Innovative chemistry for industry and academia

ucleic acids – the molecular building blocks of DNA and RNA - are at the heart of modern bioscience. Over several decades, Professor Tom Brown1, now at the , has IMPACT SUMMARY developed and commercialised a suite of innovative technologies based on chemically modified nucleic acids with increased functionality. These innovations formed the basis of three spin-outs, Interdisciplinary BBSRC-funded research into and successful products commercialised by other companies. nucleic acid chemistry has underpinned the N development of a suite of innovative technologies In 2005 Brown founded two companies, ATDBio and funding in the 1980s. “Our work was funded based on chemically modified nucleic acids with Primer Design. ATDBio2 produces and supplies chemically by the Research Councils, mostly BBSRC, throughout the increased functionality. modified nucleic acids to researchers in a ademia and the years. That provided us with the expertise and knowledge biotech and pharma industries. Primer Design3 makes use required to start to look at applications in diagnostics and The technologies, created by Professor Tom Brown, of modified nucleic acids to d velop diagnostic kits used in DNA analysis in general,” says Brown. now at the University of Oxford, led to the creation medical, genetic, and research applications. He was also co- of three spin-out companies and two innovations inventor of ‘Scorpion’ primers, commercialised by company In 2016, Brown was the overall winner of BBSRC’s Innovator commercialised by other companies. DxS, and HyBeacon probes, commercialised by international of the Year competition4, which aims to reward researchers The first company, Oswel, was based on Wellcome life sciences measurement company LGC. who harness the potential of their research. Trust funding. It supplied modified nucleic acids to researchers and industry and contributed to the All of these innovations were underpinned by many years Much of Brown’s research takes place at the interface of work of the UK forensic science service. of BBSRC-funded nucleic acid research, as well as the chemistry and biology and highlights the need to continue success of Brown’s first company, Os el, which arose from to support future generations of researchers in these areas. ATDBio was founded by Brown in 2005 to continue designing and selling modified nucleic acids to researchers and to the biotech and pharma industries.

Primer Design, also founded in 2005, developed diagnostic kits using modified nucleic acids, which are used to detect bacteria and viruses such as ebola and swine flu. The company sold for £12M in 2016.

Brown was also co-inventor of Scorpion primers and HyBeacons, commercialised by AstraZeneca spin-out DxS and by international life science measurement company LGC, respectively.

Brown has received substantial BBSRC funding since the 1990s. DNA code. Brown’s research has focussed on developing novel nucleic acids, the building blocks of DNA represented by A, C T and G. Image: MIKI Yoshihito, Flickr.

1 Innovative nucleic acid chemistry for industry and academia

“We were able, through BBSRC funding, to move into to contribute, enable them to do things they otherwise The company was set up when Brown was approached by these interdisciplinary areas which are so fruitful in terms wouldn’t be able to do. It was really fruitful, talking to each Dr Rob Powell at the University of Southampton with the of discovering new things,” Brown explains. “It’s really other,” explains Brown. idea of establishing a company. Powell’s expertise in DNA important to find rou es to get researchers involved so they diagnostics and virology complemented Brown’s chemistry can grow into biology and populate these interdisciplinary There were very few companies providing a similar service expertise and together they established Primer Design. areas.” in the UK, and unlike those companies, the team at Oswel could synthesise chemically modified nucleic acids. Th y Primer Design’s products are now sold in more than 100 Increased functionality also produced ‘oligonucleotide’ probes; relatively small countries. In May 2016, Primer Design was sold to the Brown’s innovations are based on chemically modified molecules built of nucleic acids and a fluorescent label that French diagnostics company Novacyt for more than £12M5. nucleic acids, which are altered to include fluorescent could be used to identify and visualise sections of genomic molecules, other forms of chemical ‘labels’, or other DNA. That technology was used in medical diagnostics, modifi ations that increase their functionality. genetic analysis and in forensics, and Brown and his team worked closely with the Forensic Science Service in the UK to In DNA is built from four nucleic acids, or bases – provide modified DNA or use with the UK DNA database. In adenine, thymine, guanine and cytosine, with thymine 1999 Oswel was sold to Eurogentec. replaced by uracil in RNA. By modifying these bases, and synthesising DNA and RNA molecules containing ATDBio and Primer Design other ‘minor’ bases, researchers can study the structure When Eurogentec closed its UK facility in 2005, it left a and function of DNA and RNA. They can also be used in gap in the market for modified nucleic acids. Some UK ‘probes’; small chains of nucleic acids modified to include organisations need to source such material from within fluorescent molecules, or example, that will bind with the UK for strategic, political or logistical reasons, and complementary DNA or RNA sequences in a sample and can Brown, now based at the University of Southampton, be detected using fluorescence microscopy saw an opportunity. His second company, ATDBio, followed the approach taken by Oswel, but with increased Talking to biologists specialisation. The company, which has recently opened In the 1980s, Brown joined the Chemistry Department a new R&D laboratory on the Oxford Science Park, works at the as a new lecturer. He was with researchers in academia and in the biotech and asked by the University to establish a service to provide Pharma industries to understand their needs and to design biologists at the University with small strands of DNA, and supply modified nucleic acids. TDBio continues to taking advantage of the recently-invented polymerase collaborate with Brown’s group, including through several chain reaction (PCR) process to amplify DNA. The service, BBSRC CASE studentships. The company is also a partner on based on Wellcome Trust funding, eventually outgrew the Brown’s latest Longer, Larger (LoLa) grant from BBSRC. Department hosting it and Brown was encouraged by the University to spin it out, creating the company Oswel. Later in 2005 Brown also established Primer Design. Primer Design produces diagnostic kits that utilise modified nucleic “It led to us talking to a lot of biologists, discussing their acids. These are used to diagnose a wide variety of bacterial Professor Tom Brown at BBSRC’s Fostering Innovation event 2016. research and how nucleic acid chemistry might be able and viral infections, including ebola, swine flu and zi a virus. Image: Joel Knight

2 Innovative nucleic acid chemistry for industry and academia

Scorpions and HyBeacons HyBeacons for rapid forensic identifi ation10. The HyBeacons REFERENCES In addition to establishing three spin-out companies, are incorporated into portable kits that can be used at a Brown is also the co-inventor of several technologies crime scene to give a quick yes/no answer to determine 1 Professor Tom Brown: http://research.chem.ox.ac.uk/professor-tom-brown.aspx commercialised by other companies. For instance, through whether someone is implicated in the crime. The alternative a collaboration with AstraZeneca in the late 1990s to is a time-consuming laboratory test which, although more 2 ATDBio Ltd investigate new DNA probe technologies, Brown and accurate, can take weeks to return a result. 3 Primer Design: http://www.primerdesign.co.uk/home colleagues developed ‘Scorpions’6. These were based on 4 Press Release: ‘Bioscience impact and innovation competition winners announced’, 19th May 2016. BBSRC. http://www.bbsrc.ac.uk/news/people- modified oligonucleotides that allow researchers to de ect Gene synthesis skills-training/2016/160519-n-bioscience-impact-innovation-competition- the presence of a target DNA sequence during PCR, and Brown is currently the lead researcher on a large BBSRC winners-announced/ were simpler to use, more sensitive and more specific than synthetic biology grant. Through that project, Brown and 5 Novacyt Full Year 2015 Results: [Reference/webpage no longer previous methods. colleagues have developed a technology to produce large available – May 2017] 6 D. Whitcombe, J. Theaker, S.P. Guy, T. Brown, & S. Little `Detection of strand of DNA by connecting together shorter strands. This PCR products using self-probing amplicons and fluorescence’. Nature The innovation was published in Nature in can be used to build genes containing modified nucleic Biotechnol. 1999, 17, 804-807 1999 and patented by AstraZeneca, with Brown named as a acids, which can be used to study gene expression and 7 Patents: Methods for detecting target nucleic acid sequences’, US patent co-inventor7. Scorpions were commercialised by two former epigenetics. For instance, the genes could incorporate minor number US6326145, Applicant: Zeneca Ltd.; Inventors: D. M. Whitcombe, J. Theaker, N. J. Gibson and S. Little (filed 1999, g anted 2001); `Fluorophore/ AstraZeneca employees, who bought the patent from bases i.e. bases other than the four found in nature, or could quencher labelled oligonucleotides’, Applicant: Zeneca Ltd.; Inventors: N. J. Gibson and T. Brown, UK patent number GB2337992B (filed 1999, g anted AstraZeneca and established spin-out company DxS. DxS include fluorescent d es to allow researchers to trace them. 2001). was acquired by Qiagen in 2009 for US$120M and in 2013, Many other companies can provide genes, but these do 8 ‘Scorpion Primers and the Advance of Medical Diagnostics’, REF2014 annual sales of Scorpion primer diagnostics was US$100M8. not incorporate modified nucleic acids. According to Brown, Impact Case Study: “We’ve filed pa ents with the University of Southampton, http://impact.ref.ac.uk/CaseStudies/CaseStudy.aspx?Id=43002 DxS kits using Scorpions have played a central role in and we’re looking at the possibility of setting up a new 9 D.J. French, C.L. Archard, T. Brown & D.G. McDowell. HyBeacon probes: a new tool for DNA sequence detection and allele discrimination. Mol Cell licencing for several anti-cancer drugs in Europe and the company to exploit the technology.” Probes. 2001 Dec; 15(6): 363-74.

USA. Anti-cancer drugs are not always effective against 10 Patent: N. Gale, P. Debenham, D.J. French, R. Howard, D.G. McDowell, T. every form of a certain cancer, which can prevent the drugs Brown. EP 2 217 719 B1, WO 2009/053679 (30.04.2009) from being licenced. Scorpion probes enable clinicians to identify which form of cancer a patient has by identifying the underlying genetic mutation in the cancer. This allows clinicians to target treatments, and shows that drugs which may not appear effective overall can be highly effective against a sub-population of cancers.

In 2000 Brown co-developed ‘HyBeacons’ during a collaboration with international life sciences measurement and testing company LGC9. Like Scorpions, HyBeacons are also a PCR probe. However, they use a different analysis technique suited to different applications. For instance, in 2014 LGC developed a system called ‘para-DNA’ that uses

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