Postdoctoral Fellow - Nanometre-scale in situ mechanisms of antisense oligonucleotide (ASO) induced toxicity

R-180893: Postdoctoral Fellow - Nanometre-scale in situ mechanisms of antisense oligonucleotide (ASO) induced toxicity

Location: The Discovery Centre, Cambridge Biomedical Campus, Cambridge, UK

Competitive Salary, Bonus & Benefits Package

Are you passionate about imaging technologies and have strong background in data analysis? Would you like to work in an interdisciplinary industrial and academic team at the cutting-edge of drug development and translational medicine? Then join the Imaging and AI group at AstraZeneca and unlock the power of what science can do.

About AstraZeneca

AstraZeneca is a global, science-led, patient-centred biopharmaceutical company focusing on discovering, developing, and commercialising prescription medicines for some of the world’s most serious diseases. But we’re more than a global leading pharmaceutical company. At AstraZeneca, we're dedicated to being a Great Place to Work and empowering employees to push the boundaries of science and fuel their entrepreneurial spirit.

About our Postdoc Programme

Bring expertise, apply knowledge, follow the science, and make a difference.

AstraZeneca’s Postdoc Programme is for self-motivated individuals looking to deliver exciting projects in an encouraging, engaging, and innovative environment. Being part of this programme means working with multidisciplinary scientific teams from a diverse set of backgrounds and a world-class academic mentor. Our postdocs are respected as specialists, encouraged to speak up, and supported to share their research at conferences, publish papers, achieve their goals.

Make a more meaningful impact, with greater ownership and accountability to make a contribution, whilst making a difference to the lives of our patients!

This is a 3-year programme.

About the Opportunity

This is an exciting collaboration with the MRC Toxicology Unit at the University of Cambridge, harnessing their expertise in super-resolution fluorescence imaging and volume EM-based ultrastructural pathology to complement our internal expertise with ASO toxicity, targeted delivery as well as imaging and data analysis. This project will reveal how ASO internalisation, trafficking and high-order assembly is associated with their toxicity.

The position sites within AZ’s BioPharmaceuticals unit, responsible for our key therapy areas of Cardiovascular, Renal & Metabolism and Respiratory & Immunology and Vaccines & Immune Therapies. BioPharmaceuticals is unified in our approach to deliver life-changing medicines for people living with the most common chronic diseases.

We are looking for a dedicated Postdoctoral Fellow to help develop novel RNA therapeutics making sure they are more targeted and safer for patients. We will achieve our ambition of redefining healthcare through our hardworking teams and partners using scientific, medical and commercial innovation.

Project Focus

ASOs are a novel therapeutic modality with high promise but there is little knowledge about their intracellular trafficking and molecular toxicity mechanisms. Multiple recent publications have proven how chemical modifications of ASOs can have significant effects on their subcellular localisation and resulting toxicity profiles, including to optimally reduce binding to intracellular proteins, altering localisation ameliorating toxicity, with minimal impairment of activity. For the development of novel ASO targeting methods, it is essential to understand the impact of ASO modifications on subcellular transport for successful rational design.

Analysis of cellular organisation at the nanometer scale as a readout of toxicity allows to look globally at the cell state in healthy and toxic conditions and has the potential to reveal novel mechanisms of toxicity. We strive for this project to result in high impact publication about ASO endosomal trafficking and escape. ASO endosomal trafficking is a highly relevant, unanswered question in the field, and using novel and innovative technologies that have not previously been used in this area to generate novel insights.

This is a partnership with the MRC Toxicology Unit to access pioneering technologies with the potential to address key hypotheses associated with ASO toxicity.We anticipate that development of a novel superresolution and vEM imaging pipeline will also be translatable to other tissue/cells and therapeutic modalities, and that intracellular trafficking and protein interactions will be of increasing importance with the use of biological drug modalities.

You’ll report to Stephanie Ling (Associate Director, Biopharmaceuticals Imaging Lead) in the Imaging and AI group in CPSS Imaging & Data Analytics. Stephanie has broad expertise in in vivo imaging to ex vivo imaging methodologies, from histology, immunocytochemistry, highly multiplex imaging to spatial multi-omic analysis.

Working alongside Sebastian Prill, Associate Director, Hepatic Safety, with expertise in ASO biology and advanced cell models in this project, we strive to demonstrate internal and external strengths to accelerate and deliver novel solutions to understand the trafficking of antisense oligonucleotides.

You'll also receive academic mentorship and guidance from Dr. Vito Mennella (University of Cambridge, School of Biological Sciences, MRC Toxicology Unit). Dr. Mennella employs airway primary cellular models from lung compartments to understand how different molecular insults affect pathways linked to airway defence.

What You’ll Do

We are looking for a highly independent and collaborative postdoc to:

• Establish preclinical human airway and liver cellular models and leverage super-resolution live and fixed cell imaging to establish the cellular trafficking of different ASOs, how and where endosomal escape occurs
• Track effects of the ASOs on cellular organization and function by analysing the effect of ASO treatment on multiple organelles including endosomal subcompartments, their morphology and health using volumetric EM with AI-CNN (Artificial Intelligence Convoluted Neural Network) driven segmentation.
• Collaborate with other groups within AZ and University of Cambridge to follow up on hypotheses generated using high-throughput and multi-omic methodologies including RNAseq, CRISPR screens, RNA- and protein-pull down interactome assays alongside in-depth data analysis to generate insight into ASO toxicity

Qualification, Skills & Experience

Essential Requirements

• PhD in cell biology, biochemistry, pharmacology, biophysics or related areas
• Strong experience in human (primary) cell culture models
• Strong experience in imaging (live and super-resolution preferred)
• Experience in image, data, and statistical analysis (e.g., Fiji, Segmentation algorithm, R)
• In-depth knowledge of cell biology
• Emerging scientific leadership and experience in scientific writing, evidenced by publications in peer-reviewed literature

Desirable Requirements

• Experience in endosome biology and trafficking
• An understanding of image-based AI models
• Experience with therapeutic oligonucleotides
• Experience in high-throughput sample handling and imaging
• Python coding
• Experience with EM sample preparation and imaging

Reasons to Apply

Work in an industry-leading group with a strong publication track record and be supported by a leading academic supervisor.

As a respected specialist, we will support you to take appropriate risks, lead the project and “run with it”.

Why AstraZeneca

The unique positioning of this postdoc within a pharmaceutical company such as AZ means that you will be able to access and generate publications on large datasets which are not available in the public domain. Moreover, having the satisfaction of knowing that methods and techniques developed will not only be published but have the immediate potential to also be put into practice for the development of novel therapeutics, in real-life projects, and that ultimately the work you do will directly impact patients’ lives!

As a key member of a research group and taking a leading role on a Postdoctoral project, we expect regular attendance - a minimum of 3 days per week on the AstraZeneca campus. For laboratory-based scientists, this may be higher.

Given the unique positioning of our Postdoctoral researchers, you may have an additional opportunity to spend some time with an external academic mentor. In this instance, you may be required to spend some of your time working alongside them at their facility as driven by the research project. Your flexibility to meet the needs of the research and the scope of the project is required, and we also look to support you with flexibility in accordance with our standard work policies.

Next Steps

If your passion is science be part of a team that makes a bigger impact on patients’ lives, then there’s no better place to be.

This advert will be running from Monday, 23rd October 2023 and, we welcome your application as soon as possible, but ahead of the scheduled closing date of Sunday, 14th January 2024. In the event that we identify suitable candidates ahead of the scheduled closing date, we reserve the right to withdraw the vacancy earlier than published.

Find Out More

AstraZeneca - Safety/CPSS CVRM, Biopharma: https://www.astrazeneca.com/our-therapy-areas/biopharmaceuticals.html

Dr Vito Mennella: https://www.mrc-tox.cam.ac.uk/research/research-groups/mennella-group

AZ’s Postdoc Programme: https://careers.astrazeneca.com/postdocs-astrazeneca

Life at AstraZeneca: https://careers.astrazeneca.com/life-at-astrazeneca

This is what we’re made of: https://www.youtube.com/watch?v=pmFx_jr2eFo&t=2s

AstraZeneca embraces diversity and equality of opportunity. We are committed to building an inclusive and diverse team representing all backgrounds, with as wide a range of perspectives as possible, and harnessing industry-leading skills. We believe that the more inclusive we are, the better our work will be. We welcome and consider applications to join our team from all qualified candidates, regardless of their characteristics. We follow all applicable laws and regulations on non-discrimination in employment (and recruitment), as well as work authorisation and employment eligibility verification requirements.

Date Posted

Closing Date

AstraZeneca embraces diversity and equality of opportunity. We are committed to building an inclusive and diverse team representing all backgrounds, with as wide a range of perspectives as possible, and harnessing industry-leading skills. We believe that the more inclusive we are, the better our work will be. We welcome and consider applications to join our team from all qualified candidates, regardless of their characteristics. We comply with all applicable laws and regulations on non-discrimination in employment (and recruitment), as well as work authorization and employment eligibility verification requirements.