The emergence of bacteria resistant to almost all known antibiotics is one of the most important challenges for science. If no new prevention and treatment options for bacterial infectious are developed we may soon slip back into the state of the 19th century when people died of what we very recently thought of as trivial infections. In order to develop vaccines or treatments that differ significantly from drugs like penicillin we need to understand better the ways in which bacteria cause infections. To start with, bacteria have to gain a foothold in the human body. This is achieved through a variety of molecules present on the bacterial surface. These molecules, mostly proteins that often form hairlike structures, bind to human tissue at various sites in the body (e.g. throat, lung, guts, skin). An understanding of structure and function of these surface molecules is required for the development of vaccines. Also, if it was possible to prevent the bacteria from binding to the host, it would be possible to intervene with infections at an early stage. Streptococci are among the most common pathogens affecting humans and animals. Hundreds of millions of cases of strep throat are caused by the bacteria Streptococcus pyogenes every year. So far in countries with good health care penicillin treatment has been effective at keeping this common infection at bay. But as the sudden emergence of resistant pneumococci, C. difficile and MRSA has shown, we need to be prepared for the possibility of S. pyogenes developing penicillin resistance at any time (many strains are already resistant to various other drugs), which could have devastating consequences. For example, if not treated/treatable, strep throat can develop into life-threatening diseases such as rheumatic heart disease (RHD). Despite penicillin availability, RHD is one of the biggest killers of children and youths in India and other developing nations. In RHD our immune system turns against proteins in the body and destroys tissue of the heart valves. This devastating effect is only poorly understood but is known to be linked to a family of proteins (called M proteins) that cover the bacteria in what under the microscope looks like a furry coat. M proteins were discovered over 80 years ago, and were quickly realised to be required by streptococci for causing disease. Despite their abundance and obvious importance our understanding of how they function is very limited. This lack of progress can be explained with the unusual properties of M proteins, which make them difficult subjects for conventional molecular investigations. We have shown that significant progress can be made using a combination of complementary powerful biophysical techniques (NMR and EPR) that will reveal, at the level of atoms, what M proteins look like and how they work. In this project we will specifically investigate the binding of M proteins to the most abundant human protein, collagen. Collagen is found throughout the body, and its abundance makes it a particularly attractive target for bacteria, and may aid in establishing an infection. Importantly, bacterial binding to collagen may also be the underlying cause of RHD, since collagen is the main component of heart valve tissue. Intriguingly, there are similarities between rheumatic diseases caused by bacterial infections and common autoimmune diseases such as rheumatoid arthritis. The causes of rheumatoid arthritis are unknown but it has been suggested that bacterial infection may play a role. Therefore, our research may uncover interesting links between bacterial infections and other diseases. A molecular understanding of M proteins can be considered central to the problem of research into streptococcal diseases. Our investigations will ultimately contribute to the development of urgently required new drugs or vaccines for one of the most important and dangerous infectious agents.

Marine ecosystems are under pressure from a range of human activities as well climate change, and there is a need to develop more integrated plans to maximise their value to society in a sustainable way. These pressures are peaking in the polar regions, especially the Arctic, where the well documented progressive reductions in extent of sea-ice cover represent a rapid, massive and fundamental change in the environmental conditions to which the species which make up Arctic marine food webs have, for millennia, been adapted: it is possible that the pace of change in the Arctic is now more rapid than the pace at which life can evolve. We already know that the shrinking of ice-cover is resulting in increased primary production in the Arctic seas. However, the way and extent to which this increased production at the base of the food web propagates up to the higher trophic levels and charismatic megafauna such as whales, seals and polar bears, is extremely uncertain and hard to predict. Other features of the habitat than sea-ice such as currents and waves, seabed topography and sediments, and land-based freshwater and nutrient inputs, also dictate patterns of production and suitability for individual species. In this project we will employ mathematics and computer science to predict the likely flows of nutrient through the marine food web, from microbes to megafauna, as the physical environment in the Atlantic Arctic changes, as it is expected to do over the coming decades. The mathematics will be incorporated into computer models which describe the complex network of interactions between living components of the food web and the dissolved and particulate, inorganic and organic nutrients. This whole complex web is driven by the seasonal fluctuations in sunlight arriving at the sea surface, and coupled to the physical circulation and three-dimensional mixing of the marine environment by winds, tides and freshwater-driven currents, which transport all the components of the food web around in space. To accomplish this we need to summarize scientific information from across the whole range biology, chemistry and physics and represent it in our models. We start the project with the legacy of two different working models of marine ecosystems developed for temperate shelf seas, which include most of the basic elements that we need to model the food webs in the Barents Sea, Fram Strait, and the wider Atlantic-Arctic in this project. We will be working with researchers in all of the already-funded Changing Arctic Ocean projects to develop the models, so as to best represent the special features that are needed to simulate high-latitude ecosystems, especially the role of sea-ice on the ecology. By the end of the project we will be able to quantify the extent to which climate change may affect the potential fishery yields of fish and invertebrates from the Atlantic Arctic, and also the trade-offs that exploiting these resources may entail with respect to the culturally important abundances of Arctic megafauna which rely on fish and invertebrates for their survival.

Stem cells are pluripotent cells that can both proliferate indefinitely producing cells identical to them, and specialise into more mature cells types. In adults, stem cells have a repair function in case of damage; adult stem cells are currently used in medical therapy. The major limitation of adult stem cells' medical applications is their low availability, and the difficulty to expand them in culture. Such issues were thought to be overcome thanks to the astonishing discovery of reprogramming by the Nobel Prize-winning Shinya Yamanaka: differentiated (i.e. somatic) cells can be programmed back to a stem-like state, obtaining the so-called induced Pluripotent Stem Cells (iPSCs). iPSCs can be subsequently converted into any cell type, to be used for regenerative and personalised medicine purposes. In Japan, the first clinical trial using iPSC-derived cells in humans is on going to cure age-related macular degeneration. iPSC therapy still faces, however, major challenges: it is difficult to reprogram somatic cells and maintain iPSCs in the pluripotent state; also, iPSC differentiation is often inefficient. In this research, we aim at applying state-of-the-art Synthetic Biology and Control Engineering tools to automatize and optimise the manufacturing of iPSC-derived cells. We will prove, using mouse cell lines, that each of the 3 mentioned challenges can be addressed if, while providing inputs that trigger pluripotency or differentiation, cells are continuously observed and inputs are consequently "adjusted" to obtain the target phenotype. This closed-loop strategy will be implemented by means of microfluidics and microscopy, that allow monitoring in real-time living cells, comparing relevant cellular outputs to the target one and applying control algorithms that allow acting on the cells to minimise the error. While proving that, by "closing the loop", it is possible to automatically control stem cell fate, we will provide a platform that allows, at the end of the experiment, to retrieve from the microfluidics device the desired cell type with high efficiency and reproducibility.

An array of persistent chemical pollutants are present in the Arctic in both biota and abiotic compartments, including snow and ice. These chemicals include older legacy contaminants such as PCBs and DDT, well as an array of newer 'emerging' contaminants with contrasting physical-chemical properties. Rapid changes to the physical and biological environment in the Arctic are changing the pathways and fate of pollutants, making biological exposure and impact difficult to predict; indeed changes to the Arctic may be altering the biological exposure to contaminants and even exacerbating it. The purpose of this proposal is to provide a mechanistic and quantitative understanding on the role of sea ice (particularly first year sea ice - the dominant ice type in a warmer Arctic) in the accumulation and subsequent release of chemical contaminants to the base of the marine foodweb. Preliminary evidence indicates that some newer contaminants are present in sea ice at concentrations akin to temperate coastal seas and we need to know the reasons for this, plus the likely exposure to biota once contaminants are released during ice break up and melt at the end of winter. Elucidating this process and understanding the fate and behaviour of chemicals in marine ice and snow can help shape chemical management strategies at the global level, particularly if changes to the Arctic cryosphere are also altering nutirent availability in ice and surrounding seawater. The contaminant and nutrient processes to be observed in the Arctic will be supported by artificial sea ice experiments. We plan to investigate this topic using field and laboratory studies and use these to model effects on the lower marine foodweb, examining whether nutrient and contaminant availability are linked and their impact on sea ice habitat functioning.

Many of the important ecological processes essential for life on earth and for the sustainability of our environment are performed by microbes (the bacteria and archaea) that are astonishingly abundant and diverse on the planet. Their functional diversity has arisen through many millions of years of adaptation to environmental change. Despite the contribution of microbial activity to global nutrient cycles and environmental stability, our inability to grow most microbes in the laboratory has severely limited our understanding of the ways in which they adapt to change and evolve. Recent technological innovations remove this limitation and allow us to study adaptation in microbes. The first innovation is the ability to sequence genomes of microscopic single cells extracted from the environment, allowing identification of genetic changes involved in adaptation and inference of how genomes have changed through deep evolutionary time. The second is the use of this genetic information to improve our ability to cultivate microbes, enabling physiological studies. This project aims to use these cutting-edge technological advances to answer key questions about the mechanisms that generate this vast microbial functional diversity in nature, one of the greatest and most exciting challenges in biology. It will focus on a microbial group, the Thaumarchaeota, which are very diverse and abundant and have enormous environmental and economic impacts because of their role in oxidising ammonia fertilisers (resulting in greenhouse gas production and annual loss of >$70 billion of nitrogen fertilisers). As not all Thaumarchaeota perform ammonia oxidation, it is important to understand the distribution and activity of other Thaumarchaeota in the environment. This project will therefore address important environmental concerns about soil security and environmental change. In this project, soil will be incubated at varying oxygen concentrations to determine the Thaumarchaeota that are active under different conditions. Novel thaumarchaeotal genomes will be extracted from soils with different oxygen preferences using a cutting-edge technology, single-cell genomics, which enables sequencing of the genome of individual microscopic cells. This will establish the genetic basis for the differences in these oxygen preferences. We will compare these new genomes with those previously available to trace the evolutionary origin of the genes and metabolic pathways implicated. We will test our evolutionary inferences using physiological studies of laboratory cultures, using novel techniques and genomic information, to isolate organisms never previously grown in the laboratory. Finally, the relative abundance and activity of these groups will be assessed in several ecosystems to determine their ecological relevance. The project will address the crucial and exciting scientific and technological challenge of understanding the processes leading to the enormous functional diversity of microbes in terrestrial ecosystems, and will have broad environmental and socio-economic impact. It will increase our ability to predict the impact of environmental change on microbial diversity and ecosystem functions and will ensure better management of soil by facilitating the development of improved strategies for fertilisation utilisation and reduced greenhouse gas production. As the microbes studied in this proposal are unexplored, limited current information is available but their role in biogeochemical cycles and potential involvement in plant-microbe interactions is likely, offering novel scope of environmental and ecosystem understanding. Through various events, the scientific findings of this project will be disseminated to the public of all ages and to governing bodies and policy makers to communicate the importance of understanding adaptation in the face of environmental change and the need for better management of natural capital for ecosystem services.