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Selecting appropriate host cells for genetic manipulation is a key aspect of experimental design and applies both to CRISPR screens and custom cell model generation. A trade‐off may need to be considered between physiological relevance (tissue origin and/or differentiation state) and technical feasibility. This is because most primary cells can only be cultured in the laboratory for a limited number of days and therefore researchers often choose immortalized cell lines as the next best alternative to conduct their research. For example, Yeung and colleagues used the THP‐1 cell line as a proxy for macrophages and performed a genome‐wide screen to identify loss‐of‐function mutations conferring resistance to Salmonella uptake (Yeung et al. 2019). Shang and colleagues used Jurkat cells as proxy for primary T cells and performed a genome‐wide screen to identify genes that regulate T cell activation upon anti‐T cell receptor (TCR) stimulation. Recently, strategies like gRNA lentiviral infection with Cas9 protein electroporation (SLICE) were developed to overcome the requirement for stably expressing Cas9 cells and have enabled genetic screens to occur in primary human cells (Shifrut et al. 2018). However, not many CROs have the ability to conduct such technically demanding types of genetic screens.

When work is to be carried out in non‐primary cells, several aspects should be considered to help you choose the right cellular host. These have been extensively discussed in a review by Kimberland and colleagues (Kimberland et al. 2018). They include information on chromosome ploidy, genetic stability, and clonality. For most cancer cell lines, multi‐omic information can already be accessed through datasets, such as the Cancer Cell Line Encyclopedia (https://portals.broadinstitute.org/ccle/about) (Ghandi et al. 2019), the Cell Model Passports portal (https://cellmodelpassports.sanger.ac.uk/) (van der Meer et al. 2019), or the Cancer Dependency Map portals (https://depmap.org/portal/ & https://depmap.sanger.ac.uk/). This information enables researchers to bioinformatically interogate their cell line of interest and make informed decisions on how similar it is to their tissue of interest. Moreover, online tools such as Cellector faciliate the selection of the most appropriate model to use based on similarity to patient samples (https://ot‐cellector.shinyapps.io/CELLector_App/). We would also recommend discussing with the CRO what assays they routinely use to validate the cell lines used in their work, and if needed draft additional testing as part of the contract research. In our experience, array comparative genomic hybridization (aCGH) plus SNP genome analysis provides a cost‐effective and quick survey of the host cell lines. aCGH detects structural and numeric chromosomal alterations, while SNP analysis allows detection of polyploidy, loss of heterozygosity, and uniparental disomy (Wiszniewska et al. 2014). Such information ensures that the genetic makeup of the cell line used matches the parental cell line.