed to promoting equity and inclusion and will not discriminate against any job applicant or employee on the grounds of disability, age, gender, marital status, race, colour, nationality, ethnic origin, sexual orientation or religion. Whilst working at Sanger you should always be able to feel respected and appreciated. People are at the heart of everything we do and we nurture and empower our people to thrive. We have a number of staff networks you can be involved in: Wellcome Genome Campus Hinxton Cambridgeshire CB10 1SA UK T: 01223 834244 E: [email protected] www.sanger.ac.uk