Human cells have two copies of each chromosome (one inherited from each parent) which carry their genes encoded in DNA. There are therefore two copies of each gene, one from each parent, and the equivalent pairs of DNA molecules are called ?homologues?. Each DNA molecule is a double helix with two strands. Homologous recombination is a natural mechanism, by which it is possible for the cell to move segments of DNA, and therefore genes or parts of genes, from one DNA molecule to the equivalent place on another ?homologous? one. This is the mechanism that allows a person to inherit some characteristics from his/her mother, and others from his/her father, as it mixes and matches the genes. It is therefore a very important evolutionary process. When two chromosomes are side by side, one strand of DNA on each chromosome is broken and then attached to a broken strand of DNA on the other chromosome at the equivalent position. The crossover point, which is called the ?Holliday junction?, is able to slide up and down between the two chromosomes, and a little or a lot of DNA from one molecule can be switched over from one to the other. As well as being used to exchange genes between chromosomes, and generate the obvious mixture of inherited characteristics in children, it is also used in the important process of DNA repair. Our DNA is constantly being damaged, each of our cells suffering thousands of lesions per day, and such damage leads to diseases such as cancer. Homologous recombination allows the equivalent healthy chromosome DNA to be used as a template to repair the damaged DNA, and without this system we would not survive for long. We are interested in the mechanism the cell uses to cut the Holliday junction once enough DNA has been exchanged between the chromosomes, and allow the two DNA molecules to separate again. Cells typically use specialised proteins (enzymes) to cut Holliday junctions and we have previously studied the structure of a simple one from a virus. In this project we will study the structure of several human enzymes that carry out this job to understand how they work in detail. People who inherit defective versions of these enzymes often develop cancers, and a full understanding of the mechanism should help the design of specific treatments in the future.

Capturing the 'why' of a disease and the 'how' of a treatment requires building a model of the disease and its evolution during treatment. This model ideally needs to capture everything, from the interplay of a single molecule with a molecular network, to inter-cellular communication networks that underpin the development of a phenotype. To reach this goal we need to bridge the different scales on which biology operates - the molecular, the cellular and the whole organism. One way to do this is to image cells and organisms at different scales: (i) the nanoscale to show how cells are organised at the molecular level and how molecular therapies affect molecular interactions; (ii) the microscale to show the functions of cellular organelles and their reorganisation under therapeutic challenge; (iii) the mesoscale to investigate cellular behaviour during development and/or the progress of disease; (iv) and the whole organisms level, to monitor changes and the well-being of the entire organism in response to therapy (e.g. tumour remission). Only when these jigsaw pieces are put together should one be able to understand how mutated genes and proteins affect development, predict how the "next generation" therapies can deliver breakthrough advances and elucidate how therapeutic agents can be delivered to focal areas of disease to maximize clinical benefit while limiting side effects. Cells were discovered by Robert Hooke (1635-1703) under the optical microscope. Lord Rayleigh (1842-1919) empirically determined that the resolution of a diffraction-limited microscope can be no better than ~ 1/2 of the wavelength of light (i.e. >200 nm), which defines the microscale. For centuries this was a fundamental limitation of light microscopy, as this resolution is insufficient to resolve the nanoscale processes underpinning biology. Despite this, through the availability of many organic labels and the discovery of green fluorescent protein, fluorescence microscopy has been fundamental for decades to many of the in vitro-based key discoveries in the biomedical sciences. The 'resolution limit' of light microscopy was broken at the end of the last millennium using a challenging technique, stimulated emission depletion microscopy, which showed ~20 nm resolution, followed by the less damaging structured illumination microscopy with 90 nm resolution. During the last decade, 'simpler' modes of super-resolution microscopy achieved similar resolutions by using the fundamental principle that molecules are much smaller than the wavelength of light and therefore can be considered 'single point' emitters. This is very important because their position in space can therefore be determined with nanometre accuracy via deconvolution of the 'blob'-like spot image created by the microscope optics, which incidentally is the origin of the poor resolution associated with light microscopy. High resolution images at the nanoscale are formed by putting together individual molecular images, a time-consuming process which nevertheless has already delivered spectacular results. High resolution imaging at the mesoscale is critical to understand basic mammalian biology. OCT was developed to address the need for fast imaging tools to characterise the inter-play between cells in a whole organisms in order to model human pathophysiology, and assess benefits resulting from therapeutic treatments in pre-clinical research. We have formed an interdisciplinary partnership that seeks to exploit a new generation of world-leading super-resolution microscopy in combination with state-of-the-art in vivo imaging methods (like OCT). Our principle is to break the barriers between fields to ease the exploitation of these new technologies by the wider biomedical community and to place the UK at the imaging forefront. The interdisciplinary environment and concentration of scientists at the Harwell Campus will help in our efforts to underpin fundamental discoveries in the next decade.

Currently, there is outstanding world-leading nano-material science being developed in Europe and especially the UK. The growing understanding of the physical and chemical interactions at the nanoscale is constantly revealing novel materials with a wide range of applications from catalysis, drug delivery, sensors, etc. However, the full realisation of these materials and their potential impact is hindered by the lack of a manufacturing technology capable of their production in a continuous and reproducible manner in large scale. This Fellowship project, aligned with the EPSRC Manufacturing the Future theme, will deliver a transformative technology for the large production of the next generation of nano-structured materials and catalysts. Its impact will allow the fast and effective transfer of knowledge from lab research to industrial scale which is essential to enhance global life standards while providing competitive advantages to the UK.

An analytical ultracentrifuge (AUC) is a machine capable of observing macromolecules sediment under gravity when a rotor is spun at a speeds from 1000 to 60 000 rpm. We are able to observe their sedimentation properties due to optical data capture systems mounted on the instrument. To date, these have be limited to single wavelength capture and an allied Rayleigh Interference optical system. A new AUC released by Beckman Coulter is now capable of true multi-wavelength capture so that more complex biomolecular systems can be analysed by following each component due to its unique optical signature. Where there is no unique optical signature, it is possible to label a compound either with a coloured probe, or incorporate into a protein using analogues of natural amino acids. As such, the instrument is capable of measuring a very wide range of biomolecular interactions and characterising them rigorously. In addition, the instrument will be maintained by a permanent technician, data analysis will be provided by the PI who is an expert in AUC, and new software methods will be provided through workshops. The latter is provided by a grant from the Fullbright Fund, which will allow a week long workshop to be undertaken. Given the wide range of systems that can be worked on to give information about size, shape and stoichiometry of biomolecules, this application ranges widely across BBSRC priorities and strategies.

Currently, there is outstanding world-leading nano-material science being developed in Europe and especially the UK. The growing understanding of the physical and chemical interactions at the nanoscale is constantly revealing novel materials with a wide range of applications from catalysis, drug delivery, sensors, etc. However, the full realisation of these materials and their potential impact is hindered by the lack of a manufacturing technology capable of their production in a continuous and reproducible manner in large scale. This Fellowship project, aligned with the EPSRC Manufacturing the Future theme, will deliver a transformative technology for the large production of the next generation of nano-structured materials and catalysts. Its impact will allow the fast and effective transfer of knowledge from lab research to industrial scale which is essential to enhance global life standards while providing competitive advantages to the UK.