Scope

You will collaborate with the FGSL on projects using complex human in vitro models for CRISPR screening to better understand model biology and enable target identification.

You will define the purpose of the screen and the desired outcomes.

Screens will be carried out by scientists employed at Milner Therapeutics Institute (MTI). However, all screens will be run as collaborations to ensure the best possible outcome and data.

You do not need a CRISPR library as provision has been made for library access as part of a collaboration with AstraZeneca and the MTI. However, for small and medium-sized enterprises and industry, we recommend provision of your own library to avoid a conflict of interest.

For more detailed guidance for this opportunity, please visit Connect: Health Tech at the University of Cambridge.

Duration

Duration will be decided on a case-by-case basis and will depend on:

• the model
• its expansion capacity
• the size of the proposed screen

All projects will be highly collaborative.

Input from the proposing lead applicant will be key to understand:

• the model
• the screen of interest
• likely endpoint assays

Funding available

All screens will be run by scientists employed by MTI and the costs for this are borne by MTI and AstraZeneca.

Financial support for screens (consumables) is available either from AstraZeneca (where the model is of interest to AstraZeneca) or from a screening access fund provided by MRC.

You must complete an application form through Connect: Health Tech at the University of Cambridge, where you can request to join ‘Connect: Health Tech’.

You must include details about:

• the in vitro model
• the desired screen
• the end point assay

Please read the guidance for applicants and frequently asked questions as these are likely to address initial questions that you might have. These are available under ‘Resources’.

Email your completed application form to fgslapplications@milner.cam.ac.uk

Additional information in application sections

There are several sections in the application form requesting information beyond the scientific rationale.

Some key pointers to help you are included in the following sections.

This additional information will enable the Joint Steering Committee to make an informed decision regarding the suitability of the model for arrayed CRISPR screening.

Suitability of human in vitro models for screening

Arrayed functional genomic screens can be carried out on a variety of in vitro models, if those models are genetically tractable.

For example, models that have been successfully edited using CRISPR or silenced using siRNA or shRNA can be considered.

Models must also be scalable, with enough material provided or can be produced through culture, to carry out pre-screening protocols and then a suitably sized screen.

Please consider this when indicating the size of screen you are interested in running.

How many genes can be screened?

In theory, the whole protein coding genome (approximately 19,000 genes).

However, in practice most complex in vitro human models do not scale (proliferate) to enable enough material for such a large screen. Therefore, subset CRISPR libraries will probably be recommended and will be based on a gene list of interest that you provide.

Note, arrayed guide RNA libraries for CRISPR screens use three to four guides per gene. Small screens (100 genes) can be run using one individual guide per well (with three wells replicated per guide). However, most screens use three to four guides pooled per well, with three replicate wells per gene for small or medium sized screens.

Biological replicates are not routinely used. Exceptions would be for primary immune cell screens where two to three different donors would be needed to assess the impact of donor variability on screen outcome or where models are based on material from individual patients.

Where screens are large (1,000s of genes), we recommend the initial screen is run in a model derived from one patient and then validation of hits is undertaken in models from three or more different patients.

Whole genome-wide arrayed CRISPR screens are not set up using technical or biological replicates owing to the scale of these screens.

What is meant by a gene list of interest?

Often, arrayed CRISPR screens are carried out to target a defined set of genes that previous research or publications have implicated as being involved in a specific process.

In these cases, you should provide a list of target genes.

Alternatively, CRISPR screens can be run to target genes that encode proteins with a specific function (such as G-protein-coupled receptors or protein kinases) or genes that encode proteins that are known to be druggable targets.

Does your model have licence limitations for use?

As the FGSL is prioritising human in vitro models outside of cancer cell lines, it is anticipated that some models will have use restrictions owing to licence agreements.

Examples of where model sharing could be restricted include, but are not limited to:

• material obtained from biobanks or NHS blood banks
• engineered models that use proprietary vectors or gene expression systems
• patient-derived materials
• induced pluripotent stem cells (iPSCs) from:
  • small and medium-sized enterprises
  • industry collaborators
  • cell line vendors

Please provide as much information about your model as possible

Does your model include primary human tissue (ex vivo samples)?

It will help the process substantially if you note this in the IP or freedom to operate box, indicating:

• where the cells will be sourced from
• any Research Ethics Committee or Human Tissue Authority information
• whether they can be shared with third parties and any restrictions around data sharing

Is your model new and proprietary?

Does your proposed model include cells or iPSCs that have been created (for example, genetically manipulated) by a third party and are not commercially available?

If so, please include this information in the IP or freedom to operate box at the end of the project application form.

Deadline

This is an open opportunity with no closing date.

The first application review deadline is 20 May 2024.

A second application review is planned for November 2024.

The opportunity will remain open for applications, with applications being reviewed by the Joint Steering Committee twice a year (May or June and November or December).

This timeframe may be revised based on application number.

Personal data

The application (including any personal information that it contains) will be shared with MRC (part of UK Research and Innovation (UKRI)), the Milner Therapeutics Institute and AstraZeneca. This is so that they can participate in the assessment process.

For information about how UKRI handles personal data, read UKRI’s privacy notice.

For more information on how University of Cambridge uses personal information, read University of Cambridge’s information compliance, how we use your personal information.

For more information on how AstraZeneca uses personal information, read AstraZeneca’s privacy notice.

Assessment process

The FGSL has a Joint Steering Committee (JSC) to oversee the laboratory.

The JSC has the final decision regarding which applications are accepted for screens and how they are funded.

The JSC is made up of two representatives each from MRC, AstraZeneca and Milner Therapeutics Institute.

The JSC is chaired by the MRC Director of the Functional Genomics Initiative.

The JSC reserves the right to modify the assessment process as needed.

Assessment areas

The assessment areas that will be used are:

• in vivo recapitulation and translatability of biological model
• availability and scalability of the cell model
• feasibility of assay endpoint for screening
• assay controls available
• gene editing feasibility of the cell model

Additional information might be requested from you ahead of decisions being made by the JSC.

Get help with your application

For more detailed guidance for this funding opportunity, please visit Connect Health Tech at the University of Cambridge. This page also contains a question and answer section which can be used for any additional queries.

Completed application forms should be emailed to: fgslapplications@milner.cam.ac.uk

Webinar for potential applicants

The Milner Therapeutic Institute and AstraZeneca will host a webinar on 8 May at 12:30 (UK time).

The webinar will explain the concept of arrayed CRISPR screening, the purpose of the FGSL and address any additional questions applicants might have.

Arrayed screening at the MRC-AZ-University of Cambridge Joint Functional Genomics Screening Laboratory (FGSL).

Background

The FGSL is a joint venture between MRC, AstraZeneca and the Milner Therapeutics Institute, University of Cambridge.

It has been set up to enable UK based academic groups (and where space allows UK based small medium enterprises and industry) to have access to a state-of-the-art arrayed functional genomics screening laboratory.

This is part of the MRC and Biotechnological and Biological Sciences Research Council’s functional genomics initiative.

Each party has made cash and in-kind contributions to enable the establishment and operation of this laboratory.