Research Guides

Tom Brown - Head of Nucleic Acids Research Group

We design and synthesise chemically modified DNA and RNA

http://www.browngroupnucleicacidsresearch.org.uk/

I am a member of the Departments of Chemistry and Oncology and my research interests centre on nucleic acid chemistry and its applications. Our research relies on the synthesis of novel modified nucleic acids and analogues. 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 have developed rapid methods for the identification of mutations in the human genome such as Scorpions, which are used to analyse genomic DNA at single base resolution. Developed in collaboration with AstraZeneca, Scorpions were commercialised by DxS and Qiagen, and are used in companion diagnostics to match patients with the most suitable drugs. They have led to the clinical use of cancer therapies, which were previously rejected on the basis of limited efficacy. We also work on the chemical synthesis of oligonucleotide analogues for therapeutic applications and we are modifying 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 and this led us to develop chemical methods of nucleic acid ligation and gene synthesis. I am the co-founder of three Biotech companies and I have published over 400 research papers. I am a Fellow of the Royal Society of Edinburgh, a Fellow of the Royal Society of Chemistry.

The schematic below shows the Design of artificial DNA backbones for biological applications and their structural relationships (colour-coded lines) . From JACS 139, 1575–1583 (2017).

Recognition

Royal Society of Edinburgh MakDougall-Brisbane prize for research

Royal Society of Edinburgh Caledonian Research Fellowship

Royal Society Leverhulme Senior Research Fellowship

Royal Society of Chemistry Josef Loschmidt prize

Royal Society of Chemistry award for Nucleic Acid Chemistry

Royal Society of Chemistry prize for Interdisciplinary Research

Chemistry World Entrepreneur of the Year 2014

BBSRC Innovator of the Year 2016 

Publications

Google Scholar: https://scholar.google.com/citations?user=DanQbhQAAAAJ&hl=en

Researcher id:    http://www.researcherid.com/rid/C-9185-2016

Orcid:                   https://orcid.org/0000-0002-6538-3036

From > 400

1. Shivalingam, A., Taemaitree, L., El-Sagheer, A.H. and Brown, T. Squaramides and Ureas: A Flexible Approach to Polymerase-Compatible Nucleic Acid Assembly. Angew. Chem. Int.Ed. (2020). https://doi.org/10.1002/anie.202000209
2. Taemaitree, L., Shivalingam, A., El-Sagheer, A.H. and Brown, T. An artificial triazole backbone linkage provides a split-and-click strategy to bioactive chemically modified CRISPR sgRNA. Nature Commun., 10, 1610. (2019). https://doi.org/10.1038/s41467-019-09600-4
3. Kukwikila, M., Gale, N., El-Sagheer, A.H., Brown, T.* and Tavassoli, A.* Assembly of a biocompatible triazole-linked gene by one-pot click-DNA ligation. Nature Chem. 9, 1089–1098 (2017). https://doi.org/10.1038/NCHEM.2850
4. Hardwick, J.S., Ptchelkine, D., El-Sagheer, A.H., Tear, I., Singleton, D., Phillips, S.E.V., Lane, A.N. and Brown, T. 5-Formylcytosine does not change the global structure of DNA. Nature Struct. Mol. Biol., 24, 544-552 (2017). https://doi.org/10.1038/nsmb.3411
5. 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). https://doi.org/10.1021/jacs.6b11530
6. Meng, W. et al. An Autonomous Molecular Assembler for Programmable Chemical Synthesis. Nature Chem. 8, 542-548 (2016). https://doi.org/10.1038/nchem.2495
7. 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). https://doi.org/10.1073/pnas.1101519108
8. 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). https://doi.org/10.1073/pnas.1006447107
9. 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). https://doi.org/10.1021/ja8065896
10. 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). https://www.nature.com/articles/nbt0899_804.pdf