How did life begin on Earth? While disagreements remain, one thing for certain is that the first life needed water, a source of energy and non-biologically made organic compounds; and the best candidate for the first life was a microbe. To find these on early Earth, the best place to look would be where water met unreacted rocks from the Earth's interior. Mantle rocks called peridotites, normally residing >6 km below the seafloor or 40 km below land surface, could be brought to surface by overthrust along plate boundaries due to plate tectonics. These peridotites are a reservoir of reduced metallic components, especially iron, which react with water when exposed to form gaseous hydrogen (H2). This then triggers a series of spontaneous reactions that release energy and turn carbon dioxide (CO2) into bicarbonate and methane (CH4), and other simple organic compounds. These reactions, collectively known as 'serpentinisation', thus provide the ideal setting for the emergence of life. Today, these occur in low-temperature hydrothermal systems on the seafloor, or in 'ophiolites', ancient ocean crust and upper mantle that got uplifted on land such as that found in the Sultanate of Oman. These are likely the best modern analogues of the first cradle of life. Many studies have been conducted to date using these systems to try to understand how the biosphere has been evolving on Earth and perhaps on other planets. Missing in all these investigations, however, is the source of nitrogen (N), the key element used to make DNA, enzymes and proteins. Biological growth in many ecosystems today is limited by the availability of N. Although substantial amounts of N have been present in the atmosphere as gaseous N2 since early Earth, for life to use this N the strong triple bond of N2 has to be broken, and it takes considerable energy. N could also have come as nitrite (NO2) and nitrate (NO3), but both first had to be made by lightning from atmospheric N2, and then rained into the ocean before coming in contact with exposed mantle peridotites. Recently, rock analyses have found that ammonium (NH4+) sometimes replaces certain metals (e.g. potassium) in minerals such that the solid Earth holds ~7 times the N as the atmosphere. Hence, if life can tap into this immense N source, the early biosphere would not be N-limited. On the other hand, N can exist in several forms of varying electrochemical potentials, and so its many transformations can occur spontaneously with other chemicals to generate energy to support life. Most notably, NO3 is the first-choice alternative used for breathing (respiration) when oxygen runs out, thereby burning 'food' (organic carbon) into CO2 to obtain the necessary energy for life metabolisms. Meanwhile, some microbes may harness the energy from the reactions between NO2 and NH4+ or CH4 to make their own food from CO2, akin to plants performing photosynthesis but with chemical energy instead of sunlight. Therefore, as various N-forms are present in modern subsurface serpentinising systems, various N-transformations may occur to power the microbiome within. The activities of these reactions and their impacts on the environment have never been assessed, nonetheless. This project seeks to examine how subsurface biosphere acquires N, and how subsurface N-cycling operates and interacts with the subsurface biosphere in a serpentinising system. We will use the rare heavy form of N -15N- to track N-transformations by microbes, and 15N-content in rocks and fluids as tracers, combined with state-of-the-art bioimaging and gene expression, to assess how microbes obtain their cellular N, and to what extent N-transformations are 'actively' powering subsurface life. We will use the Oman ophiolite, the world's largest, best exposed block of oceanic crust and upper mantle as a model active serpentinising system, given its easy access and the newly drilled deep boreholes and drill cores made available by the Oman Drilling Project.

MRC : Mohammad Reza Roozitalab: MR/N014308/1 Cancer cells can be expanded and studied alone outside of the body in two-dimensional plastic dishes. These simplistic conditions lack the genetic variation and complex signals found in human tumours that tell cancer cells to grow uncontrollably and spread throughout the body. To effectively identify the signals that fuel breast cancer spread and develop clinical therapies to stop them, scientists require new ways of growing cancer cells outside of the body. The student will receive world-class training in Canada to build innovative three-dimensional 'mini tumour models' that better mimic the native environment of cancer cells. By combining different cell types, they will investigate how cancer cells communicate and corrupt non-cancerous cells including neighbouring immune cells, to fuel their own growth. Using newly gained expertise, the student will establish this unique method of fabricating and analysing 'mini-tumours' back in the UK to sustain and develop new long-term collaborations in Canada.

Patients with chronic diseases must take day-to-day decisions about their care and rely on advice from medical staff to do this. However, regular appointments with doctors or nurses are expensive, inconvenient and not necessarily scheduled when really needed. Increasingly, there are low cost and highly portable sensors that can measure a wide range of physiological values. Can such 'wearable' sensors be used to improve the way that chronic conditions are managed? Patients could have more control over their own care if they wished; doctors and nurses could monitor their patients without the expense and inconvenience of visits, except when they are actually needed. Remote monitoring of patients is already in use for some conditions but there are barriers to its wider use: it relies too much on clinical staff to interpret the sensor readings; patients, confused by the information presented, may become more dependent on health professionals, whose work may be increased rather than reduced. The project seeks to overcome these barriers by addressing two weaknesses of the current systems. First is their lack of intelligence. Intelligent systems that can help medical staff in making decisions already exist and can be used for diagnosis, prognosis and advice on treatments. One especially important form of these systems uses belief or Bayesian networks, which show how the relevant factors are related and allow beliefs, such as the presence of a medical condition, to be updated from the available evidence. However, these intelligent systems do not yet work easily with data coming from sensors. The second weakness is any mismatch between the design of the technical system and the way the people - patients and professional - interact. We will work on these two weaknesses together: patients and medical staff will be involved from the start, enabling us to understand what information is needed by each player and how to use the intelligent reasoning to provide it. The medical work will be centred on three case studies, looking at the management of rheumatoid arthritis, diabetes in pregnancy and atrial fibrillation (irregular heartbeat). These have been chosen both because they are important chronic diseases and because they are investigated by significant research groups in our Medical School, who are partners in the project. This makes them ideal test beds for the technical developments needed to realise our vision and allow patients more autonomy in practice. To advance the technology, we will design ways to create belief networks for the different intelligent reasoning tasks, derived from an overall model of medical knowledge relevant to the diseases being managed. Then we will investigate how to run the necessary algorithms on the small computers attached to the sensors that gather the data as well as on the systems used by the healthcare team. Finally, we will use the case studies to learn how the technical systems can integrate smoothly into the interactions between patients and health professionals, ensuring that information presented to patients is understandable, useful and reduces demands on the care system while at the same time providing the clinical team with the information they need to ensure that patients are safe. If successful, our results will be useful not only for the examples of chronic diseases studied on the project but also for managing other chronic medical conditions, when the same techniques can be applied. Although the project will produce prototype systems, several stages of product development and clinical trials will be needed before real systems are available for patients; we will prepare for these and make a first evaluation of the economic benefits of the proposed systems during the project. Also, several technology companies are involved in the project's Advisory Board to help ensure effective commercial exploitation in the long run.

Cyanobacteria (otherwise known as blue-green algae) are bacteria that grow by photosynthesis in a similar way to plants. Chloroplasts (the photosynthetic bodies within plant cells) are descended from free-living cyanobacteria, accounting for the many similarities between cyanobacteria and chloroplasts. Cyanobacteria are widespread in the environment. For example they are very abundant in rivers, lakes, and the oceans, where they make an important contribution to the ecology of the planet. Cyanobacteria are now attracting increasing interest as possible sources of 'biofuels'. We may eventually be able to modify cyanobacteria to produce cell factories using the energy of sunlight to produce fuels such as hydrogen. Cyanobacteria have a more complex cell structure than most bacteria. Inside the cells are the thylakoid membranes, a complex internal membrane system which is the site of the 'light reactions' of photosynthesis. The thylakoid membranes contain the pigments that absorb energy from sunlight, and the proteins that carry out the first steps in converting solar energy to stored chemical energy. Although we now know a lot of detail about the photosynthetic proteins, we know rather little about how the thylakoid membranes are made. We propose to investigate this question using as a starting point genes which are believed to be important for thylakoid membrane production. It has not yet been possible to produce mutants completely lacking these genes. However, when the number of gene copies per cell is reduced, thylakoid membrane synthesis is greatly decreased. Although the genes have been identified, we do not know how the proteins that they encode are involved in thylakoid membrane generation. We will investigate this question using a 'model' cyanobacterium that can easily be genetically modified. We will modify this cyanobacterium so we can control the expression of both genes: we will be able to switch the production of the proteins on and off. This should give us a way to control thylakoid membrane generation. We will be able to watch thylakoid membrane degradation when the genes are inactivated, and reassembly when the genes are activated again. To get more detail on the function of proteins identified as being important for membrane synthesis, we will identify other proteins that interact with these proteins in the cell and we will produce mutants in which these proteins are 'tagged' with fluorescent labels. This will enable us to see the distribution and behaviour of the proteins in a fluorescence microscope. One possibility is that the proteins are initially located in the cytoplasmic membrane surrounding the cells. Here they may help to collect together other membrane components required for thylakoid membrane synthesis, and package these components into 'vesicles' - small membrane bodies which could then shuttle the membrane components to the thylakoids. By observing the distribution of the fluorescent proteins during membrane reassembly we will be able to see how they are involved. If we can understand how thylakoid membranes are assembled we will be in a better position to modify thylakoid membrane function, for example to produce hydrogen from solar energy. In the long-term we may even be able to induce the production of similar membrane systems in different kinds of bacteria, giving us a new tool for the production of microbial 'cell factories'.