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‘Couch potato’ Liggins’ syndrome – Director and origins in the What makes researchers womb you and me? honoured

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Professor Sir (left), Professor and invited guests share a joke with Her Majesty, Queen Elizabeth II. Queen opens the Liggins Her Majesty Queen Elizabeth II officially opened the Liggins Institute in February where she viewed the work of senior researchers.

The Queen, the Prime Minister Helen scientific endeavour. The Liggins Institute Sir Graham and his wife Lady Liggins to Clark, and 100 invited guests were will work to engage the community, and to the Queen. welcomed by the Chancellor of The stimulate and inform debate in areas of “Sir Graham has been our mentor, friend , Mr John Graham, public concern.” and inspiration and we plan to continue the the Vice-Chancellor, Dr John Hood, and the Following the Queen’s unveiling of a pioneering traditions he has set for New Founding Director of the Institute, commemorative plaque, Professor Zealand medical science,” Professor Professor Peter Gluckman FRS. Gluckman said her visit, and acceptance of Gluckman said. Mr Graham said the growth and success the invitation to view their work, was Sir Graham is internationally renowned of the University’s Faculty of Medical and enormously important to everyone. for his research into the fetus and newborn. Health Sciences’ research efforts – coupled “The work of scientists is often unsung His discovery that infant lung development with the vision and inspiration of Professor but has enormous potential to change the can be accelerated by giving steroids to Peter Gluckman – had provided the catalyst quality of people’s lives through the women in early labour has saved the lives of for the development of the Institute. advancements in knowledge about disease, literally hundreds of thousands premature “The Liggins brings together groups of and the potential to assist the country’s babies around the world. researchers who are at the forefront of their transition to a knowledge and innovation- Continued on page 7 fields. Their research covers the human based society,” he said. lifespan – from before birth to old age. Professor Gluckman acknowledged the “In a world of increasing complexity, contribution to medical science of Professor THE UNIVERSITY OF AUCKLAND FACULTY OF MEDICAL AND society often questions the relevance and Sir Graham Liggins – after whom the HEALTH SCIENCES the social and ethical dimensions of Institute is named – before introducing

PAGE 1 Dr Vickers... “Our research suggests that ‘couch potato’ syndrome may have its origins in the womb.” Leading role for the Liggins The Liggins Institute is taking a leading role in research that may shed light on the complex factors involved in human obesity and a host of related metabolic disorders commonly attributed to lifestyle, dietary and genetic factors.

The worldwide increase in obesity has led environment of plenty after birth, those and associated sedentary behaviour.” to international interest in appetite control, permanent physiological changes may lead The findings offer exciting potential for coupled with the development of new to an increased risk of disorders in adult new advances in understanding and research technologies and approaches. In life such as obesity, type 2 diabetes, high management of obesity and related the United States alone, over 35 percent of blood pressure and changes in the disorders, and have major implications for adults are obese and the prevalence in regulation of appetite leading to overeating. public health policy that currently is geared children has risen by more than 40 percent Liggins Research Fellow Dr Mark towards treating the symptoms of disease, in the last 16 years. Vickers is one of the Liggins’ team that not the underlying cause. Similar patterns are emerging in New showed that undernourishment in the womb Zealand where obesity and associated results in resistance to a hormone called Programming of obesity in the womb has disorders, such as type 2 diabetes, are leptin that plays a major role in regulating recently been shown in Mexican-Americans becoming a major health burden, appetite. Recently, he has discovered that and Hispanic Caucasian Americans where particularly among Maori and Pacific Island undernutrition in the womb also results in infants in the lowest third for birth weight people, where the incidence is 80 percent offspring that are more sedentary in adult have as adults the highest proportion of higher than in other races. life and that this behaviour happens before abdominal fat. the onset of obesity. Poor maternal nutrition during the Dutch Fetal programming Famine of the Second World War also Couch potatoes Researchers at the Liggins are investigating resulted in increased rates of obesity in what has been termed ‘fetal programming’ Says Dr Vickers: “Our research suggests offspring in adult life. or the fetal response to environmental cues that the ‘couch potato’ syndrome may have Alongside Dr Vickers’ work, a team in the womb, and have established that its origins in the womb and can be under the Associate Director of the undernutrition or stress in the womb exacerbated by eating a Western-style diet Institute, Professor , and triggers adaptive responses in the fetus to later on. It appears that the fetus aid survival. However, this biological permanently adapts to a limited nutrient Professor of Neonatology, Faculty of phenomenon can have significant long-term availability in the womb to ensure its Medical and Health Sciences, is health consequences. survival. An inappropriate persistence of investigating whether they can improve If nutrients in the womb are scarce, this adaptation – which leads to fetal growth by providing growth hormones adaptive responses are aimed at making the insensitivity to the hormones leptin and or supplements directly into the amniotic most of what is available. But in an insulin – predisposes to obesity, overeating fluid.

PAGE 2 Summer studentships are a winner The annual three-month Summer Studentship Programme at The University of Auckland’s Liggins Institute was a great success for students taking part. Kate Burndred

Mark Lonergan and Kate Burndred were including infection and neurological in the development of obesity, overeating, two of seven students at the Institute damage. and the development of type 2 diabetes. working on research in health-related “Apoptosis – programmed cell death – fields, including the causes of premature has been shown to occur in the fetal Regulating appetite labour, diabetes, overeating and obesity. membranes, particularly those associated Leptin is a hormone that regulates appetite Mark (22) extended a project he worked with premature rupture. and weight. It is made and secreted by fat on during his fourth year of a Bachelor of “We’ve yet to identify the cause of cells, and appears to send signals to the Technology and Biomedical Sciences premature rupture, but we think that the brain to reduce appetite when our fat cells degree at the University, supervised by Dr activation of death receptors might be are full. Jeff Keelan, Senior Lecturer in involved in weakening the membranes “It is sometimes referred to as a satiety Pharmacology. through the programmed death of cells,” signal, so under normal physiological He looked at preterm birth, premature says Mark. conditions when leptin levels are high, rupture of membranes, and the mechanisms appetite is reduced,” says Kate. behind them – specifically the so-called Identifying women at risk “While fasting and weight loss are "death receptors" in fetal membranes. “If this can be prevented, or if at-risk associated with reduced levels of leptin, His aim was to identify agents within the women can be identified by measuring a body that induce cell death in fetal biochemical marker of impending cell obesity is associated with higher levels of membranes before rupture, using a special death, clinicians may be able to prevent or leptin. It is thought that overweight people analytical technique that can measure delay premature rupture.” with high leptin levels actually have a minuscule levels of chemicals in tissue or Kate Burndred (21) from Hunua, South resistance or insensitivity to the hormone. amniotic fluid – the equivalent of Auckland, completed a Bachelor of Science “Leptin binding proteins found in the measuring one crystal of salt in a swimming (biomedical science) degree and may blood may reduce the activity of leptin in pool of water. continue with a Master of Science (medical the body, and so may play an important role Premature rupture of membranes occurs science) or a Master of Health Science. in the development of obesity and in around 10 percent of all births and The general aim of her work at the overeating. In the future this type of around 40 percent in preterm births, and is Liggins, supervised by Associate Professor research may lead to a treatment for obesity associated with a significant risk to the Dr Bernhard Breier, was to investigate the and related disorders.” baby of a number of serious complications, role of leptin-binding proteins in the blood Obesity is a worldwide problem and a major risk factor for heart and blood vessel disease and diabetes. Thirty students in all faculties were involved in the University’s summer studentships which are funded by a number of different organisations, including health research funding agencies. Professor Jane Harding, Associate Director of the Liggins and Professor of Neonatology in the Faculty of Medical and Health Sciences, says the studentships work well because they provide guaranteed work for students and offer them a taste of research in different fields, while also helping the progress of the research projects. “It is a win-win situation, good for both Mark Lonergan the University and for the students.”

PAGE 3 “This triggers the activation of a group of proteins called ‘G-proteins’. THC can activate several different types of G-protein, each one producing different physiological responses from the patient. “We’re trying to assess whether it is possible to alter the structure of the cannabis-like substances so that they drive the cannabinoid receptors to activate only one family of G-proteins, thereby producing fewer adverse effects on the patient.” Dr Glass says if distinct G-proteins cause the therapeutic and adverse actions of cannabis this would enable each of these responses to be isolated. This could lead to the development of cannabis-like treat- ments without the side effects. Beliefs and principles predominantly shape the position people take regarding the decriminalisation of cannabis and its therapeutic value. Dr Glass believes the medicinal marijuana promoters are not entirely barking up the wrong tree.

Little evidence “There is little evidence illustrating serious toxicity of cannabis or harmful effects,” she says. “In fact, cannabis has been shown to assist with appetite stimulation and nausea suppression in AIDS sufferers and cancer chemotherapy patients. “Other studies have shown that cannabis can also help reduce spastic attacks in multiple sclerosis sufferers and ease phantom limb pain.” Research discoveries made by Dr Glass and her team have the potential to advance the development of less toxic cannabis-like Taking the ‘joint’ treatments with fewer problems associated with the delivery of the drug. “THC accumulates in fatty tissues, so it is not well-delivered in pill form because out of therapeutic the absorption of the drug into the blood can be highly variable. We hope that the synthetic compounds being developed will overcome these problems. cannabis use “Also, more targeted delivery systems such as eye drops or an inhaler may enable Liggins Institute research into the active chemical in marijuana may lead patients to alleviate their symptoms with to new treatments to alleviate side effects of AIDS, cancer chemotherapy, only mild side effects and improve their and to treat pain and spastic disorders. quality of life.” With the support of a prestigious Marsden Grant, Dr Glass is now planning to Researcher Dr Michelle Glass says it’s well synthetic cannabis-like substances in an extend her cannabis research and look at recognised that patients are able to relieve attempt to find compounds that will the possibility of selectively targeting G- symptoms such as nausea, pain and produce the positive effects of cannabis, proteins with morphine-like drugs. A grant appetite suppression by smoking a joint. without the adverse effects. from the Auckland Medical Research However, they not only become “When patients smoke cannabis a drug Foundation will enable her to continue her physically dysfunctional from the ‘high’ substance called THC binds to sites in the studies seeking the ideal form of they experience, they risk developing lung brain called cannabinoid receptors,” says cancer. She is investigating alternative ways Dr Glass. therapeutic cannabis. of administering the drug as well as

PAGE 4 Director Research awarded looks to Rutherford limit Medal brain damage

Professor Gluckman FRS and Robert Lord May.

Robert Lord May, President of the Royal Society of London, recently presented the Liggins’ Founding Director, Professor Peter Gluckman David Wu... “We are looking for novel rescue agents.” FRS, with the prestigious Rutherford Medal for 2001, recognising his Research at the Liggins Institute may pave the way for a new outstanding contribution to science. The Rutherford Medal, the Royal treatment for brain damage. Doctoral student David Wu has Society of New Zealand’s highest discovered new growth factors that are showing promise in helping award, was presented at a special the brain to limit damage and speed up recovery. ceremony at The University of Auckland to induct the five new University Fellows elected in the A key factor in brain damage is the death or we can use them as a treatment for brain Society’s 2001 honours list. loss of function of neurons, the functional disorders,” he says. Among them were international cells of the brain. This may be caused by David, in his recently completed PhD expert in fetal undernutrition, Professor oxygen deprivation at birth, stroke, trauma, thesis, has reported the identification of a Jane Harding, Associate Director of the or a range of neurodegenerative diseases family of three growth factors that are Institute and Professor of Neonatology such as Alzheimer’s or Parkinson’s disease. produced in the brain as a result of injury. in the Faculty of Medical and Health In New Zealand alone, there are more than By examining their distribution, he found Sciences, and Professor Margaret 6000 new stroke victims each year, many of that these growth factors may promote the Brimble, an affiliate member of the whom die within one year or live with survival of neurons that are prone to death. Institute and researcher with NeuronZ, permanent disability. He has also discovered that they may who is widely recognised for her “We are looking for novel rescue agents assist in the extension and reconnection of contributions to medicinal chemistry. to reverse the death of neurons and restore undamaged nerve fibres that may take over their function,” says David. the role of dead or damaged neurons. Working under the supervision of Dr One of the growth factors is showing Chris Williams, Associate Professor of strong promise for further research and Neuroscience at the Liggins Institute, development as it increases the survival of David has been examining naturally- neurons when given within hours of injury. occurring growth factors in the brain. “We’re really excited about these “In the last two decades, research has findings. More work will be carried out to shown that the brain itself offers look at how these growth factors improve endogenous protection in that it produces the survival and function of neurons in the growth factors to help neurons to survive. brain. We believe that ultimately we will be This phenomenon is more prominent in the able to utilise them to help patients with young brain. If we can identify those factors brain disorders make a better recovery.” Professors Harding and Brimble.

PAGE 5 Working out what makes you and me Understanding the elegant and complex mechanisms that transform a single, fertilised cell into a human being holds a special fascination for Associate Professor Marie Dziadek.

Finding out what makes cells multiply and brain tissues of children, as well as a range wrong because of genetically inherited or what makes them differentiate into, for of other diseases and inherited conditions. environmental factors, she says. example, a muscle or nerve cell, is the focus “Fruit flies, frogs, human beings and As a single fertilized cell unfolds into a of her work at the Liggins Institute. elephants all start off as a fertilized egg. fully developed infant in just nine months, Associate Professor Dziadek, who The DNA that makes up their genetic it multiplies billions of times – a process recently joined the Institute from the information is very similar – just more or which is normally tightly controlled. University of Melbourne to set up a research less of it and put together in a different “It is not a straightforward, one-dimen- programme in developmental biology, says order, ” she says. sional process. Cells integrate a lot of the intellectual challenge involved in “But at the end of the day, that string of information inside and outside themselves grasping how human development is genetic information is what makes you and – they receive molecular signals from programmed within the genetic code what makes me, and what makes a frog a frog.” intracellular and extracellular pathways on attracted her to this line of research. In essence, the process of development whether to divide or not to divide, and when Her work could lead to greater is uniform in every human being. Better to die,” says Dr Dziadek. understanding of some cancers, in particular understanding of normal development leads “Similar processes are involved in the cancers that form in the muscle, kidney and to greater understanding when things go growth of tumours. If there is an imbalance in that network of molecular signals, cells Liggins’ Associate Director, Associate Professor Dziadek... “Development is the order, the pattern and the size.” may start to grow when they shouldn’t. Cell death is also important in this process as, without cell death, the cell number in a tissue or a cancer will build up. Flower unfolding “Cancer is development that has really gone wrong. Development is the order, the pattern and the size – it’s like a flower unfolding which has to be restrained.” Dr Dziadek was a member of one of the original research teams that revealed the important role of the body’s extracellular matrix or connective tissue in cell signaling. It was previously thought that this matrix acted solely as the “glue” holding the body’s cells together. But the research found that it has a vital part to play in regulating what cells do. “Part of the work we did showed just how heterogeneous the matrix is in a biological, molecular and structural sense, and how cells really do use it for biological information to help them multiply, migrate or die, or to give them signals to make specific proteins for the tissue to function as it should,” she says. This work provided the basis for her ongoing work on the signaling molecules that relate to cancer. Currently, she heads a research team that is working on a family of proteins they have identified as suppressing muscle cell growth. The team is looking at the mechanisms involved with the aim of being able to use the proteins to stop or start cell growth.

PAGE 6 “A lot of these molecules have multiple the father and usually only one set is “We’re also interested in the gene dosage functions. If we pursue this properly and activated.” effect and certain congenital syndromes understand the absolute basis on which Earlier work suggested that paternal that influence growth and development of they work, we will eventually be able to genes make the muscle and maternal genes the fetus and child, like Beckwith- direct that information into such things as make the brain. While Dr Dziadek says the Wiedemann syndrome where there are two treating neuronal damage or cancers,” says brain-brawn myth doesn’t really hold true, copies of the father’s gene and the mother’s Dr Dziadek. it’s correct that one of the main genes that is lost, or conditions like Downs syndrome Dr Dziadek is also exploring molecular regulates fetal growth – IGF2 – is expressed where there are too many copies of a whole approaches to fetal growth, in particular from the father, and the mother’s copy is cluster of genes. Children with these genetic imprinting and the “gene dosage” inactive. syndromes are more prone to developing effect, that have a crucial role in the Too little IGF2, and the fetus doesn’t certain cancers. development of the fetus. grow. Too much IGF2, and this may “If you have too many copies of a gene, promote the growth of tumours. too much protein is produced and this Genetic imprinting Already research has shown that in some throws out of balance all the networks “Genetic imprinting is a hugely important childhood kidney tumours and some adult which need to be tightly controlled in cells. area but it’s complex and difficult to lung and breast tumours, the maternal copy Likewise, if some genes are lost or mutated, unravel. We inherit half our genetic of the IGF2 gene has been reactivated so not enough protein is made or else it doesn’t material from our mother and half from our that more IGF2 is produced. function in the way that it should. Again, father but in essence the genes are “We are really interested in the the balance of signals is changed that identical. mechanisms of that. Understanding what normally keeps the cells in check. It is “The genes should be interchangeable, stops that maternal gene from activating, complex and fascinating stuff.” but they’re not. Somehow certain genes are may lead to new ways to treat some of these ‘marked’ as coming from the mother or from cancers.

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Following the opening, the Queen viewed the work of four Liggins Institute researchers and talked to them about their research. Professor Jane Harding, Associate Director of the Liggins Institute and Professor of Neonatology, Faculty of Medical and Health Sciences, talked about, ‘Feeding the fetus – treating intrauterine growth retardation’. Professor Harding was accompanied by Bridget France (7) who was born small for gestation dates. Children like Bridget are benefiting from Professor Harding’s research. Professor Murray Mitchell, Research Director of the Liggins Institute and Professor of Pharmacology and Clinical Pharmacology, presented, ‘The how and why of pre-term delivery’. Associate Professor Chris Williams, Associate Professor in Neuroscience for the Liggins Institute, presented, ‘Monitoring Her Majesty with the Chancellor of the University of Auckland, Mr John Graham (left), the Vice-Chancellor, Dr John Hood, and the Prime Minister, . premature infants for brain damage – a world-first technique’. He demonstrated a new device that The Liggins Institute was established measures minute changes in the electrical last year to conduct research in key activity of the brain in premature infants interrelated areas where the Institute’s soon after birth. The machine is a world- scientists have already established first developed by researchers at the international reputations – pregnancy and Institute. labour, the fetus and newborn, growth, Dr Alistair Gunn, Senior Research development and ageing, and the brain and Fellow, talked on, ‘The Liggins Cooling Cap behaviour. – a window of opportunity’. He was Parallel to the biomedical research accompanied by Cody Crump (3), who was themes the Institute has a Science resuscitated at birth then underwent head Medicine and Society Programme, with a cooling using this revolutionary technique. broader academic and public role in He is now a healthy young child with no bringing the benefits of science to the brain damage. community.

PAGE 7 DIRECTORS SCIENTIFIC ADVISORY BOARD

Professor Peter Gluckman FRS Professor John Funder, (Chair), Director Professor of Medicine, Monash University, Professor Peter Gluckman is a world renowned Melbourne Professor of Paediatric and Perinatal Biology. He is one of only two New Zealand doctors, Professor John Mattick, (Deputy Chair), and one of two paediatricians worldwide, to be Director, Institute of Molecular Biology, elected a Fellow of the British Royal Society. University of Queensland His work has focused on understanding the basic mechanisms of two major obstetric and Professor John Challis, Director, perinatal problems – infant brain injury Institute of Human resulting from oxygen deprivation and Development, Child and Youth Health, Canada intrauterine growth retardation. Professor Fiona Stanley, Director, Professor Murray Mitchell Western Australian Institute for Research Director Child Health Research, Perth Professor Murray Mitchell is Professor of Pharmacology and Clinical Pharmacology at Professor Michael Meaney, The University of Auckland. He has a Professor of Psychiatry and Neurology, worldwide reputation for his research into the McGill University, Montreal biology of premature labour and the biochemistry of hormones related to this. Professor Jeffrey Robinson, Professor of Obstetrics, Adelaide University Professor Stewart Gilmour Professor David Edwards, Professor Associate Director of Neonatology, Royal Postgraduate Medical Professor Stewart Gilmour has been Professor of Molecular Medicine and Pharmacology at School, Imperial College, London The University of Auckland since 1995. He has Professor Evan Simpson, Director, Professor Peter Gluckman FRS. led developments in biotechnology at the Faculty of Medical and Health Sciences. Prince Henry Institute for Medical Research, Melbourne Professor Jane Harding Become Part Associate Director Professor Jane Harding is internationally SCIENTIFIC PATRONS recognised as an academic neonatologist. Sir Graham Liggins FRS, Emeritus Professor, of Our Vision Her research spans both clinical and biomedical studies. She is an authority on placental The University of Auckland function, the regulation of fetal growth and If you are committed to Professor Eric Kandel NAS, Nobel Laureate, the consequences of poor fetal growth. Department of Neuroscience, Columbia advancing healthcare and Assoc. Prof. Marie Dziadek University improving quality of life, and Associate Director Professor Mel Grumbach NAS, Department want to see New Zealand take Associate Professor Marie Dziadek is a of Pediatrics, University of California highly respected specialist in mammalian greater strides in the developmental biology. She was formerly Professor FRS, Professor Associate Professor/Reader at the University of Biology as Applied to Medicine, knowledge society, then you of Melbourne’s Department for Anatomy and Department of Anatomy and Developmental Cell Biology. may wish to consider Biology, Royal Free and University College Medical School, University College, London supporting the Institute. Please contact us at: Professor David Barker FRS, Department ADVISORY BOARD of Medicine, University of Southampton Address OFFICE OF THE DIRECTOR Dr John Hood (Chair) Professor Brian Heap FRS, The Master, The Liggins Institute Vice-Chancellor, St. Edmund’s College, University of Cambridge The Faculty of Medical and The University of Auckland Health Sciences Professor Joseph Volpe NIM, Professor Warren Moran Neurologist-in-Chief, Children’s Hospital, The University of Auckland Department of Geography, Bronson Crothers Professor of Neurology, Private Bag 92019 The University of Auckland Harvard Medical School Auckland, New Zealand

Professor A. Richard Bellamy, Dean, Professor Lord Robert Winston, Tel 64 9 373 7599 ext. 6476 Faculty of Science, The University of Auckland Director of National Health Service Fax 64 9 373 7497 Research and Development for Email [email protected] Professor Peter Smith, Dean, Hammersmith Hospital, London Web www.liggins.auckland.ac.nz Faculty of Medical and Health Sciences, The University of Auckland

Professor John Mattick, Director, The Liggins Institute is committed to maximising the benefit of its research for New Zealand and, where appropriate, Centre for Molecular and Cellular Biology, seeing its research translated into effective therapies. Accordingly, in some areas it has licensed its intellectual property to the pharmaceutical industry or to start-up companies associated with the Institute.The terms of these arrangements University of Queensland provide funds which can be committed to public good (ie non-commercial and cutting-edge) research within the University. In accordance with University policy and international practice in developing start-up companies, some staff Professor John Funder, (Chair), will, or could, personally benefit from interest in these start-up initiatives. The University and, therefore, the Institute Professor of Medicine, Monash University, have taken this approach with the aim over time of increasing the capacity of the University and the Institute to undertake novel and leading-edge fundamental research. Most of the research within the Institute is, and will always Melbourne be, of this nature and can never attract commercial investment.The University and Institute are mindful of the need to ensure that donated funds are applied only to the public good research components of the Institute’s activities and Mrs Roseanne Meo, Nominee, cannot be applied (unless requested by the donor) to projects where commercial arrangements have been entered into. School of Medicine Foundation, Specific procedures have been developed to ensure this, and potential donors are invited to contact the Institute’s The University of Auckland Business Manager or the University Registrar for further information.

Mr Graham Scott, Law and Economic Dialogue is published by The Liggins Institute, Consulting Group, Wellington The Faculty of Medical and Health Sciences THE UNIVERSITY OF AUCKLAND The University of Auckland, Private Bag 92019 FACULTY OF MEDICAL AND Mr John Taylor, Headmaster, Kings College Auckland, New Zealand HEALTH SCIENCES Stories may be reproduced with acknowledgement.

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