Skip to main navigationSkip to main content
The University of Southampton
Institute for Life Sciences

Focusing in on Nucleic Acids

Focusing in on Nucleic Acids
Focusing in on Nucleic Acids

Working across the University campuses and the regional community the Institute for Life Sciences aims to develop collaborative models that address key issues in health, society and enterprise. These models are centred on areas of excellence, where Southampton and the Wessex region lead at national and international levels.

Nucleic Acid research has been identified as a BBSRC funded focus that will benefit from development within the Excellence with Impact programme, adding a new dimension to our research activities by generating a new network, tying together areas of excellence, while maturing to deliver enterprise, outreach and policy.

The Focusing in on Nucleic Acids (FioNA) community is being built for the long-term and aims to be an exemplar of the interdisciplinary research themes that sit at the core of the IfLS and the University strategy of changing the world for the better through our research, education, innovation and enterprise.

BBSRC
BBSRC Excellence with Impact

Our mission is to provide a framework to coordinate all aspects of the world-leading research in nucleic acids conducted at the University of Southampton. Our umbrella organisation encompasses policy, education, enterprise as well as scientific research.

FioNA Aims:  Through the FioNA programme the IfLS aims to deliver:

The FioNA project aims to create a cross-campus interdisciplinary nucleic acids network.

Transfer & Transport

Devices and Engineering:

A successful device for chemical or biological sensing requires first an interesting biological function or reaction that needs to be detected. A chemical probe or a 'transducer' is then employed to convert the reaction signal to a result using a technology platform. The platform is itself composed of numerous sub-systems: imaging, fluid handling, data acquistion and analysis. Microfluidics is ideally suited for uses in devices.

This is the science and technology of systems that process or manipulate small (10-9 to 10-18 litres) amounts of fluids, using channels with dimensions at the width of a human hair. Such systems are miniaturised versions of large chemical, physical and molecular sensors. They have low power usage, small sample and reagent volumes and can be used for in situ and point-of-care.

At the University of Southampton, there is extensive expertise in all areas of Devices and Engineering ranging from probe synthesis to complex system integration. Examples include:

Scorpion probes invented by Prof. Tom Brown as chemical tool in collaboration with AstraZeneca. They are self-reporting primers with improved simplicity, kinetics, sensitivity and specificity compared to other real-time PCR probes. The probes have now clinical approval to use mutation diagnosis of KRAS and EGFR genes.

A miniaturised version of a PCR instrument with integrated detection and analysis was developed as part of the EU project LABONFOIL. This involved Prof. Hywel Morgan, Dr. Tsaloglou and Dr Mowlem. The system included disposal cartridges with preserved reagents. Nucleic acid sequence-based amplification of RNA from toxic plankton K. brevis was demonstrated. More recent projects include an NIHR-funded project in collaboration with Sharp Labs of Europe and Public Health England. Recombinase polymerase amplification (RPA), an isothermal equivalent to qPCR is being miniaturised in nanolitre volumes on a hand-held device for diagnostics at the point-of-care.

On single DNA molecule level, Dr. Tracy Melvin is the principal investigator of a BBSRC-funded grant that focusses on investigating new ways to interrogate individual double-stranded DNA sequences. This uses novel oligonucleotide probes that associate with specific DNA sequences as triplexes.

The emerging community of nucleic acid Devices and Engineering has recently formed the Devices & Nucleic acids Network. This aims to connect technology developers and nucleic acid researchers across UoS and industry. Local events will be organised to connect local stakeholders from industry & healthcare with the University science and engineering community.

Genomics

Advances in sequencing technology have the potential to effect a step change in our approach to medical genetic research and clinical diagnostics. Processing and interpretation of large scale genomic data from patient samples has the potential to reveal common and rare genetic changes that predispose to disease. The development of new tools and skills necessary to analyse, interrogate and understand the importance of genomic variation is an essential prerequisite. The vast nature of the data necessitate analytical pipelines, variant annotation and variant prioritisation in order to extricate biologically relevant variation from background noise.

Genetics of Paediatric Immune Disease: Housed in University Hospital Southampton NHS Foundation Trust is the Wessex regional referral centre for children diagnosed with inflammatory bowel disease (IBD). The University of Southampton have teamed up with clinical colleagues in UHS and recruited these children to a study looking at the genetics of paediatric IBD.

We are applying Next Generation Sequencing (NGS) to the genetic analysis of patient DNA. NGS is the cutting edge technology that enables us to take a DNA sample from a patient and read ALL the letters of that person's genetic code. In any human genome there are approximately three billion base (A,T,C,G) pairs. Only about one percent of these lie in regions (genes) that contain recipes for the proteins that our bodies required to develop and function. Up to only a few years ago, it was prohibitively expensive to get continuous sequence reads for individual patients and researchers tended to analyse only intermittent letters that were known to be commonly varied in the population. NGS enables us to look at all of the letters across either the entire length of the genome, or as for the study reported in Gut, concentrate on just those gene sequences that code for proteins- the exome. As well as being cheaper - because most genetic variation that causes disease lies within genes - this study design represents the most cost efficient way of taregting the analysis to the highest risk regions of the genome. Even with this frugal approach, this type of analysis costs approximately one thousand pounds per sample.

Recently we have published a paper describing individual profiles of genetic changes across a panel of genes known to influence IBD risk. For each patient we produced a profile of their individual variation across these genes. We found that despite having common diagnoses, each individual presents with a unique profile of genetic variants. In the second phase of this project we are analysing forty two more samples. By using very detailed clinical information, we plan to build on this work to identify which specific clinical characteristics are shared by patients with similar genomic profiles. Ultimately, this may help us give much more specific diagnoses to individuals rather than the "umbrella terms" that are currently used, and this in turn may help inform clinicians of the best treatments for their patients. We expect our findings will translate into adult medicine as well as aiding screening in relatives of those affected by this familial disease. As new drugs and therapies emerge, knowing which specific biological pathways are impaired on a case-by-case basis will lead to targeted treatment tailored to individual patients.

Epigenetics in Asthma: We have been studying the origins of asthma and allergies for over twenty years in a group of people born on the Isle of Wight in 1989. We know that the chances of someone developing an allergy depends on both the genes they inherit from their parents and also on the exposures they encounter in their environment. One way the environment can alter the risk of disease by altering what is known as the 'epigenome'. The epigenome is a series of chemical modifications to DNA which is important for controlling turning genes on and off .

Our study has shown that one of the strongest risks of developing allergy is whether your mother has allergies if you are a girl, or if your father has allergies if you are a boy. One possible explanation for this lies in one specific chemical mark in the epigenome called DNA methylation. To study whether DNA methylation is the factor that is transmits risk from parent to child we are revisiting study participants on the Isle of Wight that are now having their own children. We are measuring DNA methylation in all 23,000 genes in the genome in the mother and father and also in their children. From this we can see if there are specific DNA methylation marks that are transferred from an allergic parent to a child. By following the children of the next generation as they grow up, we can also see whether these DNA methylation marks will increase the chances of these children developing allergies and asthma themselves.

Translation

Regulation of Gene Expression

Translational control mechanisms (Dr Mark Coldwell):  Central to translation initiation (the start of protein synthesis) is the selection of the initiation codon, which is usually an AUG, although a growing number of mRNAs have been found to use non-canonical near-cognate initiation codons e.g. CUG, GUG, UUG. Dr Coldwell and colleagues are investigating the usage and regulation of these alternative initiation codons in order to examine the importance of alternative initiation codon selection in the generation of protein isoform diversity, a previously neglected aspect of gene expression. This work will modify and extend our understanding of the protein-coding potential of all eukaryotic genomes, as the underlying mechanisms of translational control are conserved across species.

Selection of the correct initiation codon is mediated by several initiation factors, and part of this project explores the regulation of AUG usage versus non-AUG initiation codons. It is clear that the selection of certain initiation codons may have beneficial or detrimental effects on the cell and it is important to establish in which stages of cell growth and/or disease progression that this form of translational control occurs. Deregulation of the appropriate selection of translation initiation codons may be important in the status of certain diseases, including cancer.

Research Projects:

  • Mechanisms of alternative translation initiation codon selection in the regulation of eukaryotic gene expression - In a growing number of cases, initiation codons other than the canonical AUG triplet are used to initiate translation. We are investigating how widespread this phenomenon is, and what it means for current models of initiation.
  • Transcriptome-wide prediction of eukaryotic translation initiation - Combining bioinformatics searches with experimental data to broaden our knowledge of eukaryotic translation initiation.
  • Characterisation of BAG-1 as a therapeutic target in HER2 positive breast cancer - Working with colleagues in Medicine, this project aims to decipher the molecular mechanism for changes in BAG-1 expression HER2+ breast cancer.

Developmental Biology (Dr Claire Clarkin):  Dr Clarkin’s research is focussed on how blood vessels interact with tissues and organs during development, adulthood and disease. Specifically, she is interested in how tissue derived factors such as Vascular Endothelial Growth Factor or Transforming Growth Factor β can modulate endothelial cell behaviour and Dr Clarkin has unique models in place to modulate the expression levels of such genes in vitro and in vivo. Examples of projects she is involved in include i) study of endothelial cell interactions in bone, during remodelling, osteoporosis and following orthopaedic surgery and ii) targeting the blood supply in of islets of Langerhans to increase islet transplantation success, a current treatment for Type 1 Diabetes.

Research Projects

  • Modulating Vascular Endothelial Growth Factor gene expression in bone - working with colleagues in Engineering and Harvard University to identify new drug targets that will permit selective control of bone's bloold supply to allow sufficient support for the process of bone renewal.
  • Improving islet endothelial cell viability to improve islet transplantation success - aims to identify mechanisms which drive islet endothelial cell loss prior to and during islet graft translation.
  • Tissue specific endothelial and mesenchymal stem cell interactions - investigating mechanisms and the impact on procedures use of MSC's such as tissue translation and regeneration.

Our interdisciplinary steering committee for the Focusing in on Nucleic Acids project is composed of academic members of staff from a range of disciplines, united by their research in nucleic acids.

The University has an extensive outreach programme which is central to our commitment to increasing access to Higher Education.

The University’s Learn with US programme is designed to promote Higher Education across the breadth of subjects at the University, through targeted interactions with pupils between ages 12 and 18. Other initiatives include the Ask the Expert and TEAtime lecture series, both of which provide interactive lectures and workshops with research-active academic staff.

Large scale events include our Southampton Science and Engineering Festival and a notable achievement at the intersection of research and outreach is our pioneering LifeLab, which promotes health literacy through context-specific learning outside the classroom including CPD sessions for teachers, teaching material development and children’s’ visits to the University and Hospital.

Disseminating Southampton's nucleic acid research to the wider community supports the BBSRC Excellence with Impact aims. The FioNA programme has enriched these existing activities through collaborations with the South Wiltshire University Technical College summer schools; an arts based project with the Artist in Residence at the University’s Faculty of Medicine; creating and touring a DNA in Childhood Diseases engagement activity with the Bringing Research to Life roadshow; and seminars for the FioNA community at Southampton.

Nucleic acids are positioned in a central place with regards to biology and medicine that their study inevitably raising issues of policy and public interest.

In many cases it is important that the research community takes a lead in education and policy, ensuring as accurate a view as is possible enters into a public debate. Topical examples where this is taking place are synthetic biology and personal genotyping. It is accepted that the community has a responsibility to address this with care in order to engage the public rather than create concern.

As part of the FioNA project we have considered where Southampton might usefully contribute to these debates. Two areas of expertise spring to mind - the use of nucleic acids in sensors and point of care devices, and the developmental origins of health and disease. This latter example is wide ranging and fits well within the interdisciplinary community that lies at the heart of many Southampton initiatives and was the focus of the IfLS Conference: Epigenetics & Evolution which took place on 5 June 2015.

The conference programme showcased interdisciplinary research in the field bringing together interests on how epigenetics contributes to evolution and the causes of non-communicable disease.  The programmed focussed on four broad areas:

  • Evolutionary impacts
  • Mechanistic epigenetics
  • Health consequences
  • Relevance to policy
IfLS Conference 2015
IfLS Conference 2015

Building on the strengths of the Wessex Life Sciences Community, the FioNA programme aims to engage with local SME’s and other industrial partners to develop collaborations and opportunities to work together.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×