We design and synthesise chemically modified DNA for diagnostic and therapeutic applications.
My research is in nucleic acid chemistry and structure, and the application of nucleic acids and analogues to diagnostics and therapeutics. Using various biophysical techniques including X-ray crystallography we study the nature of base mispairing in DNA, the structure of DNA duplexes containing mutagenic lesions and the interaction of DNA with specific repair enzymes. We have also developed rapid methods for the identification of mutations in the human genome without the need for DNA sequencing. The best example is Scorpion primers which are used in fluorogenic real-time PCR to analyse genomic DNA sequences at specific loci. Scorpions were developed in collaboration with AstraZeneca (subsequently an AZ spin-out DxS), and have been used in companion diagnostics. By determining the genotype of a cancer, this technology allows the clinical use of cancer drugs which were previously rejected on the basis of limited efficacy. For example, 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 for which it is particularly effective. 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 recently obtained FDA approval of the KRAS kit in the US for use with the colorectal cancer drug Erbitux®.
We are also working on the synthesis of analogues of DNA for therapeutic applications and we have recently started a project on the synthesis of next-generation aptamers with the aim of specifically targeting cancer cells with drugs. In this project we aim to develop DNA and RNA aptamers with additional chemical functionality (such as hydrophobic - water-repelling - groups and hydrogen bonding residues) to increase target binding and selectivity beyond that which is achieved by the use of traditional aptamers.
We synthesise cyclic mini-DNA duplexes to facilitate the study of base pairing in DNA (including mutagenic lesions) at high resolution
Tom Brown came from Southampton to Oxford University in 2013 to take up a joint Chemistry/Oncology position as Professor of Nucleic Acid Chemistry. He has published over 300 scientific papers and patents and has received several awards including the Royal Society of Chemistry awards for Nucleic acid chemistry and for Interdisciplinary research. He is President of the Chemistry Biology Interface Division of the Royal Society of Chemistry, co-founder of several Biotech companies and is Chemistry World Entrepreneur of the Year for 2014. Tom is a Fellow of the Royal Society of Edinburgh and a Fellow of the Royal Society of Chemistry.
Bosaeus, N., El-Sagheer, A.H., Brown, T., Smith, S.B., Akerman, B., Bustamante, C. and Norden, B. (2012) Tension induces a base-paired overstretched DNA conformation. Proc. Natl. Acad. Sci. U. S. A., 109, 15179-15184.
El-Sagheer, A.H., Sanzone, A.P., Gao, R., Tavassoli, A. and Brown, T. (2011) Biocompatible artificial DNA linker that is read through by DNA polymerases and is functional in Escherichia coli. Proc. Natl. Acad. Sci. U. S. A., 108, 11338-11343.
El-Sagheer, A.H. and Brown, T. (2010) New strategy for the synthesis of chemically modified RNA constructs exemplified by hairpin and hammerhead ribozymes. Proc. Natl. Acad. Sci. U. S. A., 107, 15329-15334.
Graham Brown, Bioanalytical/Microscopy Core Leader
Siobhan Cunniffe, Research Assistant