Opening up the genetic ‘black box’ driving disease


Summary: Selecting the right target is the single most important decision we make in the drug discovery process because the primary reason for failure of a candidate drug in clinical trials is not down to safety or chemistry but efficacy – how effective it is at altering the course of disease. Functional genomics is a rapidly evolving drug discovery platform that specifically investigates the link between the information contained in our DNA or genome and the functional effects of this information. In other words, the ‘black box’ between our genes (genotype) and their effects (phenotype) in health and disease.


The ‘molecular scissors’ editing genes

A number of technologies are available to study functional genomics. But by far the most effective and versatile is the revolutionary gene editing technology CRISPR/Cas9 – or CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) – clusters of short, palindromic DNA sequences in the bacterial genome.

CRISPR works by deploying guide RNA (gRNA) as a homing device for a specific section of DNA within the genome. This guides Cas9 nuclease, an enzyme acting as ‘molecular scissors’, to snip the DNA at the selected point, activating the cell’s own DNA-repair apparatus. Specific sequences within the gene can then either be modified or the entire gene deleted and replaced by a new DNA sequence.

The ability to ‘edit’ genes using CRISPR may be one of the most significant discoveries in the history of biology. It not only has potential as a future therapeutic for treating diseases with a genetic basis but it also has a major role to play in drug discovery, which is why AstraZeneca became one of the first pharmaceutical companies to invest in the technology, setting up dedicated research groups in Gothenburg and Cambridge in 2014. It is now possible to create libraries of CRISPR reagents covering the activation or deletion of every gene in the genome to help identify both specific genes involved in the control of biological processes and those that mediate resistance or sensitisation to medicines. By understanding how these gene changes can affect the functionality of a protein in a cell, our scientists can start to hone-in on those that are responsible for the development of the complex diseases we are aiming to treat, modify and in the future, even cure.



Cutting edge: Pinpointing the drivers of disease

Functional genomics, enabled by CRISPR, has transformed the landscape of drug target identification.

CRISPR is fast, simple, cost-effective and reliable, generating clean, high-quality, dependable results. This precise genetic editing achievable with CRISPR enables scientists to deliber­ately activate or suppress (‘knock out’) specific genes, enabling them to pinpoint those that may cause - or worsen - disease, as well as those with potentially protective effects.


By targeting every single gene in the genome and understanding the networks in which they function, hand-in-hand with novel treatment approaches such as antisense oligonucleotides, we can expand the therapeutic world that is available to us.

Steve Rees VP Discovery Biology, Discovery Sciences, R&D

This knock-out screening has the potential to identify genes involved in resistance to cancer medicines and is fast becoming one of its most widely used applications. CRISPR can also be used to simulate human disease states by neatly manipulating genes in cell lines and animal models, creating valuable preclinical testbeds for potential drugs in far less time than previously required. CRISPR is also well suited to high throughput functional genomic screening after which bioinformatic analysis, machine learning and artificial intelligence (AI) make sense of the findings, identify the interrelationships of genes working in clusters or complex networks and gain a ‘big picture’ perspective on which pieces of the puzzle matter most.


The key to maximising the chances of success in target identification lies in the pairing of the latest genome editing technologies with bioinformatics and AI to efficiently analyse the data generated from screenings.

Davide Gianni Director, Functional Genomics, Discovery Sciences, R&D

The CRISPR collaborations accelerating the discovery of new cancer medicines

  • In 2018, we set up the Joint AstraZeneca-Cancer Research UK (CRUK) Functional Genomics Centre at the Milner Therapeutics Institute at the University of Cambridge. The centre is a world-leader in genetic screening, cancer models, CRISPR reagent design and computational approaches to big data processing, all with the aim of accelerating the discovery of new cancer medicines. Through the Functional Genomics Centre, we are developing CRISPR technology to better understand the biology of cancer and creating preclinical oncological models which are more reflective of human disease.
  • Since 2015, we have collaborated with the Wellcome Sanger Institute on CRISPR technology. This collaboration was extended in 2018, giving us access to its leading libraries of gRNA for silencing or activating every gene in the genome via CRISPR.
  • A collaboration with the Innovative Genomics Institute (IGI) at the University of California, Berkeley, led by CRISPR co-founder Professor Jennifer Doudna, has also been extended to focus on inhibiting (CRISPRi) or activating (CRISPRa) screens to uncover gene and pathway mechanisms involved in DNA damage response (DDR), one of our six key platforms in oncology.



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