Senior Laboratory Research Scientist

Job title: Senior Laboratory Research Scientist – Cell Scientist High Throughput Screening STP, Intractable Target Cell Biology, AZ-Crick-Imperial College, Molecular Glue Discovery Partnership

Reporting to: Michael Howell, Head of High Throughput Screening STP

Contact term: This is a full-time, fixed term 4 years position on Crick terms and conditions of employment.

The Partnership

The newly funded Molecular Glue Discovery Partnership represents an exciting new research partnership between the Francis Crick Institute and Imperial College working in close collaboration with AstraZeneca, to develop systematic approaches to exploit endogenous protein degradation pathways to target un-druggable disease-relevant proteins or protein complexes. By combining fundamental biology with proteomics, high throughput screening, protein engineering and chemical biology approaches, we seek to discover and develop new molecular glues to induce degradation of proteins of interests through the ubiquitin proteasome system or autophagy (Kozicka et al. Cell Chem Biol 2021, Słabicki et al. Nature 2020). The ultimate aim is to unlock novel biology and exploit the revolutionary therapeutic potential of glue degraders. This work is funded through an £11.2M leveraged public- industry grant and will bring together bringing together a team of 12 postdoctoral biochemists, cell, structural and chemical biologists and 3 PhD students working across 8 laboratories and scientific technology platforms (STPs) at the Francis Crick Institute with a wide range of expertise and biological interests:

Oncogene Biology - Head: Julian Downward  http://shorturl.at/fhmEV

Cellular Degradation Systems - Head: Anne Schreiber http://shorturl.at/cloCT

Cancer Epigenetics – Head: Paola Scaffidi  http://shorturl.at/bcxB9

Visual Biochemistry – Head: Radoslav Enchev http://shorturl.at/y3467

High Throughput Screening – Head: Michael Howell  http://shorturl.at/dDEN4 

Proteomics – Head: Mark Skehel  http://shorturl.at/deHZ0

Scientific Computing: Karen Ambrose/ Amy Strange  http://shorturl.at/acmoU

Chemical Biology - Head: Ed Tate http://shorturl.at/aboQ8

The High Throughput Screening STP

The High Throughput Screening (HTS) facility is one of the core technology platforms available to all researchers at the Crick and enables them to use screening techniques as part of their research. Activities can include, but are not restricted to, genome-wide CRISPR and RNAi screens, large-scale cell-based screens with collections of well-characterised small molecules or proof-of-concept drug discovery screens and the development of novel screening platforms as required by researchers. For example, our recent development of a high throughput neutralisation assay to assess the ability of patient serum to prevent infection by variants of concern has now been spun off as a separate unit within the Crick (see references). In addition, we use our knowledge and technologies to automate and improve current research practises e.g. making and selecting CRISPR knockout cell lines.  Areas of recent expansion include genome-wide CRISPR screening with infectious agents, arrayed CRISPRa screening in human ES and iPSC and small molecule screening in mouse organoid models.

PROJECT SUMMARY

HTS staff collaborate with researchers to create biologically relevant and informative cell-based assays for genome-wide CRISPR, siRNA or chemical screens. We also use our skills to assist in the development of smaller-scale assays, create reagents for novel assays, collaborative to improve research techniques and collaborate with internal and external pharma partners to perform proof of concept or early stage drug discovery screens.

We are seeking an enthusiastic Senior Laboratory Research Scientist to validate and execute proximity-based cell screens and cell-free assays for identification and validation of molecular glue degraders. The large majority of intractable targets may only be correctly folded in cells where they bind to other proteins, nucleic acids, metabolites, etc. to exercise their function(s). Such targets require development of high-throughput screens in cellular or reconstituted native environments; in addition, molecular glue hits in primary screen are expected to be low affinity, requiring development of sensitive cellular screening assays.

This position will require you to collaborate with researchers to co-develop assays, plan and conduct large-scale screens balancing a number of distinct projects at different levels of development simultaneously. This is an opportunity to use your accumulated biology knowledge and curiosity about other areas of biology as well as your skills at the bench and desire to try new things towards creating the most informative and valuable research data possible.  You will work with highly experienced colleagues and collaborators in an institute that values discovery without boundaries.

KEY RESPONSIBILITIES

These include but not limited to;

• Running multiple screening projects simultaneously
• in vitro and cellular assay development
• Ensuring your domain specific knowlwdge is sufficient to create optimal assays
• Managing workload, coordinating and maintaining a productive dialogue with all partnership members
• Keep up to date with the activities in the Partnership to anticipate future needs

Key experience and competencies

The post holder should embody and demonstrate our core Crick values: bold, open, and collegial, in addition to the following:

Essential

• Extensive direct experience in using and developing both cell-free and cell-based assays,
• Extensive direct experience of a range tissue culture systems.  Ideally direct experience of cell or biochemical proximity assays
• Previous direct experience of HTS campaigns in either Pharma or academia
• Demonstrable practical experience with high throughput screening techniques and associated machinery
• Able to maintain a productive dialogue with facility users and educate users in techniques and use of specific machines for high throughput screening
• Ability to quickly understand and appreciate unfamiliar areas of biology in order to create the best assay possible with users
• Capable of self-teaching. Innovation and problem solving
• Self-motivated with the ability to work both independently and as part of a team
• Excellent organisation and communication skills

Desirable:

• Familiarity with a wide range of research techniques and biological systems
• Post-doctoral research experience or extensive relevant experience in Pharma a distinct advantage
• Demonstrable organisational skills and attention to detail, with the ability to prioritise own workload.
• Excellent inter-personal skills and a willingness to learn new skills and teach these to others
• Previous experience of service provision preferred