Janet Thornton Fellowship

Sanger Institute, Genome Research Limited

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 will be awarded each year. Each Fellowship will last for three years and can be worked full time, part time or flexibly.

Fellowships will be 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 supervisor.

While the Sanger Institute provides the opportunity in its recruitment processes for job applicants to declare career breaks (taken for any reason) so that they can be taken into account when assessing applications for all roles, particularly in relation to the potential impact of time out on individuals’ scientific and career outputs, this fellowship will be open exclusively to those who have taken a career break of 12 months or more.

If you would like to learn more about a day in a life of a Janet Thornton Fellow click here

Eligibility Criteria

  • Minimum of 12 months break from scientific research, for any reason
  • At least one year’s postdoctoral research experience
  • Not currently working in a scientific research role
  • Applicants must start the Fellowship within 6 months of being offered the position.

Application process

One Fellowship per year will be awarded after a competitive selection process, with applicants applying to the broad project outlines defined below.

Applications are made via our recruitment process and applicants are asked to provide:

  • 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.

Deadline

Applications have now closed for 2021.

Details of the Fellowship

Fellowships last three years and can be worked full-time, part-time or flexibly. The Fellowship includes:

  • Full time (or equivalent) salary based on budgeted costs for postdocs for 2021, currently  – £32,780 – £41,093
  • Consumables of up to £18,000 per annum, dependant on the nature of the project.
  • A budget of £1,500 per annum for the Fellow to attend conferences or training.

 

Contact

For further information, please contact: Dr Saher Ahmed: saher.ahmed@sanger.ac.uk

Example of the 2021 Projects

Anderson/McIntyre - CRISPR/Cas screens to dissect the cellular networks that drive inflammatory bowel disease

The experimental arm of the Anderson Lab at the Wellcome Sanger Institute, 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 the Wellcome Sanger Institute last year.

Candidates with a strong background in immunology or mucosal immunology are encouraged to apply.

Teichmann Project - Genomic and computational dissection of tissue architectures

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.

 

Thomson Project - Integrating comparative high-throughput whole genome transcriptomics and phenotyping: comparing endemic and epidemic Vibrio cholerae

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.

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.

 

Thomson Project 2 - Integrative analysis of gene expression patterns and allelic diversity in circulating clinical populations of Treponema pallidum subsp. pallidum, the causative agent of syphilis

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 is 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 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 forth 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.

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.