We design and synthesise chemically modified DNA for diagnostic and therapeutic applications.
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.
Tom Brown is Professor of Nucleic Acid Chemistry at Oxford University and a member of the Departments of Chemistry and Oncology. His research interests centre on DNA sequence recognition and applications of DNA and RNA chemistry in biology, diagnostics, forensics and medicine. He is the co-founder of three Biotech companies (Oswel, ATDBio and Primer Design) and has published over 360 research papers and patents. He has received several awards including the Royal Society of Chemistry (RSC) Josef Loschmidt prize, the RSC award for Nucleic Acid Chemistry and the RSC prize for Interdisciplinary Research. He was Chemistry World entrepreneur of the year for 2014 and BBSRC Commercial Innovator of the Year and overall Innovator of the Year for 2016. Recently he was presented with a lifetime award for external engagement and promoting impact by Oxford University. Tom is a Fellow of the Royal Society of Edinburgh and a Fellow of the Royal Society of Chemistry. He is outgoing President of the Chemistry Biology Interface Division of the RSC and Editor-in-Chief of the RSC Book series on Chemical Biology. He is currently Associate Head of the Chemistry Department at Oxford with responsibility for Research.
Kukwikila, M., Gale, N., El-Sagheer, A. H., Brown, T. & Tavassoli, A. Assembly of a biocompatible triazole-linked gene by one-pot click-DNA ligation. Nature Chem., doi:10.1038/NCHEM.2850 (2017).
Hardwick, J. S. et al. 5-Formylcytosine does not change the global structure of DNA. Nature Struct. Mol. Biol., doi:10.1038/nsmb.3411 (2017).
Shivalingam, A., Tyburn, A. E. S., El-Sagheer, A. H. & Brown, T. Molecular Requirements of High-Fidelity Replication-Competent DNA Backbones for Orthogonal Chemical Ligation. J. Amer. Chem. Soc. 139, 1575–1583 (2017).
Haugland, M. M. et al. 2 '-Alkynylnucleotides: A Sequence- and Spin Label-Flexible Strategy for EPR Spectroscopy in DNA. J. Amer. Chem. Soc. 138, 9069-9072, (2016).
Meng, W. et al. An Autonomous Molecular Assembler for Programmable Chemical Synthesis. Nature Chem. 8, 542-548 (2016).
Harimech, P. K., Gerrard, S. R., El-Sagheer, A. H., Brown, T. & Kanaras, A. G. Reversible Ligation of Programmed DNA-Gold Nanoparticle Assemblies. J. Amer. Chem. Soc. 137, 9242-9245, (2015).
El-Sagheer, A. H., Sanzone, A. P., Gao, R., Tavassoli, A. & Brown, T. Biocompatible artificial DNA linker that is read through by DNA polymerases and is functional in E. coli. Proc. Natl. Acad. Sci. USA 108, 11338–11343, (2011).
El-Sagheer, A.H., Brown, T. New strategy for the synthesis of chemically modified RNA constructs exemplified by hairpin and hammerhead ribozymes. Proc. Natl. Acad. Sci. USA 107, 15329-15334, (2010).
El-Sagheer, A. H. & Brown, T. Synthesis and Polymerase Chain Reaction Amplification of DNA Strands Containing an Unnatural Triazole Linkage. J. Amer. Chem. Soc. 131, 3958-3964, (2009).
Whitcombe, D., Theaker, J., Guy, S. P., Brown, T. & Little, S. Detection of PCR products using self-probing amplicons and fluorescence. Nature Biotechnol. 17, 804-807 (1999).
Graham Brown, Bioanalytical/Microscopy Core Leader
Siobhan Cunniffe, Research Assistant