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Engineering cell lines: From basic biology to better disease models

Horizon Discovery is a world leader in gene editing and gene modulation technologies. Horizon develops genetically engineered cell models using its suite of DNA editing tools (rAAV, ZFN, CRISPR and Transposon). From this, Horizon offers a range of products and services that enable researchers to alter almost any gene or to modulate its function in human or other mammalian cell lines. This help the understanding of the role of genomics in disease; the development of drug discovery assays and screens; and the production of biotherapeutics and diagnostic tools. Based in the UK, Horizon works with the world’s leading academic institutes and top pharmaceutical companies. Here, Dr Jamie Freeman discusses how Horizon Discovery engineers cell lines to enable deeper understanding of basic biology of disease or build better disease models.

What are the key applications for Horizon Discovery’s engineered cell lines?

Engineered cell lines play a role in all aspects of cell biology research. For example, academic researchers might want to use a cell line as a better disease model to help them understand the basic biology of the disease. In pharma or biotech, drug developers might want to understand how mutations affect drug response or resistance, and this is made clearer by studying cell lines that contain these physiological mutations. Understanding the mechanisms underlying differences in drug responsiveness can help with target identification and validation, and even to stratify patients for more efficient and effective clinical trials.

What makes Horizon Discovery different?

Horizon was founded 11 years ago based on the power of the rAAV gene editing platform to generate isogenic cell lines containing virtually any genomic modification. Since then we have adopted other cutting-edge technologies, including CRISPR-Cas9 and ZFNs, and we have even developed our own transposon technology. Over the years, we have worked with more than 100 different cell lines, performing more than 2000 edits with a success rate of 95% in 2017. With each new cell line and challenge overcome, we build on our knowledge, leading to us becoming global leaders in this application of genome engineering.

Our in-house expertise with these different approaches means that we can use the best possible technology for every project we’re involved in, giving customers confidence in our ability to provide the edit they need. This includes work in innovative fields such as the use of induced Pluripotent Stem Cells (iPSCs), which are a rapidly expanding area of research. We have extensive experience of engineering our customer’s iPSCs, with around 20% of our projects in 2017 involving these technically challenging cells. By partnering with key providers of iPSCs, we can now provide access to iPS cell-derived neurodegenerative and metabolic disease models. This has extended our capabilities, allowing us to provide an end-to-end service that supplies terminally differentiated engineered and parental cells in a wide range of backgrounds.

How does the Horizon process work?

The entire process is very collaborative, with liaison and discussion throughout the lifetime of a project. We become familiar with what is needed, based around the purpose of research and the specific gene modification required. Once we know this, we can make recommendations based on our extensive experience to help determine the scope of the project, taking into consideration the predicted editing efficiency and the required level of validation.

All of our engineering is carried out on-site in Cambridge, UK, and each project is individually managed, allowing us to forge a close relationship between Horizon, our customers and the project. We see the process very much as a partnership, with recommendations on how to proceed reached through discussion with the customer and based on the utility of the final line.

Many projects that we perform are on the critical path to success for the company involved. We understand the importance of these projects to our customers and will use all of the extensive techniques and knowledge at our disposal to ensure a positive outcome.

How long does the process take?

The timeline really does depend on the biology. If we are creating a knockout edit in a commonly-used cell line, then it could take just 12 to 16 weeks. However, if it is a complex or difficult edit or a slow-growing cell line, then it takes longer. The knowledge gained from overcoming technical obstacles is then often incorporated into our standard workflow to improve our processes across the board. For example, we now routinely work with THP-1 macrophage cells after investing significant time optimising the conditions to work with this notoriously difficult cell line.

Are all of the edited cell lines bespoke products?

We have a catalogue of more than 3000 off-the-shelf edited cell lines. These provide an alternative option to the custom gene-edited cell lines, particularly for time- or cost-sensitive projects. Our Dharmacon subsidiary also supports researchers who want to carry out their own cell-line engineering by providing a variety of excellent gene-modulation reagents. As well as offering custom genome engineering services, we are leaders in the provision of comprehensive screening services, including whole genome CRISPRko, CRISPRa and CRISPRi screening.

What’s next for Horizon?

We want to continue to develop innovative technology, so we can provide access to different tools for different people. Genome editing in clinical applications is a rapidly-advancing field where we are very well placed from a skills and IP perspective to support our partners in engineering cells for direct therapeutic purposes. We also recently gained exclusive rights to a new technology platform based on a type of transposase called Helitrons. This technology allows us to deliver a gene of interest into a genome, and could have potential implications in cell and gene therapy.


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