Nucleic Acids

Tom Brown

Our focus is on the applications of chemically modified nucleic acids. Using X-ray crystallography and NMR we have studied the nature of base mispairing in DNA, the structure of DNA duplexes containing mutagenic lesions and the interaction of DNA with repair enzymes. We also design modified nucleic acids for diagnostic and therapeutic applications and have developed rapid methods for the identification of mutations in the human genome. The best example is Scorpions which are used to analyse genomic DNA at single base resolution. Scorpions were developed in collaboration with AstraZeneca spin-out DxS genotyping, and are used in companion diagnostics. They have led to the clinical use of cancer drugs which were previously rejected on the basis of limited efficacy.

A Scorpion kit is used to group patients on the basis of their KRAS mutation status; and as a result of this the drug Vectibix® was approved for the KRAS wild-type population. Similarly an EGFR kit is being used to establish the mutation status of non-small cell lung cancer tumours, to determine likely response to the drugs Iressa® and Tarceva®. The Scorpion technology has been acquired by Qiagen who obtained FDA approval of the KRAS kit in the US for use with the colorectal cancer drug Erbitux®.

We also work on the synthesis of DNA analogues for therapeutic applications including aptamers to target cancer cells with the aim of delivering drugs, and are developing CRISPR-based systems for cellular imaging and editing. We have developed a number of artificial DNA/RNA backbones that can be read through by polymerase enzymes. This led us to develop chemical methods of nucleic acid ligation and gene synthesis with the eventual aim of assembling therapeutic mRNAs on a large scale.