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PROFESSOR DAVID SPANSWICK A bioelectrical investigator Professor David Spanswick is a prominent researcher in electrophysiology and neural systems. Here, he discusses his research into the chemical and physiological components that regulate energy homeostasis Dr Zane Andrews. My travels have certainly been worthwhile and ultimately hold the key to the commercial and clinical success of our future research. Why is it important for an organism to maintain and control its energy balance? Your biomedical career has led you all over the world in the pursuit of scientific discovery. How have your travels benefited your research? Travelling has been essential to the development of my research. Having worked extensively in North America, Japan and, more recently, Australia, I have been trained by, and collaborated with, some of the best neuroscientists and physiologists in the world. This has enabled me to establish neurosciencebased companies and labs in Canada, Australia and the UK – and we are currently in the process of setting one up in Southeast Asia. Through a combination of academic and commercial research, I have developed an extensive, highly skilled and multidisciplinary research team that interfaces between industry and academia. More recently, my move to Monash University, Australia, has been incredibly rewarding and allows me to collaborate with world-class scientists such as Professors Michael Cowley, Iain Clarke, Mathew Watt, Brian Oldfield and Mark Sleeman, and 20 INTERNATIONAL INNOVATION Maintaining an energy balance is critical for survival. It is achieved by matching food intake and energy expenditure, and failure to maintain this balance can be devastating. Excessive food intake can ultimately manifest as obesity, diabetes and other co-morbidities such as high blood pressure and certain forms of cancer. The other extreme is starvation and death. To survive, animals have evolved systems that maintain energy balance within narrow limits and that adapt depending on their external environment. Which aspects of the brain are responsible for maintaining energy balance? The brain receives all manner of inputs, including short-term meal-related signals. For example, the hormone ghrelin – which is released from the stomach when it is empty – signals a state of hunger to the brain. Conversely, following a meal, the hormones GLP-1 and peptide YY signal the feeling of satiety. The hormone leptin is just one of many hormones released from fat cells and, together with insulin, signals the levels of body adiposity. Even more remarkably, certain individual nerve cells integrate all of this information in the form of electrical signals and codes and bring about the appropriate changes in behaviour to restore balance. To what extent has a multidisciplinary approach facilitated the success of your research? This approach has been fundamental. As a group comprising both commercial companies and academia, we are relatively unusual in that we have the ability to record bioelectrical activity in the nervous system at every level: from a single protein in a cell membrane to the whole intact organism. Together with our ability to relate electrophysiology to changes at molecular, genetic, biochemical, physiological and behavioural levels, this is critical to cementing our understanding of how neural systems in the brain, spinal cord and periphery regulate aspects of normal and abnormal behaviour. Without this combination there is invariably no translation to the clinical setting. Our move to Monash University has allowed our research to flourish and approach its full potential. Indeed, with our electrophysiology expertise complemented by the extensive obesity-focused research at this institution, my group is ideally positioned to translate our research into clinical reality. What are the next steps in translating your research to the clinic? To date, we have gathered sufficient intelligence to establish two clinically relevant series of experiments prior to pursuing clinical proof of concept. First, we want to look at a series of diet intervention strategies to determine if it is possible to reverse the loss of neural plasticity associated with obesity and old age. Second, we will use the same approach in combination with a therapeutic drug-based strategy. Here, we will attempt to identify the therapeutic window of opportunity for a drug-based intervention, as our current research indicates brain glucose levels need to be controlled for maximal therapeutic efficacy. Finally, we are aiming to see what happens to the glucose-sensing pro-opiomelancortin (POMC) plasticity during rebound weight gain that frequently follows ‘crash diets’. PROFESSOR DAVID SPANSWICK Balancing brain glucose Researchers based in the Department of Physiology at Monash University, Australia, are engaging in collaborative and multidisciplinary research with the goal of understanding how glucose-sensing neurons could contribute to fighting the global obesity epidemic OBESITY IS AN epidemic of enormous proportions that has overtaken many parts of the world. Defined as abnormal or excessive fat accumulation that may impair health, it is a highly visible threat in both developed and developing countries, with cases affecting both genders, and all age and socioeconomic groups. The condition puts individuals at increased risk of many conditions, including cardiovascular disease, diabetes mellitus, hypertension, stroke and certain types of cancer; consequently, it represents a major public health burden. Alarmingly, worldwide obesity has almost doubled since 1980 and this percentage is continuing to rise. This is unsurprising given the increasing abundance of energy-rich food supplies, meaning that it can be challenging for many individuals to avoid gaining weight. However, maintaining a healthy body weight contributes to a person’s mental and physical wellbeing, and is therefore of great importance. A healthy weight is achieved by balancing food intake with energy expenditure – yet the mechanisms that monitor and regulate this equilibrium are highly complex, involving the central nervous system and a series of interactive and overlapping neural and nutrient-sensing pathways. The brain plays a central role in controlling energy homeostasis, with nerve cells and circuits detecting changes in energy status. This information is then converted into electrical signals and codes, consequently triggering behavioural changes that help to restore balance. UNDERSTANDING ENERGY BALANCE Professor David Spanswick, based in the Department of Physiology at Monash University, Australia, is fascinated by the mechanisms that underpin energy homeostasis in organisms. With a research background in neurophysiology, he has worked internationally and lectured in some of the world’s top universities. Working with a multidisciplinary team of collaborators, Spanswick is primarily attempting to understand how nerve cells interpret the enormous volume of hormonal and nutrient signals they receive, and how their function changes as a result of factors including ageing, obesity, food deprivation and diet. “By understanding the physiology and pathophysiology associated with the function of these nerve cells, we hope to contribute key intelligence to help in the design of therapeutic and preventive strategies that target obesity,” he outlines. Spanswick’s research has emerged from a significant body of work that is dedicated to exploring the pathways and mechanisms by which the brain controls food intake and energy expenditure. The past two decades have seen detailed studies on the respective roles of the hypothalamus, brainstem and spinal cord in governing food intake and metabolism. More recently, scientists have paid increasing attention to the roles of reward pathways and the midbrain dopaminergic system. As established areas of addiction and substance abuse research, they also seem to underpin various food reward-based behaviours. “It is undoubtedly the integrated activity of these different neural circuits that ultimately controls behaviour,” Spanswick asserts. “For instance, aspects of the hypothalamus target the reward pathways and there are reciprocal connections between hypothalamic and brainstem centres.” A novel method One of the most pivotal moments in Spanswick’s research occurred several years ago, when he challenged three scientists in one of his companies – Neurosolutions – to determine the normal levels of brain glucose associated with health, obesity and ageing. The technical demand of this experiment was exponential, yet these scientists successfully mimicked the environment of the brain in a dish, manipulating it in functionally meaningful ways. Not only did this enable them to establish glucose levels in the brain, but it also allowed them to ascertain the correlation between brain and blood glucose levels in real-time. Since this landmark moment, the scientists have focused on profiling the levels of fatty acids, lipids and hormones in both the blood and the cerebrospinal fluid they have collected, mapping the correlations between both. Crucially, these methods have completely revolutionised the team’s strategies by introducing cutting-edge tests that establish functionally meaningful changes in the levels of glucose and other nutrients. WWW.INTERNATIONALINNOVATION.COM 21 INTELLIGENCE BRAIN GLUCOSE-SENSING: AGEAND ENERGY-STATUS-DEPENDENT PLASTICITY OF FUNCTION-SPECIFIC PRO-OPIOMELANOCORTIN (POMC) GLUCOSE-SENSING NEURONS IN THE ARCUATE NUCLEUS OF THE HYPOTHALAMUS OBJECTIVES To address questions relating to the mechanisms by which aspects of the brain and spinal cord orchestrate behavioural responses to disturbances in energy levels, and to identify and isolate the component parts at the single cell and neural brain circuit level that underpin this behaviour. KEY COLLABORATORS MONITORING ELECTRICAL ACTIVITY One of the main elements of Spanswick’s research focuses on the role of glucose-sensing neurons in controlling energy balance. After detecting changes in the levels of glucose, these cells cause behavioural changes such as modifications in food intake or metabolism, which in turn maintain or restore glucose to normal levels. Additionally, it is thought that glucose-sensing neurons are able to detect other signals regarding changes to food intake or energy metabolism. These include specific hormones that are released when the stomach is full or empty, as well as hormones that carry information about the body’s fat stores. CONTACT Pro-opiomelancortin (POMC) neurons are some of the most well-studied glucose-sensing cells. Indeed, they have a vital role in helping to maintain energy balance; mutations in POMC neurons and their target receptors are known to contribute to some of the most common forms of human monogenic obesity. “It is only relatively recently that we have begun to recognise that POMC cells do not constitute a single functional population,” Spanswick discloses. “Rather, there are clear, functionspecific subgroups, most likely related to the ultimate target organs that they innervate and the associated different behavioural outcomes.” David Spanswick Professor of Neuroscience Using electrophysiology to monitor the electrical activity and excitability of POMC Professor Michael Cowley; Professor Brian Oldfield; Professor Matt Watt; Professor Iain Clarke; Professor Mark Sleeman; Dr Zane Andrews, Monash University, Australia Dr Leo Renaud University of Ottawa, Canada FUNDING National Health and Medical Research Council, Australia Department of Physiology Monash University Building 13F Clayton Campus Wellington Road Victoria, 3800 Australia nerve cells in real-time, Spanswick and his colleagues have shown that POMC cells can help to change activities and drive behaviours that restore the levels of glucose in the body. In their experiments, they found that POMC cells were much less sensitive to glucose in both fed and high-fat diet models. Crucially, unlike their healthy counterparts, when these models were fasted the POMC cells failed to adapt and change sensitivity: “These data indicate dysfunction of the glucose-sensing POMC neural networks in terms of obesity and old age, with the failure of this system critical to the development of diabetes and the failure to regulate glucose levels,” discloses Spanswick. FORGING AHEAD These findings have been made possible by the multidisciplinary and highly technical nature of the research conducted by Spanswick and his academic and commercial colleagues throughout the world. Looking ahead, the hope is that this talented and unique group of researchers will continue to forge deeper insights into the chemical and physiological mechanisms that underlie energy homeostasis. Such insights will eventually be used to devise innovative pharmacological and diet-related interventions that effectively target obesity and related metabolic diseases. Additionally, the researchers are also planning to design preventive diet-based strategies that promote healthy ageing. Obesity in numbers In 2008, the World Health Organization (WHO) estimated that more than 1.4 billion adults were overweight T +61 3 9902 4307 E [email protected] http://bit.yl/1tfhdpV SOCIAL MEDIA Some 65% of the world’s population live in countries where overweight and obesity kills more people than underweight http://linkd.in/1yXkgFF DAVID SPANSWICK gained his MSc and PhD at the University of Birmingham, UK. Since then he has held positions at universities in Japan, Canada and, most recently, at Monash University in Australia. Spanswick has founded three spin-off companies – Pacific Discovery Services, Australia; Neurosolutions Ltd, UK; and Cerebrasol, UK and Canada. In addition to his research activities, Spanswick performs undergraduate teaching and supervises postgraduate research in his laboratory. In 2011, more than 40 million children under the age of five were overweight At least 2.8 million adults die each year as a result of being overweight or obese It has been estimated that overweight and obesity are responsible for: 44% of the diabetes burden 23% of the ischaemic heart disease burden 7-41% of certain cancer burdens 22 INTERNATIONAL INNOVATION