Wellcome Trust Sanger Institute

Postdoctoral Fellow - CRISPR screening and QTL mapping in neurodegeneration

Wellcome Sanger Institute

Cambridge, United Kingdom

Two postdoctoral positions are available that provide an exciting opportunity to use human induced pluripotent stem cell (hiPSC) derived microglia to screen for genes involved in neurodegeneration, especially Alzheimer’s disease. The positions will be based at the Wellcome Sanger Institute under the leadership of Dr Andrew Bassett, Dr Gosia Trynka and Dr Daniel Gaffney, and will also involve working with collaborators at the University of Oxford. This project forms part of the Open Targets (https://www.opentargets.org/) collaboration between EMBL-EBI (European Bioinformatics Institute), the Wellcome Sanger Institute (Sanger), GSK, Celgene, Sanofi, and Takeda.

The Wellcome Sanger Institute has an exceptional background in human disease genetics, iPSC-based cellular modelling, high throughput CRISPR screening and single cell ‘omics analysis, which will all be employed in this project. The applicants will use natural variation in the form of iPSCs from the HipSci collection to assay effects of genetic variation on gene expression through single cell transcriptomic analysis and on cellular function through high throughput phenotypic assays using QTL mapping techniques. The same phenotypic assays will form the basis for whole genome CRISPR knockout screens to understand the genes critical for these processes. The applicants will have the opportunity to develop disease-relevant phenotypic assays in iPSC-derived microglia and apply these to populations of natural or CRISPR-induced variation along with single cell ‘omics techniques which are already well established. This will allow genome-wide identification of genes involved in important microglial cellular processes that are also relevant for disease biology and will therefore be candidate drug targets for further development.

Candidates with a PhD in a relevant biological discipline with a strong background in genome engineering, human iPSC culture, in vitro differentiation and/or cell-based functional assays are strongly encouraged to apply. Excellent cell culture and molecular biology experience, a strong track record of publication and an ability to work both independently and as part of a team are essential. The post-holder will work closely with both the gene editing R&D (Bassett), immune genomics (Trynka) and genomics of gene regulation (Gaffney) groups at the Sanger Institute and also externally with the Target Discovery Institute in Oxford (Ebner and Cowley) and GSK in Stevenage (Mohamet).

Essential Skills
• PhD in a relevant subject area e.g. Genetics, Cell Biology, Molecular Biology.
• Strong track record of publications.
• Extensive proven experience of mammalian cell culture.
• In depth knowledge of genome engineering techniques (including genome-wide screening) and stem cell biology (especially in vitrodifferentiation).
• Significant experience in molecular biology techniques e.g. vector design and construction, high throughput sequencing library prep, etc.
• Self-motivated with an ability to work independently on projects to the point of publication, as well as part of a team.
• Exceptional written and oral communication, organisational and presentation skills.
• Ability to work to tight deadlines.
• Ability to test and implement new assays and techniques including their troubleshooting.
Ideal Skills
• Knowledge of microglial biology and neuroinflammation and their role in neurodegeneration.
• Practical experience with human iPS or ES cells.
• Experience with in vitro differentiation of mouse or human stem cells.
• Practical experience with genome engineering techniques (e.g. CRISPR).
• Experience in phenotypic assay development (e.g. phagocytosis, cytokine release, autophagy, etc.) in either a pooled (e.g. FACS) or arrayed (e.g. Incucyte, Luminex bead) setting.
• Practical application of genome-wide genetic screens.
• Experience with generation and analysis of genomics datasets (e.g. RNA-seq, ATAC-seq, ChIP-seq) especially single cell ‘omics.
• Experience of advanced cloning techniques (e.g. recombineering, golden gate, Gibson assembly, etc.).

Other information
One of the two positions will involve a 12-18 month secondment, starting in the first year, to the Target Discovery Institute in Oxford University (Ebner) to develop and execute a genome-wide CRISPR screen in microglia.

The cellular research and development group (Bassett) is interested in the development of genome editing techniques, cellular differentiation and cellular phenotyping systems, especially with respect to high-throughput investigation of gene and non-coding regulatory element function in neurodegenerative disease. The immunogenomics group (Trynka) aim to understand the mechanisms through which genomic variants act to disrupt critical molecular pathways in the human immune system that cause disease with a goal to map genetic variants to functional cellular effects. The genomics of gene regulation group (Gaffney) aims to understand how regulatory variants alter cellular phenotypes.

The Wellcome Sanger Institute offers a world-class academic environment, access to cutting edge sequencing facilities and extensive expertise in genome analysis and human genetics.

For further information please see https://www.sanger.ac.uk/science/groups/gene-editing-and-cellular-research-and-development, https://www.sanger.ac.uk/science/groups/trynka-faculty, https://www.tdi.ox.ac.uk/research/research/cellular-high-throughput-screening-htsand https://www.sanger.ac.uk/science/groups/gaffney-groupor contact Andrew Bassett (ab42@sanger.ac.uk) or Gosia Trynka (gosia@sanger.ac.uk) for specific details.
Closing date: 17 January 2020

About Us
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. Our findings are used to improve health and to understand life on Earth. Find out more at www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn, Youtube and on our Blog.
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Set across 130 acres, just outside of Cambridge, The Sanger Institute is located on the stunning Wellcome Genome Campus. Home to some of the world’s foremost institutes and organisations in genomics and computational biology, committed to delivering life-changing science with the reach, scale, and creativity to solve some of humanity’s greatest challenges.

Our benefits:
There’s an attractive benefits package on offer at the Genome Wellcome Campus. We appreciate the importance of achieving work-life balance and support this with a number of family and carer-friendly policies. Plus a flexible working policy for those who may wish to amend their working pattern or arrangement.
As well as the usual benefits you would expect, we go much further:
• 25 days annual leave (extra 1 day to a maximum of 30 days for every year you work)
• Auto-enrolment into a generous Group Defined Contribution Pension Scheme, with enhanced company contribution (for more information, see our Pensions page)
• Up to 2 days annual paid volunteering leave
• Up to 10 days paid Emergency Carers Leave per year
• Family friendly environment including options for flexible and part-time working, an on-site Workplace Nursery salary Sacrifice Schemes for pre-school children and Summer holiday club
• Life Assurance Cover and a Group Income Protection Scheme (if on a contract of 12 months or more)
• Enhanced maternity leave and parental leave
• Access to substantial number of courses and training events onsite
• Private Healthcare Scheme (after 6 months service)
• Eyecare and Dental payment plans
• Concessions and discounts from our corporate perks site

Being part of the Genome Wellcome Campus you will be part of the beautiful working environment with an impressive range of benefits, services and facilities also including:
• Free bus service to and from Campus, covering various routes around Cambridge, Saffron Walden and surrounding villages
• A car-share initiative
• Free parking
• A number of on-site venues where you can meet, eat and socialise with colleagues
• A thriving Sports and Social Club which provides members with subsidised access to a gym, tennis courts, sports hall, fitness classes and a vibrant social calendar of events

Find out more about our Genome Wellcome Campus.

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About Open Targets
Open Targets is a pioneering public-private partnership between EMBL-EBI (European Bioinformatics Institute), GlaxoSmithKline (GSK), the Wellcome Sanger Institute (Sanger), Celgene, Sanofi and Takeda, located on the Wellcome Genome Campus in Hinxton, near Cambridge, UK.

Open Targets brings together expertise from six complementary institutions to generate evidence on the biological validity of therapeutic targets and provide an initial assessment of the likely effectiveness of pharmacological intervention on these targets, using genome-scale experiments and analysis. Open Targets aims to provide an R&D framework that applies to all aspects of human disease, to improve the success rate for discovering new medicines and share its data openly in the interests of accelerating drug discovery.

Please apply via recruiter’s website.