The rise of CRISPR was rapid and remarkable. Only discovered in 2012, the CRISPR system is now widely used in genetic engineering for several reasons: it is a very simple and at the same time precise gene-editing technique that is easy to use and still cheaper than any other comparable method. In contrast, other state-of-the-art gene-editing tools are often difficult to handle, lack specificity and may lead to off-target effects.
CRISPR enables researchers to cut DNA precisely at a defined location. Consequently, this also allows the targeted insertion or deletion of genes or other specified DNA fragments. All you need is to know the sequence where Cas, mainly Cas9, is supposed to cut the DNA and then design the respective spacer-repeat sequence. But this is easier said than done.
Hence, the bioinformatics company Desktop Genetics, based in the UK, wants to support scientists in constructing tailored sequences for CRISPR research. “We are focussed primarily on CRISPR genome editing from the perspective of design, cloning and data analysis,” explains Leigh Brody, Director of Genomic Services at Desktop Genetics. “We aim to revolutionise the way researchers use CRISPR genome editing technology.”
Recently, Innovate UK, an organisation that promotes innovation in science and technology in the UK, funded collaboration between Desktop Genetics Ltd and the Epigenetics Unit, led by Robert Brown in the Division of Cancer at the Imperial College London with £300,000 (€388,000). One of the project's goals is to “develop and validate software tools to design and test site-specific epigenetic CRISPR systems to target drug resistance mechanisms in cancer cells”.
Brown’s research focusses on the role of epigenetics in ovarian cancer, its influence on drug resistance and how this can be overcome. “Epigenetic silencing of gene expression can affect tumour development and response to therapy,” Brown explains. DNA methylation or acetylation as well as histone modifications affect chromatin structure and thereby inhibit or enhance gene transcription. “All tumours show aberrant DNA methylation compared to normal tissue. Many of the genes that are hallmarks of cancer can become methylated and their expression silenced, including tumour suppressor genes,” details Brown, whose research mainly concerns drug resistance associated genes. “Silencing of genes, which make tumours sensitive to chemotherapy, can make them resistant, while silencing of other genes can also conversely make them more sensitive [to chemotherapeutics].”
Brown expects from the collaboration with Desktop Genetics an increased mechanistic understanding of epigenetics in cancer, optimisation of epigenetic targeting using CRISPR and a proof of concept of epigenetic editing. “The aim is to make constructs that link CRISPR with epigenetic modifiers, so that genes can be switched on or off in tumour cells in a targeted manner,” he summarises. The outcome of this project could then also be transferred to other kinds of tumours.
The data gathered by Brown and his research team in the laboratory are analysed by bioinformaticians at Desktop Genetics. “We will work with the experts at the Epigenetics Unit to interpret the data,” Brody commented. The aim is to design specific CRISPR targets in ovarian cancer cell lines using software tools and to validate their function. Brody outlines, “Short-term milestones include characterisation of the cell lines of interest and building the software tools to do so. The mid-term milestone is to find a scalable way to perform epigenetic CRISPR genome editing. In the long-term, we expect to build software tools that can support multiple -omics datasets in any cancer cell line.”
Brown’s long-term objective is to transfer the obtained results into the clinic by elucidating potential CRISPR targets and thereby overcoming drug resistance in chemotherapy. Although this current project is meant to be a proof of concept, Desktop Genetics would like to transfer its outcomes to develop software tools for a wider life science population. “Given the key role of epigenetics in all tumour types, we expect our software tools to have potential applications across all types of cancer and other diseases,” Brody explains.
Treatment of tumours by specifically targeting genes and reversing aberrant epigenetic changes that are responsible for drug resistance or tumour progression has the potential to revolutionise cancer therapy. The collaboration of Brown’s research team and Desktop Genetics could not only provide the required proof of concept but may also validate novel targets in cancer using CRISPR, bringing us one step closer to the desired aim of personalised medicine.
Stefanie Haas
Photo: www.publicdomainpictures.net/Petr Kratochvil