PhD FRSE FRSC
- Primary position:
- Visiting Professor of Chemical Biology
Tom Brown studied Chemistry at Bradford University where he completed his PhD under the supervision of Gordon Shaw in 1979. He carried out postdoctoral research at Oxford and Cambridge Universities before moving to Edinburgh University in 1985 as a lecturer. In 1995 he moved to Southampton as professor of nucleic acid chemistry and is now professor of Chemical Biology.
In the early part of his academic career Tom studied base pair mismatches and their implications for DNA repair. Notable examples that attracted international attention have appeared in the journal Nature (1985, 315, 604 and 1986, 320, 552). This approach paved the way for the elucidation of the mutagenic effect of chemically modified DNA bases, most importantly the O6-methyl guanine lesion (PNAS 1990, 87, 9573). This was the first time that the origin of a mutation caused by chemical damage to DNA had been explained at the molecular level. This was followed by studies to determine the nature of the recognition of mutagenic bases by DNA repair enzymes, most notably a collaboration with Laurence Pearl to elucidate the structural basis of excision repair by uracil-DNA glycosylases (Nature 1995, 373, 487; Nature Struct. Biol. 1998, 5, 697). The expertise gained from these fundamental studies on DNA base pairing was used to develop new methods of mutation analysis. In collaboration with AstraZeneca Tom Brown developed a novel technology for the identification of mutations in the human genome (Scorpion Probes). This was one of the first successful methods for rapid mutation detection (Nature Biotechnol. 1999, 17, 804). The resultant patent led to a spin-out from AstraZeneca (DxS Genotyping), which was recently acquired by Qiagen for $120 million. Tom is also co-inventor (with LGC) of "HyBeacon" technology, a novel fluorogenic method that utilises DNA melting as a means to identify mutations. HyBeacons also have clinical applications for the rapid diagnosis of bacterial infections and are being developed in the Forensic field for rapid human identification.
Tom's group has recently developed a click chemistry methodology which has been used to synthesise a DNA catenane (JACS 2007, 129, 6859) and to unravel the DNA binding mechanism of a novel threading intercalator (JACS 2008, 130, 14651). He has also used a related approach to construct large biologically active RNA constructs which are beyond the reach of conventional solid-phase synthesis (PNAS 2010, 107, 15329) and to synthesise DNA templates containing modified triazole backbones which are copied by DNA and RNA polymerases and are functional in vivo (JACS 2009, 131, 3958; PNAS 2011, 108, 11338; Chem. Comm. 2011, 47, 12057). The structural basis of the remarkable biocompatibility of this triazole linkage has recently been elucidated (Chem. Eur J. 2011, 17, 14714). Click nucleic acid ligation is currently being used in the chemical synthesis of genes and in several other biological applications, for which Tom and his collaborators have received substantial funding (BBSRC sLoLa grant for £4 million).
Tom Brown's work is based on the chemical synthesis and biological applications of novel oligonucleotide analogues, a field which he has pioneered (e.g. Nature Protocols 2008, 2, 615-623; Nucleic Acids Res., 2002, 30, e39; JACS 2009, 131, 2831; JACS 2009, 131, 4288; JACS 2011, 133, 279). Another very recent example is a collaboration which has led to the development of a new method for forensic and genetic analysis using SERS detection and electrochemical DNA melting (JACS 2008, 130, 15589; Angew. Chem. 2010, 49, 5917).
Tom's work has produced 300 publications/ patents and 3 successful start-up companies (Oswel, ATDBio, Primer Design). He has has received several awards including the Royal Society of Edinburgh MakDougall-Brisbane prize for research, the Royal Society of Edinburgh Caledonian Research Fellowship, the Royal Society Leverhulme Senior Research Fellowship, the Royal Society of Chemistry Josef Loschmidt prize, the Royal Society of Chemistry award for Nucleic Acid Chemistry and the Royal Society of Chemistry prize for Interdisciplinary Research. Tom is a Fellow of the Royal Society of Edinburgh and a Fellow of the Royal Society of Chemistry. He is a member of the Chemical Biology Interface Division committee of the Royal Society of Chemistry and a member of the editorial board of Chemistry World.
- Tom Brown Group, Nucleic Acids Research
- Fast and efficient copper-free click chemistry has been developed for crosslinking and versatile labelling of DNA.
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My research is interdisciplinary, focusing on nucleic acid chemistry and its applications in other fields including DNA diagnostics, forensic science and nanotechnology. In the early part of my academic career I used NMR and X-ray crystallography to study the properties of base pair mismatches in DNA and their implications for DNA repair. Examples of this research are the elucidation of the structures of DNA duplexes containing G.T (Nature 1985, 315, 604) and A.C mispairs (Nature 1986, 320, 552). This approach led us to determine the molecular basis of the mutagenic effect of a number of chemical lesions in DNA, for example O6-methyl guanine (Proc. Natl. Acad. Sci. USA 1990, 87, 9573). This was the first time that the structural basis of a mutation caused by chemical damage to DNA had been defined at the molecular level. Our studies also highlighted the fact that mispaired bases form distinct structures and cause minimal distortion to the overall conformation of the DNA duplex. Therefore enzymatic recognition of modified base pairs in living systems must depend upon subtle differences. To confirm this we investigated the origin of the recognition of mismatched and mutagenic bases by DNA repair enzymes. An example of this is our collaboration with Laurence Pearl to elucidate the structural basis of specific base-excision repair by uracil-DNA glycosylase (UDGase) and MUG (Nature 1995, 373, 487, and Nature Structural Biology 1998, 5, 697). These essential enzymes reverse the damage that is caused to DNA by oxidation of cytosine bases, recognizing the absence of a single methyl group to initiate excision-repair. UDGase is of interest as a target for antiviral therapy.
The expertise that we gained from these fundamental studies on DNA base pairing was then used in the emerging field of molecular genetics to develop new methods of mutation analysis. In collaboration with AstraZeneca we invented a novel fluorescence-based real-time PCR method for the identification of mutations and single nucleotide polymorphisms (SNPs) in the human genome. This was one of the first successful technologies for rapid mutation detection and was patented, published in Nature Biotechnology (1999, 17, 804) and marketed as “Scorpion Primers” by a spin-out from AstraZeneca (DxS Genotyping Ltd). I am also co-inventor of “HyBeacons”, novel fluorogenic probes that utilises DNA melting temperature as a means of identifying mutations. HyBeacons, the result of a collaboration with the Laboratory of the Government Chemist, have recently been licensed to an International Biotech company. They can be used for the rapid diagnosis of bacterial infections and genetically-related diseases, and are also being developed by us for Forensic applications (New Scientist Jan 14th 2006). We recently demonstrated that such methodology has potential for rapid human identification at crime scenes and in custody suites, with clear implications for crime detection and related applications (Forensic Sci. Int. Genetics. 2008, 2, 333, Org. Biomol. Chem. 2008, 6, 4553). Our work on genetic and biophysical analysis of DNA is based on the synthesis of novel fluorescent oligonucleotides, a field in which we have a strong background (e.g. Nature Protocols 2008, 2, 615-623, and Nucleic Acids Res., 2002, 30, e39). In the field of DNA sequence analysis a collaboration with Philip Bartlett in Southampton recently led to a new method for identifying mutations in the human genome by a novel combination of SERS detection and electrochemical DNA melting (J. Am. Chem. Soc. 2008, 130, 15589). My work combines fundamental studies with applications, and have always had a strong interest in taking ideas from the research laboratory and turning them into useful tools for other scientists. I was the Founder of Oswel Research Products, the first UK supplier of high quality oligonucleotides and analogues which provided an essential service to chemists and biologists for many years. In Oswel we were able to synthesise oligonucleotide analogues that were not available from any other supplier. We had a long-standing relationship with the UK Forensic Science Service in their work on the National DNA database. Recently I have co-founded two other start-ups, ATDBio (on the Oswel model) and Primer Design. I also consult for several Biotechnology companies.
I am interested in the use of modified oligonucleotides as potential therapeutic agents and in this context we are trying to develop methods of reversing the mutations that give rise to genetic diseases. The basic idea is to initiate DNA repair by the formation of triple helices at the site of the mutation. Triplex forming oligonucleotides (TFO’s) have wider applications in molecular genetics, diagnostics, therapeutics and nanotechnology and for this work we have developed a set of four base analogues that, when incorporated into TFOs, are able to recognize mixed sequence DNA with high specificity. This was the first example of full sequence recognition of a DNA in the major groove (Nucleic Acids Res. 2005, 33, 3025). This work is a collaboration with Keith Fox in Biological Sciences in Southampton. My research has very recently moved in a new direction. We are using the copper-catalysed alkyne-azide coupling reaction to synthesise large covalently closed cyclic DNA structures (DNA catenanes) for use in biological applications and as scaffolds in nanotechnology. Our first paper in this field was one of the most cited JACS papers in 2007 (J. Amer. Chem. Soc. 129, 6859), and two other publications (ChemBioChem 2008, 9, 50, ChemBioChem 2008, 9, 1280) were amongst the most accessed papers when they appeared on the ChemBioChem web site. A recent collaboration with Bengt Norden’s group in Gothenburg involved this DNA click chemistry to elucidate the binding mechanism of a novel threading DNA intercalator (J. Am. Chem. Soc. 2008, 130, 14651). We have developed this chemistry further to synthesise DNA templates containing modified backbones which can be copied by polymerases during PCR. This discovery (J. Am. Chem. Soc. in press.) promises to open up a new field. With careful design it might be possible to use such methodology to synthesise functional DNA strands greater than 1000 bases in length entirely by chemical methods, an order of magnitude longer than is currently achievable. If the aim of this research is achieved it will be an important contribution to the new discipline of Synthetic Biology. A further collaboration with the Norden group led to the synthesis of addressable high-information-density DNA nanostructures (Chem. Phys. Lett. 2007, 440, 125). These constructs constitute scaffolds on which molecules can be attached at pre-determined locations with nanometre precision so that they can communicate in a controlled manner by energy or electron transfer.
My research spans several fields and a high proportion of my publications appear in biology, biochemistry and nanotechnology journals. Our endeavours have given rise to numerous new analytical techniques that are now used in the real world, particularly in the field of genomics and diagnostics. I have received recognition intenationally, for example I was one of the selected speakers at a Nobel Workshop addressing the frontiers of proteins and nucleic acids, another speaker being Andy Fire who was awarded the Nobel Prize for his discovery of RNAi, and in 2008 I gave a plenary talk, together with the Chemistry Nobel Laureates Barry Sharpless, Ryoji Noyori and Richard Schrock, at the Molecular Frontiers Symposium in Singapore.
Research project affiliated with Biological Sciences: DNA quadruplexes and their interaction with ligands
Primary research group: Molecular Diagnostics and Therapeutics
We are exploiting the formation of DNA triplexes as a means for generating new DNA nanostructures.
We are generating mutants of this DNA repair enzyme, which have altered recognition properties, and are using these as tools in biotechnological applications.
We are part of this BBSRC-funded sLoLa project, led by Prof Tom Brown (Chemistry), and are using click-chemistry to generate unusual DNA structures and examine their biological properties.