Biological Sciences New Boundaries
2013
Understanding Alzheimer’s Inflaming the brain and Alzheimer’s disease Protein synthesis and disease Informing the development of more effective drugs Plant potential Tackling the global fuel and food dilemma Innovative blood vessel research Helping to beat diabetes and bone disease
In this issue Welcome to Biological Sciences New Boundaries, which highlights some of the world-leading research taking place at the University of Southampton’s Centre for Biological Sciences.
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From human health conditions to climate change, our multidisciplinary research focuses on some of today’s major global challenges. Our projects cross the spectrum of the biological sciences, encompassing molecular and cellular, biomedical and environmental research. Research into the relationship between inflammation and neurological conditions, described on page 4, could mean a better prognosis for people with Alzheimer’s disease, while studies investigating protein synthesis in cells are contributing to the design of more effective drugs. Find out more on page 10. The food and energy requirements of a growing global population are leading to ever-increasing pressure on the planet’s natural resources. Our researchers are finding out how plants could contribute to a more sustainable future – see page 16 for more details. Our research innovations are supported by superb facilities. For example, the Imaging and Microscopy Centre, featured on page 14, provides the high-resolution instruments necessary for research at the nanoscale. It is set to become a unique resource for researchers from the University and beyond. The dynamic, supportive research environment at the Centre for Biological Sciences makes it an attractive choice for talented researchers. On page 20, find out how our collaborative culture has benefited an early career researcher, whose studies could lead to new treatments for people with bone disease and diabetes. For more information, visit www.southampton.ac.uk/biosci
Please send us your feedback We are keen to receive any feedback you have about Biological Sciences New Boundaries. If you have any comments or suggestions, please do send them to cfbsresearch@southampton.ac.uk
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1 Understanding Alzheimer’s New insights into the impact of inflammation on the brain.
Page 4 2 Protein synthesis and disease Informing the development of more effective drugs. Page 10 3 Plant potential Tackling the global fuel and food dilemma. Page 16 4 Innovative blood vessel research Helping to beat diabetes and bone disease. Page 20
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More highlights Breaking the resolution barrier Developing a unique microscopy facility at Southampton. Page 14 In brief A roundup of research news, from wildlife conservation to smarter urban planning. Page 22
Abstract computer artwork of a nerve cell, or neuron. Neurons are responsible for passing information around the central nervous system (CNS) and from the CNS to the rest of the body
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Understanding Alzheimer’s disease Researchers at the University of Southampton have identified a biological link between inflammation and the progression of Alzheimer’s disease, opening up possibilities for a better prognosis for people with the illness.
“The dementia challenge is not just about finding a ‘cure’; it is also vital to find ways to help people with the disease to live in a more satisfactory way.” Hugh Perry, Professor of Experimental Neuropathology
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“Many of the proposed risk factors for Alzheimer’s disease, such as smoking, diabetes and obesity, are all causes of systemic inflammation. We believe we have found a biologically plausible explanation of how this inflammation might interact with the diseased brain.” Hugh Perry, Professor of Experimental Neuropathology
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Dementia is one of the biggest health challenges of our time; it affects around 800,000 people in the UK and there is currently no cure. As well as taking a huge personal toll, it is estimated that the societal cost of dementia in the UK in 2012 was £23bn. The term ‘dementia’ refers to a range of illnesses – of which Alzheimer’s disease is the most common – that cause a gradual decline in brain function. Although a diagnosis of Alzheimer’s disease can be devastating, people with the illness can be supported to manage their symptoms and live an active and enjoyable life for some time before the effects become severe.
Caption
The inflammation that plays a role in Alzheimer’s disease is associated with the macrophages of the brain, known as microglia. Previous research has shown that people with Alzheimer’s disease have more microglia in their brains than healthy people and that these cells are ‘primed’ or partially activated by the ongoing degeneration of neurons.
Recently the team at Southampton has focused on the signalling between an inflamed part of the body and the brain to try to understand how this might affect the microglia in the brains of people with Alzheimer’s disease. “When you get a disease However, clinicians and carers have often or infection, you know about it because the noticed that when a person with Alzheimer’s body communicates with the brain and you becomes ill with a secondary infection or feel ill,” explains Hugh. “You might become disease their cognitive abilities go into a rapid feverish, want to stay in bed and sleep or decline, and symptoms such as depression lose your appetite, for example. Although and anxiety worsen. unpleasant, these symptoms, known as Researchers at Southampton have generated ‘sickness behaviours’, are a beneficial new insights into the biological basis of this outcome of the body’s communication with phenomenon, knowledge that could be used the brain because they cause us to adopt to help stabilise the symptoms of Alzheimer’s behaviours that will help us fight off the and make a real difference to the quality of life illness.” of people with the illness. The infected part of the body sends signals to The body’s defences the brain via molecules that are generated at The research is part of an ongoing programme the site of infection. The molecules circulate investigating the relationship between in the blood and communicate with the brain inflammation and neurological conditions, across the barrier between the blood and the led by Hugh Perry, Professor of Experimental brain. This communication process involves Neuropathology. Inflammation is one the microglia, which, in healthy brains, are aspect of the immune system that protects kept under tight control. However, in the our bodies from infection and injury. It is brain of a person with Alzheimer’s disease activated by specialist immune cells, known this communication process causes the as macrophages, that are present in all the primed microglia to become overactive and body’s tissues. The macrophages act as a first damage healthy brain cells, speeding up the line of defence by killing pathogens, such as progress of dementia. viruses or bacteria, and promoting the repair of injured tissue.
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“By paying attention to secondary infections and illnesses, the quality of life for people with dementia could be improved significantly.” Hugh Perry, Professor of Experimental Neuropathology
Molecular mechanisms As a postgraduate researcher at Southampton, Dr Katie Lunnon was instrumental in defining the molecular components that cause the behaviour of the microglia to change from benign to aggressive. “We knew the switch occurred but we didn’t know exactly how,” says Katie. “During my PhD I ran microarrays, which measure the expression of most of the known genes in a cell to give an overall picture of what happens in the cell. This enabled us to work out which genes were being altered by systemic infection and which weren’t. “We identified a number of molecular markers that are normally carefully balanced in immune cells, and observed their behaviour in microglia affected by dementia as well as microglia affected by dementia and inflammation.” By doing so, Katie and her colleagues were able to understand the mechanism that caused the microglia to produce damaging inflammatory molecules. “These signalling pathways to the brain are part of the complex mechanism of homeostasis, through which the body keeps itself in a state of equilibrium,” comments Hugh. “It is only in relatively recent history that humans have lived long enough to develop degenerative brain diseases, so evolution hasn’t caught up and found a way to protect us from this maladaptive response to the signalling process. Instead of being beneficial, in people with dementia the process has become damaging.” Monitoring cognitive abilities To build on the findings of preclinical experiments, Hugh teamed up with
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Clive Holmes, Professor of Biological Psychiatry at the University and Honorary Consultant in Old Age Psychiatry at the Memory Assessment and Research Centre at Moorgreen Hospital in Southampton. “Clive was very interested in this line of investigation because he had often seen this phenomenon in his clinical practice,” says Hugh. Funded by the Alzheimer’s Society, Clive and his research team recruited a cohort of about 300 people with Alzheimer’s disease and monitored them over six months. The study looked at how their cognitive abilities changed as well as variations in their symptoms of sickness behaviour, such as depression, anxiety and apathy. This information was then related to whether they had had any infections during that six-month period. Blood samples were taken to detect evidence of inflammation in the body. The study found that people who had systemic inflammation – likely to be caused by secondary illnesses (comorbidities) common in older people – and an infection during the six month period declined much more rapidly than those who didn’t, showing a clear association between infection and the progression of Alzheimer’s disease. It also showed that some sickness behaviours, such as apathy, depression and anxiety, were more frequent for people with infections and systemic inflammation. Hugh says: “Given our understanding of the mechanisms by which systemic inflammation communicates with the brain, we propose that comorbidities drive the progression of Alzheimer’s disease. This could also be true for other neurodegenerative diseases.”
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Identifying drivers The findings are significant because understanding the drivers behind the illness opens up the possibility of changing its course. “So far there are no proven interventions for Alzheimer’s disease or most other dementias,” says Hugh. “However, improvements in care to ensure the early detection and treatment of low-grade infections such as bladder and respiratory infections, which are common in older people, could change the progression of Alzheimer’s as well as reducing the unwelcome symptoms associated with the disease.” Further studies are now being undertaken into a particular molecule called tumour necrosis factor (TNF) which researchers have identified as being involved in the signalling process between inflamed tissue and the brain. An ongoing pilot study is investigating whether blocking the TNF molecule might ameliorate the effects of inflammation on the brain. “We’re also interested to know whether other environmental challenges might exacerbate Alzheimer’s disease,” says Hugh. “The Alzheimer’s Society has funded a study to look at stress as a possible driver of disease.” Another study is looking at whether the gum infection periodontitis might exacerbate dementia symptoms, and further work is being undertaken to find out about the molecules are that are involved in putting the microglia in the brains of people with Alzheimer’s disease into a partially activated state.
Broad applications The University has been at the forefront of this area of research for many years, and while Alzheimer’s disease has been the focus of recent studies, the group’s work has implications for many fields of human neurodegenerative disease and has attracted wide interest. “The principles that underpin our findings are generic,” says Hugh. “For example, there are researchers worldwide looking at the role of systemic inflammation in driving other diseases such as multiple sclerosis.” Related projects at Southampton are also ongoing. For example, Dr Jessica Teeling, Lecturer in Immunology at the Centre for Biological Sciences, has teamed up with colleagues in ophthalmology to see if there is a link between inflammation and eye disease. Dr Tracy Newman, Lecturer in Clinical Neurosciences at Southampton, is working with colleagues at the University’s Institute of Sound and Vibration Research to see whether systemic disease impacts on people with hearing problems. As well as being involved in collaborations with colleagues from other disciplines at Southampton, the group works with researchers at other UK universities including Oxford, Edinburgh and York. Hugh believes this type of collaboration is essential if scientists are to break new ground. “Achieving these kinds of innovations involves crossing boundaries and sharing ideas between basic scientists, clinicians, immunologists, psychologists, neurochemists and others.” For more information, visit www.southampton.ac.uk/biosci
Microglia, the resident macrophages of the brain, are labelled with green-fluorescent protein to show their regular distribution throughout the brain tissue. These cells continually move their process to monitor their local microenvironment so that they can remove tissue debris or mount an attack on an invading pathogen. (The cell bodies of nerve cells are labelled red)
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Protein synthesis and disease Southampton is at the forefront of research into the way our cells manufacture proteins, offering significant new insights into diseases such as cancer.
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Protein synthesis – the creation of proteins within cells – is a fundamental process that enables cells to grow, divide and function. If it goes wrong it can contribute to a range of diseases. Chris Proud, Professor of Cellular Regulation at Southampton, leads a group of 14 researchers who are investigating aspects of protein synthesis. Chris says: “We are interested in how the process works in healthy cells, as well as what happens when protein synthesis doesn’t function normally and the role this plays in causing disease.” All of our cells contain DNA, the genetic code that programmes the cell and determines its function. The major role played by DNA is to give instructions to the cell about what type of proteins it should make. This is crucial because it is the proteins that differentiate one type of cell from another – for example the types of proteins in a blood cell will differ from those in a heart cell. As well as playing a vital role in the cell’s function, protein synthesis is resourceintensive, requiring large amounts of energy and nutrients. For these two reasons, cells have tight controls to regulate the amount and type of proteins they make. By gaining a deeper understanding of these molecular mechanisms, the group’s research aims to inform the development of new treatments for human disease, helping in the design of more effective drugs. Recognised as a centre of expertise in this field, the group has current funding of £3.3m and is involved in a broad range of projects. “Because protein synthesis is so important for every cell, lots of different diseases can arise if the process goes wrong,” says Chris. “This takes our research into many areas of human health and we have collaborations with other universities, the pharmaceutical industry and with clinical and science laboratories in many parts of the world.” Targeting cancer cells
Computer generated image of protein synthesis
One area where this field of research could bring real benefits to patients is the study of protein synthesis in cancer cells. Cancer cells grow and divide much more rapidly than normal cells, so they have a high demand for nutrients and oxygen to make proteins.
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“Because protein synthesis is so important for every cell, lots of different diseases can arise if the process goes wrong. This takes our research into many areas of human health.” Chris Proud, Professor of Cellular Regulation
However, tumours often have a poor supply of blood, so understanding how they cope with inadequate nutrients may reveal an ‘Achilles’ heel’ which can be targeted for cancer therapy. With funding from Cancer Research UK, Chris’ lab is also studying how cells control the production of ribosomes, the molecular machines that manufacture proteins. A better understanding of this process could pave the way for more effective treatments for cancer and perhaps other diseases. Chris explains: “All our cells contain many of the same basic components. If you use a drug to hit one of them in a cancer cell, you will affect that component in normal cells too. We have identified particular proteins that are not necessary in normal cells but seem to be important to the functioning of cancerous cells. If a way can be found to block those particular proteins, it could selectively slow down or kill cancer cells without damaging healthy cells.” The study is one of several looking at different aspects of cancer. These include joint work with Professor Gareth Thomas of University Hospital Southampton NHS Foundation Trust looking at the role specific proteins play in the spread of cancer from one part of the body to another, and work with pharmaceutical companies to study how newly developed cancer drugs work at a molecular level. Understanding the growth of heart cells With funding from the British Heart Foundation, Chris’s group is also conducting research into hypertrophy, a heart condition that is a major cause of sudden death in young people. The condition involves abnormal growth of the heart muscle, which can initially improve the functioning of the heart. However, when it goes beyond a certain stage it can stop the heart from working properly, leading to heart failure. Hypertrophy usually affects people with an underlying genetic problem; the heart muscle cells grow to try to compensate for a weakness in the way the heart functions. Chris says: “The cells grow because they are making too much protein – if we can understand the control mechanisms behind this, it may be possible to develop a drug to prevent or even reverse this condition.”
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Neurological conditions Another area of study is the inherited brain disease leukoencephalopathy with vanishing white matter (VWM), which leads to a serious loss of white matter in the brain. It usually affects children, and those with the condition gradually lose the ability to control their muscles properly. The disease is caused by mutations in the genes that contain the information to make a particular protein, called eukaryotic initiation factor eIF2B. This protein is important in controlling protein synthesis. Chris and his team are collaborating with colleagues at the Free University of Amsterdam to find out how the genetic mutations that lead to VWM affect the control and function of eIF2B, and how this leads to the loss of white matter. “VWM is almost impossible to prevent, but a greater understanding of the processes in the brain would be an important step towards finding ways to slow down the progression of the disease,” says Chris. Diabetes and obesity The group’s research has revealed some exciting, and sometimes unexpected, connections. For example, Rebecca Stead, who is in her final year of a PhD in cell signalling at Southampton, discovered that the protein she was studying seems to play a role in how the body copes with a high-fat diet. This has opened up new avenues of investigation into the relationship between obesity and type 2 diabetes, which is one of the world’s most rapidly growing diseases, particularly in emerging countries such as China and India. “My original study was related to the role of proteins in cancer, but became focused on insulin signalling pathways, which play a key role in the cellular absorption of glucose and formation of fat,” says Rebecca. “We found that inhibiting certain proteins led to protection against obesity-related insulin resistance.” In the future, this could help answer questions about why some people are more susceptible to type 2 diabetes than others and, in turn, help to find ways of managing the condition.
Dr Noel Wortham investigating the molecular basis of Vanishing White Matter, one of the many health conditions in which protein synthesis plays a key role
Chris explains: “Antibodies need to be produced in mammalian cells. But you have As well as generating knowledge about the causes of disease, the group’s expertise could to grow a huge number of cells to extract a help sophisticated new drugs to become more relatively small amount of product, which makes this type of drug very expensive. widely available to patients. Building on the knowledge we’ve gained The pharmaceutical industry is rapidly about how cells govern the amount of protein moving away from traditional ‘small they make, we are trying to understand what molecule’ drugs, which are made from limits productivity and therefore how it could chemical compounds, to drugs known as be increased. If we can help to make these monoclonal antibodies. Unlike traditional drugs more affordable, they could be made drugs, antibodies work in a much more accessible to more patients.” targeted way, so they can tackle the cause of Funded by the Biotechnology and Biological disease without affecting healthy cells in the Sciences Research Council, this work is body. However, because they are proteins a collaboration between Chris’s group at rather than simple chemicals, they are much Southampton and Professor Mark Smales at more difficult to produce than traditional the University of Kent. drugs. Innovations in drug development
Further projects being undertaken by the group range from examining the role of protein synthesis in memory formation to analysing the structure of proteins involved in cancer, to help develop better drugs. It is this breadth that Chris finds exciting. “Our research crosses different scientific disciplines and fields of human physiology, creating a deeper understanding of disease that will ultimately benefit patients.” For more information visit www.southampton.ac.uk/biosci
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Since this interview took place, Dr Hans Schuppe has, very sadly, passed away. He will be sorely missed amongst the University community and his work at Southampton will always be remembered, celebrated and continued.
Breaking the resolution barrier Offering 10 different microscopy and scanning instruments and with plans for new cutting-edge equipment, the University’s Imaging and Microscopy Centre (IMC) is set to become a unique resource for researchers. Facility Manager Dr Hans Schuppe explains how the IMC’s services are essential for studies undertaken by scientists across the University and beyond.
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What is the IMC’s role?
The IMC is a core facility that provides access to microscopes and imaging equipment, enabling researchers to examine the basic processes and structures that are fundamental to their field of study. It is available to researchers across the University’s disciplines, such as biosciences, chemistry, medicine and engineering, as well as to external users from other universities, colleges and businesses. We provide courses and one-to-one training so that people can use the equipment, and we carry out imaging for industry clients. Another important aspect of my role is supporting colleagues across the University to develop funding applications for the acquisition of instruments.
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What type of research takes place at the IMC?
Our technology supports a spectrum of scientific research, from studies
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investigating human health conditions to research that aims to solve environmental problems. For example, microbiologists at the University use microscopy to examine communities of bacteria known as biofilms, to help find ways of controlling hospital acquired infections. Medical studies conducted here have looked into human immune responses at cellular level and the potential role of nanoparticles in the delivery of drugs to the central nervous system. An example of industrial use is a bioplastics company that was looking at the uniformity of materials.
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How does microscopy work?
One of our focus areas is fluorescence microscopy, which works by illuminating the sample with light of a certain wavelength. This puts the fluorescent molecules into an activated state, and they emit light of longer wavelengths, which can be detected in microscopy. Some molecules are inherently fluorescent, but often samples need to be
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prepared in order to introduce fluorescence either as a dye or a probe. We have widefield microscopes, which capture the full field of view in one shot, or confocal microscopes, which allow researchers to obtain very thin optical ‘slices’ which can be combined to create a three-dimensional reconstruction. Recently we enhanced the facility’s capabilities with the acquisition of a spinning disc system. This confocal microscope has additional electrophysiology equipment which allows researchers to introduce electrodes into the sample, for example to measure cell membrane channels. With new high-resolution technology, still under development, we aim to host the next generation of microscopy equipment.
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Why is it important to have a dedicated microscopy facility?
High-end microscopy equipment is too expensive for individual labs to acquire and maintain and is better situated in a central microscopy facility. Here continuous access
is guaranteed, the equipment can be used to capacity and managed in a sustainable way, and we can provide training and advice to users. We also can accommodate innovative microscopy equipment which has been developed as part of a time-limited research project, making it accessible to scientists on a more permanent basis.
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How does the IMC contribute to the University’s outreach work?
Recently we were involved in a project with students from Peter Symonds College in Winchester, which was very well received. The aim was to inspire young people to consider a future in science by enabling them to experience practical research. A group of students generated and prepared samples for examination using the spinning disc system and watched the imaging of their samples over a Skype connection. They also had a session here at the Centre and were very keen to have a go at using the microscopes.
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hat has the move to the new Life W Sciences Building meant for the IMC?
We’ve got a superb new facility and we’ve been able to establish a new containment area, which means we can work with a wider range of sample types. The building itself is very stable and there are few vibrations, which is particularly important in microscopy. We’re located in the same building as other facilities such as the microbiology lab and the cell and tissue culture facility, so we form part of an excellent resource for researchers.
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What plans are in place for the future?
We are working with colleagues from Chemistry to install two different methods of Raman spectroscopy here; Surface Enhanced Raman Spectroscopy (SERS) and Coherent anti-Stokes Raman Spectroscopy (CARS). The instruments will allow chemistry researchers to examine the properties of molecules in biological
surfaces, and will also be made available to other University and external researchers. In addition, I’m delighted that we have been awarded £394,000 matched funding from the University for a new high-end confocal microscope. We are also working with the University’s Optoelectronics Research Centre on projects that will be developed at the Centre for use in biological and biomedical research – another good example of our multidisciplinary approach. A superresolution microscope, planned here, will break the resolution barrier, enabling researchers to see structures far below 100 nanometers, something that is not possible with conventional confocal microscopes. The microscope will be a unique resource, putting Southampton at the forefront of super-resolution technology. For more information visit www.southampton.ac.uk/biosci/imaging
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Plant potential Balancing increased global energy demands with the urgent need to address environmental issues is one of the biggest challenges facing societies worldwide. Research at Southampton is showing that plants could be part of the solution.
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The coming decades will bring complex environmental and social challenges that place increasing – and sometimes conflicting – demands on the planet’s resources. While demand for energy is predicted to rise by as much as 30 per cent by 2030, governments are seeking to reduce greenhouse gas emissions. The nutritional needs of a larger global population will need to be met, but climate change is likely to result in poorer crop yields. Biofuels made from plant matter could contribute to renewable energy supplies, but need land and water resources that will also be in demand for food production. The University of Southampton is one of the UK’s leading centres for research into the role plants could play in tackling some of these problems. Professor Gail Taylor is Director of Research at the Centre for Biological Sciences and Principal Investigator (Plants and Environment). She says: “Plants will provide an important part of the solution to the planet’s fuel and food dilemma. The Environmental Bioscience Group is conducting projects in a number of areas to enhance the yield and resilience of biofuel crops, to evaluate the overall environmental impact of biofuels and to increase the nutritional value and sustainability of food plants.” Maximising resources Water plays a crucial role in the success or failure of crops; in the drought of 2003, for example, crop productivity across Europe fell by over 30 per cent. However, the availability of water has been identified as the main pressure on societies as they adapt to climate change in the future. Southampton researchers are contributing to a major study that aims to harness natural genetic variation to develop water-efficient bioenergy crops. The WATBIO project involves studying a large collection of crop plants from contrasting environments – for example hot, dry areas in Spain and Italy
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and wetter environments in Germany and the Netherlands – using molecular genetic techniques. “Plants’ responses to resources are controlled by an interactive network of genes,” explains Gail. “Through DNA sequencing we can identify the natural variants in the genomes to find out the genetic factors that enable plants to survive in more challenging environments. An understanding of this genetic variation will help us to develop crops that need less water.” The University is one of 22 partner organisations involved in WATBIO, which is funded by a European Union grant of €11m. Trees for fuel As well as developing water-efficient bioenergy crops, Gail’s group is interested in improving their yield. The cell walls of woody plants contain cellulose, a sugar that can be used to make bioethanol, one of the most commonly used biofuels. As part of the ENERGYPOPLAR project, researchers are examining the mechanisms that control the cell wall composition and structure in poplar trees. “We’re interested in wood where the cell walls collapse easily, because this optimises the cellulose yield,” Gail explains. The research involves testing wood samples from the University’s unique collection of over 6,000 poplar trees, to find out which break down and release the cellulose easily. The researchers then identify the genes that affect the cell wall traits. Gail says: “We have developed a pioneering genotyping chip that enables us to quickly screen trees to establish the presence or absence of particular genes.” The overall aim is to develop sustainable bioenergy trees that produce an optimum yield but have a small carbon footprint. Assessing environmental impact Agricultural practices are responsible for about a quarter of the greenhouse gas emissions that contribute to climate change.
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However, there is currently little quantitative data to enable comparisons between the emissions created by food crop and energy crop production, or by grassland. “If land use is going to change from food to energy crop production, it is vital to know whether the volume of greenhouse gases emitted will be higher or lower, and whether the landscape can be managed to reduce the emission of gases,” says Gail. Researchers from Gail’s group are playing a key role in the Ecosystem Land-Use Modelling (ELUM) project, which aims to answer some of these questions. The researchers are collecting data from a commercial energy crop field to measure how much carbon dioxide the crops take up and how much is released back to the environment. The data will be compared to similar measurements from grassland sites, and will contribute to recommendations on the most environmentally efficient techniques for bioenergy crop production. A collaboration involving several UK partners, ELUM is a £3.2m project funded by the Energy Technology Institute (ETI). Forecasting yields As part of another ETI-funded modelling project, Gail and her colleagues have developed tools to determine the potential contribution of bioenergy to overall UK energy supplies. Gail says: “Bioenergy is predicted to meet up to 10 per cent of the UK’s energy demand in future, so it is vital to understand when and where crops could be grown to achieve the best yields and minimise impact on food production and the environment.” The research has created a unique model that can predict the yield of bioenergy poplar and willow trees to a resolution of 1km2 for the period to 2050. It can also generate different scenarios, taking into account data about climate change and the use of different bioenergy technologies.
“Southampton offers an excellent multidisciplinary environment for bioscience research. Our projects tap into the expertise of colleagues from engineering, medicine, web science and data management.” Professor Gail Taylor, Director of Research at the Centre for Biological Sciences and Principal Investigator (Plants and Environment)
The findings have underpinned government policy developments, with information from the model used in key publications such as the Department of Energy and Climate Change Bioenergy Strategy. The data has also been incorporated into the ETI’s Energy System Modelling Environment (ESME), a whole-system analysis of the potential use of bioenergy in the UK.
some plants than others. Using a collection of watercress plants from all over the world, researchers are testing samples to find out which are the most effective at killing breast cancer cells in order to identify their genetic characteristics. “We are working with some of the big supermarkets towards the commercialisation of salads that offer greater health benefits,” comments Gail.
Sustainable, healthy foods
Further projects are establishing more sustainable, water-efficient growing methods for salad crops, which will be essential as water supplies diminish.
While much of Gail’s work relates to the development of plants for fuel, she is also interested in improving the nutritional value and sustainability of food crops. A series of projects funded by Vitacress Salads is investigating the longevity, health-giving properties and sustainable production of a range of salad plants. For example, watercress has been found to have anti-cancer properties, but these are found at a much higher concentration in
Like many of the group’s projects, this work benefits from the superb facilities at the Centre for Life Sciences, such as the new purpose-built glasshouse facility in the Life Sciences Building which was funded by a donation of £800,000 from Vitacress Salads. For more information visit www.southampton.ac.uk/biosci
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Innovative blood vessel research Dr Claire Clarkin became Lecturer in Developmental Biology at the University of Southampton in 2011. She tells New Boundaries about how the University’s collaborative, multidisciplinary environment has benefited her research into blood vessels – work that could lead to new treatments for people with conditions such as osteoporosis and diabetes.
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What is your area of research?
I study the cells which line our blood vessels, the vascular endothelial cells. I’m particularly interested in how the different tissues in the body regulate and maintain communication with the blood supply from early development into adulthood, and what happens when this communication goes wrong, for example in disease. One area I’ve been working on is how the vasculature (the distribution of blood vessels) is regulated in bone diseases such as osteoporosis. Bone is a dynamic tissue that is renewed throughout life, so it relies on a constant blood supply to deliver oxygen and nutrients. My long-term aim is to identify new drug targets that will permit selective control of the blood supply to allow sufficient support for the bone to renew itself. I am also looking at ways to improve the effectiveness of islet transplants for people with type 1 diabetes. Islets are clusters of cells that secrete insulin in the pancreas, but which are destroyed in people with type 1 diabetes. Transplants are a promising way forward because the procedure is noninvasive and can have very positive results, however the procedure itself doesn’t work very well, requiring two or three donor pancreases for each transplant. I have been conducting in vitro mechanistic work to try to retain the endothelial cells in the
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islets during the culture process prior to transplant, in order to help the cells survive during the procedure.
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What sparked your interest in this branch of research?
I became interested because the involvement of the vasculature in many diseases is so poorly understood, so it’s an area where there is lots of scope to gain new insights and develop the knowledge base.
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What is the impact of your work beyond the laboratory?
The new method of maintaining endothelial cells in islets is something that could soon benefit people with type 1 diabetes, because the technique can easily be introduced to the transplant procedure. It has been tested in the laboratory here and in collaboration with colleagues at Kings College London, so we are now reaching the stage when it can be tested in patients. The work on osteoporosis is still at an early stage, but many bone diseases are associated with too much or too little blood supply, so by targeting this it is likely that we’ll be able to treat some of those diseases in the future.
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How important is a multidisciplinary, collaborative approach?
Collaboration is essential as it means I can tap into expertise from other fields and access technologies that are not available
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here. For example, I have been working with Dr Philipp Thurner of Engineering at Southampton on the visualisation of vasculature in bone. Because bone is a hard, mineralised tissue it is difficult to see the blood vessel network. Philipp has developed a unique computer programme where we can visualise the bone structures using three-dimensional X-ray technology and see where the blood vessels would have been. I also have collaborative links with Harvard Medical School which provides access to high-resolution imaging equipment and genetic tools that we currently don’t have in the UK.
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Why did you choose to work at Southampton?
There are many researchers here who are at the forefront of my areas of interest, including Dr Nick Harvey, Professor Cyrus Cooper, and Professor Richard Oreffo, leaders in bone research, as well as Professor Richard Holt in diabetes and Professor Geraldine Clough in vascular biology. Having well-established researchers at your institute working in your area helps with funding applications as reviewers can see that you are in the best environment and more likely to succeed. Also Southampton is not too far from London, where I did my postdoctoral work, so I have been able to maintain useful contacts and collaborations.
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What is the environment like for an early career researcher?
There is a genuine culture of collaborative working here so I’ve found it easy to form partnerships and get projects going. Initiatives such as the Biomedical Forum run by Professor Tom Fleming, where researchers can seek feedback on funding proposals from University colleagues, have been really helpful. There are also some internal grant schemes that researchers can apply for. For example, I was lucky to benefit from a grant from the University’s Internationalisation Fund to maintain collaborative partnerships in the USA, and a University Adventures in Research grant towards the bone vascular visualisation project. This is being used to generate pilot data for future grant applications.
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What has been your biggest achievement since joining the University?
I was really pleased to win an award at last year’s Diabetes Annual Professional Conference. I was presented with the Lilly Diabetes Poster Award, which recognises outstanding research conducted in the field of basic science by researchers under the age of 35.
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In brief Combating malaria An increase in drug-resistant strains of malaria means there is an urgent need to find alternative treatments. Research at Southampton is focusing on enzymes that enable the malaria-causing pathogen Plasmodium to make vitamins. Because vitamins are essential for the pathogen to function, these biosynthetic pathways are potential targets for a new generation of drugs.
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Dr Ivo Tews, Lecturer in Structural Biology, is using protein crystallography to get closer to the target. Ivo and his team first turn the enzymes into crystals, then analyse them using X-rays. By determining the enzymes’ atomic structures, the team is creating a starting point for the design of inhibitors that target the enzymes. The Institute for Life Sciences has the latest nanodrop robotic technology and UVmicroscopy to perform crystallisation
Biological Sciences New Boundaries | University of Southampton
experiments. “We are well equipped to support the growing interest in these techniques from interdisciplinary research groups across the University,” says Ivo. The group uses the X-ray sources of the Southampton Diffraction Centre and the Diamond Light Source national synchrotron facility in Oxfordshire. Ivo’s group is part of a consortium for the development of new X-ray sources at Diamond that will be operational from 2018.
Understanding life’s earliest stages Scientists at Southampton have been awarded €500,000 as part of a major European collaboration to investigate how the environment at the earliest stages of life can affect health in the long term.
Exploring DNA structures
Spin-out success
Cutting-edge research that focuses on unusual DNA structures could lead to new ways of tackling disease.
The Centre for Biological Sciences’ entrepreneurial approach has led to the establishment of three of the 13 companies spun out of the University since 2000. The enterprises are making an impact in the environmental and health technology sectors.
Most people are familiar with DNA’s doublestranded helix structure. However, under certain circumstances DNA can adopt different Since they were first used in the 1970s, assisted shapes. Researchers at Southampton think these shapes may play a role in the regulation of reproduction techniques such as in vitro gene expression – the process through which fertilisation (IFV) have helped thousands of couples to have children. However, research has the genetic code is used to generate the cell’s characteristics. shown that the treatment of embryos during IVF may lead to a higher risk of conditions such Professor Keith Fox, Principal Investigator as high blood pressure in later life. (Nucleic Acids), says: “Working with Professor Tom Fleming, Professor of Developmental Biology, is working with Dr Neil Smyth on the project. Tom explains: “By establishing any associations between the culture and storage of embryos and long-term health and ageing, we hope that ways can be found to prevent the occurrence of adverse health effects.” Alongside laboratory research, Nick Macklon, Professor of Obstetrics and Gynaecology at Southampton and a specialist in IVF research, will be analysing data derived from clinical research to see if there are any links between health characteristics in babies and young children and treatments they had as embryos. Funded by the European Union, the EpiHealth project is a collaboration between the universities of Southampton, Manchester and Cambridge and several European universities.
Tom Brown of Chemistry we are using ‘click ligation’, a chemical method that fixes these unusual DNA structures in place so that we can look at their effect on biological systems. Understanding their role in modifying gene expression could have implications for the treatment of cancer, for example, where genes are often over-expressed.” Another project uses DNA to build structures at the nanoscale. Keith explains: “We can create box-like DNA shapes with a space inside that could carry a protein or drug molecule and deliver it within a cell. This could open up possibilities for the precise targeting of drugs.” Both projects are collaborations between biological sciences and chemistry researchers at Southampton, and are funded by the Biotechnology and Biological Sciences Research Council.
Exosect produces intelligent, environmentally friendly pest management solutions, based on technologies developed at Southampton, to help food producers and processors reduce the use of insecticides. Spun out of the University in 2001, Exosect now employs 30 people and was recently shortlisted for a global crop protection award. Another company, initially called Southampton Polypeptides, was spun out of Biological Sciences in 2002. Peptides occur naturally in living cells, but can also be created chemically for therapeutic benefit. The company was established to develop new technologies to produce novel peptides for the next generation of drugs. It joined forces with Activotec, a leading specialist provider of synthesis instrumentation and chemicals across Europe, in 2005. The third spin-out company to result from Southampton’s biological sciences research is Capsant Neurotechnologies. Formed in 2002, it has commercialised techniques developed at the University to grow cell cultures that have characteristics similar to those of living brain tissue for use in the screening of new drugs.
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In brief
Miracle metal Southampton researchers are at the forefront of research into the use of copper to eliminate superbugs.
Informing ‘smart’ urban planning
Research has shown how different types of urban development could impact on key The emergence of antibiotic-resistant strains of ecosystem services, as cities expand to meet the needs of a growing UK population. bacteria poses a global threat to public health. Recent research at Southampton has focused The study took two scenarios – the on copper’s ability to prevent the spread of development of dense urban conditions and antibiotic resistance, which can take place suburban ‘sprawl’ – and used sophisticated through the transfer of plasmid DNA from one modelling techniques to assess their impact bacterium to another. on three ecosystem services: agricultural Researchers looked at bacteria that produce extended spectrum beta-lactamase, a plasmid encoded enzyme that confers resistance and can be transferred between different strains of superbug. The team also examined the transfer of metallo-beta-lactamase genes, which confer resistance to all penicillins.
production, carbon storage in soil and flood mitigation.
The studies, led by Professor Bill Keevil, Head of the Microbiology Group and Director of the Environmental Healthcare Unit, indicate that touch surfaces are a previously unrecognised source of antibiotic resistance transfer. “Everyday systems such as air conditioning in public transport could be acting as reservoirs for resistance emergence; this could be prevented simply by using copper alloys,” says Bill.
that are quite dense so they do not take up too much space, but still have enough green spaces to offer benefits to the people who live there, including flood mitigation services. There is an opportunity, with clever planning, to try and maximise the benefits identified from both scenarios.”
The findings showed, for example, that the increase in concrete and asphalt associated with dense housing reduces flood mitigation services. On the other hand, low-density housing uses more land, which means less is available for food production, carbon storage They found that both types of bacteria could and the natural habitats that contribute to survive for weeks on a stainless steel surface. However, copper surfaces not only rapidly killed biodiversity. the bacteria but also prevented the transfer of Dr Felix Eigenbrod, the lead author of the study antibiotic resistance. explains: “The challenge is to have smart cities
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Biological Sciences New Boundaries | University of Southampton
Safeguarding endangered species in Belize Southampton researchers are leading a collaborative project to implement a wildlife corridor in Belize, safeguarding the future of animals such as jaguars, ocelots and tapirs. The project’s focus is a narrow but vital strip of wilderness that provides the only connection between Belize’s two major forest blocks. Without it, large predatory mammals and their prey, which need to roam across large areas, would become isolated and endangered. Researchers have been mapping the habitats and movements of animals including jaguar, puma, tapir, deer and peccaries, providing the data needed to establish an effective wildlife corridor. Dr Patrick Doncaster, Principal Investigator and Reader in Population Ecology, says: “The project was instrumental in the formation of the Environmental Research Institute at the University of Belize, which will help Belizeans acquire the skills to monitor their own natural resources in the long term.” Since the project began in 2009, the Belizean government has recognised the Central Belize Corridor as a conservation priority, setting the stage for its protection into the foreseeable future. Part of the area became a designated Wildlife Sanctuary in 2010. Funded by the Darwin Initiative, the project is a collaboration with Panthera, the University of Belize and the Belize Forest Department.
Tackling food security The University is leading a multi-million pound consortium project to encourage sustainable environmental practices and alleviate hunger in Columbia and Malawi. The project could make a difference to the lives of up to two million people in poor communities in the two countries. Guy Poppy, Professor of Ecology, explains: “There is continued pressure to cut down rainforests to increase agricultural output. However, this is counter-productive because as well as being vital for climate and water systems, the forests are themselves a source of food security for many people.�
Researchers are working with rural communities to understand how they use the environment as well as modelling future scenarios based on factors such as climate change and population growth. The aim is to help governments and communities to make decisions that will enable them to sustain food production while maintaining the valuable ecosystem services provided by the forests. Funded by the Ecosystem Services for Poverty Alleviation progamme, the consortium includes partners in Columbia, Spain, USA, and Malawi.
Southampton is also at the forefront of training the next generation of researchers in the science of food security. The University is one of five partners to be awarded ÂŁ1.8m for the Doctoral Training Partnership scheme, funded by the Biotechnology and Biosciences Research Council. By match funding the award, the partners will train 36 PhD students who will contribute to tackling the global food security challenge.
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Journal papers published from January to October 2012 Academics from the Centre for Biological Sciences have contributed to numerous papers during the last year. For more research papers, please view individual staff profiles online.
E. T. F. Rogers, J. Lindberg, T. Roy, S. Savo, J. E. Chad, M. R. Dennis, N. I. Zheludev A super-oscillatory lens optical microscope for subwavelength imaging Nature Materials 2012 Vol.11 pp. 432-435 M. J. Coldwell, U. Sack, J. L. Cowan, R. M. Barrett, M. Vlasak, K. Sivakumaran, S. J. Morley Multiple isoforms of the translation initiation factor eIF4GII are generated via use of alternative promoters, splice sites and a non-canonical initiation codon Biochemical Journal 2012 Vol. 488 pp. 1-11 R. J. Edwards, N. E. Davey, K. O’Brien, D. C. Shields Interactome-wide prediction of short, disordered protein interaction motifs in humans Molecular Biosystems 2012 Vol. 8 pp. 282-295 A. S. Cardew, T. Brown, K. R. Fox Secondary binding sites for heavily modified triplex forming oligonucleotides Nucleic Acids Research 2012 Vol. 40 pp. 3753-3762 D. A. Rusling, I. S. Nandhakumar, T. Brown, K. R. Fox Triplex-directed recognition of a DNA nanostructure assembled by crossover strand exchange ACS Nano 2012 Vol. 6 pp. 3604-3613 S. L. Warnes, V. Caves, C. W. Keevil Mechanism of copper surface toxicity in Escherichia coli O157:H7 and Salmonella involves immediate membrane depolarization followed by slower rate of DNA destruction which differs from that observed for Gram-positive bacteria Environmental Microbiology 2012 Vol.14 pp. 1730–1743 A. S. Penn, T. C. Conibear, R. A. Watson, A. R. Kraaijeveld, J. S. Webb Can Simpson’s paradox explain co-operation in Pseudomonas aeruginosa biofilms? FEMS Immunology and Medical Microbiology 2012 Vol. 65 pp. 226-235
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Biological Sciences New Boundaries | University of Southampton
F. W. Jaffe, G.-E. C. Freschet, B. M. Valdes, J. Runions, M. J. Terry, L. E. Williams G protein-coupled receptor-type G proteins are required for light-dependent seedling growth and fertility in Arabidopsis The Plant Cell 2012 Vol. 24 pp. 3649-3668 N. C. Harvey, K. A. Lillycrop, E. Garratt, A. Sheppard, C. McLean, G. Burdge, J. Slater-Jefferies, J. Rodford, S. Crozier, H. Inskip, B. S. Emerald, C. R. Gale, M. Hanson, P. Gluckman, K. Godfrey, C. Cooper Evaluation of methylation status of the eNOS promoter at birth in relation to childhood bone mineral content Calcified Tissue International 2012 Vol. 90 pp. 120-127 M. Caleo, L. Restani, E. Vannini, Z. Siskova, H. Al-Malki, R. Morgan, V. O’Connor, V. H. Perry The role of activity in synaptic degeneration in a protein misfolding disease, prion disease PLoS ONE 2012 Vol. 7 e41182 V. Iadevaia, Z. Zhang, E. Jan, C. G. Proud mTOR signalling regulates the processing of premRNA in human cells Nucleic Acids Research 2012 Vol. 40 pp. 2527–2539 X. Wang, N. C. Wortham, R. Liu, C. G. Proud Identification of residues that underpin interactions within the eukaryotic initiation factor (eIF2) 2B complex Journal of Biological Chemistry 2012 Vol. 287 pp. 8263-8274 S. John, L. Thiebach, C. Frie, S. Mokkapati, M. Bechtel, R. Nischt, S. Rosser-Davies, M. Paulsson, N. Smyth Epidermal transglutaminase (TGase 3) is required for proper hair development, but not the formation of the epidermal barrier PLoS ONE 2012 Vol. 7 e34252 U. Püntener, S. G. Booth, V. H. Perry, J. L. Teeling Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia Journal of Neuroinflammation 2012 Vol. 9 146
J. L. Teeling, R. O. Carare, M. J. Glennie, V. H. Perry Intracerebral immune complex formation induces inflammation in the brain that depends on Fc receptor interaction Acta Neuropathologica 2012 Vol. 124 pp. 479-490
P. Marius, Y. M. Leung, T. J. Piggot, S. Khalid, P. T. Williamson Probing the oligomeric state and interaction surfaces of Fukutin-I in dilauroylphosphatidylcholine bilayers European Biophysics Journal 2012 Vol. 41 pp. 199-207
G. Guédez, K. Hipp, V. Windeisen, B. Derrer, M. Gengenbacher, B. Böttcher, I. Sinning, B. Kappes, I. Tews Assembly of the eukaryotic PLP-synthase complex from Plasmodium and activation of the Pdx1 enzyme Structure 2012 Vol. 20 pp. 172-184
L. J. Clements, A. M. Salter, C. J. Banks, G. M. Poppy The usability of digestate in organic farming Water Science and Technology 2012 Vol. 66 pp. 1864-1870
C. R. Pigott, H. Mikolajek, C. E. Moore, S.J. Finn, C. W. Phippen, J. M. Werner, C. G. Proud Insights into the regulation of eukaryotic elongation factor 2 kinase and the interplay between its domains Biochemical Journal 2012 Vol. 442 pp. 105-118 P. Marius, M. R. de Planque, P. T. Williamson Probing the interaction of lipids with the non-annular binding sites of the potassium channel KcsA by magic-angle spinning NMR Biochimica et Biophysica Acta 2012 Vol. 1818 pp. 90-96 J. H. Bolivar, N. Smithers, J. M. East, D. Marsh, A. G. Lee Multiple binding sites for fatty acids on the potassium channel KcsA Biochemistry 2012 Vol. 51 pp. 2889-2898 D. A. Rusling, I. S. Nandhakumar, T. Brown, K. R. Fox Triplex-directed covalent cross-linking of a DNA nanostructure Chemical Communications 2012 Vol. 48 pp. 9592-9594 J. H. Bolivar. J. M. East, D. Marsh, A. G. Lee Effects of lipid structure on the state of aggregation of potassium channel KcsA Biochemistry 2012 Vol. 51 pp. 6010-6016 T. P. Fleming, M. A. Velazquez, J. J. Eckert, E. S. Lucas, A. J. Watkins Nutrition of females during the peri-conceptional period and effects on foetal programming and health of offspring Animal Reproduction Science 2012 Vol. 130 pp. 193-197
R. F. Mills, K. A. Peaston, J. Runions, L. E. Williams HvHMA2, a P(1B)-ATPase from barley, is highly conserved among cereals and functions in Zn and Cd Transport PLoS ONE 2012 Vol. 7 e42640 A. D. Hart, A. Wyttenbach, V. H. Perry, J. L. Teeling Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences Brain, Behavior, and Immunity 2012 Vol. 26 pp. 754–765 Y. Huo, V. Iadevaia, Z. Yao, I. Kelly, S. Cosulich, S. Guichard, L. J. Foster, C. G. Proud Stable isotope-labelling analysis of the impact of inhibition of the mammalian target of rapamycin on protein synthesis Biochemical Journal 2012 Vol. 444 pp. 141-151 C. J. Kelsall, S. P. Hoile, N. A. Irvine, M. Masoodi, C. Torrens, K. A. Lillycrop, P. C. Calder, G. F. Clough, M. A. Hanson, G. C. Burdge Vascular dysfunction induced in offspring by maternal dietary fat involves altered arterial polyunsaturated fatty acid biosynthesis PLoS ONE 2012 Vol. 7 e34492 A. Cheung, P. L. Newland, M. Zaben, G. S. Attard, W.P. Gray Intracellular nitric oxide mediates neuroproliferative effect of neuropeptide y on postnatal hippocampal precursor cells Journal of Biological Chemistry 2012 Vol. 287 pp. 20187-20196 X. Jing, D. M. Simpson, R. Allen, P. L. Newland Understanding neuronal systems in movement control using Wiener/ Volterra kernels: a dominant feature analysis Journal of Neuroscience Methods 2012 Vol. 203 pp. 220-232
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