New fluorescent probes for labelling nucleic acids

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The human body is composed of billions of cells of different types. Each cell type (e.g. skin cells, liver cells, red blood cells) has its own specific roles. Many diseases arise from a breakdown or defect in the complex biochemistry within specific types of cells. A clinically important example of this is thalassaemia. The alpha and beta thalassaemias are common severe inherited forms of anaemia caused by imbalance of alpha and beta globin gene expression which affects the production of haemoglobin, the protein that carries oxygen through the body. Current therapy involves lifelong blood transfusion and iron chelation therapy, but these are invasive and only moderately effective. Consequently new therapies to correct globin chain imbalance are urgently needed. A crucial requirement in the development of new treatments is a detailed understanding of the regulation of alpha and beta globin gene expression, i.e. why these genes do not make their products in the correct amounts in patients suffering from thalassaemia. It is now recognized that the ability of many genes to make proteins is regulated by enhancer elements in their DNA. These are binding sites for proteins that switch genes on or off, and mutations at these sites underlie many human diseases. It has been shown by special fluorescence cell imaging techniques that enhancers and promoters can be located far apart on DNA, but come together when they are controlling protein synthesis. However it is not clear how this physical interaction exerts its effect. To analyse this we must obtain much clearer physical pictures of the process to determine how dynamic this enhancer-promoter association is, when it occurs and how long it persists. This will require new methods for high-resolution imaging of genomic DNA using small and intensely bright pieces of DNA (fluorescent probes). These probes will be much brighter than those currently available. They will be synthesised chemically by high-throughput automated methods using a modular approach which will greatly reduce the cost of their manufacture. This new approach to DNA and RNA imaging is generic and will be used in a wide variety of clinical and research applications by scientists working in academia, research institutes and the pharmaceutical industry.